Review Article

An overview of prolonged disorders of consciousness for the General Practitioner

Authors
Adam Boardman & Ganesh Bavikatte
Article Citation and PDF Link
BJMP 2020;13(1):a007
Abstract / Summary
Abstract: 

The incidence of hospital admissions due to acquired brain injury is increasing, and due to increased survival rates there are a higher proportion of patients are discharged with complex disabilities including prolonged disorders of consciousness. These patients are largely cared for in the community by General Practitioners, with occasional input from specialist teams. This article combines latest guidance from the British Medical Association and Royal College of Physcians with our own experience as Rehabilitation Medicine physicians, with the aim of improving confidence in managing patients with vegetative state and minimally conscious state, and increasing understanding of the associated medicolegal and ethical issues.

Abbreviations: 
ABI: acquired brain injury; PDOC: prolonged disorders of consciousness; MCS: minimally conscious state; VS: vegetative state; GP: General Practitioner ; RCP: Royal College of Physicians; BMA: British Medical Association; EEG: electroencephalography; WHIM: Wessex Head Injury Matrix; CRS-R: JFK Coma Recovery Scale-Revised; SMART: Sensory Modality Assessment and Rehabilitation Technique; CPR: cardiopulmonary resuscitation; MDT: multidisciplinary team; CANH: clinically assisted nutrition and hydration; COP: Court of Protection
Keywords: 
Prolonged disorders of consciousness; Vegetative state; Minimally conscious state

Introduction

Since 2005, there has been an increase of 10% in hospital admissions with acquired brain injury (ABI), with 348,453 United Kingdom (UK) admissions in 2016-17.1 With improvements to both medical and surgical management, a higher proportion of patients survive to hospital discharge, resulting in more people with complex physical and cognitive disabilities reaching the community.2,3

Prolonged disorders of consciousness (PDOC) can occur following ABI. This can vary from coma, to vegetative state (VS), and minimally conscious state (MCS). Following acute stabilisation, the treating team must provide the correct diagnosis, prognosis, and management. Ethical and legal issues, such as best interests decision-making (considering patient wishes, advanced decisions, and best possible quality of life), deciding when appropriate to provide end-of-life care, and understanding the legal framework around these issues can further complicate the process.

Whilst there is currently no national registry for patients with PDOC, information taken from patients in nursing homes in the UK give an estimated 4000 – 16000 patients in VS, and up to three times this many in MCS.4

Early and ongoing assessment of the patient is vital, as is good communication with those close to the patient, and an understanding of the legal requirements of the treating clinician. These are likely to present even more of a challenge to General Practitioners (GP) in the community who are managing these patients as part of their larger responsibilities.

This review article summarises guidance from the Royal College of Physicians (RCP) and British Medical Association (BMA), in conjunction with our own clinical experience, to improve understanding surrounding the assessment, long term management, and the ethical and legal issues in patients with PDOC, aiming to improve the confidence of clinicians managing these patients.5,6

Identifying Patients

Consciousness requires a combination of wakefulness and awareness (self and environment). Patients with significant deficits in either of these can be said to have a disorder of consciousness. Various brain injuries can result in disorders of consciousness (see Table 1).

Table 1: Aetiology of acquired brain injury.5

Cause Examples
Vascular Stroke, subarachnoid haemorrhage
Hypoxic Cardiac arrest, hypovolaemia
Infection / inflammatory Encephalitis, vasculitis
Trauma Primary brain trauma, diffuse axonal injury
Metabolic / Endocrine Hypoglycaemia, drug overdose, alcohol
Degenerative Primary neurodegenerative conditions such as dementia

This article focuses on acute causes of PDOC rather than those with primary neurodegenerative conditions, as they present separate clinical entities with different issues affecting prognosis and management choices.

Disorders of consciousness, like a sliding scale, vary from coma, to VS, and MCS:

  • Coma - unrousable unresponsiveness. Patients cannot be roused, lack a sleep-wake cycle, exhibit no purposeful movement, and do not respond to stimuli.
  • VS - wakefulness but not awareness. Patients have a sleep-wake cycle and open their eyes spontaneously, but lack awareness of self or their environment. These patients can exhibit spontaneous and reflexive movements, and external stimuli can produce arousal responses.
  • MCS - wakefulness but reduced or inconsistent awareness. Patients have a sleep-wake cycle and demonstrate reproducible but inconsistent awareness of self, and ability to interact with others and their environment.

Diagnosis

As per RCP guidance 2020, patients with impaired consciousness for over 4 weeks are deemed to have PDOC.5 It is first important to differentiate possible VS / MCS from other conditions:5

  • Abnormalities on electroencephalography (EEG) can aid diagnosis of coma. These patients tend to progress to VS or death within weeks, so assessments of consciousness are not appropriate during this period.
  • Patients with locked-in syndrome have wakefulness and awareness, but paralysis of the limbs and majority of facial musculature, preventing communication by these means. EEG in locked-in syndrome is usually normal, and patients may be able to communicate using eye movements.
  • Patients with brainstem death have loss of all brainstem reflexes and respiratory effort, and organ survival is only temporarily achieved with life support machines.

Once ‘mimic’ conditions are ruled out, making a diagnosis of VS or MCS in patients with a suspected disorder of consciousness follows a 3-step process with input of clinicians trained in the management of PDOC:

1. Establishing a cause

This can be straightforward in some cases, such as those with direct trauma to the brain, or acquired brain infections or inflammation causing structural damage to the brain. In other cases this can be more difficult, and it may not possible to reach an exact diagnosis. The treating clinician must establish that the patient’s current condition is due to a brain injury, and take reasonable steps to determine the cause.

2. Reversible causes should be excluded

This includes reviewing medications to stop sedative medications whenever possible, blood tests to look for infection or metabolic / electrolyte abnormalities, up-to-date imaging to rule out new onset hydrocephalus, or performing an EEG to rule out subclinical seizures needing antiepileptic medication. This step also includes establishing that neurological pathways are intact, so that any assessment of consciousness provides an accurate reflection of the patient’s condition. Briefly, this involves examination and investigations to confirm that sensory, visual, auditory, and motor pathways are intact.

3. Structured assessment

There are several tools available which can confirm the diagnosis of VS or MCS. All of these require a trained assessor and an appropriate environment. These tools provide a structured method of assessing the patient to:

  • Observe spontaneous behaviours.
  • Observe the patient’s reaction to stimuli from different sensory modalities.
  • Document the findings of family / friends / members of the healthcare team following their interactions with the patient.

Tools available include the Wessex Head Injury Matrix (WHIM), the JFK Coma Recovery Scale-Revised (CRS-R), and the Sensory Modality Assessment and Rehabilitation Technique (SMART), amongst others. As per RCP guidance, the CRS-R should be the primary assessment tool, and WHIM or SMART can be used to provide additional information. Furthermore, assessments need to be performed on at least 10 occasions, at several different times of the day, and over the course of a 2-3 week period.5,7-9

The 2020 RCP guidance also addresses how to manage patients that do not present through the acute hospital pathway.5 In these ‘late assessment’ cases, formal assessment is still required to establish their level of consciousness and guide management. These patients should be referred to an experienced PDOC assessor to establish the cause of PDOC, rule out reversible causes, and arrange formal evaluation. This should ideally be achieved by outreach assessments, but if this is not possible, structured interviews should be held with family and care staff to complete the CRS-R. If these measures do not provide a definite diagnosis, admission to a PDOC centre can be considered.5,8

Vegetative State & Minimally Conscious State

Patients in VS are unable to interact with their surroundings or those around them (no voluntary behaviours / communication / purposeful movements), and show no evidence of awareness of self. The patient may demonstrate reflexive behaviour (such as increased heart rate or startle response to noise), or spontaneous, purposeless movements (such as eye movements, teeth grinding, or limb movements). These behaviours can be misleading, which is why an objective and structured assessment method is vital.

Patients in MCS have some evidence of awareness of self or their environment, on a reproducible but inconsistent basis. Patients demonstrate behaviours such as: following simple commands, verbalisation, and purposeful behaviour MCS which is further classified based on the level of responsiveness:

  • MCS-minus - less complex behaviours such as orientation to noxious stimuli, or purposeful eye movements.
  • MCS-plus - more complex behaviours such as following instructions or interacting with objects.

Prognosis depends on cause, time since brain injury, and the trajectory of improvement (better prognosis for those who quickly progressed from VS to MCS). Those with traumatic brain injury are more likely to regain awareness and have a longer window for potential recovery. The majority of VS patients that regain consciousness tend do so within 12 months in traumatic cases, and 3 months in non-traumatic cases. The majority of MCS patients that regain consciousness do so within 2 years post injury, although others can emerge at up to 4 years. Whilst these are the expected outcomes, there are, however, rare case reports of patients emerging later than this.

VS / MCS-minus are classed as ‘continuing’ at >4 weeks post brain injury, and ‘chronic’ at >3 months for non-traumatic cases, or >12 months in traumatic cases. MCS-plus is classed as ‘continuing’ at >4 weeks post brain injury, and ‘chronic’ at >9 months for non-traumatic cases, or >18 months in traumatic cases. Chronic VS / MCS can be classed as ‘permanent’ when there has been no further change in trajectory of serial CRS-R for 6 months. In permanent PDOC it is predicted that consciousness is highly improbable to recover. It is important to remember these time frames, and their implications during discussions with family, when making best interests decisions and planning further assessments of consciousness.5,10,11

With the longer time period for potential emergence, and improved survival rate compared to VS, GPs are more likely to come across these patients in the community. Figure 1 outlines the key time points for assessment of VS and MCS.12

Figure 1: Timeline for assessment of VS & MCS.5

Emergence

A patient is considered to have ‘emerged’ from PDOC if they are able to consistently demonstrate awareness of self and surroundings. The RCP advise that patients who have emerged are able to do at least one of the following:5

  • Functional interactive communication (accurate yes/no responses to 6/6 basic questions on 2 consecutive evaluations).
  • Functional use of objects (intelligent use of ≥2 objects on 2 consecutive evaluations).
  • Consistent discriminatory choice-making (correct identification between 2 pictures, 6/6 times, on 2 consecutive evaluations).

Specialist Involvement

Early specialist input from a neurological rehabilitation team is recommended. The Royal College of Physicians Guideline Development Group advise that those with an ongoing disorder of consciousness at 4 days (Glasgow Coma Scale ≤10/15) should be referred for assessment, and advice regarding neurological disability and prevention of complications.5,13 At 2 weeks the patient should be referred for specialist neurological evaluation to identify the cause of the disorder of consciousness, assess the primary neurological pathways, and advise on further investigations.

Patients with ongoing disorder of consciousness at 4 weeks should have regular input from a specialist neurological rehabilitation team, led by a consultant in Rehabilitation Medicine. Once stable the patient should ideally be transferred to a specialist neurorehabilitation unit for multidisciplinary care, objective assessment of level of consciousness, formal best interests decision-making, and discharge planning.

Following this initial period, the patient should be placed in a unit away from the acute setting, where they can be monitored until it is evident that they are likely to remain in VS / MCS. These ‘slow-stream’ rehabilitation units, are designed to deliver care to patients with complex neurological disability, and provide appropriate maintenance therapy to manage physical disability. Medical input is usually provided by the GP surgery covering the area, although units should also have access to rehabilitation medicine physicians with experience in managing PDOC.

If it is agreed that a patient has permanent VS / MCS, then longer-term of care can be provided in a nursing home or, if appropriate, in the patient’s own home. A skilled assessor should review the patient yearly, with formal assessment of consciousness until either the patient emerges or dies.

Medicolegal & Ethical Issues

Capacity Assessments

By definition a person in PDOC lacks capacity to make decisions about medical treatment. The Mental Capacity Act 2005 requires this to be formally documented in the medical notes. A Deprivation of Liberty Safeguard should be put in place during hospital admission or nursing / residential home stay, providing that restraint and restrictions are in the patient’s best interests.14

Identifying Advance Decisions

The team providing care need to identify as early as possible whether the patient has a valid and relevant Advance Decision, Health and Welfare Lasting Power of Attorney, or Court-appointed Welfare Deputy. If one of these is in place, the team need to request to see the relevant documentation to understand what exactly it entails.

Best Interests Meetings

All medical treatment provided must be in the patient’s best interests. In the UK, the treating clinician must by law identify those people close to the patient that can provide insight into the patient’s beliefs / previous expressed wishes / likely wishes, and take part in best interests meetings. If there is nobody to fulfil this role then an Independent Mental Capacity Advocate must be appointed. An initial best interests meeting should be held to discuss the diagnosis, likely prognosis, and to plan treatment. Further meetings should be held at planned regular intervals, for major medical decisions, and following repeat assessments to decide future management, discharge planning, and ceilings of care.

Ceiling of Care Discussions:

Many relatives may not feel comfortable bringing up these topics themselves, so it is advisable to make the discussion part of a routine review as standard for PDOC patients.

In patients with PDOC, cardiopulmonary resuscitation (CPR) has a very low success rate, and will likely result in further brain injury due to hypoxia. For the majority of patients where emergence is not expected, or if it is felt that the patient would not accept their level of quality of life, CPR could be considered to be futile. This is because CPR would not provide a perceivable benefit to the patient, but would carry significant risks of harm (worsening brain injury, injury related to the CPR itself, undignified end of life). Decisions regarding ceiling of care or appropriateness of resuscitation should either follow the instructions set out in existing advanced directives, or be discussed together with the treating multidisciplinary team (MDT). It is highly advisable to involve close family / friends in discussions, but ultimately it is a medical decision.

For similar reasons, it should be considered whether hospital admission for treatment of acute deterioration is in the patient’s best interests. For example in a patient with permanent VS, treating an acute chest infection may improve their lungs, but will not improve the patient as a whole in a way that can be perceived and appreciated by that patient, so may be considered futile. Additionally, it may be considered appropriate to stop medications not aimed at providing comfort, or stop performing observations and investigations. As with all major medical decisions, this should be discussed within the MDT and with those close to the patient. Although patients with PDOC have absent / reduced awareness, care should be taken to maximise patient comfort, and if appropriate consider input from the palliative care team.

Decisions relating to withdrawing clinically assisted nutrition and hydration (CANH) have previously been managed differently than withdrawal of life-sustaining treatment. Until recently, the decision to withdraw CANH could not be made without referring to the Court of Protection (COP). More recent guidance published by the BMA advises that in PDOC this is not always necessary. The treating team should first establish whether there are any valid and relevant advance directives / health and welfare attorney with relevant power, and then follow a best interests decision-making process. If all parties are agreed that withdrawal of CANH is in the patient’s best interests, then a second opinion should be obtained (from an independent, expert PDOC physician); if they also agree, then CANH can be withdrawn. If there is any doubt or disagreement about the decision, then an application to the COP is required. Now in the UK, it is essential to have best interests meetings to decide whether provision or continuation of CANH is of benefit to the patient, rather than deciding whether to withdraw it. If CANH is determined to not be of overall benefit to the patient, then it should not be continued. Prior to the withdrawal of CANH, an appropriate end-of-life care plan should be agreed and be ready to put in place.6

Conclusion

Disorders of consciousness can occur following brain injury, and vary from coma to MCS. If the disorder of consciousness continues for 4 weeks, it is described as a PDOC. Diagnosis requires structured assessment by trained clinicians, once the patient is medically optimised and reversible causes are excluded. Ongoing assessment is crucial to monitor recovery, guide prognosis, and establish when the disorder is permanent.

There are many ethical and medicolegal issues involved in managing patients with PDOC, which are mainly centred on the patient’s loss of mental capacity to make decisions. The cost implications of providing care as outlined in these guidelines can be quite significant. This article reflects our experience working within the National Health Service (NHS) within the UK, which provides free healthcare to all at the point of delivery. Therefore the costing is less relevant to the patients, although this does need to be considered when commissioning services. In other private healthcare settings, costs may vary widely based on hospital and wider multidisciplinary team costs, and this may need to be taken into account when commissioning services. Also, we appreciate that in other countries there are likely to be different laws surrounding PDOC, and varying views regarding the ethical decisions discussed.

Currently, these guidelines are based on expert opinion from the Royal College of Physicians Guideline Development Group. In future, management of patients with PDOC could be improved with the establishment of a national registry, further studies into PDOC, and better integration with community services. Furthermore, an improved education about PDOC and the issues surrounding it, as we have aimed to outline in this article, will help physicians understand their responsibilities and provide the best possible patient care.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ADAM BOARDMAN, MBChB, MRCP UK, Complex Rehabilitation Unit, Sid Watkins Building, The Walton Centre Foundation Trust, Lower Lane, Liverpool, L9 7BB, United Kingdom. GANESH BAVIKATTE, MBBS, MD (Medicine), FRCP (London), FEPRM (Europe), Complex Rehabilitation Unit, Sid Watkins Building, The Walton Centre Foundation Trust, Lower Lane, Liverpool, L9 7BB, United Kingdom.
Corresponding Author Details: 
Adam Boardman, Complex Rehabilitation Unit, Sid Watkins Building, The Walton Centre Foundation Trust, Lower Lane, Liverpool, L9 7BB, United Kingdom.
Corresponding Author Email: 
adam.boardman1@nhs.net
References
References: 
  1. Headway. Acquired brain injury 2016-2017 statistics based on UK admissions. 2018. https://www.headway.org.uk/about-brain-injury/further-information/statistics/, (accessed 29 July 2019).
  2. Caplan H, Cox C. Resuscitation Strategies for Traumatic Brain Injury. Current Surgery Reports Epub 2019 May 15. 7. 10.1007/s40137-019-0237-x.
  3. Stroke Association. State of the nation: Stroke statistics. February 2018. Available online at {https://www.stroke.org.uk/system/files/sotn_2018.pdf}.
  4. Vegetative and Minimally Conscious States. Houses of Parliament POSTNOTE. PN489, 2015.
  5. Prolonged disorders of consciousness following sudden onset brain injury: National clinical guidelines. London: Royal College of Physicians, 2020.
  6. British Medical Association. Clinically-assisted nutrition and hydration (CANH) and adults who lack the capacity to consent: Guidance for decision-making in England and Wales. 2019.
  7. Shiel A, Horn SA, Wilson BA, et al. The Wessex Head Injury Matrix (WHIM) main scale: a preliminary report on a scale to assess and monitor patient recovery after severe head injury. Clin Rehabil 2000; 14:408-16.
  8. Giacino, J & Kalmar, K. (2006). Coma Recovery Scale-Revised. The Center for Outcome Measurement in Brain Injury. 
  9. Gill-Thwaites H, Munday R. The Sensory Modality Assessment and Rehabilitation Technique (SMART): A valid and reliable assessment for vegetative state and minimally conscious state patients. Brain Inj 2004;18(12):1255-1269.
  10. Luaute J, Maucort-Boulch D, Tell L et al. Long-term outcomes of chronic minimally conscious and vegetative states. Neurology 2010;75:246–52.
  11. Katz DI, Polyak M, Coughlan D et al. Natural history of recovery from brain injury after prolonged disorders of consciousness: outcome of patients admitted to inpatient rehabilitation with 1–4 year follow-up. Prog Brain Res 2009;177:73–88.
  12. Faugeras F, Rohaut B, Valente M, Sitt J, Demeret S, Bolgert F., et al. Survival and consciousness recovery are better in the minimally conscious state than in the vegetative state. Brain Injury 2018; 72–7. 
  13. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974 Jul 13;2(7872):81-4.
  14. Mental Capacity Act 2005. London: HMSO.

Self-adhesive mesh in open inguinal hernia repair, how does it compare to conventional suture fixation?

Authors
Ali W & Nugud O
Article Citation and PDF Link
BJMP 2019;12(3):a023

Introduction

Lichtenstein tension-free mesh repair has been the standard practice in open inguinal hernia repair for many years. The procedure involves suture fixation of the mesh via an anterior approach to the inguinal canal. It is hypothesised that this invasive fixation contributes to the development chronic postoperative inguinal pain (CPIP), a condition which can cause significant morbidity.

A sound repair should restore the groin anatomy whilst minimising recurrence and not adversely affecting the patient quality of life. Considering the large number of these operations performed each year, reducing complications such as chronic postoperative pain will have a significant impact on healthcare resources.

The introduction of anatomical self-adhesive meshes such as Parietx ProGripTM addresses this concern in theory by obviating the need for mesh fixation. This mesh is a macro porous polyester mesh that utilizes polylactic acid micro grips (PLA) to aid placement within 60 seconds1 without the need for additional fixation. The manufacturer does suggest, however, that additional fixation is left to the discretion of the operating surgeon.

We conducted a review of the literature to evaluate the reported outcomes of using this mesh in open inguinal hernia repair.

Methods

We conducted a PUBMED/MEDLINE search using the search words “Self-adhesive mesh”, “Lichtenstein repair”, “Open inguinal hernia repairand “Self-gripping mesh” .We looked primarily at the outcomes of postoperative pain and recurrence. The result highlighted five well-structured meta-analyses and several RCTs and retrospective reviews.

Results

In a retrospective review of 211 patients who underwent open inguinal hernia repair with self-adhesive mesh, Tarchi P et al reported a recurrence rate of 0.5% at 1 year and 2.4% at 2 years. They incidence of chronic pain was less than 3%. There were no cases of seroma, testicular complications or mesh infection at 1, 2 and 3-year follow-up. The report highlighted the shorter operative duration with no effect on recurrence rates as a point in favour of self-adhesive mesh. The authors acknowledged the limitation of the study design and the need for randomised trials to address the issue.8 A few other small non-randomised trials draw similar conlusions.9

A randomised blinded trial from the Danish Multicentre DANGRIP Study Group allocated 163 vs 171 patients to self-adhesive and suture fixation respectively. There were no significant differences between the groups in postoperative complications (33.7 versus 40.4 %; P = 0·215), rate of recurrent hernia within 1 year (1.2 % in both groups) or quality of life. The 12 month prevalence of moderate or severe symptoms was 17.4 and 20.2% respectively (P = 0.573).

The study concluded that the avoidance of suture fixation using a self-gripping mesh was not accompanied by a reduction in chronic symptoms after inguinal hernia repair. 5

The FinnMesh trial is a randomised multicentre trial from Finland that Compared glue fixation, self-gripping mesh, and suture fixation of mesh. 625 patients were randomised to cyanoacrylate glue (Histoacryl, n = 216), self-gripping mesh (Parietex ProGrip, n = 202), or conventional non absorbable sutures (Prolene 2-0, n = 207) There was no significant differences postoperatively in pain response or need for analgesics between the study groups at 1 year follow up. The mean operative duration was lower in the self-adhesive mesh group.6

The HIPPO trial is a randomised double-blinded trial of 165 patients. The reported hernia recurrence rate after 24 months was 2.4% for the ProGrip mesh and 1.8% for the sutured mesh (P = 0.213).

The incidence of CPIP was 7.3% at 3 months declining to 4.6% at 24 months and did not differ between both groups. 7 The mean duration of surgery was significant shorter with the ProGrip mesh (44 vs 53 minutes, P < 0.001).

In a systematic review of 7 studies comparing self-gripping versus sutured mesh for inguinal hernia repair totalling 1353 patients, Zhang C et al found no difference in recurrence (risk difference -0.02 [95% confidence interval -0.07 to 0.03], P = 0.40) or chronic pain (risk difference -0.00 [95% confidence interval -0.01 to 0.01], P = 0.57). 2 This review found no difference in wound infection, hematoma, and seroma formation. Self-adhesive mesh was again associated with a shorter mean operative duration. In its conclusion, the authors surmised that both mesh types are comparable in outcome but further long term analysis might be needed.

Pandanaboyana S published a meta-analysis of 5 RCTs and 1170 patients, that also found no significant difference in recurrence or chronic pain. Wound infection was lower in the self-gripping mesh group compared to sutured mesh but this was not statistically significant (risk ratio (RR) 0.57, 95% confidence interval 0.30-1.06, P = 0.08). The duration of operation was significantly shorter with self-gripping mesh compared to sutured mesh with a mean difference of -5.48 min [-9.31, -1.64] Z = 2.80 (P = 0.005).3

In another meta-analysis, Li J et al included 5 RCTs and 2 prospective comparative studies and 1353 patients. Statistically, there was no difference in the incidence of chronic pain [odds ratio = 0.74, 95% confidence interval (CI) (0.51-1.08)]. There was no statistical difference in the incidence of acute postoperative pain [odds ratio = 1.32, 95% CI (0.68-2.55)], hematoma or seroma [odds ratio = 0.89, 95% CI (0. 56-1.41)], wound infection [risk difference = -0.01, 95% CI (-0.02 to 0.01)], and recurrence [risk difference = 0.00, 95% CI (-0.01 to 0.01)]. The self-gripping mesh group was associated with a shorter operating time (1-9 minutes).10

In Ismail A et al’s meta-analysis of 12 randomized controlled trials and 5 cohort studies, 3722 patients were included in the final analysis. The two groups, using self-gripping mesh or sutured mesh fixation, did not differ significantly in terms of recurrence rate (odds ratio = 0.66, 95% confidence interval 0.18-2.44; P = 0.54) or postoperative chronic groin pain (odds ratio = 0.75, 95% confidence interval 0.54-1.05; P = 0.09). The operative time was less in the self-gripping mesh group (mean difference = -7.85, 95% confidence interval -9.94 to -5.76; P < .0001). There were comparable risks between self-gripping mesh and sutured mesh fixation groups in terms of postoperative infection (odds ratio = 0.81, 95% confidence interval 0.53-1.23; P = 0.32), postoperative hematoma (odds ratio = 0.97, 95% confidence interval 0.7-1.36; P = 0.9), and urinary retention (odds ratio = 0.66, 95% confidence interval 0.18-2.44; P =0.54).11

A more recent meta-analysis including 10 RCTs and 2541 patients also draws similar conclusions, with no significant difference in the incidence of chronic pain (odds ratio = 0.93; 95% confidence interval, 0.74-1.18), recurrence (odds ratio = 1.34; 95% confidence interval, 0.82-2.19), or foreign body sensation (odds ratio = 0.82; 95% confidence interval, 0.65-1.03).4 The mean operating time was significantly shorter (odds ratio = -7.58; 95% confidence interval, -9.58 to -5.58) in the self-gripping mesh group which is consistent with the reported literature.

Discussion

Open inguinal hernia repair is a routinely performed operation and chronic postoperative inguinal pain is a significant cause of morbidity that can impact negatively on patients’ quality of life. Eliminating the need for suture fixation seems theoretically a step in the right direction.

The published literature, however, seems to arrive at similar conclusions. Whilst using self-adhesive mesh results in a shorter operative duration and seemingly does not affect the outcome negatively otherwise, there is no evidence that it reduces postoperative chronic pain and therefore should not be advocated on this merit. A shortened operative time coupled with a non-inferior outcome does seem like a more reasonable evidence-based argument for its proponents.

The decision of which mesh fixation technique to use can be left to the discretion of the operating surgeon. Further long-term follow up data is required to arrive at more definitive conclusions as the mean follow up duration in the reviewed studies ranged from 4 months to 3 years. The cost implications involved in the choice of mesh used should also be taken into account in future studies.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
WADAH ALI, MBBS MRCS(Glas) CABHS, General Surgery Registrar, Health Education, England North East. O NUGUD, Consultant General and Laparoscopic Surgeon, England.
Corresponding Author Details: 
waddahabdelazim@hotmail.com
Corresponding Author Email: 
waddahabdelazim@hotmail.com
References
References: 
  1. Philippe Chastan, MD (2006). Tension-Free Open Inguinal Hernia Repair Using an Innovative Self-Gripping Semi-Resorbable Mesh. Journal of Minimal Access Surgery; pp 139-43.
  2. Zhang C1, Li F, Zhang H, Zhong W, Shi D, Zhao Y. Self-gripping versus sutured mesh for inguinal hernia repair: a systematic review and meta-analysis of current literature. J Surg Res. 2013 Dec; 185(2):653-60.
  3. Pandanaboyana S, Mittapalli D, Rao A, Prasad R, Ahmad N. . Meta-analysis of self-gripping mesh (Progrip) versus sutured mesh in open inguinal hernia repair. Surgeon. 2014 Apr; 12(2):87-93.
  4. Molegraaf M, Kaufmann R, Lange J. Comparison of self-gripping mesh and sutured mesh in open inguinal hernia repair: A meta-analysis of long-term results. Surgery. 2018 Feb; 163(2):351-360.
  5. Jorgensen L N, Sommer T,   Assaadzadeh S,   Strand L,  Dorfelt  A, Hensler M, Rosenberg J. Randomized clinical trial of self‐gripping mesh versus sutured mesh for Lichtenstein hernia repair. Br J Surg. 2013 Mar; 100(4):474-81.
  6. Rönkä K1, Vironen J, Kössi J, Hulmi T, Silvasti S, Hakala T, Ilves I, Song I, Hertsi M, Juvonen P, Paajanen H. Randomized Multicenter Trial Comparing Glue Fixation, Self-gripping Mesh, and Suture Fixation of Mesh in Lichtenstein Hernia Repair (FinnMesh Study). Ann Surg. 2015 Nov;262(5):714-9.
  7. Molegraaf MJ, Grotenhuis B, Torensma B, de Ridder V, Lange JF, Swank DJ. The HIPPO Trial, a Randomized Double-blind Trial Comparing Self-gripping Parietex Progrip Meshand Sutured Parietex Mesh in Lichtenstein Hernioplasty: A Long-term Follow-up Study. Ann Surg. 2017 Dec;266(6):939-945.
  8. Tarchi P, Cosola D, Germani P, Troian M, De Manzini N. Self-adhesive mesh for Lichtenstein inguinal hernia repair. Experience of a single centre. Minerva Chir. 2014 Jun; 69(3):167-76.
  9. Yilmaz A, Yener O, Kaynak B, Yiğitbaşi R, Demir M, Burcu B, Aksoy F. Self-gripping Covidien™ ProGrip™ mesh versus polypropylene mesh in open inguinal hernia repair: multicentre short term results. Prague Med Rep. 2013; 114(4):231-8.
  10. Li J1, Ji Z, Li Y. The comparison of self-gripping mesh and sutured mesh in open inguinal hernia repair: the results of meta-analysis. Ann Surg. 2014 Jun; 259(6):1080-5. 
  11. Ismail A1, Abushouk AI2, Elmaraezy A1, Abdelkarim AH3, Shehata M3, Abozaid M4, Ahmed H3, Negida A3. Self-gripping versus sutured mesh fixation methods for open inguinal hernia repair: A systematic review of clinical trials and observational studies. Surgery. 2017 Jul; 162(1):18-36. 

Conundrums of the Association Between Creativity and Psychopathology

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2019;12(3):a022
Abstract / Summary
Abstract: 

Background: Creativity has been historically linked with psychopathology. Creativity is a complex phenomenon and is a more emergent quality of living systems. Numerous scientific papers devalued creativity as being a psychopathological phenomenon. The present trend in psychiatry of medicalising all unusual behaviour is counter-productive to fostering creativity among children. Consequently, creative children are at risk for being both mislabelled and misdiagnosed.  Psychiatry is using a ‘brain disease model’ to understand creativity.

Aim: To evaluate the different psychological and psychopathological views as well as some of the future directions, and to suggest new lines of research.

Method: Selective survey of the literature including previous reviews to collect different interpretations which also help to form a framework to study creative process. Psychological, psychopathological and biological views separately analyzed.

Results: Psychopathology is only a mediator and not the producer, and creativity can be cathartic. The association between genius and mental illness is a social belief and partly this confusion has a journalistic origin. It is always the healthy part of the mind that generates outstanding creative works, whilst creativity of the highest order is more a product of laborious intellectual work.The scientific literature does not substantiate the reported high incidence of mental Illness among the creative people that exceeds chance expectation. Inspiratory part of creativity remains an enigma.

Conclusions: Let alone that we do not know the true aetiology of schizophrenia and bipolar disorder, but we do not have even an approximate model of the brain-mind-consciousness complex. So, it would be prudent to suspend our psychopathology linked views of creativity until we know more about psychiatric conditions that may have phenomenological similarities with creative minds. Creativity continues as a permanent mystery.

Keywords: 
creativity, psychopathology, substance abuse,inspiration, biological correlates

Introduction

The creative process is an enigma; there are conflicting opinions about creativity and creative people. Research studies on creativity have produced contradictory results. The long-standing belief that creativity results from a strange clairvoyant state is still occasionally associated with psychiatric disorders. 1 Although a decline in creativity with aging indicates that it is biologically based, a relationship between creativity and psychopathology is overstated in both print and media. Reductionism tends to misconstrue creativity as a product of psychopathology. Nonetheless, whilst psychopathology can facilitate creativity, it does not produce creativity. The inspirational characteristics of creativity remain shrouded in mystery.

Methodological issues that include both a definition and an evaluation of creativity impede the research into creativity. These challenges make the correlations between the studies problematic, and they deliver opposing outcomes. Although there is no confirmed relationship between psychopathology and creative accomplishment, the search for such a relationship hinders our understanding of human potential and the deeper levels of consciousness. Early detection of creative talents in children might enable providing them with special guidance, thereby averting potential psychiatric problems.

The superficial reductionism of 20th century biological psychiatry compressed all mental phenomena, including creativity, into compact neurobiological compartments, and the only way to achieve this was to medicalise it. Any assumed correlations between creativity and mental disorders will be clarified only when we gain a greater understanding of the creative process. In cases where creativity and mental illness indeed coexist, a psychiatric understanding of creativity may provide insights into patient functioning and assist in defining both normalcy and psychopathology.

Whilst human beings have existed on this planet for millions of years, the technological advancements of the last few centuries transpired without any perceptible changes in the development of the human brain. Historically, our ancestors were drawing two-dimensional pictures until just a few centuries ago. No one has hitherto been able to explain this sudden burst of creativity. An expanded model of brain-mind-consciousness that can appreciate the wonder of creativity is needed.

Defining Creativity

Researchers have long been interested in a potential connection between creativity and mental illness. The major challenge here is to define creativity and establish measurable indicators. Creativity has been described as the process of bringing something new into existence. It involves the capacity to take unrelated structures and combine them harmoniously in different ways for new purposes. The creative mind is alert to unexpected connections. An individual with a rich reservoir of knowledge is regarded as intelligent, whereas an individual who uses that knowledge in an original and constructive way is considered creative. 2 The creative process is not fully understood; some even feel that a precise definition is unattainable.3 Nonetheless, creativity can be described as the process of bringing something new into being where the outcome is larger than the input received by the creative mind. 4,5 Creative individuals are sensitive to gaps in human knowledge and these voids act as catalysts in their search for solutions. This is the highest form of human adaptation; whether to a greater or a lesser degree, it may exist in all people.

The creative process can be likened to a four-stage computer process. 6 If information processing and storage is the primary process, the second stage is the incubation or pondering phase, during which ideas germinate at a subconscious level. The third phase involves illumination, or flashes of insight, and the fourth is the period of elaboration during which the new idea is developed and tested. These stages can be additionally likened to the biological rhythm of conception, gestation, birth and infancy. This pattern is not strict. As a rule, the process of illumination is gradual with countless small bursts of insight, such as with Charles Darwin’s elaborations on his theory of evolution.

Dream processes shed some light on creativity. As with poetry, dreams are replete with visual and highly idiosyncratic metaphors. Dreams are the art of the unconscious; whilst dreaming, we tap into a creative source. The dreaming psyche has seemingly unlimited creative potential. An anecdote about Kekule, the chemist, recounts that he conceived the benzene ring after a dream in which he saw a serpent biting its tail.

The Creative Personality

Creative people must be assessed on an individual basis. Not all persons of superior intelligence are creative, and not all creative people have superior intelligence. Although creative potential is dependent on intelligence, actual creative achievement is independent of intelligence (e.g. one does not have to be tall to be a successful basketball player). Highly intelligent people are prone to self-criticism, which has an inhibiting effect on the development of creativity. A combination of high intelligence and special aptitudes appears to promote creativity. Unconventionality, egocentrism, flexibility, tolerance for ambiguity and a preference for complexity are among the attributes of creative individuals. 7 Psychological testing has shown that creative individuals are frequently more emotionally troubled than are non-creative individuals; however, they also have more ego strength for dealing with problems. Their personal qualities include imagination, persistence, perseverance, dedication and stamina. Creative children tend to be egotistic and gullible. This egotism provides them with the confidence to believe that they are capable of unique achievements, whilst momentary gullibility enables them to break through scepticism and into creativity.

McClelland illuminated a controversial notion when he described the creative individual as one who is characterised by competition, either with an external standard of excellence or with his or her own internal aspirations. 8 Driving absorption, the ability to ignore failure and adversity and tremendous curiosity are noted as a predictive set of personality traits.9Although creative individuals are difficult to live with, whether their creativity flourishes or not frequently depends on the support that they receive from others. 10 Among the characteristics of creative people, Tarlaci (2014) included openness to experimentation and change, rebelliousness, individuality, sensitivity, playfulness, self-assertiveness, curiosity and simplicity. 11

Although there is a compulsion for order, symbolisation and communication are at the core of creativity. Intelligence, domain-specific knowledge/expertise, motivation and adaptive traits such as openness, broad interests and self-confidence are closely associated with creativity (Feist 1999). 12 Despite the fact that these characteristics of creative people are obviously independent of psychopathology, they point towards better mental health. Research on creativity in neuroscience has revealed that creativity is associated with ‘ordinary’ rather than psychopathological brain processes.13

Psychopathology

Since the time of Plato, philosophers have debated a conceivable connection between creativity and psychopathology. He proposed a logical paradox when he stated that a poet does not know what he is going to write, and yet he cannot produce a poem if he has no picture of what he describes. As a Greek philosopher, Plato was a reincarnationist. He obviously solved his own riddle by attributing hidden creative knowledge to remembrances of a previous life and to springing from ‘Divine madness’. Aristotle noted the predisposition of great artists and poets to melancholia, but he perceived creativity as a rational process. Shakespeare repeated the older perspective through one of his characters who states, ‘the lunatic, the lover, and the poet are of imagination, all compact’. During the 20th century, systematic investigations into this relationship were unable to either support or refute this association. Cesare Lombroso failed to clarify this confusion in his book, Genius and Mental Illness. Nonetheless, his influence led to speculation that genius is an ‘ancestral gift’ transmitted in families in the same manner as mental disorders.

Recent empirical research has shown that creative individuals have a higher tendency towards psychopathology than those in non-creative professions. This propensity is expressed in personality traits, behaviours and experiences similar to those identified in clinically ill patients (Jamison 1989). The evidence has not clarified whether the psychopathology linked to creativity relates more closely to features of schizophrenia or affective disorders. Countless novelists and dramatists have family histories of psychiatric disorders. Severe personality deviations have been observed among visual artists and writers and possibly among thinkers and scholars as well. Jamison noticed mood disorders among writers and artists. 14

Bipolar disorder may be more frequent among creative individuals than in the normal population. One study reported a higher incidence of depression and bipolar disorder among creative people, and especially among writers.15Another study noted a higher incidence of depression and alcoholism among writers and artists. Following recent epidemiological studies with large samples, Kyaga et al. (2013) argued in favour of an association between professional authors and psychiatric disorders. 16 They illuminated familial associations between the creative professions and schizophrenia, bipolar disorder, anorexia nervosa and possibly autism. 16They noted that this association was more evident in cases of self-employed artists and less so in scientific creativity, where the subjects had passed through several professional screening procedures.

In another epidemiological study, Parnas et al. (2019) found that the relatives of academics have a significantly increased risk of suffering from schizophrenia or bipolar disorder. 17 In another study, they suggested that ‘creativity and an increased risk for mental disorders seem to be linked by a shared vulnerability that is not manifested by clinical mental disorders in the academics.’ 18 The literature has made significant connections between bipolar disorder and creative accomplishment, with much of the thinking inspired by biographical accounts of poets and musicians who presented with signs of bipolar disorder. 19 Studies by Burkhardt et al. (2018) suggest that, in persons at-risk for bipolar disorder, their mood swings are strongly associated with creativity, but whilst there is evidence of increased creativity, there is no evidence of higher creative achievement. 20

Observations of the bipolar mood domain identify a high prevalence of changes in intuition, empathy, appreciation of danger and predictive capacity. However, these changes do not necessarily include supra-sensory changes in the primary senses of smell, taste, vision, touch or hearing. Parker et al. (2018) suggested that clinicians should be aware of non-psychotic, supra-sensory phenomena in patients with bipolar disorder and that the identification of such features could explain the increased creativity evident in those with a bipolar condition. 21

After examining the life of Charles Dickens, Longworth and Carlson (2018) maintained that there was very little historical evidence for the suggestion that he experienced bipolar disorder. 22 However, they did suggest that he displayed characteristic bipolar symptoms. They also maintained that his childhood was an outstanding example of personal resilience and that his own story was just as fascinating, if not even more intriguing, than any of those that he had created. Their investigations concluded that Dickens’ story confirmed the connection between writers, creativity and mood disorders. Retrospective psychiatric assessment of historical figures and the slotting of these celebrities into biological compartments may be risky. Biographical studies of creative people are criticised for having possible recall, interviewer, selection and cultural sampling bias. 23

The suicide rate is high among artists, and this has been linked to manic depression. Adverse financial circumstances and disappointments due to the rejection of their artistic productions are sufficient to explain this apparently high rate. In contrast, musicians have a low suicide rate, very likely reflecting the healing effect of music. In addition to alcohol, opium has been a historical favourite addictive drug of writers, of which Charles Dickens is an example; opium addiction was partially responsible for his death. 24 Ludwig’s study on 1000 outstanding individuals found an upsurge in alcohol abuse in artists, especially writers. 25 Post (1994) found a similar result among prose writers and playwrights. 26 Although Ernest Hemingway, the Nobel Prize winner for literature, may be a good example of this phenomenon, he committed suicide later in his life. Creative individuals may be notorious for their alcohol and drug misuse; however, it is not clear whether drug induced psychopathology promotes their creative expression. Whilst it is possible that the disinhibiting influence of mild psychopathology and the judicious use of alcohol or drugs could facilitate creativity, this phenomenon has potentially contributed to the confusion in which psychopathology is described as the ‘producer’ of creativity.

Absence of Psychopathology

Alongside these studies, other reports glorify the mental health of geniuses and eminent individuals. The Stanford 35-year follow-up study of over 1000 geniuses, the MacKinnon study of creativity in architects and Havelock Ellis’s psycho-biographical study of eminent men all emphasised the absence of psychopathology among these creative individuals. 27

In an investigation on the prevalence of psychopathology, in a sample of 291 famous men, Post (1994) noted that they all excelled by virtue of their abilities, originality, drive, perseverance, industry and meticulousness. 26Even though most of them had unusual personality characteristics and minor neurotic abnormalities, all of the subjects in this study were emotionally warm, with a gift for friendship and sociability. Post additionally noted that, among creative individuals, scientists show the fewest psychological abnormalities. Functional psychoses are less frequent than epidemiology would suggest. Depressive conditions, alcoholism and possible psychosexual problems are more prevalent than expected in some professional categories, particularly among writers. Hare (1987) noted that banning stimulant drugs in sports did not lower the achievements significantly, and that the same should be true of creativity. Poetic vision has been equated with psychedelic experiences. 28 Creative activity has been observed to be at its highest level in patients who are moderately ill, and at its lowest level in groups identified as severely ill. 29

Although there is no significant difference in the incidence of psychotic illness among males and females, there is less creativity among the latter. If the hypothetical connection between creativity and psychopathology were valid, the incidence of creativity should be proportional to gender. Historically, unfavourable social pressures and opposing cultural factors have represented major explanations for the lower incidence of creativity among women. This disparity points towards the fact that creativity has to be nurtured and is not automatically generated by psychopathology. Despite an equal incidence of mental illness in men and women, there have been few female geniuses in any culture; this challenge the probability of a clear connection between psychopathology and creativity. The same argument may be used against a pure biological view of creativity; both men and women have the same biological make up, yet fewer geniuses have been identified among female population.

Psychodynamic Perspectives

Psychoanalysts have postulated dynamic psychopathologies for the creative process. Analysts incline towards seeing artists as neurotics and their productions as sublimations of sexuality and regression in the service of the ego. 30 They consider the motives for creative activity as impulses that compensate for dissatisfaction and as defences against depression. Some perspectives differ from traditional psychoanalytical ideas, emphasise the crucial role of synthetic ego operations and draw distinctions between psychopathology and creativity. 31Analysts suggest that novel ideas exist in the subterranean regions of the mind. Whilst the conscious mind has no access to these hidden areas in the normal state, it is easier for a disturbed mind to tap information from the unconscious or preconscious. 32 Sims suggests that the psychotic and the creative states are subjectively indistinguishable and that delusions arrive in the minds of the mad in the same manner that ideas drop into the minds of the creative.33In contrast,Slater and Meyer report only minor psychiatric disorders among creative people. 34Although it would appear that psychopathology does not preclude creative activity, it may release it. In general, the creative person enjoys conflict free intimacy with the preconscious and is a model of psychological health. 35

Orderly Mind

The neurobiological model of schizophrenia suggests that a deficit in the systems involved in information-processing could contribute to its symptomatology. 36It has been hypothesised that such a deficit could favour the creative association between information units.37Psychopathology linked creativity has even been associated with abstract disciplines such as mathematics. If these views were accepted, creativity and schizophrenia would be separated only by a ’neurological difference’. Andreasen challenged the hypothesis of a connection between creativity and schizophrenia.38He argued that the bizarre nature of schizophrenic experiences is far from original, and that the cognitive impairment of such patients inhibits their creativity.

The creative intelligent person experiences an attention surplus, whereas a schizophrenic patient suffers from an attention deficit. As a case in point, a creative child may figure out in two seconds what the teacher is going to say, after which he may be looking around, waiting for the teacher to finish and appearing as if he is not paying attention. In contrast, because of a failure in the normal filtering of stimuli, schizophrenics tend to make unusual associations that result from over-inclusive thinking in which countless disconnected elements are included in their reasoning. 39 Although higher cognitive individuals also demonstrate ‘pseudo over-inclusive thinking’, this is due to their capacity to conceive and utilise two or more contradictory concepts simultaneously.40

Bleuler (1950) described intellectual ambivalence as both characteristic of schizophrenia and as superficially similar to the janusian process of oppositional thinking that involves conceiving of two or more opposites simultaneously. 41 The Kent-Rosanoff word association test has been used to assess this process. 42 In contrast to the creative thinker who is fully aware of logical contradictions, the schizophrenic patient is unconscious of the contradictory nature of his or her utterances. For example, when Albert Einstein derived his theory of relativity, derived from the fact that a man falling from the roof of a house was both in motion and at rest, he was fully aware of the contradictory nature of his thinking. 43 Another example is Frank Lloyd Wright’s revolutionary design of Falling water, in which nature and interior space coexist. The janusian process was initially identified in highly creative writers, visual artists and scientists. The fluency of association observed among creative individuals can be mistaken for over-inclusive thinking. 44Since their brains process increased sensory input effectively without cognitive overload, creative individuals derive an advantage from their higher levels of associative thinking.

Contrary to popular belief, in their cognitive and conceptual style, creative writers resemble those suffering from the manic phase of affective disorders, rather than schizophrenics. However, whereas the over-inclusiveness of maniacs is based on bizarre associations, that of writers is due to an imaginative recognition of original associations. Whilst writers are capable of controlled flights of fancy, manic imaginations are bizarre and based on personalised reason. The racing thoughts of a creative intellect are productive, whereas those of the manic are destructive. Albert Einstein claimed that he discarded a new idea every two minutes.

Creative thinking is polythetic and should not be confused with flight of ideas. Schuldberg (1990) investigated the overlap between schizotypal and hypomanic traits and suggested that affective symptoms may be more important than primary process thinking in determining creativity within the general population. 45 The fluctuation of thoughts experienced by higher cognitive ability individuals can be mistaken for mood swings. Fink et al. (2014) challenged the connection between creativity and psychopathology and proposed that the domains of artistic and scientific creativity should be analysed separately. 46

Although the creative potential of autistic people has been recognised, they differ from over perceptive children in many respects. One fundamental difference is that the creative potentials of the latter are polythetic, whereas such potentials of the of autistic individuals are generally monothetic. A key diagnostic criterion for autism—restricted and repetitive behaviours and interests—combined with a small number of research studies, suggest that generating original ideas or artefacts may be challenging for autistic individuals. 47Nonetheless, a minority within this population has exceptional artistic gifts, and a wider group embraces activities typically associated with creative expression, including visual art, music, poetry and theatre.

A three-level multilevel meta-analytic approach investigated the relationship between creativity and schizophrenia. The analyses of Acar et al. (2018), with 200 effect sizes gathered from 42 studies, detected a mean effect size of r =−0.324, 95%CI [−0.42, −0.23]. 48When the analyses focused on the moderators, they found that the relationship between schizophrenia and creativity was moderated by the type and content of the creativity measure, the severity of the schizophrenia and the patient status. The negative mean effect size was firmer with semantic-category or verbal-letter fluency tasks than the divergent thinking or associational measures. They submitted that when these findings are analysed along with previous meta-analyses on the association between creativity, psychoticism and schizotypy, creativity and psychopathology appear to have an inverted-U relationship. Whilst a mild expression of schizophrenia symptoms may support creativity, a full demonstration of the symptoms challenges it.

Schizophrenia and schizotypy have frequently been associated with above average creativity; nonetheless, empirical studies on the relationship between schizophrenia spectrum disorders and enhanced creativity have generated inconsistent results. 49 Even though some mental processes may appear to be similar in creative and psychotic thinking, the current literature challenges this conclusion. 50,51,52Psychopathology does not play a role in the genesis of higher order creativity; nonetheless, the psychological defence mechanism of overcompensation goes some distance towards explaining the high achievements of mentally or physically disabled individuals. 53

The Myth of Drug Induced Creativity

The belief that brain alone is the source of creativity led to the idea that altering brain chemistry could make people more creative. The truth may be that the gentle psychopathology created in the brain might serve as a facilitator of creativity rather than a producer of creativity. The psychopathology generated by the psychedelic drugs might help to open Aldous Huxley’s ‘doors of perception.’ Huxley (1954) proposed “Doors of Perception” to illustrate the enlightenment induced by LSD etc.54 Interestingly, such a proposal is close to Zizzi and Pregnolato’s depiction of ‘very fast switches from the quantum logic of the unconscious to the classical logic of consciousness’ (Zizzi & Pregnolato,2012). 55Those who glorify such drug induced creativity are unaware that long term substance misuse can only kill creativity as the ‘switches’ become permanently damaged and lead to psychopathological states.

When one’s sense of self is suspended and space-time sense dissolves, psychedelic experiences occur, and such experiences should not be confused for true mystical experiences. Psychedelic experiences are pseudo-mystical experiences. True mystical perceptions and cognitions relate to what is essentially ineffable, pertaining to the nature of existence rather than being limited to familiar objects that are intrinsic to everyday experience. The hallucinating drug user or alcoholic is functioning at the level of impaired consciousness, while the mystic is operating at a higher level of consciousness. Mystics have full awareness of their altered state of consciousness and they are also in a position to switch back to their ordinary mode of perception, unlike a hallucinating patient. It may be true that psychedelic experience has created an interest in artistic activity and the raw materials obtained in such experience may be useful in eventual artistic creation, but the psychedelic experience as such is not a creative experience because motor functioning is impaired during psychedelic experience and information flow to the hands and fingers are affected. 56 The natural state of a relaxed, happy, and well-adjusted person is more creative rather than the perplexed psychedelic state. There may be ‘psychedelic artists,’ but not psychedelic scientists indicating the difference in the creative process of scientific generativity and artistic.

Drug induced creativity is a conundrum that need serious clarification as many young people are trapped in such faulty perceptions. Cannabis is the most widely used illegal substance globally. Schafer et al (2011) suggested that cannabis produces psychotomimetic symptoms, which in turn might lead to connecting seemingly unrelated concepts.57Such divergent thinking is considered primary to creative thinking. They argue that a drug induced altered state of mind may indeed lead to breaking free from ordinary thinking and associations, thereby, increasing the likelihood of generating novel ideas or associations. But the harmful effects of cannabis use have been extensively evaluated.58,59,60,61,62,63Cannabis abuse is quite unlikely to generate any sustainable creativity-‘the creative Big Bang’ would soon end up as a big crunch.

If creativity is a neurological phenomenon, creative people should have additional neural pathways, but psychedelic drugs have not been proven to create such new neural pathways. Speculations about specific brain regions promoting creativity is of great scientific interest. Creativity involve an architect and a set of engineers. According to Amit Goswami, quantum unconscious domain is the architect and the real source of creativity if brain does the engineering works. 64 Psychoactive substances do not act directly on the quantum consciousness but may help to open the gates to the hidden dimensions of consciousness. When quantum views of creativity are given due significance, the neurologically based psychedelic promotional views of creativity crumble. If not having creative abilities is deemed as a ‘brain deficit,’ use of illegal drugs to promote creativity can be compared to using medications to treat ADHD. But only if we use the ‘brain disease model’ of psychiatry, the argument of ‘brain deficit model’ will hold water. It may be even true that psychedelic drugs may have a quick and transient destressing effect and that could promote a creative mental state, but the production of any direct creativity through the use of such drugs is questionable.

Problematic Childhood

Some children of superior intelligence attempt to mask their creativity by being over-talkative and overactive. Such children run the risk of being misdiagnosed as ADHD. Creative children frequently have a unique sense of humour that their peer group cannot appreciate. Creative children are every so often resented by peers because of crazy or unusual ideas and their forcefulness and passion in presenting them or for pushing their ideas on others. Their divergent thinking is not helpful in school examinations, which require convergent thinking, and this could explain the poor academic achievement of several geniuses. The divergent thought processes of creative children must be differentiated from inattention and underachievement. For example, a highly intelligent child might fathom out what the teacher is going to say next and become inattentive. Although creativity is associated with divergent thinking, this alone does not correlate well with creative achievement.65 Creative children overflow with ideas and play with new ideas and concepts. They are not motivated or even concerned about high grades and need individualized attention lest they might fall on the wayside. There is nothing more frustrating than being a creative intelligent and become underachieved.

Creative children demonstrate certain unusual traits such as daydreaming, wanting to work alone, sharing bizarre thoughts and conflicting opinions. These qualities will not please the traditional teachers and bring them in conflict with them and their lack of conformity to the classroom structure can be even confused with attention deficit hyperactivity disorder. Highly critical parents kill creativity; unfortunately, countless creative individuals have chaotic childhoods leading to psychological problems in their adult lives. Mismatching due to variation in I.Q could lead to mismatching with parents and siblings. Mother and father may be of average intelligence, but the child can be above average intelligence, and could cause mismatching leading to behavioural problems.

There is a special group of children around the world who have high intelligence and intuition, healing abilities, and a strong spirituality and they are grouped as Indigo people in appropriate cultures. It can be stated that Indigo is people with high sensitivity level, unique creativity, high intuition ability, healer, and people with their own charisma for those around. 66According to the proponents of these new ideas, these children are often mislabelled as having behaviour disorders. Little is known from scientific research about the Indigo phenomenon. Indigenous populations are familiar with Indigo-like children. The purpose of studying these children when they are adults is to better understand these children when they are older and advance behaviour health sciences by increasing awareness of the Indigo phenomenon and learning about their lived experiences. There has been hardly any serious scientific study on the Indigo phenomenon.

A phenomenological study looked at the lived experiences of 10 adult Indigos. The study explored the lived experiences of 10 adult Indigos on the island of Oahu, Hawai'i (> or = 18+ years old-7 females, 3 males; mean age = 52.4 + SD). 67 Through in-depth semi-structured personal interviews, the experiences of these adults were analysed and interpreted to identify the common experiences faced during childhood, what worked for their assimilation into society, and recommendations for parents, educators, and health professionals on how to work with Indigos. Bioenergy field photographs of each participant were also taken. Statements related to the phenomenon were placed into themes, coded, and categorized as the investigators reached a consensus of common themes. Seven primary themes and nine secondary themes emerged from the findings.

The primary themes were: grandmother/mother had a similar gift; guided by a higher power to heal self and others; felt 'different' or misunderstood; did not openly share their unique abilities; having challenges with partner relationships; history of abuse/violence or frequently disciplined; and use of intuition at work and/or school. Secondary themes included: Using Hawaiian and cultural healing methods; everyone has a degree of intuition and the use of intuition to know when to see a doctor or not; various unique abilities from body and multiple careers; mental health institutions, and financial struggle. Self-reports on participants' life purpose, their unique abilities, and being misunderstood were also collected. It was concluded that Indigos felt mislabelled or misunderstood throughout their lives despite their belief that their life purpose was to help humankind.

Academic psychologists are sceptical about Indigo phenomenon and argue that the phenomenon is a cover up to normalise the odd behaviour of children who could otherwise be included under the category of attention deficit disorder, attention deficit hyperactivity disorder, autistic spectrum disorders and learning disabilities. Health experts are concerned that labelling a disruptive child an "indigo" may delay proper diagnosis and treatment that could help the child or investigate the parenting style that may be causing the behaviour.

Inspiration and Perspiration

Creativity is regarded as the product of inspiration or creative imagination combined with meticulous, disciplined effort. The Edisonian perception of invention as 1% inspiration and 99% perspiration is explained by the hypothesis of interactive creativity; it assumes that the inspirational aspect has a paranormal component. In his thesis on interactive creativity, Laszlo supported his hypothesis with observations on cultural creativity. 68These observations included the collective advance of entire populations through the typical creative activity of their members and by documented incidents in modern science in which different investigators developed scientific insights simultaneously, without any known contact. 68 Early cultures developed similar 7tools; calculus was discovered simultaneously by Newton and Leibni and biological evolution was described independently by Darwin and Wallace. Similarly, Graham Bell and Elisha Grey both applied to patent the telephone on the same day. The Rubic’s cube was conceived simultaneously and designed both by Rubic and a Japanese inventor. Nylon was discovered in both New York and London, hence, the name NyLon.

Jung’s research into the phenomenon of creative synchronicity helped him to formulate his concept of the collective unconscious. Psychological disturbances may represent the consequences of creative endeavour and Jung (1973) considered them the price to be paid for persistent exploration of the unknown.69 Polayni (1994) suggested that scientific discovery is informed by the imagination and integrated by intuition, and vice versa.70 This statement is close to the Edisonian perception of creativity: If imagination is a property of the brain, intuition occurs in the unconscious realm. Whilst Laszlo’s views are not definitive, they indeed supplement our existing knowledge about creativity. The inspirational aspect can be better explained by an expanded model of brain-mind-consciousness, and Xavier suggests a para-psychodynamic.71

Biological Perspectives

Particularly gifted individuals have determined the evolution of civilisation. Karlsson (1984) commented regarding creative individuals: ‘Without their genes, men might still live in caves’. 72Nonetheless, countless gifted individuals have a very ordinary family background, with no ancestral history of creativity. For example, Newton came from an undistinguished family. Genetics researchers look for the biological roots of creativity, with some believing that the mind is reducible to chemistry. Whilst intelligence may be a trait that can be cloned, creativity may not be attached, and it may prove even more complex than genetic manipulation. Kelly et al. (2007) suggested that creative inspiration is akin to mysticism. 35

Responses to both dopamine inhibiting drugs and to the psychoses triggered by the drugs that increase dopamine activity underlie the dopamine hypothesis of psychosis. However, dopamine over-activity in psychosis should not be confused with dopamine fluctuations in creative individuals. Dopamine diminishes with aging, which may explain the decreasing powers of creativity after the age of twenty.73

The relationship between age and outstanding achievement has captured the attention of researchers into creativity.Whilst Lehman maintained the perspective that creative achievement has a curvilinear single-peak function for age, other researchers have described two separate age-peaks. 74Outstanding contributions among mathematicians after the age of fifty are exceptions. The age-related observations support a biological basis for creativity.

Future Directions

Study of creativity is an important area of research where consciousness studies and psychopathology meet each other. Cognitive scientists have pondered over the link between psychopathology and creativity for a long time without making any firm conclusions and appear to be barking at the wrong trees. The very process of creativity ought to be explored before any progress in this area of research could be achieved and the current reductionist model of mind stands as a hindrance. The following suggestions may be helpful for future researchers.

1. Establish the psychopathology of psychotic disorders

2. Creativity linked genetic studies are warranted, biological correlates of creativity need further elucidation.

3. Expand the current model of brain-mind-consciousness complex so as to explain the inspirational element of creativity.

4. More longitudinal, international and multicultural studies recommended.

5. Given the affinity of psychosis-proneness to the artistic creativity domain,

studies should be focussing artistic creativity and scientific creativity separately.

Clinical Implications

The study of creativity has clinical implications: A) Psychiatric understanding of creativity provides a better picture of patient functioning that could assist in clarifying the definitions of both normalcy and psychopathology. B) Early detection of creative talents in children might help to give special guidance for such children and thereby prevent potential psychiatric problems. C) When they coexist, differentiating creativity and mental illness is useful: The former might require nurturing and the latter warrant clinical intervention.

Discussion

Whilst it is true that investigators have observed a high incidence of psychiatric symptomatology of an affective nature among creative writers and artists, it is debatable whether this relationship is causal, an effect or a contributory factor. The increased psychopathological states observed in artistic creative individuals suggest that art and science reflect two different arenas of creativity. The mechanism of generation of novel ideas may be identical in art and scientific creativity, but they are evaluated differently by the two groups resulting in different types of products. Creativity and mental illness can coexist, and the creative impulse has a therapeutic effect on the psychiatric condition. Creativity can be therapeutic for those who are already suffering from mental illness; creative art therapies applied in clinical and psychiatric settings report positive health-related outcomes. 75 Even in rare cases of psychopathology induced creativity, the individual will require highly developed intellectual protective factors. It is the disciplined portion of the mind that enables outstanding creative achievements. Creativity of the highest order is a product of laborious intellectual effort. When they coexist, psychopathology is a mediator, not the producer of creativity, and the creativity may be cathartic.

There is no scientific consensus regarding the association between psychopathology and creative achievement. The literature does not substantiate the high reported incidence of mental illness among creative people. It is possible that predispositions to mental illness and creativity tend to co-occur because they reflect an underlying personality and cognitive style predisposed to both creativity and mood disorder. The high reported incidence of mental illness potentially signifies an ‘occupational hazard’ and creativity stands independent of psychopathology. The normal creative person can swing back to reality from a transient ‘creative psychical shift’ (e.g. such as a diver who searches for diamonds in the deep sea and then returns to the shore). The sensitivity and intensity that facilitate creative expression may additionally make highly creative people more susceptible to depression.

Early investigations of geniuses were retrospective. Formal meta-analyses were not considered justifiable. All forms of creativity were mixed in the studies, without distinguishing the different domains of creativity. Most of the studies were confined to English speaking people, whilst creativity is a global phenomenon. A multiplicity of literature does not mean that the ideas expressed are established scientific truth. This is true of creativity, which may be as mysterious as creation itself. The prevailing model of the mind may be inadequate for a full appreciation of the creative process. It would be easier for a ‘camel to pass through the eye of a needle’ than to explain creativity from a reductionist perspective. The inspirational component of creativity continues to be an enigma. It is my contention that creativity is essentially an inner, psychic phenomenon. We do not have even an approximate model of the brain-mind-consciousness complex, let alone know the true aetiology of schizophrenia and bipolar disorder. Therefore, it would be prudent to suspend our psychopathology allied perspectives of creativity until we develop a deeper understanding of consciousness.The association between creativity and psychopathology has soared to the level of cultural myth and this is evident in many films in which mentally ill persons are portrayed as extraordinarily creative. 76

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
JAMES PAUL PANDARAKALAM, Consultant Psychiatrist, North West Boroughs Healthcare NHS Foundation Trtsust, Hollis park Hospital, Warrington, UK.
Corresponding Author Details: 
JAMES PAUL PANDARAKALAM, Consultant Psychiatrist, North West Boroughs Healthcare NHS Foundation Trust. Hollins Park Hospital & AFG hospitals, Hollins Lane, Warrington WA2 8WA, U.K.
Corresponding Author Email: 
jpandarak@hotmail.co.uk
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Combination Therapy for Treatment Resistant Schizophrenia

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2019;12(2):a016
Abstract / Summary
Abstract: 

The pharmacological management of treatment resistant schizophrenia provides clinicians with a broad range of clinical challenges. Antipsychotic combinations involve pharmacokinetic and pharmacodynamic interactions with physical side effects. Consideration of the effect of long-term progress and physical consequence of medications are central to therapy selection. Clozapine is the gold standard for treatment resistant schizophrenia in spite of the various side effects, but clozapine may fail or be refused by patients.  Clinicians are left with very little choices in such circumstances and combination of antipsychotics is considered as one option. Olanzapine-amisulpiride combination may be a choice in pre-clozapine clinical situations and in cases where clozapine fails.

Abbreviations: 
SCZ- schizophrenia
Keywords: 
resistant schizophrenia, combination, clozapine, olanzapine, amisulpiride

Schizophrenia (SCZ) is a chronic relapsing and remitting disorder with a lifetime prevalence of 4 per 1000 persons.1Positive symptoms include delusions and hallucinations. Negative symptoms are characterised by deficits in normal behaviour, which are categorised into five domains: blunted affect, alogia, social withdrawal, anhedonia, and avolition. In clinical practice, when monotherapy fails multiple augmentation strategies – such as another antipsychotic, mood-stabilisers, benzodiazepines, lithium, electroconvulsive therapy, and repetitive trans-cranial magnetic stimulation – have been used to improve the clinical state of these patients, but evidence relating to the use of these interventions is lacking.2None of the regulatory bodies has openly endorsed polytherapy with antipsychotics.

The introduction of chlorpromazine in the 1950s revolutionised psychiatry, and the coming of slow-release, slow-acting forms (depot medication) contributed to the closure of asylums and paved the way to community psychiatry. Second-generation antipsychotics ameliorated the situation for a number of psychotic patients, but some remained resistant to all forms of psychopharmacology. In 1958, clozapine was formulated and marketed commercially in 1972. 3 The arrival of clozapine facilitated the rescue of some schizophrenia sufferers for a short time, but the drug disappeared from the scene because of initial untoward incidents. 4,5 The observation that clozapine has the potential to control the motor symptoms of tardive dyskinesia and to treat the psychotic symptoms of patients already diagnosed with tardive dyskinesia, led to its reintroduction, but with restrictions. 6,7,8 Clozapine is recommended for use only after a trial of two other antipsychotics. Combining depot antipsychotics with oral drugs of a different class has been the practice ever since the introduction of depot medications, and this practice has come to have general clinical acceptance.

Treatment resistance

Historically, it was observed that a specific group of chlorpromazine users remained symptomatic. They were considered to be refractory to phenothiazines. The availability of clozapine led to a better definition of treatment resistance. ‘Response to treatment’ means a reduction in the severity of symptoms, while ‘remission’ implies an absence of symptoms for a considerable period. ‘Recovery’ signifies absence of the disease for a long period.9‘Treatment resistant schizophrenia’ (TRS) is the term used for persistence of psychotic symptoms despite a certain number of adequate treatments. Since the introduction of first-generation antipsychotics, clinicians have been cognizant of TRS and operational definitions have been used such as those developed by Kane et al. 10 Sometimes, treatment has been based on algorithms such as the Texas Medication Algorithm Project (TMAP).

According to the most common definition of TRS, if patients present with persistent, moderate to severe, positive disorganization or negative symptoms together with poor social and work function over a prolonged period of time after at least 2 adequate trials of neuroleptic drugs, they may meet the criteria of having TRS. 11 A common agreement is that adequate drug treatment requires a duration of 4 to 10 weeks, a dosage equivalent to 1000 mg/d of chlorpromazine, and trials of 2 to 3 different classes of antipsychotic drugs. 12 The current treatment guidelines recommend 2 or more treatment trials of atypical antipsychotics at adequate dosages. Adequate response to treatment has been defined as at least a 20% reduction in symptoms as measured by rating scales. Typical antipsychotics can also be used for 4 to 6 weeks to screen for TRS.

Resistance to treatment and poor outcome are different from genuine TRS. Resistance to treatment may be defined as a state in which the patient has access to medication, but the effectiveness of the treatment is suboptimal. TRS may be conceptualised as a state in which medication has reached target receptors but does not seem to be effective. Chronicity has often been misconstrued with treatment-resistance. Schizophrenia is a chronic disorder that progresses to various levels of clinical deterioration without sustained remission or full recovery. Poor-outcome SCZ applies to 50% of patients, and TRS comprises a subset of such patients. In these, cognitive impairment, negative symptoms and mood symptoms are independent of positive symptoms, resulting in poor-outcome SCZ.

It is generally accepted that 30% of SCZ sufferers have TRS. Many people with SCZ do not achieve a satisfactory treatment response to their initial antipsychotic drug treatment. They may manifest a poor response to therapy because of intolerance to medication, poor adherence and inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Assessing treatment resistance is a priority in the management of TRS. 13 TRS has to be closely evaluated before a comprehensive management plan is developed (Table 1). From a multidimensional point of view, TRS is dependent on manifold factors, such as longer duration, several episodes, gender, early onset, poor pre-morbid personality, family history, substance misuse, presence of soft neurological signs and a long untreated period.14 Genes are thought to be involved in the development of TRS; reliable genetic prediction of which patients will be TRS would have serious clinical implications. Structural neuroimaging techniques have revealed that TRS patients do not differ importantly than those responsive SCZ in terms of brain abnormalities.15

When clozapine fails or rejected

Clozapine may be the preferred drug for TRS – effectively the gold standard – but its side effects put off many patients to the extent that some of them refuse clozapine therapy. It is a unique atypical antipsychotic and there is robust evidence supporting its use in people with TRS. Though clozapine often represents the best hope for recovery, it is associated with severe and enduring adverse reactions that may delay its prescription and increase morbidity and mortality. The major side effects are a) agranulocytosis; b) metabolic side effects; c) myocarditis; d) seizures; e) severe constipation with gastrointestinal complications such as intestinal obstruction, bowel perforation, paralytics ileus and toxic megacolon; and f) sialorrhea. These side effects hinder the popular use of clozapine in TRS. It is a life-saving drug, but without extra care it may itself shorten the life span. Side effects are more common with higher doses. It has been estimated that between 10 and 60% of patients resistant or intolerant with other antipsychotic drugs respond to clozapine.

The side effects mentioned above are inevitably an impediment to its common use. When standard doses (300mg to 5oomg) do not produce the desired effects or patients develop unwanted effects, combining clozapine with other antipsychotics is a common practice for TRS. To mention a few antipsychotics, amisulpride and aripiprazole are atypical antipsychotics ordinarily used in combination with clozapine. The anti-salivatory effect of amisulpride and the alerting effect of aripiprazole are added advantages of such a combination, and these drugs are fairly weight neutral – in contrast to clozapine. Clozapine, representing a second generation of so-called atypical antipsychotic drugs, has shown positive effects in desperate cases of TRS. Furthermore, two epidemiological studies have shown that clozapine has the lowest mortality rate among antipsychotics.

Nevertheless, even supported by the literature as the best-known antipsychotic in terms of efficacy and rates of response, a sizeable number of patients remain resistant to clozapine therapy and continue as symptomatic and dysfunctional. It has been estimated that 40–70% of patients on clozapine may not respond satisfactorily to it.16 When patients do not respond to clozapine, they are categorised as super-refractory, but the very concept of super-refractory state is debatable. They do not differ from the refractory cases in terms of demographical factors but have high score of positive symptoms. It may be simply explainable that the aetiological mechanism of the illness of such patients may be different from the clozapine responders and that makes them unresponsive to clozapine. There are no operational definitions for super-refractory schizophrenia. According to the schizophrenia algorithm of the International Psychopharmacology Algorithm Project (www.jpap.org), persistence of psychotic symptoms after a trial with adequate doses of clozapine(300-900mg/day) for at least six months is designated as super-refractory cases. 17

Many predictors of clozapine response have been suggested without any firm ground. These include severe clinical symptoms, higher levels of functioning before the onset of schizophrenia, low levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid, reduced metabolism in the prefrontal cortex, reduced volume of the caudate, and the improvement of P50 gating at the 500-ms prepulse interval. 18 However, none of these factors is consistent or specific as a predictor of clozapine response. More genetic and brain imaging studies are warranted with such patients. In these cases, augmenting strategies are necessary, and some have been in use: typical and atypical antipsychotics, mood stabilizers, antidepressants and electroconvulsive therapy. Some studies have favoured ECT, but no definitive conclusion has been drawn. So also, half of clozapine patients discontinue taking the medication on their own accord. In a retrospectively studied sample of patients who discontinued clozapine, the majority terminated the treatment as a result of their own decision or because of non-compliance with medical procedures such as blood sampling.19

There are currently no evidence-based pharmacotherapies for the TRS patients who do not respond to clozapine 20,21 or those who terminate clozapine therapy due to adversative reactions. 22 In the nutshell, clinicians should be prepared to try different alternative treatment options for TRS and super-refractory cases. Thus, combination therapy may become a choice as pre-clozapine therapy or post-clozapine therapy. Clozapine is not a drug that could normally be imposed on patients, but it has to be earned by the patient.

Combination therapy

The range of antipsychotic medications available is wide, with variable effectiveness, and there are also differing profiles for typical and atypical agents, adding to a confusing array of terminologies and dilemmas regarding what the best drug for service users is.23 Combination therapy involves the addition of a second antipsychotic to the therapy regimen. It is different from adjunctive therapy, in which a second agent is employed to reverse an emergent side effect or to obtain a complementary clinical effect. Augmentation involves the use of a non-antipsychotic along with the antipsychotic already in use. Combination therapy and augmentation therapy are sometimes used interchangeably. In general, ‘combination’ refers to the use of more than one type of disease-specific treatment to treat a particular illness.

A change from one antipsychotic to another in same class seldom produces any additional benefit, whereas switching to an antipsychotic with a different mechanism of action has proved to produce a more impressive response rate. Combination becomes desirable when the drug already in use produces some favourable effect, but that is not sufficient to control the symptoms. It is imperative to distinguish between partial response and no response when considering a change in medication. Past antipsychotic drug response, adverse effect profile differences, concomitant medical disorders and concurrent drug therapy are factors to be considered when choosing between switching and combination or augmentation approaches. A switch is indicated when there is no response to the drug and combination therapy; augmentation is recommended for partial response. Another antipsychotic combination may become necessary as an option for TRS patients who cannot be treated with clozapine for various reasons. It is common practice in such situations to add a second antipsychotic, in combination with the original one.

Clinical team do not have to be disheartened or disillusioned when clozapine therapy fails due to non-response or clozapine intolerance, and also when augmentation and combination therapies do not bring about the desired outcome. Switching back to atypical drugs once again may turn out to be effective in some cases and clozapine is not to be considered as the last resort. A multicentre open label 18-week trial evaluated a switch to olanzapine in 48 clozapine resistant or intolerant patients. 24 Switching to olanzapine 5-25 mg per day resulted in a mean drop in total scores on the Positive and Negative Syndrome Scale (PANNS) and Brief Psychiatric Rating Scale (BPRS) of 17.7 (14.2%) and 9.8 points (20.2%) respectively.

Cautions

Monotherapy is the most desirable form of treatment for SCZ. There is no good objective evidence to support dual antipsychotic therapy except in combination with clozapine. The evidence base supporting such combinations consists mostly of small open-label studies and case series.25 Combination therapy should be considered only when several attempts at monotherapy, including one atypical antipsychotic, fail. It is assumed that two different treatments together may have a different mechanism of action and therapeutic response from that of either drug alone. Studies have been conducted to determine whether treatment with antipsychotic combinations is effective for SCZ and whether such treatment is safe for the same illness. The results of trial studies are based on very low or low-quality results, and research that provides high-quality evidence is needed before firm conclusions may be drawn. The results so far show that there may be some clinical benefit in combination therapy in that more people receiving a combination of antipsychotics showed an improvement in symptoms. For other important outcomes – such as relapse, hospitalisation, adverse events and discontinuing treatment – no clear differences between the two treatment options were observed. Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials; the assessment of long-term efficacy and safety is limited. There is some very low-quality evidence that a combination of antipsychotics may improve the clinical response.

There are published case reports of serious side effects, such as a higher prevalence of extrapyramidal symptoms (EPS), metabolic side effects, paralytic ileus, grand mal seizures and prolonged QTc in association with a combination of antipsychotics.26Combining three antipsychotics may be extremely dangerous; studies have revealed that such a procedure substantially increases mortality.27A negative case control study exists.28 It should be usual practice to document the rationale for combined antipsychotic use in individual cases in clinical records, along with a clear account of benefits and disadvantages, including side effects.

Newer combinations and augmentation strategies are supported only by case reports and open trial data. Along with advantages, a number of potential concerns regarding antipsychotic combinations have been identified (Table 2) and specific clinical cautions have to be implemented in combination therapy (Table 3). Yet, fixed combinations of drugs are common in medicine and at one time were common in psychiatry. An example is small doses of an antipsychotic in combination with an antidepressant for treating major depression; this lost popularity because of side effects. Also, SNRI-NaSSA combination therapy (e.g. California Rocket Fuel) is prevalently used for treatment-resistant depression.

Olanzapine–amisulpride combination

In spite of the objections put forward against combination therapy, there are isolated case studies favouring the olanzapine–amisulpride combination. Zink et al. (2004) performed a retrospective study, aiming at the systematic evaluation of patients on combined olanzapine and amisulpride. The open study designed as a retrospective chart review of Zink et al. concludes that the olanzapine–amisulpride combination for TRS is encouraging, but requires further evaluation in prospective and randomised studies.29They point out that a reduction of the daily dose of both drugs helped to minimise the side effects of these drugs – such as weight gain and EPS – resulting in better compliance. They did not notice any additional side effects or undesirable drug interactions.

Within the heterogeneous group of atypical antipsychotics, the thienobenzodiazepine derivative olanzapine has a receptor profile that is quite similar to that of clozapine, indicated by having a greater affinity for serotonergic 5-HT2A receptors than for dopaminergic D2 receptors. The positive and negative symptoms of schizophrenic psychoses usually respond well to this drug. In contrast to clozapine, olanzapine does not induce major agranulocytosis but may, in a significant number of cases, lead to troublesome side effects including significant weight gain, type ii diabetes, sedation, anticholinergic effects and transient increases in liver enzymes. Assertive weight management from the start of treatment is recommended. Weight should be monitored and also waist circumference measurements made. In addition, blood lipids should be assessed routinely. A suggested schedule for these investigations would be at 3, 6, and 12-month intervals, and biannually thereafter.30The pharmacology of antipsychotics is not the only factor that determines their effect on weight. Olanzapine has also been shown to elevate prolactin significantly in some patients.31 As indicated earlier, Olanzapine can succeed in some cases even where clozapine fails.24

Amisulpride is an atypical antipsychotic of the benzamide class. It blocks D2 and D3 receptors (presynaptic in low doses, postsynaptic in higher). Unlike other atypical or typical antipsychotics, it has low affinity for serotonin, α-adrenergic, histaminergic, muscarinic and sigma receptors including D1, D4 and D5 receptors. It can lead to dose-related EPS that are significantly less than those of typical antipsychotics such as haloperidol and comparable to risperidone.32It is recognised that amisulpride is only sparingly metabolised by liver enzymes, and thus it is not known to participate in many drug interactions.33 Amisulpride may elevate prolactin, which may cause sexual dysfunction, osteoporosis, amenorrhoea, gynaecomastia or galactorrhoea. It is a weight-neutral compound and may ameliorate negative symptoms.34 Both olanzapine and amisulpiride are not associated with QTc prolongation.

One advantage of the combination of these drugs is that when olanzapine and amisulpride are combined, they may be given at a lower dose, which will spare the patients from the main unwanted side effects of the individual drugs: the over-sedation and weight gain of olanzapine; and the hyperprolactinemia of amisulpride, resulting in sexual side effects of a particularly undesirable extent. Our limited studies have found that this combination was well tolerated by TRS patients and its efficaciousness was similar to that of clozapine, but without any major side effects. Patients have been fully compliant. The combination of these drugs is managed by slowly introducing them one at a time and has been transformative in many cases. More studies of the olanzapine–amisulpride combination are needed in order to report on such outcomes as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life.

Table 1. Assessing Treatment Resistance

Re-evaluate current antipsychotic treatment
Has an adequate trial been given?
Suboptimal dose and non-adherence can lead to pseudo-resistance-poor adherence is unwaveringly associated with adverse effects, poor insight, and a poor therapeutic alliance.
Consider exceeding BNF limits-recommended only in specialist centres
Review the differential diagnosis eg schizo-affective disorder or bipolar affective disorder-Bipolar Disorder can present with first rank symptoms in the initial stages, it could take up to 10 years to establish a diagnosis of BD.
Asses for psychotic symptoms
Re-evaluate personal history and psychological pressures
Investigate co-morbid psychiatric symptoms eg substance misuse or alcohol dependency, depression, obsessive compulsive disorder and panic attacks
Investigate organic factors-temporal lobe epilepsy, endocrinopathies
Check blood levels if facilities available
Longer duration
Multiple episodes
Male gender
Onset of illness at an earlier age
Poor pre-morbid functioning
Length of untreated psychosis
Family history of schizophrenia
Soft neurological signs-lateral and third ventricular enlargement and low catecholamine level in CSF
Suicidal tendencies
Aggression
Asses adverse effects of psychiatric and other medications that may mimic worsening of positive and negative symptoms
Complete physical and neurological examination
and specialist consultation, as appropriate
Rule out the desire to to be ill

Table 2. Advantages and disadvantages

Advantages:
Discontinuation symptoms due to the withdrawal of the first antipsychotic could be avoided
Patients unresponsive to the initial antipsychotic may achieve clinical response when the second agent is introduced
Patient does not have to cope with another waiting period for the substituted drug to produce full results
The benefits of the first drug are preserved in addition to the favourable effects of the added drug
Switching involves tapering off the initial drug, wash out period and delay in the onset of the second drug
Switching of antipsychotic drug requires additional supervision and care in the transitional period and could be delayed due to discontinuation symptoms; the addition of a second antipsychotic drug solves these problems
Disadvantages:
The possibility of unnecessarily high doses
An increased acute and/or chronic side-effect burden
Adverse pharmacodynamic and pharmacokinetic interactions
Difficulties in determining cause and effect of multiple treatments
Potential increased mortality,
Higher costs
Poorly documented risks and benefits of this practice
Reduced compliance

Table 3 Physical cautions with combination

History of cardiac disorder
(eg, MI, arrythmias, abnormal ECG)
Hepatic impairment
Renal impairment
Obesity (high BMI)
Heavy smoking
High alcohol intake
Substance misuse
Hyperlipidaemia
Above age 70
ECG, Haematological investigations.
Side effect rating scales
Physical effects
Record justification for combination

Summary

Combination therapies are the second choice when monotherapy fails. Clozapine is the first choice in severe cases of TRS, but there are super-refractory cases of TRS where clozapine fails. At least in isolated cases, the combination of olanzapine and amisulpride (Ami-olan combination) is worth considering for TRS patients who are reluctant to go on to clozapine therapy or in instances when clozapine failed, or patents dropped out. Combination therapies are normally avoided, but clinicians’ helplessness and patients’ despair justifies such measures in hard-to-treat cases of TRS. Only time will tell whether this combination will become an important part of clinical practice in future or will be ruled out as just another dual antipsychotic therapy.

The aetiology of SCZ remains obscure. The symptoms of different psychotic disorders are not clearly demarcated and there are no physiological parameters on which to make a firm diagnosis. In such a situation, the treatment of TRS has to be tailored on an individual basis. Even though it is normally well calculated, it may be somewhat hit and miss. Finding the right combination of antipsychotics or augmenting agents when the clinician is stranded and torn between monotherapy and polypharmacy is a gargantuan task. Clinical judgement along with patient preference must take over when treatment algorithms fall short. Given the data on polytherapy with antipsychotics that is available, it is hard to make any firm recommendation regarding its efficacy and safety of its use. Clinicians should be reminded that they should try monotherapy in adequate dosages before considering combinations.

For the management of TRS, comprehensive treatment strategies that integrate pharmacological, psychological, and psychosocial approaches are highly relevant and for that to happen, TRS should be clearly recognised. NICE offers very little guidance on clozapine resistant cases of SCZ. Combination of antipsychotics is not a panacea or a permanent solution for TRS. More investigation of schizophrenic illness is the only way forward. In comparison with other medical conditions (eg,HIV), research into it is making little progress. As it stands now, deconstructing clozapine’s unique pharmacology may offer ‘light at the end of the tunnel’ for patients who are clozapine intolerant or non-responders.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
I wish to thank the staff of Lea Court Treatment and Recovery centre, Dallam, Warrington
Competing Interests: 
None declared
Details of Authors: 
James Paul Pandarakalam, Consultant psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, AFG Rehab Hospitals, Winnick Lane, Warrington WA2 8WN
Corresponding Author Details: 
Dr James Paul Pandarakalam, Consultant psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, AFG Rehab Hospitals, Winnick Lane, Warrington, WA2 8WN, UK
Corresponding Author Email: 
jpandarak@hotmail.co.uk
References
References: 
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  2. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Journal of Biological Psychiatry. 2012 Jul;13(5):318-78.
  3. Crilly J.The history of clozapine and its emergence in the US market: a review and analysis". History of Psychiatry 2007; 18 (1): 39–60.
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  5. Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva IP. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 1977;11(3):193-198.
  6. Simpson GM, Lee JH, Shrivastava RK. Clozapine in tardive dyskinesia. Psychopharmacology (Berl) 1978;56(1):75-80.
  7. ltzer HY, Luchins DJ. Effect of clozapine in severe tardive dyskinesia: a case report. J Clin Psychopharmacol 1984;4(5):286-287. 
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  9. Leucht S, Kane JM. Measurement based psychiatry:  definition of response, stability and relapse in schizophrenia. J. Clin Psychiatry 2006; 67:1813-1814.
  10. Kane J, Hognifield G, Singer J, Meltzer HY. Clozapine for the treatment-resistant schizophrenia: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-796.
  11. Meltzer HY, Robinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL, Thompson PA. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry 1997; 154:475-482.
  12. Kane JM, Marder SR, Schooler NR, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month and double-blind comparison. Arch Gen Psychiatry. 2001; 58:965-972.
  13. Leucht S, Kane JM. Measurement-based psychiatry: definition of response, remission, stability and relapse in Schizophrenia. J Clin Psychiatry 2006; 67:1813-1814. 
  14. Huber CG, Naber D, Lambert M. Incomplete remission and treatment resistance in in first epi-sode psychosis: definition, prevalence, predictors. Expert Open Pharmacother 2008; 9:2027-2038.
  15. Elkis H, Meltzer H.Y. Therapy-Resistant Schizophrenia. London: Krger, 2010.
  16. Mossaheb N & Kaufmann R M. Role of Aripiprazole in treatment-resistant Schizophrenia. Neu-ropsychiatr Dis Treatment 2012; 8:235-44.
  17. Elkis H, Meltzer HY. Refractory schizophrenia. Rev Bras Psiquitarr 2007;29(suppl 2):541-547.
  18. Chung C, Remington G. Predictors and markers of clozapine response. Psychopharmacology (Berl). 2005; 179:317-335.
  19. Pai NB, Vella SC. Reason for clozapine cessation. Acta Psychiatrica Scandinavica 2011; 124: 39–44.
  20. Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull. 1992;18(3):515–542. 
  21. Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2016;171(1–3):215–224. 
  22. Mustafa FA, Burke JG, Abukmeil SS, Scanlon JJ, Cox M. “Schizophrenia past Clozapine”: reasons for clozapine discontinuation, mortality, and alternative antipsychotic prescribing. Pharmacopsychiatry. 2015;48(1):11–14.
  23. The Cochrane Collaboration. Antipsychotic combinations for schizophrenia (Review) Published by John Wiley & Sons, Ltd,2017.
  24. Dossenbach MRK, Beuzen JN, Avnon M, Belmaker RH, Elizur A, Mark M, et al.  The effec-tiveness of olanzapine in treatment refractory schizophrenia when patients are non-responsive to or unable to tolerate clozapine. Clin Ther 2000; 22:1021-1034.  
  25. Kane JM et al. A multicentre, randomised, double-blind, placebo-controlled,16-week study of adjunctive aripiprazole for schizophrenia or schizo-affective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychitatry 2009; 70:1348-1357.
  26. Carnaham RM et al Increased risk of extrapyramidal side effect treatment with atypical antipsychotic polytherapy. Acta Psychiatr Scand 2006; 113:135-141.
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  34. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garrean G, Lemperiere T, et al. Consensus on the practical case of amisulpiride, an unusual “atypical” antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001; 44(1) :41-44.

Serum Procalcitonin in Lower Respiratory Tract Infections in Adult Patients

Authors
Amer Saleem
Article Citation and PDF Link
BJMP 2019;12(2):a013
Abstract / Summary
Abstract: 

Procalcitonin is a protein (that consists of 116 amino acids) and is a peptide precursor of the hormone calcitonin. Calcitonin is involved in the homeostasis of calcium. In healthy people, procalcitonin blood levels are negligible. Based on the current data, raised serum procalcitonin levels indicate activation of the innate immune system due to invasion of microbes (bacteria, some fungi, and malaria). Procalcitonin levels are used to support the diagnosis of bacterial infection or sepsis in the emergency departments. This biomarker can be used, along with clinical judgment, in a hospital setting to guide antibiotic treatment in cases of pneumonia and non-pneumonic lower respiratory tract infections.

Abbreviations: 
TNF = tumour necrosis factor, IL = interleukin, CAP = community acquired pneumonia, VAP = ventilator associated pneumonia, COPD = chronic obstructive pulmonary disease, AECOPD = acute exacerbation of COPD
Keywords: 
procalcitonin, calcitonin, pneumonia, lower respiratory tract infections, guiding antibiotics therapy

Background

In the absence of systemic inflammation, procalcitonin synthesis is mainly restricted to the neuroendocrine cells of the thyroid.1 This is not released into the blood until cleaved/mature form (i.e. calcitonin). Therefore, procalcitonin levels remain undetectable.2 Almost all body tissues can produce procalcitonin. The main triggers for its synthesis are bacterial toxins (endotoxins) and cytokines released in response to bacterial infections (TNF alpha, IL-1-beta and IL-6). See Table 1. Cytokines released due to viral infections (e.g. interferon-gamma) inhibit TNF-alpha production.1, 3 During an inflammatory response, procalcitonin levels start rising within 2-4 hours and peak in 24-48 hours. Peak levels correlate to the severity of the bacterial infection. When inflammation resolves, procalcitonin levels fall quickly, falling by 50% every 24-36 hours. If the inflammation is ongoing, procalcitonin levels plateau (due to ongoing production of procalcitonin).4

Table 1: Points to remember: 5-11
1. Most bacterial infections will cause a rise in procalcitonin levels (levels >0.25ng/ml).
2. The following bacterial infections will not cause a rise in procalcitonin levels:
a. Mycoplasma pneumoniae.
b. Chlamydia pneumoniae.
3. Parapneumonic effusions, empyema and lung abscesses may not cause a rise in procalcitonin levels.
4. Mycobacterium tuberculosis, can and can’t cause a rise in the procalcitonin levels
5. Viral infections will not cause a rise in procalcitonin levels (levels <0.25ng/ml).
6. Amongst fungal organisms, candida infections can cause a rise in procalcitonin levels (levels >0.25ng/ml).
7. Malaria can cause a rise in procalcitonin levels (levels >0.25ng/ml).
8. Clostridium difficile colonization will not cause a rise in procalcitonin levels (levels <0.25ng/ml).
9. Lung cancers (especially neuroendocrine) and medullary thyroid cancers can cause a rise in procalcitonin levels (levels >0.25ng/ml).
10. Renal insufficiency (which hinders the clearance) can cause a rise in the baseline procalcitonin levels.
11. Physiological stress can cause a rise in procalcitonin levels (levels >0.25ng/ml). This includes trauma, surgery, burns, bowel ischemia, cerebrovascular accident (infarct and haemorrhage), pancreatitis and any kind of shock-like situation.

Community Acquired Pneumonia (CAP) and Procalcitonin

As we know, it can take 24-48 hours for the procalcitonin to reach its peak levels, hence in an acute clinical setting (where CAP is the diagnosis, or suspected), the decision to start antibiotics can’t depend on the initial procalcitonin levels (because of high morbidities associated with CAP). Nevertheless, serial levels will help in guiding antibiotic therapy.
a. If procalcitonin levels are persistently <0.25ng/ml in a CAP patient with suspected viral aetiology (based on history and investigations), antibiotics can be stopped. We should keep in mind that procalcitonin levels do not normally rise in the case of mycoplasma and chlamydia pneumonia.
b. Suspected or known CAP patients should receive empiric antibiotics as per local protocol in an acute setting.
c. Antibiotics can be stopped in patients with suspected or known bacterial CAP who have received antibiotics for at least five days and shown clinical improvement with procalcitonin levels dropping <0.25ng/ml.
d. CAP patients who are not clinically improving, and procalcitonin levels are rising or not decreasing, will need a review of antibiotics.
e. Optimal threshold for discontinuing antibiotic therapy has not been established.12
f. Procalcitonin levels have prognostic value. Again, there is no optimal threshold. Serial levels have more prognostic value than a single level.

Ventilator Associated Pneumonia (VAP) and Procalcitonin

Patients with VAP are usually very unwell. Antibiotics should be started as soon as VAP is suspected. Procalcitonin can be used to stop antibiotics in VAP patients. As per ProVAP trial, stopping antibiotics when procalcitonin level drops <0.5ng/ml, or >80% from its peak value, did not result in an adverse outcome.

Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) and Procalcitonin

Use of procalcitonin to guide antibiotic therapy in patients with AECOPD has not been established yet. Some experts use the levels to help in making decisions about stopping antibiotics (in a similar way as mentioned in the above section of CAP). Infections in AECOPD are less invasive and pathogens differ from CAP; procalcitonin levels may not correlate well with the severity of the episode. In one trial, antibiotic use was found to be of no benefit in patients with AECOPD with levels <0.1ng/ml.13

Acute Bronchitis and Procalcitonin

Mostly acute bronchitis is caused by viral infections and do not need antibiotics. In patients where the need for antibiotics is unclear, serum procalcitonin levels can help in making this decision.

Summary

Table 2: Procalcitonin levels in lower respiratory tract infections:

Level (ng/ml) Likelihood of bacterial infection
<0.10 Very unlikely
0.10 – 0.25 Unlikely
0.25 – 0.50 Likely
>0.50 Very likely

(This should aid clinical decision making i.e. decision should not be solely based on these levels).

In an acute clinical setting, where pneumonia is suspected or is the cause for sepsis, empirical antibiotics should be started according to a local protocol without considering the serum procalcitonin levels. If serial serum procalcitonin levels remain below 0.10 ng/ml on day 3, antibiotics can be stopped, aided by clinical judgment. The above-mentioned points should be kept in mind with the fact that certain bacterial infections do not cause a rise in serum procalcitonin levels. The levels also have prognostic value in case of CAP and VAP. Usually, acute bronchitis is a viral illness; if symptoms are not improving or bacterial infection is suspected, raised serum procalcitonin levels can aid the clinical judgment in starting antibiotics. In the case of infective AECOPD, the levels are not very helpful in making a decision about starting antibiotic therapy. In respiratory tract infections, where the patient has received adequate duration of antibiotic therapy, and procalcitonin levels fall <0.10 ng/ml, treatment can be stopped safely (if clinical judgment allows). See Table 2.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DR AMER SALEEM; BSC, MBBS, MCPS MEDICINE (PAK), MRCP (UK), FCPS PULMONOLOGY (PAK), FRCP (GLASGOW), FCCP (USA), EUROPEAN DIPLOMA IN ADULT RESPIRATORY MEDICINE, SPECIALITY CERTIFICATE IN RESPIRATORY MEDICINE (RCP UK); Consultant Chest Physician, Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Details: 
DR AMER SALEEM, Consultant Chest Physician, Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Email: 
amersaleemmalik@gmail.com
References
References: 
  1. Becker KL, Nylén ES, White JC, Müller B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004; 89(4):1512.
  2. Maruna P, NedelníkováK, Gürlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000; 49 Suppl 1:S57.
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  4. Meisner M. Update on procalcitonin measurements. Ann Lab Med. 2014;34(4):263. Epub 2014 Jun 19.
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  6. Scheinpflug K, Schalk E, Grabert E, Achenbach HJ. Procalcitonin is not useful to discriminate between infectious and noninfectious CRP elevation in patients with non-small cell lung cancer. Infect Control Hosp Epidemiol 2015; 36:1117.
  7. Rao K, Walk ST, Micic D, et al. Procalcitonin levels associate with severity of Clostridium difficile infection. PLoS One 2013; 8: e58265.
  8. Li G, Zhu C, Li J, et al. Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke. Neurosci Lett 2018; 662:242.
  9. He D, Zhang Y, Zhang B, et al. Serum procalcitonin levels are associated with clinical outcome in intracerebral hemorrhage. Cell Mol Neurobiol 2017.
  10. Reinink AR, Limsrivilai J, Reutemann BA, et al. Differentiating Clostridium difficile colitis from Clostridium difficile colonization in ulcerative colitis: A role for procalcitonin. Digestion 2017; 96:207.
  11. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis 2014; 59:1761.
  12. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009; 302(10):1059.
  13. Wang JX, Zhang SM, Li XH, Zhang Y, Xu ZY, Cao B. Acute exacerbations of chronic obstructive pulmonary disease with low serum procalcitonin values do not benefit from antibiotic treatment: a prospective randomized controlled trial. Int J Infect Dis. 2016; 48:40. Epub 2016 May 4.

Hyperglycaemia and Myocardial Infarction

Authors
Sharan Badiger
Article Citation and PDF Link
BJMP 2019;12(2):a010

Introduction

Hyperglycaemia is a condition in which an excessive amount of glucose circulates in the blood plasma. The origin of the term is Greek: hyper-, meaning excessive; -glyc-, meaning sweet; and -aemia, meaning "of the blood". Hyperglycaemia, or high blood glucose, is a serious health problem for those with diabetes. Normal fasting glucose is <100 mg/dl, impaired fasting glucose is 100–125 mg/dl, and diabetes mellitus is defined as a fasting glucose >126 mg/dl 1. Several values above normal are indicated before making a diagnosis of impaired fasting glucose or diabetes. Two types of hyperglycaemia can be seen in diabetic patients, they are, fasting hyperglycaemia defined as a blood sugar greater than 126 mg/dl after fasting for at least 8 hours and postprandial or after-meal hyperglycaemia defined as a blood sugar usually greater than 180 mg/dl. In people without diabetes postprandial or post-meal sugars rarely go over 140 mg/dl but occasionally, after a large meal, a 1-2 hour post-meal glucose level can reach 180 mg/dl.

Consistently elevated high post-meal glucose levels can be an indicator that a person is at high risk for developing type 2 diabetes. Stress hyperglycaemia also called as stress diabetes or diabetes of injury is a medical term referring to transient elevation of the blood glucose due to the stress of illness. It usually resolves spontaneously, but must be distinguished from various forms of diabetes mellitus. It is often discovered when routine blood chemistry measurements in an ill patient reveal an elevated blood glucose. Blood glucose can be assessed either by a bedside ‘fingerstick’ glucose meter or plasma glucose as performed in a laboratory. The glucose is typically in the range of 140-300 mg/dl but occasionally can exceed 500 mg/dl especially if amplified by drugs or intravenous glucose. The blood glucose usually returns to normal within hours unless predisposing drugs and intravenous glucose are continued.

Stress hyperglycaemia is especially common in patients with hypertonic dehydration and those with elevated catecholamine levels. Steroid diabetes is a specific and prolonged form of stress hyperglycaemia. In some people, stress hyperglycaemia may indicate a reduced insulin secretory capacity or a reduced sensitivity, and is sometimes the first clue to incipient diabetes (do you mean insipidus diabetes). Because of this, it is occasionally appropriate to perform diabetes screening tests after recovery from an illness in which significant stress hyperglycaemia occurred Table 1.

Table 1: Aetiology of Hyperglycaemia

Glucose Tolerance Test Impaired fasting glucose
Medications Corticosteroids, growth hormone, estrogen, oral contraceptives, nicotinic acid, salicylates, NSAIDs, thiazide, loop diuretics, phenytoin, epinephrine
Diabetes mellitus Diabetes mellitus type I, Diabetic ketoacidosis, Diabetes mellitus type II, Gestational diabetes
Pancreatic disease Acute or chronic pancreatitis, Pancreatectomy, Pancreatic carcinoma, Haemochromatosis, Cystic fibrosis
Increased counter-regulatory hormones Myocardial infarction, Stroke or other neurological disease, Renal insufficiency, Hepatic insufficiency
Endocrine disorders Acromegaly, Cushing's syndrome, Pheochromocytoma, Hyperthyroidism (thyroid storm), Glucagonoma
Others Amyloidosis

 

Prevalence and risk of hyperglycemia

Acute hyperglycaemia is common in patients with ST- elevation myocardial infarction (STEMI) even in the absence of a history of type 2 diabetes mellitus (DM). Hyperglycaemia is encountered in up to 50% of all STEMI patients, whereas previously diagnosed DM is present in only 20% to 25% of STEMI patients 2 .The prevalence of type 2 DM or impaired glucose tolerance may be as high as 65% in myocardial infarction patients without prior DM when oral glucose tolerance testing is performed 3. Elevated plasma glucose and glycated haemoglobin levels on admission are independent prognosticators of both in-hospital and long-term outcome regardless of diabetic status 4, 5. For every 18-mg/dl increase in glucose level, there is a 4% increase in mortality in nondiabetic subjects 6. When admission glucose level exceeds 200 mg/dl, mortality is similar in non-DM and DM subjects with myocardial infarction (MI). Admission glucose has been identified as a major independent predictor of both in-hospital congestive heart failure and mortality in STEMI 7.

Fasting glucose the day after admission appears to be a better predictor of early mortality than glucose level on admission 8. Patients with both an elevated admission glucose and an elevated fasting glucose the next day have a 3-fold increase in mortality. Similarly, failure of an elevated glucose level to fall within 24 hours of admission is associated with excess mortality in STEMI patients without DM 9. The presence and degree of hyperglycaemia may not correlate with infarct size, as is commonly thought 6. Counter regulatory hormones like catecholamine, growth hormone, glucagons and cortisol are released in proportion to the degree of cardiovascular stress and may cause hyperglycemia and an elevation of free fatty acids, both of which lead to an increase in hepatic gluconeogenesis and a decrease in insulin-mediated peripheral glucose disposal.

Pathogenesis of hyperglycaemia

When acute coronary artery occlusion leads to symptoms, aid this is not always the case, there is stimulation of postganglionic sympathetic nerve endings with release of norepinephrine, and of the adrenal medulla with release of epinephrine. Both catecholamines are present in high concentrations in plasma and urine during the first 24-48 hours after the onset of symptoms. The concentrations of these catecholamines in plasma reach high levels within the first few hours after the onset of symptoms and later appear to be related to the severity of the infarct. Norepinephrine acts through beta-adrenergic receptors, to activate the adenylcyclase system in adipose tissue causing conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP) and cyclic AMP activates a lipolytic system leading to hydrolysis of stored triglycerides to diglycerides, free fatty acids (FFA) and also glycerol. While some reesterification of FFA occurs, the net effect is release of FFA and glycerol into the circulation. In acute myocardial infarction, plasma FFA concentrations are elevated within 4 hours of the onset of symptoms. The highest values are found on the first day, and by the sixth day normal values are usually reached.

Glycerol levels are also elevated. There is a close relationship between blood catecholamine and FFA values in myocardial infarction. Epinephrine has a weak effect on adipose tissue lipolysis but its main action at this time is to stimulate glycogenolysis in liver and muscle with elevation of blood glucose levels. Epinephrine also suppresses beta cell activity in the pancreas with a decrease in insulin secretion leading to further elevation of blood glucose. Thus, hyperglycaemia occurs after acute myocardial infarction, and more than half of these patients have an abnormal glucose tolerance test during the first 72 hours of the attack. Reduction of insulin secretion has been demonstrated in patients after acute myocardial infarction following an intravenous glucose load and an intravenous Tolbutamide test. The degree of failure in these responses has been positively correlated with the severity of the illness and with the presence of cardiogenic shock.

Cortisol secretion and plasma growth hormone levels are increased during the first 24 hours after the onset of acute myocardial infarction. As the clinical condition improves, the degree of glucose intolerance diminishes and insulin secretion increases. In the second week plasma insulin levels are above normal, and at this stage the anabolic effect of insulin in enhancing the transport of amino acids into cells and their incorporation into protein is important for repair of the injured myocardium. Cortisol stimulates the breakdown of protein for gluconeogenic purposes and also the key gluconeogenic enzymes, but it is doubtful whether these actions operate until the acute period has passed 10, Figure 1.


Figure 1

Cardiovascular effects of hyperglycaemia

Acute hyperglycaemia is associated with numerous adverse effects that contribute to a poor outcome in STEMI. Acute hyperglycaemia rapidly suppresses flow-mediated vasodilatation, likely through increased production of oxygen derived free radicals 11. Hyperglycaemia increases intranuclear nuclear factor-B binding and activates proinflammatory transcription factors, which increase the expression of matrix metalloproteinase, tissue factor, and plasminogen activator inhibitor-1. The degree of oxidative stress correlates most closely with acute, not chronic, glucose fluctuations 12.

Increased oxidative stress interferes with nitric oxide mediated vasodilatation and reduces coronary blood flow at the micro vascular level. In STEMI subjects, acute hyperglycaemia is associated with reduced TIMI grade 3 flow before intervention compared with euglycemia and is the most important predictor of the absence of coronary perfusion 13. Similarly, diabetic subjects have reduced myocardial blush grades and diminished ST-segment resolution after successful coronary intervention in STEMI, consistent with diminished micro vascular perfusion 14.

Acute hyperglycaemia is associated with impaired microcirculatory function as manifest by “no reflow” on myocardial contrast echocardiography after percutaneous coronary intervention 15. Pre-existing HbA1c levels and diabetes status do not differ between subsets with and without no reflow, suggesting that acute, not chronic, hyperglycaemia is the dominant factor. Finally, the well-known adverse effects of hyperglycaemia on platelet function, fibrinolysis, coagulation, and ischaemic preconditioning likely contribute to the adverse effects of acute hyperglycaemia in STEMI. Hyperglycaemia is a reflection of relative insulinopenia, which is associated with increased lipolysis and free fatty acid generation, as well as diminished myocardial glucose uptake and a decrease in glycolytic substrate for myocardial energy needs in STEMI. Myocardial ischemia results in an increased rate of glycogenolysis and glucose uptake via translocation of GLUT-4 receptors to the sarcolemmal 16. Because glucose oxidation requires less oxygen than free fatty acid oxidation per molecule of ATP produced, myocardial energetics are more efficient during the increased dependence on glucose oxidation with ischaemia.

With relative insulinopenia, however, the ischaemic myocardium is forced to use free fatty acids instead of glucose as an energy source because myocardial glucose uptake is acutely impaired. Thus, a metabolic crisis may ensue as the hypoxic myocardium becomes less energy efficient in the setting of hyperglycaemia and insulin resistance. Acute hyperglycaemia may precipitate an osmotic diuresis. The resulting volume depletion may interfere with the frank starling mechanism for the failing left ventricle in which increased end diastolic volume leads to increased stroke volume thus decreasing the cardiac output 17, Table 2.

Table 2: Acute Cardiovascular Effects of Hyperglycaemia

Endothelial dysfunction
Platelet hyperreactivity
Increased cytokine activation
Reduced glycolysis and glucose oxidation
Increased lipolysis and free fatty acid levels
Increased oxidative stress (? Increased myocardial apoptosis)
Impaired microcirculatory function (“no-reflow” phenomenon)
Impaired ischaemic preconditioning
Impaired insulin secretion and insulin based glucose uptake



Conclusion

An essential diagnostic feature of diabetes is increased blood glucose concentration and the principal aim of diabetes treatment is normalisation of blood glucose. Hyperglycaemia can also occur when normal hormonal control of blood glucose concentration is disturbed by the stress associated with acute myocardial infarction.

The blood glucose is raised in the immediate period following acute myocardial infarction irrespective of diabetes status. In this review article the current understanding of the significance of hyperglycaemia occurring as a result of acute myocardial infarction is discussed.

A significant part of the review is directed to the discussion of epidemiological prevalence that confirms an association between hyperglycaemia and mortality following myocardial infarction.

It remains clear and undisputed that there is association between hyperglycaemia and increased mortality following acute myocardial infarction. Review of various articles ranging from experimental and clinical studies have demonstrated several mechanisms by which hyperglycaemia could adversely affect outcome of myocardial infarction. The final part of the review concluded that if treatment is aimed at normalising blood glucose improves outcome of acute myocardial infarction patients who present with hyperglycaemia.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SHARAN BADIGER, MD, Professor, Department of Medicine, Sri B M Patil Medical College, Vijayapur, Karnataka, India.
Corresponding Author Details: 
SHARAN BADIGER, MD, Professor, Department of Medicine, Sri B M Patil Medical College, Vijayapur, Karnataka, India.
Corresponding Author Email: 
sharanrb@rediffmail.com
References
References: 
  1. Avel C. Powers Diabetes Mellitus In: Kasper, Braunwald, Fauci Hauser, Longo, and Jameson editors. Harrison’s Principles of Internal Medicine, Vol-2.17th Ed; Newyork: McGraw Hill; 2005; 2126-2127.
  2. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol. 2002; 40:1748 –1754.
  3. Norhammar A, Tenerz A, Nilsson G, Hansten A, efendic S, Ryden L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002; 359:2140 –2144.
  4. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000; 355:773–778.
  5. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation.1999; 99: 2626 –2632.
  6. Stranders I, Diamant M, van Gelder R, Spruijt H, Twisk JWR, Heine RJ, Visser FC.  Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med. 2004; 164:982–988.
  7. Zeller M, Steg P, Ravisy J, Laurent Y, Janin- Manificat L, L’Huillier I, Beer J, Oudot A, Rioufol G, Makki H, Farnier M, Rochette L, Verges, Cottin Y. Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction. Arch Intern Med. 2005; 165:1192–1198
  8. Suleiman M, Hammerman H, Boulos M, Kapeliovich M, Suleiman A, Agmon Y, Markiewicz W, Aronson D. Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction. Circulation. 2005; 111:754-760
  9. Goyal A, Mahaffey K, Garg J, Nicolau JC, Hochman JS, Weaver WD, Theroux P, Oliveira GBF, Todaro TG, Mojcik CF, Armstrong PW, Granger CB. Prognostic significance of the change in glucose level in the first 24h after acute myocardial infarction: results from the CARDINAL study.EurHeartJ.2006; 27:1289 –1297.
  10. Oliver MF.  Metabolic Response during Impending Myocardial Infarction. Clinical implications II Circulation 1972; 45; 491-500
  11. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T,Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium- dependent vasodilation of brachial artery. J Am Coll Cardiol. 1999; 34:146 –154.
  12. Monnier L, Mas E, Ginet C, Michel F, Willon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006; 295:1681–1687.
  13. Timmer J, Ottervanger J, de Boer M, Dambrink JE, Hoorntje JCA, Gosselink ATM, Suryapranata H, Zijlstra F, Van’t Hof AWJ, for the Zwolle Myocardial Infarction Study Group. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005; 45:999 –1002.
  14. Prasad A, Stone G, Stuckey T, Costantini CO, Zimetbaum PJ, McLaughlin M, Mehran R, Garcia   E, Tcheng JE, Cox DA, Grines CL, Lansky AJ, Gersh BJ. Impact of diabetes mellitus on myocardial perfusion after primary angioplasty in patients with acute myocardial infarction. J Am Coll Cardiol. 45:508 –514.
  15. Iwakura K, Ito H, Ikushima M, Kawano S, Okamura A, Asano K, Kuroda T, Tanaka K, Masuyama T, Hori M, Fujii K. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol. 2003; 41:1–7.
  16. Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ. Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo. Circulation. 1997; 95:415– 422.
  17. Sarah E Capes, Dereck Hunt, KlasMalmberg, Hertzel C Gerstein. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: Lancet 2000; 355:773-777.

Acanthosis Nigricans in Pre-diabetic states

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2018;11(1):a1105
Abstract / Summary
Abstract: 

Abstract: The high incidence of type 2 diabetes mellitus has become for many a heavy penance for enjoying the luxuries of modern living. Today’s western life style is characterised by sedentary habits and high-calorie food intake, which are contributory factors for this condition. If the prediabetic stage if identified early, it may be prevented from progressing into full diabetes. A significant percentage of occurrences of type 2 diabetes may be reversed if loss of weight and maintenance of a healthy body mass index (BMI) is achieved. At the same time as the life-style changes, the use of atypical antipsychotic medication is resulting in an increase in a specific metabolic syndrome among the psychiatric population. Along with other symptoms that herald this disease, darkened patches on the skin may be a warning signal to alert potential sufferers from diabetes to take precautionary measures. If acanthosis nigricans is proven to have autoimmune components, the same could be true of Diabetes Mellitus Type-ii.

 

Keywords: 
Key words: overweight, Acanthosis nigricans, insulin resistance, autoimmunity, risk factors.

The identification of dark patches on the skin may be the first indication of type 2 diabetes mellitus (DM type 2). DM type 2 is a complex heterogeneous group of metabolic conditions characterised by elevated levels of serum glucose. Causative factors are impairment in both insulin action and insulin secretion. The darkening of the skin is usually evident on the hands and feet, in folds of skin, along the neck, and in the patient’s groin and armpits.1 The affected skin differs from that which surrounds it, and it feels velvety and also thicker. That skin may have hanging from it the small, soft, skin-coloured growths known as tags, and the area affected may be pruritic. This condition is a nonspecific dermatological disorder termed acanthosis nigricans (AN), which often occurs in patients with high insulin levels. Hud et al. (1992) found that 74% of the obese population exhibits AN.2The association of AN, skin tags, and diabetes mellitus due to insulin resistance – along with obesity in adolescents and young adults – is a well-defined syndrome.3,4,5

High-insulin levels in the blood may increase the body’s production of skin cells, many of which have increased pigmentation that gives the skin a darkened appearance – dark patches appear on the skin. These are often the outcome of insulin receptors in the skin being triggered, causing mutations of normal tissue that are dark in colour and/or irregular in shape. The condition may be an indication that the blood sugar is persistently high. The term ‘acanthosis nigricans’ was originally proposed by Unna et al. in 1891, but the first descriptions of it were made a year earlier by two researchers working independently of each other: Pollitzer and Janovsk.6 Kahn and colleagues tried to clarify the link between AN and insulin resistance in 1976.7 Eventually, its presence became established as an indicator of insulin resistance or diabetes mellitus in obese patients.8 In 2000, the American Diabetes Association formally accepted AN as such.9 It should be borne in mind that AN must not be considered a characteristic feature of DM type 2; it is not a condition that is developed by all those who suffer from the disease.




Figures 1,2,3 - Acanthosis Nigrans

Pathogenesis

Although the pancreas produces insulin in DM type 2, the body cannot make use of it efficiently. The outcome is a build-up of glucose in the bloodstream, which may lead to high levels of blood glucose and insulin. At low concentrations, insulin regulates the metabolism of carbohydrates, lipids, and protein and may promote growth by binding to ‘classic’ insulin receptors. High concentrations of insulin may stimulate keratinocyte and fibroblast proliferation through high-affinity binding to the insulin-like growth factor 1 (IGF-1) receptors.10 In obese patients elevated IGF-1 levels may contribute to keratinocyte and fibroblast proliferation;11 the binding stimulates the proliferation of keratinocytes and fibroblasts, which leads to AN.

To put this simply, AN is the outcome of a toxic effect of hyperinsulinemia. Excess insulin causes the normal skin cells to reproduce rapidly rate, and it has been demonstrated to cross the dermo-epidermal junction and reach keratinocytes. In those who have dark skin, these new cells have increased melanin. The higher level of melanin results in the creation of a patch of skin that is noticeably darker than the skin surrounding it. The presence of AN is therefore a strong indicator of increased insulin production and, therefore, it is also a predictor for future DM type 2.

When the occurrence of AN is recognised, a prediabetic person has the opportunity to become more alert to their symptoms and to take precautions in the form of diet restrictions and weight loss. This is because overweight people tend to develop resistance to insulin over time. If too much insulin is the cause of AN, it is relatively easy for the patient to counter it by changing to a healthier diet, taking exercise, and controlling their blood sugar. Obesity-associated AN may be a marker for higher insulin needs in obese women with gestational diabetes,12andAN has been shown to be a dependable early indicator for metabolic syndrome in paediatric patients.13

Autoimmunity?

Unknown autoantibodies other than insulin receptors have been implicated in AN, which may explain the effectiveness of cyclosporine treatment. Kondo and colleagues identified a very rare occurrence – without type B insulin resistance – of generalised AN with Sjögren's syndrome and systemic lupus erythematosus-like features.14Theirs was the first report of generalised AN involving an area from the mucosa of the larynx to the esophagogastric junction, accompanied by autoimmune disorder (AD) responding to systemic immunosuppressive therapy. AN skin lesions and mucosal papillomatosis were medicated with oral cyclosporine A and were accompanied by lower autoantibody titres. That was an outcome of the development of antibodies to insulin receptors in AD such as systemic lupus erythematosus.15

Raymond et al. have reported on the association of AN with disordered immunoreactivity.16 The onset of AN may precede a variety of classic ADs, and different categories of ADs may be present at the same time. If AN is an AD, DM type 2 may also represent a slow and subtle autoimmune process. AN and DM type 2 then become two different expressions of the same disease process, but the former is apparently benign and the latter is ultimately potentially fatal. Autoimmunity is a well-known pathogenic component in DM type 2. The assumption that its pathogenesis encompasses autoimmune aspects is increasingly recognised. That is based on the presence of circulating autoantibodies against β cells, self-reactive T cells, and also on the glucose-lowering efficacy in DM type 2of some immunomodulatory therapies.17 The autoimmune hypothesis of AN has the potential to modify the direction of DM type 2 research.

The symptoms of ADs are inconstant and this is in divergence to the mechanisms of antigen recognition and effector function that are alike in the response to pathogens. 18 The symptoms basically depend on the triggering autoantigen and the target tissue. In certain conditions, autoantibodies function as receptor antagonists and in other situations, they function as receptor agonist. Autoantibodies of both types can be made against insulin receptor. When they serve as antagonists as in DM Type 2, the cells of patients are unable to take up glucose, the consequence is hyperglycaemia whereas in patients with agonistic antibodies, cells deplete blood glucose resulting in hypoglycaemia.18 One wonders whether AN may be an early by-product of such an autoimmune process.

Vitiligo which is the result of depigmentation of the skin is in fact an opposite disorder to AN. Vitiligo is recognised as an AD.19Thyroid disorders, particularly Hashimoto thyroiditis and Graves’ disease, other endocrinopathies, such as Addison disease, diabetes mellitus, alopecia areata, pernicious anaemia, inflammatory bowel disease, psoriasis, and autoimmune poly-glandular syndrome are all associated with vitiligo. 20 Kakourou et al identify that Hashimoto's thyroiditis is 2.5 times more frequent among children and adolescents with vitiligo than in a healthy age- and sex-matched population and it usually follows the onset of vitiligo. 21

As in the case of other ADs, vitiligo susceptibility may involve both target organ-specific genes and immune response genes. 22 The autoimmune theory suggests alteration in humoral and cellular immunity in the destruction of melanocytes of vitiligo. 23. Vitiligo lesions have an infiltrate of inflammatory cells, particularly cytotoxic and helper T-cells and macrophages;histological evidences further back up an autoimmune aetiology. 24 Like AN, Vitiligo is thus gene linked; immunity derangements may be providing the matrix and genes are the craftsmen in both conditions.

Vitiligo occurs more commonly in DM Type 1. A few recent studies have revealed its increased incidence in DM Type 2. 25 These may be isolated case studies, but offer new insight into the pathogenesis of DM Type 2. There is a logical thread running between the autoimmune assertion of AN and its depigmentation counterpart (vitiligo) which is recognised as an AD. If AN is proven as an AD, the AD hypothesis of DM Type 2 becomes more binding. The autoimmune process of AN warrants further consideration and further study is needed to confirm or falsify the hypothesis of an autoimmune spectrum disorder between AN, vitiligo and DM Type 2.

Even though the common assumption that bacteria flora occupying human body outnumber the body cells has been proven wrong, their revised ratio of 1:1 is still astounding.26 The exact role of the resident microbial colony in human body is unclear. There are less ADs observed among the hunters’ tribal population of Tanzania whose faecal matter contain more varieties of microbes than people in developed countries. 27,28 This is an observation that need further verification. It is possible that the occupied microbial army may be maintaining the harmony among the human body cells from attacking each other and serving as moderators. Now that anti-autoimmune activity in molecules produced by parasites have been confirmed in haematology lab, these findings may have clinical significance. The aetiology of ADs is multifactorial. Genetic, environmental, hormonal, psychological stress and immunological factors are all considered important in their development. I content that the clue to the mechanism of development of certain ADs and ways of counteracting them may be embedded in the bacterial colony and their interaction with human cells.

International studies

A pilot study by Bhagyanathan and colleagues demonstrated that children with AN have a high incidence of insulin resistance.29 They posit that the detection of insulin resistance in children may present an opportunity to prevent the onset of microvascular changes before the development of DM type 2. Once DM type 2 by hyperglycemia is diagnosed it may be too late for that. Insulin resistance is one of the mechanisms involved in the pathogenesis of DM type 2; therefore, early recognition of insulin resistance is paramount in the prevention or delay of the onset of diabetes. Their study was of 62% of children who had AN alongside high insulin resistance. In children with AN and a high BMI, the incidence of insulin resistance was about 80%. This is evidence that the easily detectable symptoms are of value in the screening of children who are at high risk of developing DM type 2. Bhagyanathan et al. conclude that AN has potential as a screening method because those who have high insulin resistance as well as AN are at high of future DM type 2.

An earlier US study, by Brickman and colleagues, had yielded somewhat similar results.30 This involved 618 youths from different ethnic groups at nine paediatric practices. They were aged from 7 to 17 years. A survey was made of their demographics and their family history with regard to DM type 2, and their weight and height were also measured. AN was scored and digital photographs of their necks were taken. AN was identified in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth respectively. It was also found in 62% of those studied who had a BMI greater than the 98th percentile. Using multiple logistic regression, the researchers found that the level of BMI, the presence of maternal gestational diabetes, female gender, and not being Caucasian, were all independently associated with AN. AN was common among the overweight young people and was associated with risk factors for glucose homeostasis abnormality. Brickman et al. concluded that identification of AN offers an opportunity to advise families about the causes and consequences of the condition. 30 That has the potential to motivate those with responsibility for the young people to encourage and effect healthy lifestyle changes that decrease the risk of the development of DM type 2 and cardiovascular disease.

In their research in India, Vijayan et al. determined that BMI, waist circumference and AN are three physical markers for the recognition of insulin resistance in children.31 They conducted a cross-sectional school-based study in a semi-rural environment in the state of Kerala, which has become known as the diabetic capital of the country. Their study encompassed 283 children between the ages of 10 to 17. The prevalence of insulin resistance was 35%; this estimate was arrived at by using a homeostasis model assessment of insulin resistance (HOMA-IR). Of the children studied, 30% had a waist circumference above the 75th percentile and 18.7% had a BMI above 85th percentile. AN was diagnosed in 39.6% of the population studied. A significantly high prevalence of insulin resistance was observed among the children with a waist circumference exceeding the 75th percentile, a BMI above the 85th percentile, or a diagnosis of AN. The most sensitive physical marker of insulin resistance was AN (90%) and the most specific was BMI (91%). By combining these parameters their sensitivity may be increased to 94% and their negative predictive value to 96%. Vijayan et al. conclude that these easily recognisable physical markers are an efficient warning of insulin resistance among children.

Acanthosis nigricans in different conditions

AN is not a disease, but a symptom of disease. A high prevalence has been observed recently, and there are a number of varieties. These include benign, obesity associated, syndromic, malignant, acral, unilateral, medication-induced, and mixed AN.32,33 It has been established that AN may occur in a number of conditions, and a brief discussion of these is appropriate for this paper. Different types of AN are listed in Table 1. It often appears gradually in the prediabetic state, but abruptly in malignancy.

AN may be triggered by a plethora of medications, such as birth control pills, human growth hormones, thyroid medications, and even some bodybuilding supplements. All these medications may cause changes in insulin levels. Medications used to ease the side effects of chemotherapy have also been linked to AN. In most cases, the condition clears up when the medications are discontinued. In rare cases, AN may be caused by gastric cancer (especially gastric adenocarcinoma) or an adrenal gland disorder such as Addison’s disease. Hypothyroidism, Cushing’s disease, and polycystic ovarian disease are also common causes of AN. 34,35

When AN is present without any identifiable cause in middle-aged and older patients with extensive skin findings, internal malignancy needs to be ruled out. AN has been reported in association with many kinds of cancer, by far the most common being an adenocarcinoma of gastrointestinal origin. In these patients it is a rapid-growing dermatological pigmentation disorder. The skin changes are typically more extensive and severe than those seen in benign AN. Findings may include thickening, unusual roughness and dryness, and/or potentially severe itching (pruritus) and irritation of the skin regions affected. Pigmentary changes may be more pronounced than those observed in benign AN and they are not restricted to areas of hyperkeratosis. Malignant AN is frequently associated with the mucous membranes and with distinctive abnormalities of the oral (mouth) region. For example, reports indicate that the lips and the back and sides of the tongue may have an unusually ‘shaggy’ appearance, sometimes with elevated, wart-like, non-pigmented tissue growths (papillomatous elevations). Malignant AN is also commonly characterised by wart-like thickening around the eyes, unusual ridging or brittleness of the nails, thickening of the skin on the palms of the hands, hair loss, and sometimes other symptoms. Investigators have reported that the development of malignant AN may occur as much as five years before the onset of other symptoms, although the time span before malignancy is typically of shorter duration.

Table 1. Different types of acanthosis nigricans

1. Obesity-associated acanthosis nigricans. Obesity-associated acanthosis nigricans, once labelled pseudo-acanthosis nigricans, is the most common type. Lesions may appear at any age but are most common in adulthood. The dermatosis is weight dependent, and lesions may completely regress with weight reduction. Insulin resistance is often present in these patients. It is slow growing.
2. Acral acanthosis nigricans. Acralacanthosis nigricans (acral acanthotic anomaly) occurs in patients who are otherwise in good health. Acral acanthosis nigricans is most common in dark-skinned individuals, especially those of African-American or sub-Saharan-African descent. The hyperkeratotic velvety lesions are most prominent over the dorsal aspects of the hands and feet, with knuckle hyperpigmentation often most prominent.
3. Unilateral acanthosis nigricans. Unilateral acanthosis nigricans, sometimes referred to as nevoid acanthosis nigricans, is believed to be inherited as an autosomal dominant trait. Lesions are unilateral in distribution and may become evident during infancy, childhood, or adulthood. Lesions tend to enlarge gradually before stabilising or regressing.
4. Generalised acanthosis nigricans. Generalised acanthosis nigricans is rare and has been reported in paediatric patients without underlying systemic disease or malignancy.
5. Syndromic acanthosis nigricans. Syndromic acanthosis nigricans is the name given to acanthosis nigricans that is associated with a syndrome. The type A syndrome and type B syndrome are special examples.
6. Hereditary acanthosis nigricans. Familial acanthosis nigricans is a rare genodermatosis that seems to be transmitted in an autosomal dominant fashion with variable phenotypic penetrance. The lesions typically begin during early childhood but may manifest at any age.
7. Drug-induced acanthosis nigricans. Drug-induced acanthosis nigricans, although uncommon, may be induced by several medications, including nicotinic acid, insulin, pituitary extract, systemic corticosteroids, and diethylstilbestrol. Rarely, triazinate, oral contraceptives, fusidic acid, and methyltestosterone have also been associated with it.
8. Malignant acanthosis nigricans. Malignant acanthosis nigricans, which is associated with internal malignancy, is the most concerning variant of acanthosis nigricans because the underlying neoplasm is often an aggressive cancer.
9. Mixed-type acanthosis nigricans. Mixed-type acanthosis nigricans refers to those situations in which a patient with one of the above types develops new lesions of a different ethology.

Genetic links

It is worth noting that certain types of AN may be genetically linked.36 The interaction of genes and the environment is not clearly understood and the different variables of DM type 2 are not established. It is a heterogenous disorder and there is a general consensus that diabetic comorbidities may be the outcome of genetic and environmental susceptibilities.37,38,39,40,41 Such factors may have an influence independently or in combination with one another that brings about hyperglycaemic conditions.It would be interesting to explore the possibility of a link between the diabetic genes and the AN gene. DM type 2 may be potentiated by poor quality of insulin or decreased production of insulin, and the distinction between those manifestations is not well recognised. The controversy concerning the relative roles of insulin deficiency and insulin resistance in DM type 2 continues to be unresolved.42 Despite the early demonstration that obese people have elevated plasma insulin concentrations, many studies over the years have failed to control satisfactorily for the influence of obesity.43 Another difficulty with the interpretation of plasma insulin concentrations is that sustained hyperglycaemia may have detrimental effects on insulin secretion.44 Diabetes mellitus affects every cell of the body, and therefore it affects the beta cells of the pancreas in turn. The spiralling effect of hyperglycaemia adds to the malfunctioning of beta cells, and that results in impaired quantity and quality of insulin. Only a subset of diabetic patients shows AN, and other groups of obese diabetic patients do not develop AN. AN is linked with higher insulin production and obesity, whereas AN may not be present in diabetes with a reduced quantity of insulin. The presence of AN may serve as one of the biological markers to determine subtypes of DM type 2.

The incidence of AN varies in different races, which is evidence that AN may have a genetic contribution – indeed, it has been regarded by some as being strongly influenced by genetic factors. It is thought to be autosomal in nature. AN is common among African-Americans, Hispanics, and American Indians, but it is rare among white people.45,46 A study from the USA reports the prevalence of AN as 3% among Caucasians, 19% in Hispanics, and 28% in American Indians. 47 More recently, studies from Sri Lanka and south India show the prevalence of AN as high as 17.4% and 16.1% respectively in the adult population in general.48,49

Type 2 diabetes mellitus and schizophrenia

DM type 2 is relatively common among people who have mental health issues. Increased risk for cardiovascular disease and other serious illnesses related to insulin resistance – for example, certain epithelial cell carcinomas, AN, and polycystic ovary syndrome – are long-term concerns associated with the cluster of metabolic abnormalities stemming from insulin resistance. These are often referred to as the metabolic syndrome.50 Impaired action of insulin in patients with schizophrenia was reported over fifty-five years ago and later confirmed in Australia.51 The prevalence of DM type 2 in patients with schizophrenia was found to be higher than it was in the general population, even before antipsychotic medication was in widespread use.

The mechanisms underlying the relationship between schizophrenia and diabetes remain unexplained. The present author has argued in favour of the autoimmune hypothesis of a subset of schizophrenia.52,53 The proposal is that if AN is an AD, it may be co-existing with DM type 2, or the DM type 2 itself may even be an extension of the same autoimmune process. In other words, there may be a continuum of pathological process between AN and DM type 2. It follows that schizophrenia sufferers may have a predisposition to develop DM type 2; schizophrenia may even be considered as a clinical surrogate of DM type 2.

When AN occurs in a schizophrenic patient, they sometimes develop a delusional misinterpretation of the condition, such as that it is a result of skin cancer or even a manifestation of an external agency. Such situations may result in severe anxiety. Schizophrenia is frequently associated with poor lifestyle choices on the part of the patient, such as a diet high in fat, reduced levels of physical activity, and high rates of smoking-all of these may contribute to the development of a metabolic syndrome and insulin resistance.54,55 It is worth considering investigation into the early warning signs for DM type 2 – including the AN – before commencing a patient on antipsychotic drugs that lead to a metabolic syndrome.

It is now well recognised that patients treated with clozapine or olanzapine are more often classified as having DM type 2 or impaired glucose tolerance in comparison with patients treated with other second-generation antipsychotics. Clozapine increases the risk of diabetes if there is a history of pre-existing diabetes or a family history of diabetes. According to a US study, the risk is higher if the patient is African-American or of Hispanic origin. Such patients may need close blood sugar monitoring during the initiation of clozapine treatment. I contend that if a patient already has AN, weight-increasing antipsychotics should be avoided. Even though aripiprazole is the most metabolic-sparing agent among the second-generation antipsychotics, Manu et al. report a case of AN in a patient treated with it. That patient did have a family history of DM type 2, which adds to the interest of the case.56

Diagnosis and treatment

There is no specific treatment for AN. Treatment is directed towards the specific symptoms that are apparent in each individual. It should be borne in mind that such treatment may require the coordinated efforts of a team of medical professionals. Correcting the underlying disease improves the skin symptoms. Steps that may be taken, depending on what the disease is, include correcting hyperinsulinemia through diet and medication, encouraging the loss of weight in those with obesity-associated AN, removing or treating a tumour, and discontinuing a medication that causes AN. The control of obesity contributes significantly to reversing the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. However, the pigmentary changes may persist. In drug-induced AN, offending medicines should be stopped. In hereditary AN, lesions tend to enlarge gradually before stabilising and/or regressing on their own.

For those with AN, the recommended treatment may include the use of certain synthetic, vitamin A-like compounds (retinoids). For individuals with malignant AN, disease management requires treatment by oncologists. Reports indicate that AN has improved with therapy used to treat underlying malignancies and has reappeared with tumour recurrences. Other treatment for this disorder is symptomatic and supportive. The treatments considered are used primarily to improve appearance, and include topical retinoids, dermabrasion, and laser therapy. The final outcome of AN varies depending on the cause of the condition. Benign conditions, either on their own or through lifestyle changes and/or treatment, have good outcomes. The prognosis for patients with malignant AN is often poor as the associated cancer is often advanced.

AN may be diagnosed on the basis of thorough clinical evaluation, identification of characteristic physical findings, a complete patient history including medication history, a thorough family history, and various specialised tests.57 The age at detection will vary, depending upon the form of AN present and on other factors. For example, benign forms of AN often become evident during childhood or puberty. It is less common for benign AN to be apparent at birth or to develop in adulthood. The latter cases most typically involve AN in association with obesity.

In individuals with skin changes that suggest AN, diagnostic assessment may include various laboratory tests. Examples are the glucose tolerance test and the glycated haemoglobin (HbA1c) test. Additional laboratory studies or other specialised tests may also be utilised in diagnosis in order to help detect or rule out certain other underlying disorders – including a number of endocrine and autoimmune conditions – that may be associated with AN. In addition, in some instances, particularly where the patient presents with signs suggestive of malignant AN, testing may include biopsy and microscopic evaluation of small samples of skin tissue affected.

The onset of malignant AN usually occurs after the patient reaches 40 years of age. Various factors may be indicative of malignant AN in association with an underlying cancer. These include symptom onset in adulthood that is not associated with the use of particular medications, obesity, a positive family history, and certain underlying disorders known to be associated with AN. It is rare for malignant AN to develop during childhood. In such instances, warning signs may include skin changes that progress rapidly and also involvement of the mucous membranes.58

AN may be metaphorically linked to the dark pigmentation that appears on the skin of the ripe Sharon fruit. Sharon fruit is the trade name for a variety of persimmon that is grown in Israel. In the fruit the dark patches on the ripe and sugary fruits are the result of condensed tannins. Insulin-resistant AN may be referred to as the Sharon fruit sign in order to emphasise the diagnostic value of the condition. It has been suggested that the official terminology for AN is inappropriate for a significant warning of an increasingly common disease for which early diagnosis is imperative. Because the complex name may have a negative impact on its identification by both clinicians and patients, a less formal term is in use among some of those who are concerned with patient care. It must be borne in mind that AN, otherwise Sharon fruit sign, manifests only in those with the insulin-resistant condition and should not be considered a characteristic feature of DM Type 2. Identification of the Sharon fruit sign may be helpful in the early diagnosis of DM type 2.

Discussion

Diabetes puts an enormous burden on patients, their families, and the health-care system. Detection of the disease at an early state using physical markers and instituting preventive measures will reduce the economic strain on society to a great extent. According to the latest global data from the World Health Organization (2016), an estimated 422 million adults are living with DM type 2 and diabetes prevalence is increasing rapidly.59 In 2013 the International Diabetes Federation estimated that 381 million people were living with diabetes.60 That number is anticipated to almost double by 2030.61 About 3.8 million people in the UK have DM type 2, and the charity Diabetes UK has made predictions that it may become as high as 6.2 million by 2035/36.

Most often a diagnosis of DM type 2 is made only when such symptoms as loss of weight, polydipsia, and polyurea have become manifest. By that time the damage to the body may have already come about. Complications arising from diabetes cover the entire area of medical science, so early detection is crucial. Intervention at the prediabetic stage helps to arrest the progress of this condition. AN may herald DM type 2, endocrinopathies, and malignancies. This cutaneous disorder is easily detectable and highly useful in the early detection of the disorders associated with it. Early screening for AN in preadolescent and adolescent people would provide a relatively simple, inexpensive, and non-invasive tool for identifying those young people who have hyperinsulinemia and could benefit from early intervention. That would prevent the development of DM type 2. Young people tend to be reluctant to undergo traditional screening measures and definitive diagnostic tests as they find them invasive and unpleasant.

A sedentary life style and unhealthy dietary habits – as well as the side effects of antipsychotics – make chronically ill psychotic patients more vulnerable to DM type 2 than the general population. Long-standing detained patients in particular are restricted in their mobility and may become more prone to obesity and insulin resistance. It is not clear whether the pathogenesis of psychosis itself has a diabetogenic effect. It is evident that because of the high incidence of DM type 2 among mental health service users, psychiatrists need to become more alert in the diagnosis, management, and prevention of the complications of DM type 2.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Dr James Paul Pandarakalam, Consultant Psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, Warrington WA2 8WN, UK
Corresponding Author Details: 
Dr James Paul Pandarakalam, Consultant Psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, Hollins Park Hospital & AFG Rehab Hospitals, Winnick Lane, Warrington WA2 8WN, UK
Corresponding Author Email: 
jpandarak@hotmail.co.uk
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Depression in older adults

Authors
Claire Pocklington
Article Citation and PDF Link
BJMP 2017;10(1):a1007
Abstract / Summary
Abstract: 

Despite being the most common mental disorder in older adults, depression is under- recognised. It poses diagnostic difficulties in this population for several reasons; for example, symptomatic and phenomenological differences, age-related biological and psychological factors, and the presence of physical comorbidities. Depression in older adults is an important clinical topic because outcomes are worse in comparison to younger adults. It is also associated with higher rates of morbidity and mortality, increased healthcare utilisation and economic costs. It is likely to become a more pressing issue in the future due to the projected increase in the older adult population. This article explores the topic of depression in older adults. 

Introduction

Depression is a clinical syndrome. The International Classification of Diseases (ICD) diagnostic classification systems describe three core symptoms of depression; low mood, anhedonia and reduced energy levels1. Other symptoms include impaired concentration, loss of confidence, suicidal ideation, disturbances in sleep and changes in appetite. Symptoms must have been present for at least a period of two weeks for a diagnosis of depression to be made. Major depression refers to the presence of all three core symptoms and, in accordance with ICD criteria, at least the presence of a further five other symptoms1. See Table 1 for severity criteria of a depressive episode according to ICD criteria.

Table 1: Severity criteria of a depressive episode according to ICD-101

Criteria A – General: Criteria B – Presence of ≥2 of the following: Criteria C – ‘Other’ symptoms:
Symptoms for at least 2 weeks
Symptoms not attributable to psychoactive substance use or organic mental disorder
Low mood
Anhedonia
Reduced energy levels/ increased fatigability
Loss of confidence and self-esteem
Feelings of guilt
Suicidal thoughts
Impaired concentration/ability to think
Changes in psychomotor activity
Sleep disturbance
Changes in appetite with weight changes
Criteria for severity of depressive episode:
Mild episode:
2 symptoms of criteria B
Moderate episode:
≥2 symptoms of criteria B
+ symptoms of criteria C until minimum of 6 symptoms in total
Major episode:
all 3 symptoms of criteria B + symptoms of criteria C until a minimum of 8 symptoms in total

Depressive symptoms, which can be clinically significant, can be present in the absence of a major depressive episode. Depressive symptoms are those that do not fulfil diagnostic criteria for a diagnosis of depression to be made. Depressive symptoms can be collectively referred to as sub-threshold depression, sub-syndromal depression or minor depression2.

It has been proposed that there are two types of depression; early-onset and late-onset depression. Late-onset depression refers to a new diagnosis in individuals aged 65 years of age or older. Over half of all cases of depression in older adults are newly arising (i.e. the individual has never experienced depression before) and thus late-onset type depression. Late-onset type depression is associated more with structural brain changes, vascular risk factors and cognitive deficits. It has been suggested that late-onset depression could be prodromal to dementia3.

The Kings Fund has estimated that by 2032 the proportion of older adults aged 65-84 years old will have increased by 39% whereas the proportion over the age of 85 years will have increased by 106%4. This increase in population will consequently see the incidence and prevalence of depression rise. By 2020 it is estimated that depression will be the second leading cause of disability in the world regardless of age5. Recognising, and so diagnosing, depression in older adults will become more important because of a greater demand on existing healthcare services and provisions, due to physical health consequences, impact upon healthcare utilisation and greater economic healthcare costs.

Presentation of depression in older adults

The presentation of depression in older adults is markedly different to that in younger adults. The most significant and fundamental difference in presentation in older adults is that depression can be present with the absence of an affect component, i.e. subjective feelings of low mood or sadness are not experienced3,6-9. The absence of an affective component is referred to as ‘depression without sadness’8-9. It is common instead for older adults to report a lack of feeling or emotion when depressed8-9.

Anhedonia is also less prevalent in this population. However, reduced energy levels and fatigue are frequently reported8-9.

Compared to younger adults, psychological symptoms of depression occur more frequently and are more prevalent in older adults10. Such psychological symptoms include feelings of guilt, poor motivation, low interest levels, anxiety related symptoms and suicidal ideation. The presence of irritability and agitation are key features as well7. Hallucinations and delusions are also more common in older adults, particularly nihilistic delusions (i.e. a person believing their body is dead or a part of their body is not working properly or rotting).

Cognitive deficits are characteristic of depression in older adults7,11 and are described as ‘substantial and disabling’12. Such deficits mainly concern executive function13-14. Pseudodementia is a phenomenon seen in older adults15. The term refers to cognitive impairment secondary to a psychiatric condition, most commonly depression16. Pseudodementia has become synonymous with depression. Pseudodementia can be mistaken for an organic dementia and so older adults who are depressed can present primarily to mental health services with memory problems. Pseudodementia is classically associated with ‘don’t know’ answers, whereas older adults with a true dementia will often respond with incorrect answers17.

‘Depression-executive dysfunction syndrome’ is a more specific and descriptive term to describe the cognitive deficits found in older adults with depression14. It is associated with psychomotor retardation, which can be a core feature of depression in this population7,14,18. Psychomotor retardation describes a slowing of movement and mental activity19. Like pure cognitive deficits, psychomotor retardation contributes significantly to functional impairment19. Both executive dysfunction and psychomotor retardation have been found to be related to underlying structural changes in the frontal lobes14, 20-21. Psychomotor retardation is further related to white matter changes in the motor system, which leads to impaired motor planning21. There is conflicting evidence of whether the presence of psychomotor retardation is related to depression severity18-19.

Somatisation and hypochondriasis are associated with depression in older adults and increasing age in general22-23. Somatisation is often overlooked in older adults by healthcare professional who actively search to attribute such symptoms to a physical cause. Somatisation is more common in those who have physical comorbidities. Somatisation in older adults is associated with structural brain changes and cognitive deficits24.

Depression in older adults is associated with functional impairment cognitively, physically and socially7,12,25. Such functional impairment is linked to loss of independent function and increased rates of disability26. Withdrawal from normal social and leisure activities can be marked7,25. Social avoidance reduces interaction with others and is often a maintaining factor for depression25.

Self-neglect is a classical feature of depression7, with the presence of depressive symptoms in older adults being predictive of it27. Behavioural disturbances can be a common mode of presentation, especially for older adults living in institutionalised care 6-7. Behavioural disturbances include incontinence, food refusal, screaming, falling and violence towards others7.

Diagnostic difficulties

Depression in older adults has been a condition that has constantly been under-recognised. Several issues account for this. Firstly, phenomenological differences are present. Many have argued that phenomenological issues contribute heavily to diagnostic difficulties28; both the DSM and ICD classification systems do not have specific diagnostic criteria for depression in older adults. Potentially invalid diagnostic criteria for depression in older adults could result in fundamental difficulties in understanding, with consequent impact on both clinical practice and research.

Diagnostic difficulties are also encountered because depression in older adults can present with vague symptoms, which do not correspond to the classical triad of low mood, low energy levels and anhedonia, which can all be cardinal symptoms in a younger population. Reports of fatigue, poor sleep and reduced appetite can be attributed to a host of causes other than depression and therefore it is no surprise that a diagnosis of depression is overlooked and goes undetected by healthcare professionals29.

The absence of an affective component (i.e. low mood) can lead to healthcare professionals disregarding the potential for the presence of depression and consequently not exploring for other symptoms.

Furthermore, symptoms of depression, especially somatic ones, are often attributed to physical illnesses. Depressive somatic symptoms often lead to a diagnosis of depression being over looked; such symptoms ‘mask’ the clinical diagnosis of depression and hence the term ‘masked depression’30. Depressive somatic symptoms – e.g. low energy levels, insomnia, poor appetite and weight loss - are often attributed to physical illness and/or frailty by both the individual and healthcare professional7-8, 31.

Further complicating diagnostic difficulties and under-recognition is the fact that older adults are less likely to report any symptoms associated with mental health problems and ask for help in the first place7,10,32; explanations for this include older adults being less emotionally open, having a sense of being a burden or nuisance, and believing symptoms are a normal part of ageing or secondary to physical illness7,10,29,33.Older adults also have a reluctance to report mental health problems due to their perception of associated stigma; many older adults hold the view the mental health problems are shameful, represents personal failure and leads to a loss of autonomy7.

There is an overlap between symptoms of depression and symptoms of dementia. It is quite common for older adults with dementia to initially present with depressive symptoms. Depression has a high incidence in those with dementia, especially those with vascular dementia. Depression is particularly difficult to diagnose in dementia due to communication difficulties; diagnosis is often based on observed behaviours8,33.

Depression and comorbidity in older adults

In those with pre-existing physical health problems, depression is associated with deterioration, impaired recovery and overall worse outcomes34. For example, the relative risk of increased morbidity related to coronary heart disease is 3.3 in comparison to individuals without depression35. Mykletun et al. established that a diagnosis of depression in older adults increased mortality by 70%36. Several causative routes account for poor physical illness outcomes. Older adults with depression are less likely to report worsening health. Depressive symptomatology indirectly affects physical illness through reduced motivation (often secondary to feelings of helplessness and hopelessness) and engagement with management. Poor compliance with management advice, notably adherence to medications is observed37. Feelings of hopelessness, helplessness and negativity will contribute to the failure to seek medical attention in the first place or report worsening health when seen by a healthcare professional.

Depression affects biological pathways directly, which impairs physical recovery. Such biological effects include pro-inflammatory factors, metabolic factors, impact upon the hypothalamic-pituitary axis and autonomic nervous system changes38.

Older adults who are depressed are more likely to have existing physical health conditions and more likely to develop physical health conditions15. Depression is particularly associated with specific physical illnesses; cardiovascular disease and diabetes mellitus. A study by Win et al. found that cardiovascular mortality is higher in older adults with depression because of physical inactivity; the study established that physical inactivity was accountable for a 25% increased risk in cardiovascular disease39. The relationships between depression and cardiovascular disease and depression and diabetes have been described as “bidirectional”38.

Higher incidents of cardiovascular disease and diabetes mellitus are seen in people with depression regardless of age. A study by Brown et al. found that older adults with depression had a 1.46 relative risk increase for developing coronary heart disease compared to those without depression40. The hypothalamic-pituitary axis dysfunction found in depression leads to increased levels of cortisol, which in turn, increases visceral fat. Increased visceral fat is associated with increased insulin resistance, promoting diabetes mellitus, and increased cardiovascular pathology38.

Depression is a risk factor for the subsequent development of dementia; this is especially so if an older adult has no previous history of depression (i.e. depression is late-onset)13.

Healthcare utilisation and economic impacts

Older adults are less likely to report depressive symptoms to healthcare professionals explaining the under-utilisation of mental health services for depression32,41. Despite older adults under-utilising mental health services they over utilise other healthcare services26,41. For example, those presenting with non-specific medical complaints or somatisation have been found to have an increase use of healthcare services. Non-specific medical complaints and somatisation lead to an unnecessary use of resources, such as unnecessary consultations with healthcare professionals and investigations41. Increase in service utilisation means an increase in the associated economic cost of depression in older adults41-43.

Healthcare costs of older adults with a comorbid physical illness and depression are far greater than those without depression – findings in diabetes mellitus are a good example43. The majority of the increased healthcare costs are associated with the chronic physical disease and not the care and treatment of the depression44. Poor compliance with physical illness management is associated with missed appointments and a greater number of hospital admissions, which both have financial implications.

Aetiology and associations of depression in older adults

Late-onset type depression in older adults has been associated with the term ‘vascular depression’45-47. Studies have found a significant higher rate and severity of white matter hyperintensities on MRI imaging in older adults with depression compared to those without depression46,48,50. White matter hyperintensities represent damage to the nerve cells; such damage is a result of hypo-perfusion of the cells secondary to small blood vessel damage49. White hyperintensities are associated with vascular risk factors (e.g. age, hypertension, hypercholesterolaemia, obesity, diabetes mellitus, smoking) and are linked to cerebrovascular disease, such as stroke, vascular dementia. A relationship has been found between psychosocial stress and consequent development of vascular risk factors, which further supports the hypothesis of ‘vascular depression’46. Clinically, ‘depression-executive dysfunction syndrome’ and psychomotor retardation are associated with vascular changes48.

In older adults with depression, white matter hyperintensities are associated with structural changes to corticostriatal circuits and subsequent executive functional deficits. Loss of motivation or interest and cognitive impairment in depression are hallmark features of structural brain changes associated with the frontal lobes, which in turn are associated with a vascular pathology20. A study by Hickie et al. established that white matter hyperintensities in older adults with depression are associated with greater neurological impairment and poorer response to antidepressant treatment50. It is not fully understood why vascular depression responds less well to antidepressants; poor response has been linked directly to vascular factors but has also been associated with deficits in executive function46-47.

The relationship between cerebrovascular disease and depression is described as ‘bi-directional’45,51; depression has been found to cause cardiovascular disease and vice versa51. Baldwin et al. direct the reader to the presence of post-stroke depression and the occurrence of depression in vascular dementia45.

Younger and older adults share a number of fundamental risk factors for depression; such as female gender, personal history and family history7. Older adults have additional risk factors related to ageing, which are not just physiological in nature.

Age related changes:

Age related changes occurring in the endocrine, cardiovascular, neurological, inflammatory and immune systems have been directly linked to depression in older adults3.

The normal ageing process sees changes to sleep architecture and circadian rhythms with resultant changes to sleep patterns52. Thus sleep disturbances are common in older adults and positively correlated to advancing age52; over a quarter of adults over the age of 80 years report insomnia, and research has well-established that this is a risk factor for depression53-54. A meta-analysis by Cole et al. found sleep disturbances to be a significant risk factor for the development of depression in older adults53.

Sensory impairment:

Sensory impairments, whether secondary to the ageing or a disease process, are risk factors53,55. Research has found that hearing and vision impairments are linked to depression56. A sensory impairment can lead to social isolation and withdrawal, which, in turn, are further risk factors for depression.

Physical illness:

Physical illness, regardless of age, is a risk factor for depression. Older adults are more likely to have physical illnesses and so in turn are more at risk of depression. See Table 2. Physical illness is associated with sensory impairments, reduced mobility, impairment in activities of daily living and impaired social function, all of which can lead to depression. Physical illnesses associated with chronicity, pain and disability pose the greatest risk for the subsequent development of depression7,53,55. Physical illness affecting particular systems of the body, such as the cardiovascular, cerebrovascular and neurological, are more likely to cause depression3. Essentially, however, any serious or chronic illness can lead to the development of depression. It should be noted that a large proportion of older adults have physical illness but do not experience depression symptoms, therefore other factors must be at play5,57.

Treatments of physical illness are directly linked to aetiology in depression, for example, certain medications are known to cause depression; cardiovascular drugs (e.g. Propranolol, thiazide diuretics), anti-Parkinson drugs (e.g. levodopa), anti-inflammatories (e.g. NSAIDs), antibiotics (e.g. Penicillin, Nitrofurantoin), stimulants (e.g. caffeine, cocaine, amphetamines), antipsychotics (e.g. Haloperidol), anti-anxiolytics (e.g. benzodiazepines), hormones (e.g. corticosteroids), and anticonvulsants (e.g. Phenytoin, Carbamazepine)7,29. Polypharmacy is present in many older adults further increasing the risk of depression. Pharmacokinetic and pharmacodynamic age related changes also contribute to an increased risk of medication induced depression in older adults.

Table 2: Table of physical illnesses associated with depression3,7

Cardiovascular Endocrine Cerebrovascular/neurological
Ischaemic heart disease
Myocardial infarction
Addison’s disease
Cushing’s disease
Hypothyroidism
Hyperthyroidism
Diabetes mellitus
Hypoglycaemia
Cerebral arteriosclerosis
Cerebral infarction
Intracranial tumour
Parkinson’s disease
Multiple sclerosis
Temporal lobe epilepsy
Dementia
Metabolic Autoimmune disorders
Electrolyte abnormalities
• Hypernatraemia
• Hypercalacaemia
• Hyperkalaemia
• Hypokalaemia
Folate deficiency
Thiamine deficiency
Rheumatoid arthritis
Systemic lupus erythematosus
Pernious anaemia

Dementia:

Dementia is common in old age and those with dementia are at higher risk of developing depression compared to those who do not have it58. 20-30% of older adults with Alzheimer’s disease have depression59. Depression is a risk factor for the subsequent onset of dementia.

Psychosocial:

When compared to younger adults, older adults are at a greater risk of developing depression due to the increased likelihood of experiencing particular psychosocial stressors, in particular adverse life events. Stressors include lack of social support, social isolation, loneliness and financial hardship. Financial hardship and functional impairment often sees older adults downsizing in property. Deteriorating physical health often sees older adults no longer being able to manage living independently at home necessitating a move into institutional living. Bereavement, especially spousal, and the associated role change that follows this are risk factors for depression3.

Sub-threshold depression:

Sub-threshold depression is an established risk factor for major depression.

Prevalence and epidemiology

The prevalence of depression in older adults in England and Wales was found to be 8.7% in 2007; however, if those with dementia are included this figure rises to 9.7%60. A meta-analysis by Luppa et al. established a 7.2% point prevalence of major depression and a 17.1% point prevalence of depressive disorder in older adults61. The projected lifetime risk of an older adult developing major depression by the age of 75 years old is 23%62.

Sub-threshold depression is 2-3 times more prevalent than major depression in older adults26,63. These depressive symptoms are often clinically relevant26,29. 8-10% of older adults per year with sub-threshold depressive symptoms go onto develop a major depressive episode63.

Incidence and prevalence are greater in women; 10.4% of women over the age of 65 years have depression compared to 6.5% of men60. Older women are more likely to experience recurrent episodes of depression compared to older men62. The gender gap in incidence and prevalence becomes narrower with increasing age3. It should be acknowledged however that women are more likely to present to healthcare services and seek help in comparison to men64-65.

The prevalence of major depression in older adults varies by setting66. Highest rates are seen in long-term institutional care and inpatient hospital settings67. Table 3 summaries prevalence rates of major depression by setting.

Table 3: Prevalence rate of major depression by setting 7, 67

Setting Prevalence rate (%)
Community 5 – 10
Primary care 10 – 30
Hospital inpatient 11 – 50
Long-term institutional care 10 – 43

Prognosis of depression in older adults

Depression in older adults is associated with a slower rate of recovery9, worse clinical outcomes compared to younger adults3 and is associated with higher relapse rates68. Worse prognosis in older adults correlates with advancing age, physical comorbidities and functional impairment70. The structural brain changes associated with depression in older adults are linked, as discussed, to poorer treatment response.

Morbidity and mortality associated with depression can be described as primary or secondary; primary morbidity and mortality arises directly from the depressive illness; whereas secondary morbidity and mortality arises from physical health problems, which are secondary to depression.

Outcomes from sub-threshold depression are on par with those of major depression; however sub-threshold depression which develops into major depression is associated with worse outcomes2.

Proportionally more people over the age of 65 years commit suicide compared to younger people71. Depression is the leading cause of suicide in older adults29,71; one study reports that 75% of older adults who killed themselves were depressed72.

The vast majority of older adults who commit suicide have had contact with a health professional within the preceding month9; this figure has been quoted as high as 70%3. This further supports and suggests the fact the depression is under-detected. Unlike younger adults, older adults are less likely to report suicidal ideation and can experience suicidal ideation without feeling low in mood3,7. Older adults have few suicide attempts, compared to younger adults, because their suicide methods are more lethal13.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NONE.
Competing Interests: 
None declared
Details of Authors: 
CLAIRE POCKLINGTON, MBChB MSc MRCPsych, ST5 Old Age Psychiatry, South West Yorkshire Partnership NHS Foundation Trust, Drury Lane Health and Wellbeing Centre, Wakefield, WF1 2TF, UK.
Corresponding Author Details: 
CLAIRE POCKLINGTON, Drury Lane Health and Wellbeing Centre, Drury Lane, Wakefield WF1 2TF.
Corresponding Author Email: 
pocklington.c@gmail.com
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Perioperative hypertensive crisis. The anaesthetic implications. A Review of Literature

Authors
Mohamed A. Daabiss, MD
Article Citation and PDF Link
BJMP 2016;9(3):a922
Abstract / Summary
Abstract: 

Hypertensive emergencies involve a series of clinical presentations where uncontrolled blood pressure (BP) leads to progressive end-organ dysfunction affecting the neurological, cardiovascular, renal, or other organ systems. In these situations, the BP should be controlled over minutes to hours. Many causes are involved in severe elevation of blood pressure; inadequate treatment of hypertension, renal diseases, head trauma and pre-eclampsia. Intraoperative hypertension is also common and has many causes. It is usually successfully controlled by anaesthetists. However, there is a lack of agreement concerning treatment plans and appropriate therapeutic goals, making common management protocols difficult. A wide range of pharmacological alternatives are available to control blood pressure and reduce the risk of complications in these patients. This article reviews the perioperative hypertensive crisis and the common strategies used in management.

Perioperative hypertension commonly occurs in patients undergoing surgery. Accurate adjustment of treatment and monitoring of patient’s response to therapy are essential to safe and effective management of perioperative hypertension.  

Abbreviations: 
blood pressure (BP), mean arterial pressure (MAP),
Keywords: 
Hypertension, crisis, perioperative, anaesthesia.

Introduction

Hypertension is the most common risk factor for perioperative cardiovascular emergencies. Acute episodes of hypertension may arise due to the aggravation of a pre-existing chronic hypertensive condition or as de novo phenomena1.

Emergency, anaesthesia, intensive care and surgery are among the clinical settings where proper recognition and management of acute hypertensive episodes is of great importance. Many surgical events may induce sympathetic activity, leading to sudden elevations in BP2.

The long term end-organ effects add to patient morbidity and mortality. Ensuring cardiovascular stability and pre-optimization of BP allows safe manipulation of physiology and pharmacology during anaesthesia2. Different medications are available for the management of hypertensive emergencies. The greatest challenge is the acute care setting where the need for proper and sustained control of BP exists.

Definition

Acute severe elevations in BP have several terms. The syndrome characterized by a sudden increase in systolic and diastolic BPs (equal to or greater than 180/120 mmHg) associated with acute end-organ damage that requires immediate management otherwise it might be life-threatening was defined as malignant hypertension3. The international blood pressure control guidelines removed this term and replaced it with hypertensive emergency or crisis4.  

Criteria for hypertensive emergencies (crises) include: dissecting aortic aneurysm, acute left ventricular failure with pulmonary oedema, acute myocardial ischemia, eclampsia, acute renal failure, symptomatic microangiopathic haemolytic anemia and hypertensive encephalopathy5.

While they suggest 'hypertensive urgency' for patients with severe hypertension without acute end-organ damage3.  The difference between hypertensive emergencies and urgencies depends on the existence of acute organ damage, rather than the absolute level of blood pressure5.

Causes of hypertensive crises

Cessation of antihypertensive medications is one of the main causes. Other common causes are autonomic hyperactivity, collagen-vascular diseases, drug use (stimulants, e.g. amphetamines and cocaine), glomerulonephritis, head trauma, pre-eclampsia and eclampsia, and renovascular hypertension6.

Signs and symptoms of hypertensive crisisinclude severe chest pain, severe headache accompanied by confusion and blurred vision, nausea and vomiting, severe anxiety, shortness of breath, seizures and unresponsiveness.

Pathogenesis

Humoral vasoconstrictors released in the hypertensive crises episodes result in a sudden increase in systemic vascular resistance. Endothelial injury accompanies severe elevations of BP resulting in fibrinoid necrosis of the arterioles with the deposition of platelets and fibrin, and a breakdown of the normal autoregulatory function. The resulting ischemia speeds the further release of vasoactive substances completing a vicious cycle7.

Perioperative hypertension

At least 25% of hypertensive patients who undergo noncardiac surgery develop myocardial ischemia associated with the induction of anaesthesia or during the intraoperative or early post-anaesthesia period8. Previous history of diastolic hypertension greater than 110 mmHg is a common predictor of perioperative hypertension. The level of risk depends on the severity of hypertension9.

Sympathetic activation during the induction of anaesthesia increases the BP by 20 to 30 mmHg and the heart rate by 15 to 20 beats per minute in normotensive individuals8. These responses may be more obvious in patients with untreated hypertension in whom the systolic BP can increase by 90 mmHg and heart rate by 40 beats per minute.

Intraoperative hypertension is associated with acute pain induced sympathetic stimulation besides certain types of surgical procedures like carotid surgery, intrathoracic surgery and abdominal aortic surgery. Paix et al, analysed 70 incidents of intraoperative hypertension and reported that drugs were the precipitating cause (inadvertent vasopressor administration by the anaesthetist or surgeon, intravenous adrenaline with local anaesthetic and failure to deliver a volatile agent or nitrous oxide) in 59% of the cases. Light anaesthesia and excessive surgical stimulation represented 21% of incidents, while equipment related causes (ventilation problems e.g. stuck valve, hypoventilation, soda lime exhaustion and endobronchial intubation) were 13% of incidents. Awareness under general anaesthesia, myocardial infarction and pulmonary oedema represented 7% of incidents10.

In the early postanaesthesia period, hypertension often starts within 10 to 20 minutes after surgery and may persist for 4 hours. Besides pain induced sympathetic stimulation, hypoxia, intravascular volume overload from excessive intraoperative fluid therapy and hypothermia can promote postoperative hypertension. If untreated, patients are at high risk for myocardial ischemia, cerebrovascular accidents and bleeding11. Hypertension might happen 24 to 48 hours postoperative due to fluid mobilisation from the extravascular space, besides cessation of antihypertensive medication in the early postoperative period12.

The absolute level of BP is as important as the rate of increase. For example, patients with chronic hypertension may tolerate systolic BPs (SBP) of 200 mm Hg without developing hypertensive encephalopathy, while pregnant women and children may develop encephalopathy with diastolic BPs of 100 mm Hg13.

Preoperative general considerations for hypertensive patients

During preoperative assessment we have to review associated medical problems such as ischaemic heart disease, cerebrovascular disease and renal failure. This can assess the risk for anaesthesia and so the hypertensive end-organ damage. Some patients with hypertension are asymptomatic and accidentally discovered during preoperative assessment. Incidental hypertension may suggest long standing hypertensive disease1. Idiopathic hypertension comprises about ninety percent of hypertensive patients6.

Management of perioperative hypertension crises

The treatment plan of perioperative hypertension differs from treatment of chronic hypertension. Hypertensive patients undergoing elective surgery are at risk for increased perioperative hypertensive attacks. Postponement of elective surgery is recommended in chronic hypertensive patients if the diastolic BP is ≥110 mm Hg until the BP is controlled14. We have to determine if it is a hypertensive emergency or urgency, besides the underlying causes of the patient’s BP elevation.

The most appropriate medication for management of hypertensive emergency should have a rapid onset of action, a short duration of action, be rapidly titratable, allow for dosage adjustment, have a low incidence of toxicity, be well tolerated and have few contraindications2,15. A parenteral antihypertensive agent is preferred due to rapid onset of action and ease of titration5.

The goal of therapy is to halt the vascular damage and reverse the pathological process, not to normalise the BP. Guidelines by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP for treating hypertensive emergencies include starting intervention with reducing systolic BP by 10 to 15%, up to 25% within the first hour. Followed

by gradual reduction of the absolute BP to 160/110 mmHg over the following two to six hours5,16.

Hypertension that occurs with tracheal intubation, surgical incision and emergence from anaesthesia is best treated with short-acting β-blockers, calcium channel blockers, vasodilators, or angiotensin-converting enzyme inhibitors. Postoperative hypertension is best managed by correction of precipitating factors (pain, hypothermia, hypervolemia, hypoxia and hypercarbia)17.

Unintentional hypotension and associated organ hypoperfusion happens with aggressive attempts to lower BP since the homeostatic mechanisms depend on higher blood pressure for adequate organ perfusion. While inadequate lowering of BP may result in increased morbidity and mortality. However, the alteration between overshooting BP and severe hypotensive states and using vasopressors to get the normotensive levels may damage end-organs and the vasculature - precise control of BP in a hypertensive crisis is a challenge18.

Since chronic hypertension shifts cerebral and renal perfusion autoregulation to a higher level, the brain and kidneys are prone to hypoperfusion with rapid decrease in blood pressure. So control of blood pressure to baseline levels should take 24 to 48 hours5.

In cases of aortic dissection, the systolic BP should be reduced to less than 120 mmHg within twenty minutes. In ischemic stroke, BP must be lowered to less than 185/110 before administration of thrombolytic therapy19. Gentle volume expansion with intravenous saline solution will maintain organ perfusion and prevent sudden drop in BP with using antihypertensive medications5. Preoperative hypertension is a hypertensive urgency, not an emergency, as it rarely involves end-organ damage with adequate time to reduce the BP18.  Longer acting oral medications such as Labetalol and Clonidine may be more suitable 20

Common antihypertensive medications used in hypertensive crises

Sodium Nitroprusside is a combined venous and arterial vasodilator which decreases both afterload and preload. The onset of action is within seconds and duration of action lasts for one to two minutes, so continuous BP measurement is recommended. If the infusion is stopped, the BP rises immediately and returns to the pretreatment level within one to ten minutes. Prolonged intravenous administration with infusion rates more than 2 mcg/Kg/min may result in cyanide poisoning. Thus, infusion rates greater than 10 mcg/Kg/min should not be continued for prolonged periods21

Labetalol, an alpha- and beta-blocking agent has proven to be beneficial to treat patients with hypertensive emergencies. Labetalol is preferred in patients with acute dissection and patients with end-stage renal disease. The onset of action is five minutes and lasts for four to six hours. The rapid fall in BP results from a decrease in peripheral vascular resistance and a slight fall in cardiac output22.  A reasonable administration protocol is to give an initial intravenous bolus of Labetalol 0.25 mg/Kg, followed by boluses (0.5 mg/Kg) every 15 minutes until BP control or a total dose 3.25 mg/Kg. Once an adequate BP level is achieved, we can start oral therapy with gradual weaning from parenteral agents22

Fenoldopam, a peripheral dopamine-1-receptor agonist, induces peripheral vasodilation; administered by intravenous infusion. Duration of action from 30 to 60 minutes. Gradual decrease in blood pressure to pretreatment values occurs without rebound once the infusion is stopped because of short elimination half-life. A starting dose of 0.1 μg/kg/min, titrated by 0.05 to 0.1 μg/kg/min up to 1.6 μg/kg/min. Fenoldopam provides rapid decline in blood pressure with reflex tachycardia so beware in patients at risk of myocardial ischemia23

Clevidipine, a dihydropyridine calcium channel blocker, produces rapid and precise BP reduction. It has a short half-life of about one to two minutes with potent arterial vasodilation without affecting venous capacitance, myocardial contractility or causing reflex tachycardia24.  Start intravenous infusion of Clevidipine at 1-2 mg/h; titrate the dose at short intervals (90s) initially by doubling the dose. Systolic pressure decreases by at least 15% from baseline within 6 minutes post-infusion24.  A 1-2 mg/h increase in infusion rate produces an additional 2-4 mmHg reduction in SBP14.  Clevidipine is an ideal agent to manage acute severe hypertension moreover safe for patients with hepatic and renal dysfunction2

Rational approach to the management of hypertensive crises

Neurological emergencies

Subarachnoid haemorrhage, acute intracerebral haemorrhage, hypertensive encephalopathy, and acute ischemic stroke require rapid BP reduction. In hypertensive encephalopathy, reduce the mean arterial pressure (MAP) 25% over 8 hours. Labetalol, Nicardipine and Esmolol are the preferred medications; Nitroprusside and Hydralazine should be avoided25

For acute ischemic stroke, the preferred medications are Labetalol and Nicardipine. The target BP is < 185/110 mm Hg especially if the patient is receiving fibrinolysis25

In acute intracerebral haemorrhage, Labetalol, Nicardipine and Esmolol are preferred; avoid Nitroprusside and Hydralazine. If signs of increased intracranial pressure (ICP) exist, keep SBP < 180 mm Hg, while maintain SBP < 160 mm Hg in patients without increased ICP for the first 24 hours after onset of symptoms25.  Early intensive BP control is recommended to reduce hematoma growth26,27 

In subarachnoid haemorrhage, Nicardipine, Labetalol and Esmolol are also the preferred agents; while Nitroprusside and Hydralazine should be avoided. Maintain the SBP < 160 mm Hg until the aneurysm is treated or cerebral vasospasm happens25

Cardiovascular emergencies

Rapid BP reduction is also indicated in cardiovascular emergencies such as aortic dissection, acute heart failure, and acute coronary syndrome. Labetalol, Nicardipine, Nitroprusside (with beta-blocker), Esmolol, and Morphine are preferred in aortic dissection. Beta-blockers should be avoided if there is aortic valvular regurgitation or suspected cardiac tamponade. Keep the SBP   < 110 mmHg unless signs of end-organ hypoperfusion exists28.  

In acute coronary syndrome if the BP is >160/100 mm Hg, Nitroglycerin and beta blockers are used to lower the BP by 20-30% of baseline but, thrombolytics are avoided if the BP is >185/100 mm Hg28.  In acute heart failure use intravenous Nitroglycerin and intravenous Enalaprilat. Give vasodilators (besides diuretics) when SBP is 140 mm Hg28.  

Cocaine toxicity/Pheochromocytoma

Diazepam, Phentolamine and Nitroglycerin/Nitroprusside are the preferred drugs. In cocaine toxicity, tachycardia and hypertension rarely require specific treatment. Phentolamine is proper for cocaine-associated acute coronary syndromes. In pheochromocytoma, beta blockers can be added after alpha blockade for BP control29.  

Pre-eclampsia/eclampsia

The proper medications are Hydralazine, Nifedipine and Labetalol however avoid Nitroprusside, Esmolol and angiotensin-converting enzyme inhibitors. The BP should be <160/110 mm Hg in the antepartum period and during delivery. The BP should be maintained below 150/100 mm Hg if the platelet count is less than 100,000 cells mm3. Intravenous Magnesium Sulphate should also be used to prevent seizures30.  

Perioperative hypertension

Nitroprusside, Nitroglycerin and Esmolol are used. Target the perioperative BP to within 20% of the patient's baseline pressure. Perioperative beta blockers are best to use in patients undergoing vascular procedures or at risk of cardiac complications28.  

CONCLUSION

Perioperative hypertension commonly occurs in patients undergoing surgery. The permitted value is based on the patient’s preoperative BP. It is approximately 10% above that baseline however more reduction in BP may be warranted for patients at high risk of bleeding or with severe cardiac problems. Accurate adjustment of treatment and monitoring of patient’s response to therapy are essential to safe and effective management of perioperative hypertension.  

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MOHAMED A DAABISS, MD, Consultant Anaesthesiologist, Department of Anaesthesia, Pharos University, Alexandria, Egypt.
Corresponding Author Details: 
DR MOHAMED A DAABISS, Department of Anaesthesia, Pharos University, Canal El Mahmoudia Street, Alexandria, Egypt.
Corresponding Author Email: 
madaabiss@yahoo.com
References
References: 
  1. Varon J. Treatment of acute severe hypertension: current and newer agents. Drugs 2008;     68(3):283-97.
  2. Awad AS, Goldberg ME. Role of clevidipine butyrate in the treatment of acute hypertension in the critical care setting: a review. Vasc Health Risk Manag 2010; 6:457-64.
  3. Kaplan NM: Treatment of Hypertensive Emergencies and Urgencies. Heart Dis Stroke 1992; 1:373-8.
  4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003; 289(19):2560-71.
  5. Prisant LM, Carr AA, Hawkins DW. Treating Hypertensive Emergencies. Controlled Reduction of Blood Pressure and Protection of Target Organs. Postgrad Med 1993; 93:92-6, 101-4, 108-10.
  6. Varon J, Polansky M. Hypertensive Crises: Recognition and Management. http://www.uam.es/departamentos/medicina/anesnet/journals/ija/vol1n1/articles/htncrise.htm.
  7. Ault MJ, Ellrodt AG. Pathophysiological Events Leading to the End-Organ Effects of Acute Hypertension. Am J Emer Med; 1985; 3(6):10-5.
  8. Reich DL, Bennett-Guerrero E, Bodian CA, Hossain S, Winfree W, Krol M. Intraoperative tachycardia and hypertension are independently associated with adverse outcome in noncardiac surgery of long duration. Anesth Analg 2002; 95:273–7.
  9. Erstad BL, Barletta JF. Treatment of hypertension in the perioperative patient. Ann Pharmacother. 2000; 34:66–79. 
  10. Wongprasartsuk P, Sear JW. Anaesthesia and isolated systolic hypertension: pathophysiology and anaesthesia risk. Anaesth Intensive Care 2003; 31:619–28.
  11. Paix AD, Runciman WB, Horan BF, Chapman MJ, Currie M. Crisis management during anaesthesia: hypertension. Qual Saf Health Care 2005; 14:e12-8.
  12. Varon J, Marik PE. Clinical review: the management of hypertensive crises. Crit Care 2003; 7(5):374-84.
  13. Saguner AM, Dür S, Perrig M, Schiemann U, Stuck AE, Bürgi U, et al. Risk factors promoting hypertensive crises: evidence from a longitudinal study. Am J Hypertens 2010; 23(7):775-80.
  14. Levy JH. The ideal agent for perioperative hypertension and potential cytoprotective effects. Acta Anaesthesiol Scand Suppl. 1993; 99:20–5.
  15. Polly DM, Paciullo CA, Hatfield CJ. Management of hypertensive emergency and urgency. Adv Emerg Nurs J. 2011; 33(2):127-36.
  16. Flanigan JS, Vitberg D. Hypertensive emergency and severe hypertension: what to treat, who to treat, and how to treat. Med Clin North Am 2006; 90(3):439-51.
  17. Weiss SJ, Longnecker DE. Perioperative hypertension: an overview. Coron Artery Dis. 1993; 4:401–6.
  18. Goldberg ME, Larijani GE. Perioperative hypertension. Pharmacotherapy. 1998; 18(5):911-4.
  19. De Gaudio AR, Chelazzi C, Villa G, Cavaliere F. Acute severe arterial hypertension: therapeutic options. Curr Drug Targets 2009; 10(8):788-98.
  20. Rodriguez MA, Kumar SK, De Caro M. Hypertensive crisis. Cardiol Rev 2010; 18(2):102-7.
  21. Fromm RE, Varon J. Cardiovascular Disorders in the ICU. In: Varon J (Ed.): Practical Guide to the Care of the Critically Ill Patient. St. Louis: Mosby-Year Book, Inc. 1994:64-94.
  22. Pearce CJ, Wallin JD. Labetalol and other agents that block both alpha- and beta-adrenergic receptors. Cleve Clin J Med. 1994; 61(1):59-69.
  23. Bodmann KF, Tröster S, Clemens R, Schuster HP. Hemodynamic profile of intravenous fenoldopam in patients with hypertensive crisis. Clin Investig. 1993; 72:60–4.
  24. Aronson S, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb PD, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008; 107(4):1110-21.
  25. Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008; 7(5):391-9.
  26. Anderson CS, Huang Y, Arima H, Heeley E, Skulina C, Parsons MW, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT). Stroke. 2010; 41(2):307-12.
  27. Cheung AT, Hobson RW. Hypertension in vascular surgery: aortic dissection and carotid revascularization. Ann Emerg Med. 2008; 51(3 Suppl):S28-33. 
  28. Diercks DB, Ohman EM. Hypertension with acute coronary syndrome and heart failure. Ann Emerg Med. 2008; 51(3 Suppl):S34-6.
  29. Hollander JE. Cocaine intoxication and hypertension. Ann Emerg Med. 2008; 51(3 Suppl):S18-20.
  30. Barton JR. Hypertension in pregnancy. Ann Emerg Med. 2008; 51(3 Suppl):S16-7.

On the rise worlwide: Bed Bugs and Cimicosis

Authors
Sibylle Rahlenbeck, Jochen Utikal and Stephen Doggett
Article Citation and PDF Link
BJMP 2016;9(3):a921
Abstract / Summary
Abstract: 

After they became rare in developed nations over some 30-50 years ago, bed bugs have dramatically increased in incidenceand rapidly spread worldwide over the last two decades. Insecticide resistance along with an increase in travel and trade are thought to be the main contributing factors for the resurgence of this public health pest. Bed bugs are not only a hoteliers’ nightmare, but they have also conquered many a private home.

Keywords: 
bed bugs,inseciticides, bullae, hygiene, cimicosis

Introduction

Bed bugs belong to the family Cimicidae and there are two species involved in the modern resurgence; the Common bed bug, Cimex lectularius and the Tropical bed bug, Cimex hemipterus. They are wingless insects with an oval-flat shape that allows them to hide in narrow cracks and crevices. The adults are dark brown, 4-5mm long, becoming to around 10mm when fully blood-engorged. There are five smaller juvenile stages (nymphs) that are similar in appearance, although lighter in colour. All nymphs require a blood meal to moult to the next stage, and both adults also bloodfeed for nutrition, and egg development in the case of the female. Bed bugs are solely haematophagous ectoparasites. After feeding they return to a harbourage and do not remain on the host. The main hosts are humans, but pets, bats, and birds may act as secondary hosts.

Epidemiology

In the past, bed bugs were particularly an affliction of the poor. However, in the early part of the modern resurgence it was the tourist areas and the hospitality sector that were initially impacted.1-3 Today, bed bugs have conquered quite diverse locations, ranging from hospitals, hotels and homes, to trains, cruise ships, and even airplanes. Most commonly, bed bugs travel in comfort as stowaways in luggage, although they can be transferred via furnishing and other belongings, as well by spreading to adjoining properties. Unfortunately, exact figures on the occurrence of bed bugs are unknown, as there are no mandatory reporting requirements. Additionally, due to the stigma associated with bed bugs, many infestations are simply not reported.

During the day, the largely nocturnal bed bugs will crawl deep into crevices of bed frames and mattresses (Fig.1), or behind wallpaper, and floor moldings. Here they tend to lay their eggs, often several hundred during the female lifetime. Live bed bugs, shed nymphal skins, and dark excrement spots indicate an active infestation. At night they are attracted by carbon dioxide, heat and other host odours to a victim, from which they may take a blood meal every 3-5 days. The adult bugs can survive long periods of starvation, up to five months at 22oC or even longer at cooler temperatures. When a host is found, they insert their mouthparts into the skin, blood feeding for 5-10 minutes. When bed bugs are in large numbers, often lines of bites occur on the unfortunate victim and this sign is almost a sure indication of the presence of the insect. The bites tend to occur along the arms and legs, down the back and across the shoulders.4,5

There has been long speculation whether bed bugs can transmit diseases, and in fact more than 40 different pathogens have been implicated. This has included Hepatitis B and C viruses, Human Immunodeficiency Virus (HIV), and Coxiella burnetii (Q fever). Recently, research has indicated that bed bugs are capable of transmitting the agent of Chagas Disease, Trypanosoma cruzi,in the laboratory. However, to date there is not one piece of evidence that bed bugs have transmitted any pathogen to humans.4,6

Clinical Features

During the act of feeding, saliva is injected which contains a variety of anticoagulants as well as other proteins whose function has yet to be determined. Contrary to popular belief, there is no evidence that bed bugs inject an anaesthetic. One protein, Nitrophorin, is involved in the transport of nitric oxide into the wound. This results in local vasodilation that increases blood supply to the feeding insect. The same protein can also induce a sensitivity to the bite.6

The diagnosis of Cimicosis is via the clinical appearance of the bite reaction and confirmation of an actual bed bug infestation (Table 1).3,5 The most commonly affected body parts are those that are left uncovered during sleep (Fig. 2,3,4), notably the arms, shoulders and legs. In young children, the face and even the eyelids can be bitten. Rarely, however, armpits are bitten, which are often preferred by other insects and ticks (Table 2).

Table 1. Bed bug infestation
Bites on the body Wheals, 4-6cm in diameter, lines of bites
Any exposed body part
Often intense itching
Occasional central haemorrhage
Bed Sheet,
mattress
(clothing)
Small blood spots
Droppings (black dots)
Shed nymphal skins
Eggs, small (~1mm in length), white, oblong,
glued to the substrate
Space Pungent smell (mostly commonly noticed when an insect is squashed, or during the control program)
Table 2. Differential diagnosis of epidermatozoonoses
  Bite preference Pattern Itching Notes
Bed Bugs Any exposed parts of the body, arms, legs, face, torso In small infestations, bites will be random. In larger infestations, bite can occur in lines along the limbs and across the shoulder. Large wheals (up to 6cm across) may form, even some 14 days after the bite Often intense, especially in the morning, but can be variable between individuals Often associated with travel or used furniture
Fleas Exposed parts of the body, especially the legs Random, usually not grouped or in lines During the day Usually associated with pets
Mosquitoes Exposed skin, particularly legs and arms Random Variable between individuals Most commonly outdoors
Ticks Potentially anywhere on the body Erythema migrans with Lyme disease. Localised macules/papules at the bite site may occur Low / no Those who work or recreate in native forests are at greatest risk.
Itch Mites (Scabies, Sarcoptes scabiei) Forearms, inter digital, genital area Skin rashes, subcutaneous courses At night Most common in the elderly and infirmed
Harvest mites (Trombidiosis) Skin surfaces under tight clothing Red macules and wheals Severe itching Often occurs in gardens or meadows, most active during summer and autumn
Cheyletiellosis Arms and trunk, contact points with pets Polymorphic rash Variable Tends to be associated with pets
Bird mites All over Macular rash Variable itching Most commonly in homes as a result of birds roosting in roof cavities
Head Lice (Pediculosis) In the hair of the head Bar-shaped scratch effects with lichenification and hyper-pigmentation (Vagabond’s disease) Night and day, generally mild itching Most common in school aged children
Spiders, e.g. long-legged sac spiders Arms, face Necrotic lesion at bite site Immediate severe pain, no itching Uncommon

Figure 1: Typical appearance of bed bugs

Figure 2: Bites on the back, note the lines of bites common in moderate to large infestations

Figure 3: Bed bug bites on the arm, typical formation

Figure 4: Bed bug bites on the torso and arm

Figure 5: Bullae due to bed bug bites

Figure 6: Bed bugs, their droppings and eggs underneath a mattress

The degree of the bite reaction often depends on the level of prior exposure. With low level sensitization, individuals may develop a 1-2 cm wheal, with a small central haemorrhagic point. This haemorrhagic point can be recognized easily by diascopy. In contrast, a highly sensitized person will react immediately and may develop a wheal up to 15cm across (6 inches). If many bed bugs are present, an urticarial rash may develop as a result of the large number of bites and subsequent trauma to the area from scratching. On rare occasions, vesicles and bullae (Fig. 5) may form on the arms and legs. In the course of Cimicosis, papules that are extremely itchy may develop and can persist for several days to weeks. Due to the strong pruritus eczematous lesions, bacterial infections may occur, although this is extremely rare. There are case reports of systemic reactions such as anaphylaxis and asthma, although these are uncommon.

Through repeated exposure, some individuals may develop a tolerance to the bites. The clinical symptoms are then largely inapparent with small punctures at the bite site. Small blood spots are then the only clues that an infestation may be present.

Differential Diagnosis

Since reactions to stings and bites of various arthropods are non-specific, bed bug bites are commonly misdiagnosed. Single bites, notably that of other insects such as mosquitoes, fleas and biting midges may appear very similar morphologically (Table 2).

Consideration of where the bites are on the body can assist in the differential diagnosis. For bed bugs, lines of bites are very common in moderate to large infestations and this clinical picture is virtually unique amongst blood sucking arthropods. For the most part, the identification of the actual pest is required to confirm the diagnosis. Histologically, bed bug bites resemble perivascular eosinophilic infiltrates through the superficial and deep dermis, with minimal spongiosis.

Other possible diagnostic confounders can be various allergic reactions and other medical conditions such as urticaria, chickenpox, prurigo subacuta, and erythema multiforme.7,8 These do not show a central haemorrhagic point in the lesion which allows a correct diagnosis. However, in young children the diagnosis can sometimes be difficult. 

Treatment

The treatment of Cimicosis is symptomatic. Local lesions can be treated with antipruritics e.g. Polidocanol 2-4% in Lotio alba (aqueous lotion) and topical antiseptic. Spirit of menthol may also be helpful. Local treatment with antihistamines is controversial. In severe reactions topical glucocorticoids such as Betamethasone may be required. In severe itching, the use of oral antihistamines is recommended. With infected bites, antibiotic therapy may be required. Uncomplicated bed bug bites tend to stop itching within 1-2 weeks, although temporary scarring from the bite may remain for several months.

Management

Treatment of patients with bed bug bites ultimately comes down to removing the source of the irritant, namely the eradication of the active infestation. Bed bugs have a typical pungent odor. This can be used to detect bed bugs through specially trained sniffer dogs that can rapidly locate the insects.9 Due to insecticide resistance, bed bugs are very difficult to control with traditional insecticides alone, and non-chemical means of eradication must be employed to reduce the overall insect biomass. Bed bug control should be undertaken by professionals trained in bed bug management, and the process may take some weeks to achieve.

Prevention

When travelling (1) always inspect the bed and surrounds for bed bugs hiding beneath the mattress and/or in seams of the bedding. Also, look for blood stains or small black dots (Figure 6, Table 1). (2) If present, request another room. (3) Always keep your luggage on the desktop or the luggage rack. A good preventative is to seal luggage in plastic or garbage bags during travelling, even when in transit. (4) When returning home, all clothing should be washed in at temperatures exceeding 60°C or frozen for one week with delicate fabrics. If there is no choice, then repellents containing N, N-Diethyl-meta-toluamide (DEET) should reduce the biting rate, but will not completely prevent all bed bug bites.10,11

Bed bugs can enter homes via an array of additional ways, particularly from objects bought second hand at flea markets or thrift stores, for example wooden frames, vintage clothes, furniture and the like. These should be heat-treated for a minimum of 10-20 minutes to kill bugs and their eggs.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SIBYLLE RAHLENBECK, MD, MPH, Consultant in Public Health, Berlin, Germany. JOCHEN UTIKAL, MD, Dermatologist, Dep. of Dermatology, Venereology and Allergology, University Medical Center Mannheim and German Cancer Research Center Heidelberg Germany. STEPHEN DOGGETT, Dr. Sc, Dep. Medical Entomology, Westmead Hospital, Locked Bag 9001, Sydney, NSW 2145, Australia.
Corresponding Author Details: 
Sibylle Rahlenbeck, MD, MPH, Consultant in Public Health, Berlin, Germany.
Corresponding Author Email: 
rahlenbeck@hotmail.com
References
References: 
  1. Cooper R, Wang C, Singh N. Mark-release-recapture reveals extensive movement of bed bugs (Cimex lectularius L.) within and between apartments. PLoS One 10(9), e0136462.doin:10.1371/journal.pone.0136462
  2. Bernadeschi C, Le Cleach L, Delaunay P, Chosidow O. Bed bug infestation. BMJ 2013;346:f138doi: http://dx.doi.org/10.1136/bmj
  3. Kolb A, Needham GR, Neyman KM, High WA. Bedbugs. Dermatol 2009;22:347-52. doi: 10.1111/j.1529-8019.2009.01246.x.
  4. Doggett SL, Dwyer De, Penas P, Russell R. Bed bugs: clinical relevance and control options. Clin Microbiol Rev 2012; 25:164-92 doi: 10.1128/CMR.05015-11
  5. Goddard J & deShazo R. Bed bugs (Cimex lectularius) and clinical consequences of their bites. JAMA 2009;301:1358-66
  6. Salazar R, Castillo-Neyra R, Tustin AW, Borrini-Mayorí K, Náquira C, Levy MZ. Bed bugs (Cimex lectularius) as vectors of Trypanosoma cruzi.Am J Trop Med Hyg 2015 Feb;92(2):331-5. doi: 10.4269/ajtmh.14-0483
  7. Scarupa MD, Economides A. Bedbug bites masquerading as urticaria. J Allergy Clin Immunol 2006;117(6):1508-9
  8. Braun-Falco’ s Dermatology, 6th edition; Burgdorf W.H.C., Plewig G., Wolff H.H., Landthaler M. (Eds.). Springer Berlin Heidelberg, 2012; ISBN 978-3-642-24162-8 
  9. Vaidyanathan R & Feldlaufer MF. Bed bug detection, current technologies and future directions. Am J Trop Hyg 2013;88:619-25. doi: 10.4269/ajtmh.12-0493
  10. Todd RG, 2011. Repellents for Protection from Bed Bugs: The Need, the Candidates, Safety Challenges, Test Methods, and the Chance of Success. IN: G. Paluch & J.Coats (eds): Recent Developments in Invertebrate Repellents. Merican Cehmical Soc., Washington, DC, 2011
  11. Wang C, Lü L, Zhang A, Liu C. Repellency of selected chemicals against the bed bug (Hemiptera: Cimicidae). J Econ Entomol 2013;106:2522-9

Striae distensae: What’s new at the horizon?

Authors
Mohammad Abid Keen
Article Citation and PDF Link
BJMP 2016;9(3):a919
Abstract / Summary
Abstract: 

Striae distensae, commonly known as stretch marks, are benign skin lesions associated with considerable cosmetic morbidity. Despite considerable investigations into their origins, the pathogenesis of striae distensae remains unknown.Currently, there is no treatment which consistently improves the appearance of striae. With a high incidence and unsatisfactory treatments, stretch marks remain an important target of research for an optimum consensus of treatment. The aim of present article is to appraise the readers with various newer treatment options in the management of this difficult condition.

Keywords: 
Striae distensae, stretch marks, cosmetic

Introduction

Striae distensae, or stretch marks, are linear scars in the dermis which arise from rapid stretching of the skin over weakened connective tissue. It is a common skin condition that rarely causes any significant medical problems but is often a significant source of distress to those affected. Striae distensae were described as a clinical entity hundreds of years ago, and the first histological descriptions appeared in the medical literature in 1889.1 With a high incidence and unsatisfactory treatments, stretch marks remain an important target of research for an optimum consensus of treatment. These appear initially as red, and later, as white lines on the skin, representing scars of the dermis, and are characterized by linear bundles of collagen lying parallel to the surface of the skin, as well as eventual loss of collagen and elastin. The estimated prevalence of striae distensae range from 50 to 80%.2,3 The anatomical sites affected vary, with areas commonly affected including the abdomen, breasts, thighs and buttocks.4 The three maturation stages of striae include the acute stage (striae rubra) characterized by raised, erythematous striae, the sub-acute stage characterized by purpuric striae, and the chronic stage (striae alba), characterized by white or hypo-pigmented, atrophied striae.5 Although stretch marks are only harmful in extreme cases, even mild stretch marks can cause distress to the bearer6 (Table 1).

Table 1: Histological comparisons between striae rubrae and striae albae

Epidermis Oedema
Increased melanocytes
Epidermal atrophy
Loss of rete ridges
Decreased melanocytes
Papillary dermis Dilatation of blood vessels No vascular reaction
Reticular dermis Structural alteration of collagen fibres
Reduced and reorganized elastic fibres
Fine elastic fibres in dermis
Densely packed collagen parallel to skin surface.
Thick elastic fibres in dermis
Inflammatory cells Lymphocytes and fibroblasts Eosinophills

Aetiology

Striae may result from a number of causes, including, but not limited to, rapid changes in weight, adolescent growth spurts, corticosteroid use or Cushing Syndrome, and generally appear on the buttocks, thighs, knees, calves, or lumbosacral area.7 In addition, approximately 90% of all pregnant women develop stretch marks either on their breasts and/or abdomen by the third trimester.8 Genetic predisposition is also presumed, since striae distensae have been reported in monozygotic twins.9,10 There is decreased expression of collagen and fibronectin genes in affected tissue.11 The role of genetic factors is further emphasised by the fact that they are common in inherited defects of connective tissue, as in Marfan’s syndrome.12,13 Obesity and rapid increase or decrease in weight have been shown to be associated with the development of SD.14 Young male weight lifters develop striae on their shoulders.15 Striae distensae also occurs in cachetic states, such as tuberculosis, typhoid and after intense slimming diets.16 Rare etiologies include human immunodeficiency virus positive patients receiving the protease inhibitor indinavir and chronic liver disease.13,15 A case of idiopathic striae was also reported.17

Rosenthal18 proposed four aetiological mechanisms of striae formation: insufficient development of tegument, including elastic properties deficiency; rapid stretching of the skin; endocrinal changes; and other causes, possibly toxic.

Pathogenesis

The pathogenesis of striae is unknown but probably relates to changes in the components of extracellular matrix, including fibrillin, elastin and collagen.19 There has been emphasis on the effects of skin stretching in the pathogenesis of striae because the lesions are perpendicular to the direction of skin tension.20 A possible role of glucocorticoids in the pathogenesis of striae has been suggested because of an increase in the levels of steroid hormones and other metabolites found in patients exhibiting striae.21 There are studies suggesting the role of fibroblasts in the pathogenesis of striae. Compared to normal fibroblasts, expression of fibronectin and both type I and type III procollagen were found to be significantly reduced in fibroblasts from striae, suggesting that there exists a fundamental aberration of fibroblast metabolism in striae distensae.22

Pathological aspects

The earliest pathological changes are subclinical to be detected by electron microscopy only. These changes include mast cell degranulation and the presence of activated macrophages in association with mid-dermal elastolysis.23 When the lesions become become clinically visible, collagen bundles start showing structural alterations, fibroblasts become prominent, and mast cells are absent.23 On light microscopic examination, Inflammatory changes are conspicuous in the early stage, with dermal oedema and perivascular lymphocytic cuffing.24 In later stages, there is epidermal atrophy, loss of rete ridges and other appendages including hair follicles are absent.25

Evaluation of striae distensae

Approaches to evaluating SD severity visually include the Davey 26 and Atwal scores,27 although these have not been validated specifically for SD. An objective evaluation of SD may be carried out using skin topography, imaging devices including three-dimensional (3D) cameras, reflectance confocal microscopy and epiluminescence colorimetry.28,29,30

Table 2: Visual scoring systems for the assessment of striae distensae

Davey method Used for evaluating striae rubrae and albae.
Divide the abdomen into quadrants using midline vertical and horizontal lines.
Each quadrant given a score (0 no SD; 1 moderate number of SD; 2 many SD).
Score given out of 8.
Atwal score Used for evaluating striae rubrae and albae.
Six sites chosen (abdomen, hips, breasts, thigh/buttocks).
Each site given a maximum score of six.
Total score out of 24.
Score 0–3 for the presence of striae (0 no SD; 1 < 5 SD; 2 5–10 SD; 3 > 10 SD).
Score 0–3 for the presence of erythema (0 no erythema; 1 light red/pink; 2 dark red; 3 purple).

Management

Striae distensae (striae alba) is a very challenging cosmetic problem for dermatologists to treat. Various modalities of treatment have been tried. Although therapeutic strategies are numerous, there is no treatment which consistently improves the appearance of striae and is safe for all skin types.31 Weight loss by diet alone or a combination of diet and exercise do not change the degree of striae distensae.32

Topical treatments

Topical tretinoin (0.1%) ameliorates striae and the improvement may persist for almost a year after discontinuation of therapy.33 More recently, tretinoin has been shown to improve the clinical appearance of stretch marks during the active stage (striae rubra), although with not much effect during the mature stage (striae alba).34 Some of the studies have proven the inefficacy of the vitamin A derivative in the treatment of SD, but most of the patients included in these early studies presented with old lesions that had evolved into whitish atrophic scars.35 A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.36

Hydrant Creams: 1) Trofolastin (a cream containing Centella asiatica extract, vitamin E, and collagen-elastin hydrolysates). The exact mechanism of action was identified as the stimulation of fibroblastic activity 37 and an antagonistic effect against glucocorticoids.38 2) Verum (a cream containing vitamin E, panthenol, hyaluronic acid, elastin and menthol). The results suggest that the product may show the benefit of massage alone.39 3) Alphastria (a cream composed of hyaluronic acid, allantoin, vitamin A, vitamin E, and dexpanthenol). Only one study was conducted, which concluded that the product markedly lowered the incidence of stretch mark development after pregnancy.40

Glycolic acid (GA): The exact mechanism of action of GA in the management of striae distensae is still unknown because, although GA is reported to stimulate collagen production by fibroblasts and to increase their proliferation in vivo and in vitro, which may be useful for the treatment of stretch marks.41,42 A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.43

Trichloroacetic acid (TCA; 10–35%): It has been used for many years as a treatment option for striae distensae and is repeated at monthly intervals with reported improvement in texture and color of marks.44

Other topical products: Several oils have been used in the prevention of SD. A non-randomized, comparative study investigated the effect of almond oil in the prevention of SD in which they noted significant differences in the frequency of SD between the groups (almond oil and massage 20%, almond oil alone 38.8%, control 41.2%).45

Overall, there is limited evidence for the efficacy of topical therapy for the treatment of SD.

Microdermabrasion

Microdermabrasion may improve many skin problems including acne scars, skin texture irregularities, mottled pigmentation and fine wrinkles. Karimipour et al reported that microdermabrasion induces epidermal signal transduction pathways associated with remodelling of the dermal matrix.46 However, studies documenting the efficacy of rnicrodermabrasion in treatment of striae are lacking. Published in 1999, a book on microdermasion written by a French dermatologist, Francois Mahuzier, and translated to English, has a chapter "Microdermabrasion of stretch marks.47 The author states that 10-20 sessions of microdermabrasion at an interval of not less than 1 month, each session resulting in bleeding points, provide satisfactory results. The author concludes that, "microdermabrasion is the only effective treatment of stretch marks today."

Lasers

Lasers have recently become a popular therapeutic alternative to ameliorate and improve the appearance of stretch marks. Most commonly used lasers used include pulsed-dye laser (PDL), short- pulse carbon dioxide and erbium-substituted yttrium aluminium garnet (YAG), neodymium- doped YAG (Nd:YAG), diode, and Fraxel.

Pulsed dye laser: The dilated blood vessels render the striae rubrae a good candidate for PDL.48 The 585- nm pulsed dye laser has a moderate beneficial effect in the treatment of striae rubra.49 To evaluate the effectiveness of the 585-nm flashlamp-pumped pulse dye laser in treating cutaneous striae, 39 striae were treated with four treatment protocols.50 Subjectively, striae appeared to return toward the appearance of normal skin with all protocols. Objectively, shadow profilometry revealed that all treatment protocols reduced skin shadowing in striae. Laser treatment of SD should be avoided or used with great caution in darker skin types (IV–VI), because of the possibility of pigmentary alterations after treatment.51

Excimer laser: Studies have shown temporary repigmentation and improvement of leukoderma in SD with excimer laser, although it failed to show any improvement in skin atrophy.52,53 To evaluate the true efficacy of the 308-nm excimer laser for darkening striae alba, 10 subjects were treated using the excimer laser on the white lines of striae, while the normal skin near to and between the lines was covered with zinc oxide cream. The results of this study showed the weakly positive effect of the 308-nm excimer laser in the repigmentation of striae alba.54

Copper Bromide laser: copper-bromide laser (577-511 nm) has been used for stretch marks. A clinical study was conducted in 15 Italian women with stretch marks, treated with the CuBr laser (577-511 nm) and followed-up for 2 years.55 The results of the study concluded that the copper-bromide laser was effective in decreasing the size of the SD and there were some pathogenic considerations that justified the use of this laser.

1,450-nm Diode Laser: The non-ablative 1,450-nm diode laser has been shown to improve atrophic scars and may be expected to improve striae. To evaluate the efficacy of the 1,450-nm diode laser in the treatment of striae rubra and striae alba in Asian patients with skin types 4-6, striae on one half of the body in 11 patients were treated with the 1,450-nm diode laser with cryogen cooling spray with the other half serving as a control.56 None of the patients showed any noticeable improvement in the striae on the treated side compared to baseline and to the control areas. The study concluded that the non-ablative 1,450-nm diode laser is not useful in the treatment of striae in patients with skin types 4, 5, and 6.

1,064-nm Nd:YAG Laser: A study was aimed to verify the efficacy of this laser in the treatment of immature striae in which 20 patients with striae rubra were treated using the 1,064-nm long-pulsed Nd:YAG laser.57 A higher number of patients (55%) considered the results excellent when compared to the same assessment made by the doctor (40%).

Intense Pulsed Light: In order to assess the efficacy of IPL in the treatment of striae distensae, a prospective study was carried out in 15 women, all of them having late stage striae distensae of the abdomen.58 All the study subjects showed clinical and microscopical improvement after IPL. It seems to be a promising method of treatment for this common problem with minimal side-effects, a wide safety margin and no downtime.

Fractional Photothermolysis: To determine the efficacy of fractional photothermolysis in striae distensae, 22 women with striae distensae were treated with two sessions each of fractional photothermolysis at a pulse energy of 30 mJ, a density level of 6, and eight passes at intervals of 4 weeks and response to treatment was assessed by comparing pre- and post-treatment clinical photography and skin biopsy samples.59 Six of the 22 patients (27%) showed good to excellent clinical improvement from baseline, whereas the other 16 (63%) showed various degrees of improvement. This study concluded that Fractional photothermolysis may be effective in treating striae distensae, without significant side effects.

Ablative 10,600-nm carbon dioxide fractitional laser: Ablative 10,600-nm carbon dioxide fractional laser systems (CO₂ FS) have been used successfully for the treatment of various types of scars. To assess the therapeutic efficacy of CO₂ FS for the treatment of striae distensae, 27 women with striae distensae were treated in a single session with a CO₂ FS and clinical improvement was assessed by comparing pre- and post-treatment clinical photographs and participant satisfaction rates.60 The evaluation of clinical results 3 months after treatment showed that two of the 27 participants (7.4%) had grade clinical 4 improvement, 14 (51.9%) had grade 3 improvement, nine (33.3%) had grade 2 improvement, and two (7.4%) had grade 1 improvement. None of the participants showed worsening of their striae distensae.To assess and compare the efficacy and safety of nonablative fractional photothermolysis and ablative CO(2) fractional laser resurfacing in the treatment of striae distensae, 24 ethnic South Korean patients with varying degrees of atrophic striae alba in the abdomen were enrolled in a randomized blind split study and were treated with 1,550 nm fractional Er:Glass laser and ablative fractional CO(2) laser resurfacing.61 These results of the study support the use of nonablative fractional laser and ablative CO(2) fractional laser as effective and safe treatment modalities for striae distensae of Asian skin with neither treatment showing any greater clinical improvement than the other treatment.

UVB/UVA1 Combined Therapy: Besides lasers, light sources emitting ultraviolet B (UVB) irradiation have been shown to repigment striae distensae. A study was conducted on 9 patients with mature striae alba who received 10 treatment sessions, and biopsies were taken at the baseline and end of the study.62 At the end of the study, all patients reported some form of hyperpigmentation that was transient and did not affect any surrounding tissues. No changes were seen on biopsy to indicate an effective remodelling collagen effect of the device, although it needs further assessment. Another study was conducted to analyse the histologic and ultrastuctural changes seen after UVB laser- or light source-induced repigmentation of striae distensae in which analyses of biopsied skin after treatment with both the UVB laser and light source showed increased melanin content, hypertrophy of melanocytes, and an increase in the number of melanocytes in all patients.63

Radiofrequency devices: RF devices are based on the principle of heat generation that occurs in response to poor electrical conductance according to Ohm’s law (heat generation is directly correlated with tissue resistance). The heat that is generated is sufficient to cause thermal damage to the surrounding connective tissue,64 which is responsible for the partial denaturation of pre-existing elastic fibers and collagen bundles.65 Initial collagen denaturation within thermally modified deep tissue is thought to represent the mechanism for immediate tissue contraction; subsequent neocollagenesis further tightens the dermal tissue and reduces striae.66 The efficacy and safety of combination therapy with fractionated microneedle radiofrequency (RF) and fractional carbon dioxide (CO2) laser in the treatment of striae distensae has been evaluated revealing that this combination therapy is a safe treatment protocol with a positive therapeutic effect on striae distensae.67 A recent study evaluating the effectiveness of a RF device in combination with PDL subjected 37 Asian patients with darker skin tone with SD to a baseline treatment with a RF device and PDL.68 All histological evaluations demonstrated an increase in the amount of collagen fibers, and six of the nine specimens showed an increase in the number of elastic fibers.TriPollar RF device appears to be a promising alternative for the treatment of striae distensae in skin phototypes IV-V.69

Needling therapy:

To evaluate the effectiveness and safety of a disk microneedle therapy system (DTS) in the treatment of striae distensae, 16 Korean volunteers with striae distensae alba or rubra were enrolled which received three treatments using a DTS at 4-week intervals.70 Marked to excellent improvement was noted in seven (43.8%) patients, with minimal to moderate improvement in the remaining nine. This study revealed that Disk microneedle therapy system (DTS) can be effectively and safely used in the treatment of striae distensae without any significant side effects. Another study assessed and compared the efficacy and safety of needling therapy versus CO2 fractional laser in treatment of striae and the results supported the use of microneedle therapy over CO2 lasers for striae treatment.71

Platelet-rich plasma:

Platelet-rich plasma has these wound-healing properties, affecting endothelial cells, erythrocytes, and collagen,72 which potentially aids in the healing of the localized chronic inflammation believed to be a factor in the aetiology of striae distensae. Platelet-rich plasma is well tolerated by the patients and is a safe and cost effective treatment option for striae distensae.

Platelet-rich plasma alone is more effective than microdermabrasion alone in the treatment of striae distensae, but it is better to use the combination of both for more and rapid efficacy.73

The plasma fractional radiofrequency and transepidermal delivery of platelet-rich plasma using ultrasound has also been found to be useful in the treatment of striae distensae.74

Since thermal damage from intradermal RF has characteristics similar to those of many wounds, combination treatment with intradermal RF and autologous PRP would eventuate in enhanced localized collagen neogenesis and redistribution. In one of the studies, three sessions of intradermal RF were used combined with autologous PRP administered once every four weeks.75 All of the participants showed satisfactory changes and no patient was reported to show no improvement.

Transepidermal retinoic acid:

Transepidermal retinoic acid delivery using ablative fractional radiofrequency associated with acoustic pressure ultrasound has also been used for the treatment of stretch marks.76

Conclusion

Striae distensae are an extremely common, therapeutically challenging form of dermal scarring. Adequate scientific knowledge and the evidence behind both preventative and therapeutic agents are vital in order to understand striae and to offer patients the best therapeutic options. The treatment of this cosmetically distressing condition has been disappointing and there is no widely accepted surgical procedure for improving the appearance of stretch marks. Laser therapy has been advocated as a treatment for striae distensae.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MOHAMMAD ABID KEEN (MBBS, MD DERMATOLOGY, STD and LEPROSY), Senior Resident, Postgraduate Department of Dermatology, STD and Leprosy, Government Medical College and Associated SMHS Hospital Srinagar.
Corresponding Author Details: 
DR MOHAMMAD ABID KEEN (MBBS, MD DERMATOLOGY, STD and LEPROSY), Senior Resident, Postgraduate Department of Dermatology, STD and Leprosy, Government Medical College and Associated SMHS Hospital Srinagar., Jammu & Kashmir, Pin code: 190010
Corresponding Author Email: 
keenabid31@gmail.com
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Pharmacological and Non-Pharmacological Interventions for Persistent Auditory Hallucinations in Schizophrenia

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2016;9(2):a914
Abstract / Summary
Abstract: 

Refractory auditory hallucinations warrant evidence-based pharmacological and non-pharmacological treatment strategies. The current psychotropic medications have only modest anti-hallucinatory effect and the efficacy of non-pharmacological therapies is not well established. While clozapine seems to have the maximum anti-hallucinatory effect, some patients remain super-refractory even to clozapine treatment. Thus, going forward research should focus on the discovery of a derivative of clozapine that is free from the haematological side-effects, as this could lead to remarkable advancements in the treatment of schizophrenia. Recent years have witnessed an interest in the development of various forms of non-pharmacological approaches to addressing this problem alongside pharmacotherapy. Pharmacotherapy alone may not be the answer to refractory auditory hallucinations and a greater spectrum of non-pharmacological therapies is clearly needed. In this work, different forms of non-pharmacological therapies are reviewed, including CBT, which has gained popularity as a psychological intervention and an efficacious form of voice therapy. Antipsychotics are also reviewed, revealing that, despite having only modest anti-hallucinatory properties, they are essential for reducing the psychic pain and correcting the underlying psychotic process.

Keywords: 
Schizophrenia, hallucinations, clozapine, voice therapies, rTMS

Schizophrenia sufferers feel like abstract entities with non-animated bodies, often experiencing auditory verbal hallucinations (AVH) due to morbid “objectification” of inner dialogue.1 From the patient’s perspective, AVHs are a subjective–objective phenomenon. AVH is a non-consensual, dynamic and psychologically charged experience and the voices often echo significant emotions. Derogatory voices are common representations of unconscious self-hatred that cannot stand up to the external world’s logic. Thus, patients need help to incorporate it. Auditory hallucinations may be arising because of an interaction between biological predisposition, perceptual and cognitive factors. According to an integrated model of auditory hallucination (AHs) suggested by Waters et al,2 AHs arise from an interaction between abnormal neural activation patterns that generate salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories. Recently, neuro-quantologists have proposed that AVHs may be an objectification of parallel thinking/quantum thinking.3 Parallel thinking is a source for thought insertion. There may be different variables of AVHs. Experiencing AVH has serious impact on the quality of life of the affected individual, and is a significant factor in prevalence of suicides among schizophrenic patients.4

Incidence

One in four schizophrenia sufferers experiences persistent AVH .5 AVHs are experienced by approximately 53% of schizophrenia sufferers 6 and are present in 28% of major affective disorders (Goodwin& Jamison, . 7 Evidence indicates that each patient responds differently to the voices, according to his/her evaluation of them (Table 1), which influences the degree of interventions. Specific dimensions of AVHs can give hints to the future likelihood of treatment resistance. Although the percentages differ in various studies, it is assumed that about 30% of patients have command hallucinations and they are seen as the ultimate betrayal of the mind. 8 Often, the content of such messages is negative; thus, commanding AVHs are more distressing than commenting ones. Schizophrenia predisposes them to a greater risk of suicides and homicides. Command hallucinations are more prevalent among forensic patients and contribute to their forensic status.

Table1. Patients’ Response to AVH

1.Anxiety and panic feelings
2.Fear
3.Feelings of humiliation
4.Entrapment
5.Self harm thoughts
6.Harm to others
7. Avoidant or withdrawn
8.Shouting and swearing
9.Ritualistic behaviour
10. Substance or alcohol abuse
11. Resistance.
12. Amusements
13. Engagement and courting the voices
14. Appeasement

The multi-factorial polygenic model of schizophrenic disorders has received great support and signifies that genetic factors play a bigger role than environmental factors in familial transmission of these disorders. Relevant studies provide little support for the mechanism of single major locus inheritance. A mechanism involving two, three, or four loci cannot be ruled out even though there is no compelling support for such models.9 It has also been proposed that a single gene may be even responsible for hallucinatory experiences 10 implying that those who have not inherited such a gene may not experience auditory hallucinations, but still could experience other characteristic symptoms of schizophrenia. One may also hypothesise that an individual who has inherited such a “hallucinatory gene” but not all the schizophrenia genes could hear non-clinical voices without having other schizophrenic symptoms. It is also arguable that those who carry such a specific gene are more vulnerable to experience hallucinations when they abuse psychoactive substances and could get misdiagnosed as having schizophrenia, but hallucinations may cease to occur once they abstain from illicit drug abuse.

Measurements for Assessment

AVH is a subjective experience and is hard to measure objectively. Several rating scales are now available for an efficient evaluation of different aspects of voice activities. Some are general and a number of them are specifically designed. Using rating scales facilitates better engagement with patients and helps in reinforcing the message that patients and the distress they experience are carefully considered.

Beliefs About Voice Questions (BAVQ) is an assessment scale useful in measuring the key beliefs about the voices.11 It is typically used in conjunction with the Cognitive Assessment Schedule (CAS).12 Voice Compliance Scale (VCS) is an observer rated scale aimed exclusively at measuring the frequency of command hallucinations and the level of obedience or confrontation with each recognized command.13 Voice Power Differential Scale (VPD) is another measure that can be applied to rate the perceived relative power differential between the voice and voice experience. 14 On the other hand, Omniscience Scale (OS) is intended to quantify the voice hearer’s beliefs about their voices’ knowledge regarding the bio data. 15 Another measure presently in use is Risk of Acting on Commands Scale (RACS), designed to assess the level of risk of acting on commands and the amount of associated distress. 16

The Bonn Scale (BSABS) is used for the assessment of basic symptoms, 17while the Schizophrenia Proneness Instrument (SPI-A) 18and the Examination of Anomalous Self Experience (EASE) 19 are useful aids in identifying minimal changes in subjective experience and for longitudinal monitoring (Table 2). In the extensively used Positive and Negative Syndrome Scale (PANSS), the hallucination item is one of seven in the positive subscale, which also includes delusions, conceptual disorganization, excitement, grandiosity, suspiciousness, and hostility. Given such a great number of scales in use, there is an obvious risk that differential anti-hallucinatory efficacy among antipsychotic drugs may be obscured by means of sum scores for the whole sample in clinical trials.

Table 2. Measurement scales

Beliefs About Voice Questions (BAVQ) Cognitive Assessment Schedule (CAS ).
Voice co Voice Power Differential Scale (VPD)
Voice Compliance scale (VCS)
Voice Power Differential Scale (VPD)
Omniscience Scale (OS)
Risk of Acting on Commands Scale (RACS)
Bonn Scale (BSABS)
Schizophrenia Proneness Instrument (SPI-A)
Examination of Anomalous Self Experience (EASE)
Positive and Negative Syndrome Scale(PANSS)

Treatments

Although many forms of treatments aiming to eliminate AVH or improve quality of life are available, use of medication seems to be the most prevalent. Besides drug treatment, non-invasive physical treatments, such as TMS and different forms of psychological interventions, have recently evolved. Drug therapies are aimed at symptom eradication, whereas psychological therapies tend to foster healing, recovery and personal growth. Rather than being specifically anti-hallucinatory, typically, neuroleptics offer a generalised calming effect and patients are given some “breathing space” to work through their voices. Usage of non-pharmacological tools is needed in the long-term management of refractory cases. Presently, intervention strategies for AVH are based on different models of hallucinations, but regrettably no clear models have been established.

Pharmacotherapy

The current understanding of AVH and the neural mechanisms involved is limited, and knowledge on how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations is inadequate. Consequently, using pharmacotherapy in the management of AVH remains very challenging. 20 Despite multiple trials of different combination and adjunctive therapies to an antipsychotic regime, AVH can remain drug resistant. It is also important to note that all antipsychotics are potentially anti-hallucinatory, even though these effects are usually modest. Moreover, given that, even when medications are effective, concordance can be an issue, antipsychotics should be used prudently and weighed up against effectiveness and side effects (Table 3). There are no clear guidelines for the drug treatment of AVH and comparisons of the efficacy of antipsychotics for AVHs are few. Clinical drug trials very rarely focus on single symptom scores, such as hallucinations, and tend to report group mean changes of overall psychopathology, or at best the positive subscale scores.

Evidences show that AVHs persist in spite of treatment in 32% of chronic patients 21 and 56% of acutely ill patients.22 Trifluperazine was popular as an anti-hallucinatory drug before the advent of atypical antipsychotic drugs. Clozapine is currently favoured for intractable AVHs and is beneficial in 30–60% of unresponsive patients.

Antipsychotic co-treatment is an option for clozapine augmentation. Olanzapine and risperidone may be alternative drugs in first episode psychosis. However, it is being debated whether clozapine should be used in such cases.

Table 3. Drug Treatment

Choice of antipsychotics
Cautions and contraindications
Titration of dose
Switching antipsychotics
Assessment of side effects, EPS, TD, Haematological effects etc.
Measuring the beneficial effects
Assess worsening of symptoms
Compliance

Clozapine

Use of clozapine is suggested only after two other antipsychotics have been tried. It works better with continued usage and clinicians have to be patient in its upward titration. At six months, improvement in Global Assessment of Functioning score is significantly higher for clozapine in comparison to other antipsychotic drugs.23 However, when prescribing clozapine, cautions and contraindications must be noted (Table 4).

While higher doses of clozapine may not have more anti-hallucinatory effect, they still carry the risk of inducing the potential side-effects of this highly efficacious drug (Table 5). The most dreaded haematological side-effects are usually manifested within six months. For that reason, during clozapine therapy, patient has to be closely monitored, bearing in mind its limitations in achieving the anti-hallucinatory effects. If higher doses do not have the desired effect, clozapine dose should be titrated downwards to a point of its maximum anti-hallucinatory effect in a particular patient. Such an endeavour can prevent the emergence of serious side-effects, resulting in a complete failure of the therapy. The dose can also be adjusted to a safer level in cases where the psychological interventions are found to be successful. Clozapine can be effective even in lower doses, such as 200 mg/day. Only in the presence of command hallucinations, higher doses should be prescribed to patients whose other positive symptoms are well under control.

Prophylaxis with an antiepileptic drugs, such as lamotrigine or sodium valproate, or similar should be commenced before titrating the dose above 600 mg daily. Close monitoring and active treatment of metabolic dysregulation should be initiated concurrent with clozapine therapy. In clozapine therapy, weighing up safety and superior antipsychotic efficacy and educating the patients on “clozapine lifestyle” is immensely important, as it helps in treating refractory cases of AVH. Thirty percent of patients treated with clozapine may remain unresponsive and clinicians have to lower their expectations to the level of achievement without being cynical. Isolated cases of clozapine-induced joint visual and auditory hallucinations have been reported. 24 In spite of Clozaril treatment having the highest anti-hallucinatory effect, a good percentage of AVH sufferers remain symptomatic and are classed as super-refractory.8 According to Gonzales (2006), 25 50% of patients receiving antipsychotics achieve full remission, while 25% hear voices occasionally and 25% are unresponsive.

Table 4. Cautions & Contraindications of Clozapine

1.Patients with myeloproliferative disorders, a history of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia / agranulocytosis from previous chemotherapy)
2.Bone marrow disorders
3-Patients with active liver disease, progressive liver disease and hepatic failure.
4-Severe CNS depression or comatose state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse,
5. Alcoholic/toxic psychosis and previous hypersensitivity to clozapine.
6.Pregnancy and breast feeding

Table 5. Benefits and risks of Clozapine

Benefits
1. Lower risk of suicide
2. Superior anti-delusional and anti-hallucinatory effects in refractory cases
3. Lower risk of tardive dyskinesia and suppression of TD.
4. Improvement in cognition
5.Higher quality of life and better adherence
6.Decreased relapse
7. Sexual functions unaffected
Risks
1.Agranulocytosis
2.Metabolic syndrome
3.Myocardites
4.Chronic constipation and bowel complications
5.Incresed risk of seizure
6.Hypersalivation
7.Abrupt withdrawal cause marked discontinuation symptoms.

Benzodiazepines are often abused by voice hearers aiming to reduce their anxiety. Such patients might benefit by the addition of antidepressant, as this could enhance their mental resources to cope with the voices, even though they have no anti-hallucinatory effects per se. Mood stabilisers are sometimes used to augment the efficacy of antipsychotics without any clinical validation. Despite multiple trials of different adjuvant therapies to an antipsychotic regimen, there have been few promising results. Still, in practice, clinicians may get frustrated, as they struggle to provide symptomatic relief to the voice hearers at any cost. Recently allopurinol, an anti-gout agent has been used as an adjunctive therapy and based on three randomized controlled trials, the result has been encouraging. 26

Psychological Interventions

Persistent AVHs alone may not warrant pointless alteration of medication, as non-pharmacological interventions may achieve some control. When clinicians are not cognizant of non-pharmacological therapies, AVH patients that do not respond to antipsychotics alone may be mislabelled as having refractory AVH. In fact, they are only unresponsive to drug treatment, and could potentially respond to an integrated approach. Similarly, patients with treatment-refractory AVH are often over-diagnosed as suffering from hard to treat schizophrenia, even when other positive symptoms have been ameliorated.

There exists a false dichotomy between physical and psychological treatment approaches to AVH. In practice, both treatment modalities have to be modified in a personalised form. After all, psychiatry was originally known as psychological medicine. Presently, even though different forms of non-pharmacological interventions are available for drug-resistant AVH, some have questionable effects. 27,28,29 (Table 6).

Table 6. Psychological Interventions

1.Cognitive behavioural therapy (C.B.T.)
2. Acceptance and commitment therapy (ACT)
3. Competitive memory training (COMET)
4.Compassionate Mind Training therapy (CMT)
5.Hallucinations focussed integrative therapy (HIT)
6.Midfulness-based therapy
7.Normalizing techniques
8. Enhanced supportive psychotherapy
9. Attention training technique.
10. Distraction techniques
11. Self help approaches

CBT therapists predicate that AVHs are a manifestation of the morbid objectification of inner dialogue (thinking in words),and accordingly verbalised thoughts are the raw material for AVHs.Verbal thinking differs from external speech in many respects and has several distinct features. CBT therapists believe that cognitive dysfunctions underlie AVH and they target them with cognitive remediation strategies. Those experiencing voices commonly think that they are caused by a powerful external agency, and are controlling and potentially harmful. Psychological factors, such as meta-cognitive biases, beliefs, and attributions concerning the origins and intent of voices, also play critical modulatory role in shaping the experience of AVH. Teaching patients to recognize the source of the voices alone has yielded beneficial effects.

Specific techniques have been designed to modify the frequency of AVHs and restore a sense of control over them. Earlier methods involved behavioural approaches based upon addressing hypothesized antecedents and reinforcers of voices and explored a variety of specific interventions such as relaxation training, graded exposure to voice triggers, manipulation of environmental possibilities and even aversion therapy. 30 These behavioural techniques were eventually expanded on by the application of cognitive methods. The primary aim of psychological therapy is to change the belief that voices are omnipotent and uncontrollable and to suppress the associated attributes of false identity, wrong intentions, and urges to harm oneself and others. They encourage patients to challenge irrational interpretations and modify maladaptive behaviour, diverting attention from voices with distraction techniques (Table 7).

Reality testing and behavioural experiments are one form of CBT intervention, based on the view that behavioural changes can prompt cognitive changes. Attention switching can also be used to challenge the belief that hallucinations are uncontrollable. Command AVHs are more prevalent among the forensic population and are more distressing than the commenting ones. The risk of the sufferer acting on them is high when voices are perceived as omnipotent and uncontrollable. CBT has been proven beneficial in tackling command hallucinations. Lack of insight and formal thought disorder may not necessarily disqualify CBT for AVH; nonetheless, negative symptoms may pose a barrier to this form of psychological intervention. The current model of CBT for psychosis has been criticized, suggesting that it is simply an extension of general CBT concepts without taking into account the specificities of psychosis. 31 Patients with higher intelligence, who have the ability to grasp abstract concepts, might gain greater benefits from CBT. 32

Table 7. Goals of CBT

1. Change false beliefs about AVH .
2. Challenge irrational interpretations.
3. Modify maladaptive behaviour – e.g. fear of the voices or hiding from them.
4. Divert attention, using distraction techniques.
5. Build and maintain treatment strategies
6.Develop cognitive behavioural strategies
7.Develop newer understanding of hallucinatory experience
8. Address negative self-evaluation.

Combining psycho-education and supportive psychotherapy has been found to enhance the functioning and self-esteem of voice hearers, providing a therapeutic structure. In the increasingly popular self-help voice-hearing groups, the ethos of recovery is understanding, accepting and integrating the sufferer’s turmoil. Acceptance and non-judgemental support of people with similar experiences has helped many patients cope with the condition. In response, the number of books on AVH, aiming to educate the sufferers and carers, has grown considerably.

Newer Psychological Interventions

Attention Training Technique (ATT) focuses on negating psychological distress through cognitive and meta-cognitive modification. 33,34 Patients focus on up to five neutral sounds, such as a dripping tap, before switching their attention between different sounds. They then practise listening to all the sounds simultaneously. After a few weeks, they focus on neutral sounds and then on the AVH. Once this process is mastered, they switch attention between voices and other sounds, before being asked to divide their attention among them. This exercise continues for several weeks, whereby the aim is to replace the self-regulatory process with new processing configurations.

Acceptance and commitment therapy (ACT) is aimed at achieving psychological flexibility. It incorporates mindfulness and acceptance, considering AVH as a private experience and asserting that patients experience distress only when they try to deafen the voices. . By reducing struggle with voices and engagement with them, key responses such as arousal, attention and activation of brain areas are hypothesised to be reduced. 35 The ideas behind ACT are consistent with the emphasis on the recovery movement of finding a way to live a valued life despite the ongoing problems. To this effect, unique and effective coping strategies are offered, whereby patients are given the insights that parts of the self are behind the voices. Thus, accepting them means sending a loving message of compassion, acceptance and respect to oneself Two randomised control studies have yielded promising results. 36,37ACT follows a set manualised structure, rather than relying upon the complex and lengthy process of belief modification: therapy can be much briefer and potentially practiced by a wider range of clinicians and cost effective. 38

There are verbal and non-verbal routes to emotions. As CBT uses the former in voice therapy, it is less effective when patients are negatively involved with the voices. On the other hand, Competitive Memory Training (COMET) uses the non-verbal route. Generally COMET sessions involve four stages.39 A. identification of aspects of negative self-esteem reinforced by the voice; B. retrieval and re-living of memories associated with positive self-esteem; C. positive self-esteem is brought to compete with the content of the voices to weaken associations between voice content and negative self-valuation; and D. learning to disengage from the voices and to accept the voices as psychic phenomenon.

The significant past comes back to the conscious mind in AVH, as life experiences charged with emotion make a compelling impression on the brain. The observation that voices are knowledgeable about patients suggests that auditory hallucinations are linked to memory. In other words, negative experiences from memories evoke emotions, which should be deactivated. Distancing and decentring techniques could help patients to interpret voices as false mental events. As a result, incompatible memories could become tools to modify the power of voices—they are deactivated by new learning. Thus, when voices torment hearers, telling them that they are failures, a competing memory of such success as passing a significant examination is introduced. Posture, facial expression, imagination, self-verbalisation and music are all procedures included in the COMET protocol.40

Compassionate mind training (CMT) is used to encourage better resilience to unpleasant commenting voices.CMT involves practicing exercises which promote self-compassion and compassion towards others. It is targeted to activate brain systems involved in social and self-soothing that amend threat systems active when experiencing unfriendly voices. 41

Mindfulness is paying attention in a particular way – on purpose, in the present moment and non-judgementally. Clinical literature cautions against use of meditation in psychosis, but the effectiveness of mindfulness-based approaches for people with psychosis has been demonstrated in controlled clinical settings. 42and in the community. 43 Abba et al. 44 argue that effectiveness of mindfulness is a three-stage process: a. Becoming knowledgeable and developing more awareness of psychotic experiences and observing the thoughts and emotions that follow them. B. Permitting psychosis to come and go without reacting in order to cultivate understanding that distress is produced by the meanings one attaches to thoughts and sensations. C. Becoming autonomous by accepting psychosis and the self by acknowledging that the sensations only form part of the experience, and are not a definition of the self.

Neuroimaging studies are beginning to explain the neural mechanisms of how mindfulness might be working clinically. Structural changes have been observed in the anterior cingulate cortex, which is an area of the brain associated with emotional regulation. 45 . There is evidence to suggest that mindfulness practice is correlated to reduced brain activity in the default mode network. 46

Limited improvements with mono-therapy have prompted the development of multi-modular approaches. Hallucination-focused Integrative Therapy (HIT) is geared towards integrating CBT with neuroleptics, coping strategies, psycho-education, motivational intervention, rehabilitation and family treatment.47 Extant studies indicate that integrated treatment is more effective than TAU (treatment as usual).

The continuum model of psychosis and ordinary mental events has incited the development of normalisation of the voice hearing experience.48 Most psychiatric symptoms occur in normal people—just as breathlessness and palpitations occur while exercising—but are potential clinical symptoms. It is the frequency and duration that determine the borderline. According to the cognitive model, an internal mental event receives external attribution. Through normalisation, the external attribution can be reversed.

Although drug treatment may be the most practical way of managing AVH, refractory cases pose formidable challenges and it must be emphasized that psychological treatments are not counterproductive if applied skilfully. Clinicians who espouse the view that psychosis is a medical condition dismiss the usefulness of psychological interventions. The counter argument would be that a patient with a medical condition, such as stroke, benefits from physiotherapy, occupational therapy and psychological approaches.49

Repetitive Trans-cranial Magnetic Stimulation

There are several ongoing trials in which the aim is to treat refractory AVH (Table 4). Repetitive transcranial magnetic stimulation (rTMS) is thought to alter neural activity over language cortical areas. Several studies on rTMS have shown improvement in the frequency and severity of AVHs, albeit without offering any strong conclusive evidence for its efficacy .50 Moderate rates of AVH attenuation following rTMS have been noted in three meta analyses. Given that remarkable improvements in isolated cases have also been claimed, this suggests that rTMS may be appropriate mode of therapy for some patients.

Available data suggest that .rTMS selectively alters neurobiological factors that determine the frequency of AVH. However, a recent meta-analysis indicated that the effect of rTMS may be short-lived (less than one month).51 Studies seem to indicate that rTMS may be effective in reducing the frequency of AVHs, with little effect on their other topographical aspects.50,52 Sham stimulation has also led to improvements in a number of AVH parameters. Compared to bilateral stimulation, rTMS of left tempero-parietal region appears more effective in reducing the AVH frequency . 53 To reduce the distress associated with AVH and help patients to cope with hallucinatory predilection, rTMS could be combined with CBT. The side-effect profile is much cleaner for this biological approach when compared to medications. Still, like any other anti-hallucinatory treatments, neuro-stimulation technique does not guarantee long-term elimination of AVH. Electroconvulsive therapy (ECT) is considered a last resort for treatment resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucinations severity has never been demonstrated.

Avatar Therapy

Computer-assisted voice therapy is a budding form of computerised psychological treatment that is currently undergoing trials.28 In this novel therapy, persecutory voices are directly depowered with the aid of a computerised dummy of the alleged persecutor through voice dialogue. Analytically-oriented therapists can even converse with “voices” and such committed clinicians will find computerised voice therapy as another helpful tool. It is hard to ascertain whether the benefits of the avatar therapy were due to the specific technique involved or simply the increased attention and care, and Leff’s team acknowledged the limitations of their work.54

Sound Therapy

Another important development in voice therapy is the use of tinnitus control instrument (TCI)—a form of sound therapy—in treating refractory AVH. Similar to AVH, subjective tinnitus is defined as the false perception of sound in the absence of acoustic stimuli. Even though their definitions are similar, the origin and underlying causes of these two conditions differ. Tinnitus is characterised by a simple sound—a monotone—and is non-verbal. In tinnitus, the brain is believed to interpret an internally generated electromagnetic signal as an acoustic sound or sounds.

Kaneko, Oda, and Goto29 reported successful intervention in two cases of refractory AVH with sound therapy, using tinnitus control instrument (TCI) alongside antipsychotic medications. They posited that, in sound therapy, the auditory system is directly helping the limbic nervous system and the neuro-mechanism for AVH is sensitive to sound therapy .55 They concluded that low-level auditory stimulation might be hindering the progression of voices and brain might be getting a breathing space to initiate self-healing process.

Future Directions

Hallucinogenic drugs, anti-hallucination medications and neuroimaging studies may lead to a better understanding of AVH. Animal models of hallucinations and pharmacogenetics might help to find more efficacious anti-hallucinatory drugs. AVHs themselves may have a genetic origin.10 Thus, not all patients that develop schizophrenia would experience AVHs. Such a finding might help shed more light on the genetics-linked mechanism and remedial measures of hallucinations in schizophrenia. Because the biological substrates facilitating drug effects on hallucinations remain largely unidentified, future studies with translational designs should address this important issue to find a more targeted drug treatment of psychosis.56

If a derivative of clozapine without the haematological side-effects is formulated in the future, it might be an important milestone in the treatment of refractory AVHs and schizophrenia because clozapine has the most potent anti-hallucinatory effect. Such a novel drug could become the first line of treatment for schizophrenia, as it would address many of schizophrenic symptoms at their onset. This is crucial, as symptoms and habits become stronger and more resistant the more frequently they occur. Fatty acid amide derivatives of clozapine, such as DHA-clozapine, are found to have better pharmacological properties and enhanced safety. However, such claims are awaiting substantiation in clinical trials.57 Thus, more attention needs to be directed into this potentially rewarding research arena. It is, however, very likely that, even after a better pharmacological cure is found for AVHs, a few symptoms might linger on for long periods. With this view, efficient non-pharmacological remedies have to be designed to deal with such residual symptoms.

Discussion

Medications help reduce the psychic pain, and protect the dignity of patients, as well as prevent suicides and homicides. From the patient’s perspective, the calming and relaxing effects of pharmacological therapies are a priority for relief from the distress due to AVH. Among the antipsychotics, clozapine has the maximum anti-hallucinatory effect and it is a shame that it cannot be used as a first line treatment choice. Treatment of AVH should be individualistic and clinicians should be prepared to apply several clinical and non-clinical approaches in concert to address them.

More research into the aetiology and mechanism of AVH is warranted in order to find effective treatment strategies. There is no shortage of theories about the mechanism of AVH, but there is no consensus among the investigators. It is unlikely that AVH is a pure neuro-chemical experience or a biological glitch, and this is where the currently available drug treatments fail. The distinction between primary and secondary symptoms was lost with the triumph of biological psychiatry in the last century. Thus, some authors presently claim that AVHs may even be a secondary symptom or a neuroquantological manifestation of an underlying biological disorder. We should not minimise the importance of eliminating symptoms when such symptoms are incapacitating, as in the case of hallucinatory experiences.

The present recovery model that emphasises and supports the patient’s potential for recovery involving hope, supportive relationship, empowerment, social inclusion, coping skills and meaning cannot be achieved without the help of psychological interventions. In this respect, CBT is a useful tool in the rehabilitation of psychotic patients with residual AVH. Jauhar et al.58 argued that the effectiveness of CBT in schizophrenia is influenced by failure to consider sources of bias. Consequently, the benefits are more apparent than real, prompting the question of whether CBT has been oversold.49 The verdict of Maudsley debate on the issue has been that CBT has not been oversold, but rather has a great impact on symptom reduction and enhancing concordance and insight. Perhaps the most informative trial so far accomplished has been the work on cognitive therapy for command hallucinations, which has proven the benefit of specific model development, and which productively, combined measurement of process and a targeted outcome.59

There is ample evidence suggesting that a combination of family and psychological interventions, alongside pharmacotherapy, can be the most effective way of dealing with refractory AVH.60 The inner dialogue hypothesis of AVH held by CBT therapists has its opponents.61 Patients respond to the voices they experience by utilising inner speech. Some observations with corresponding features weaken the inner-dialogue hypothesis. David and Lucas have demonstrated in a single case study that short-term maintenance of phonological representation (inner dialogue) may co-exist with AVHs – they are not synonymous experiences. The cost-effectiveness of psychological interventions is poorly studied, despite being highly relevant for policy decisions in healthcare.

Computerised voice therapy works better with technically minded, highly intelligent patients. In contrast, individuals of low to average intelligence may require a primarily behavioural approach, with limited efforts to understand concepts, such as automatic thinking and schema. Unlike sound therapy through music playing instruments (iPad, iPod, iPhone, etc.), TCI causes no disruption to daily functioning and can be used continuously. Computerised voice therapy and sound therapy warrant standardised case trials. When it comes to treating AVHs, optimizing compliance, reducing the burden of symptoms, and improving control, quality of life and social functioning should be the therapeutic goals.62 Neuroquantological views of AVHs63 explain the limitations of pharmacotherapy and the usefulness of psychological interventions.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAMES PAUL PANDARAKALAM, Trust Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, United Kingdom.
Corresponding Author Details: 
JAMES PAUL PANDARAKALAM, Trust Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Hollins Park Hospital, Hollins Lane, Warrington WA2 8WA, United Kingdom.
Corresponding Author Email: 
jpandarak@hotmail.co.uk
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Ventilator-associated pneumonia: A review of the clinically relevant challenges in diagnosis and prevention

Authors
Varun Goel, Savita Gupta and Tarun Goel
Article Citation and PDF Link
BJMP 2016;9(2):a910
Abstract / Summary
Abstract: 

Ventilator-associated pneumonia is one of the most commonly encountered nosocomial infections in the intensive care units and is associated with high morbidity and high costs of care. Inspite of extensive studies for decades, a clear diagnostic and prevention strategy is still eluding Ventilator-associated pneumonia. Clinical diagnosis has been criticized to have poor accuracy and reliability. Quantitative cultures obtained by different methods seem to be rather equivalent in its diagnosis. Blood cultures are relatively insensitive to diagnose Ventilator-associated pneumonia. Thus, the Centers for Disease Control and Prevention has introduced a new definition based upon objective and recordable data. New preventive strategies are focused on the improvement of secretions drainage and prevention of bacterial colonization. We performed a literature review to describe the evidence-based Ventilator-associated pneumonia-diagnosis and prevention strategies that have resulted in clinically relevant outcomes. An integrated approach should be followed in diagnosing and preventing Ventilator-associated pneumonia.

Keywords: 
Pneumonia, Nosocomial Infections, Ventilator Associated Pneumonia, ventilator bundle

INTRODUCTION

Ventilator-associated pneumonia (VAP) is a type of nosocomial pneumonia that occurs in patients who receive mechanical ventilation and is usually acquired in the hospital setting approximately 48–72 hours after mechanical ventilation.1 VAP is one of the most frequent hospital-acquired infections occurring in mechanically ventilated patients and is associated with increased mortality, morbidity, and health-related costs. Several risk factors have been reported to be associated with VAP, including the duration of mechanical ventilation, and the presence of chronic pulmonary disease, sepsis, acute respiratory distress syndrome (ARDS), neurological disease, trauma, prior use of antibiotics, and red cell transfusions.2 VAP occurrence is closely related to intubation and the presence of the endotracheal tube (ETT) itself.

Since there are inadequate objective tools that are utilized to make an assessment of bacterial-induced lung injury in a heterogeneous group of hosts, the diagnosis of VAP is challenging. Around 90% of ICU-acquired pneumonias occur during mechanical ventilation, and 50 % of these ventilator-associated pneumonias begin in the first 4 days after intubation.3 VAP has a cumulative incidence of 10-25% and accounts for approximately 25% of all ICU infections and 50% of its antibiotic prescription, making it the primary focus for risk-reduction strategies.1,4 For all these reasons, early diagnosis and prevention of VAP has held a prominent position on the research agenda of intensive care medicine in the past 25 years, with an ultimate goal of improving patient outcome, preferably by reducing mortality.

The keywords, ‘ventilator-associated pneumonia,’ in PUBMED revealed a total of 3612 titles and 625 review articles within the search limit of 10 years, between 2005 and 2014. Only articles in English were chosen.

PATHOGENESIS

Understanding the pathogenesis of VAP is the first step in the formulation of its appropriate preventive and therapeutic strategies. The initial step in the pathogenesis of VAP is bacterial colonization of the oropharynx and gastric mucosa, followed by translocation of the pathogens to lower respiratory tract. The most common means of acquiring pneumonia is via aspiration which is promoted by supine position and upper airway and nasogastric tube placement.2,5 In a mechanically ventilated patients, aspiration occurs around the outside of the endotracheal tube rather than through the lumen. Secondly, aerobic Gram-negative bacteria presumably reach the lower airway via aspiration of gastric contents or of upper airway secretions. Other means by which VAP can be acquired include aspiration from the stomach or nose and paranasal sinuses. Figure 1 depicts the essential elements favoring colonization of lower respiratory tract with the bacterial pathogens with subsequent development of pneumonia.2,5,6

Figure 1: Pathogenesis of Ventilator-associated pneumonia5
*Gastric alkalinization; prior antimicrobials; ICU stay; intubation; supine position; circuit/airway manipulation and mishandling; device cross-contamination; sedation; diminished cough reflex; and malnutrition predispose to colonization and aspiration. As the duration of ICU stay increases, colonization with MDR Gram-negative pathogens like Pseudomonas and Acinetobacter increases.
†Via contaminated nebulizers/aerosols
Reproduced with permission from the publisher.

COMMON CAUSES

The specific microbial causes of VAP vary widely depending in epidemiological and clinical factors. Common pathogens include aerobic gram negative bacteria such as Pseudomonas aeruginosa and members of family Enterobacteriaceae, staphylococci, streptococci, and Haemophilus species. Microorganisms like Pseudomonas spp., Acinetobacter spp. and Methicillin-Resistant Staphylococcus aureus occur commonly after prior antibiotic treatment, prolonged hospitalization, mechanical ventilation or when other risk factors are present.6,7

Moreover, deliberated ill patients may have defect in phagocytosis and behave as functionally immunosuppressed even prior to emergence of nosocomial infection as seen by many recent studies.8,9

DIAGNOSIS

Clinical Diagnosis

No gold standard of diagnosis for identifying VAP is there inspite of variety of proposed definitions. VAP has traditionally been diagnosed by clinical criteria of Johanson and colleagues (appearance of new or progressive pulmonary infiltrates, fever, leucocytosis and purulent tracheobronchial secretions), which are non-specific. When findings on histologic analysis and cultures of lung samples obtained immediately after death were used as references, a new and persistent (>48-h) infiltrate on chest radiograph plus two or more of the three criteria (i) fever of >38.3°C, (ii) leukocytosis of >12 × 109/ml, and/or (iii) purulent tracheobronchial secretions had a sensitivity of 69% and a specificity of 75% for establishing the diagnosis of VAP.10

Because of the poor specificity of the clinical diagnosis of VAP and of qualitative evaluation of ETAs, Pugin et al. developed a composite clinical score, called the clinical pulmonary infection score (CPIS), based on six variables: temperature, blood leukocyte count, volume and purulence of tracheal secretions, oxygenation, pulmonary radiography, and semi-quantitative culture of tracheal aspirate. The score varied from 0 to 12. A CPIS of >6 had a sensitivity of 93% and a specificity of 100%.11 Accuracy of CPIS in diagnosis of VAP is debated, despite of its clinical popularity. In one meta-analysis study evaluating the accuracy of CPIS in diagnosing VAP reported pooled estimates for sensitivity and specificity for CPIS as 65 % (95 % CI 61-69 %) and 64 % (95 % CI 60-67 %), respectively.12 The poor accuracy of clinical criteria for diagnosing VAP is due to purulent tracheobronchial secretions in patients receiving prolonged mechanical ventilation which are rarely caused by pneumonia. Moreover, in pneumonia systemic signs such as fever, tachycardia, and leukocytosis are nonspecific; they can be caused by any state that releases the cytokines interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor alpha (TNFα), and gamma interferon.13,14 The weak point of CPIS is probably the inter-individual variability (kappa= 0.16), since a subjective evaluation is required when we are judging the quality of tracheal secretion (purulent/not purulent) and the presence of infiltrate at chest ray.15

Radiologic Diagnosis

Radiographical evidence of pneumonia in ventilated patients is also notoriously inaccurate. In a study of autopsy proven VAP, of the total population, only air bronchograms correlated with pneumonia and no specific roentgenographic sign correlated with pneumonia in patients with adult respiratory distress syndrome. The differential diagnoses of VAP based on radiographical appearance, include adult respiratory distress syndrome, congestive heart failure, atelectasis, pulmonary embolism and neoplastic infiltration.16

Microbiologic Diagnosis

The type of specimen that should be obtained for microbiologic processing as soon as VAP is suspected is another area of importance. The use of quantitative cultures is one of the main issues for any diagnostic laboratory because there is oropharyngeal bacterial contamination of all respiratory secretion samples, despite this is not always undertaken in many hospitals today.16,17

Blood cultures

Blood cultures have limited value because organisms isolated from blood in suspected VAP cases are often from extrapulmonary sites of origin.18 Blood cultures in patients with VAP are clearly useful if there is suspicion of another probable infectious condition, but the isolation of a microorganism in the blood does not confirm that microorganism as the pathogen causing VAP.

Quantitative cultures of airway specimens

Simple qualitative culture of endotracheal aspirates has high percentage of false-positive results due to bacterial colonization of the proximal airways observed in most patients in the ICU.20 Quantitative culture techniques suggest that endotracheal aspirate cultures (QEA) may have an acceptable overall diagnostic accuracy, similar to that with several other, more invasive techniques including BAL, protected BAL (pBAL) ,protected specimen brush (PSB) or tracheobronchial aspirate(TBA).7,19,20 Threshold values often employed for diagnosing pneumonia by quantitative cultures are ≥105 to 106, ≥104, and ≥103 CFU/ml for QEA, bronchoscopic BAL, and PSB, respectively, with ≥105 CFU/ml being the most widely accepted value for QEA.21,22,23 Also, blind aspiration sampling can lead to errors but bronchoscope also carries risks, such as inducing cardiac arrhythmia, hypoxemia, bleeding, pneumothorax, along with greater costs both in terms of time and resources. It is accepted that before administering the first dose of antibiotic or before any change in treatment patient specimens for culture should be taken, so that the results interpreted are valid.24 Lalwani et al., in their study, observed that culture results of a properly collected tracheal aspirate should be taken into consideration along with Centre for Disease Control and Prevention (CDC's) diagnostic criteria to maximize the diagnosis of VAP.25

The recent guidelines of Society for Healthcare Epidemiology of America/ Infectious Diseases Society of America (SHEA/IDSA) recommend Gram staining of endotracheal aspirates. However, the sensitivity (57-95%) and specificity (48-87%) of this technique are highly variable. The role of procalcitonin and other biomarkers for the diagnosis of VAP is yet unsubstantiated.5,26

Since VAP diagnosis founded on radiographic findings of pneumonia, which have intrinsic variability in technique, interpretation, and reporting, and on clinical signs and symptoms- that are subjective- in 2011 a Working Group of the CDC proposed a new approach to surveillance for Ventilator-Associated Events (VAE). Table 1 According to the new CDC definition algorithm, VAP is an Infection-related Ventilator-Associated Complication (IVAC) occurring after 3 days of mechanical ventilation and 2 days before or after the onset of worsening oxygenation, if purulent respiratory secretions with positive cultures or objective signs of respiratory infection have been found.27

Table 1: CDC Algorithm for VAP diagnosis30

1= Purulent respiratory secretions AND one of the following: 2= One of the following (without requirement for purulent respiratory secretions):
Positive culture of endotracheal aspirate, ≥ 105 CFU/ml * Positive pleural fluid culture
Positive culture of bronchoalveolar lavage, ≥ 104 CFU/ml* Positive lung histopathology
Positive culture of lung tissue, ≥ 104 CFU/ml* Positive diagnostic test for Legionella spp.
Positive culture of protected specimen brush, ≥ 103 CFU/ml* Positive diagnostic test on respiratory secretions for influenza virus, respiratory syncytial virus, adenovirus, parainfluenza virus

On or after calendar day 3 of mechanical ventilation and within 2 calendar days before or after the onset of worsening oxygenation, criteria 1 or 2 is met (*or equivalent semi-quantitative result).

Table 2: Practices for which insufficient evidence or no consensus exists about Efficacy8,57

Rotational or turning therapy Routine use of turning or rotational therapy, either by ‘kinetic’ therapy or by continuous lateral rotational therapy
Systemic antimicrobial agent prophylaxis Routine administration of systemic antimicrobial agent(s) to prevent pneumonia in those receiving mechanically-assisted ventilation.
Changes in the antimicrobial agents class used for empiric therapy
Oral chlorhexidine

rinse for oropharyngeal colonization

Routine use of an oral chlorhexidine rinse for the prevention of healthcare-associated pneumonia in all postoperative or critically ill patients and/or other patients at high risk for pneumonia.
Ventilator breathing circuits with HMEs No recommendation can be made for the preferential use of HMEs to prevent pneumonia in patients receiving mechanically assisted ventilation
No recommendation can be made for placing a filter or trap at the distal end of the expiratory-phase tubing of the breathing circuit to collect condensate
Suctioning of respiratory tract secretions No recommendation can be made for the preferential use of either the multiuse closed-system suction catheter or the single-use open-system suction catheter
Prevention of aspiration associated with enteral feeding Small-bore tubes for enteral feeding
Enteral feedings continuously or intermittently should be given
Patient care with tracheostomy Daily application of topical antimicrobial agent at the tracheostoma
Gloving Wearing sterile rather than clean gloves when performing endotracheal suctioning

STRATEGIES FOR VAP PREVENTION

There are multiple recommended measures for prevention of VAP. Practices for which insufficient evidence or no consensus exists about efficacy are summarized in Table 2. Preventive VAP strategies can be grouped into two classes: non-pharmacologic strategies, which are focused on preventing aspiration, and pharmacologic strategies, which are aimed at preventing colonization.

Non-Pharmacologic Strategies

Staff Education in the Intensive Care Unit

Various barriers to adhering to VAP prevention recommendations include disagreement with the reported results of source studies, resource paucity, elevated costs, inconvenience for nurses, fear of potential adverse effects and patient discomfort. There is considerable variability in practice between countries regarding humidification systems, intubation route, endotracheal suction system, kinetic therapy beds, subglottic secretion drainage and body position. For efficient patient care staffing must be sufficient while ensuring that staff is able to comply with essential infection control practices and other prevention strategies.17,28

Hand Hygiene

Microorganisms can be spread easily from patient to patient on the hands of healthcare workers. Moreover, wrist watches, rings, bangles and other jewelry commonly act as reservoirs for organisms, and impede effective hand cleaning. Moreover, healthcare workers compliance to hand hygiene is low, and high workload decreases their compliance.29

Impact of patient position

Patients positioned semi-recumbently 45 degrees have significantly lower incidence of clinically diagnosed VAP compared to patients positioned supinely.30 Moreover, the incidence of clinically diagnosed VAP among patients positioned prone, does not differ significantly from the incidence of clinically diagnosed VAP among patients positioned supine.31,32

Kinetic Beds

Critical patients often for a long time remain immobile in the supine position so the functional residual capacity is decreased because of alveolar closure in dependent lung zones and impaired mucociliary clearance. This leads to the accumulation of mucus, atelectasis onset and ensuing infection.33 Rotational therapy uses a special bed designed to turn continuously, or nearly continuously, the patient from side to side; specific designs include kinetic therapy and continuous lateral rotation therapy (CLRT).34,35

Artificial Airway Management

Oral vs Nasal Intubation: Both nasogastric and nasotracheal tubes can cause oropharyngeal colonization and nosocomial sinusitis. Thus, use of the oral route for both endotracheal and gastric intubation should be considered to decrease the risk of VAP.36

Endotracheal tube cuff pressure: The secretions that pool above inflated endotracheal tube cuffs may be a source of aspirated material and ensuing VAP. The pressure of the endotracheal tube cuff should be optimized in order to prevent the leakage of colonized subglottic secretions into the lower airways. Persistent pressures into the tube cuff below 20 cm H2O have been associated with the development of VAP.37

Silver-Coated Endotracheal Tubes: Silver-coated endotracheal tubes appear to be safe, reduces bacterial biofilm formation, has bactericidal activity, reduces bacterial burden and can delay airway colonization. However, further studies are needed to for determing its efficacy.38,39

Mechanical Ventilation Management

Ventilator Circuit Change: The CDCs recommendation was ‘do not change routinely, on basis of duration of use, the breathing circuit that is in use on an individual patient. Change the circuit when it is visibly soiled or mechanically malfunctioning.40

Humidification With Heat and Moisture Exchangers: The effect of HME in preventing VAP is still controversial and recent studies have failed to show a significant difference in rates of infection.41

Subglottic secretion drainage: Intermittent subglottic secretions drainage using inspiratory pause during mechanical ventilation results in a significant reduction in VAP.42 SSD reduces VAP in patients ventilated for >72 hours and should be considered with other recommended strategies such as semi-recumbent positioning.43

Pharmacologic Strategies

Modulation of Oropharyngeal Colonization

Policies encouraging routine tropical oral decontamination with chlorhexidine for patients merit reevaluation. It is a cheap measure, but whether is it a safe one − it does not select resistant microorganisms − remains to be investigated.8,44

Selective Decontamination of the Digestive Tract

Selective decontamination of the digestive tract (SDD) is the decontamination ofpotentially pathogenic microorganisms living in the mouth and stomach, whilst preserving the indigenous anaerobic flora. SDD is an effective and safe preventive measure in ICUs where incidence rates of MRSA and VRE are low, but in ICUs with high rates of multi-resistant microorganisms it is a measure that is effective but not safe.45,46

Stress Ulcer Prophylaxis

Patients at risk from important gastrointestinal bleeding (shock, respiratory failure requiring mechanical ventilation or coagulopathy) should receive H2 antagonists such as ranitidine rather than sucralfate.47

Ventilator sedation protocol

In patients receiving mechanical ventilation and requiring sedative infusions with midazolam or propofol, the use of a nurse-implemented sedation protocol decreases the rate of VAP and the duration of mechanical ventilation.48 An objective assessment-based Analgesia-Delirium-Sedation (ADS) protocol without daily interruption of medication infusion decreases ventilator days and hospital length of stay in critically ill trauma patients.49

Antibiotic Policy and Infection Control

Rational antibiotic policy is a key issue for better patient care and preventing antimicrobial resistance.50,51 Infection control programs like using a scheduled switch of antibiotic class have demonstrated efficacy in reducing nosocomial infection rates and restraining multidrug resistant (MDR) microorganism emergence.52

VAP prevention in low resource/developing countries

Though the incidence of VAP has declined in the developed countries, it continues to be unacceptably high in the developing world. Its incidence in these countries is 20 times that in the developed nations with significant morbidity, mortality, and increase in ICU length of stay, which may represent an additional burden on the scarce resources in developing countries.53 Insufficient preventive strategies and probably inappropriate antibiotics administration may have lead to this scenario. Since microbiology and resistance pattern in India is different from other countries, there is need for data from our country to choose appropriate antimicrobials for management.54 Simple and effective preventive measures can be instituted easily and at minimal costs. Such measures might include hand hygiene, diligent respiratory care, elevation of head, oral and not nasal cannulation, minimization of sedation, institution of weaning protocols, judicious antibiotics use, de-escalation, and leveraging PK/PD characteristics for antibiotics administered. More costly interventions should be reserved for appropriate situations. Strategies to prevent VAP, probably by emphasis on practical, low-cost, low technology, easily implemented measures is need of the hour.

Ventilator-associated events (VAE) surveillance: an objective patient safety opportunity

Surveillance for ventilator-associated pneumonia is challenging and contains many subjective elements, including the use of chest x-ray evidence of pneumonia. In January 2013, CDC convened a VAP Surveillance Definition Working Group which transitioned VAP surveillance to ventilator-associated event (VAE) surveillance in adult inpatient settings.55 The VAE algorithm—which is a surveillance algorithm and not intended for use in the clinical management of patients—consists of 3 tiers of definitions: Tier 1, Ventilator-Associated Conditions (VAC); Tier 2, Infection -related Ventilator-Associated Complications (IVAC); and Tier 3, Possible and Probable VAP.27 The tier 1, VAC attempts to identify sustained respiratory deterioration episodes, and capture both infectious and noninfectious conditions and complications occurring in patients receiving mechanical ventilation. The tier 2, IVAC, is intended to identify the subset of VACs that are potentially related to pulmonary and extra pulmonary infections of sufficient severity to trigger respiratory deterioration. The tier 3, possible and probable VAP, attempts to identify IVAC patient subsets with respiratory infections as manifested by objective evidence of purulent respiratory secretions (where purulence is defined by using quantitative or semi-quantitative criteria for the number of neutrophils on Gram stain) and/or positive results of microbiological tests done on respiratory specimens. Because of the wide range of the lower respiratory tract specimens, their collection procedure as well as in laboratory processing and reporting of results, the Working Group of CDC determined that it was not appropriate to include these data elements in the VAC and IVAC definitions.56

This 3 tier approach is ineffective to accurately identify VAP for surveillance purposes and focuses on more mechanical ventilation complications. This approach may also reduce the likelihood of manipulation that could artificially lower event rates. Most VAEs are caused by pneumonia, pulmonary edema, atelectasis, or acute respiratory distress syndrome. In few recent studies concordance between the VAE algorithm and VAP was found to be poor.57 Thus, more studies are needed to further validate VAE surveillance compared with conventional VAP by using strong microbiologic criteria, particularly bronchoalveolar lavage with a protected specimen brush for diagnosing VAP and to better characterize the clinical entities underlying VAE.

Bundle approach to prevention of VAP

One of the five goals of the ‘Saving 100,000 Lives’ campaign, launched by the Institute for Healthcare Improvement is to prevent VAP and deaths associated with it by implementing a set of interventions for better patient care known as the ‘ventilator bundle’. The interventions should have scientific support of effectiveness, based on randomized controlled trials. All the elements of the bundles must be executed at the same time. The bundles for VAP includes four components: (a) elevation of the head end of the bed to 30-45º, (b) daily interruption of sedation, (c) daily assessment of readiness to extubate and (d) prophylaxis for deep venous thrombosis and peptic ulcer disease. The bundle approach to prevention of VAP has been found to be highly effective in reducing the incidence, mortality and ICU stay.5,58,59 The ventilator bundle should be modified and expanded to include specific processes of care that have been definitively demonstrated to be effective in VAP reduction. A multidimensional framework with a long-lasting program can successfully increase compliance with preventive measures directly dependent on healthcare workers bedside performance.

CONCLUSION

Ventilator Associated Pneumonia is one of the most common nosocomial infections in ICU presenting with non specific symptoms and clinical signs. Quantitative culture obtained by different methods, including EA, BAL, pBAL, PSB or TBA seem to be rather equivalent in diagnosing VAP. Clinical criteria used in combination, may be useful in VAP diagnosis; however, inter-observer variability and the moderate performance are to be considered.

Preventive strategies should focus on better secretion management and on reduction in bacterial colonization. Further research on targeted interventions is needed to effectively reduce VAP incidence. For VAP an approach based on multidisciplinary group is required including setting preventive benchmarks, establishing goals and time lines and providing appropriate education and training, audits and feedback to the staff, while continually updating themselves based on relevant clinical and preventive strategies.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NIL
Competing Interests: 
None declared
Details of Authors: 
VARUN GOEL MD Microbiology, AIIMS, New Delhi, India; SAVITA GUPTA MD Anaesthesia, LNJP, New Delhi, India; TARUN GOEL MRCP, HOLY FAMILY HOSPITAL, New Delhi, India.
Corresponding Author Details: 
Dr Varun Goel, Senior Resident, Clinical Microbiology division, Department of Laboratory Medicine, AIIMS, New Delhi-110029.
Corresponding Author Email: 
drvarun21@gmail.com
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A review of NICE guidelines on the management of Borderline Personality Disorder

Authors
Syed Ali and Christopher Findlay
Article Citation and PDF Link
BJMP 2016;9(1):a909
Abstract / Summary
Abstract: 

Aims and objectives: This report aims to review the current guidelines regarding the management of Borderline Personality Disorder and explore the literature according to the research recommendations. The psychological/psychosocial and pharmacological aspects will be the focus of this review.

Methods: A summary of the NICE guidance was made and each recommended psychotherapy (i.e. mentalization-based therapy, dialectical behaviour therapy, cognitive analytic therapy, cognitive behavioural therapy, schema-focused therapy and transference focussed therapy) and pharmacological options were dissected and analysed using the literature.

Results: All of the psychotherapies showed promising results when applied to borderline personality disorder. Two were seen as superior due to there being more evidence to support their use. In terms of psychotropics, despite the NICE guidance negating their use, the literature found evidence that some second-generation antipsychotics and mood stabilisers could improve symptoms in the short term. Those pharmacological agents that carry the strongest evidence base should be considered if off-label use is deemed appropriate.

Conclusion: Specialist psychological treatments such as dialectical behaviour therapy and mentalization based therapy substantiate the use of psychotherapy in borderline personality disorder. By crystallising the important aspects of the array of psychotherapies available, a more comprehensive approach could be developed. By understanding the disorder in terms of psychological and biological aberrations, it will enable a more specific dual approach to its management in the future. 

Abbreviations: 
BPD - Borderline Personality Disorder, DSM-5 - The Diagnostic and Statistical Manual of Mental Disorder, ICD-10 - The International Classification of Diseases, NICE - The National Institute for Health and Care Excellence, DBT - Dialectical Behaviour Therapy, MBT - Mentalization Based Treatment, CAT - Cognitive Analytic Therapy, NHS - National Health Service (UK), CBT - Cognitive behavioural therapy, TFT - Transference focussed therapy, NHMRC - The National Health and Medical Research Council of Australia.
Keywords: 
Borderline Personality Disorder, Emotionally unstable personality disorder, Personality disorder.

INTRODUCTION

During my placement in Psychiatry at the Brooker Centre, Runcorn, UK, I have come into contact with a wide array of psychiatric disorders, none more so than borderline personality disorder (BPD). It is undoubtedly one of the most prevalent problems in the area which the Brooker Centre serves. I can recall an example of a patient with BPD who had been quite unwell for a prolonged period of time and had struggled with affective instability. This patient had been quite successfully treated with Lithium therapy, has exhibited stability and is happy on the current treatment. There is a pattern of pharmacological treatment in BPD patients despite the fact that guidelines suggest otherwise…

Personality disorders are defined as ‘an enduring pattern of inner experience and behaviour that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment’ . Personality disorders are representative of long-term functioning and are not considered in terms of episodes of illness 1.

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), groups the various personality disorders into three clusters based on their descriptive similarities.

Cluster A includes the Paranoid, Schizoid, and Schizotypal personality disorders which are categorised as ‘odd/eccentric’;

Cluster B includes the Antisocial, Borderline, Histrionic, and Narcissistic personality disorders which are categorised as ‘dramatic/emotional/erratic’;

Cluster Cincludes the Avoidant, Dependent, and Obsessive-compulsive personality disorders which are categorised as ‘anxious/fearful’ 2.

The International Classification of Diseases, 10th edition (ICD-10), specifies the condition of emotionally unstable personality disorder which has two subtypes: The impulsive type and the borderline type. The borderline type in essence overlaps with the DSM-5 definition 3.

It has proven difficult to provide robust clinical recommendations with regards to the treatment of personality disorder. This is, in part, due to the fact that study populations are diverse but also compounded by the use of different assessment criteria. Furthermore, it is important to consider that personality disorders often present with a great deal of psychiatric comorbidity. Of the personality disorders, particular attention has been paid to borderline personality disorder (BPD) as the symptom clusters which it involves have been shown to improve considerably with treatment 4.

Figure 1: Diagnostic Criteria for Borderline Personality Disorder according to DSM-5 2:

A pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity, beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the following:
1. Frantic efforts to avoid real or imagined abandonment. (Note: Do not include suicidal or self-mutilating behaviour covered in Criterion 5.)
2. A pattern of unstable and intense interpersonal relationships characterised by alternating between extremes of idealization and devaluation.
3. Identity disturbance: markedly and persistently unstable self-image or sense of self.
4. Impulsivity in at least two areas that are potentially self-damaging (e.g. spending, sex, substance abuse, reckless driving, binge eating). (Note: Do not include suicidal or self-mutilating behaviour covered in Criterion 5.)
5. Recurrent suicidal behaviour, gestures, or threats, or self-mutilating behaviour.
6. Affective instability due to a marked reactivity of mood (e.g. intense episodic dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days).
7. Chronic feelings of emptiness.
8. Inappropriate, intense anger or difficulty controlling anger (e.g. frequent displays of temper, constant anger, recurrent physical fights).
9. Transient, stress-related paranoid ideation or severe dissociative symptoms.

Borderline personality disorder is characterised by a pervasive instability in mood, interpersonal relationships, self-image and behaviour. The condition was first recognised in the United States by Adolf Stern in 1938. He described that these are a group of patients who neither fit into psychotic or psychoneurotic group, which gave rise to the term ‘borderline’. BPD is often diagnostically comorbid with depression and anxiety, eating disorders (notably bulimia), post-traumatic stress disorder, substance misuse and bipolar affective disorder. Furthermore, psychotic disorders have also been found to overlap. Due to this extent of comorbidity it is rare to see a patient who has a pure BPD 5.

The pharmacological treatments of BPD are tailored according to the symptom clusters that present. These include impulsivity, affective instability, transient stress-related psychotic symptoms and suicidal & self-injurious behaviours 5,6.

Recommended Psychological and Pharmacological treatment, 2009 National Institute for Health and Clinical Excellence (NICE) guidelines on Borderline Personality Disorder 5, 7:

Psychological

NICE guidelines state that when offering psychology for BPD or for the individual symptoms of the disorder, brief psychological interventions (i.e. less than a 3 month period) should not be used. It states that the frequency of psychotherapy sessions should be adapted to the patient’s needs and ‘context of living’ and suggests that twice-weekly session may be considered. The guidelines also specify that for women with BPD for whom recurrent self-harm is a priority, a comprehensive dialectical behaviour therapy programme should be considered. NICE recommends that when psychological treatment is provided in BPD, the effects should be monitored using a broad range of outcomes. These should include personal functioning, drug and alcohol use, self-harm, depression and the symptoms of BPD.

Pharmacological

The NICE guidance states that drug treatment should not be used specifically for BPD or for the individual symptoms or behaviour associated with the disorder (e.g. repeated self-harm, marked emotional instability, risk taking behaviour and transient psychotic symptoms). It goes on to suggest that antipsychotics should not be used for the medium- and long term treatment of BPD. However, with regards to the management of comorbidities, it specifies that drug treatment may be considered and that in each case, the NICE guidelines for each comorbid condition must be referred to. Antidepressants, mood stabilisers and antipsychotics are commonly used in clinical practice. The guidelines mention that short-term use of sedative medication may be considered in a crisis. ‘Short-term’ denotes treatment lasting no longer than one week.

With regards to drug treatment during a period of crisis, NICE recommends that there should be a consensus among prescribers and other involved professionals about the proposed drug treatment and also that a primary prescriber should be identified. There should be an appreciation of the likely risks of prescribing, including alcohol and illicit drug use. NICE emphasises that the psychological role of prescribing (both from the patient’s and prescriber’s perspective) should be taken into account, and the impact that such prescribing decisions may have on the therapeutic relationship and overall care plan. NICE recommends that a single drug be used and that polypharmacy is to be avoided as much as possible.

In a crisis NICE recommends prescribing ‘a drug that has a low side-effect profile, low addictive properties, minimum potential for misuse and relative safety in overdose.’ The minimum effective dose is favourable, prescribing fewer tablets more frequently if there is a significant risk of overdose and also agreeing with patient on the symptoms that are being targeted. NICE suggests that following a crisis, a plan should be made to stop drug treatment that was started during a crisis. If this is not possible, a regular review of the effectiveness, side effects, misuse and dependency of the drug is advised. BPD patients can often have concomitant insomnia and for this, NICE details basic advice regarding sleep hygiene and forwards on to the guidance on the use of zaleplon, zolpidem and zopiclone for the short-term pharmacological management of insomnia.

AIMS AND OBJECTIVES

This report will review the current guidelines specifically regarding the management of borderline personality disorder and explore the literature according to the research recommendations that are set by NICE. The report is to focus on the two aspects of the management of BPD – The psychological/psychosocial aspect and the pharmacological aspect.

CURRENT NICE GUIDELINES ON PSYCHOLOGICAL AND PHARMACOLOGICAL TREATMENT OF BPD 7:

Psychology

Mentalisation-based therapy and dialectical behavioural therapy are proposed in the setting of a ‘well structured, high quality community based service’ e.g. a day hospital setting or a community mental health team. NICE suggests that these techniques should be compared with ‘high-quality community care delivered by general mental health service without the psychological intervention for people with BPD’ in order to measure efficacy. For outpatients, cognitive analytic therapy, cognitive behavioural therapy, schema-focussed therapy and transference focussed therapy are suggested and are catered to those with less severe BPD (i.e. fewer comorbidities, higher level of social functioning, greater ability to depend on self-management methods). Randomised controlled trials reporting medium term outcomes (e.g. quality of life, psychosocial functioning, employment outcomes and BPD symptomatology) of a minimum of 18 months are recommended

Pharmacology

Mood stabilisers are proposed as it is detailed that emotional instability is a key feature in BPD. In particular, topiramate and lamotrigine are mentioned as they have been shown to produce encouraging results in small-scale studies. A randomised placebo-controlled trial with medium to long-term follow up is recommended.

ANALYSIS

Psychology: Dialectical Behaviour Therapy (DBT)

Dialectics can be defined as the art of investigating the relative truth of opinions, principles, and guidelines 8. Dialectical in DBT refers to a means of arriving at the truth by examination of the argument i.e. the ‘thesis’ and ‘antithesis’ and resolving the two into a rational synthesis. DBT was introduced in 1991 by Marsha Linehan (a psychology researcher) and colleagues tailored as a treatment for BPD. In this, patients are supported in understanding their own emotional experiences and are taught new skills for dealing with their stresses. A combination of individual and group sessions are used. More adaptive responses and effective problem-solving techniques are integrated to improve functioning and quality of life as well as improving morbidity and mortality 9, 10.

A study published in 2015 by M. Linehan et al detailed a randomized clinical trial that set out to compare

1) Standard DBT (DBT group skills training + DBT individual therapy) with

2) A treatment that evaluated DBT group skills training with manual case management (i.e. with the removal of DBT individual therapy) and

3) A treatment that removed DBT skills training by providing only DBT individual therapy with an activities group and prohibited individual therapists from teaching DBT skills.

All 3 versions of the treatment were found to be comparably effective at reducing suicide attempts, suicidal ideation, medical severity of intentional self-harm, use of crisis services owing to suicidality and improving reasons for living 11.

Psychology: Mentalization based therapy

Mentalization is ‘the process by which we make sense of each other and ourselves, implicitly and explicitly, in terms of subjective states and mental processes.’ It is a social construct suggesting that we are attentive to the mental states of those we are with, physically or psychologically 12. Mentalization based treatment is a psychosocial treatment for BPD in which therapists monitor attachment and mentalizing capacity, and use interventions that aim to reinstate or maintain the capacity of patients to mentalize 13.

A longitudinal study, published in 2008, involving an eight-year follow-up of patients treated for BPD evaluated the effect of mentalization-based treatment (MBT) with partial hospitalization compared with treatment as usual. Five years after discharge from MBT, the MBT group exhibited clinical and statistical superiority to treatment as usual measured on suicidality, diagnostic status, service use, medication use, global function and vocational status 14. A more recent review article, published in 2015, emphasises the consideration of disruptions in three closely related domains in individuals with BPD. These are ‘in attachment relationships, in different polarities of mentalizing, and in the quality of epistemic vigilance and trust’. It is suggested that this approach allows seemingly paradoxical features of BPD patients appear more coherent. It is supposed that this approach provides a clear focus for the therapist enabling them to monitor the therapeutic process in terms of imminent mentalizing impairments and epistemic mistrust due to activation of the attachment system.

The article goes on to assert that the effectiveness of MBT in BPD may be elucidated due to the fact that it ‘enables the therapist to maintain and foster a mentalizing stance, even–and perhaps particularly–under high arousal conditions that are so characteristic of work with these patients’ 15.

Psychology: Cognitive analytic therapy (CAT)

CAT is a brief focal therapy that is informed by cognitive therapy, psychodynamic psychotherapy and elements of cognitive psychology. It was originally developed by Anthony Ryle tailored towards the needs of the NHS 16. It is based on a collaborative therapeutic position which sets out to create narrative and diagrammatic reformulations with patients concerning their difficulties. The theory centres on descriptions of sequences of linked external, mental and behavioural events. At first, the emphasis was on how such procedural sequences prevented revision of dysfunctional ways of living. More recently, this has been extended to understanding the origins of reciprocal role procedures in early life and their repetition in current relationships and self-management 17.

One study detailed a randomised controlled trial which aimed to investigate the effectiveness of time-limited CAT for participants with personality disorder. The study found that participants receiving CAT exhibited reduced symptoms and showed considerable improvement compared with the control group who showed signs of deterioration during the treatment period. They concluded that CAT is superior to treatment as usual in improving outcomes associated with personality disorder 18.

Psychology: Cognitive behavioural therapy (CBT) and Schema-focussed therapy

CBT is a time-limited, problem focussed psychotherapy that has been applied to a wide range of psychiatric disorders. The development of this technique was born out of the observation that patients referred for psychotherapy often would hold ingrained, negatively skewed assumptions of themselves, their future and their environment. The therapy is based on the notion that disorder is caused not by life events, but by the view the patient adopts of events. The therapy focusses on current problems and helps to develop new skills to provide symptom relief and sustain recovery 9, 19.

Initially CBT was predominantly insight-orientated, using introspection to bring about change. Beck et al began to integrate a range of behavioural techniques to improve the impact on dysfunctional controlling belief systems (schemas). The goal of treatment is not to replace the dysfunctional schemas; it aims to modify beliefs and develop new ones allowing the patient to cope more effectively in challenging situations 20, 21.

A 2013 review article that set to explore schema-focussed therapy concluded that schema-therapy is based on a ‘cohesive theoretical model’ and that there seems to be sufficient evidence supporting its validity. Regarding effectiveness, it goes on to indicate that one should be encouraged by the results of studies, however it points out that due to the small number of ‘methodologically-good efficacy studies’ it is difficult to be certain. The article claims that when evaluated against other psychotherapeutic treatments, specifically DBT and MBT, schema-therapy requires more investigation 22. A pilot study (2013) set out to monitor the effects of group schema-based CBT on global symptomatic distress in young adults with personality disorders or features of personality disorder. Their findings provide preliminary evidence that schema-based CBT might be an effective treatment 23.

Furthermore, there is a multicentre randomized controlled trial being conducted with the aim of investigating schema-focussed therapy versus treatment as usual in BPD, which has a closing date of 1st February 2016 24.

Psychology: Transference focussed therapy (TFT)

The classic use of the term transference originates in psychoanalysis and comprises “the redirection of feelings and desires and especially of those unconsciously retained from childhood toward a new object” 25. Transference-focussed psychotherapy is an evidence-based manualised treatment using a psychodynamic approach with a focus on object relations theory 26. TFT aims to ‘facilitate the reactivation, under controlled circumstances, of the dissociated internalised object relations in the transference relationship to observe the nature of the patient’s split polarised internal representations, and then, through a multistep interpretive process, work to integrate them into a fuller, richer, and more nuanced identity 27.

Yeomans et al produced an article in 2013 consisting of vignettes to illustrate the techniques used in TFT with the view to evaluate its use in treating BPD. Their findings supported the validity of TFT in treating BPD patients who specifically had difficulty with relationships.

They distilled TFT down to three important components 28:

1) The treatment contracting/setting the frame

2) Managing one’s affective response

3) The interpretative process

Pharmacology

A Cochrane intervention review assessing the effects of drug treatments in BPD, included twenty-eight randomised control trials, published in the period 1979-2009 (20 of 28 trials dating from 2000 or later), involving a total of 1742 participants 29.

Figure 2: The pharmacological agents that were tested included the following:

First-generation antipsychotics:
Flupenthixol decanoate
Haloperidol
Thiothixene
Second-generation antipsychotics:
Aripriprazole
Olanzapine
Ziprasidone
Mood stabilisers:
Carbamazepine
Valproate semisodium
Lamotrigine
Topiramate
Antidepressants:
Amitriptyline
Fluoxetine
Fluvoxamine
Phenelzine sulfate
Mianserin
Dietary supplementation:
Omega-3 fatty acid

The authors arrived at the conclusion that pharmacotherapy in BPD ‘is not based on good evidence from trials’. The review found that there is support for the use of Second-generation antipsychotics (in improving cognitive-perceptual symptoms and affective dysregulation); Mood stabilisers (in diminishing affective-dysregulation and impulsive-aggressive symptoms); and Omega-3 fatty acids.

However, these claims were made based on single study effects and therefore require replication. No drug was found to significantly affect the symptom clusters, specific to BPD, including avoidance of abandonment, chronic feelings of emptiness, identity disturbance, and dissociation.

One noteworthy finding was that Olanzapine was associated with an increase in self-harming behaviour. Furthermore, the review states that ‘special attention’ is needed in BPD when prescribing tricyclic antidepressants (due to toxic effects in overdose) and hypnotics & sedatives (due to there being potential for misuse or dependence). Another problem that was highlighted was that in comorbid eating disorders the use of Olanzapine can contribute to weight gain and Topiramate can produce weight loss.

The review goes on to elucidate that there is not any evidence from randomised controlled trials that any drug reduces the severity of BPD and that it consists of ‘distinct pathology facets’. They recommend that the pharmacotherapy of BPD should be targeted at ‘defined symptoms’ and that polypharmacy is not supported by the latest evidence and should be avoided as much as possible.

The authors end by reaffirming that the evidence is not robust and that the studies may not satisfactorily reflect certain characteristics of the clinical environment. They propose that further research is needed in order to produce reliable recommendations. They detail the complications that arise from the ‘polythetic nature’ of BPD i.e. each patient is likely to experience different aspects of the disorder. There lacks a consensus among researchers about a common battery of outcome variables and measures. They comment that there is a fragmentary view on drug effects and that it is unknown as to how the alteration of one symptom affects another.

Comorbidity

Comorbidity is a foremost concern in the interpretation of data concerning personality disorders 30. A majority of individuals diagnosed with one personality disorder often meet criteria for at least one other personality disorder 30. A large proportion of patients with personality disorder have one axis I 31 disorder comorbidly, mostly depression, anxiety and alcohol and substance use disorders 32. [Axis I is a reference to the multi-axial classification system used in the Diagnostic and Statistical Manual of Mental Disorders that was removed in the latest version, DSM-5 2

It is important to consider therefore that, an improvement in the symptom clusters in personality disorders might be an improvement in comorbid axis I disorder symptoms. It is reported that the rates of depression are very high in BPD 33 and that the response to antidepressants in depressed individuals with comorbid personality disorders appears lower than in those without comorbid personality disorder 32.

The most recent guidance on the treatment of BPD from the National Health and Medical Research Council of Australia (NHMRC), which reviewed the literature and integrated a series of meta-analyses, details that pharmacotherapy does appear to be effective in altering the nature and course of BPD and that evidence does not warrant the use of pharmacotherapy as a sole or first-line treatment for BPD 34.

DISCUSSION

All of the aforementioned psychotherapy techniques are shown to produce promising results when applied to the treatment of BPD, with some standing out, such as DBT and MBT, due to the presence of a relatively robust evidence base. With such a wide variety of different approaches that all show some propensity for successful treatment of BPD it is clear that these approaches must be taken more seriously in clinical practice. These treatments have been shown to considerably improve symptomatic outcomes however there is a shortcoming in that they have failed to significantly improve social functioning. Each of the therapies follow distinct theories, however, when each treatment modality is applied to BPD, similar effects are seen. This is intriguing and should be explored further.

An analysis of these therapies revealed some common features which are now suggested as core requirements for all effective psychotherapeutic treatments:

Figure 3: Five common characteristics of evidence-based treatments for BPD 35, 36.

1. Structured (manual directed) approaches to prototypic BPD problems
2. Patients are encouraged to assume control of themselves (i.e. sense of self-agency)
3. Therapists help connections of feelings to events and actions
4. Therapists are active, responsive, and validating
5. Therapists discuss cases with others, (including personal reactions)

An update to the aforementioned Cochrane review 29 was published in 2013. The update focussed on the psychotherapies that are available for the treatment of BPD and included a total of 1804 participants spread over 28 studies. The psychotherapies discussed were divided into ‘comprehensive’ if they substantially involved an individual psychotherapy element or as ‘non-comprehensive’ if they did not. The comprehensive therapies included dialectical behaviour therapy, mentalization-based therapy (delivered in either a partial hospitalisation or outpatient setting), transference-focussed therapy, cognitive behavioural therapy, dynamic deconstructive psychotherapy, interpersonal psychotherapy and interpersonal therapy for BPD. These were assessed against a control condition and also with some direct comparisons against each other. Non-comprehensive psychotherapies included DBT-group skills training, emotion regulation group therapy, schema-focussed group therapy, systems training for emotional predictability and problem solving for borderline personality disorder (STEPPS), STEPPS plus individual therapy, manual assisted cognitive treatment, and psychoeducation 37.

The authors concluded that both comprehensive and non-comprehensive therapies indicated beneficial effects for the core pathology of BPD and associated general psychopathology. The authors identified that dialectical behaviour therapy had been studied the most comprehensively followed by mentalization-based therapy, transference-focussed therapy, schema-focussed therapy and STEPPS. However, the authors do state that none of the treatments presented a very robust evidence base and that there are concerns over the quality of individual studies 37.

In terms of pharmacotherapy, the NICE and NHMRC guidelines agree with the 2006 Cochrane interventional review among others 38, 39 that there is some evidence that some second-generation antipsychotics (aripriprazole and olanzapine) and some mood stabilisers (topiramate, lamotrigine and valproate) could improve BPD symptoms in the short term. However, for some of these agents, it is necessary to balance risks against benefits as they have considerable long-term risks (e.g. with antipsychotics, extrapyramidal side effects such as tardive dyskinesia can persist even after withdrawal of the drug 40). Such risks are not a problem in psychological treatments and it is probable that this influences guidelines. In practice, off-label use of psychotropics is widespread, despite the fact that the NICE guidance negates their use. It is arguable that clinicians should preferentially use pharmacological treatments that have the strongest evidence base (i.e. antipsychotics and mood stabilisers) and refrain from using agents with the least evidence (i.e. antidepressants and benzodiazepines).

CONCLUSION

Specialist treatments, in particular DBT and MBT substantiate the use of psychotherapy in BPD and these findings support the validity of the NICE guidance. However, the array of such treatments must be amalgamated with the view to provide a comprehensive, multi-faceted treatment approach. Each treatment must be broken down in order to outline the components that are particularly useful in BPD with the view to understand the condition in greater depth and to provide more focussed therapies.

The 2013 Cochrane review 37 highlights that further psychotherapies are available and have been shown to successfully treat BPD core pathology, however, as it is clearly stated the evidence base lacks robustness and there is a need for further studies that can replicate results. The therapies that have been included in this Cochrane review that have not been covered in the guidelines (e.g. STEPPS) may prove to be superior to those put forward by NICE, and I recommend that these be explored thoroughly when the guidelines are due for update.

While the NICE guidance emphasises that the use of psychotropics is reasonable in the management of comorbidities, it worth noting that to understand BPD, it is necessary to explore both the underlying aberrant psychological processes and biological processes that manifest in the disorder. This will enable the use of more specific pharmacological therapies in targeting the symptoms of BPD in the future.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SYED ALI, 5th Year Medical Student, University of Liverpool. CHRISTOPHER FINDLAY, BSc MB ChB MMedSc MRCP (UK) FRCP Edin MRCGP FRCPsych DRCOG, Consultant Psychiatrist, The Brooker Centre, Halton General Hospital, Hospital Way, Runcorn, Cheshire, WA7 2DA.
Corresponding Author Details: 
SYED ALI, 5th Year Medical Student, University of Liverpool.
Corresponding Author Email: 
syedali103@gmail.com
References
References: 
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A comprehensive review on the pregnancy dermatoses.

Authors
Mohammad Adil,Tasleem Arif and Syed Suhail Amin
Article Citation and PDF Link
BJMP 2016;9(1):a906
Abstract / Summary
Abstract: 

Pregnancy results in cutaneous changes in more than 90% of women. This is the result of the altered endocrine, metabolic and immunological state in the female. Many cutaneous changes are common and benign; these are referred to as the physiological changes of pregnancy. They may be of cosmetic concern to the patient and seldom require intervention. These changes are so well recognized that they act as contributory evidence of pregnancy. Many pre-existing dermatological conditions tend to change in pregnancy; some are aggravated while others may be relieved. Knowledge of these conditions is important to forewarn the patient and to prepare for upcoming complications. There are a group of dermatoses specific to pregnancy and there has been much confusion in the literature about their classification and nomenclature. Atopic Eruption of Pregnancy is the most common pregnancy specific dermatoses followed by Polymorphic Eruption of Pregnancy. These are benign conditions with no risk to the mother or baby. Pemphigoid Gestationis and Intrahepatic Cholestasis of Pregnancy carry fetal risk and require antepartal surveillance. This article discusses the current knowledge of the various cutaneous changes of pregnancy with emphasis on their clinical features, diagnosis, management and prognosis.

Abbreviations: 
Melanocyte Stimulating Hormone (MSH), Systemic Lupus Erythematosus (SLE), Pemphigoid Gestationis (PG), Herpes Gestationis (HG), Polymorphic Eruption of Pregnancy (PEP), Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP), Prurigo of Pregnancy (PP), Pruritic Folliculitis of Pregnancy (PF), Intrahepatic Cholestasis of Pregnancy (ICP), Atopic Eruption of Pregnancy (AEP), Bullous Pemphigoid Antigen 2 (BPAg2)
Keywords: 
Dermatoses, endocrine, physiological changes, pregnancy.

INTRODUCTION

The state of pregnancy results in a multitude of cutaneous changes in the female. These are a reflection of the profound alterations in the endocrine, metabolic and immunological profiles that occur during this period.1 Skin manifestations occur due to the production of a number of proteins and steroid hormones by the fetoplacental unit and also by the maternal pituitary, thyroid and adrenals.2 The placenta, a new endocrine organ in the woman, produces progesterone. Dehydroepiandrosterone is produced by the fetal adrenals from pregnenolone and this is aromatized to estriol. At term, the level of progesterone is 7 times, estradiol is 130 times and prolactin level is 19 times of that present at 8 weeks of gestation.3 There occurs an overall preference for the Th2 cytokine profile, which helps in fetal protection from the immune system.4 This is due to the high levels of progesterone, which promotes Th2 cytokines like IL-4, IL-5 and IL-10 and has inhibitory effects on TNF alpha production. Oestrogen suppresses IL-2 production. The postpartum period is marked by withdrawal of hormones and consequent elevation of Th1 cytokine levels.4

Cutaneous changes develop in more than 90% of all pregnant females.5 These include common cutaneous changes that occur in most cases to severe diseases, some of which are seen exclusively in the pregnant and postpartum state. Cutaneous manifestations can be grouped into three broad categories: physiological cutaneous changes related to pregnancy; diseases modified by pregnancy and specific dermatoses of pregnancy.6

PHYSIOLOGICAL CHANGES IN PREGNANCY

These changes are so common that they are not considered abnormal. Rather, they provide contributory evidence of a pregnant state. This however, does not mean they are cosmetically acceptable to all patients. The various physiological changes during pregnancy have been summarized in Table 1.

Table 1: Physiological changes in pregnancy

Pigmentation
Generalized hyperpigmentation
Pigmentation of inner thigh, genitalia, axilla
Secondary areola
Linea nigra
Chloasma
Prominence/ appearance of pigmentary demarcation lines
Enlargement and darkening of freckles, naevi and scars
Connective tissue changes
Striae distensae (Striae gravidarum)
Molluscum fibrosum gravidarum
Vascular changes
Oedema of distal extremities and hands
Spider angiomas
Palmar erythema
Leg varicosities
Rectal haemorrhoids
Cutis marmorata
Capillary haemangioma
Glandular changes
Miliaria
Dyshidrotic eczema
Montgomery’s tubercles
Aggravation of acne
Oral mucosal changes
Oedema and hyperaemia of gingivae
Pregnancy epulis
Hair changes
Hirsuitism
Hypertrichosis
Delayed anagen release after delivery
Nail changes
Brittle nail plate
Onycholysis
Beau’s lines after delivery

Pigmentation:

Hyperpigmentation is one of the most common and early signs of pregnancy, seen in more than 90% of patients.7 High levels of Melanocyte Stimulating Hormone (MSH), oestrogen and progesterone are believed to be responsible for hyperpigmentation. Progesterone augments the oestrogen mediated melanin output, the levels of which correlate with pigmentary changes.8

Generalized hyperpigmentation is seen which is more marked in the dark haired skin.6 Pigmented areas of the body, namely the genitalia, perineum, areolae and upper medial thighs, demonstrate more pronounced pigmentation. Linea nigra, a hyperpigmented line extending from the pubic symphysis to umbilicus and further up to the xiphisternum, replaces the linea alba.9 Chloasma, also termed as mask of pregnancy, is the well marginated brownish pigmentation of the face like melasma. It is seen in 45-75% of pregnant women in western literature but in less than 10% cases in women with pigmented skin.5,10,11 Pigmentary demarcation lines appear on the limbs with borders of abrupt transition; freckles, naevi and scars tend to darken and enlarge.12

The pigmentation gradually fades after delivery, though the resolution of skin colour is usually incomplete. Chloasma tends to persist in 30% cases postpartum.13 Sun protection and reassurance is all that is needed. Topical formulations containing hydroquinone and tretinoin are avoided in pregnancy and can be added after delivery.

Physiological connective tissue changes:

Gross distension of abdomen with adrenocortical activities are responsible for the red-blue depressed streaks seen on abdomen and breasts in 70-90% pregnancies, called striae distensae.5,14 These usually develop in the second trimester. Females with pre-existing striae on breasts and thighs are more likely to develop striae gravidarum15, seen in White women more than Asian and African-American.14 Preventive therapies are controversial and postpartum treatment options include topical tretinoin, excimer laser or surgery.10

Soft tissue fibromas of pregnancy are called molluscum fibrosum gravidarum. They appear in the second trimester on the neck, face and beneath the breasts. These disappear after delivery.16

Physiological vascular changes:

Vascular growth factors released during pregnancy by the pituitary, adrenals and placenta are believed to be causative and this has been demonstrated in vitro as well.17 Non-pitting oedema of the face, hands and feet is present in around half of all females in the later part of pregnancy.13 This is probably due to sodium and fluid retention and pressure of the gravid uterus on the inferior vena cava. Spider naevi or spider angiomas are small raised lesions with a central pulsatile punctum and radiating telangiectatic vessels frequently present over the area drained by the superior vena cava. They are present in 67% of White women and 11% Black women during the second trimester.5 Palmar erythema is seen in two-thirds of White and one-third of Black women.8 Other vascular changes include varicosities of legs and anus (40%)13, cutis marmorata (0.7%)18 and capillary haemangioma (5%)9. These changes revert after the postpartum period.

Physiological glandular changes:

Eccrine gland activity is usually increased but the palms show decreased sweating. Thus, the incidence of miliaria and dishidrotic eczema is increased. There is inconclusive evidence to suggest that apocrine gland activity is decreased during pregnancy.19 Sebaceous activity increases in the third trimester leading to acne and enlargement of Montgomery’s tubercles.14 One-third to half of all pregnant women develop these tubercles, which are modified sebaceous glands.5,8 However, sebum excretion has not been found to decrease in lactating females post-delivery.20

Oral mucosal changes:

Oedema and hyperaemia of the gingivae in pregnancy is attributable to local irritation and nutritional deficiencies and is seen in around 80% women.5 Gingivitis not related to poor oral hygiene may occur. Granuloma gravidarum or pregnancy epulis might occur that regresses postpartum.

Hair changes:

Hair changes are seen in 3-12% of pregnant females.21 Hirsuitism and hypertrichosis occurs due to oestrogen. This leads to an increase in the percentage of hair in anagen.2 Approximately 2-3 months after delivery, loss of telogen hair occurs.22 This is termed as late anagen release as the hair follicles are no longer stimulated to stay in anagen phase by the maternal hormones. The hair recovery occurs in 3-12 months. A small number of females may experience episodic shedding of hair for long periods. This has been proposed to be due to the inability of some hair follicles to revert to asynchronous shedding.23 Rarely, male pattern baldness may occur in women.2

Nail changes:

Nail growth increases during pregnancy.6 Brittleness of the nail plate and distal onycholysis may be seen.19 Beau’s lines may develop after delivery.12 Reassurance is all that is needed for these benign nail problems.

DISEASES MODIFIED BY PREGNANCY

Many pre-existing dermatoses may be exacerbated or ameliorated by pregnancy. Certain tumours may also show remission or exacerbation. This is due to the shift in pregnancy to the Th2 state and a return to Th1 state in the postpartum period and also the discontinuation of some drugs due to their teratogenic potential.

Infections:

Depressed cell-mediated immunity makes the pregnant woman susceptible to more severe and frequent infections.24

Candidiasis is quite common and was found to be the commonest cause of white discharge per vagina, being present in 22% pregnant females.5 Half of all neonates born to infected mothers are positive for Candida and some may show signs of infection.25 Pityrosporum folliculitis, caused by Pityrosporum ovale, is more common in pregnancy.25

Genital warts are the commonest sexually transmitted disease seen in 4.7% subjects, these increase in size during pregnancy.9,25 Prophylactic caesarian section to prevent laryngeal papillomas in the neonate is not recommended now.26 Herpes simplex virus infection carries 50% risk of transmission to neonate in the primary episode and 5% risk in recurrent episode, caesarean section might be warranted to prevent such transmission.26 Varicella zoster virus infection has been reported to cause pneumonia in 14% of mothers and death in 3%.27 Bowenoid papulosis, caused by human papilloma virus appears first during pregnancy or may get aggravated.6

Pregnancy prepones the clinical manifestations in HIV infected females, possibly due to additive immune suppression. Pneumocystis pneumonia or listeriosis may prove to be fatal.27 Kaposi’s sarcoma may occur in these females.27 20-30% women present with leprosy for the first time in pregnancy and the postpartum period.28 The disease tends to downgrade towards the lepromatous pole in pregnancy and upgrades during lactation.29 Type 1 lepra reactions are more frequent in the first trimester and after delivery, whereas type 2 lepra reactions peak in third trimester.29 Trichomoniasis is diagnosed in 60% of pregnant women.25

Autoimmune diseases:

Systemic Lupus Erythematosus (SLE) is associated with a better prognosis than previously thought, if the disease is in remission and nephropathy and cardiomyopathy are not present.10 If the disease is active, half of the patients’ disease will get worse and there might be fatalities.14 SLE tends to be more severe if it first presents in pregnancy.14 Babies of such mothers are likely to develop neonatal lupus.

Patients with scleroderma are usually unaffected and some are improved in pregnancy. However, occasional reports of renal crisis, hypertension and pre-eclampsia are reported.30 Course of dermatomyositis is usually unaltered but the disease may worsen in some patients.31

Pemphigus tends to be exacerbated or present for the first time in pregnancy.32 The clinical presentation in pregnancy is similar to that of the regular presentation. Differentiation from herpes gestationis is important.

Metabolic diseases:

Effect of pregnancy on porphyria cutanea tarda is not clear, though some females show biochemical and clinical deterioration.33 Acrodermatitis enteropathica shows clinical worsening.34

Connective tissue diseases:

Pregnancy can lead to bleeding, uterine lacerations and wound dehiscence in patients of Ehlers-Danlos syndrome. Pseudoxanthoma elasticum patients may suffer massive gastrointestinal bleeds.35 Lichen sclerosis et atrophicus of the vulva usually improves in pregnancy and a normal delivery is mostly possible.

Disorders of glands:

Acne can aggravate during pregnancy. Hidradenitis suppurativa and Fox-Fordyce disease become better as a result of decreased apocrine gland activity.27

Keratinization diseases:

The course of psoriasis remains unaltered in 40% females during pregnancy while it improves in a similar percentage of females and worsens in the remaining.36 It is more likely to deteriorate in the postpartum period.37 Psoriatic arthritis has been found to worsen or present for the first time in pregnancy.2

Generalized pustular psoriasis of Von Zambusch may rarely occur. Though most patients have a preceding or family history of psoriasis, some may develop the disease without ever having a preceding episode.38 Peak incidence is seen in the last trimester and the disease tends to recur.38 Multiple, discrete, sterile pustules at the margins of erythematous macules on the umbilicus, medial thigh, axillae, inframammary folds, gluteal creases and sides of neck are seen. These break to form erosions and crusts. Painful, circinate mucosal erosions may form. Prednisolone is used for management.12 Von Zambusch pustular psoriasis of pregnancy was earlier termed ‘Impetigo Herpetiformis’ but the term is best avoided as it is impossible to differentiate it from the former, both clinically and histologically.6 Erythrokeratoderma variabilis is reported to worsen during pregnancy.27

Tumours:

A melanoma that develops during pregnancy carries worse prognosis but if pregnancy occurs after the tumour is resected, the prognosis is unaltered.39 Metastasis in the fetus has been seen and a minimum period of two years following tumour resection is recommended.32 A female with neurofibromatosis may develop neurofibroma for the first time in pregnancy or older neurofibromas may grow in size. Rupture of major vessels may occur.6 Pregnancy may worsen mycosis fungoides and eosinophilic granuloma.6

Miscellaneous diseases:

Prognosis of atopic dermatitis is unpredictable in pregnancy, with reports of both improvement and worsening.27 Predisposed patients may first develop atopic dermatitis during pregnancy.40 Allergic contact dermatitis may improve in pregnancy.12 Hand eczema may worsen in the puerperal period.6 Erythema multiforme may be precipitated by pregnancy.6 Autoimmune progesterone dermatitis has been described in pregnancy.12 This disease is characterized by hypersensitivity to progesterone demonstrated by a positive intradermal skin test and cutaneous lesions resembling urticaria, eczema, erythema multiforme and dermatitis herpetiformis.41 The disease is associated with fetal mortality and recurs in subsequent pregnancies.12

PREGNANCY SPECIFIC DERMATOSES

These are a heterogeneous group of inflammatory skin diseases specific for pregnancy.42 Most of these conditions are benign and resolve spontaneously in the postpartum period but a few of these are associated with fetal complications.42 Almost all of them present with pruritus and a cutaneous eruption of varying severity.5

Classification:

The first attempt to classify these conditions was made by Holmes and Black in 1982-83 who classified them into: a) Pemphigoid Gestationis (PG) or Herpes Gestationis(HG), b) Polymorphic Eruption of Pregnancy (PEP) or Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP), c) Prurigo of Pregnancy (PP) and d) Pruritic Folliculitis of Pregnancy (PF).43,44 Shornick was of the view that all patients with PF also had papular dermatitis, so he included PF in the PP group. He included Intrahepatic Cholestasis of Pregnancy (ICP) in his classification for dermatoses where secondary skin lesions due to scratching are produced. He proposed that failure to consider ICP in the classification has led to confusion in terminology of pregnancy specific diseases. Thus, his classification included PG, PEP, PP and ICP.45 Ambros-Rudolph et al carried out a retrospective review of 505 pregnant patients over a 10 year period and gave a more rationalised classification system in 2006. They clubbed PP, PF and eczema of pregnancy in one group called Atopic Eruption of Pregnancy (AEP) due to their overlapping features and found this group to be the most common pruritic condition in pregnancy. Thus, they proposed four conditions: a) AEP, b) PEP, c) PG and d) ICP.46 The various specific pregnancy dermatoses have been elaborated in Table 2.

Table 2: Comparison of different pregnancy specific dermatoses in relation to clinical characteristics, prognosis, investigations and treatment.

  AEP PEP PG ICP
Pruritus + + + +
Primary cutaneous involvement + + + -
Skin lesions Eczematous or papular Papules, vesicles and urticarial lesions Vesiculo bullous lesion on urticarial base Excoriations, papules secondary to scratching
Site of lesions Trunk, extensors of limbs, rest of the body also involved Abdominal involvement, in striae distensae, periumbilical sparing Abdominal, particularly periumbilical involvement Palms and soles followed by rest of the body
Time First trimester Third trimester, Post partum Second and third trimester, post partum Second and third trimester
Risk with primigravidae - + - -
Association with multiparity - + - +
Flare at delivery - - + -
Recurrence + - + +
Family history + + - +
Histopathology Non-specific Non-specific Specific, sub epidermal vesicle Non-specific
Immunofluorescence - - Linear deposition of C3 -
Other lab findings Ig E elevated - Indirect IMF + Increased serum bile acids
Maternal risk - - Progression to pemphigoid, thyroid dysfunction Gallstones, Jaundice
Fetal risk - - Prematurity, Small for age baby, neonatal blistering Premature births, fetal distress, stillbirth
Treatment Steroids, antihistaminics Steroids, antihistaminics Oral steroids, antihistaminics Ursodeoxycholic acid

Atopic eruption of Pregnancy (AEP): (Syn: Besnier’s prurigo, prurigo gestationis, Nurse’s early onset prurigo of pregnancy)

It is the most common pregnancy specific dermatoses that includes eczematous or papular lesions in females with personal or family history of atopy and elevated IgE - accounting for nearly half of all patients.46 The disease tends to recur in subsequent pregnancies with 75% of all cases occurring before the start of the third trimester.47 It carries no risk for the mother or baby however, infant may develop atopy later in life.48 Treatment is symptomatic with antihistamines and corticosteroids.

E-type AEP: This group comprises of 67% of AEP patients and includes patients with eczematous features; previously referred to as Eczema of Pregnancy (EP). It was not until 1999 that a high prevalence of atopic eczema was noted in pregnancy.49 80% of pregnant women develop the first episode of atopic dermatitis during pregnancy.46 This is attributed to the Th2 cytokine profile in pregnancy and a dominant humoral immunity.4 It is more common in primigravida, in single gestation, begins in early pregnancy and affects whole body including face, palms and soles.46

P-type AEP: This group includes what was referred to previously as Prurigo of Pregnancy and Pruritic Folliculitis of Pregnancy. Prurigo of Pregnancy (PP) is seen in one out of 300 to 450 pregnancies and occurs predominantly in the second to third trimester.50 Excoriated or crusted papules are seen over the extensors of extremities and abdomen and are associated with some eczematization. The eruption lasts up to 3 months after delivery and recurrences in subsequent pregnancies are common.51 PP is associated with ICP with the differentiating feature being the absence of a primary lesion in the latter.50 Personal and family history of atopic dermatitis or raised IgE may be seen in PP.52 Serology is normal. There are no specific changes on histopathology and immunofluorescence results are found to be negative.50 There appears to be no maternal or fetal risk.45

Pruritic Folliculitis of Pregnancy (PF), first described by Zoberman and Farmer, is now believed to be as common as PG or PP, though only a few cases have been reported.50 It begins in the latter two trimesters and affects roughly one in 3000 pregnancies.51 Pruritus is not a defining feature, despite what the name suggests.2 Multiple, follicular papules and pustules occur on the shoulders, arms, chest, upper back and abdomen and are acneiform in nature.42 The lesions tend to resolve in a couple of months following delivery. Histopathological examination reveals non-specific features with sterile folliculitis and immunofluorescence studies are negative.50 No maternal or fetal risk is described except for low birth weight neonates in a single study.52 Pathogenesis of PF is unknown with no definite role of androgens or immunologic abnormalities.53 There is no evidence to suggest that it is a hormonally aggravated acne as proposed by some workers.54

Polymorphic Eruption of Pregnancy (PEP): (Syn: Pruritic Urticarial Papules and Plaques of Pregnancy or PUPPP, Bourne’s Toxaemic Rash of Pregnancy, Toxic Erythema of Pregnancy, Nurse’s Late Prurigo of Pregnancy)

With a prevalence of a case in every 130-300 pregnancies, this disease is the second most common pregnancy specific dermatoses and was seen in 21.6% pregnancies reviewed by Ambros-Rudolph et al.46 They found it began in late pregnancy in 83% cases and 15% in the postpartum period.46 The disease occurs predominantly in primigravida and a familial predisposition is present.55 Lesions are pleomorphic, usually urticarial but purpuric, vesicular, polycyclic and targetoid lesions may be present. The striae on the abdomen are the first to be involved and there is a characteristic periumbilical sparing.56 The lesions seldom occur on the body above the breast and on hands and feet.12 The lesions resolve with scaling and crusting in six weeks. The disease is more common in excessive weight gain during pregnancy and in multiple gestation.57,58 Histopathology is non-specific and shows spongiosis, occasional subepidermal split and eosinophilic infiltration. Serology and immunofluorescence is negative.50 Treatment is symptomatic, oral steroids are needed in severe cases. There are no associated maternal or fetal complictions,59 although infants may later develop atopic dermatitis.2

The pathogenesis is unknown however, the abdominal distension leading to collagen and elastic fibre damage in striae is hypothesized, leading to formation of antigens and triggering inflammatory cascade.60 The role of progesterone has been suggested by the increased progesterone receptor immunoreactivity in skin lesions of PEP.61 The discovery of fetal DNA in skin lesions of women with PEP has furthered the hypothesis that abdominal distension leads to increased permeability of vessels and permit chimeric cell migration in the maternal skin.62 Linear IgM dermatosis of pregnancy is an entity characterized by pruritic, red, follicular papules and pustules on the abdomen and proximal extremities seen after 36 weeks gestation and a linear band of IgM deposition on basement membrane zone. It has been characterized as a variant of PEP or PP by different authors.12

Pemphigoid Gestationis (PG): (Syn: Herpes Gestationis or HG, Gestational Pemphogoid, Dermatitis Herpetiformis of Pregnancy)

PG is the most clearly characterized pregnancy dermatosis and the one which also affects the fetal skin.63 It is a rare, self-limiting, autoimmune bullous disease with an incidence of 1:1700 to 1:50000 pregnancies.63 Mean onset occurs at 21 weeks gestation, though it occurs in the postpartum period in a fifth of all cases.64 Constitutional symptoms, burning and itching herald the onset of the disease. Half of patients develop urticarial lesions on the abdomen, particularly in the periumbilical region, that change rapidly to a generalized bullous eruption usually sparing the face, palms, soles and mucosae. Vesicles may arise in herpetiform or circinate distribution. Face is involved in 10% cases and oral mucosa in 20%.12 The disease shows spontaneous improvement in late gestation but flares may occur at the time of delivery in 75% of the cases.63 Though the disease may remit after a few weeks after delivery, a protracted course, conversion to bullous pemphigoid or recurrence with menstrual cycle and use of oral contraceptive pills has been reported.50 PG tends to recur in subsequent pregnancies in a more severe form and at an early stage with longer stay in postpartum.50 Skipped pregnancies have been described.63,65 The disease is also linked with hydatiform mole and choriocarcinoma.66

The classical histopathological finding is the presence of a subepidermal vesicle, spongiosis and an infiltrate consisting of lymphocytes, histiocytes and eosinophils.64 An inverted tear drop appearance due to oedema in the dermal papilla is seen in early urticarial lesions.15 Direct immunofluorescence reveals a linear deposition of C3 along the dermo-epidermal junction in 100% cases and is diagnostic of the disease, while a salt split skin shows an epidermal staining.67 Antithyroid antibodies may be present but thyroid dysfunction is not common.63 Systemic corticosteroids are the mainstay of management. About one in ten children born to women with PG develop blisters due to passive transfer of antibodies, this resolves on its own. Severity of the disease has been correlated with the risk of prematurity and small for gestational age babies.68

Pathogenesis of PG involves the production of IgG1 antibodies against NC16A domain of carboxyl terminus of Bullous Pemphigoid Antigen 2 (BPAg2), leading to activation of complement, recruitment of eosinophils to the local site and damage of the basement membrane and consequent blistering.2 The aberrant expression of MHC class II antigens of paternal haplotype is believed to stimulate an allogenic response to placental basement membrane and this is believed to cross react with the skin in PG.63,69

Intrahepatic Cholestasis of pregnancy (ICP): (Syn: Obstetric Cholestasis, Pruritus Gravidarum, Icterus Gravidarum, Recurrent Jaundice of Pregnancy, Idiopathic Jaundice of Pregnancy)

Pruritus in pregnancy is fairly common and can be due to various reasons like pregnancy specific dermatoses and other co-existing dermatoses such as scabies, urticaria, atopic dermatitis, drug reactions etc. It was found to be present in more than half of 170 pregnant women in an Indian study.70 This must be differentiated from ICP where the skin lesions arise secondary to itching.

ICP was first described by Kehr in 1907.63 ICP being referred to Pruritus Gravidarum (for pruritus without skin changes occurring early in pregnancy and related to atopic diathesis and no cholestasis) and Prurigo Gravidarum (for pruritus associated with PP like skin lesions and associated with cholestasis) lead to much confusion regarding nomenclature.63 The disease has an incidence of 10-150 cases per 10,000 pregnancies71, being more common in South America and Scandinavia, probably due to dietary factors.50 Patients complain of sudden onset pruritus beginning from the palms and soles and later generalizing to the whole body. Skin lesions are secondary to itching and range from excoriations to prurigo nodularis, extensors are more severely involved. Jaundice is seen in 20% cases only.72 Clay coloured stools, dark urine and haemorrhage secondary to vitamin K malabsorption can occur. Family history can be elicited in half of the cases and an association with multiple gestation is described.73 Resolution of ICP occurs soon after delivery. Recurrence in subsequent pregnancies is seen in 45-70% cases and routinely with the use of oral contraceptive pills, though no detectable abnormalities are seen in the duration between two pregnancies.63 Histopathology is non-specific and immunofluorescence is negative. Diagnosis is made by increased serum bile acid levels, transaminases are elevated. Prothrombin time may be prolonged. A 2.7 times increased risk of gallstones is reported in primigravida with ICP compared to non-pregnant women.74 ICP is associated with significant fetal morbidity including premature births in 20-60% cases, intrapartum fetal distress including meconium aspiration in 20-30% and fetal mortality in 1-2%.71 Risk is particularly more if serum bile acid levels exceed 40 micromoles per litre.75 Meconium may cause umbilical vein compression and induction of labour at 36 weeks gestation has been recommended in severe cases.50 The goal of treatment is reduction of serum bile acids. Ursodeoxycholic acid, given in the dose of 15mg/kg orally daily is the only proven therapeutic agent that decreases fetal mortality.63,76 Cholestyramine reduces vitamin K absorption and increases the risk of haemorrhage. Other agents like S-adenosylmethionine, dexamethasone, silymarin, phenobarbitone, epomediol and activated charcoal are not that effective and do not affect fetal risk.63 Topical emollients and antipruritic agents offer symptomatic relief but antihistamines are not that effective.50

The key event in the pathogenesis of ICP is elevation of bile acids. Oestrogens are said to have cholestatic properties by reducing hepatocyte bile acid uptake and also by inhibiting basolateral transport proteins.50 Progesterone may additionally saturate the transport capacity of these transport proteins in hepatocyte.71 Genetic predisposition occurs due to mutation in genes encoding bile transport proteins, with cholestasis developing in pregnancy as their capacity to secrete substance is exceeded.63 Bile acids passing through the placenta produce vasoconstriction of placental veins, fetal cardiomyocyte dysfunction and also abnormal uterine contractility, all leading to fetal hypoxia.71

CONCLUSION

Pregnancy is associated with a wide variety of cutaneous changes. These may range from common, benign changes termed physiological or more severe, posing significant risk to the mother as well as the baby. Physiological pregnancy changes may be of cosmetic concern to the patient and seldom need anything more than counselling. Pre-existing dermatoses may aggravate during this period, posing a challenge to the treating physician. Women suffering from such diseases need to be warned of complications and risks before trying to conceive. A strict watch for possible complications and appropriate management at an early stage is warranted. Women should also be looked for pregnancy specific dermatoses and their complaints should not be lightly overlooked as non-specific or physiological. Careful history and examination with a judicious use of investigations will help to arrive at a diagnosis and in prompt institution of treatment.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
MOHAMMAD ADIL; MBBS, MD (Dermatology, STD’s & Leprosy); Senior Resident, Postgraduate Department of Dermatology, STDs and Leprosy; Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, India. TASLEEM ARIF; MBBS, MD (Dermatology, STD’s & Leprosy); Assistant Professor, Postgraduate Department of Dermatology, STDs and Leprosy; Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, India. SYED SUHAIL AMIN; MBBS, MD (Dermatology, STD’s & Leprosy); Head of the Department, Postgraduate Department of Dermatology, STDs and Leprosy; Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, India.
Corresponding Author Details: 
TASLEEM ARIF; MBBS, MD (Dermatology, STD’s & Leprosy); Assistant Professor, Postgraduate Department of Dermatology, STDs and Leprosy; Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, India.
Corresponding Author Email: 
dr_tasleem_arif@yahoo.com
References
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Optimising stroke prevention in patients with atrial fibrillation in primary care

Authors
Yassir Javaid
Article Citation and PDF Link
BJMP 2016;9(1):a904
Abstract / Summary
Abstract: 

In clinical practice, atrial fibrillation (AF) is the most common cardiac arrhythmia seen, and with an ageing population its prevalence is expected to rise. Guidelines recommend anticoagulant therapy for AF-related stroke prevention, based on an individual’s predicted risk of stroke; options include vitamin K antagonists (VKAs) and the non-VKA oral anticoagulants (NOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban. The NOACs fulfil most criteria associated with an ideal anticoagulant and have demonstrated improved benefit–risk profiles compared with warfarin in patients with non-valvular AF. Although patients with AF commonly have other chronic conditions that may complicate treatment, a recent meta-analysis showed a similar treatment effect of NOACs in almost all challenging-to-treat subgroups encountered in clinical practice compared with the general patient population. Encouragingly, data on the real-world efficacy and safety of NOACs are growing and lend support to the increased use of NOACs in this indication.

Keywords: 
Anticoagulation, atrial fibrillation, real-world, stroke prevention

Summary points

  • The non-vitamin K antagonist oral anticoagulants have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients representative of those encountered in routine clinical practice and including those deemed ‘challenging-to-treat’
  • Accurate detection of atrial fibrillation and assessment of stroke and bleeding risk is crucial in identifying patients who should receive anticoagulation
  • Elderly populations represent a significant proportion of patients seen in general practice, and advanced age should not be regarded as a contraindication to treatment; acetylsalicylic acid is not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular atrial fibrillation (except for those declining oral anticoagulation), particularly in fragile elderly patients, for whom this drug was historically prescribed
  • The frequency of follow-up visits, in particular to check compliance, should be tailored according to patients’ clinical characteristics and needs, but there is no requirement for routine coagulation monitoring, unlike vitamin K antagonists

Atrial fibrillation: a clinical and economic burden to society

Atrial fibrillation (AF) is the most frequently encountered sustained cardiac arrhythmia, with a prevalence of about 1.5–2% in the general population1,2. Its incidence is predicted to rise sharply over the coming years as a consequence of the ageing population and increased life expectancy in those with ischaemic and other structural heart disease2. In addition to being associated with significantly increased rates of mortality3, AF is also associated with significantly increased rates of heart failure, which is both a common cause and consequence of AF and greatly worsens the prognosis4. However, it is stroke that is the most devastating consequence of AF, with an average fivefold increased risk5.

AF-related strokes are often more severe than other strokes6,7because the clots that embolise from the left atrium or left atrial appendage are often much larger8than from other sources of emboli. These clots usually lodge in large cerebral vessels, commonly the middle cerebral artery, resulting in huge neurological and functional deficits and increased mortality compared with other stroke types. Moreover, the strokes suffered by patients with AF are more likely to lead to extended hospital care than strokes in patients without AF, thus impacting on patients’ quality of life7.

Current evidence suggests that, in the UK, AF has a causative role in almost 20% of all strokes9. This is likely to represent a significant underestimate given that long term electrocardiogram (ECG) monitoring in patients who would previously have been diagnosed as having cryptogenic stroke has demonstrated a significant AF burden in these patients10.

With improved AF detection and stroke prevention, it is estimated that approximately 8000 strokes could be avoided and 2100 lives saved every year in the UK, resulting in substantial healthcare savings of £96 million11,12.

A key objective of this short review is to provide primary care clinicians with the confidence to manage patients with AF in need of anticoagulation, including the safe and appropriate use of the non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, rivaroxaban (approved in the EU, US and several other countries worldwide) and edoxaban (approved in the EU, US and Japan).13-20The focus will be on how to accurately identify, risk-stratify and counsel patients on the risks and benefits associated with the different treatment options.

Who to treat. Accurate detection and assessment of stroke and bleeding risk

Many patients with AF are asymptomatic, particularly the elderly, less active patients who may not notice the reduction in cardiac performance associated with AF. Unfortunately, it remains the case that AF is undetected in up to 45% of patients21, and stroke is very often the first presentation of AF.

Both the National Institute for Health and Care Excellence (NICE) and the European Society of Cardiology (ESC) guidelines recommend opportunistic screening in patients aged ≥65 years by manual pulse palpation followed by ECG in patients found to have an irregular pulse1,22. Opportunistic screening (manual pulse palpation) was shown to be as effective as systematic screening (ECG) in detecting new cases23, and this simple strategy should be used to screen at-risk patient groups as often as possible. Hypertension and increasing age are the two leading risk factors for developing AF, but other high-risk groups include patients with obstructive sleep apnoea, morbid obesity or a history of ischaemic heart disease24-26. In the context of proactive AF detection, many initiatives have been launched worldwide to encourage primary care clinicians to integrate manual pulse checks into their routine practice. The Know Your Pulse campaign was launched by the AF Association and Arrhythmia Alliance during Heart Rhythm Week in 2009 and was quickly endorsed by the Department of Health in the UK and by many other countries. This initiative has assisted in diminishing some of the gaps in AF detection21.

The most frequently used tools to evaluate stroke risk in patients with non-valvular AF (AF that is not associated with rheumatic valvular disease or prosthetic heart valves) are the CHADS227 and CHA2DS2-VASc28scores, with recent guidelines favouring the use of the latter and emphasising the need to effectively identify ‘truly low-risk’ patients1. The CHA2DS2-VASc score is superior to CHADS2 in identifying these truly low-risk patients, who should not be routinely offered anticoagulation1. Patients with any form of AF (i.e. paroxysmal, persistent or permanent), and regardless of whether they are symptomatic, should be risk stratified in this way. The risk of stroke should also be assessed using CHA2DS2-VASc in patients with atrial flutter and probably for the majority of patients who have been successfully cardioverted in the past22. Unless the initial underlying cause has been removed (e.g. corrected hyperthyroidism) and there is no significant underlying structural heart disease, the risk of patients suffering from a recurrence of AF following ‘successful’ cardioversion remains high29. The ESC guidelines recommend that anticoagulation should be offered to patients with a CHA2DS2-VASc score ≥1 based on assessment of risk of bleeding complications and the patient’s clinical features and preferences1.

The new Quality and Outcomes Framework (QOF) for 2015–2016 now recommends the use of CHA2DS2-VASc for risk stratification and no longer recommends antiplatelet agents as a therapeutic option for stroke prevention in patients with non-valvular AF30; this should result in significantly more patients receiving anticoagulation for this indication. The changes to QOF 2015–2016 compared with 2014–2015 are summarised in Table 130.

Table 1. Summary of changes to UK the Quality and Outcomes Framework (QOF) 2015–201630

NICE indicator ID Changes 2014–2015 points 2015–2016 points
NM45: Patients with AF and CHADS2=1 currently treated with anticoagulant therapy or antiplatelet therapy Retired 6
NM46: Patients with AF and a latest record of a CHADS2 ≥1 currently treated with anticoagulant therapy Replaced by NM82 6
NM82: Patients with AF and CHA2DS2-VASc ≥2 currently treated with anticoagulant therapy Replacement 12
NM81: Patients with AF in whom stroke risk has been assessed using the CHA2DS2-VASc risk-stratification scoring system in the preceding 12 months (excluding those with a previous CHADS2 or CHA2DS2-VASc ≥2) New indicator 12

Key: AF = atrial fibrillation; CHADS2 = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); CHA2DS2-VASc = Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 years (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74 years, Sex category (female); NICE = National Institute for Health and Care Excellence

The Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation (GRASP-AF) clinical audit software detection tool is now very widely used in primary care to improve clinical outcomes in the AF population by identifying patients likely to benefit from anticoagulation. GRASP-AF systematically scans general practice software systems and calculates CHADS2 and CHA2DS2-VASc scores in patients who are coded as having AF, thus enabling physicians to identify high-risk patients who are not adequately treated for stroke prevention31. Identification of AF patients who are poorly controlled on warfarin (defined as having a time in therapeutic range <65% or a labile international normalised ratio [INR], e.g. one INR value >8 or two INR values <1.5 or >5 within the past 6 months)22 is crucial because these patients are more likely to experience major bleeding or stroke. These patients should be reviewed and, if possible, the cause for the poor warfarin control should be identified. The Warfarin Patient Safety Audit tool is another software tool that has been developed to help identify patients with poor warfarin control32.

Primary care clinicians are being urged to objectively assess the bleeding risk of AF patients who are receiving, or about to receive, anticoagulation1,22,32. HAS-BLED is the bleeding assessment scheme advocated by both NICE and the ESC1,22, this has been validated in several independent cohorts and was shown to correlate well with the risk of major bleeding, in particular intracranial bleeding1. The key aspect of HAS-BLED is that, unlike CHADS2 and CHA2DS2-VASc, it consists of risk factors that are modifiable. It should, therefore, not be a tool to influence the decision of whether to anticoagulate, but instead to identify ways to reduce the risk of bleeding in patients receiving an anticoagulant; for example, optimising blood pressure control, stopping unnecessary antiplatelet or anti-inflammatory agents and reducing alcohol consumption can all significantly reduce HAS-BLED scores and bleeding risk1. In addition, it needs to be emphasised that the absolute number of patients with AF experiencing a serious bleeding event while receiving anticoagulant therapy is low (~2–3%/year in the XANTUS, PMSS and Dresden NOAC Registry real-world studies) , with prospective real-world studies indicating that most bleeding events can be managed conservatively33-35. Whilst concerns have been raised about not having a reversal agent to counter the anticoagulant action of NOACs in patients who experience serious bleeding, the low incidence of major bleeding in real-world and phase III studies and its conservative management in most cases demonstrate that such agents would not be required routinely. Despite these low rates of major bleeding, reversal agents have been developed and successfully completed phase III studies and undergone approval in some markets, including idarucizumab in the UK36,37. Notably, high-risk patients with AF were shown to be more willing to endure bleeding events in order to avoid a stroke and its consequences38, thus reinforcing the message that “we can replace blood but we cannot replace brain tissue”.

Adequate anticoagulation therapy should follow appropriate patient identification

Identifying the right treatment option for patients with AF is likely to improve clinical outcomes. Involving patients in the decision-making process and rationale, and ensuring they understand the net benefit–risk of treatment options, is likely to lead to better compliance and improved clinical outcomes. The ESC guidelines consider patients with valvular AF (patients with AF in the presence of either rheumatic mitral stenosis [very rare now in the UK] or prosthetic heart valves) to be at high risk, and these patients should be anticoagulated with a VKA regardless of the presence of any other risk factors1. Warfarin is very effective at reducing the risk of stroke compared with acetylsalicylic acid (ASA)39,40, but an unpredictable dose–response relationship and multiple drug and food interactions can be problematic for some patients, and many patients remain sub-optimally treated41. ASA is also not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular AF especially in frail, elderly patients in whom ASA was historically prescribed. The GARFIELD-AF registry (10,614 patients enrolled in the first cohort) revealed that real-world anticoagulant prescribing in AF populations deviates substantially from guideline recommendations: 40.7% of patients with a CHA2DS2-VASc score ≥2 did not receive anticoagulant therapy, and a further 38.7% with a score of 0 received anticoagulant therapy. At diagnosis, 55.8% of patients overall were given a VKA, just over one quarter (25.3%) received an antiplatelet drug alone, and ~4.5% received a NOAC24. Inappropriate prescribing was further confirmed by data from UK general practices (n=1857, representing a practice population of 13.1 million registered patients) using the GRASP-AF tool. Only 55% of patients with high-risk AF (CHADS2 ≥2) were receiving oral anticoagulation (OAC) therapy, whereas a further 34% of patients with no known contraindication did not receive OAC therapy42.

The NOACs have altered the landscape in terms of stroke prevention management by increasing the available options for patients. These agents exhibit some important practical advantages over traditional therapy (e.g. no requirement for routine anticoagulation monitoring, simple fixed dosing oral regimens, fast onset of action, fewer drug reactions and no food interactions), leading to their increased uptake in primary care.

Key patient groups who are likely to benefit from the NOACs include patients poorly controlled on VKAs, those predicted to require medications that interact with VKAs (e.g. patients who require frequent antibiotics), those without severe renal impairment or those with a prior ischaemic stroke while receiving a VKA with an adequate INR. These agents could also be a good choice for patients living a considerable distance from their local hospital or surgery and commuters. The NICE guidelines state that primary care clinicians should consider clinical features and patient preference before deciding on the most appropriate option for patients22. In addition, cost may be important in some settings. All of the NOACs have demonstrated cost-effectiveness versus warfarin, and although cost models vary by country, there is little doubt that these agents provide cost-effectiveness largely through the number of adverse events avoided and their associated costs43.

Choice of anticoagulant: which to choose?

The demonstration of a favourable benefit–risk profile (stroke prevention vs bleeding events) in large phase III studies involving over 70,000 patients has resulted in the regulatory approval of apixaban, dabigatran, edoxaban and rivaroxaban44-47for the prevention of stroke and systemic embolism in patients with non-valvular AF and one or more risk factors.

Overall, NOACs have demonstrated an improved benefit compared with warfarin, with lower rates of intracranial haemorrhage (for all NOACs) and similar or superior efficacy for stroke prevention44-48. Statistically significant relative risk reductions (RRRs) in the incidence of fatal bleeding events were seen with low-dose dabigatran (110 mg twice daily [bd]; RRR=42%), both tested doses of edoxaban (30 mg once daily [od] and 60 mg od; RRR=65% and 45%, respectively) and rivaroxaban (20 mg od; RRR=50%)46,47,49; rates of fatal bleeding were also lower in patients treated with apixaban compared with warfarin (34 patients vs 55 patients, respectively)44. These data are promising, especially considering the current lack of a specific antidote for any of the NOACs, and it is likely that the very short half-life of these drugs play an important role in mitigating the bleeding risk.

Owing to a lack of head-to-head comparisons between the NOACs in phase III clinical trials, patient characteristics, drug compliance, tolerability issues and cost may be important considerations1. In addition, subanalyses of phase III trial data for rivaroxaban, apixaban and dabigatran indicate that the challenging-to-treat patient groups often encountered by primary care clinicians can be treated effectively and safely with the NOACs (Table 2). A recent meta-analysis showed a similar treatment effect for almost all subgroups encountered in clinical practice; NOACs appeared to be at least as effective as VKAs in reducing the risk of stroke and systemic embolism and no more hazardous in relation to the risk of major bleeding events, irrespective of patient co-morbidities50.

Table 2.Novel oral anticoagulants studied in key patient subgroups*

Subgroup analysis Rivaroxaban Dabigatran Apixaban
Factors related to disease ROCKET AF RE-LY ARISTOTLE
Heart failure ü59 ü60 ü61
Renal impairment ü62 ü63 ü64
Prior stroke ü65 ü66 ü67
VKA-naïve ü68 ü69 ü70
Prior MI or CAD ü(prior MI)71 ü(CAD or prior MI)72 üCAD73
PAD ü74
PK/PD ü75 ü76
East Asian patients ü77 ü78 79
Elderly ü80 ü49 ü81
Major bleeding predictors ü82
Obesity
Diabetes ü83 ü84 ü85
Valvular heart disease ü86 ü87
Paroxysmal versus persistent AF ü88 ü89 ü90

*No subgroup analyses have been presented for edoxaban Key: AF = atrial fibrillation; ARISTOTLE = Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; CAD = coronary artery disease; CHADS2= Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); MI = myocardial infarction; PAD = peripheral artery disease; PK/PD = pharmacodynamics/pharmacokinetics; RE-LY = Randomized Evaluation of Long-term anticoagulation therapy; ROCKET AF = Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; VKA = vitamin K antagonist

Because patient selection in clinical trials is based on strict inclusion/exclusion criteria, patient populations in such studies are not always representative of patients routinely seen in real-world practice. In addition, bleeding events may be managed differently in clinical trials versus routine clinical practice. Real-world data are, therefore, needed to help validate drug safety and effectiveness in unselected patient populations. Following phase III clinical trials and the widespread approval of the NOACs in stroke prevention in patients with non-valvular AF, real-world experience has been steadily accumulating. The current real-world data for rivaroxaban, apixaban and dabigatran have been very reassuring and bridge the evidence gap between clinical studies and real-world experience33-35,51-57.

The lack of routine coagulation monitoring with NOACs does not remove the necessity for regular follow-up. Instead, the frequency of visits can be tailored according to patients’ clinical characteristics and needs. NOACs are all partially eliminated by the kidneys; therefore, regular monitoring of renal function is important either to use a lower recommended dose of these drugs or to avoid them. For example, renal function should be monitored every 6 months in patients who have stage III chronic kidney disease (creatinine clearance [CrCl] 30–60 ml/min)58. Apixaban, rivaroxaban and edoxaban are not recommended in patients with CrCl <15 ml/min, and dabigatran is contraindicated in patients with CrCl <30 ml/min13,15,17,19. Reduced-dose regimens of NOACs are recommended for patients at higher risk of bleeding events, including those with reduced renal function. For example, a reduced apixaban dose of 2.5 mg bd is indicated in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg or serum creatinine ≥1.5 mg/dl (133 μmol/l); a reduced rivaroxaban dose of 15 mg od is indicated in patients with CrCl 15‒49 ml/min58; edoxaban is recommended at a reduced dose of 30 mg od in patients with CrCl 15‒50 ml/min and contraindicated in patients with CrCl >95 ml/min58; and a reduced dose of 110 mg bd dabigatran should be considered in patients with CrCl 30‒50 ml/min who are at a high risk of bleeding58. Follow-up visits should also systematically document patient compliance, thromboembolic and bleeding events, side-effects, co-medications and blood test results58.

Conclusions

The NOACs have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients, including those deemed challenging to treat. The NOACs also address many of the limitations associated with VKA use, thus assisting with their integration into clinical practice for stroke prevention in patients with non-valvular AF. In addition, the results from subgroup analyses should provide primary care clinicians with the confidence to manage stroke-prevention strategies in a wide variety of patients with AF.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The author would like to acknowledge Sofia Konisti, who provided editorial support with funding from Bayer HealthCare Pharmaceuticals.
Competing Interests: 
Dr Javaid has received honoraria and/or travel grants from a number of pharmaceutical companies, including Bayer, Boehringer Ingelheim, Pfizer/BMS and Astra Zeneca.
Details of Authors: 
YASSIR JAVAID, Primary Care Cardiovascular Lead, East Midlands Strategic Clinical Network, Danes Camp Surgery, Northampton, NN4 0NY, United Kingdom.
Corresponding Author Details: 
Yassir Javaid, Danes Camp Surgery, Northampton, NN4 0NY, United Kingdom.
Corresponding Author Email: 
submission4044@hotmail.co.uk
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  66. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9:1157-1163.
  67. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012;11:503-511.
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  71. Mahaffey KW, Stevens SR, White HD, et al. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or Factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35:233-241.
  72. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012;125:669-676.
  73. Bahit MC, Lopes RD, Wojdyla DM, et al. Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial. Int J Cardiol. 2013;170:215-220.
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  75. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: Results from ROCKET AF. J Clin Pharmacol. 2014;54:917-927.
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  82. Goodman SG, Wojdyla DM, Piccini JP, et al. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014;63:891-900.
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Bednar tumour: an infrequent diagnosis

Authors
Manveen Kaur,Varsha Dalal and Anju Bansal
Article Citation and PDF Link
BJMP 2015;8(4):a836
Abstract / Summary
Abstract: 

Bednar tumour is a pigmented variant of dermatofibrosarcoma protuberans (DFSP), constituting 1 to 5% of all DFSPs, which in turn, represent 0.1% of skin malignancies. It is histopathologically characterised by scattered melanosome-containing dendritic cells within an otherwise typical DFSP. Bednar tumour poses a clinical diagnostic challenge and requires histopathological and immunohistochemical examination to arrive at the correct diagnosis. We report a case of Bednar tumour occurring on the shoulder of a 29-year-old male.

Keywords: 
Bednar, DFSP, pigmented tumour

Introduction

Bednar tumour, first described by Bednar in 1957, is a pigmented variant of dermatofibrosarcoma protuberans (DFSP).It is a rare entity, constituting1 to 5% of all DFSPs, which in turn, represent 0.1% of skin malignancies. It differs from DFSP by the presence of dendritic cells containing melanin, interspersed between the fusiform cells characteristic of DFSP. The most frequent location is in the trunk followed by upper and lower extremities and the head and neck region. We report a case of Bednar tumour occurring on the shoulder of a 29-year-old male.

Case report

A 29 year old male patient presented with a slow-growing swelling on his left shoulder for the past two years. Physical examination revealed a large, nodular, subcutaneous mass measuring 8x7 cm in left suprascapular region. Clinical impression was of soft tissue tumour and total resection with 3-cm margins was performed. Grossly, tumour measured 9x4.5 cm, with grey white to grey black cut surface (Figure 1a, 1b). Microscopy showed spindled cells arranged in a tight storiform pattern admixed with scattered heavily pigmented cells (Figure 2). On immunohistochemistry, tumour cells were positive for vimentin and CD34 (Figure 3a, 3b) and negative for S100, SMA and desmin. Pigmented cells were found positive for S100 and HMB 45 (Figure 4a, 4b) and negative for other markers. Thus, a final diagnosis of Bednar tumour was rendered.


Figure 1
- Gross appearance of the tumour with cut surface grey white to grey black


Figure 2 -
Spindle cells in storiform pattern admixed with scattered heavily pigmented cells


Figure 3 -
Tumour cells were positive for vimentin (3a) and CD34 (3b)


Figure 4 -
Pigmented cells showed positivity for S100 (4a) and HMB 45 (4b)

Discussion

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive soft tissue neoplasm with intermediate malignant potential, regarded as a low grade sarcoma by the WHO classification of tumours of the skin.1,2,3

It was first described by Darier and Ferrand as a distinct cutaneous disease entity called progressive and recurring dermatofibroma in 1924. The term dermatofibrosarcoma protuberans was officially coined in 1925 by Hoffman.4

Histopathologically, DFSP is characterised by irregular, short, intersecting fascicles of tumour cells arranged in a characteristic storiform pattern. Cells have spindle-shaped nuclei which are embedded fairly uniformly in a collagenous stroma. There are several histological variants of DFSP. These include Bednar tumour, fibrosarcomatous, fibrosarcomatous with myoid/myofibroblastic change, myxoid, granular cell, palisaded, giant cell fibroblastoma, combined and indeterminate.5

Pigmented DFSP (Bednar tumour), first designated as storiform neurofibroma by Bednar, is a clinically and morphologicallydistinct variant of DFSP, constituting 5%-10% of all cases of DFSP.1,5 Clinical presentation is in the form of erythematous blue or brown coloured plaque lesions, with a smooth or irregular surface, often adhering to the deep tissue. The tumour may be exophytic, nodular or multilobulated and is generally firm in consistency.2 The lesions present as a slow growth, over a period of months or years. They have been described in all ethnic groups, with preponderance in blacks. They occur in third and fourth decades of life, however they may also occur in infancy and show a slight male predominance.1,5

The histogenesis of Bednar tumour is controversial. Some authors regard these tumours as being of neuroectodermal origin because of the presence of dendritic melanocytes and cells suggestive of Schwannian differentiation; while others believe attribute the origin to various kinds of local traumas, such as previous burns, vaccination scars, insect bites or vaccination such as BCG.3,6

Histopathologically, Bednar tumour is characterised by scattered melanosome-containing dendritic cells within an otherwise typical DFSP. The number of melanin-containing cells varies from case to case. Abundant pigmented dendritic cells can cause black discoloration of the tumor, whereas scant pigmented cells can be only identified microscopically.3,5 They grow invasively into the dermis and may reach the subcutaneous strata, fascia and musculature, in a manner similar to that of dermatofibrosarcoma protuberans. Occasionally, Bednar tumour may undergo fibrosarcomatous transformation with rare examples of pulmonary metastasis.5 Wang et al have reported a case of Bednar tumour with prominent meningothelial- like whorls.7

Immunohistochemically, most of the tumour cells stain positively with CD 34 and vimentin, and are negative for neuron-specific enolase, HMB-45 and protein S-100. However, cells containing melanin are positive for the usual melanocytic markers such as S-100 protein.5 On electron microscopy, three populations of cells have been identified, most of the cells being represented by fibroblasts. The second population exhibits fine elongations, enclosed in basal membrane while the third population consists of dendritic cells containing melanosomes and premelanosomes.3,5

The differential diagnoses include pigmented (melanotic) neurofibroma, psammomatous melanotic schwannoma, and desmoplastic (neurotrophic) melanoma. Pigmented neurofibroma can be differentiated from Bednar tumour by more extensive storiform growth and strong positivity for CD34 in latter. Psammamatous melanotic schwannoma is circumscribed, heavily pigmented with psammoma bodies, tumour cells being S- 100 positive and CD34 negative. Desmoplastic melanoma shows junctional activity and neurotropism.

Treatment consists of complete excision of the tumour with maximum preservation of normal tissue to maintain function and for optimal cosmesis. Moh’s Micrographic Surgery (MMS) or staged wide excision “Slow Moh’s “(with formal histopathological sectioning and delayed reconstruction for complete circumferential peripheral and deep margin assessment) has become the standard surgical treatment for DFSP.6,8

Bednar tumour presents a diagnostic challenge to the clinician because of resemblance to other commonly occurring pigmented lesions. Histopathological and immunohistochemical examination are necessary to arrive at the correct diagnosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MANVEEN KAUR, MD (Pathology), Senior Resident,National Institute of Pathology (ICMR),Safdarjang Hospital Campus,New Delhi – 110029, India. VARSHA DALAL, MD (Pathology), Senior Resident, National Institute of Pathology (ICMR), Safdarjang Hospital Campus, New Delhi – 110029, India. ANJU BANSAL, MD (Pathology), Scientist D, National Institute of Pathology (ICMR), Safdarjang Hospital Campus, New Delhi – 110029, India.
Corresponding Author Details: 
DR ANJU BANSAL, MD (Pathology), Scientist D, National Institute of Pathology (ICMR), Safdarjang Hospital Campus, New Delhi – 110029, India.
Corresponding Author Email: 
dranjubansal@yahoo.com
References
References: 
  1. Bednar B. Storiformneurofibromas of the skin, pigmented and nonpigmented. Cancer. 1957; 10:368-76.
  2. De Morais PM, Schettini APM, Chirano CA, et al. Bednartumor (pigmented dermatofibrosarcomaprotuberans): a case report. An Bras Dermatol. 2005;80(3):273-6.
  3. Weyers W, Mentzel T, Kasper RC, et al: Dermatofibrosarcomaprotuberans. In: World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours. LeBoit PE, Burg G, Weedon D and Sarasain A (eds). IARC Press, Lyon, pp259-261, 2006.
  4. AboudKA. BlahoslavBednar (1916-1998) and the tumour which bears his name. Our Dermatol Online. 2012; 3(3): 239-240.
  5. Weiss SW, Goldblum JR. Bednartumor (pigmented dermatofibrosarcoma protuberance, storiformneurofibroma). Fibrohistiocytictumors of intermediate malignancy. Weiss &Goldblum eds. Enzinger and Weiss’s Soft Tissue Tumours, 5th ed. 2008, Mosby, Inc. P371-402.
  6. Llombart B, Serra-Guillén C, Monteagudo C, et al. Dermatofibrosarcomaprotuberans: a comprehensive review and update on diagnosis and management. Seminars in Diagnostic Pathology 2013; 30: 13-28.
  7. Wang J, Yang W. Pigmented dermatofibrosarcomaprotuberans with prominent meningothelial-like whorls. J CutanPathol 2008; 35 (Suppl. 1): 65–69.
  8. CampbellRM, ReganL, DufresneRG, et al. Bednar Tumor: Treatment With Mohs Micrographic Surgery. Cosmetic Dermatology 2006; 19(6): 422-4.

The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2015;8(4):a831
Abstract / Summary
Abstract: 

Despite progress in neurotransmitter identifications and the emergence of novel antipsychotics, the treatment of schizophrenia remains frustrating. There is now a flurry of research trying to figure out the aetiology of schizophrenia and potential etiological models other than neurotransmitter dysfunction deserve consideration. Recent years have witnessed a revival of interest in the viral and immunity based etiological models of schizophrenia. . A subset of schizophrenia may have a pure biological aetiology. There are several commonalities between schizophrenia and autoimmune disorders. Coexistence of established autoimmune disorders along with schizophrenia is suggestive that the latter could also have an autoimmune component. Antipsychotics may be working on the principle of immune modulatory and neuro- modulatory mechanisms.   The well recognized 1% global consistency of the incidence of schizophrenia indicates that the aetiology of schizophrenia involve an evolutionary genetic vulnerability and universally present environmental factors. There may be a genetic predisposition to the hypothetical “schizovirus” determining the development of schizophrenia in certain individuals. Certain people are genetically vulnerable to microbial infections in the sense that they have a highly sensitive surveillance system to the microbial infection and respond to the microbial adversary in an exaggerated way. Such a vulnerability and anomalous reaction to infection could result in the schizophrenia psycho-pathogenesis.

Keywords: 
schizophrenia, autoimmune disorders, schizovirus, genetic vulnerability

Introduction

A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation. The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology. The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection. Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter. To gain a detailed understanding of aetiological models of a subset of schizophrenia, herein the author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia. Genetic vulnerability has been highlighted in the schizophrenia literature alongside environmental factors. The veracity and contestability of the immunity- and viral-based aetiological hypothesis of schizophrenia merits further investigation.

Schizophrenic Syndromes

A prerequisite for incorporating autoimmune and viral aetiology into a scientific discussion would be acceptance of the heterogeneous hypothesis of schizophrenias; they may be a cluster of entities with different aetiologies and the end-stage of different disease processes. 1 Autoimmune or viral aetiology may account for one subgroup.

Schizophrenia has diverse signs and symptoms, and a long history of controversy. Nosologists designate it as polythetic, whereas most other mental illnesses are monothetic, seemingly affecting only one brain system. 2 In the second half of the twentieth century, the psychosocial model gave way to evidence that it is a brain disorder. Schizophrenia has a long history of controversies and there has been much contention over the aetiology, psychopathology, nomenclature, and diagnostic criteria. Schizophrenia is currently seen as a neurodevelopmental encephalopathy, in which the cognitive deficits are produced due to the errors during the normal development of the brain 3 or a neuro-degenerative disorder and the cognitive deficits are derived from a degenerative process that goes on unalterably. Modern neuroimaging techniques and an intensification of studies of necropsy tissue have been responsible for this shift. Researchers seem to agree that a neurodevelopmental or degenerative assault precedes the symptoms by several decades.

The aetiology of the cognitive deficits is unidentified and several potential factors, genetic and epigenetic, are envisaged. Environmental factors—including infectious agents and disturbance in utero through malnutrition—account for a few cases. Autoimmunity and viral theories would fit in with the neuro-developmental and neurodegenerative hypotheses. Proponents of viral aetiology view viruses as acting alongside susceptible genes to initiate a trajectory that manifests as psychotic symptoms.

Lessons from Autoimmunity

Disorders of an autoimmune nature are known to occur with increasing frequency in patients with another autoimmune disease. This is somewhat like the coexistence of multiple psychosomatic disorders in a person; as per Halliday’s psychosomatic formula, association of other psychosomatic afflictions justifies the diagnosis of a new psychosomatic condition. 4 It is well recognised that the central nervous system (CNS) may be directly affected by autoimmune processes, as in the case of multiple sclerosis (MS) and autoimmune limbic encephalitis. A physical autoimmune disease, such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome are also associated with psychiatric morbidity. Paediatric autoimmune neuropsychiatry disorder is a post-infection (group A Beta-haemolytic streptococcal infection) autoimmune disorder characterised by abrupt onset of obsessive compulsive disorder (OCD) and Tourette’s syndrome, brought about by molecular mimicry. 5 Nicholson et al observed that 20% of OCD patients were positive for anti-basal antibodies, considered to be part of a post-streptococcal autoimmune reaction. 6

Autoimmunity is a misdirected response occurring when the immune system attacks the body; it is the loss of tolerance to self-antigens. Immunological tolerance to one’s own tissue is probably normally acquired during foetal life, helping to prevent the occurrence of the autoimmune process (see Table1). Some clones of cells that can produce auto-antibodies (forbidden clones) are thought to be produced throughout life, and are suppressed by large amounts of self-antigens or antigen-specific T cells. Auto-antibodies are produced for a wide variety of antigens; some are organ-specific and others are non-organ-specific. Some microorganisms or drugs may trigger changes in individuals who are genetically vulnerable to autoimmunity.

Table 1- Mechanisms preventing and causing autoimmunity

Tolerance to self molecules a. Clonal deletion-removing any lymphocytes that might react to self molecules
b. Clonal anergy-decreasing the responsiveness of lymphocytes that recognise self-molecules.
c. Receptor editing-rearrangement of B-cell receptors.
d. Reduction or inhibition of molecules or antigens that may cause self recognition.
Failure of self tolerance
a. Release of isolated auto antigens-tissue trauma or infection may cause breakdown of anatomic barriers and may expose the hidden antigens for recognition of T cells that were not deleted during development.
b. Structural alterations in self peptides- Once structurally altered by a trigger such as infection , the self-peptides become more antigenic and are subsequently recognised by the undetected T-cells evoking immune response.
c. Molecular mimicry-based on a structural similarity between a pathogen or metabolite and self structures, evoking an immune response against the foreign particles but also an autoimmune response against the self molecules they resemble.
d. Polyclonal activation-Infectious agents activate our immune system, B cells and T cells are stimulated resulting in abnormal production of immunoglobulin specific for self molecules.
e. Genetic predisposition

A human disease may be considered of autoimmune origin on the basis of knowledge from molecular biology and hybridoma technology, 7 along with the Witebsky postulations. It is established by the presence of auto-antibodies and T cells that react with host antigens. Approximately 25% of patients with an autoimmune disease (AD) tend to build up additional auto-antibodies. Strausburg et al (1996) explained several hypotheses for the virally-triggered autoimmune mechanism (see Table 2). 8 Allergy is the consequence of a strong response to a harmless substance, but ADs are caused when the destructive potential of the immune system is misdirected to oneself. ADs share common effect or mechanisms with hypersensitivity reactions and can be classified into three main types corresponding to the type ii, type iii, and type IV categories of hypersensitivity reactions (see Table 3)

Table 2 - Virally triggered autoimmune mechanisms

a. Molecular mimicry -a protein or polysaccharide on the virus may be structurally homologous to a host molecule and the immune system being unable to differentiate between the two, may then cross react with host cells and tissues expressing this molecule. b. The virus may cause release into the circulation of auto antigens that are normally hidden from the immune system.
c. The virus might pick up host proteins from the cell membranes that become immunogenetic since they are present on the virus particle.
d. The virus in the process of replication may structurally change the host proteins that in turn become recognized as foreign to the immune system.

Table 3 - Classification of Autoimmune disorders

Type i-no autoimmune diseases are caused by lgE, the source of type i hypersensitivity reactions. Type ii-caused by antibodies directed against components of cell surfaces or the extracellular matrix
Type iii-caused by soluble immune complexes deposited in tissues
Type iv- caused by effector T cells.

Shared Aetiology

ADs are characterised by shared threads in terms of their propensity to co-exist in a patient or direct relatives. Two major autoimmune clusters have been recognised via, thyrogastric—mostly organ-specific—diseases and lupus-associated—mainly multi systems—diseases. 9 Some ADs are distributed within either cluster and there are also overlaps within each cluster. These patterns of concurrence depend predominantly on genetic determinants.

Poly-autoimmunity is the term proposed for the association of multiple autoimmune disorders in a single patient and such co-occurrences indicate a common origin of the disease. 10 Adriana et al, by grouping diverse ADs in the same patient, demonstrated that they are true associations as part of autoimmune tautology rather than chance findings.

Co-Occurrence of ADs

Theories for autoimmune aspects of schizophrenia raise the concept of early infection by microorganisms with antigens so analogous to CNS tissue that resulting antibodies act against the brain.Some data suggest that an autoimmune process precedes schizophrenia, non-affective psychosis, and bipolar disorder, 11 but do not establish whether this is affected by viral attack, as viral footprints may be hard to detect, especially in the target organ, once the autoimmune process has begun. Psychosis is reported in 25% of SLE cases.

A Danish study revealed that schizophrenia is associated with a large range of ADs. 12 The researchers found that a history of any AD in the patient is allied with a 45% increase in the incidence of schizophrenia. Specifically, nine ADs have a higher prevalence rate among patients and 12 ADs have a higher prevalence rate among their parents than among comparison groups. In comparison with the control group, Thyrotoxicosis, Celiac disease, Acquired haemolytic anaemia, interstitial cystitis, and Sjogren’s syndrome had a higher prevalence rate among schizophrenia sufferers and their family members.

Three of the Ads—namely, celiac disease, thyrotoxicosis, and acquired haemolytic anaemia—have been previously associated with schizophrenia. Celiac disease involves an immune reaction to wheat gluten. This could be due to increased permeability of the intestine, raising the level of antigen exposure, resulting in increased risk of an autoimmune response to brain components or it may be that gluten proteins are broken down into psychoactive peptides. Eaton et al opined that the association of schizophrenia and ADs could be due to common genetic causes, perhaps related to the HLA or other genes, and some cases of schizophrenia may be consequential to the production of autoantibodies that disrupt the brain function.

Researchers for a Taiwan study identified a greater variety of ADs in schizophrenic patients than anticipated and recommended further research. 13 Chen et al. found that 15 ADs are significantly associated with the schizophrenia group. Their studies also confirmed an earlier observation of a negative relationship between schizophrenia and rheumatoid arthritis (RA). It has been observed in a small sample study that mothers of schizophrenia patients have a lower risk for RA.14

Rheumatoid Connection

The negative correlation between schizophrenia and RA is puzzling. 15 Such dissociation was interpreted as the effect of antipsychotic medication. Similarly, the metabolic changes associated with one disease may inhibit another.16 Genes predisposing a person to have one disorder may have a protective influence against another and, in that way, the negative rheumatoid connection with schizophrenia is consistent with an autoimmune model.

RA has a genetic predisposition partly mediated by major histocompatibility complex (MHC) alleles and triggered by infection. Similarly, schizophrenia has genetic and environmental associations and has been cautiously connected with MHC genes other than those perhaps involved in RA. In addition to gene products accountable for antigen presentation, the MHC gene complex holds a multitude of genes-controlling aspects of immune response. Hypothetically, depending on the set of genes an individual has inherited at the MHC complex, a viral assault will lead the immune system to an immune cascade toward the development of RA, or along a genetically-predetermined path with a network of cytokines and immune mediators and directed against CNS components, resulting in schizophrenia. 17

The negative rheumatoid connection may be attributable to two mutually-exclusive alleles of the same gene. Such associations may lead to novel treatment strategies; sickle cell anaemia patients are thought to be less affected by malaria. Of note, the combined research of Karolinska Institute in Sweden and John Hopkins’s University School of Medicine in the United States have recently discovered the genes and the specific deoxyribonucleic acid (DNA) sequences that regulate them plot together to the progress of RA; rheumatology may be inching close to an early detection method and effective treatments. Such a development could hopefully happen in the schizophrenia research.

Commonalities

Even though ADs superficially seem different, the vast majority of them share several similarities. Like ADs, schizophrenia, as such, is neither infectious nor congenital. Schizophrenia and ADs have well-established genetic propensities, and a combination of genes, rather than a single gene, is thought to be responsible for their manifestations. Both schizophrenia and ADs can be triggered by environmental toxins and they have a remitting and relapsing course. Worsening of symptoms is observed when patients are exposed to stress and both conditions have a peak increase in late adolescence or early adulthood. These similarities argue in favour of an autoimmune aetiological model of schizophrenia. 18

Apparently, there is an interesting epidemiological dissimilarity between ADs and schizophrenia. The incidence of ADs is on the increase in developed countries, whereas schizophrenia has a consistent incidence of 1% globally. According to the hygiene hypothesis of ADs, the widespread practice of hygiene, vaccination, and antibiotic therapy in rich countries have disabled children’s immune systems to deal with proper infections and are more geared to charge with one’s own tissues in highly-destructive ways. 19 The incidence between the sexes was thought to be almost similar in the case of schizophrenia, but a recent study shows that for every three males with schizophrenia, there are two females with the disease. 20 ADs are slightly higher among the female population.

Immune Modulation of Clozapine

Antipsychotics may have an immunosuppressant effect; plasma levels of IL-6, soluble IL-6R and transferrin-receptor (TfR) were significantly lower after antipsychotic drug treatment. Activation of cell-mediated immunity may occur in schizophrenia; neuroleptic agents may modulate this through suppression of IL-6 or IL-6R-related mechanisms. 21 The antipsychotic effect may involve a counter-effect on the brain-mediated immune system.

Clozapine, the gold standard for refractory schizophrenia, is a dibenzodiazepine and lowers D2 receptor occupancy and is also a 5-hydroxytryptamine antagonist. Studies indicate that among the atypical antipsychotics, clozapine seems to have an immunosuppressant effect along with neuro-modulatory effect. It has been suggested that clozapine may diminish antibody synthesis in hematopoietic cells and also argued that a possible immunosuppressive action may contribute to its superior antipsychotic efficacy. 22 The long-term immunosuppressive effects of antipsychotics may inhibit putative autoimmune responses against neurological sites and could, thus, act synergistically with the direct antagonistic action on brain receptors for the evident improvement of psychotic symptoms. 23 It is also conjectured that the increase of soluble IL-2 receptor levels in Clozapine-treated patients indicates an immunosuppressant mechanism. 24

Haloperidol may also be a neuro-immune-modulating drug. A study of in-vitro effects of clozapine and haloperidol on cytokine production by human whole blood suggested that both drugs, at concentrations within their therapeutic range, may exert immunosuppressive effects through an enhanced production of IL-1 receptor antagonists. 25

It is well recognised that unlike other antipsychotics, clozapine works better over time, as immune modulation may take longer than neuro modulation. In addition to the neuro modulation, antipsychotics may be working on the principles of immune modulation, as well. If a derivative of clozapine, without its haematological and metabolic side effects is discovered, such a drug would become the first line of choice among the antipsychotics, and that could be a significant event in schizophrenia research. The immunosuppressant effects of clozapine seem to have public health awareness that patients on clozapine are advised to have the winter flue jab. Elderly patients on antipsychotic medications are more prone to get pulmonary infections, indicating that such drugs have a delicate immunosuppressant property.

Autoimmune-Neuropsychiatric Disorder?

If schizophrenia is an AD, a higher rate of other ADs may be expected among schizophrenics. Most studies confirm that it is tied to irregularities affecting multiple levels of the immune axis.There are multiple interlinked causative factors in the aetiology of schizophrenia. There are suggestions that the neuro-behavioural changes follow an abnormal response to microbial invasion, but that does not necessarily lead to an autoimmune process. The literature deciphering the role of viruses in neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. For those who adhere to the autoimmune model of schizophrenia, the simplest suggestion would be that the pathogenesis of the subset of schizophrenia studied may be caused by antibodies in the plasma and CSF that react with brain proteins, resulting in a neuro-autoimmune process.

Lessons from Viral Infections

The concept that certain psychiatric disorders are the neuro-behavioural sequel of the body’s immune response to viral infections was prevalent in the early part of the 20th century. That was an outcome of research conducted into rabies in the late 1880s, which revealed the affinity of viruses for the nervous system. Research into tertiary syphilis also provided evidence of an infectious aetiology for specific psychiatric disorders. Investigation of the encephalitis lethargica pandemic (1919 - 1928) contributed to recognition of viral causation on account of similarities apparent between the psychotic symptoms associated with encephalitis lethargica and the clinical presentation of schizophrenia. 26

Post-influenza depression, depression following mononucleosis, and hallucination associated with herpes encephalitis are well recognised. Menninger, who studied post-influenza psychosis, promulgated the first acceptable viral hypothesis for schizophrenia. 27 In the mid-twentieth century, psychodynamic studies began to encompass the origins of schizophrenia and viral aetiology lost its novelty. Dementias associated with Acquired Immune Deficiency Syndrome (AIDS) have reawakened interest in the correlation between virology and psychiatric disorders, and different authors have revisited these hypotheses in the last three decades. 28-36

The immune response to influenza and other viruses involves cell-mediated immunity and cytokine activity, which tend to turn tryptophan into kynurenic instead of serotonin. The outcome of this deviation is mood disturbance. It is the body’s immune response that blocks the conversion of tryptophan into serotonin, thereby resulting in post-influenza depression. It is arguable that there may be other psychiatric disorders consequential to a slow immune response of the body to viral infections. The possibility of viral oncogenesis was originally ridiculed, but now there is some evidence to support the view that viruses are responsible, at some stage, for approximately 20% of human malignant diseases. 31

In theory, a virus could induce schizophrenic symptoms or depression by stimulating antibodies that cross-react with brain tissue, without necessarily gaining entry into the brain. At different developmental stages, the immune response may become less efficient and viral agents may become potentiated, leading to neuropsychiatric conditions. The supposedly inflammation-mediated brain diseases occur at different stages—for instance, schizophrenia in late adolescence or early adulthood, and Alzheimer’s typically at an advanced age. It is well established that the human immunodeficiency virus (HIV) may lead to a form of AIDS dementia, and other common viruses that infiltrate the neurons may cause other types of dementia. HIV/AIDS and Borna Disease Virus (BDV) in animals help to bring the infection-based model of schizophrenia to the realm of scientific imagination

Viruses can influence the human genome. After becoming effective, viral sequences are integrated into the genome of brain cells. These sequences are not thought to be inheritable, but may cause mutations that interfere with brain functions and contribute to the development of psychiatric disorders. 37 It may be arguable that the combination of the body’s sustained immune response and the constant release of antigens of a hypothetical slow virus (schizovirus) may account for the neuro-behavioural alterations. In the following paragraphs, the author discusses how viral pathogens and other potential contributors could interact and lead to schizophrenic psychopathology.

Immune Responses

Neuro-developmental theories of schizophrenia fit the hypothesis that viral insult occurs early in sufferers, not proximally to a psychotic episode. The interaction between host and virus is affected by coordinated activity of the immune system and the brain. There is evidence that schizophrenia is accompanied by mutations in the immune system. Innate immunity is the first defence against microbes; infection results in invasion by live microorganisms and their toxic products, stimulating an inflammatory response. Neuronal functions are disrupted by pathogens and the brain’s inflammatory responses. Non-cytolytic viruses may affect neurones without causing cyto-architectural alteration, but disturbing neurotransmitter production and weakening hormones involved in neurodevelopment. 38 In schizophrenia, immune infiltration is absent, as are vital inclusion bodies and minimal gliosis. There is subtle disruption of neuronal function and brain development, but no significant loss of neuronal cells. Thus, the schizophrenia subset may have a viral aetiological origin, bringing about anomalous, specific immune responses, an autoimmune basis, or both. What triggers the autoimmune process is uncertain, but microbial triggers are a strong possibility.

Immune dysfunctions including lymphocytic abnormalities, protein abnormalities, auto-antibodies, and cytokines have been suggested in seriously-ill patients 39. One study showed significantly higher plasma levels of interleukin-6 (IL-6) in schizophrenics, and soluble IL-6R and soluble IL-2R were significantly high in mania. 40 A few early investigators claimed to have microscopically visualised virus-like particles in the cerebrospinal fluid (CSF) of patients or in chicken embryos inoculated with CSF. Studies of viral antibodies, viral antigens, viral genomes, the cytopathic effect of specimens on cell cultures, and animal transmission experiments are other avenues for exploring the viral infection hypothesis.

The subset of schizophrenics in question may have a highly-sensitive surveillance system, but a less-discerning immune mechanism than the general population. It could be the over-reaction of the immune system to the microbial adversary that may eventually lead to the schizophrenia pathogenesis. The fault may lie in the surveillance system, as well as in the body’s anomalous response to the microbial invasion. 17 In general, innate and acquired immune mechanisms interact and cooperate, but any derangement can lead to deviant immune responses that may result in neuropsychiatric abnormalities.

From an evolutionary perspective, innate immunity is less evolved and the mammalian brain is endowed with a complex immune response system, implying that the neurobehavioral aberrations of schizophrenia could be more linked with deviant and vigorous specific immune responses. 17 It is possible that the proposed subset of schizophrenia may have either an autoimmune basis or a viral aetiological origin, bringing about anomalous, specific immune responses, or both. It has been argued that a gene family involved in the specific immune system and autoimmunity is involved in schizophrenia. 41 The genome-wide association studies (GWAS) have been disappointing in schizophrenia, whereas the major histocompatability complex (MHC) region continues to be the best replicated.

Epidemiological Findings

Epidemiological studies offer useful supporting evidence for viral aetiology (see Table 4). Epidemiological studies characterised by certain broad patterns of incidence and distribution of schizophrenia offer evidence to suspend the scepticism of the viral causal hypothesis. In a study of adults at risk of exposure in utero to the 1957 influenza A2 epidemic in Helsinki, those at risk during the second trimester had significantly more hospitalisations for schizophrenia than those potentially exposed during the other trimesters or immediate years. 42 Researchers for nine subsequent epidemiological studies scrutinised the risk of schizophrenia after possible intrauterine exposure to influenza in Europe and the USA; these identified a small majority claiming to find an association.43 Falsifying the influenza link with the origin of schizophrenia does not altogether make the viral aetiology null and void. There could still be an unknown virus (schizo-virus) as the causative agent. The Hepatitis C virus came to medical attention only 15 years ago. At least these epidemiological studies illustrated that viruses can help set the stage for schizophrenia as a long-term sequel

Table 4 - Suggested Evidences for Viral aetiology

A. Direct evidences: 1.Neuropathology
2.Transmission to laboratory animal
3.Detection of viral genome
4. Sero-epidemiological studies-Detection of Antigen or antibody
B. Indirect evidences:
1.Seasonality of schizophrenic births
2.Prevalence studies
3. Immune alterations
4.Antiviral effects of antipsychotic drugs
5.Possible immunosuppressant effect of antipsychotic drugs
6.Studies of identical twins
7. Migration and high risk
8. Gender differences-males are younger at disease onset and have a more severe course.

A worldwide average of 1% prevalence of “core schizophrenia” is generally accepted, 44 even though such a concept of universal distribution and gender equality has opposition. 45 However, there is evidence to assume that there may not be gross variations in this global prevalence. Cross-culturally stable rates, despite decreased fecundity in affected individuals, support an external biological aetiology. These point toward biologically-interlinked and multifactorial causation including an evolutionary genetic factor, as a single biological factor would be insufficient. The preservation of susceptibility genes for schizophrenia in the human gene pool is an evolutionary enigma; gene carriers or first-degree relatives may have some compensatory evolutionary advantage. 46 In a multifactorial aetiological model of schizophrenia, infectious theories are contestable. 17

Such a consistent prevalence, if true, could also be argued in favour of a biologically-inter-linked and multi-factorial causation of schizophrenia, as it is obvious that a single biological factor would be insufficient to maintain a delicate and consistent global prevalence of a disease. Many viruses are relatively constantly distributed, while genetic diseases present distinct geographical clustering due to inbreeding. One may hypothesise that where viral loading is high, genetic input may be less and vice versa. The consistent global incidence points toward universal microbes, a readily-available environmental factor, or, more specifically, a “schizovirus.” The interaction of vulnerable host genes with a virus could yield epidemiology like that of schizophrenia.

Birth patterns rank highly among epidemiological observations in schizophrenia. 47 Many more schizophrenics are born in winter and spring than in summer and fall. 48 Infectious aetiology is a plausible explanation, as many viruses show a surge in the same months and viral aetiology is a more convincing explanation of the consistency in question. While gene coding for particular proteins is inherited, environmental and developmental factors are undoubtedly implicated in modulating genes’ expression.

Exposure to prenatal infections and other obstetric complications are neuro-developmental assaults that increase vulnerability to schizophrenia. 49-52 In obstetrics, infection in the mother generates antibodies transmitted to the foetus, producing auto-antibodies that upset neural development and increase the schizophrenia risk. 53

Schizo-Virus or any Microbe?

It is not certain whether it is body’s abnormal response to any virus and other microbes or a specific unknown virus that results in “schizophrenic reactions.” It is even unclear that the unbeatable antigens of this hypothetical virus alone are capable of inducing the neuro-behavioural changes associated with schizophrenia. The hepatitis C virus came to medical attention only 15 years ago. The rotavirus was isolated in 1973 and the HIV virus was isolated in 1983. Non-detection of a pathogen does not exclude its role in the pathogenesis. If a specific virus is responsible for schizophrenia, it should have been with human society for a very long time, as the illness has been reported from the beginning of recorded human history. Some people may have a genetic vulnerability to the hypothetical schizovirus; inheritability would lie in contracting the specific virus. Poliomyelitis has a concordant rate of 36% among monozygotic twins; the rest are attributed to environmental factors. The majority of children exposed to the polio virus may not develop poliomyelitis and a genetic propensity may be required for the viral manifestation. It is even reported that 10% of the world population rarely catch influenza, in spite of its yearly mutation.

Cardiac disease due to endocarditis (caused by an autoimmune process affecting many parts of the body), a sequel to acute rheumatic fever, is an analogy to demonstrate how, theoretically, a microbial infection may lead to impaired neurodevelopment and psychiatric disorders in a different scenario. Endocarditis is triggered by a reaction to streptococcal bacteria, not a bacterial infection. It may begin a chronic process, leading to valvular cardiac disease. Generally, rheumatic heart diseases are diagnosed 10 - 20 years following rheumatic fever. Similarly, schizophrenia could be an autoimmune complication of a subtle microbial infection; finding and countering the antigenic triggers of ADs may lead to an effective cure.

HIV/AIDS

Patients with HIV are at risk for developing psychiatric symptoms and disorders similar to those seen in the general population, as well as those that are direct effects of HIV. HIV is a neurotropic and lymphotropic virus that causes immune suppression and allows the entry of opportunistic pathogens with an affinity for the CNS. There is some evidence that HIV may trigger a psychotic episode and contribute to first-onset schizophrenia. 54 Serious CNS complications occur late in the course of HIV infection, when the immunity function has diminished considerably. The viral load is closely associated with the degree of cognitive impairment. HIV-associated dementia (AIDS dementia complex) is defined as acquired cognitive abnormality in two or more domains and is associated with functional impairment and acquired motor or behavioural abnormality in the absence of other aetiology. It is estimated that 30% to 60% of patients experience some CNS complications during the course of their illness and 90% reveal neuropathological abnormalities at autopsy.

Pearce argued that HIV-related encephalitis could engender a scenario for a viral aetiology of schizophrenia. 17 HIV produces symptoms after being latent for several years. HIV was not identified as the aetiological agent of AIDS until the conditions for viral replication in lymphoid cell lines were identified. Prior to the evolution of PCR serology techniques, it was debatable whether the virus was in circulation at all. This indicates that the absence of a demonstrable virus does not mean the absence of a subtle virus-induced disease process. No virus, as such, is currently detectable in the schizophrenia disease process. Even in the absence of opportunistic infections, HIV infection of the brain causes severe neuro-behavioural syndromes, such as AIDS dementia, without infecting neurons, but by complex interaction with host molecules and non-neuronal cells. All these suggest that a rare or unknown infectious agent is involved; it would not be identified unless it was specifically tested for.

The finding that the neurophysiological and psychological stress of HIV infection can aggravate an underlying psychotic illness implies that viruses, without being a direct causative agent in psychotic episodes, can unmask pre-existing psychiatric vulnerabilities, acting on the brain physiology through unknown pathways. A curious aspect of HIV-related psychosis is that it responds to anti-psychotic treatment and to anti-retroviral drugs. Several anti-psychotic drugs have been shown to have antiviral properties, both in vitro 55 and in vivo. 56 The deduction is that a virus could initiate events resulting in psychosis, and anti-psychotic drugs can interrupt that sequence. All these features of HIV infections are consistent with the idea that a virus can cause neurobehavioral abnormalities after several years.

Borna Disease Virus

It has been recognised that Borna disease virus (BDV) could cause neuropsychiatric complications including neurological, behavioural, and mood alterations in animals. 57 A ribonucleic acid (RNA) virus from the family Bornaviridae, it is a neurotropic virus with an affinity to a variety of hosts, particularly hoofed animals, and can cause persistent infection of the CNS. Such an infection may be either latent or chronic and slow, but BDV presents with the latent type, characterised by a lack of viral particles. It may resemble the alleged pathogens in non-affective psychosis. The severity of clinical symptoms depends on the immune response of the host.BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions.

Depending on the host’s age and the integrity of the immune response, an infection may be asymptomatic or involve a broad spectrum of behavioural disorders. The severity of clinical symptoms depends on the immune response of the host.58, 59 Unusual features of BDV biology include nuclear localisation of replication and transcription, varied strategies for the regulation of gene expression, and interaction with signalling pathways, resulting in subtle neuropathology.60 BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions. The issue of human BVD infection has been recently questioned by American researchers who reported an absence of association of psychiatric illness with antibodies to BDV or with nucleic acids in serially-collected serum and white blood cell samples from 396 participants. 61 However, BDV in animals helps to bring the infection-based model of schizophrenia to the realm of the scientific imagination.

Neurotransmitters

It is an overstatement to say that schizophrenia is a neurotransmitter disease, although it is well established that it incorporates a derangement of dopamine activity. Some viruses have been shown to alter dopamine metabolism. 62 The literature deciphering the role of viruses in bringing about neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. 63 It has been reported that in rodents, BDV could crash neurotransmitter systems, including dopamine, neuropeptides, and glutamate. 64 How viruses alter neurotransmitters is a central issue. Communication between the immune system and the brain is crucial to defend against viral infection; this is mediated through neurotransmitters. Viruses are bound to tamper with the intrinsic communication system as part of their cellular offensive. Some viruses have been shown to alter dopamine metabolism. 65

Genetics

The undisputed genetic factor in schizophrenia may be posited to discount the viral hypothesis. However, genetic factors do not exclude environmental contributions. Monozygotic twins have a concordance rate of only 48%. Brief reactive psychosis due to acute sequels to viral infection, though regarded as unrelated to schizophrenia, may still be schizophrenic reactions and they do not progress to schizophrenia only because the sufferers are not genetically predisposed to schizophrenia. Genetic predilection may be attributable to genes that determine idiosyncratic differences in immune responsiveness to common viral pathogens.

Susceptibility and immune response to infectious agents are known to be subject of genetic control and may involve multiple interacting susceptibility genes. 66 The genetic component of schizophrenia may engross multiple interacting susceptibility genes. These together or singularly may moderate the virus, and the virus and gene product may act at different points. Many cases would have a genetic foundation and it may be extremely rare to develop schizophrenia independently of a genetic anomaly. A small subset of patients may have a purely genetic form. Research should also be directed at identifying risk genes and why they assert themselves and cause the disease. Any future research which sheds more light on some people are affected more readily than others would bring researchers closer to more effective treatments and early intervention (see Table 5).

Table 5 - Future Directions

1. Critical research studies should target in establishing the viral and autoimmune aetiology of a subset of schizophrenia as the illness may be due to both factors. Detection criteria/ tests are vital in isolating this subset from the rest of schizophrenia syndromes 2. Robust epidemiological studies to be conducted to find putative infectious agents and possible models of transmission.
3. Developing new methods for detection of viral agents, directed at the analysis of previously identified pathogens and identification of novel viruses. Vigorous studies with PCR and other sensitive methods for nucleic acid detection to be carried out for the detection of viral nucleic acids in the body fluids of schizophrenia sufferers.
4.To find a method to turn off autoimmune attacks from the body or selectively disable the immune response
5. Identify risk genes and to find the specific DNA molecules and their tagging patterns vital for the progress of the illness.
6. To develop drugs to target specific genes which would mean they would be far more effective and have fewer side effects.
7. Finding psycho-physiological parameters for early detection to minimise the damage.
8. In the event of future discovery of effective antiviral agents, the subset of schizophrenia in question could take advantage of the clinical benefits of such discoveries.
9. Viral aetiology, if proven true, could lead to finding a vaccine against the disease.
10. Selective immune-suppressants could be a future addition into the psychiatric armamentarium.
11. A derivative of cloazapine without its haematological and metabolic side effects would be highly promising.

Summary

There are multiple interlinked causative factors in schizophrenia and viral infection may be only a trigger. Viral infections may be the cause of vigorous immune responses or triggering an autoimmune process that lead to neuro-behavioural aberrations and a subset of schizophrenia would emerge as viro-immuno-neuropsychiatric disorder or autoimmuno-neuro-psychiatric disorder. If such a subset of schizophrenia contains an autoimmune component, either triggered by infectious agents or due to unidentified intrinsic factors, the disease process would be determined by genetic vulnerability. There is not sufficient evidence established to identify viruses as being implicated in the aetiology of schizophrenia, but researchers have reason to anticipate further laboratory studies, as newer, more sensitive laboratory technologies are evolving. A viral or autoimmune model of schizophrenia may illuminate its pathogenesis, but not necessarily the diversity of psychiatric symptomatology. In the last few decades, schizophrenia research has been focussed on neurotransmitter derangements and neuro-developmental anomalies. The cause of a tsunami is not in the sea water, but due to the tectonic shifts under the sea bed; the aetiology of schizophrenia may be similarly due to immune alterations.

Pellagra psychosis due to niacin deficiency was hidden under the schizophrenia umbrella. 67 There may be other psychotic disorders grouped under schizophrenia, and they may have a pure biological aetiology—chemical or infectious—but with genetic vulnerability. No one can be sure whether it is the toxic chemical of the pathogens or the immune response of the host, or both, that may lead to the psychopathology. Searching for this hypothetical virus is a challenging task, but if researchers found it, the benefits would be enormous. A viral aetiology of certain types of schizophrenia, if demonstrable, could affect radical changes in treatment and management. In fact, the hypothesis of viral aetiology is more promising than any other biological hypothesis, as it gives a message of potential drug cure. In this contest, it is interesting to note that the antigenic similarity between components of the streptococcus and cardiac tissue resulted in rheumatic heart diseases, but with the advent of penicillin, this disease has virtually disappeared. Only time will determine the validity and therapeutic prospects of the viral and autoimmune aetiology of schizophrenia.

Davison opined that as evidence accumulates about the autoimmune basis of at least a subset of psychiatric disorders, clinicians should keep abreast of immune-neuropsychiatric research. 68 Psychiatry must constantly expand to meet the growing needs with the emergence of novel ideas in other medical specialities and it is high time to introduce a new terminology—“Psycho-immunovirology”—to study the viral aetiological mechanisms involved in psychiatric disorders like schizophrenia. Neuro-virology and psycho-immuno-virology could develop as an interdisciplinary field which represents a melding of virology, psychiatry, the neurosciences and immunology.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAMES PAUL PANDARAKALAM, Trust Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Warrington WA2 8WA.
Corresponding Author Details: 
JAMES PAUL PANDARAKALAM, Trust Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Hollins Park Hospital, Hollins Lane, Warrington WA2 8WA.
Corresponding Author Email: 
jpandarak@hotmail.co.uk
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  67. Miller R.S ,Glasg MD, Ismail Chafick Ahmed. Pellagra and Pellagra psychosis: A study of 757 Insane Egyptian Pellagrins. The Lancet, 2:788-789  (1920).
  68. Davison Kenneth. Autoimmunity in psychiatry.  British Journal of Psychiatry 200: 353-355  (2012).

Hypertensive Crises – the Acute Take

Authors
Andrew Kristian Grech
Article Citation and PDF Link
BJMP 2015;8(3):a823
Abstract / Summary
Abstract: 

Despite chronic hypertension affecting over one billion individuals worldwide, presentation with acute hypertensive crises has been associated with low rates of appropriate management. According to established guidelines this includes lowering of pressure by 25% over the first hour following diagnosis, with target definition and treatment options described hereunder. Oral treatment can prove sufficient in many instances, with potential precipitous pressure drop and inherent detriment to patients borne in mind.

Female gender, coronary artery disease and history of antihypertensive therapy (particularly with poor adherence to the latter) are thought to represent risk factors for acute crises. Presenting symptomatology includes headache, chest pain and shortness of breath, dizziness and nausea and emesis. End organ damage is a distinguishing feature in the subtypes of hypertensive crises, with investigation of presenting crises focusing on making this distinction.

Keywords: 
hypertension crisis emergency acute

Introduction

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has long reported chronic hypertension as affecting over one billion individuals worldwide1. While the role of primary care providers in the long term management of this ubiquitous condition cannot be overstated, the hypertensive patient can also present challenges to an acute physician when the control of arterial blood pressure reaches crisis level.

The What

The clinical entity extravagantly referred to as a hypertensive crisis describes an elevated systolic blood pressure of >180mmHg with diastolic pressure of >120mmHg. Within this category of acute presentations, two subcategories are defined – the hypertensive urgency and the hypertensive emergency. Flamboyant terminology aside, what distinguishes the latter ‘emergency’ from the former ‘urgency’ is evidence of acute end-organ damage. Emergencies therefore include various incipient pathologies of the cardiovascular, renal and central nervous systems. Fortunately these are less common encounters for receiving physicians, with a recent large multicentre study identifying acute pulmonary oedema (30.9%), myocardial infarction (17%), acute aortic dissection (7.9%), acute kidney injury (5.9%), cerebrovascular accident (22%) and hypertensive encephalopathy (4.9%) as features of hypertensive emergencies in 25.3% of hypertensive crises, with the remainder of the presenting population demonstrating a hypertensive urgency with inherent lack of evidence of end organ damage2.

The Why

The pathophysiology of acute hypertension remains yet to be fully elucidated, however authors in the field of hypertensive crisis3,4 appear to converge on the point of two common proposed pathophysiological events. A sharp elevation in systemic vascular resistance is thought to be one precipitating factor, with an aberrance of cerebral autoregulation of blood flow being another.

For the purposes of an acute clinician faced with a bleeping blood pressure monitor, what is perhaps more applicable to everyday clinical practice is the potential role of non-adherence to regular antihypertensive medications5,6as discussed below.

The Who

A longitudinal study carried out in Switzerland and led by Saguner7identifies several potential risk factors for manifestation of a hypertensive crisis. Female gender, obesity and concurrent somatoform disorder accompany hypertensive and coronary artery related cardiac disease as potential red flags. Perhaps unsurprisingly, a history of multiple antihypertensive therapies was also associated with greater likelihood of presentation with hypertensive crises, as was non-adherence to the same therapeutic regimen. The latter compliance related issue was identified as the most significant by the study’s authors.

Elderly patients and also those of African American ethnicity have been shown to demonstrate higher rates of hypertensive crises in general8, while Caucasian patients are reported to have higher rates of emergencies as opposed to the more benign urgency equivalent9.

The When

The findings of a comparatively small Italian hospital-based study10utilising 360 patients were recently supported by a larger United States-based analysis11of over 400,000 patients, with a seasonal variation in presentation of hypertensive crises noted. A winter peak and summer trough was reported by both groups of authors, suggesting transcontinental extrapolation of a potential seasonal phenomenon.

Evaluation

Comprehensive disposition notwithstanding, acute physicians are urged to adopt a targeted approach when considering a presentation with alarming blood pressure readings.

Present…

By nature of definition, the presentation of a hypertensive crisis encompasses a wide variety of symptomatology depending on whether a hypertensive urgency or incipient emergency is manifested.

The symptomatology of a patient demonstrating hypertensive urgency can be fairly non-specific to acute blood pressure elevation. A 2014 study into clinical presentation of hypertensive crises reported headache as the most prevalent symptom (74.11% of patients), followed by chest discomfort and dyspnoea (62.35%), vertiginous dizziness (49.41%), nausea and emesis (41.47%)12 as demonstrated in Figure 1.


Figure 1. Symptomatology in hypertensive crises (adapted from Salkic S, Batic-Mujanovic O, Ljuca F, et al12)

While all of these common presenting complaints can bring a patient to a physician’s attention, what often alerts the attending physician to the particular possibility of an acute hypertensive condition is the blood pressure reading obtained on initial assessment of the patient (for instance for triage purposes) even in the absence of overt symptomatology as reported above. Indeed, patients with minimal symptomatology may be prompted to present themselves for acute medical care by no more than the sounding of an ominous alarm on a home blood pressure reader or the disconcerted look of a perturbed primary care physician, sphygmomanometer in hand!

…and Past

The history taking process of an acute physician faced with a hypertensive crisis should target several key areas which may prove essential in differentiating a case of urgency from an evolving emergency. With the potential for end organ heart, kidney and brain-related complications in mind, a physician should probe the possibility of chest discomfort, dyspnoea and signs of congestive cardiac failure (as indicators for incipient cardiovascular complications), headache, visual changes, dizziness and altered consciousness (potential harbingers of neurological complications) as well as recent history of oliguria as a marker of possible related renal insult.

Having conducted an interrogation for worrisome symptomatology, evaluation should proceed to a ‘hypertension history’. Prior diagnosis of hypertension and hypertensive crises in particular should be elaborated on, with this including a history of any prescribed regular antihypertensive therapy and both the adherence to and effect of the latter. Relevant to the notorious polypharmacy patients, any history of concurrent medication use must be clarified so as to give an indication of potential interactions.

Of historical note is the potential for hypertensive crisis following interaction of tyramine with mono-amine oxidase inhibitors (the so-called cheese effect), while a provoked hypertensive crisis more relevant to modern medicine is the potential effect of illicit substances including cocaine and amphetamine-based products13.

Examination

As with the evaluation of the hypertensive crisis patient’s history, examination should place particular emphasis on distinguishing urgency from emergency.

Parameters

Assessment of vital signs can provide valuable indicators. Whilst initial systolic pressure is not necessarily a predictor of the ability to achieve a prespecified target range pressure within thirty minutes14, the presence of tachycardia has been shown to be an ominous sign more prevalent in emergency than urgency, with a strong statistical association demonstrated with hypertension-related left ventricular failure15.

Physical

Cardiovascular examination should assess for the presence of signs of cardiac failure (including an elevated jugular venous pressure, added S3 heart sound or pulmonary rales) as well as the feared asymmetric pulses or new mid-diastolic murmur associated with aortic dissection. Auscultation for renal bruits should be performed, and a neurological assessment for possible stroke indicators undertaken.

Whilst chronic hypertension patients will often have subtle fundoscopic abnormalities, ophthalmological review for evidence of acute changes including new retinal haemorrhages or exudates together with papilloedema should be carried out.

Investigation

The unique circumstances of individual presentations aside, the prompt acute medical investigation of a hypertensive crisis should include a minimum number of bedside, laboratory and imaging investigations16as suggested in Figure 2. Comparison of each of these to pre-existing baseline investigations may be invaluable in giving an indication of level of acute pathology and therefore care required.


Figure 2. Investigations in hypertensive crises

Bedside

Electrocardiography affords rapid exclusion of major acute ischaemic cardiac events, as well as providing an indication of chronic hypertrophic changes and a quantitative indicator of heart rate elevation. Simple dipstick urine testing can assist in exclusion of significant proteinuria pending formal urinalysis studies16.

Laboratory

Full blood count analysis will give an indication of haemoglobin level where dissection is suspected, while serum markers of renal profile including creatinine level in particular may suggest varying degrees of acute kidney injury where present. Cardiac biomarkers may complement electrocardiography in exclusion of acute events.

As ever, a metabolic panel and blood gas analysis represent valuable tools in the acute physician’s arsenal where acute and evolving physiological disturbances are suspected.16

Imaging

Presence of pulmonary congestion in keeping with left ventricular failure as well as the mediastinal widening of an aortic dissection may be assessed via simple chest radiography. More complex imaging such as computerised tomographic (CT) scanning may be indicated as dictated by clinical presentation, as in the event of neurological manifestations16.

Treatment

Established guidelines1 suggest definitive management of a hypertensive emergency should involve lowering of blood pressure by 25% in the first hour and then to 160/100-110mmHg thereafter if stable, as indicated in Figure 3. Meticulous and continuous monitoring in an intensive care setting for parenteral administration of antihypertensive agents including labetalol17, clevidipine18–20 and fenoldopam21 is beyond the scope of most practising acute physicians.


Figure 3. Broad management of a hypertensive emergency (adapted from Chobanian A V, Bakris GL, Black HR, et al1 and Börgel J, Springer S, Ghafoor J, et al26

Hypertensive urgency, however, need not require such invasive interventions, with oral therapy utilising labetalol, captopril or clonidine followed by a period of vigilant observation usually proving sufficient1,17. A once popular practice of oral nifedipine is advised against, owing to the precipitous drop in pressure with inherent risk of tissue ischaemia observed on administration of this agent1. Emergent pharmaceutical options including novel felodipine formulations22 may also be considered.

A pitfall of physicians, perhaps, panicked by the jargon ‘hypertensive urgency’ has been observed, with inappropriate management in such cases reported in multiple independent studies in recent years23–25, with a 42.6% appropriate treatment rate in one study25. A chief consideration when faced with hypertensive crises therefore, may be to avoid rash intervention.

Worthy of mention is the potential for common co-prevalent secondary causes of hypertension including sleep apnoea, renal artery stenosis or a state of hyperaldosteronism; present in 15% of cases in one series26, recommendations have been made for consideration of these prior to therapeutic intervention26.

Outcome

There…

Indicators of greater likelihood of admission in patients presenting with severe hypertension may include presence of age >75 years, dyspnoea, altered mental status or creatinine elevation27.

…And Back Again

Following discharge after an admission for acute severe hypertension, a 90-day readmission rate of up to 35% has been reported28; this includes a multiple readmission rate of 41% with similar re-presentation accounting for 29% of this data. Curiously, dyspnoeic initial presentation is emphasised by the same data source as a risk factor for readmission, with additional risk factors including ictal phenomena at initial presentation and history of both drug abuse and prior severe hypertensive admission.

Key Points

Definition

  • A hypertensive crisisinvolves pressures of >180mmHg systolic and >120mmHg diastolic
  • Ahypertensive urgency does not include end organ damage
  • A hypertensive emergency implies end organ damage

Symptomatology

  • The commonest symptoms are headache (74.11%), chest discomfort & dyspnoea (62.35%), vertiginous dizziness (49.41%) and nausea & emesis (41.47%)

Investigations

  • Bedside should include urinalysis and echocardiography
  • Laboratory should include creatinine level
  • Imaging should include plain chest radiography

Management

  • Blood pressure should be lowered by 25% over the first hour
  • In hypertensive urgency, oral therapy is often sufficient
  • Consider co-prevalent secondary causes
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ANDREW GRECH, M.D. (MELIT.), Department of Emergency Medicine, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Details: 
ANDREW GRECH, Department of Emergency Medicine, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Email: 
andrew-kristian.grech@gov.mt
References
References: 

 

  1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-52. doi:10.1161/01.HYP.0000107251.49515.c2.
  2. Pinna G, Pascale C, Fornengo P, et al. Hospital admissions for hypertensive crisis in the emergency departments: a large multicenter Italian study. PLoS One 2014;9(4):e93542. doi:10.1371/journal.pone.0093542.
  3. Smithburger PL, Kane-Gill SL, Nestor BL, et al. Recent advances in the treatment of hypertensive emergencies. Crit. Care Nurse 2010;30(5):24-30; quiz 31. doi:10.4037/ccn2010664.
  4. Varon J. Treatment of acute severe hypertension: current and newer agents. Drugs 2008;68(3):283-97. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18257607. Accessed December 2, 2014.
  5. Lip GY, Beevers M, Potter JF, et al. Malignant hypertension in the elderly. QJM 1995;88(9):641-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7583078. Accessed December 4, 2014.
  6. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest 2000;118(1):214-27. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10893382. Accessed December 4, 2014.
  7. Saguner AM, Dür S, Perrig M, et al. Risk factors promoting hypertensive crises: evidence from a longitudinal study. Am. J. Hypertens. 2010;23(7):775-80. doi:10.1038/ajh.2010.71.
  8. Varon J, Marik PE. Clinical review: the management of hypertensive crises. Crit. Care 2003;7(5):374-84. doi:10.1186/cc2351.
  9. Vilela-Martin JF, Vaz-de-Melo RO, Kuniyoshi CH, et al. Hypertensive crisis: clinical-epidemiological profile. Hypertens. Res. 2011;34(3):367-71. doi:10.1038/hr.2010.245.
  10. Marchesi C, Dentali F, Maresca AM, et al. Seasonal and monthly variation in occurrence of hypertensive urgency. Intern. Emerg. Med. 2013;8(3):269-71. doi:10.1007/s11739-012-0878-6.
  11. Pant S, Badheka AO, Mehta K, et al. Seasonal and monthly variation in occurrence of hypertensive urgency. Intern. Emerg. Med. 2013;8(3):273. doi:10.1007/s11739-013-0905-2.
  12. Salkic S, Batic-Mujanovic O, Ljuca F, et al. Clinical presentation of hypertensive crises in emergency medical services. Mater. Sociomed. 2014;26(1):12-6. doi:10.5455/msm.2014.26.12-16.
  13. Varon J, Polanski M. Hypertensive Crises: Recognition and Management. Internet J. Anesthesiol. 1997;Vol I.
  14. Farias S, Peacock WF, Gonzalez M, et al. Impact of initial blood pressure on antihypertensive response in patients with acute hypertension. Am. J. Emerg. Med. 2014;32(8):833-6. doi:10.1016/j.ajem.2014.03.021.
  15. Al Bannay R, Böhm M, Husain A. Heart rate differentiates urgency and emergency in hypertensive crisis. Clin. Res. Cardiol. 2013;102(8):593-8. doi:10.1007/s00392-013-0570-5.
  16. Stewart DL, Feinstein SE, Colgan R. Hypertensive urgencies and emergencies. Prim. Care 2006;33(3):613-23, v. doi:10.1016/j.pop.2006.06.001.
  17. Varon J. The diagnosis and treatment of hypertensive crises. Postgrad. Med. 2009;121(1):5-13. doi:10.3810/pgm.2009.01.1950.
  18. Varelas PN, Abdelhak T, Corry JJ, et al. Clevidipine for acute hypertension in patients with subarachnoid hemorrhage: a pilot study. Int. J. Neurosci. 2014;124(3):192-8. doi:10.3109/00207454.2013.836703.
  19. Ndefo UA, Erowele GI, Ebiasah R, et al. Clevidipine: a new intravenous option for the management of acute hypertension. Am. J. Health. Syst. Pharm. 2010;67(5):351-60. doi:10.2146/ajhp080692.
  20. Awad AS, Goldberg ME. Role of clevidipine butyrate in the treatment of acute hypertension in the critical care setting: a review. Vasc. Health Risk Manag. 2010;6:457-64. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2922306&tool=pmcentrez&rendertype=abstract. Accessed December 2, 2014.
  21. Rodriguez MA, Kumar SK, De Caro M. Hypertensive crisis. Cardiol. Rev. 18(2):102-7. doi:10.1097/CRD.0b013e3181c307b7.
  22. Basalious EB, El-Sebaie W, El-Gazayerly O. Rapidly absorbed orodispersible tablet containing molecularly dispersed felodipine for management of hypertensive crisis: development, optimization and in vitro/in vivo studies. Pharm. Dev. Technol. 18(2):407-16. doi:10.3109/10837450.2012.659258.
  23. Devlin JW, Dasta JF, Kleinschmidt K, et al. Patterns of antihypertensive treatment in patients with acute severe hypertension from a non-neurologic cause: Studying the Treatment of Acute Hypertension (STAT) registry. Pharmacotherapy 2010;30(11):1087-96. doi:10.1592/phco.30.11.1087.
  24. Fursov AN, Potekhin NP, Chernov SA, et al. [Hypertensive crisis: problems of diagnostics and paradigm of the treatment]. Voen. zhurnal 2012;333(7):11-5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23038954. Accessed December 2, 2014.
  25. Monteiro Júnior F das C, Anunciação FAC, Salgado Filho N, et al. Prevalence of true hypertensive crises and appropriateness of the medical management in patients with high blood pressure seen in a general emergency room. Arq. Bras. Cardiol. 2008;90(4):247-51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18516384. Accessed December 2, 2014.
  26. Börgel J, Springer S, Ghafoor J, et al. Unrecognized secondary causes of hypertension in patients with hypertensive urgency/emergency: prevalence and co-prevalence. Clin. Res. Cardiol. 2010;99(8):499-506. doi:10.1007/s00392-010-0148-4.
  27. Kleinschmidt K, Levy P, Wyman A, et al. Emergency department patients with acute severe hypertension: a comparison of those admitted versus discharged in studying the treatment of acute hypertension registry. Crit. Pathw. Cardiol. 2014;13(2):66-72. doi:10.1097/HPC.0000000000000014.
  28. Gore JM, Peterson E, Amin A, et al. Predictors of 90-day readmission among patients with acute severe hypertension. The cross-sectional observational Studying the Treatment of Acute hyperTension (STAT) study. Am. Heart J. 2010;160(3):521-527.e1. doi:10.1016/j.ahj.2010.06.032. 

                            

Medical Pain - A Forgotten Cousin, or Lost Cause?

Authors
Andrew Kristian Grech
Article Citation and PDF Link
BJMP 2015;8(3):a820
Abstract / Summary
Abstract: 

Poorly recognised over the years, medical pain - as opposed to its surgical cousin - continues to be associated with ineffective management and distasteful patient reports. Definitions and practice guidelines are conspicuous by their relative absence, with the disproportionate involvement of specialist pain physicians with non-medical cases and the consequent dependence on less experienced junior medical staff precipitating a rampantly inadequate medical pain experience for patients.

Several barriers to effective practices in the field of medical pain are proposed herein, with seedlings of potential solutions proffered in the interest of stimulating awareness and propagating interest in this neglected area of practice.

Keywords: 
medical; pain; anaesthesia; education; chronicity; fear

Introduction

What is medical pain? One answer would be a poorly defined concept which suffers the ignominy of poor management.

A quick internet search for the term brings up several hits to clinics offering the services of medical practitioners with pain specialty training. Definitions of ‘medical pain’ however, as opposed to those of its more easily construed post-surgical cousin, are both sparse and elusive in the learned literature. One potential candidate is provided by the International Association for the Study of Pain (IASP), whose professional presence on the web offers both a respectable description of pain syndromes of medical aetiologies as well as a taxonomical guide thereto1.

With a struggle to even define the concept, is it any wonder that medical patients with pain complaints continue to score reprehensible figures on studies into pain incidence and effective relief? This is far from a new phenomenon, with the British Journal of Anaesthesia (BJA) reporting a staggering 52% of medical inpatients in one study (N=1594) of a UK district general hospital to be in pain on the medical ward, with 20% and 12% of those in pain rating this complaint as severe and unbearable respectively2. What is particularly distressing about these statistics is the fact that data collection in the same study occurred over five days; more than ample time for complaints to be reported or recognised and appropriate relief strategies implemented. Barriers clearly exist to the provision of adequate medical pain relief, with practice shown to fall below standards recommended by the Royal College of Anaesthetists.3 A sketchy definition is perhaps one such barrier, but what other challenges exist to management of medical pain?

Predictability & On-Call Skills

In contrast to the anticipated pain following an elective surgical procedure, medical pain is less predictable in onset and consequently more the realm of an on-call physician than a specialist pain management team.  One unambiguous fact when equating specialist pain rounds and the on-call services of a more junior recruit is that the former clearly benefit from greater levels of experience, even allowing for acquisition of specialist training. The latter inevitably rely more heavily on the knowledge base afforded them by theoretical education, which sadly tends to be rather scant in undergraduate medical programmes.

The lack of early teaching of junior staff on the subject represents one barrier to pain management in general, with formal teaching on the subject of medical pain management a particular shortcoming in several international medical curricula. This fact is supported by the findings of a cross-sectional study in one Sydney hospital utilising a multinational population of medical interns and residents4, indicating some 56.2% of responders felt education on pain management to be inadequate. Up to 68.8% of responders were willing to receive additional lectures on opiate use to increase their knowledge base in this regard, suggesting a definite dearth of dedicated teaching.

In recognition of similar sentiments, a dedicated junior doctor-targeted postgraduate pain curriculum was suggested in 2011 by the Faculty of Pain Medicine (FPM) of the Australia & New Zealand College of Anaesthetists (ANZCA)5. This not only recognises the need for effective pain management skills at an early career stage, but also proposes a core set of competencies and assessments thereof for application to early postgraduate physicians’ skill sets.

A Surgical Predilection?

Skills of junior on-call medics aside, the provision of committed specialist pain services undoubtedly represents one of the major advancements in acute pain patient care. And yet, the needs of medical patients have often been overlooked in favour of acute surgical pain relief, and presumably continue to be so in the face of a lack of convincing evidence to the contrary. One study published in 2008 reporting data from over 220 United Kingdom National Health Service (NHS) hospitals revealed a paltry 16% incidence of routine acute pain service in medical wards6. The same study revealed that 82.2% of clinical leads in acute pain services actually recognise this problem of inadequate pain control on medical wards. With this stark admission from front line algologists in mind, why do elderly and general medical patients consistently appear to produce disconcertingly poor results in pain studies?

Perhaps the lack of adequate medical pain services in the light of a frank admission to a predilection for surgical patients reflects inadequate training, staffing or application of resources as a barrier to effective management of medical pain.

Community Confounders

Limitations of secondary care pain services aside, the primary care setting also exhibits a confounding factor for professional provision of medical pain management – the propensity for patients to easily self-medicate their complaints with non-prescription remedies. The immemorial complaint of headache in the community provides a convenient example of the potential for patients to self-manage their pain symptom. In doing so however, they simultaneously skirt the legion of adverse drug reactions, drug interactions and other implications including paradoxical rebound pain which may complicate management later on in the professional setting. Data published following a recent review of literature sources7 indicate codeine-based compound analgesics to be the most popular over-the-counter medications dispensed across several international populations. This telling fact may be suggestive of a trend in non-professional pain management which impedes effective management according to professional standards. Assuming a relative deficit of surgical to medical pain patients in the community, this may represent a unique challenge to providers of medical pain services.

Chronicity

One further important consideration to be made in medical pain is its potential for chronicity, with prevalence of leading pain disorders including lower back pain and chronic migraine indicated at 10.2%8 and 1-3%9 respectively in recent studies. The former in particular has exhibited an explosive trend in prevalence over recent years, with a more than 2.5-fold increase since 1992 in relative prevalence observed in one 2006 American study of households state-wide (N=5357)8.

Implicit in the chronicity of pain complaints exist a number of secondary disorders which can prove troublesome for effective engagement of pain management services. The European Journal of Pain quotes a large transnational study of chronic pain patients (N=46,394)10 as finding 21% of patients to have been diagnosed with depression because of their pain. Interestingly while almost half of subjects were self-administering over-the-counter analgesics and only 2% were being seen by a pain specialist, an astonishing 40% reported inadequate pain relief –an almost anticipated outcome of the ‘do it yourself’ approach to pain management in chronic, refractory cases? This may be less relevant in surgical pain experiences which intuitively represent a more acute event in a more controlled environment, and therefore may be more amenable to effective management than a drawn out pain experience over several years!

Fear of Pain

Chronicity of pain in turn evokes a largely self-explanatory phenomenon known as fear of pain, which can present a potentially sizeable obstacle to management of patients. High levels of fear of pain and also movement as a provocative agent thereof have been described in 38.6% of fibromyalgia syndrome patients (N=233)11, with this heightened fear of a painful experience linked to increased disability, depressed mood and most importantly pain severity. This latter component alludes to one of the more insurmountable barriers to management of chronic medical pain – the impasse resulting from a vicious circle of pain, fear and infinite vice versas.

The fear of pain may in turn be compounded by a fear of narcotic analgesic therapy on both the part of the patient and the prescribing physician, with this being an issue in non-cancer pain as well as malignant disease. The fear of commencing and continuing long term opiates is traditionally said to be particularly prevalent in the primary care setting12. Fear can arise in view of a number of reasons, including the potential for addiction and major side effects as well as the notion that opiate drugs represent a terminal stage in a disease process. Mention of opiates has been linked to accusations of ‘hidden diagnoses’ on the part of the physician, where patients suspect malignant pathology has been concealed from them by their care provider out of a deep-rooted belief that opiate analgesia is merited solely by cancerous conditions13. Whether this signifies an already fragile patient-doctor relationship or a contribution to the deterioration thereof, the connotation for effective management of medical pain remains a significant one. Repeated careful review of patients on long term opiate therapy for chronic non-cancer pain must be emphasised however, with up to 19% of chronic pain patients found to have some form of addictive disorder in a 2001 paper on the subject14 courtesy of the BJA.

Conclusion

In summary, patients requiring relief of medical pain issues are clearly disadvantaged by the presence of numerous hurdles to effective management of their complaints. The literature base in this regard is conspicuous by its absence, with practices in medical pain management being poorly evidence-based as a result. This represents a major potential target for investigative studies and research into potential trends and best practices. Exploration of effective methods for implementation of improved education for newer staff and also resource allocation for more experienced practitioners would also be of benefit to the standard of care in medical pain.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ANDREW GRECH, M.D. (MELIT.), Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Details: 
ANDREW GRECH, Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Email: 
andrew-kristian.grech@gov.mt
References
References: 
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  8. Freburger JK, Holmes GM, Agans RP, et al. The rising prevalence of chronic low back pain. Arch. Intern. Med. 2009;169(3):251-8. doi:10.1001/archinternmed.2008.543.
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Phytochemicals in cancer prevention and management?

Authors
Robert Thomas, Elizabeth Butler, Fabio Macchi and Madeine Williams
Article Citation and PDF Link
BJMP 2015;8(2):a815
Abstract / Summary
Abstract: 

Phytochemicals are compounds found in plants, which are responsible for the colour, taste and aroma of foods. Over and above these pleasant attributes, they protect us from environmental and ingested carcinogens by arming our antioxidant enzymes, enhancing DNA repair pathways and have direct effects on the fundamental hallmarks of cancer progression and metastasis. It is not a surprise then that analysis from the World Cancer Research Fund and other academic bodies, report that individuals eating phytochemical-rich foods have a lower risk of cancer or relapse after treatments.  The debate lies in whether concentrating these foods, or elements of these foods, into nutritional supplements may boost their health attributes. One notable randomised controlled trial (RCT) has demonstrated benefits for men with prostate cancer, but other trials of extracted chemicals have shown no benefit or even an increased cancer risk. This article provides a clinical overview, for medical practitioners, of the major classes of phytochemicals with examples of their common food sources. It reviews the international evidence for their anti-cancer mechanisms of action and their clinical benefits, as well as discussing the pros and cons of concentrating them into nutritional supplements. 

Keywords: 
Cancer, diet, phytochemicals, polyphenols

Introduction

Phytochemicals, are not regarded as essential nutrients in humans although an increasing number of well-conducted studies are linking higher intake with a lower risk of developing cancer, as well as lower relapse after initial treatment completion 1,2,3. There is a wide range of dietary phytochemicals, but one of the largest and well-known groups being the polyphenols [Table.1]. The average total dietary intake of polyphenols is reported to be over 1g per day, which is up to ten times higher than that of all other classes of phytochemicals and known dietary antioxidants4. The health benefits of phytochemical rich foods or concentrated nutritional supplements are often being highlighted in the medical and popular media and hence they are an increasing topic of conversation between medical practitioners and their patients especially those with cancer who have a particular interest in over the counter self help strategies 5,6. This article provides an overview of the major classes of phytochemicals with examples of their common food sources. It highlights the international evidence for their anti-cancer mechanisms of action, their clinical benefits, as well as discuss the pros and cons of concentrating them and, into nutritional supplements in an attempt to harness and boost their health benefits. Hopefully this review will provide some useful learning points to aid communication between patients and clinicians [Table. 2].

Classification

There are three major groups of phytochemicals: the polyphenols which can be subcategorized as the flavonoids, phenolic acids and other non-flavonoid polyphenols; the terpenoids, which can be subcategorized as the carotenoids and non-carotenoid terpenoids; and the thiols, which includes the glucosinolates, allylic sulfides and non-sulphur containing indoles (Table. 1). There are other phytochemical group, which although have some properties within these groups, have been classified within a miscellaneous category and examples of these include the betaines, chlorophylls and capsaicin.

Table.1 Classification of phytochemicals with notable food rich sources

Polyphenols

1. Flavonoids

o Flavonols:quercetin, kaempferol (onions, kale, leeks, broccoli, buckwheat, red grapes, tea, apples)

o Flavones: apigenin, luteolin (celery, herbs, parsley, chamomile, rooibos tea, capsicum pepper)

o Isoflavones: genistein, daidzein, glycitein (soya, beans, chick peas, alfalfa, peanuts)

o Flavanones: naringenin, hesperitin (citrus fruit)

o Anthocyanidins (red grapes, blueberries, cherries, strawberries, blackberries, raspberries, tea)

o Flavan-3-ols (tannins): catechins, epicatechin, epigallocatechin gallate (tea, chocolate, grapes)

o Flavanolols: silymarin, silibinin, aromadedrin (milk thistle, red onions)

o Dihydrochalcones: phloridzin, aspalathin (apples, rooibos tea)

2. Phenolic acids

o Hydrobenzoic acids: gallic acid, ellagic acid, vanillic acid (rhubarb, grape seed, raspberries, blackberries, pomegranate, vanilla, tea)

o Hydroxycinnamic acids: ferulic acid, P-coumaric acid, caffeic acid, sinapic acid (wheat bran, cinnamon, coffee, kiwi fruit, plums, blueberries)

3. Other non-flavonoid polyphenols

o Other tannins (cereals, fruits, berries, beans, nuts, wine, cocoa)

o Curcuminoids: curcumin (turmeric)

o Stilbenes: cinnamic acid, resveratrol (grapes, wine, blueberries, peanuts, raspberries)

o Lignans: secoisolariciresinol, enterolactone, sesamin (grains, flaxseed, sesame seeds)

Terpenoids

1. Carotenoid terpenoids

o Alpha, beta and gamma carotene (sweet potato, carrots, pumpkin, kale)

o Lutein (corn, eggs, kale, spinach, red pepper, pumpkin, oranges, rhubarb, plum, mango, papaya)

o Zeaxanthin (corn, eggs, kale, spinach, red pepper, pumpkin, oranges)

o Lycopene (tomatoes watermelon, pink grapefruit, guava, papaya)

o Astaxanthin (salmon, shrimp, krill, crab)

2. Non-carotenoid terpenoids

o Saponins (chickpeas, soya beans)

o Limonene (the rind of citrus fruits)

o Perillyl Alcohol (cherries, caraway seeds, mint)

o Phytosterols: natural cholesterols, siosterol, stigmasterol, campesterol (vegetable oils, cereal grains, nuts, shoots, seeds and their oils, whole grains, legumes)

o Ursolic acid (apples, cranberries, prunes, peppermint, oregano, thyme)

o Ginkgolide and bilobalide (Ginkgo biloba)

Thiols

o Glucosinolates: isothiocyanates (sulforaphane) and dithiolthiones (cruciferous vegetables such as broccoli, asparagus, brussel sprouts, cauliflower, horseradish, radish and mustard)

o Allylic sulfides: allicin and S-allyl cysteine (garlic, leeks, onions)

o Indoles: Indole-3-carbinol (broccoli, Brussel sprouts)

Other phytochemicals

o Betaines found in beetroot

o Chlorophylls found in green leafy vegetables

o Capsaicin found in chilli

o Peperine in black peppers

Table. 2 learning points

Higher intake of phytochemical-rich foods such as colourful fruit, vegetables, herbs, pulses, spices and teas is associated with a lower risk of cancer and relapse after treatments.

Their anti-oxidant properties help to protect our DNA from ingested or environmental carcinogens.

Phytochemicals, particularly polyphenols have direct anti-cancer mechanism of action via inflammation, modulation of cellular and signalling events involved in growth, invasion and metastasis.

Concentrating element of foods such as minerals, vitamins and phytoestrogenic polyphenols to potentially boost their health effects have largely been unsuccessful in preventing cancer in clinical trials.

Whole food phytochemical-rich supplements have demonstrated significant benefits in phase II and well conducted RCT and their true potential is been evaluated in ongoing studies.

Clinical evidence for cancer prevention.

Although not all, many studies have linked a higher intake of phytochemical-rich foods, such as vegetables, fruit, legumes, nuts, herbs and spices, with a lower incidence of cancer as highlighted in the latest comprehensive review from the World Cancer Research Fund and other systemic reviews2,3.

More specifically, certain elements of food have been addressed within a number of cohort studies. Carotenoids found in leafy green vegetables and carrots have been linked with a lower risk of breast cancer in a recent meta-analysis demonstrated7 and a lower risk of ovarian and pancreatic cancers, especially among smokers in either questionnaire or serum-based studies8, 9, 10. Higher intake of cruciferous vegetables such as cabbage, cauliflower, Brussel sprouts, radishes and broccoli have been associated with a lower prostate cancer risk11, as have foods rich in isoflavones such as pulses and soy products12, lycopene rich colourful fruits and tomatoes13. Foods with abundant levels of flavonoids such as onions, rich in quercetin, have been shown to reduce the incidence of numerous cancers particularly those arising from the lung, especially amoung smokers14, 15. The anthoxanthins, in dark chocolate, have been reported to lower the risk of colon cancer16 and higher green tea intake lowers the risk of breast, prostate, ovarian and oesophageal cancer, again particularly among smokers and alcoholics17, 18. Finally, coffee consumption has been shown to reduce the risk of non-melanomatous skin cancers and melanoma, even after removing other factors such as ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake and smoking history19,20.

Clinical evidence for a benefit after cancer

The benefits of healthy foods do not stop after a diagnosis, especially if combined with other healthy lifestyle habits. For example, breast cancer survivors who regularly consumed more than the government recommended five portions of fruit and vegetables a day, had a third lower breast cancer recurrence risk if combined with regular physical activity21. In another study, women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, cruciferous vegetables and soya, were reported to have the lowest risk of death22. Likewise, a lignan and polyphenol rich diet was associated with a lower colorectal cancer relapse rate23.

The large Shanghai Breast Cancer Survival Study demonstrated that women with the highest intake of the phytoestrogenic polyphenols isoflavones and flavanone found in soya and other beans, had a 29% lower risk of relapse and death24. Similar findings were seen for green tea after breast25 and colorectal cancer23. Green tea also decreased the abnormal white cell count in 30% of patients with chronic leukaemia and reduced the levels of several markers of proliferation, as well as serum Prostate Specific Antigen (PSA) among men with prostate cancer26. A slowing of PSA progression has similarly been observed in other dietary studies, most notably the randomised trial involving a plant-based diet together with other lifestyle changes27 and a phase II study of pomegranate juice28.

Another cancer influenced by nutrition is skin cancer, as highlighted by a study of individuals who have been treated for basal cell carcinoma or squamous cell carcinoma, and who have a high risk of further lesions due to their on-going solar damage. Those who consumed the highest levels of lutein and zeaxanthin-rich foods, such as leafy green vegetables, had the lowest levels of new cancer formation29.

A number of other studies evaluating the impact of phytochemicals are underway, the largest and probably most comprehensive is the UK’s DietCompLyf prospective trial involving 3159 women treated for breast cancer30.

What are the likely anti-cancer mechanisms of phytochemicals?

The precise biochemical mechanisms through which phytochemicals exert their anti-cancer effects are still being explored, as their actions are wide-ranging and complex but significant advances have been made of late in the understanding the mode of action. The most quoted cancer prevention mechanism is via their antioxidant activity, elicited either through direct free radical absorption or through induction of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione via a variety of molecular mechanisms31, 32. One of these mechanisms is activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes31, 32. Phytochemicals, particularly the thiol class such as sulforaphane,have also been shown to inhibit the conver­sion of procarcinogens to their electrophilic, DNA damaging, chemicals32,33.

A number studies involving known, common carcinogens have highlighted the antioxidant properties of phytochemicals. A good example of their protective effect was an experiment involving the known house-hold carcinogen triclocarban, commonly found in detergents and cleaning agents. Healthy cells exposed to triclocarban tend to mutate into pre-malignant cells, however, the amount and rate of carcinogenesiswas significantly reduced byadding curcumin to the petri dish culture feeds34. In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to have improved SOD activity and higher urinary concentration of these polyphenols35. Rats exposed to cigarette smoke given indole-3-carbinol, a phytochemical rich in cruciferous vegetables, had a lower lung cancer rate than those not given idole-3-carbinol36. Subjects eating a meal of onions, which increased their serum levels of quercetin, demonstrated decreased levels of oxidative metabolites including 8-hydroxydeoxyguanosine (8-OHdG) a marker of DNA damage and repair1618, 37. Quercetin supplementation has also been shown to improving mitochondrial dysfunctions induced by the toxin 3-nitropropionic acid38. A clinical study in Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, and found a similar effect on urinary markers of DNA damage39. Finally, marinating meat in rosemary and thyme, has been reported to reduced the serum levels of carcinogenic heterocyclic amines (HCA) by 87% compared to subjects who eat the meat unseasoned40.

Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inflammation. It is now well established that inappropriate inflammation is intimately involved in the cancer process, particularly in the promotion and progression stages of cancer. Inflammation is closely associated with oxidative stress and activation of NF-kappa B family of transcription fac­tors. These factors regulate more than 150 genes involved in mechanisms of cell survival and these target genes are not just pro-inflammatory but also oncogenic. Numerous phytochemicals have been shown to inhibit NF-kappa B signalling, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid and caffeic acid phenethyl ester and the phytochemicals within bilberries31,41.

More recently, it has been reported mainly from laboratory studies that phytochemicals have an affect on several cancer process through modulation of cellular and signalling events involved in growth, invasion and metastasis32. Pomegranate, for example, rich in the polyphenol ellagic acid, has been shown to directly inhibit cell growth and induce apoptosis in androgen sensitive and aggressive human prostate cancer cells42. Pomegranate extract has also been reported to inhibit processes involved in cancer metastasis in a study involving oestrogen sensitive and resistant breast cancer cell lines, showing increased markers of cell adhesion and migration in cancer but not normal cells43. In another study it inhibited a chemokine that attracts breast cancer cells to the bone44. Curcumin slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells45, 46, 47, 48. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells49. Curcumin has been shown to modulate miRNA expression in breast cancer cells leading to a reduced expression of Bcl-250 and stabilisation of tumour suppressor gene in colorectal cancer cell lines52. Green tea, rich in epigallocatechin gallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis26, 52, 53. It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis50, 54. Resveratrol has demonstrated epigenetic regulatory properties which influence regulate proliferation, cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor46. Caffeic acid and phenethyl ester, as well as inhibiting NF-κB signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo47. Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition which is a basic biological process related to cancer initiation and development47.

Finally some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism. Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells, yet at the same time blocking the binding of more harmful oestrogens, including those produced endogenously39. This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavones and flavanones-rich foods had a lower risk of death24. In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels. This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer.

Can concentrating foods into supplements enhance their anti-cancer effect?

If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with poor diets or further enhance the benefits in those whoes diets are already adequate. People living with and beyond cancer (PLWBC) are certainly attracted to the potential health benefits of food supplements, as over 65% report regular intake5,6. There are two main categories of supplements commercially available: the first involves chemicals extracted from food, or made synthetically, such as minerals and vitamins; the second involves purifying and concentrating whole foods:

Vitamins and mineral supplements: The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals. Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse57. The SU.VI.MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium and zinc, or a placebo, and found no reduction in mortality or cancer-specific mortality overall58, although a further analysis in men found a reduction in the risk of prostate cancer. The authors postulated that this difference between the sexes was related to French men having a lower baseline micro-nutrient status59. A major trial of selenium and vitamin supplements in a poor region of China, demonstrated reduced risks of oesophageal cancer; at the time this population was known to have widespread micro-nutrient deficiencies60.

Unfortunately, most other studies of vitamin, minerals and other extracted nutrients have shown no benefit, or have actually shown an increased risk of cancer. For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer61. The Health Professionals Follow-up study (HPFS) which followed the lifestyle habits of 51,529 male professionals for over 15 years found that men who took very high doses of zinc (>100mg/day), or took it for long durations were more than twice as likely to develop advanced prostate cancer compared with controls62. The randomised SELECT study demonstrated an increased prostate cancer incidence with vitamin E and selenium supplementation63. A further analysis of the HPFS found that of the 4,459 men who had developed prostate cancer, those who took selenium supplementation of ≥ 140 μg/d after diagnosis were associated with a 2.60-fold greater risk of prostate cancer mortality64.

The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed that men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation, and that those with high levels had a higher risk, particularly in smokers65. This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer66. These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency67, which is rarely routinely detected unless individuals have self funded micro-nutrient analysis (cancernet.co.uk).

Whole food supplements: More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies. Despite some initial encouragement from smaller evaluations, studies of extracted lycopene or genistein given on their own in more scientifically robust analyses have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy68, 69, 70 neither were there links with the reduction in the risks of breast cancer with regular intake5. Of more concern, a randomised study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation (25.8 g twice a day) added to laboratory tumour cells caused them to proliferate faster (Increased K67 expression) and overexpress the tumorigenic growth factor receptor FGFR271. This supports the notion that phytoestrogen foods are healthy, but concentrating them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements has shown any detrimental effects on cancer outcomes and some have beneficially influenced progression rates. For example, a study carried out at John Hopkins involving pomegranate seed extract, found that men taking the supplements had a reduction in PSA progression rate72. A study conducted at the Mayo Clinic found that green tea concentrate decreased the abnormal white cell count in 30% of patients with chronic leukaemia, and a small study from Louisiana University reported that green tea concentrate significantly reduced levels of several cancer-promoting growth factors as well as PSA levels in participants26. In the Vitamins and Lifestyle (VITAL) cohort study, a regular intake of grapeseed extract was shown to be linked with a lower risk of prostate cancer70, and another small RCT found that a dietary supplement containing isoflavones, plus other phytochemicals and anti-oxidants delayed PSA progression73. Interestingly one of the most popular supplements, Saw Palmetto, despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation74. Likewise, another popular supplement, lycopene, despite similar suggestions from smaller non-randomised trials68, 69, demonstrated no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts was the National Cancer Research Network adopted Pomi-T study75. This study combined four different food types (pomegranate, green tea, broccoli and turmeric) in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical. It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse, following initial radical interventions.

The results, presented as an oral presentation at the American Society of Clinical Oncology Conference (ASCO), Chicago, showed a statistically significant, 63% reduction in the median PSA progression rate compared to placebo in both men on active surveillance and experiencing a PSA relapse post-treatment. A further analysis of MRI images, demonstrated the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect75. It was well tolerated, apart from some mild loosening of the bowels in 10% of men, and there was no effect on testosterone levels. At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis and erectile dysfunction75.

A number of other RCT’s involving whole food phytochemical-rich supplement have demonstrated benefits for some of the distressing symptoms common after cancer treatments, such as fatigue76 and urinary infections77. There are currently over ten, on-going studies registered with the National Institute of Health. In the UK, the Institute of Preventative Medicine has plans to include the Pomi-T supplement into the next national prostate cancer prevention study. This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study, co-ordinated by the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer. In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer.

Conclusion

There is increasingly convincing evidence to show that plant phytochemicals, particularly polyphenols have significant benefits for humans. Not only do they improve our daily lives by helping our food taste, smell and look appetising, they also reduce our risk of cancer and help people living with and beyond treatments. Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical-rich diets, along side other lifestyle factors, largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as ASCO. Going a step further and concentrating these foods, or extracted elements of these foods, into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects, but have their pitfalls. Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects. No study has reported detrimental effects of whole, non-phytoestrogenic food supplements and some have reported significant advantages. Despite these potential benefits and reports that over 60% of patients living with and beyond cancer take nutritional supplements, oncologists have been reluctant to discuss their pros and cons due to a lack of RCTs from academic institutions55, 56. Hopefully this trend will change, particularly following the success of the Pomi-T study75 and ongoing studies registered with the National Cancer Institute.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. ELIZABETH BUTLER, MSc Dip ION. Body Soul Nutrition, Level 2, 25 Petersham Road, Richmond, Surrey, UK. FABIO MACCHI, M.Sc. Head of Scientific & Clinical Development, Helsinn Healthcare S.A. PO Box 357 6915 Lugano/Pambio-Noranco, Switzerland. MADELEINE WILLIAMS, BA(Hons) PgDip. Research Manager, The Primrose Oncology Unit, Bedford Hospital, Bedford, UK.
Corresponding Author Details: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. MK42 9DJ.
Corresponding Author Email: 
rt@cancernet.co.uk
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A Study On Clinical Features And Cost Incurred By Dengue Syndrome Patients Admitted To Tertiary Care Hospital

Authors
Manjunath M N, Chaithanya C Nair and Sharanya R
Article Citation and PDF Link
BJMP 2015;8(2):a811
Abstract / Summary
Abstract: 

Background: India is one of the seven identified countries in Southeast Asia regularly reporting dengue fever (DF)/dengue haemorrhagic fever (DHF) outbreaks. India may soon transform into a major niche for dengue infection in the future with more and more new areas being struck by dengue epidemics.

Objectives: 1) To study the clinical manifestations, trends and outcomes of all confirmed dengue cases admitted to a tertiary care hospital. 2) To study the cost incurred by these patients during hospital stay.

Materials and Methods: This record-based study was conducted on 757 serologically (NS1 Ag/ IgM/ IgG) positive dengue cases admitted to KIMS Hospital & Research Centre, Bangalore during January 2012 to December 2012. Required data from the entire laboratory confirmed cases were collected from the Medical Records Department (MRD) and analysed.

Results: The seropositive case rate for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and the most vulnerable age group was found to be between 5 to15 years of age. The median age was 8 years. The percentage of cases presented as dengue fever without warning signs was 88.5%, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%.

Conclusion: Increased awareness, better transport facilities and case management according to the WHO guidelines is needed to further reduce mortality and cost burden of dengue cases.

Abbreviations: 
DF - Dengue Fever, DHF - Dengue Haemorrhagic Fever, DSS - Dengue Shock Syndrome, ARDS - Acute Respiratory Distress Syndrome, MODS - Multiple Organ Dysfunction Syndrome.

Introduction:

Dengue made its debut as early as 1780, when Benjamin Rush described the condition as “break bone fever”. This hitherto unfamiliar infection has now grown to demand the attention of all public health care providers. It is a mosquito borne, fast emerging, viral infection manifesting in four serotypes (1). Approximately 2.5 billion people, living mainly in urban areas of tropical and subtropical regions, are estimated to be at risk of acquiring dengue infection (2). While dengue is endemic in more than 100 countries, most cases are reported from Southeast Asia and the western Pacific regions. Around 50 million cases and 24,000 deaths are estimated to occur in these 100 endemic countries. This includes hospitalisation of nearly half a million cases of dengue haemorrhagic fever (DHF), of which 90% are children. Treated (DHF)/dengue shock syndrome (DSS) is associated with a 1% mortality rate while mortality rate among untreated cases escalates to 20%(3,4).

India is one of the seven identified countries in the Southeast Asia region regularly reporting incidence of DF/DHF outbreaks. The first confirmed report of dengue infection in India dates back to 1940s, and since then more and more new states have been reporting the disease which mostly strikes in epidemic proportions often inflicting heavy morbidity and mortality, in both urban and rural environments.(5)

The various manifestations of dengue may not have a distinct line of demarcation: apart from the classic features, reports of rare presentations have recently become more frequent (6,7). During recent outbreaks in India, the clinical manifestations which were shown by the patients were slightly different from those in previous years(8).. There have been many reports of difficulties in the use of the previous classification, which were summarised in a systematic literature review (9). Difficulties in applying the criteria for dengue haemorrhagic fever in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria, led to the request for the classification to be reconsidered .Hence, WHO revised the dengue case classification into dengue (with or without warning signs), and severe dengue (10).The present study was done to analyse the clinical features, complications, cost incurred and outcome of cases admitted to a tertiary care teaching hospital in Bangalore.

Methodology:

A record based descriptive study was conducted in paediatric patients admitted with signs and symptoms suggestive of dengue fever to KIMS hospital Bangalore, during the period between January 2012 to December 2012. SD BioLine kit was used for testing with NS1 antigen\ IgM\ IgG. The medical records were perused for collecting data about these cases using a pre-designed proforma. Data was analysed for the clinical presentations, outcome and direct cost incurred in respect to hospital charges and laboratory investigations.

Results:

Out of 1230 cases admitted with clinical signs and symptoms suggestive of dengue syndrome 757 (61.5%) cases were found to be NS1 antigen\ IgM\ IgG positive for dengue. Among the 757 positive cases, males were 499 (65.9%) and females 258 (34.1%). The majority of the cases were in the school going age group and this consisted of 310 cases (41%) and adolescent children which accounted for 249 cases (33%), the median age being 8 years of age. The least number of cases were seen in infants which accounted for 45 cases (6%).

Table 1. Sex distribution

Age group Male Female Total
Infant 31 14 45
Toddler 114 39 153
School going 208 102 310
Adolescent 146 103 249
TOTAL 499 (65.9%) 258(34.1%) 757

The majority, 88.5% of cases presented as dengue fever without warning signs, 6.34% with dengue fever with warning signs and 5.15% with severe dengue. Of the cases with warning signs 92.3% of cases had fever, 42.5% cases had vomiting and 38.2% cases had abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority (87%) presented with petechiae followed by haematemesis (9%) and epistaxis (4%). Rashes were seen in 4% and arthralgia in 13% of cases. Pleural effusion was seen in 21% of cases and ascites was seen in 16% of cases. Complications in the form of acute respiratory distress syndrome (ARDS) was seen in 12.06% cases, 6% cases showed neurological manifestations in the form of encephalopathy and 1.3% cases had renal failure.

Table 2. Severity of dengue

SEVERITY PERCENTAGE
DF without warning signs 88.5
DF with warning signs 6.3
Severe dengue 5.15

Table 3. Presenting complaints

Presenting Complaints Number (%)
Fever 699(92.3)
Myalgia 148(19.5)
Haemorrhagic manifestations 34(4.5)
Vomiting 321(42.5)
Abdominal pain 289(38.1)
Headache 201(26.5)
Arthralgia 99(13)
Diarrhoea 80(10.5)
Others 121(16)

Fig 1 presenting complaints.

Haemoglobin level of > 12gm% was found in 73.4% cases, 9-12gm% in 23.4%, 6-9gm% in 2.1% and <6 gm% in 1.1% of cases. Platelet count of < 20,000 was found in 21.5% of cases, 20-50 thousand in 39.5% , 50,000 to 1.5 lakh in 36% of cases and >1.5 lakh was found in 3% of cases. Majority (65.5%) of cases were NS1 Ag positive alone or with IgM/ IgG/ or both positive.

Remaining were positive for either of the antibodies.13.7% cases werepositive for all the three i.e. Ag, IgM,& IgG. The mortality rate was found to be 8.6%

Figure 2: outcome

Cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and laboratory investigations, medications, hospitalisation, food) was found to been average of Rs.12,611=00. The indirect cost loss of wages of patient &attendants) was found to be an average of Rs.3, 109=00. The hidden cost (out of pocket expenses) was found to be an average of Rs.50=00. The cost of treatment of other co-morbid conditions was found to be an average of Rs.2, 275=00. The total cost of treating dengue syndrome was 18,045=00

Discussion:

In the present study it was found that males were commonly affected and the most common age group was between 5 to 15 yrs of age. Similar results were reported in a study by Faridi et al, 76% of all cases of DHF /DSS were aged 6 years or more[11].

In the present study, the most common presenting symptoms was fever followed by vomiting and abdominal pain which is similar to study done by Kumar A et al showed fever in 99.2% followed by myalgia (64.6%), vomiting (47.6%), headache (47.6%) and abdominal pain (37.5%) (12).

In the present study, the most common bleeding manifestation was haematemesis and epistaxis. In a study by Ratageri et al, common bleeding manifestations were gastrointestinal bleeding (22%) and petechiae (18%) [13]. The gastrointestinal tract was reported as the commonest site of bleeding (61%) in a study by Ahmed et al [14].

In the present study majority of cases had platelet count between 20,000 to 50,000/mm3.In a study by Kamath et al, platelet counts less than 50,000/mm were noted in 62.3% [15]. In our study complicated cases showed ARDS and neurological manifestations in the form of encephalopathy. Almost all the cases which expired were found to have ARDS. Dengue associated ARDS is associated with a high mortality [16]. Dengue infection is found to cause neurological manifestation ranging from non-specific symptoms to encephalitis and rarely Guillain-Barre Syndrome [17]. In our study the mortality rate was found to be 8.6% , in the study by Anju et al overall mortality seen was 6% [18], compared to 3% by Ahmed et al [14].

Conclusion:

The seropositivity for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and most vulnerable age group was found to be 5-15 year olds. The median age was 8 years. 88.5% of cases presented as dengue fever without warning signs, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%. Acute Respiratory Distress Syndrom (ARDS) and multiple organ dysfunction syndrome (MODS) was found to be the most dreadful complications with high rates of mortality .

In this study it was found that cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and lab investigations, medications, hospitalisation, food) was found to bean average of Rs. 12,611=00. Thus dengue syndrome also causes significant economic burden on the patients.

In the recent few years, the world has seen varied clinical presentation of the dengue fever in different epidemics, even in the same regions and even with the period of time. Where some known features are still manifesting, few atypical features are noted from several parts of the world. A continuous seroepidemiological surveillance and timely interventions are needed to indentify the cases, so that its complications, outbreak and mortality can be minimised.

Moreover community awareness, early diagnosis and management and vector control measures need to be strengthened, especially during peri-monsoon period, in order to curb the increasing number of dengue cases.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DR MANJUNATH M N, Fellow in Paediatric Critical Care, Narayana Hrudayalaya, Bangalore, India. DR CHAITANYA NAIR, Post Graduate, Kempegowda Institute of Medical Sciences, Bangalore, India. DR SHARANYA R, Post Graduate, Kempegowda Institute of Medical Sciences, Bangalore, India.
Corresponding Author Details: 
DR MANJUNATH M N, Fellow in Paediatric Critical Care, Narayana Hrudayalaya, Bangalore, India.
Corresponding Author Email: 
drmanju.drmanju@gmail.com
References
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Current Management of Achalasia – A Review

Authors
Hanna Winter, Rajeev Shukla, Mohamed Elshaer and Amjid Ali Riaz
Article Citation and PDF Link
BJMP 2015;8(2):a810
Abstract / Summary
Abstract: 

Introduction: Achalasia is a rare oesophageal motility disorder characterised by oesophageal aperistalsis and incomplete relaxation on swallowing of the lower oesophageal sphincter. This review aims to identify and critique literature detailing the available management options for these patients and provide an up to date account of current thoughts and controversies in the treatment of achalasia.

Methods: An extensive literature search was performed for articles and reviews published on the management of achalasia, using Ovid MEDLINE, Cochrane library and PubMed search databases.

Results: The management of achalasia is controversial. Simple options such as pharmacological treatments and Botulinum toxin A injections do not provide sufficient relief of symptoms but may serve to treat those not suitable for surgery or dilatation. However, in those who are deemed suitable, the literature suggests that the optimum treatment is laparoscopic transabdominal Heller myotomy which has demonstrated the best long term results with few complications or perforations.

Conclusion: It is not possible to treat the underlying cause of achalasia but only to improve symptoms. Whilst the literature may suggest that the Heller myotomy is the best method to achieve this, it is clear that the outcomes are dependent on surgeon or physician technique and experience. It is important therefore that these patients are treated in a specialist centre with experience with such procedures. Recent advances in surgical and endoscopic technologies, with robotic Heller myotomy and per-oral endoscopic myotomy, provide promising progress for the treatment for achalasia

Keywords: 
Achalasia, manometry

INTRODUCTION

Achalasia is a rare oesophageal motility disorder, typically presenting with symptoms of dysphagia, regurgitation of food and retrosternal chest pain made worse on eating. The annual incidence in the UK, Ireland and USA is between 0.5 to 1.2 per 100,0001 and seems to affect both sexes and all races equally.

The aetiology of achalasia remains largely unknown. However, suggested influences include a genetic predisposition, infection and autoimmunity2,3. The changes responsible for achalasia include a combination of both poor oesophageal contractility and impairment of relaxation of the lower oesophageal sphincter resulting in oesophageal distension and symptoms described above. Reaching a diagnosis relies on oesophageal manometry in addition to barium swallow and oesophagogastroduodenoscopy (OGD).

The condition was first described by a British physician in 1674, Sir Thomas Willis, and treated with dilatation using a sponge attached to a whale bone4. It was not until many years later in 1913 that a German surgeon, Heller, performed the first cardiomyotomy5. The optimal treatment for achalasia remains controversial with treatment largely dependent on the preference of the physician. Cases are few and far between and therefore large studies reviewing the optimal treatments are limited.

This review aims to identify and collaborate relevant literature detailing the management options available to treat achalasia.

METHODS

An extensive literature search was performed using Ovid MEDLINE, Cochrane library and PubMed databases for relevant articles relating to medical, endoscopic and surgical management of patients with achalasia. Keywords including achalasia, Heller’s myotomy and balloon dilatation were used and relevant articles included.

MANAGEMENT

Diagnosis

All patients presenting with dysphagia should initially be investigated with OGD to exclude a mitotic lesion. OGD has little value however in diagnosing achalasia but remains an essential component of the investigation of the upper gastrointestinal tract. The gold standard for diagnosing achalasia is oesophageal manometry6,7. This typically shows a high resting pressure in the lower oesophageal sphincter which fails to relax on swallowing with associated impaired oesophageal contractility. A barium swallow may show very little in early disease, but in more advanced disease may demonstrate a ‘bird’s beak’ appearance or a sigmoid oesophagus, distension due to longstanding obstruction at the gastro-oesophageal junction (GOJ)8.

Achalasia Subtypes

Whilst the diagnosis of achalasia is dependent upon the above, high resolution manometry can further classify achalasia into three subtypes dependent on the pattern of oesophageal peristaltic abnormalities and oesophageal pressure dynamics (Figure 1). The three subtypes differ in responsiveness to treatment and as such, can be used to guide the most appropriate treatment and counsel patients appropriately.

Figure 1: The Chicago classification for achalasia subtypes9

Type I (classic) Achalasia with minimal oesophageal pressurisation
Type II Achalasia with oesophageal compression
Type III Achalasia with oesophageal spasm

Treatment

The treatment for achalasia is aimed entirely at symptom control. The underlying pathological processes which lead to myenteric plexus neurodegeneration are not fully understood and as such, cannot as yet be prevented or reversed. Current treatment options exist therefore to reduce the contractility of the lower oesophageal sphincter and hence improve the obstruction to passage of food and symptoms of dysphagia.

Various options exist for this, including pharmacological therapies which are available in the form of nitrates, calcium channel blockers, anticholinergic agents and beta agonists. Endoscopic therapy is a preferable alternative, with pneumatic balloon dilatation or intrasphincteric Botulinum toxin injection being the most commonly used techniques. The ultimate and generally accepted optimal treatment, however, is the surgical Heller’s myotomy (Figure 2).

Figure 2: Treatment options available for the management of achalasia

Pharmacological options Oral nitrates (GTN, Isosorbide dinitrate)
Calcium channel blockers (Nifedipine, verapamil)
Anticholinergics
Opioids (loperamide)
Phosphodiesterase inhibitors
Β2 agonists
Nitric oxide agonists
Endoscopic techniques Pneumatic balloon dilatation
Botulinum toxin injections
Peroral endoscopic myotomy (POEM)
Surgical options Heller’s cardiomyotomy (transabdominal or transthoracic / open or laparoscopic)

Medical

Pharmacological therapies as treatment for achalasia have been largely superseded by improvements in both endoscopic and surgical techniques. However, their potential role still exists in those with early disease, in elderly patients unsuitable for surgery or dilatation and in whom Botulinum toxin injections have failed. They may also have potential use in patients awaiting surgery for interim symptom control10,11,12. Most trials reviewing the effect of drug therapy for achalasia are limited by small numbers and short follow up so long-term benefits remain poorly understood13.

As with all achalasia treatments, the aim of drug therapy is to relax the lower oesophageal sphincter. Nitrates have been used as vasodilators within cardiovascular disease since the 1970s. Within the smooth muscle of the gastrointestinal tract, they behave similarly by increasing the production of cyclic GMP and in turn, causing dephosphorylation of the myosin light chain and subsequent inhibition of smooth muscle contraction. It is with this concept in mind that medical treatment with nitrates can cause relaxation of the lower oesophageal sphincter. There are only two randomised controlled trials which have reviewed the effect of nitrates on patients with achalasia and compared them to alternative treatment modalities14,15. However, as a Cochrane review has established, the results of these studies cannot be reliably interpreted due to both the methodology and the limitations with regards to follow up13. Regardless, nitrates are not without side effects and can cause headaches and changes in blood pressure. In view of this, their routine use is not recommended.

Calcium channel blockers, including Nifedipine, are more commonly used and are given sublingual 15-30 minutes before meals16. These limit the intracellular uptake of calcium and hence reduce the contractility of muscle cells. Reports of success as high as 65-80% have been documented17,18,19. However, up to 30% experience significant side effects.

Additional agents that have been described include β2- agonists, anticholinergics and phosphodiesterase inhibitors, the latter of which induces nitric oxide release and thereby relaxation of lower oesophageal sphincter muscle but can also result in significant side effects, including angina, and so routine use is again not advised20,21. It is for these reasons, that progress has been encouraged elsewhere with developments in both endoscopic and surgical techniques for the treatment of achalasia.

Endoscopic

Endoscopic treatments are again aimed at reducing the contractility of the lower oesophageal sphincter and several options exist for this. Injection of Botulinum toxin A is the most commonly performed and has fewer associated side effects and complications than its alternatives, hence is often used as first line treatment and especially in patients not suitable for surgical intervention. Alternative options include pneumatic balloon dilatation and more recently, per-oral endoscopic myotomy (POEM).

Botulinum toxin A is used as an intrasphincteric injection and exerts its action by inhibiting the release of acetylcholine, necessary for muscular contractions. This in turn lowers the tone and pressure of the lower oesophageal sphincter. 80-100 units of Botulinum toxin A are injected in divided doses in all four quadrants at the level of the squamocolumnar junction via endoscopic guidance. Patients recover quickly and can go home the same day22, typically seeing improvements in symptoms between days 1-323. Results are variable. Certainly the side effects are minimal and it appears to be a safe procedure without the risk of perforation seen with other techniques24,25. Short term improvement in symptoms is described as high as 85%. However, over time this is seen to decrease significantly to only 30% at one year. Most will require further injections or alternative treatments such as pneumatic balloon dilatation or surgical myotomy24.

Pneumatic balloon dilatation includes inflating a 30mm balloon at the level of the GOJ26,27. This process fractures the muscular fibers of the lower oesophageal sphincter hence disrupting the sphincter mechanism. It can be performed under fluoroscopic or endoscopic guidance dependent on operator experience and preference. The major risk is oesophageal perforation, which in experienced hands occurs in 1.9% (range 1-16)28. In addition, gastro-oesophageal reflux post procedure can be troublesome, affecting 4-16% of patients29.

A Cochrane review compared outcomes with Botulinum toxin injections and pneumatic balloon dilatation30. Whilst little difference in short term improvement was noted, longer term remission rates were considerably higher in those treated with balloon dilatation. However, even with balloon dilatation, up to a quarter require further treatments at five years31,32.

An emerging endoscopic technique is the peroral endoscopic myotomy (POEM). This is performed by incising the mucosa endoscopically, dissecting and developing a plane in the submucosal layer and performing a myotomy inferiorly to beneath the gastro-oesophageal junction. The mucosa is thereafter closed with staples. Studies have shown it to be both safe and effective with short term results demonstrating similar relief in dysphagia and improvements in Eckardt scores as patients undergoing laparoscopic myotomy33,34. The added benefit of POEM is the potential for faster return to normal activities34 and with preserving the need for surgery, dissection at the hiatus can be avoided which may reduce symptoms of post-operative reflux. However, it is technically challenging and studies demonstrating long term outcomes are not yet available.

Surgical

The surgical treatment for achalasia involves performing a myotomy at the level of the gastro-oesophageal junction. There has been controversy regarding the most appropriate method of achieving this and experience includes open versus laparoscopic, transthoracic versus transabdominal. Further controversy exists in the importance of performing simultaneous antireflux surgery.

With the development of laparoscopic abdominal surgery, there is little doubt that this has lowered the complications and improved patient recovery and inpatient hospital stay35,36,37. Not only is the approach to the GOJ easier via the abdomen, also single lung ventilation is not required and so pulmonary complications are fewer.

Surgical myotomy offers superior long-term relief of achalasia-related symptoms compared to medical and endoscopic alternatives, alleviating dysphagia in 88%-94% at ten years following surgery36,38. Improvements have also been demonstrated in patient satisfaction and quality of life post operatively39. Performing a complete myotomy is essential to outcome and prevention of recurrent symptoms, hence accuracy and precision is paramount40. Where this is concerned, robotic surgery is becoming more accessible and early results would suggest improvements over conventional laparosopic surgery41.

The risk of perforation is small with laparoscopic myotomy42 and even smaller with robotic surgery. The main complication associated with performing a myotomy is symptomatic reflux. Controversy exists regarding simultaneous anti-reflux procedure and some would argue that in the absence of posterior dissection at the level of the GOJ, there is not the need43. A meta-analysis performed by Lyass et al reviewed patients undergoing surgery for achalasia44. The authors concluded that the rates of reflux post operatively were no different between those who had anti-reflux procedures and those who did not. Ultimately, the decision to proceed with anti-reflux surgery will vary surgeon to surgeon. However, what is generally accepted is that a complete 360 degree Nissen’s fundoplication is not required, and may serve only to give the patient ongoing symptoms of dysphagia. Therefore, Toupet (posterior 270 degrees) or Dor (anterior 180 degrees) fundoplication are more commonly used, the latter providing cover to the myotomy and thus potentially protecting any unidentified mucosal breach45.

Surveillance

Studies have demonstrated that patients with a diagnosis of achalasia have an increased risk of squamous cell carcinoma of the oesophagus46. For this reason, guidelines developed by the American Society for Gastrointestinal Endoscopy suggest surveillance oesophagogastroduodenoscopy every 1-3 years for 15-20 years47.

CONCLUSIONS

Achalasia is a difficult condition to diagnose and treat. All treatments are aimed at disrupting the lower oesophageal sphincter mechanism and none are without risk or complication. Treatment modalities vary in their short and long term success rates. Pharmacological treatments are of limited value and Botulinum toxin injections have limited long term results but both may play a role in patients who cannot tolerate more invasive procedures48. The main debate has historically lain between advocating the use of endoscopic dilatation versus laparoscopic Heller myotomy.

Studies looking at endoscopic dilatation versus myotomy have comparable initial symptomatic relief. Direct comparison between the long term outcomes does, however, favour laparoscopic myotomy49,50. Traditionally, endoscopic dilatation has been the first line treatment, with surgery reserved for those in whom dilatation has failed51. However, subsequent intervention is common and there are many studies examining outcomes of second treatment with either surgery or dilatation. In cases where initial treatment has failed and recurrent symptoms of dysphagia present, dilatation has been shown to be more effective in those who have had surgery rather than those who have had previous dilatations or Botulinum toxin injections52,53. Importantly, there is not a greater risk of perforation in these patients than in those who have not undergone myotomy54.

Performing a surgical myotomy after previous treatment with dilatation or injection may complicate the surgery slightly and has been shown to increase complications and failure of myotomy55,56, providing an argument for surgery as first line treatment. That said, surgery is still recommended in these patients as the most successful option57.

Ultimately, the optimal treatment will vary dependent on physician or surgeon technique and experience. Cases are limited and so it is recommended that these patients are treated in a specialist Upper GI unit where all options are presented to the patient and the risks and benefits of each counselled appropriately. It is an exciting time for achalasia as new treatment options including POEM come to light and robotic surgery becomes more available.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Prof.A A RIAZ, Hunterian Professor and Consultant Upper GI, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. HANNA WINTER, Surgical Registrar, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. RAJEEV SHUKLA, Surgical Registrar, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. MOHAMED ELSHAER, and Surgical Registrars, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK.
Corresponding Author Details: 
Professor A A Riaz, Hunterian Professor and Consultant Upper GI, Laparoscopic and General Surgeon, Department of Surgery, West Hertfordshire Hospitals NHS Trust, Vicarage Road, Hertfordshire, WD18 0HB.
Corresponding Author Email: 
mrariaz@hotmail.com
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Current management of oesophageal cancer

Authors
Naufal Rashid, Mohamed Elshaer, Michael Kosmin and Amjid Riaz.
Article Citation and PDF Link
BJMP 2015;8(1):a804
Abstract / Summary
Abstract: 

Background: Oesophageal cancer is the eighth most common cancer and it’s the sixth leading cause of death in the world. The five years overall survival is reported to be between 15-20%. The aim of this review is to highlight the current trends of management of oesophageal cancer.

Methods: A literature search of PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014 was conducted.

Results: Oesophageal cancer accounts for almost 3% of all cancers and is the ninth most common malignancy in the UK. Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. The management of oesophageal cancers requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required.

Conclusions: Treatment of oesophageal cancer is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Keywords: 
Oesophageal cancer, staging, Transhiatal oesophagectomy, Ivor-Lewis oesophagectomy, chemotherapy.

Introduction

Oesophageal cancer (OC) is the eighth most common cancer affecting an estimated 481,000 people worldwide with a rapidly rising incidence. Due to the poor prognosis of patients with these cancers it is the sixth leading cause of cancer related mortality with 406,000 deaths.1,2 Although the overall 5-year survival has increased from 4% in the 1970s3 to currently ranging between 15 to 20%4, it remains a challenge to treat as clinical presentation is often late and diagnosis is made at advanced stages. Incidence and mortality rates for OCs are two fold higher in males compared to females, however this ratio rises to up to 5-10:1 for oesophageal adenocarcinomas. Cohort studies have shown that the incidence of OC increases with age; the average of onset is between 65 to 70 years. 14 This article seeks to discuss the epidemiology, diagnosis and staging, prevention and current trends in the management of OC.

Methods

We searched PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014. Our search strategy used a combination of MeSH, textwords, and appropriate words variants of “oesophagus”, “cancer”, “epidemiology”, “adenocarcinoma”, or “squamous cell carcinoma”, and “staging”, “transhiatal oesophagectomy”, “transthoracic oesophagectomy”, “chemotherapy”, “radiotherapy”. This was supplemented with selected systematic reviews, evidence based guidelines and consensus statements.

Epidemiology

There have been major changes in the epidemiology of OC over the last thirty years. The two key histological types of OC are adenocarcinoma and squamous cell carcinoma (SCC) and they differ significantly in their fundamental patterns of incidence and aetiological factors. Oesophageal SCC comprises the majority of cases worldwide and represents 90% of all OCs in most Eastern countries. However the incidence of adenocarcinoma has risen rapidly over the last three decades and it is now the predominant histological type in Western Europe, USA and Australia, particularly amongst white males.5, 6 There are other rare histological types, which include lymphoma, leiomyosarcoma, melanoma, rhabdomyosarcoma and small cell carcinoma.7 OC accounts for almost 3% of all cancers in the UK and is the ninth most common malignancy in the UK. There were 8,173 new cases in 2008; incidence rates have increased over the last thirty years in the UK and are now one of the highest in Europe.8 Incidence rates of OC differ markedly by geographical locations and between ethnic groups; overall, rates are twice as high in less developed regions compared with more-developed regions and the highest rates occur in Asia. In this region, especially in Iran, Turkey, Kazakhstan and China, a very high incidence of oesophageal SCC exists with greater than 100 cases per 100,000 population annually. A similar trend is also seen in South Africa.9-12 In contrast, the rate of rise in incidence of oesophageal adenocarcinoma in more-developed countries has exceeded that of oesophageal SCC, which has remained the same or decreased. Oesophageal adenocarcinoma now comprises approximately 50% of all OCs in these countries. 13

Who gets oesophageal cancer?

The aetiology of OC is multifactorial, with interactions between environmental risk exposures and genetic factors. These can be divided between the two different histological types of OC.

Pathology of oesophageal tumours

Oesophageal tumours are classified as epithelial and non epithelial. Epithelial tumours include papilloma, intraepithelial neoplasia, carcinoma and carcinoid tumours. Non epithelial tumours include leiomyoma, lipoma and gastrointestinal stromal tumours (Table 1).

Table 1: WHO histological classification of oesophageal tumours

Epithelial Non Epithelial
Squamous cell papilloma Intraepithelial neoplasia
· Squamous
· Glandular (adenoma)
Carcinoma
· Squamous cell carcinoma
· Verrucous (squamous) carcinoma
· Basaloid squamous cell carcinoma
· Spindle cell (squamous) carcinoma
· Adenocarcinoma
· Adenosquamous carcinoma
· Mucoepidermoid carcinoma
· Adenoid cystic carcinoma
· Small cell carcinoma
· Undifferentiated carcinoma
· Others
Carcinoid tumour
Leiomyoma Lipoma
Granular cell tumour
Gastrointestinal stromal tumour
· benign
· uncertain malignant potential
· malignant
Leiomyosarcoma
Rhabdomyosarcoma
Kaposi sarcoma
Malignant melanoma
Others
Secondary tumours

Oesophageal adenocarcinoma

Established risk factors for oesophageal adenocarcinoma (Fig. 1) include gastro-oesophageal reflux disease, Barrett’s oesophagus, obesity, male sex, tobacco smoking and a low intake of fruit and vegetables.15, 16 There is evidence to suggest that previous infection with Helicobacter Pylori and the use of non-steroidal anti-inflammatory drugs may decrease the risk of OC. 17

Fig. 1: Adenocarcinoma of the oesophagus (from Lewin et al. Gastrointestinal pathology and its clinical implications)

Barrett’s oesophagus (Fig. 2) occurs when there is metaplastic change in the lining of the oesophagus from normal stratified squamous mucosa to single layered columnar glandular mucosa with variable degrees of goblet cell differentiation.18 This transition usually occurs in the context of chronic gastro-oesophageal reflux disease, which causes exposure of the epithelium to refluxate. Gastro-oesophageal reflux disease is a major contributory factor and 5% of people with reflux disease develop Barrett’s oesophagus. The estimated prevalence of Barrett’s oesophagus is just under 2% amongst adults in the West and the annual incidence is approximately 0.1%. However, there is evidence to suggest that the rate of diagnosis is increasing by 2% annually.19 There has been a rise in the incidence of gastro-oesophageal reflux disease, which may be explained by a number of factors. The rise in the prevalence of obesity, specifically central and intra-abdominal obesity has been found to have a link with oesophageal adenocarcinoma. This can be explained by the fact that an increase in adiposity will cause a rise in intra-abdominal pressure thereby increasing reflux that may be asymptomatic. However, studies also suggest that obesity is a strong independent risk factor for oesophageal adenocarcinoma regardless of gastro-oesophageal reflux symptoms implying an underlying link. 20, 21 Another factor that may contribute to the rise in reflux disease is the increased use of drugs that relax the lower oesophageal sphincter. There is evidence to suggest that individuals with previous H. Pylori infections are less likely to develop oesophageal adenocarcinoma.22 This might be explained by the gastric atrophy that results from this infection, which will reduce the acidity and quantity of gastric secretions and thus decreasing the chances of gastro-oesophageal reflux. However, the prevalence of H. Pylori infections is decreasing in the Western population, which may contribute to the rising incidence of oesophageal adenocarcinoma. Gastro-oesophageal junction (GOJ) adenocarcinoma was classified by Siewert and Stein into three types. Type I arises from 1 to 5 cm proximal to the GOJ (tumours of the distal oesophagus), type II arises from 1 cm proximal to 2 cm distal to the GOJ (true cardiacarcinoma), and type III arises from 2 to 5 cm distal to the GOJ (subcardial gastric carcinoma). 61

Fig. 2: Barrett’s oesophagus (adapted from WHO classification of oesophageal tumours)

Oesophageal squamous cell carcinoma

The major risk factors for the development of oesophageal SCC (Fig. 3,4) are tobacco use and alcohol consumption; particularly a combination of both.23, 24 Nitrosamine exposure in tobacco smoking and the alcohol metabolite aldehyde, which is a known carcinogen, are probably the underlying reasons for these two risk factors. The high incidence of oesophageal SCC in Northern China, Iran and areas of Southern Africa may be related to a diet rich in nitrosamines and deficient in trace elements and vitamins A & C.

Other risk factors for oesophageal SCC in the Western world include low socioeconomic status, poor oral hygiene, achalasia, history of thoracic radiation, caustic injury, hereditary tylosis and Plummer-Vinson Syndrome.25

Fig. 3: Squamous cell carcinoma of the oesophagus

Fig. 4: Microscopic picture of squamous cell carcinoma (adapted from WHO classification of oesophageal tumours)

How does oesophageal cancer present clinically?

Patients presenting with symptoms of OC almost invariably have advanced disease. The most common presenting symptom is progressive dysphagia with 74% of patients reporting difficulty swallowing.26 This is graded according to the following: 27

  • Grade 1: Able to swallow most foods
  • Grade 2: Able to swallow soft foods only
  • Grade 3: Able to swallow liquids only
  • Grade 4: Unable to swallow anything

17% of patients will also report pain on swallowing food and liquids (odynophagia). 26 Typically, patients with oesophageal adenocarcinoma will be white males with a background of gastro-oesophageal reflux disease who have developed dysphagia. On the other hand, patients with oesophageal SCC will present with dysphagia, associated with weight loss and a history of smoking and increased alcohol intake may exist.

Other less common symptoms include dyspnoea, cough, hoarseness, acute haemorrhage and pain which may be retrosternal, back or right upper abdominal. These will usually represent the existence of metastatic disease.

Physical examination is often normal; positive clinical findings may include cachexia, lymphadenopathy and hepatomegaly in the presence of metastases.

How is oesophageal cancer diagnosed?

It is essential to have a low threshold if cancers are to be detected at an early, treatable stage. National Institute for Health and Clinical Excellence (NICE) guidelines state that a patient presenting with symptoms suggestive of upper gastrointestinal cancer should be referred to a team specialising in the management of these cancers. Specifically; patients of any age presenting with dyspepsia in association with alarm symptoms should be urgently referred for endoscopy or to a specialist. The classical ‘alarm’ symptoms associated with OC includes dysphagia, vomiting, anorexia, weight loss and symptoms associated with gastro-intestinal blood loss. Patients aged 55 or more with persistent, recent onset, and unexplained dyspepsia should be referred urgently for an endoscopy.

Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. Suspicious lesions including oesophageal strictures may require repeated biopsies if initial results are negative.

Once diagnosis is made patients should be urgently referred to an Upper Gastro-intestinal team at a specialist centre for investigations to stage disease and further management.

Staging oesophageal cancers

It is essential to accurately stage disease to exclude patients with widespread metastatic disease for whom surgery will not be curative and to identify subgroups of patients who will require neo-adjuvant therapies. Whilst it is difficult to completely eliminate the possibility of ‘open and shut’ cases where tumours are found to be inoperable at the time of surgery; it is important to develop a staging strategy with investigations and procedures that help to minimise this risk. The TNM (Tumour, Node, Metastasis) staging system is used to classify the depth of tumour invasion into or through the oesophageal wall, the status of regional lymph nodes and metastases to distant sites. The TNM7 categories are shown in Tables 2 and the current stage groupings is shown in Table 3. 28

Table 2: TNM7 staging system

Primary Tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis High-grade dysplasia
T1 Tumour invades lamina propria, muscularis mucosae, or submocusa
T1a Tumour invades lamina propria, muscularis mucosae
T1b Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades adventitia
T4 Tumour invades adjacent strictures
T4a Resectable tumour invading pleura, pericardium, or diaphragm
T4b Unresectable tumour invading other adjacent structures, such as aorta, vertebral body, trachea etc.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastases in 1-2 regional lymph nodes
N2 Metastases in 3-6 regional lymph nodes
N3 Metastases in ≥ 7 regional lymph nodes
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis

Table 3: Stage classification for oesophageal cancer in the 2010 TNM7 staging system

Squamous-cell carcinoma
Stage Tumour Node Metastasis Grade Tumour location
0 Tis (HGD) N0 M0 1, X Any
IA T1 N0 M0 1, X Any
IB T1 N0 M0 2-3 Any
T2-3 N0 M0 1, X Lower, X
IIA T2-3 N0 M0 1, X Upper, middle
T2-3 N0 M0 2-3 Lower, X
IIB T2-3 N0 M0 2-3 Upper, middle
T1-2 N1 M0 Any Any
IIIA T1-2 N2 M0 Any Any
T3 N1 M0 Any Any
T4a N0 M0 Any Any
IIIB T3 N2 M0 Any Any
IIIC T4a N1-2 M0 Any Any
T4b Any M0 Any Any
Any N3 M0 Any Any
IV Any Any M1 Any Any
Adenocarcinoma  
Stage Tumour Node Metastasis Grade  
0 Tis (HGD) N0 M0 1, X  
IA T1 N0 M0 1-2, X  
IB T1 N0 M0 3  
T2 N0 M0 1-2, X  
IIA T2 N0 M0 3  
IIB T3 N0 M0 Any  
T1-2 N1 M0 Any  
IIIA T1-2 N2 M0 Any  
T3 N1 M0 Any  
T4a N0 M0 Any  
IIIB T3 N2 M0 Any  
IIIC T4a N1-2 M0 Any  
T4b Any M0 Any  
Any N3 M0 Any  
IV Any Any M1 Any  

Initial staging assessment includes Computed Tomography (CT) (Fig. 5) of the thorax, abdomen and pelvis and its major role will be in evaluating the T stage to detect local tumour invasion into adjacent structures and determining the presence or absence of metastatic disease. However CT will not be able to determine the depth of tumour invasion. Endoscopic ultrasound (EUS) (Fig. 6) is the main modality used to stage the primary tumour and primarily aids in distinguishing T1 lesions from T2-4 lesions. This method has an accuracy ranging from between 73% to 89% in tumour staging.29 Accurately distinguishing tumour stage will affect treatment as T1 lesions may be treated with endoscopic therapy or with oesophagectomy whereas T2-4 lesions may require neo-adjuvant chemo-radiotherapy prior to surgery. EUS is also used for evaluation of regional lymph nodes however although sensitivity is approximately 80%, the specificity is lower at approximately 70%. 30 It is best to perform a EUS-guided lymph node biopsy for confirmation of involvement.

Fig. 5: CT scan shows irregular wall thickening of the esophagus and enlarged metastatic lymph node.

Fig. 6: Endoscopic ultrasound (EUS) of oesophagus showing T3 tumour

FDG-PET (18F-fluoroudeoxyglucose PET) (Fig. 7) is a key modality for the detection of distant metastatic disease in OC.31, 32 PET may reveal previously occult distant metastases in nodal and non-nodal sites with a sensitivity of 67% and high specificity of 97%. 33 It can also reveal metastases to bone, which may not be detected using conventional methods. An investigation has shown PET to be the only modality that predicted intended curative resection and it may also be used to prevent unnecessary surgical explorations.34 The use of PET has been shown in a study to change the management of patients from curative to palliative due to detection of previously unknown metastases.35 It has also been used in a prospective study to assess response early after neo-adjuvant chemotherapy to determine the need for urgent surgery or further chemotherapy. The usage of CT and PET in combination has become increasingly available and is useful in selective cases.36

Fig. 7: FDG PET/CT image demonstrating increased uptake at the distal oesophagus and coeliac lymph node in oesophageal cancer case

Minimally invasive surgery is also used as a method to stage OC in many specialist centres.37 A staging laparoscopy can visualise the primary tumour, identify metastases such as hepatic and regional nodal and can accurately detect intraperitoneal dissemination of disease, which may not have been appreciated on other radiological staging investigations. Samples of peritoneal ascites or washings for cytology can also be obtained at this stage if present.

Endoscopic mucosal resection (EMR) can provide accurate histological staging for high grade dysplasia and intramucosal carcinomas. 38 In many cases EMR alone can be a therapeutic intervention depending on the depth of invasion on the specimen.

Treatment

The management of OCs requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required. Patients considered for surgery or chemo-radiotherapy will require a fitness assessment. In addition to pulmonary function tests, ECG and echocardiogram, cardio-pulmonary exercise testing (CPEX/CPET) is now being increasingly used to assess fitness for major surgery.

OCs can be managed with surgery, chemotherapy or radiotherapy, a combination of the three or palliation in many cases. Disease that is locally advanced without signs of distant metastases is treated with an intention to cure and this will involve a multimodal approach. Metastatic, disseminated and recurrent disease will be treated with palliative intent with chemotherapy to increase survival or measures such as radiotherapy or stent placement for symptomatic relief.

Surgical

Surgical resection can be part of a multimodal approach or alone and is the main option for curative treatment. There are a number of surgical procedures that can be used however it is important to ensure removal of macroscopic and microscopic tumour in association with dissection of lymph nodes with either method as these are vital prognostic factors following surgery.

Open oesophagectomy (OO):

Options for resection include trans-hiatal oesophagectomy and transthoracic approaches and the choice of approach will depend on the location of the tumour, access to lymph nodes and surgeon preference. An Ivor Lewis oesophagectomy (also known as Lewis-Tanner oesophagectomy) involves abdominal mobilization of the stomach and right thoracic approach for resection of the oesophagus. The three-stage modified McKeown oesophagectomy involves a laparotomy, right thoracotomy and neck anastomosis. A resection margin 8-10 cm proximally and 7 cm distally is recommended to achieve an R0 resection (recommendation class IIB, level of evidence C). The next step is to construct a conduit for the anastomosis and this can be achieved by using a gastric tube, large or small bowel. A gastric tube is preferred due to the following factors; ease of use, tension free and longest term conduit survival (recommendation class IIA, level of evidence C). The anastomosis can be performed in the chest or the neck. This relies on multiple factors such as ease of the anastomosis, tension on the repair, ability to diagnose and treat complications and the oncological status. Circular staplers or hand sewn technique usually used with no significant differences in the outcomes. A drainage procedure such as pyloroplasty is recommended to avoid delayed gastric emptying (recommendation class I, level of evidence B). 62

Radical oesophagectomy using either approach has a perioperative mortality of 5-10% and morbidity of 30-40%. 39 Lymph node dissection plays an important role owing to the extensive submucosal lymphatic drainage of the oesophagus. This has meant that nearly 80% of patients undergoing surgery have positive lymph nodes and prognostically this is of importance.40, 41 However, there has been controversy with regards to the extent of lymph node dissection required. For optimal staging 10 lymph nodes for T1 and 20-30 lymph nodes for T2 and T3 tumours should be harvested. 62 In order to perform a curative resection for carcinoma of the middle and lower third of the oesophagus it is recommended to dissect the abdominal and mediastinal lymph nodes. Three-field lymphadenectomy in the abdomen, chest and neck, is performed in Japan for oesophageal SCC.42 Proponents of radical lymphadenectomy argue that it does allow optimal staging, improves loco-regional disease free survival improving the quality of life for these patients.

Minimally invasive oesophagectomy (MIO):

Minimally invasive approaches, which involve laparoscopic mobilisation of the stomach, thoracoscopic mobilisation of the oesophagus and hybrid or robotic approaches, are increasing in many specialist centres. Benefits of this approach include shorter recovery times, decreased post-operative pain and reduced cardiopulmonary complications without jeopardising the oncological outcomes. Luketich et al. reported a mortality rate of 1.7%, leak 5% and empyema 6% following MIO. 63Several randomised controlled trials (RCTs) and comparative studies were conducted to investigate the efficacy and outcomes of MIO. A study by Li et al was conducted on 407 patients underwent MIO and OO found that the overall incidence of complications was lower in the MIO patients. The incidence of pulmonary complications was 20.7% in contrast to 39.7% in the OO group. However, there was no difference in the overall survival among the groups. Another comparative retrospective study by Mu et al. didn’t reveal any difference in the morbidity, anastomotic leak rate, pulmonary complications and length of stay between the approaches and the authors concluded that both techniques are equivalent. 63, 64

Neo-adjuvant chemotherapy

This aims to improve operability; achieving this by shrinking the tumour prior to surgery, down-staging the disease as well as treating occult metastatic disease. Response to treatment can be assessed prior to surgery with repeat radiological investigations. It is now common for patients in the UK with locally advanced disease to undergo neo-adjuvant chemotherapy followed by resection. This is based on the results of a multi-centre study conducted by the Medical Research Council (OEO2), which showed a 9% improvement in two-year survival in patients given 2 cycles of Cisplatin and 5-Fluorouracil chemotherapy compared to those who were not. Five-year survival with surgery alone was 17%, compared with 23% with neoadjuvant chemotherapy.43 The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to chemotherapy with surgery or to surgery alone and it was found that patients in the chemotherapy group (who received Epirubicin, Cisplatin and infused 5-Fluorouracil, ‘ECF’) had a significant improvement in progression-free survival and a 13% increase in 5-year survival.45

In a meta-analysis of neoadjuvant chemotherapy, there was an overall all-cause absolute survival benefit of 7% at 2 years with the addition of chemotherapy. When analysed by subtype, chemotherapy had no significant effect on mortality for patients with squamous cell carcinoma; however, there was a significant survival benefit for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014). 47

As a result of this evidence, neoadjuvant chemotherapy is a standard of care for patients with operable mid and lower oesophageal and GOJ adenocarcinoma. The ongoing MRC OEO5 trial is evaluating optimal neoadjuvant chemotherapy regimens: 4 cycles of chemotherapy with ‘ECX’ (Epirubicin, Cisplatin and Capecitabine) compared to two cycles Cisplatin and 5-Fluorouracil, as in OEO2.44

Patients who are deemed suitable for surgical management of mid or distal oesophageal (including GOJ) adenocarcinomas are referred to the GI oncology team to assess fitness for chemotherapy. Many of the criteria assessed are similar to those in the pre-operative assessment, particularly performance status and medical comorbidities. Significant history of renal disease or cardiovascular disease, especially ischaemic heart disease would be a relative contraindication to systemic chemotherapy. Toxicities from chemotherapy are wide-ranging and include gastrointestinal upset, hair loss, skin rash, neurotoxicity, renal toxicity, bone marrow suppression (with risk of neutropaenic sepsis, thrombocytopaenia, and anaemia), cardiovascular toxicity, and chemotherapy-related fatigue. In the MAGIC trial, three cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy were given both before and after surgery, and approximately one quarter of patients had CTCAE grade 3 or 4 neutropaenia. 45

The REAL 2 trial 48 was a 2x2 factorial non-inferiority comparison of cisplatin versus oxaliplatin and 5-fluorouracil (5-FU) versus oral capectiabine in patients with oesophageal, gastro-oesophageal junction and gastric tumours. Treatment was given as triplet chemotherapy: epirubicin plus platinum agent (cisplatin or oxaliplatin) plus 5-FU or capecitabine. The trial results showed that oxaliplatin was at least as effective as cisplatin, and oral capectibine was at least as effective as intravenous 5-fluorouracil. There was less grade 3 and 4 neutropaenia with oxaliplatin versus cisplatin, but this was offset by an increase in neuropathy and diarrhoea. As a result of this trial, EOX chemotherapy can be used as an alternative to ECX in both the neoadjuvant and metastatic settings (Table 4).

Table 4: Efficacies of major combination chemotherapy drugs

Drug Histologic type No. of cases Response rate (%)
5-FU + cisplatin Squamous cell carcinoma 39 36
Cisplatin + paclitaxel Squamous cell carcinoma/adenocarcinoma 32 44
Cisplatin + irinotecan Squamous cell carcinoma/adenocarcinoma 35 57
Cisplatin + gemcitabine Squamous cell carcinoma/adenocarcinoma 32 45
5-FU + nedaplatin Squamous cell carcinoma 38 40

Neo-adjuvant chemo-radiotherapy

In contrast to the UK, patients in the USA commonly receive neo-adjuvant chemo-radiotherapy (CRT) for locally advanced oesophageal carcinoma. There is evidence that preoperative CRT is superior to surgery alone. A meta-analysis of ten randomised controlled trials showed a hazard ratio for all-cause mortality of 0.81 (95% CI 0.70 to 0.93; p=0.002). This corresponded to a 13% absolute survival benefit at 2 years.47 In the subgroup analysis of the Dutch CRT trial (which used paclitaxel and carboplatin combination chemotherapy), the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared to adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16).49

There has been no direct head-to-head comparison of neoadjuvant chemotherapy and neoadjuvant CRT in the context of a phase III randomised control trial. Concerns regarding the added morbidity of CRT have meant that chemotherapy alone is the standard neoadjuvant treatment of choice in the UK. However, the role of neoadjuvant CRT is currently being reassessed in the Neo-SCOPE trial.

Definitive chemo-radiotherapy (CRT)

According to current UK consensus guidelines, CRT is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus. 50 Localised squamous cell carcinoma of the middle or lower oesophagus may be treated with CRT alone, or CRT plus surgery. 50

In a pivotal study, US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma or adenocarcinoma to receive CRT (cisplatin and 5-Fluorouracil with 50 Gray in 25 fractions), or radiotherapy alone (64 Gray in 32 fractions). This trial 46, together with a subsequent systematic review 55, demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61; 95% CI 0.31 to 0.89; p<0.001). This was at the expense of increased toxicity.

This and similar studies 56-57 have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.

CRT practice in the UK is somewhat varied, but within the authors’ multidisciplinary team Cisplatin and 5-Fluorouracil chemotherapy is given in weeks 1 and 5 of a five-and-a-half week course of radiotherapy. The radiation dose used is 50.4 Gray in 28 daily fractions, treating Mondays to Fridays. An alternative radiation dose-fractionation which is supported by the Royal College of Radiologists guidelines is 50 Gray in 25 daily fractions. 58

There are few trials directly comparing surgery alone with CRT. A study of 80 patients with squamous cell carcinoma randomised to surgery or CRT failed to show superiority of either strategy in terms of early disease free survival or overall survival. 51 Adding surgery to CRT can improve local control rates compared with CRT alone, but combined-modality therapy has not been shown to improve survival. It predictably also leads to significantly more treatment-related morbidity.52

The French FFCD 9102 trial recruited 444 patients with potentially resectable OC (90% squamous cell carcinoma) to receive induction CRT. Those patients who showed evidence of response to CRT were then randomised to further CRT or surgery. Median overall survival was 19.3 months in the CRT alone arm, and 17.7 months in those randomised to surgery. The trial met its endpoint of non-inferiority for 2 year overall survival. Again, toxicity was shown to be significantly higher in patients who received both CRT and surgery.53

Although definitive CRT is a current recommended standard of care for localised squamous cell carcinoma of the oesophagus, there is insufficient evidence to to support either a surgical or non-surgical approach 50. Surgery should be considered in patients who have histologically-confirmed residual disease at the end of CRT.

For patients deemed unsuitable for surgery with localised adenocarcinoma of the oesophagus, CRT is a valid option for treatment. An American case series of 25 patients with a median age of 77 years showed that CRT using two cycles of mitomycin-C and 5-fluorouracil in combination with radiation (dose 50.4Gy in 28 daily fractions) was effective and tolerable. 68% of these patients had no evidence of residual disease on post-treatment endoscopy. This small series of patients had a two year overall survival of 64%, with a median overall survival of 35 months.54

Salvage surgery after definitive CRT

Local recurrence occurs within the first year in 10-30% of patients treated with definitive CRT.50 Salvage curative oesophagectomy may be considered within a multidisciplinary team setting. Repeat staging investigations including a CT-PET and EUS are required before a final decision for salvage surgery is made. Survival benefit is limited, and such surgery is associated with an increased in-hospital mortality rate and increased morbidity.59 Informing patients of the potential high risks and poor outcomes is an integral part of the decision-making process for salvage surgery.

Palliation

The majority of patients diagnosed with OC are never treated with curative intent as a result of advanced disease or their physical fitness and comorbidities not allowing for radical treatment. It also includes patients who have developed recurrent or metastatic disease following resection. For this group of patients, there are a number of palliative treatments available for relief of symptoms, prolonging and maximising their quality of life. Once again, a multidisciplinary, holistic approach is required to provide the best treatment.

Treatments to provide symptomatic relief such as dysphagia can include intraluminal brachytherapy, endoscopic stenting using self-expanding metal stents or repeated endoscopic dilatations. Dysphagia can also be palliated by chemotherapy or external beam radiotherapy. Laser-thermal Nd-YAG endoluminal tumour destruction and photodynamic therapy can also be administered however this requires a number of treatments and may be more suitable for short exophytic tumours. It is essential to manage pain and nutrition and feeding options through a gastrostomy, jejunostomy or even intravenously can be provided to ensure adequate nutritional status. In addition to providing symptomatic relief it is important to also ensure that these patients receive social and psychological support by identifying and addressing the needs of the patients as well as their carers.

Palliative radiotherapy can be offered to patients with symptomatic primary oesophageal tumours in the context of metastatic or inoperable disease. Palliative dose and fractionation options are varied, but include 27 Gray in 6 fractions treating twice a week for 3 weeks; 30 Gray in 10 fractions treating daily for 2 weeks; 20 Gray in 5 fractions treating daily for 1 week.58 The aim of such radiation treatment is to palliate dysphagia. This effect is not immediate, and therefore patients with significant dysphagia are better served initially by endoscopic stenting.

Chemotherapy has been shown to be effective in improving symptoms and overall survival. Patients with good performance status are offered combination chemotherapy. This can be with EOX, as per the MAGIC trial, 45or with Cisplatin and 5-Fluorouracil, with or without the addition of Epirubicin (CF or ECF). 5-Fluorouracil can be substituted for oral Capecitabine (i.e. CX or ECX) without any adverse effects on outcomes.45

When choosing palliative systemic chemotherapy for patients with incurable OC, the primary aim should be about maximising quality of life. Improvements in outcome with more intensive chemotherapy regimens, such as docetaxel, cisplatin and 5-Fluorouracil, have been shown to be offset by significantly more toxicity.60 As a result, Docetaxel containing regimens are not approved in the UK for this indication.50

Conclusions

The incidence of oesophageal carcinoma is increasing and despite advances in management and treatment the overall prognosis remains poor. It is essential to recognize and diagnose early, to have a clear pathway for subsequent investigations to ensure accurate staging. This will allow appropriate therapy to be administered to ensure the best possible outcomes are achieved. Treatment of OC is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAUFAL RASHID, Department of Upper GI Surgery, West Hertfordshire Hospitals, England. MOHAMED ELSHAER, Department of Upper GI Surgery, West Hertfordshire Hospitals, England. MICHAEL KOSMIN, Department of Oncology, Mount Vernon Hospital, England. AMJID RIAZ, Department of Upper GI Surgery, West Hertfordshire Hospitals, England.
Corresponding Author Details: 
AMJID ALI RIAZ, Department of Upper GI Surgery, Watford General Hospital, Vicarage road, Watford, WD18 0HB, United Kingdom.
Corresponding Author Email: 
mrariaz@hotmail.com
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Legal Highs - Not so new and still growing in popularity

Authors
Francis J Dunne, Khalid Jaffar and Shazia Hashmi
Article Citation and PDF Link
BJMP 2015;8(1):a801
Abstract / Summary
Abstract: 

Designer or synthetic drugs which include legal highs and other “club drugs” are substances which have a propensity to cause euphoria, central nervous system stimulation, and hallucinations. Based on chemical formulae for opioids, mescaline, and cannabis, they are created in laboratories under lax conditions for no defined medical purposes. Because they vary in composition from batch to batch they are potentially dangerous for users. Furthermore, the chemical structure is continually changing in order to avoid legislation and therefore users can never be sure what they are taking.

For the purpose of this article readers should use the terms legal highs, designer drugs, bath salts, herbal highs, ‘research’ chemicals, and novel psychoactive substances, interchangeably. Their main purpose is to induce psychoactive effects that mimic amphetamines, cannabinoids or psychedelic drugs.  The term ‘research’ only infers that very little is known about these substances and information on adverse effects is often sparse. The reader should also bear in mind that it is beyond the scope of this article to include many other agents. 

Keywords: 
legal highs, bath salts, designer drugs

Overview

The term ‘designer drug’, coined in the 1980s, generally referred to various synthetic opioids based mostly on the fentanyl molecule (α-methylfentanyl) and MDMA (methylenedioxymethamphetamine) commonly known as ecstasy. Fentanyl is an extremely potent analgesic, some 100 times more potent than morphine. MDMA and fentanyl compounds were the most popular synthetic drugs initially. The terminology is confusing because although the description ‘designer drug’ seems to imply the creation of new drugs, many are not new. For example, cathinone derivatives have been reported since the late 1920s. MDMA was first synthesised in 1912, methcathinone in 1928, and mephedrone in 1929. Cathinone is chemically similar to ephedrine, cathine, methcathinone and other amphetamines.

Legal highs generally comprise cathinone stimulants and synthetic cannabinoids. Hallucinogenic agents such as salvia divinorum are also included, the latter sometimes described as herbal ecstasy. Synthetic amphetamines are not regarded as hallucinogenic, though hallucinations are experienced by some users.

Thus, the term ‘designer drugs‘ covers an array of substances which are used recreationally, are not controlled under the Misuse of Drugs Act (1971), are not licensed for ‘legal’ use, and are not regulated under the Medicines Act (1968). They are chemicals produced by tweaking or altering the molecular structure of previous well-known psychoactive agents. By stating they are ‘not for human consumption’, or are just ‘bath salts’, they can be sold legally. Hundreds of such substances are now available, reflecting the ease at which chemists can produce them.

Availability and Consumption

The World Drug Report (available on the Internet) produced annually by the UN Office on Drugs and Crime (UNODC), provides information on the worldwide manufacture and marketing of illegal drugs. The 2013 report highlights a striking rise in the availability of new substances. Part of the challenge lies in their variety - some are derived from plants, for instance, the mint plant Salvia divinorum, native to Mexico, with synthetic cathinones and cannabinoids also being major contributors in other countries.

Ease of synthesis, low cost, and resourceful marketing have contributed to the problem. Information provided via the internet, combined with minimal difficulty in the manufacture and transport from distant regions, together with lax legal enforcement, creates an ideal opportunity for legal highs to flourish. The low cost is particularly attractive though ironically legal highs probably cost more these days: for example, 1g of mephedrone costs about £16.00 more than when legislation was introduced in 2010. On the other hand MDAI (methylenedioxy-2-aminoindane), a legal stimulant and club drug which is snorted or bombed, costs about half the price of cocaine (£20 per gm). It is sometimes cheaper to buy legal highs over the internet than from a drug dealer. Part of the increase in use of legal highs may be a result of decreasing purity of other ‘buzz’ drugs such as cocaine and MDMA.As with other illegal drugs regulatory measures drive the drugs ‘underground’ and into the hands of drug dealers and the price then varies with the purity of the drug and its ease of manufacture and availability.

Some users will revert to taking an illegal drug when the legal alternative is prohibited. There is also a certain curiosity to experiment with new drugs. Even so, to keep things in perspective, consumption of more harmful familiar illegal drugs (for example, cocaine, amphetamines) has not abated, with over 315 million people worldwide thought to be using them. More worrying is that millions of individuals inject more harmful drugs such as opiates with resultant increased rates of HIV, hepatitis B and hepatitis C infection. Readers are also likely to be aware of the violence and deaths associated with drug manufacturing and supplying within countries such as Latin America.

Government Control

The Medicines Act 1968 (UK) governs the control of medicines for human and veterinary use. It defines three categories of medicines: a) prescription only medicines (POM), available solely from a pharmacist and requiring an appropriate practitioner to issue, b) pharmacy medicines (P), available only from a pharmacist, without the need for a prescription, and c) general sales list (GSL) meaning medicines bought without a prescription. The Medicines Act 1968was set up to protect patients from unscrupulous suppliers of medicines. Safeguarding the public from illegal medicines or any inaccurate and misleading labelling of medicines isparamount. However, manufacturers have managed to sell legal highs by passing them off as bath salts or research chemicals.

Phenylalkylamines analogues such as amphetamine are widely misused and because of their simple structure hundreds of amphetamine analogues have been introduced for decades. This is the reason why so many legal highs are available. Amphetamine (phenylisopropolamine), a familiar central nervous system (CNS) stimulant, has effects which last for several hours after oral intake. Methamphetamine is closely related to amphetamine and ephedrine (a mixed-acting sympathomimetic). Ephedrine and pseudoephedrine (often used for relief of nasal congestion) undergo reduction to methamphetamine, or oxidation to methcathinone. As with methamphetamines, methcathinones can be readily ‘cooked’ in the laboratory and hence the term ‘synthetic’.

Background biochemistry

Morphine, the most abundant opiate alkaloid found in the poppy plant, papaver somniferum, was first isolated in 1804. The actual term alkaloid is derived from "alkaloide" introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meisner, from the Latin root ‘alkali’, and the Arabic word al-qalwī meaning "ashes of plants".

Alkaloids are a group of naturally occurring organic nitrogen-containing bases, a base being a substance with a pH above 7 which turns red litmus paper blue. They include related compounds with neutral and even weakly acidic properties and more than 3,000 different types have been identified. In addition to nitrogen, hydrogen and carbon, most alkaloids contain oxygen, sulfur, and to a lesser extent, chlorine, bromine, and phosphorus. Generally, an alkaloid contains at least one nitrogen atom in an amine-type structure, i.e. one derived from ammonia (NH3) replacing the hydrogen atoms with hydrocarbons, for example, CH3 or CH2. Alkaloids generally are weak bases and some act as acid or base (amphoteric).

Alkaloids are produced primarily by flowering plants and organisms such as bacteria, fungi, and animals. Several alkaloids may be extracted from one plant.They can be purified from crude extracts by acid-base extraction and tend to have a bitter taste. Those containing a ring system are known as indole alkaloids (for example, terpenoids and steroids). Some are named after the biological species from which they are derived (morphine from the poppy plant Papaver somniferum, cocaine from erythroxolon coca, and so on). Other common examples include psilocin, caffeine, nicotine, vincristine, reserpine, atropine, quinidine, ephedrine,strychnine and quinine. Atropine is the tropane alkaloid isolated from the deadlynightshade plant Atropa belladonna, and strychnine is derived from the seeds of the Strychnos nux-vomica tree. Caffeine, cocaine, codeine (methylmorphine) and nicotine are water-soluble alkaloids. Morphine and yohimbine are highly water-soluble. Other alkaloids dissolve poorly in water yet readily in organic solvents such as chloroform or ether. The biological precursors of most alkaloids are amino acids, such as phenylalanine, tyrosine, tryptophan, histidine, and aspartic acid, among others. 1

How are they used?

The synthetic cathinones (usually mephedrone and methylone, or M-Cats) are most commonly used intranasally (insufflated) or ingested. “Bombing” is a method of ingestion whereby mephedrone powder is wrapped in cigarette paper and swallowed. Because sniffing the drug may cause nasal burns users will often resort to ‘bombing’. “Keying” is the practice of dipping a key into powder and then insufflating, with approximately five to eight “keys” per gram. Rectal administration, gingival delivery, inhalation, intramuscular and intravenous injection have also been described. Multiple concomitant routes of administration are reported. Self-reported doses range from a few milligrams to over 1 g of powder. A typical dose of mephedrone would be 100-200mg every 1-2 hours.

Users cannot be certain of the actual contents or indeed of the purity of the drug, therefore actual dosage and exposure is highly variable. For example, when MDAI (methylenedioxy-2-aminoindane) known as Sparkle (a granular, brownish powder) is snorted or bombed, it has an effect similar to ecstasy causing mood enhancement and hallucinations. Onset of action is usually within one hour and the effects are then almost immediate, perhaps a minute or so. The high lasts about six hours with a peak of two hours. It may cause hyperthermia, paranoid ideation and panic attacks.2

Cathinone is a naturally-occurring beta-ketone amphetamine analogue found in the leaves of the khat plant. Other synthetic cathinones such as methcathinone and MDVP (methylenedioxypyrovalerone) produce similar effects. Beta-ketone refers to the possession of a ketone group in the beta position of the aminoalkyl chain attached to the main molecular methylenedioxyphenyl ring.

Synthetic cannabinoids share some functional similarities with Δ9-tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they can have sedative, depressant and hallucinogenic effects. They have been detected in herbal smoking mixtures such as ‘Spice’ as well as resins that mimic cannabis resin.

Khat (Catha edulis)

Some knowledge of this plant is necessary in order to explain the background to many of the synthetic designer drugs. Khat is an evergreen shrub the leaves of which are chewed for their stimulant properties. An understanding of its chemical composition helps to explain the use of its constituents in the formation of designer drugs. Khat contains more than 40 alkaloids as well as many other compounds. The khat pheylalkylamines consist of cathinone, cathine and norephedrine: these alkaloids are structurally related to amphetamine and noradrenaline. Although similar to methylamphetamine, methcathinone (variously known as Cat, Kat, Qat, Ghat, and Chat) possesses a chemical structure resembling cathinone; its side effects and addictive properties are more potent.

The plant is chewed into a ball and kept in the cheek for a while. When khat leaves dry, cathinone (benzoylethanamine) decomposes within 48 hours leaving behind the milder chemical, cathine (a phenethylamine compound). Therefore, to maintain the potency of the drug, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve moisture. It is common to sprinkle the plant with water or use refrigeration during transportation. Khat is therefore best used within 12-48 hours when the leaves are still moist.

Catha edulis is a flowering plant (one that produces seeds) native to the Horn of Africa (Eritrea, Djibouti, Ethiopia and Somalia) and the Arabian Peninsula. In these countries chewing the leaves and stalks is a social custom dating back thousands of years. It may take 7-8 years for the shrub to reach its full height (6-12 feet or more). Globally it is estimated that some 10 million males (usually) use khat on a daily basis.

Cathaedulis leaves containa beta-ketone amphetamine analogue. Ketones contain a carbonyl group (C=O) bonded to two other carbon atoms. Phenylalkylamines (derived from phenethylamine) are often termed “bk-amphetamines” for the beta-ketone moiety.

The principal active components in khat are cathinone and cathine. By chewing khat these substances are secreted into saliva. The effects are similar to amphetamine though less potent. Psychological dependence does occur in some though generally khat is not addictive. It is freely available in many countries and its production, sale and consumption are legal, including the Horn of Africa. In the Arab Peninsula it is known as Arabian tea and in South Africa it is referred to as Bushman’s tea.

Although its stimulant effect was originally attributed to cathine, extracts from fresh leaves of khat were shown to contain cathinone, isolated in 1975 and its properties recognized in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine which belong to the phenylpropanolamine family, a subset of the phenethylamines and the catecholamines adrenaline and noradrenaline.

When the leaves are chewed the active ingredients are absorbed through the oral and gastric mucous membranes. The action of cathine and cathinone on the reuptake of adrenaline and noradrenaline results in the wakefulness associated with amphetamine derivatives. The effects of cathinone peak after 30 minutes, with nearly 98% of the substance metabolized by the liver into noradrenaline. Cathine has a half-life of about three hours in humans. Typically, an individual consumes 100–200 g of khat leaves (one bundle) in a session, and its effects last for several hours.

Symptoms are rather similar to the ingestion of strong coffee or amphetamines, for example, overtalkativeness and hyperactivity. The effects of oral cathinone occur more rapidly than those of amphetamine, 15 minutes compared to 30 minutes respectively. Khat causes constipation, dilated pupils (mydriasis), tachycardia and increased blood pressure, reflecting the sympathomimetic effects of the drug. Withdrawal symptoms, as would be expected, include mild depression and irritability, lethargy, rebound anxiety causing nightmares, tremulousness and loss of appetite. Long-term use may cause hepatic dysfunction, a permanent greenish tinge darkening of the teeth, and diminished libido. Rarely, dilated cardiomyopathy and myocardial infarction result from chronic use. 3

Mephedrone

Mephedrone (‘meow meow’) is a synthetic stimulant chemically related to cathinone, the psychoactive substance present in the khat plant. It is usually sold as a white crystalline or off-white-yellow powder (as a hydrochloride salt) for about £10 per gram. Consumption is usually oral or intranasal and rarely, by injection. Sellers avoid attracting the attention of regulatory bodies by labelling the substance “not for human consumption,” which means that no advice on safer use and dosing is provided.4

In one study the most commonly seen drug class were piperazines, followed by the cathinones, with significant variation in the content in one quarter of these compounds. The authors stated that it was relatively easy to purchase a number of legal highs from different Internet suppliers, though there times when not all of the products were available leading to the problem of users buying different active drugs to those they are used to, raising the prospect of potential toxicity to unknown agents.5A cross-sectional survey of 947 of mephedrone users found it to be the sixth most frequently used drug in the previous month after tobacco, alcohol, cannabis, cocaine and MDMA. Users typically were young males; 15% reported using weekly or more frequently; nearly 50% used between 0.5 and 1g during a typical session; intranasal use was the most common route of use (70%). Almost 55% of those who used cocaine reported that the ‘high’ obtained with mephedrone was better: intranasal use was also more likely addictive than oral use. Mephedrone appears to be the most widely abused synthetic cathinone in Europe, in contrast to the USA where MDVP and methylone are the most frequently abused. 6 7

Classification of mephedrone has had a limited effect on controlling its availability and use. Before the introduction of the legislation users generally obtained it via the internet. Now it is bought from street dealers, on average at double the price. Mephedrone was defined as a Class B drug under the Misuse of Drugs Act (1971) in the UK in April 2010. 4

Mephedrone produces similar effects to ecstasy, amphetamines and cocaine. It is detected in 20% of ecstasy tablets. It simulates the release of and inhibits the reuptake of monoamine neurotransmitters. The onset of psychoactive effects after insufflation is usually 10–20 minutes with an expected duration of effect of 1–2 hours; after oral ingestion onset is about 15–45 minutes with duration of 2–4 hours, and intravenous users report symptoms peaking at 10–15 minutes with a 30-minute duration of the desired effect.

Mephedrone users report that it has a better quality high than cocaine. It is speculated that mephedrone’s popularity reflects dissatisfaction with the purity and consistency of available cocaine and ecstasy. Concerns are also raised when it is considered that mephedrone is readily available from street dealers and may be taken by young people who have little previous experience of drug use.

Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

Mephedroneinduces a greater increase in dopamine than serotonin release whereas MDMA (‘ecstasy’) induces a huge increase in serotonin with an insignificant rise in dopamine. Amphetamine results in a surge in dopamine release with an insignificant increase in serotonin. Mephedrone, amphetamine, and MDMA have decay values of 25, 50 and 300 minutes respectively. Therefore, the rapid rise and fall of dopamine levels could explain the addictive properties of mephedrone in some users. The effects are often described as somewhere between ecstasy and cocaine. As with cocaine, the ‘high’ generally lasts around an hour before wearing off. Furthermore, prolonged high –dose use of the substances can produce long-lasting neurotransmitter deficits in humans. 8 9

According to Mixmag (the online drug-use clubbing survey magazine for the UK) published in March 2012, 42% of clubbers had tried mephedrone the drug, and 34% had taken it in the last month. Some 30% of mephedrone users had reported using more ecstasy since the ban came into effect, while 19% reported using more cocaine. Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

In 2011, Mixmag and the Guardian newspaper which draws on previous Mixmag surveys collected 15,500 responses from around the world, mostly the United Kingdom. In 2010/11, reported levels of use of mephedrone in the last year and last month were three times higher among clubbers (30 % and 13 %) than non-clubbers (10 % and 3 %).

Mephedronepredictably, causes increased alertness, restlessness, euphoria, excitement, the urge to talk, openness, time rushes, hot flushes, increased libido and elation. Hyperhidrosis, headache, palpitations, a Raynaud–type syndrome, and nausea are other relatively common unpleasant effects. Dizziness, hallucinations, panic attacks, and psychosis may occur. Other physical symptoms include dry mouth, blurred vision, and epistaxis. Symptoms of intoxication include agitation, aggression, violence, seizures and hyperthermia. Fatigue and insomnia are common residual effects. Mephedrone is generally used by nasal insufflation or ingestion of powder, liquid, capsule or tablets. The majority of users source mephedrone from street level dealers.10 Mephedrone induces strong feelings of craving in most users. If the unstable ecstasy market situation persists, the potential of mephedrone to substitute for MDMA might be substantial. Mephedrone, sold as ecstasy, is therefore more likely to be a cause for concern in the future.

Bath salts

This is the street name for substances which contain synthetic cathinone stimulants, such as methylenedioxypyrovalerone (MDPV) and mephedrone.11Bath salts components act synergistically at the dopamine transporter site and enhanced dopamine transmission may increase the potential for abuse. MDPV is consumed with other illicit drugs of abuse. It is the primary ingredient in "bath salts." Being a synthetic, cathinone-derivative it produces a high similar to cocaine or methamphetamine. It can be administered orally, by nasal insufflation, smoking, intravenously/intramuscularly, or per rectum, and intoxication lasts many hours.

MDPV may cause cardiac problems and disturbance of perception. During the withdrawal period after MDPV use, bone and muscle pain, and visual disturbances may occur. In the metabolism of MDPV, the most important catalyst is the CYP2C19 isoenzyme; the CYP1A2 and the CYP2D6 isoenzymes also play a role. The formed catechols are conjugated with either glucuronic acid or sulphate.

These compounds are not true bath salts in the traditional sense of household products. Cathinone is an amphetamine-like stimulant found naturally in the khat plant, described in more detail below. MDPV is much more potent than cocaine and its effect is longer lasting.12

Because of the sympathomimetic activity side effects are predictable and include cardiac arrhythmias, hypertension, arrhythmias, and hyperthermia. Chest pain, myocardial infarction, sweating, rhabdomyolysis, seizures, stroke, cerebral oedema, cardiorespiratory collapse, and rarely, death, have been reported. Psychiatric manifestations include hypersomnia, panic attacks, agitation, paranoia, suicidal ideation, self-mutilation, and aggressive behaviour.

The mode of action is thought to be the result of disruption and interference with central monoamine systems. In other words, synthetic cathinones increase extracellular monoamines by blocking transporter reuptake and increasing presynaptic neurotransmitter release. The dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) tightly regulate the amount of neurotransmitters within the synaptic cleft. Monoamine release also may be driven by presynaptic input from cholinergic or glutaminergic systems.12 7

Psychoactive bath salts are sold as tablets, capsules, or powder and purchased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts may mimic cocaine, lysergic acid diethylamide (LSD), methamphetamine, or MDMA. The most common bath salts are the cathinone derivatives MDPV, mephedrone and methylone. The drugs have the potential for addiction because they cause intense stimulation, euphoria, elevated mood, and a pleasurable "rush". 13 14

In the United Kingdom (UK) to avoid being controlled by the Medicines Act, legal highs are sometimes described as bath salts, fertilizer (plant food), or incense, even though they have never been used for these purposes. In other words, legal highs are not covered by current drugs laws yet are used by individuals in the same way as illegal drugs such as cocaine or cannabis. The easy availability of legal highs marketed as "bath salts", ‘incense’ and ‘plant foods’, with the added proviso that they are not to be consumed by humans allows the drugs to circumvent current legislation. When legislation is changed the molecular structure is easily altered to produce a new legal high.

Synthetic cannabinoids

Marketed as ‘incense’ and labeled “not for human consumption”, these drugs were increasingly popular with students and young adults being initially legal and easily available from stores, online, head shops (outlets selling drug paraphernalia/counterculture magazines) and petrol stations. The structure of synthetic cannabinoids does not resemble that of tetrahydrocannabinol (THC] contained in marijuana or hashish, yet the drugs affect individuals in the same manner and are much more potent. Synthetic cannabinoids are sold under countless names such as ‘Mr Nice Guy,’ ‘Spice’, ‘Sabbaba’ and ‘Lemon Grass’, to name a few. Spice is a designer drug derived from herbs sprayed with synthetic chemicals which mimic the effects of cannabis. The ingredients are thus similar to but not identical to THC. Synthetic cannabis can precipitate psychosis, especially in individuals with a previous history and a chronic psychotic disorder may persist in some vulnerable patients.

A great variety of synthetic cannabinoids, most often cannabicyclohexanol, are used in an attempt to avoid prosecution. Some are sold in 'herbal' smoking mixtures and the latter have been found on occasion not to contain any synthetic cannabinoids at all. Cannabicyclohexanol is a cannabinoid receptor agonist drug. It has been sold under various brands such as Black Mamba, Bombay Blue, Fake Weed, Genie, Bliss, Blaze, Yucatan Fire. Spice products sometimes sold as “incense,” more closely resemble potpourri. Although Spice is usually smoked, sometimes individuals mix it with cannabis or prepare a herbal infusion for drinking.

To create the herbal products, synthetic cannabimimetics are dissolved in an organic solvent (e.g. acetone) and the resulting solution is sprayed on plant material. The doped plant material is then dried and smoked in a similar fashion to actual cannabis. Spice products typically have a pleasurable smell and taste. They are often referred to as herbal or legal highs because of their legal status and ‘natural’ herbal make-up. They are distributed in the form of dried leaves or resin, and powder, and are sold without age restriction in metal-foil sachets, usually containing 3 g of vegetable matter, to which one or more of the synthetic cannabinoids have been added. Spice is typically smoked, using a pipe or by rolling in a cigarette paper, and can also be ingested as an infusion, or inhaled.15 16

Table 1: Side effects of mephedrone

Common:
Hyperhidrosis
Headache
Palpitations
Nausea
Raynaud-type syndrome

Uncommon < 10%
Dizziness
Hallucinations
Psychosis
Dry mouth
Increased sociability
Chest pain
Blurred vision
Agitation, aggression, violence,
Hyponatraemia
Seizures and hyperthermia
Fatigue and insomnia

Drugs of the 2C family (phenethylamines containing methoxy groups attached to a benzene ring) have hallucinogenic and stimulant effects. The term ‘2C’' refers to the 2 carbon atoms between the benzene ring and the amino group in these compounds. The effects are a cross between MDMA and LSD. They are relatively new to the market and not widely available in the UK. An excited delirium presentation seems to be consistent in deaths attributed to 2C drugs and at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. One agent known as 2C-1 or Smiles, which first appeared in 2003,has more potent effects than MDMA and LSD. Users report an intense energy with vivid visual and auditory hallucinations lasting hours to days.. Patients may exhibit symptoms consistent with serotonin toxicity. Doctors need to be vigilant as synthetic drugs do not show up on routine testing. Treatment of 2C intoxication is primarily supportive.17

Despite widespread Internet availability, many of these drugs remain unfamiliar to doctors and yet ‘bath salts’, have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. As with other illicit substances designer drugs may compromise cardiac function causing hypertension and tachycardia and users who inject run the well-known risks of contracting hepatitis C or HIV, thrombophlebitis and embolus formation.

Methoxetamine

Methoxetamine (also known as ‘mexxy’) is available on the Internet and marketed as ‘legal ketamine.’ It is an arylcyclohexylamine chemically related to ketamine and PCP (phencyclidine). Methoxetamine is longer acting and more potent than ketamine. The drug, a white powder, is usually taken sublingually, snorted, ‘bombed’, or injected intramuscularly. Doses are typically between 5mg-90mg orally. After snorting the drug it may take 30-90 minutes for its effects to become apparent. When injected the onset of action is usually within five to ten minutes. The overall duration of effect is within the range of 1–3 hours, sometimes longer. The drug induces feelings of detachment (dissociative state), paranoid symptoms, visual hallucinations, restlessness and increased energy in some. Other reported symptoms include confusion, catatonia, depression, tachycardia and hypertension. Methoxetamine is now a Class B drug under the Misuse of Drugs Act.18 19

Piperazine derivatives

The piperazine derivatives, a class of amphetamine-like compounds that includes BZP (benzylpiperazine) and TFMPP (trifluoromethylphenylpiperazine) are making a comeback as "legal ecstasy." Often perceived as safe by the public, adverse effects may range from minimal to life-threatening. Co-ingestion of BZP and TFMPP causes increased action of dopamine and serotonin, similar to MDMA. Severe symptoms include seizures, hyperthermia, hyponatremia, dystonic reactions, rhabdomyolysis, renal failure, metabolic acidosis, DIC, and respiratory failure. 20 Over the last few years piperazine derivatives are being sold as ecstasy pills, or under the names of “Frenzy”, “Bliss”, “Charge”, “Herbal ecstasy”, “A2”, “Legal X” and “Legal E”. Although piperazine designer drugs enjoy a market reputation of being safe, they may cause distorted perceptions after ingestion. There are several reports of toxic symptoms experienced by users after drug intake.The piperazinic compounds are derived from piperazine, a cyclic molecule containing two opposite nitrogen atoms and four carbon atoms distributed between the two and were originally used as anti-helminthic agents in the 1950s. Designer drugs of this class can be divided into the benzylpiperazines such as benzylpiperazine (BZP) and its methylenedioxy analogue methylenedioxybenzylpiperazine (MDBP), and phenylpiperazines such as chlorophenylpiperazine (CPP), trifluoromethylphenylpiperazine (TFMPP), and methoxyphenylpiperazine (MeOPP). A third group includes the thienylmethylpiperazines. Chlorophenylpiperazine is an active metabolite of drugs such as trazodone, and nefazodone used as antidepressants. A survey in the UK found that piperazines are among the most common active drugs in tablets purchased from internet supplier sites.Piperazine-derived compounds are therefore emerging designer drugs, whose abuse has increased remarkably worldwide.21

Naphyrone

Naphyrone(naphthylpyrovalerone) or NRG-1 (or Energy1) is a cathinone derivative available to buy on a number of websites and is gaining popularity. It is sold as an alternative to mephedrone. Belonging to the designer drugs class, it is similar in structure to pyrovalerone, a monoamine uptake inhibitor and as it is somewhat similar to other cathinone derivatives it has the potential to produce anxiety, paranoia, and cardiovascular side effects. Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones - 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled 'not for human consumption', they are essentially legal highs and are available online. 22 23

Table 2: Some commonly used psychoactive substances

Drug Mode of Action How used
MDMA (‘ecstasy’) ‘Molly’ is the pure crystalline powder form Releases and inhibits reuptake of dopamine, serotonin and noradrenaline Tablet or capsules

Sometimes one or more tablets taken at one time (‘bumping’)

Salvia divinorum Partial dopamine receptor agonist; also works on kappa receptors Smoked, inhaled, ingested, used sublingually
Mephedrone Effects similar to MDMA, cocaine and amphetamines Nasal insufflation, ingestion
MDVP (see text) Related to cathinone. Effects similar to ‘ecstasy’ Nasal insufflation, inhalation, ingestion
Spice Similar to THC Smoked; sometimes prepared as a herbal infusion for drinking
Naphyrone Effects similar to mephedrone Usually snorted, sometimes swallowed in paper wraps (‘bombing’)

Discussion

New designer drugs have increased in popularity over the past several years because of their euphoric effects. Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for patients. They are all potentially dangerous. For example, an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs.

From the above description it can be seen that synthetic drugs fall into three broad categories: synthetic cathinones (bath salts), synthetic cannabinoids (spice or incense), and amphetamine-like drugs (methamphetamine, ephedrine, MDMA). Cathinones being related to the amphetamine family will cause dilated pupils, hypertension, hyperventilation, paranoia, agitation, hyperthermia, tremors and seizures. Many countries have made certain cathinones illegal, for example, mephedrone, methylone and MDPV. Indeed, the robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Furthermore, pyrovalerone is much more potent than cocaine at inhibiting the uptake of dopamine and norepinephrine.

Methcathinone was previously used in Russia as an antidepressant, also known as “Cat” and “Jeff” when used recreationally. Nowadays the drugs are sold as bath salts, plant food, insecticides, chicken feed additives, or research chemicals with names such as like NRG (Energy) and meow, meow. Bath salts are water-soluble, usually inorganic, solid products designed to be added to water during bathing. Numerous nicknames are used to describe them including Ivory Wave, Purple Wave, Red Dove, Zoom, Bloom, Cloud Nine, Ocean Snow, Lunar Wave, Vanilla Sky, White Lightning, and Hurricane Charlie.

Although ‘legal highs’ are commonly referred to as bath salts they are not Epsom salts (magnesium sulphate) or other water softeners within the usual meaning. In many cases the chemical ingredients are changed without the consumer knowing, making risks unpredictable. Some legal highs contain active ingredients controlled under the Misuse of Drugs Act 1971 (UK). Therefore any individual found in possession of these products would be liable to prosecution and the associated penalties, even if unaware that he/she has purchased a controlled drug. However, claiming a product to be "not intended for human consumption" can potentially circumvent the entire legal process. Drug designers are already showing skilful exploitation of the law and remain far ahead of criminalization efforts. Furthermore, the irony of prohibition is that the supply and slump in the market for cocaine and ecstasy in 2009 led to individuals resorting to untried and untested substances that are now easily available online. 24 25

Synthetic cathinones are mostly excreted via the urine and can be measured via gas or liquid chromatography-mass spectrometry in the blood, urine and stomach contents. They can also be analysed in hair. Unlike traditional cosmetic bath salts, which are packaged and sold for adding to bath water for soaking and cleaning, synthetic designer drugs sold as "bath salts" have no legitimate use for bathing and are intended for abuse. Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses produce euphoria and increase alertness, but high doses or chronic use may cause serious adverse effects.26

Treatment

Treatment should be tailored to the specific drug of abuse. Medical and psychological needs require examining. Generally, treatment uses a combination of counselling and medication to reduce the need or desire (craving) for the drug and give the person the skills to refrain from future drug use. Other treatments might include cognitive behavioural therapy, detox, and relapse prevention techniques.

Supportive care is the mainstay of treatment for untoward serious side effects. Sedation with benzodiazepines is indicated for agitation, seizures, tachycardia, and hypertension. Extreme hypertension that persists despite benzodiazepines may be treated with vasodilators. Beta blockers should be avoided due to the potential to cause unopposed alpha-adrenergic stimulation, worsening the hypertension. Significant hyperthermia may require passive or active cooling. All moderately to severe symptomatic patients should have an electrocardiogram (ECG), be placed on a cardiac monitor, and receive serial temperature checks. Electrolytes, liver function tests, cardiac enzymes creatine, and toxicology should be carried out. Asymptomatic patients with no other suspected ingested drugs or psychiatric symptoms generally may be discharged.

Prevention

Banning legal highs is probably futile because it is impossible to keep up with newer drugs because they are synthesized as soon as the ‘illegal’ drug becomes banned. Some would argue that arresting users creates more harm for individuals, their families and society, as they are then caught up in the criminal system. Others may argue that ‘legal highs’ are not generally harmful and not as dangerous as opiates or their derivatives, or indeed alcohol. It might be more worthwhile making legal highs ‘uncool’, much in the same way that cigarette consumption is now frowned upon. However, it would require a great deal of public money to subsidise such an advertising venture.

Users of legal highs need to be made aware that such drugs purchased on-line may contain illegal substances and therefore may render them subject to prosecution if found in possession. 27

Pre-school family based programmes, and programmes involving the school and community, motivational interviewing for adolescents, and individual programmes, may be beneficial in reducing drug use and other harmful outcomes. Importantly, none of these approaches focus exclusively on particular substances or groups of substances, and although there have been relatively few investigations of intervention processes they most likely work by targeting a number of important precursors of drug use behaviour.28

Preventing designer drug abuse begins with understanding the warning signs of addiction which in many respects are similar to alcohol or more common street drugs.

Club drugs are now widely available and their harmful effects are increasingly becoming more evident. Their effects are unpredictable as they are often ‘contaminated’ with other harmful substances. It is unlikely that legislation will have a meaningful impact. Increasing public awareness about these drugs is paramount, and medical and nursing staff should consider intoxication in those patients who present with agitation and psychosis who have no previous history of mental health problems.

Pharmacists are in a pivotal position to observe changes in patterns of drug use and report worrying trends to health care practitioners. Counselling for young people especially and prevention programmes based in schools could prove useful in pointing out the dangers of these drugs to teenagers. Health care professional too should endeavour to keep up with recent information on these substances by attending hospital-based lectures or conferences as part of continuing professional education.

Urine drug testing will generally be unhelpful as many club drugs are undetectable on standard urine drug screens.29 Mental health staff should enquire about club drugs as part of routine drug and alcohol assessment and be aware that these patients may not fit the stereotype of a drug misuser.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Dr Francis J Dunne, FRCPsych, Consultant Psychiatrist, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH. Dr Khalid Jaffar, MRCPsych, Specialist Registrar ST6, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH. Dr Shazia Hashmi, MRCPsych, Specialist Registrar ST6, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH.
Corresponding Author Details: 
Francis J Dunne, Thorpe Coombe Hospital, The Larkswood Centre, Walthamstow, E17 3HP.
Corresponding Author Email: 
dunnefrancis@googlemail.com
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Cognitive Behavioural Therapy for anxiety in children and adolescents with Autism Spectrum Disorder

Authors
Dr Hadi Shaker-Naeeni, Dr Trinisha Govender and Professor Uttom Chowdhury
Article Citation and PDF Link
BJMP 2014;7(3):a723
Abstract / Summary
Abstract: 

This article is a review of the use of Cognitive Behavioural Therapy for anxiety in children and adolescents with high functioning Autism Spectrum Disorders (ASD). It first briefly outlines some of the key features of ASD, comorbid anxiety, and the increasing necessity to identify effective intervention strategies for use in this group of individuals, before providing a critique of the literature available. It looks at the adaptations that are commonly suggested to tailor a CBT intervention to the specific needs of an ASD population, and at the studies done so far.

Autistic Spectrum Disorder is a term used to describe a condition in which the person has difficulties in social reciprocation, communication and ritualised or rigid behaviour. Most people on the Autistic Spectrum will have social skills difficulties but not necessarily meet criteria for other clinical problems. Look for associated co-morbid conditions such as Depression and Attention Deficit Disorder. A common associated presentation which can be debilitating but often overlooked is anxiety.

People on the Autistic Spectrum should have access to a range of treatments for anxiety as other clinical populations. Modified Cognitive Behavioural Therapy can be successfully used to manage anxiety disorders in people on the Autistic Spectrum.

Abbreviations: 
ASD;Autism Spectrum Disorder. CBT;Cognitive Behavioural Therapy.
Keywords: 
ASD, Anxiety, CBT, Group therapy, Autism, children, Adolescent

Description of the disorder

Autism Spectrum Disorders (ASD) is the umbrella term increasingly used to describe the set of pervasive developmental disorders that included the diagnosis of Autism, Asperger’s Syndrome, and Pervasive Developmental Disorder Not Otherwise Specified under DSM IV. These are a group of disorders characterised by pervasive difficulties in a combination of the key areas of social communication interaction, and restrictive repetitive behaviours or activities 1, 2. The Diagnostic and Statistical Manual of Mental Disorders (the DSM-5), released by the American Psychiatric Association, officially eliminated many familiar autism spectrum diagnoses and now incorporated them into the single diagnosis of autism spectrum disorder. In DSM-IV, Asperger Syndrome was diagnostically differentiated from Autism by the lack of a significant language delay and intellectual functioning within the normal range.

The epidemiology of ASD is approximately estimated 30 in 10,000, although with increasing awareness of the disorder, this has led to greater rates of diagnosis, more recent estimates suggest the rate may be as high as 60 in 10,000 3. ASD may be as common as 1 in every 68 children according to the United States Centre for Disease Control 4.

Difficulties with an understanding of prevalence possibly related to early studies relying on clinically identified cases rather than community-based surveys, which may have resulted in cases not in treatment were being missed, and possibly only the most severe cases being recorded. Previous estimates may also have been incorrect due to previous narrower case definitions. As sampling methods have improved and better diagnostic instruments are used more cases have been identified and there has been a better delineation of ASD from other psychotic disorders. As more children with ASD are identified, there will be a likely rise in the number of families and children seeking treatment.

Comorbidities

There are very high levels of co-morbid psychiatric difficulties amongst this population with estimates ranging from 7-15%. Anxiety related concerns are among the most common presenting problems for school age children and adolescents with ASD 5. Several studies have examined the prevalence of anxiety within the ASD population. A review by white et al 6 of 11 such studies reported a prevalence to range from 11-84%. This large range in the prevalence may be accounted for by difference in methods used to measure anxiety, differences in definitions and in diagnostic subtypes.

Studies have also looked at prevalence rates of anxiety within the ASD population to other populations. Compared to groups of typically developing children, those with autism had a higher occurrence of anxiety 7, 8. Comparison with other groups considered to be at risk
(children with conduct disorders and learning disabilities) children with ASD were more likely to be diagnosed with an anxiety disorder and/or have more intense anxiety symptoms 9,10.

A formal diagnosis of anxiety disorder in this group is hard for therapists due to overlap between comorbid anxiety and the core symptoms of ASD makes. Several anxiety disorders in DSM- IV and ICD 10 have autism as an exclusion criterion, implying that an anxious procession style is a feature of ASD.

The development of anxiety among children with ASD may relate to their cognitive impairment as they may lack the cognitive flexibility to generate strategies to adapt to varying circumstances and may experience distress over even trivial changes in the environment. The information processing style in children with ASD termed ‘weak central coherence’ is similar to non ASD anxious children whereby they selectively attend to threatening cues which results in the misinterpretation of ambiguous situations as threatening 11,12. As a consequence these cognitive deficits can result in a repertoire of social and communication difficulties resulting in children experiencing severe difficulties in social relationships which may in turn lead to the development of anxiety 13. If a child or adolescent has a co-occurring anxiety disorder, this could further negatively impact on the overall social impairment associated with ASD. This can impact on the child or adolescents ability to participate in activities at school, at home and within the community. Children with significant anxiety symptoms are at risk for serious educational difficulties, later unemployment, substance abuse and other psychiatric problems 14.

Some of the most frequently reported anxiety disorders and symptoms seen in children with Autistic Spectrum disorders are simple phobia, generalised anxiety disorder, separation anxiety disorder, obsessive-compulsive disorder and social phobia.

Treatment with Cognitive Behavioural Therapy

Pharmacological and psychosocial treatment have been the most common approaches to the treatment of anxiety in children with ASD but no single anxiety treatment has emerged to attain well established or probably efficacious empirically supported treatment status for children with an autistic spectrum disorder. Evidence for pharmacological intervention is limited. Also the effects of medication only appear to last as long as the medication is used, with relapse once regime is ceased.

The recommended treatment of choice by NICE guidelines for mood and anxiety disorders is cognitive behavioural therapy (CBT) and the primary psychosocial treatments have used CBT.

Despite the fact that CBT has been shown to be an effective empirically supported treatment for typical children, there continues to be differing views as to whether or not it can be used effectively with other populations. Some of the difficulties associated with treating children with ASD are due to suggestions from research that children with ASD have difficulty in identifying emotions and cognitions both in themselves and others. As CBT relies on the child’s ability to infer their own emotional states and thoughts in order to shift their cognitive style and in turn their anxious behaviour, standard CBT treatments need modification to address the difficulties associated with this.

Although there is recognition of the high comorbidity of anxiety with ASD, there have also been suggestions to the use of strict behavioural analysis 15 and an argument against using a cognitive component to treat this population. Lindsay 16 provides a different view, arguing children with ASD can benefit from the use of a cognitive component.

Various modifications have been proposed on the approach of CBT in this population. Some of the models have suggested adjustment of the developmental level to reflect the child’s ability, the use of coping model instead of curative model, the involvement of caretakers, and extending treatment both by the number of sessions and by overall session duration 17. Attwood 18 has recommended the use of role-plays and visuals, the involvement of special interests of the young person, the adjustment of material according to the developmental level and the incorporation of a social skills module due to the vast deficits associated with ASD. Anderson and Morris 19 recommend a more directive approach to treatment and the use of specifically in vivo practice to aid in the generalisation of skills. Each of these variations may contribute differently to the adaptation of CBT to meet the specific needs of the child being treated; however, the most appropriate pattern of practical and functional strategies is yet to be determined.

Chorpita and Daleiden 20 in their review of evidence based treatment for children and adolescents noted the most commonly used techniques to treat anxiety in typically developing children. These include exposure, relaxation, cognitive restructuring and modelling in that order. The most commonly used techniques to treat ASD include communication skills training, modelling, social skills training, goal setting and parent psycho-education.

CBT generally consists of six components which include assessment of the nature and degree of the disorder, affective education, cognitive restructuring, stress management, self-reflection and a schedule of activities to practice new cognitive skills. It is important to ensure that the young person has the same definition and interpretation of words, and affective education can help increase their vocabulary of emotional expression.

Attwood 21 has described several intervention components which can be added to CBT. Some of the suggestions include; a) Increasing the use of visual aids. b) Associating emotions with tangible objects. c) An emphasis on coping strategies that do not require the use of abstract language for instance the use of relaxation. d) Use of alternative communication modes. e) Embedding the use of preservative interests into CBT sessions. f) Increasing the focus on teaching social skills.

Attwood also developed the concept of an emotional toolbox and focused on working with the young person in identifying different tools to ‘fix’ problems that occur as a consequence of negative emotions including anger, anxiety and sadness. The ‘tools’ are further divided into those that constructively release or reduce energy and those that improve thinking. The therapist generally works together with the young person to draw a variety of tools and activities which encourage constructive emotions repair.

Cognitive restructuring aims to enable the young person to correct distorted conceptualisations and dysfunctional beliefs. It involves challenging the current thinking with logical evidence and ensuring rationalisation and cognitive control of their emotions. Young people with ASD can make false assumptions of their circumstances and intentions of others due to impaired or delayed theory of mind abilities. These young people also tend to make literal interpretations and are less able to seek alternative explanations or responses.

Summary of Case Reports, Case Series, and Randomised Control Trials

Method

Studies that used CBT with the aim of reducing anxiety symptoms in young people with an ASD diagnosis were looked at.

Search Procedures

A search was carried out in electronic bases: Psychinfo and Medline. The publication year was not restricted but the search was limited to English- language peer reviewed journals. Over the databases, the terms ‘Asperger’, ‘Autism’, or ‘developmental disability’, plus ‘anxiety’ or ‘CBT’ and the search was limited to children and adolescents.

Review of Case series and reports

There have been five case studies that used CBT in treatment of anxiety as well as one case report that used CBT in treatment of OCD in children with ASD.

The first case study by Reaven and Hepburn (2003)22 reported a 7 year old girl with Asperger syndrome who markedly responded to a 6 month modified CBT treatment which was primarily tailored for her OCD. Afterwards, Greig and MacKay (2005) 23, Sze and Wood (2007) 24 and (2008) 25, Reaven et al (2009) 26, and White et al (2009) 27 reported further successful outcomes of using modified CBT for treatment of Anxiety in children with ASD. See table 1 for a summary of published case reports and series of studies.

Table 1: A Summary of Published Case Reports and Series of studies using CBT for anxiety symptoms in young people with an ASD diagnosis

AUTHOR
(year)
Sample Anxiety Measure Characteristics of intervention Outcome
Reaven & Hepburn (2003)22 a 7 year old girl with Asperger syndrome   6 months modified CBT treatment based upon the work of March and Mulle Obsessive-compulsive symptoms improved markedly
Greig and MacKay (2005) 23 12 year old male with ASD and unspecified anxiety disorder TSCC, Teacher Report, SWQ 15 sessions Anxiety score on TSCC reduced from 19 to 5. Teacher report suggested improvements at school.
Sze and Wood (2007) 24 11year old female SAD, OCD, GAD, HFA ADIS 16 sessions 90 minutes each over 4 months family cognitive behavioural therapy (FCBT) No longer met criteria for SAD, GAD or OCD on the ADIS by child or parent report
Sze and Wood (2008) 25 10 year old male with ASD,GAD, SAD ADIS, CGI, MASC, CBCL, SSRS, VABS Enhancing CBT No longer met criteria for Social phobia or GAD, on the ADIS, improvement CGI , MASC
Reaven et al (2009) 26 7 male, 3 female mean age 11years, 12 weeks Active Treatment 10 parent-child dyads(n = 10) Wait List Control (n = 23)based on order of enrolment, not random assignment SCARED 12 weekly sessions of 1.5 hours

Large group time, separate parent and child group meetings, and parent-child dyads

Parent report on SCARED showed significant decrease in severity of anxiety symptoms in treatment group
White et al
(2009) 27
14 year old male with ASD, 14 yr old female with PDD-NOS,12 year old male with ASD, 12 year old female with ASD ADIS MCIT 12-13 individual therapy modules delivered over 11 weeks. On the CASI-20 parent rated measure of anxiety, 3 out of 4 participants demonstrated significant improvement from baseline to endpoint.

CY-BOCS children’s Yale-Brown Obsessive Compulsive Scare, SAD- Separation Anxiety Disorder, OCD- Obsessive Compulsive Disorder, GAD- Generalised Anxiety Disorder, HFA – High Functioning Autism, ADIS – Anxiety Disorder Interview Schedule, CGI – Clinical Global Scale, MASC – Multidimensional Anxiety Scale for Children, CBCL – Child Behavioural Checklist, SSRS –Social Skills Rating System, VABS – Vineland Adaptive Behaviour Scales, SWQ – Social Questionnaire, MCIT – Multi- Component Integrated Treatment, PARS – Paediatric Anxiety Rating Scale, RCMSA- Revised Children’s Manifest Anxiety Scale, SRS- Social Responsiveness Scale, CASI-Anx - Child and Adolescent Symptom Inventory-4 ASD Anxiety Scale

Review of Randomised Control Trials

There have been eight studies that have met criteria for a randomised controlled trial that identified CBT as a treatment for anxiety in children with ASD. See table 2 for published randomised controlled trials.

Table 2: Published randomised controlled trials of cbt

AUTHOR (year) Age range/
Sample size
Anxiety Measure Characteristics of intervention Characteristics of Controlled Outcome
Sofronoff, Atwood, Hinton (2005) 28 age 10-12

(n=71)

SCAS, SCAS-Parent,

child report measure

a 6 week CBT

child based (n=23) or combined child and parent (n=25) intervention

a waiting list group Significant decreases Parent reports SWQ at follow-up and a significant increase in the child’s ability to generate positive strategies in an anxiety-provoking situation.
Chalfant, Rapee, and Carroll (2006) 29 age 8-13

(n=47)

ADIS, SCAS, Revised Children’s Manifest Anxiety Scale, Children’s Automatic Thoughts Scale, SDQ-Parent, SCAS-Parent a 12 week group CBT based on ‘Cool Kids’ program(n=28) Approx. 7 months waiting list (n=19) 71.4% of the treated children no longer met criteria for an anxiety disorder compared to 0% in the wait list condition (n=19)
Wood et al
(2009) 30
ages 7-11
(n=40)
Anxiety symptom checklists at baseline and post treatment/ post waitlist 16 sessions of standard CBT augmented with multiple treatment components (n=17) A 3 month wait list (n=23) 78.5% CGI improved compared to only 8.7% of the waitlist group, Remission of anxiety in CBT group, but child reported anxiety had no significant effect
Sung et al
(2011) 31
age 9–16

(n=70)

SCAS-C,CGI-S a 16-week CBT

program
(n = 36)

a Social Recreational (SR) program on anxiety
(n =34)
Children in both programs showed significantly lower levels of generalized

anxiety and total anxiety symptoms at 6-month follow-up on SCAS-C

Reaven et al (2012) 32 age 7-14

(n=50)

ADIS-P modified CBT (n=24) TAU (n=26) 50% in the CBT compared to 8.7% TAU group had a clinically meaningful positive treatment response, group CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety
White et al (2012) 33 age 12-17
(n=30)
ADIS-C/P,SRS,
CASI-Anx
CGI-I, PARS
Multimodal

Anxiety &Social Skills Intervention (MASSI) (n=15, 13 completed)

wait-list control (n=15, 12 completed) 16 % improvement in ASD social impairment MASSI is a feasible treatment program and further evaluation is warranted

On the CGI-I, 6 of 15 (40 %) MASSI participants were rated as responders compared to 3 of 15 (20 %) of WL participants

Storch et al (2013) 34 age 7- 11
(n=45)
ADIS IV C/P, PARS,CGI, MASC-P, RCMAS BIACA –CBT; child & parent focused sessions (n=22) TAU(n=21) 18 (75 %) of CBT arm, were treatment responders, versus only 3 of 21 (14%) in the TAU arm. CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms.
McNally et al (2013) 35 age 8-14

(n=22)

ADIS-P, SCAS-P, SCAS a modified version of the Coping Cat program CBT package(n=12) waiting-list

(n=10)

ADIS-P 58% of children with CBT had no anxiety / 36% after 2 month follow up. A modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with ASD.

Sofronoff, Atwood, and Hinton (2005) 28 evaluated the impact of a six week cognitive-behavioural intervention for anxiety in 71 school children aged between 10 to 12 with Asperger’s Syndrome. The authors also looked at the potential impact of parent involvement on outcome. The diagnosis of Asperger’s Syndrome was confirmed by semi-structured telephone interview and anxiety symptoms were based on parent report in the initial telephone interview. Children were randomly assigned to one of three groups: child based intervention, combined child and parent intervention or a waiting list group. The intervention focused on teaching the children strategies to manage feelings and expanding emotional knowledge and was delivered weekly in a group format. The focus was on teaching the children strategies to effectively manage feelings and expanding emotional knowledge. Parents served as co-therapists in the combined parent-child intervention as they were trained in all aspects of the intervention.

Using the Spence Child Anxiety Scale-Parent report, children in the combined parent-child intervention reported fewer symptoms of anxiety post–treatment and at a six week follow up than children in the child-only intervention. A child report measure (James and the Maths Test) was used to identify the number of strategies the child could identify for coping with anxiety. Compared to children on the waiting list, children who received either intervention were able to develop more coping strategies. Those in the combined intervention generated significantly more coping strategies at endpoint compared to those in the child only intervention.

Parental involvement is an important aspect of treatment of young people with ASD in ensuring better generalisation and therapy outcome. Authors of this study found that children whose parents were involved in treatment were significantly more improved at follow up than those whose parents were not involved. There are different models of parents involvement and include either only direct participation in each session or with a separate parent only component or both. It seems that regardless of which approach is used parent involvement increases the sustainability and success rate of CBT. Involvement of parents helps to improve their understanding of exposure and practice and helping the young person to learn how to master the skills on their own.

Limitations of this study include the reliance on the parent report of anxiety symptoms and both Asperger’s Syndrome and anxiety symptoms were not formally diagnosed. Parents who were involved in the delivery of treatment may have had a more vested interest in their children’s progress with higher expectations for improvement affecting outcome measure reports. However, no independent (blinded) ratings of anxiety were gathered.

Chalfant, Rapee, and Carroll (2006) 29 evaluated a 12 week group delivered cognitive –behavioural treatment for anxiety in 47 school children aged between 8 to 13 with ASD and no intellectual disability. The intervention was adapted from the ‘Cool Kids’ program (Lyneham et al, 2003), a 12 week group based activity for treatment of childhood anxiety. Cognitive strategies were simplified in the intervention, with a greater focus on visual aids, structured worksheets and homework and exposure and the programme was extended over a 6 month period of time.

The authors randomly assigned participants to either the CBT (n=28) or waiting list (n=19) before beginning of each treatment group. Those under waiting list condition were offered treatment after approximately 7 months, when the waiting list period ended. Multi-modal and Multi-person assessment of anxiety were used. At pre-treatment, over 75% of the sample met criteria for more than one anxiety disorder.

Structured diagnostic measures used in the study included the ADIS (Albano& Silverman, 1996), Spence Children’s Anxiety Scale (Spence, 1998), The Revised Children’s Manifest Anxiety Scale (Reynolds & Richmond, 1978), and Children’s Automatic Thoughts Scale (Schniering& Rapee, 2002). Parent report measures included the SDQ-Parent Report (Goodman, 1997), and SCAS-Parent Report (Spence, 1998).

At post treatment, 71.4% of the treated children (n=28) no longer met criteria for an anxiety disorder compared to 0% in the wait list condition (n=19). It was also found that children in the CBT condition were largely able to identify their automatic thoughts indicating some theory of mind ability and had a significant reduction in automatic thoughts, in comparison to the wait list condition.

Limitations of this study include the small sample size so the data may not be reflective of the wider population with high functioning autism and anxiety. Also the lack of confirmation of the diagnosis of ASD by the investigating clinicians reduced the validity of the participant’s diagnostic status. Participants were accepted based on previous evaluations completed within the community setting.

There was no time spent with the waiting list group to help ensure that the benefits of treatment could be attributed to the treatment alone and not to time spent with the therapist. Also the issue of the waiting list group being aware of the treatment programme and knowledge of future treatment may have attenuated the response of those on the waiting list. Clinicians who implemented the CBT groups and collected the relevant pre-and post-treatment data were not blind to the study’s aims.

Wood et al (2009) 30 used a standard CBT program augmented with multiple treatment components as a randomised controlled trial for 40 children aged between 7 to 11. It was designed to accommodate the social and adaptive skill deficit of children with ASD that could pose barriers to anxiety reduction. They also used a family based intervention program adapted for use with children with ASD. Enhancements included addressing of poor social skills, adaptive skill deficits, circumscribed interests and stereotypes, poor attention and motivation, common co-morbidities as well as school based problems. During modules, children were given social coaching by the therapist, parents and available school providers on appropriate ways to enter interactions and maintain conversation with peers.

Children were randomly assigned to 16 sessions of CBT (n=17) or a 3 month wait list (n=23). Independent evaluators blind to treatment condition, were involved in structured diagnostic interviews. Parents and children completed anxiety symptom checklists at baseline and post treatment/ post waitlist.

The Clinical Global Impressions Improvement Scale (CGI) criteria showed that 78.5% of the CBT group showed positive treatment response at post treatment as compared to only 8.7% of the waitlist group.

Children randomised to CBT had primary outcomes comparable to those of typically developing children receiving CBT for anxiety disorder, which were remission of all anxiety disorders for over half the children in immediate treatment at post treatment and follow up and a high rate of positive treatment response on the CGI. However child- reported anxiety did not yield a significant treatment effect.

Limitations of this study include the small sample size which precluded tests of moderation. The study was also undertaken by researchers who developed the intervention and would need independent replication to validate the intervention.

Also using measures not designed for children with ASD had major impact on the outcomes. The child report of Multidimensional Anxiety Scale for Children (MASC) scores did not yield a significant effect for treatment group largely due to a decrease in MASC scores from pre to post treatment for children in both groups. This may have been due to the MASC being not particularly effective in this population and children’s scores at baseline were relatively low on average. Parental scores showed less of a change from pre to post treatment in the waiting list group. The MASC does not specifically measure OCD and GAD symptoms and as there was a wide range of anxiety symptoms, the type of change that some children may have experienced may not have been properly assessed.

Sung et al (2011) 31 compared the effects of a 16-week cognitive-behavioural therapy program and a Social Recreational (SR) program for 70 children with ASD aged between 9 to16. 36 of them were randomised to CBT and 34 to Social Recreational program. Children in both programs showed significantly lower levels of generalized anxiety and total anxiety symptoms at 6-month follow-up on SCAS-C. They suggest factors such as regular sessions in a structured setting, consistent therapists, social exposure and the use of autism-friendly strategies are important components of an effective framework in the management of anxiety in children and adolescents with ASD.

Reaven et al (2012) 32 used a modified CBT intervention for anxiety in 50 children aged between 7 to 14 with high-functioning ASD and anxiety, who were randomized to group CBT (n=24) or treatment-as-usual (TAU) (n=26) for 12 weeks. Independent clinical evaluators blind to condition, completed structured ADIS-P pre- and post-intervention condition. They found a significant difference between CBT and TAU group.

47 children completed either the CBT or TAU condition. They also had 3 and 6 month follow-ups. Results indicated markedly better outcomes for the CBT group. Clinician Severity Ratings, diagnostic status, and clinician ratings of global improvement showed significant differences by group. In the intent-to-treat sample, the CBT group, 10 of 20 children (50%) had a clinically meaningful positive treatment response, compared to 2 of 23 children (8.7%) in the TAU group. Initial results from this randomized, designed treatment study suggest that a group CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety.

Limitations of this study include small sample size, lack of an attention control group, use of outcome measures normed with typically developing children, and no use of teacher or child measures. TAU remained variable, and the study did not mention the situation of the children in TAU as were or weren’t receiving any treatment.

White et al (2012) 33 combined treatment approaches, and evaluated the feasibility and preliminary outcomes of the Multimodal Anxiety and Social Skills Intervention (MASSI) program in 30 adolescents aged between 12 to 17 with ASD and anxiety symptoms of moderate to greater severity who were randomised to CBT (n=15) or Wait list group (n=15). A 16 % improvement in ASD related social impairment (within-group effect size = 1.18) was observed on a parent-reported scale. Although anxiety symptoms declined by 26 %, the change was not statistically significant. These findings suggest MASSI as a feasible treatment program and further evaluation is warranted. High subject adherence and therapist fidelity demonstrate the treatment was acceptable to families.

Storch et al (2013) 34 examined the efficacy of the Behavioural Interventions for Anxiety in Children with Autism (BIACA), a modular cognitive behavioural therapy protocol, relative to treatment as usual (TAU) among 45 children with ASD aged between 7 to 11. Children with clinically significant anxiety (including OCD), and no intellectual disability, were randomised to receive 16 sessions of weekly CBT (n=22, 2 drop out) or TAU (n=21). After screening, assessments were conducted at baseline, post-treatment, and 3-month follow up for only CBT group which was not blind. The raters were blind to treatment condition. They did also use both child- and parent-report versions of ADIS. Children receiving CBT showed substantial improvement relative to TAU on primary anxiety outcomes. Of 24 children randomised to the CBT group, 18 (75 %) were treatment responders, versus only 3 of 21 children (14%) in the TAU group. Treatment gains were generally maintained at 3-month follow up for CBT responders. They concluded that relative to usual care, CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms.

The limitations of this study include that only about 75% of the TAU children were in fact getting treatment of any kind at all, as 25% of their TAU weren’t getting anything. Also TAU group was extremely variable, therefore the control group were getting a variety of treatments, or none, making comparisons with the children who received CBT difficult.

McNally et al (2013) 35 used a modified version of the Coping Cat Program in reducing anxiety in children with ASD. They randomly assigned 22 children with ASD aged between 8 to14, with clinically significant anxiety and no intellectual disability, to 16 sessions of the Coping Cat cognitive-behavioural therapy (CBT) program or a 16-week wait list group.

They used ADIS-parent at pre-treatment and post-treatment phases, and they also video-recorded therapy sessions to check for treatment fidelity. Children in the CBT condition evidenced significantly larger reductions in anxiety than those in the waitlist. Treatment gains were largely maintained at two-month follow-up. Results provide preliminary evidence that a modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with high-functioning ASD.

The limitations of this study include small sample size which recommended statistical and effect size to be interpreted with caution, and also the outcome measures were largely based on parent- ADIS reports by parents who were not blind to the treatment. Also, examining treatment response was limited to the primary author who delivered all of the treatment. Similarly, with waiting list as a comparison, there was a danger of getting placebo effects with the intervention arm, especially with parent-report measures, as most parents were very keen to get any help at all for their children.

Discussion and future perspective

It is clear from the 8 randomised controlled studies that young people on the autistic spectrum benefit from some form of CBT when modified as part of a therapeutic package. Unfortunately it is not clear what specific aspect of the therapy is making the difference. Cognitive Behavioural Therapy has many components to it as well as the actual cognitive, i.e. ‘thinking’ part and behavioural part. Which bit of the therapy is making a difference to the anxiety? Is it the cognitive reframing, the relaxation, the exposure, the parental involvement, or simply the therapeutic relationship with a therapist? As with CBT studies which are delivered as part of a package, positive results are often obtained when there is no control group or when compared to a waiting list.

Other limitation to research papers cited above include fairly small sample sizes, and outcome measures that are normed with a non ASD cohort.

Only 2 studies had non waiting list comparison 32, 34. These studies did show significant clinical improvement in anxiety levels. These studies have shown that CBT can be effective if modified for the ASD population. Many clinics often fail to pick up associated anxiety difficulties in the ASD cohort and if present, often are under the impression that CBT would not work in this population due to misunderstanding and ill informed prejudices about the ASD population. As there is such a high comorbidity with anxiety disorders, young people on the autistic spectrum should be offered effective interventions such as CBT. Research should focus on modifications of the CBT package to enable better engagement and better understanding of the CBT constructs.

Practice Points

  • Children with high-functioning Autism Spectrum Disorder (ASD) are at high risk for developing significant anxiety
  • Anxiety can adversely impact on functioning across school, home and community environments
  • Cognitive Behavioural Therapy (CBT) is frequently used with success for children with anxiety symptoms
  • Standard CBT treatments need modification to address the anxiety difficulties associated with ASD
  • Modified CBT interventions for anxiety in children with ASD have also yielded promising results
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
HADI SHAKER NAEENI MRCPSych, Bedfordshire CAMHS, UK. TRINISHA GOVENDER MRCPsych, Bedfordshire CAMHS, UK. UTTOM CHOWDHURY MRCPSYCH, Bedfordshire CAMHS, UK.
Corresponding Author Details: 
Dr Hadi Shaker Naeeni, Beech Close Resource Centre, 5 Beech Close, Dunstable LD6 3SD.
Corresponding Author Email: 
hadi.shakernaeeni@nhs.net
References
References: 
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  3. Fombonne E. The Prevalence of Autism: JAMA 2003;289(1):87-89
  4. United States Centers for Disease Control and Prevention (2007). Prevalence of autism spectrum disorders: Autism and developmental disabilities monitoring network, (No.SS-1). Surveillance Summaries, MMWR 2007;Vol56.:1-40
  5. Ghaziuddin,M .Asperger Syndrome: Associated psychiatric and medical conditions. Focus on Autism and Other Developmental Disabilities 2002 ;17:138-144
  6. White SW, Oswal D, Ollendick T, et al. Anxiety in children and adolescents with autism spectrum disorders. Clinical Psychology Review 2009; 29:216-229
  7. Gillot A, Furniss F, Walter A. Anxiety in high-functioning children with autism. Autism 2001;5:277-286
  8. Bellini S. Social skills deficits and anxiety in high-functioning adolescents with autism spectrum disorders. Focus on Autism and Other Developmental Disabilities 2004;19:78-86
  9. Burnette CP, Mundy PC, Meyer JA, et al. Weak central coherence and its relation to theory of mind and anxiety in autism. Journal of Autism and Developmental Disorders 2005;35: 63-73
  10. Green J, Gilchrist A, Burton D, et al. Social and psychiatric functioning in adolescents with Asperger syndrome compared with conduct disorder. Journal of Autism and Developmental  Disorders 2000; 30:279-293
  11. Happe F, Briskman J, Frith U. Exploring the cognitive phenotype of autism :weak ‘central coherence’ in parents and siblings of children with autism .I. Experimental  tests. Journal of Child Psychology and Psychiatry 2001;42:299-307
  12. Morgan B, Maybery M, Durkin K. Weak central coherence, poor joint attention, and low verbal ability: Independent deficits in early autism. Developmental Psychology 2003; 39: 646-56.
  13. Ginsburg G, La Greca AM, Silverman WK. Social Anxiety in children with anxiety disorders: Relation with social and emotional functioning. Journal of Abnormal Child Psychology 1998; 26:175-85.
  14. Velting O, Setzer J, Albano A. Update on and advances in assessment and cognitive-behavioural treatment of anxiety disorders in children and adolescents 2004; 35:42-54.
  15. Sturmey P. on recent claims for the efficacy of cognitive behavioural therapy for people with intellectual disabilities. Journal of Applied Research in intellectual Disabilities 2005; 19; 109-107
  16. Lindsay WR. That poor Laddie Cannae tells his thoughts for his actions: a reply to Sturmey. Journal of Applied Research in Intellectual Disabilities 2005; 19: 119-120
  17. Beebe DW, Risi S. Treatment of adolescents and young adults with High-functioning Autism or Asperger syndrome. In cognitive therapy with children and adolescents: A casebook for clinical practice. New York: Guildford Press  2003; 369-401
  18. Attwood T. Modifications to cognitive behaviour therapy to accommodate  the cognitive profile of people with Asperger’s Syndrome;1999
  19. Anderson S, Morris J .Cognitive behaviour therapy for people with Asperger syndrome. Behaviour and Cognitive Psychotherapy 2006 ; 34 :293-303
  20. Chorpita BF, Daleiden EL. Mapping evidence based treatments for children and adolescents: Application of the distillation and matching model to 615 treatments. Journal of Counselling and Clinical Psychology ;2009: 77 : 566-579
  21. Attwood T.  Cognitive behaviour therapy for children and adults with Asperger’s syndrome. Behaviour change; 2004 21:147-161
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  23. Greig A, Mackay T. Asperger’s syndrome and cognitive behaviour therapy: New applications for educational psychologists. Educational and Child Psychology 2005;22:4-15
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Physical activity after cancer: An evidence review of the international literature

Authors
Robert James Thomas, Mea Holm and Ali Al-Adhami
Article Citation and PDF Link
BJMP 2014;7(1):a708
Abstract / Summary
Abstract: 

The importance of physical activity during and after cancer treatments is now being appreciated, as emerging evidence suggests that it improves several common side-effects of cancer treatments, as well as correlating with improving overall survival and reduced the probability of relapse. The biological mechanisms through which these benefits are achieved may include effects on cell growth regulatory pathways, levels of hormones, gene expression patterns and tumour immunity. Here we review the evidence for the benefits of exercise during and after cancer, discuss the possible underlying biological mechanisms, and suggest ways in which this knowledge may be used to improve mainstream care of cancer patients.

Keywords: 
Exercise, cancer, survival, side effects.

Introduction

The number of individuals surviving cancer is expected to rise by one-third according to estimates from the American Cancer Society and the National Cancer Institute1. This means that in the UK over 3 million individuals, and in the USA over 18 million individuals, will be living with the consequences of cancer by 2,022. The increase in the number of survivors is attributed to earlier diagnosis, an aging population, better cure rates and more effective systemic therapies to keep patients with metastatic disease alive for longer. To achieve these benefits, patients often have to endure more complex and arduous therapies, frequently leaving them beleaguered with acute and long-term adverse effects. In addition to being unpleasant, these adverse effects result in financial implications for patients and their families, as well as resulting in a greater usage of health resources.

Although the importance of exercise is beginning to be recognised by health professionals, advocacy groups and charities, it still remains an under-utilised resource. This article highlights the evidence that a physically active lifestyle and formal exercise programmes can help relieve many of the common concerns and adverse effects which plague individuals in the cancer survivorship period.

Physical activity improves well-being after cancer

Dozens of interventional studies have tested the feasibility and potential benefits of exercise in cancer survivors2,3,4. Recent meta-analyses of randomised trials involving exercise interventions after cancer, encouragingly demonstrate that the benefits of exercise spanned across several common cancer types and following a range of treatments including surgery, radiotherapy, chemotherapy, hormones and even the newer biological therapies. The most recent meta-analysis of 34 randomised trials published in the BMJ in 2012 involving patients exercising after cancer, demonstrated a benefit for a number of troublesome symptoms particularly fatigue, mood, anxiety and depression; muscle power, hand grip, exercise capacity and quality of life5.

The American College of Sports Medicine also published a comprehensive review of exercise intervention studies in cancer populations which included data from 85 RCT’s of exercise in cancer survivors. Evidence consistently demonstrated that exercise could be performed safely in adjuvant and post-treatment settings. Exercise led to significant improvements in aerobic fitness; increased flexibility and strength; quality of life; anxiety and depression; fatigue, body image, size and composition4.

The individual categories of symptoms which commonly afflict cancer survivors are now discussed in more detail:

Cancer related fatigue (CRF) is one of the most distressing symptoms experienced by patients during and after their anti-cancer therapies. It is reported by 60-96% of patients during chemotherapy, radiotherapy or after surgery, and by up to 40% of patients taking long-term therapies such as hormonal or biological therapies6. The first step to treating CRF is to correct, if possible, any medical conditions that may aggravate it, such as anaemia, electrolyte imbalance, liver failure and nocturia; or to eliminate drugs such as opiates, anti-histamines and anti-sickness medication7. The role of exercise was reviewed in 28 randomised, controlled trials (RCTs) involving 2083 participants in a variety of exercise programmes and showed that exercise improved CRF, although the benefit overall was small8. A second review of 18 RCTs involving 1,109 participants, sub-divided the data into types of exercise and demonstrated that supervised exercise programmes had the most impact on CRF9. Further meta-analyses and reviews have also showed that supervised exercise programmes had better results, with a greater reduction in CRF amongst breast cancer survivors assigned to exercise programmes compared to home-based programmes4,5,8,10.

Psychological distress, including anxiety and depression, is common after cancer with reported prevalence rates of 25-30%11. Patients with psychological distress have also been shown to have reduced survival compared to those who are psychologically healthy12. Exercise may help alleviate this symptom and improve mood, as a number of observational studies have shown that cancer patients who exercise have reduced levels of depression and anxiety, better self-esteem and are happier, especially if they involve group activities13. The recent meta-analyses of RCTs also demonstrated a reduction in anxiety and depression among individuals assigned to exercise programmes4,5.

Quality of life (QOL) is lower in many cancer sufferers and survivors, linked to other physical and psychological symptoms of cancer and its’ treatment. Meta-analyses of studies of exercise intervention programmes have demonstrated an improvement of QOL at all stages of the illness for the common cancer types and following several types of treatment4,5. For example, in a study involving 1,966 patients with colorectal cancer, patients achieving at least 150 minutes of physical activity per week had an 18% higher QOL score than those who reported no physical activity, as measured by the QOL FACT-C14. Another study showed similar benefits for breast cancer survivors who had completed surgery, radiotherapy or chemotherapy, and also demonstrated that change in peak oxygen consumption correlated with change in overall QOL15.

Weight gain:45% of women with breast cancer report significant weight gain16, and in a study of 440 prostate cancer survivors, 53% were overweight or obese17. For patients with bowel cancer, the CALBG 8980 trial showed that 35% of patients post-chemotherapy were overweight (BMI 25.0–29.9), and 34% were obese (BMI 30.0–34.9) or very obese (BMI >35)16. The reasons for this are multifactorial, but may include other symptoms of cancer treatment such as fatigue and nausea, causing patients to stop exercising. Regardless of the reasons for weight gain, numerous reviews and a comprehensive meta-analysis of the published literature have demonstrated that individuals who gain weight after cancer treatments have worse survival and more complications18. Fortunately, supervised exercise programmes have been shown to reduce weight and have significant other benefits on body constitution and fitness, such as improved lean mass indices, bone mineral density, cardiopulmonary function, muscle strength and walking distance18,19.

Bone mineral density (BMD): Pre-menopausal women who have had breast cancer treatment are at increased risk of osteoporosis, caused by reduced levels of oestrogen brought on by a premature menopause due to chemotherapy, surgery or hormones. Men who receive hormone deprivation therapy for prostate cancer are also at an increased risk of developing osteoporosis. Accelerated bone loss has also been reported for many other cancers, including testicular, thyroid, gastric and CNS cancers, as well as non-Hodgkin’s lymphoma and various haematological malignant diseases20,21. Lifestyle factors linked to an increase in the risk for developing osteoporosis include a low calcium and vitamin D intake, a diet low in plant-based protein, lack of physical activity, smoking and excessive alcohol intake22. A number of studies have linked regular physical activity with a reduction in the risk of bone mineral loss. Sixty six women with breast cancer were randomized to a control group or an exercise programme. The rate of decline of BMD was -6.23% in the control group, -4.92% in the resistance exercise group, and -0.76% in the aerobic exercise group. The statistically significant benefit was even greater in pre-menopausal women23. In another RCT of 223 women with breast cancer, it was found that exercise, over 30 minutes 4-7 times a week, helped preserve bone mineral density even when bisphosphonates (risedronate), calcium and vitamin D had already been prescribed24.

Thromboembolism: Those with pelvic involvement, recent surgery and immobility, previous history of varicose veins or thrombosis or receiving chemotherapy, are at higher risk25. Although strategies such as compression stockings, warfarin and low molecular weight heparin are essential, early mobilisation and exercise remains a practical additional aid in reducing this life-threatening complication18,26.

Constipation caused by immobility, opiate analgesics or anti-emetics during chemotherapy is a significant patient concern. Exercise reduces bowel transit time, and ameliorates constipation and its’ associated abdominal cramps26.

Physical activity improves survival and reduces relapse

In addition to improving the side effects of treatment for cancer, regular physical activity during and after cancer appears to improve overall survival and reduces the probability of relapse. One of the most convincing studies was an RCT in which 2,437 post-menopausal women with early breast cancer were randomised to nutritional and exercise counselling, or no counselling, as part of routine follow-ups19. In the group receiving counselling, fewer women relapsed and overall survival was greater in the oestrogen-negative subgroup. In another RCT, men with early prostate cancer were randomised to an exercise and lifestyle intervention or standard active surveillance. The average PSA in the intervention group went down, whilst in the control group it went up27. This supports a previous RCT of which the primary end point evaluated a salicylate-based food supplement, but it required men in both arms to receive exercise and lifestyle counselling. Although there was no difference in the primary end point, 34% of men, who’s prostate specific antigen (PSA) was climbing before trial entry, stabilized28.

The majority of the other published evidence for a reduced relapse rate and improved survival after cancer originates from retrospective analysis or prospective cohort studies. The National Cancer Institute, in a recent meta-analysis, reviewed 45 of these observational studies. The strongest evidence was demonstrated for breast cancer survivors; the next strongest evidence was for colorectal cancer survivors, followed by prostate cancer10. The most notable are summarised below:

Breast cancer: The five most prominent prospective cohort studies (in aggregate more than 15,000 women), have examined the relationship between physical activity cancer and prognosis:

  • Irwin et al. (2008)29 investigated a cohort of 933 breast cancer survivors and found that those who consistently exercised for >2.5 hours per week had a 67% lower risk of all deaths compared to sedentary women.
  • Holmes et al. (2005)30 performed a separate evaluation of 2,987 women in the Nurses’ Health Study and found that women walking >3 hours a week had lower recurrence rates, and better overall survival.
  • Holick et al. (2008)31 performed a prospective observational study of 4,482 breast cancer survivors, and found that women who were physically active for >2.8 hours per week had a 35-49% lower risk of dying from breast cancer.
  • Pierce et al. (2007)32 found that the benefits of 3 hours of exercise were even greater if combined with a healthy diet.
  • Sternfeld et al. (2009)33 in the LACE study, evaluated 1,870 women within 39 months of diagnosis. There was a significant difference in overall death rate between the highest and lowest quartile of exercise levels.

Colorectal cancer: The scientific community eagerly awaits the results of the CHALLENGE RCT mentioned above, but a number of retrospective analyses of randomised chemotherapy and cohort trials have been published:

  • Haydon et al. (2006)34retrospectively analysed a RCT involving patients with stage III bowel cancer and found a significant association between exercise and a 31% reduction in relapse rate.
  • Giles et al. (2002)35found that of 526 patients recruited into the Australian Cohort Study, those participating in recreational sport 1-2 days per week had a 5 year overall survival of 71%, as opposed to 57% in non exercisers.
  • Meyerhardt et al. (2006)16 found in an analysis of the Intergroup CALGB study, that physically active patients with bowel cancer had 35% reduction in relapse rate in after chemotherapy.
  • Meyerhardt et al. (2009)36 analysed 668 patients with colorectal cancer within the Health Professionals Study. Men who exercised >27 vs. < 3METS-hours / week had a lower cancer-specific mortality.

Prostate cancer: Three cohort studies have demonstrated a survival benefit for physically active men with prostate cancer:

  • Kenfield et al. (2011)37performed a subset analysis of 2,686 men with prostate cancer, within the Health Professional Study, who exercised >30minutes per week or >3 MET-hours of total activity, had a 35% lower risk of overall death, and men who walked at a brisk pace for >90 minutes had a 51% lower risk of overall death.
  • Richman et al. (2011)38 reported that 1,455 men with prostate cancer, walking more than 3 hours a week, correlated with an improved survival but only if >3miles/hour.
  • Giavannucci (2005)39, within a prospective analysis, reported that men who exercised vigorously had a lower risk for fatal prostate cancer, although this effect was only seen for men over the age of 65.

Quantity and type of exercise recommended for cancer patients

For reduced cancer relapse and improved well-being, most of the cohort studies summarized above suggest moderate exercise of around 2.5 to 3 hours a week for breast cancer survivors. However, for prostate cancer survivors, mortality continues to decrease if the patient walks 4 or more hours per week, and more vigorous activity is also associated with significant further reductions in risk for all-cause mortality37. When the mode of exercise is primarily walking, a pace of at least 3 miles/hour (for >3 hours/week) is recommended for a reduced risk of relapse 38. Therefore, both the pace and duration of exercise affect the survival benefit achievable from exercise, with more vigorous activity generally having a greater benefit (see Table 1). The best results appear to be with programmes including a combination of aerobic and resistance exercises, particularly within a social group.

Table 1: Summary of exercise guidelines for cancer survivors

· Exercising for >3 hours/week has proven benefits for cancer survival
· A pace of at least 3 miles/hour when walking provides greater benefit than a slower pace
· For optimal benefit, exercise should consist of a combination of resistance and aerobic exercises
· Supervised exercise programmes have shown greater benefits for cancer survivors than home-based programmes

The precise amount of exercise has to be determined on an individual basis and depends on pre-treatment ability, current disability caused by the cancer itself or the treatment, as well as time proximity to major treatments. An exercise programme supervised by a trained professional has major advantages, as they can design a regimen which starts slowly and gradually builds up to an acceptable and enjoyable pace. In addition, they can help motivate the individual to continue exercising for the short and the long-term, and they can judge the optimal exercise levels to improve fatigue, and not aggravate it.

The underlying mechanisms of the potential anti-cancer effects of exercise

The body’s chemical environment significantly changes after exercise, best demonstrated in the Ornish study, which found that serum from prostate cancer patients who exercised, had an almost eight times greater inhibitory effect on the growth of cultured androgen dependent prostate cancer cells compared to serum from patients in the control group27. The precise chemical mechanism, which the anti-cancer effect remains incompletely understood, but one of the most likely mechanisms involving growth factors such as insulin-like growth factor (IGF-1) and its’ binding proteins insulin-like growth factor binding proteins (IGFBPs), due to the central role of these proteins in the regulation of cell growth (see Table 2). After binding to its receptor tyrosine kinase, IGF-1 activates several signalling pathways including the AKT pathway, leading to the inhibition of apoptosis and the promotion of cell growth and angiogenesis34,40,41. An inverse relationship of cancer risk with IGFBP3 levels has also been shown, although this effect has not been confirmed in all studies42. Exercise has been shown to increase the levels of IGFBP3, and this was associated with a 48% reduction of cancer-specific deaths in a large prospective cohort study of 41,528 participants43. Decreased levels for IGF-1 in physically active patients have been reported with an associated survival benefit44.

Table 2: Summary of the potential biochemical pathways of the anticancer effects of exercise

Class of Effector Molecule Effector Molecule Effects of Exercise on Effector Molecule

Cell growth regulators

IGF1 Decreased levels
IGFBP3 Increased levels

Proteins involved in DNA damage repair

BRCA1 Increased expression
BRCA2 Increased expression
Regulator of apoptosis and cell cycle arrest p53 Enhanced activity

Hormones

Oestrogen Decreased levels
Vasoactive intestinal protein (VIP) Decreased levels
Leptin Decreased levels (indirect)

Immune system components

NK cells Enhanced activity
Monocyte function Enhanced activity
Circulating granulocytes Increased proportion

Exercise has also been shown to have a large impact on gene expression, although the mechanisms through which the patterns of gene expression are affected remain to be determined. In a recent study of the mechanisms through which exercise impacts prostate cancer survival, it was found that 184 genes are differentially expressed between prostate cancer patients who engage in vigorous activity, and those who do not 37. Amongst the genes that were more highly expressed in men who exercise were BRCA1 and BRCA2, both of which are involved in DNA repair processes.

Another neuropeptide which changes after exercise is Vasoactive Intestinal Protein (VIP). Breast and prostate cancer patients have been found to have higher VIP titres compared to individuals who regularly exercise, and who have increased production of natural anti-VIP antibodies45. In hormone-related cancers such as cancers of the breast, ovaries, prostate and testes, the association between high levels of circulating sex hormones and cancer risk is well established46. Another mechanism through which exercise may affect cancer, is through decreasing the serum levels of these hormones. For breast cancer survivors, the link between exercise and lower levels of oestrogen has been shown13,34,47. An indirect, related mechanism is that exercise helps reduce adiposity, and adiposity in turn influences the production and availability of sex hormones48. In addition, greater adiposity leads to higher levels of Leptin, a neuropeptide cytokine with has cancer promoting properties49,50.

Other pathways include the modulation of immunity, such as improvements in NK cell cytolytic activity 11; the modulation of apoptotic pathways through impacting on a key regulator, p5351, and an exciting recent discovery, the messenger protein irisin, which is produced in muscle cells in response to exercise and is found is to be an important molecule in linking exercise to the health benefits52 , However, we are only beginning to scratch the surface with these and the other mechanisms discussed here, and much more research needs to be done to in this area.

Incorporating exercise into mainstream cancer management

The challenge for health professionals is how to encourage and motivate individuals with cancer to increase their exercise levels. Some, of course, are motivated to increase physical activity or remain active after cancer. However, a recent survey of 440 men with prostate cancer found that only 4% of patients exercised for more than the 3 hours a week recommended by the WCRF17. Macmillan Cancer Relief has produced a series of helpful booklets and web-based patient information materials designed to inform and motivate individuals to exercise as part of its ‘Move More’programme. The Cancernet website has a facility to search for local exercise facilities by postcode, which can be an aid for health professionals when counselling patients. It highlights activities that men will hopefully find feasible and enjoyable such as golf, exercise groups and walking groups, and are encouraged to attend in addition to work place activity and gardening.

Several pilot schemes have been started throughout the UK with the aim to incorporate exercise programmes into standard oncology practice. The difficulty with small schemes is that they tend to be poorly funded, often poorly attended and are unlikely to be sustainable in the longer term. Many agree that the gold standard model would be similar to the cardiac rehabilitation programme53. This would involve a hospital scheme run by a physiotherapist or an occupational therapist, supervising patients immediately after surgery, radiotherapy and even during chemotherapy. This is followed by refering the patient to a community-based scheme for the longer term. Unfortunately, this type of scheme is expensive and unlikely to be funded at present, despite the obvious savings by preventing patient relapsing and ultilising health care facilities to help late effects of cancer treatment54. However, expanding existing services, such as the National Exercise Referral Scheme, is a practical solution. The National Exercise Referral Scheme exists for other chronic conditions such as cardiac rehabilitation, obesity and lower back pain. The national standards for the scheme to be expanded to include cancer rehabilitation were written and accepted in 2010. Training providers have now developed training courses for exercise professionals set against these standards. Trainers completing the course gain a Register of Exercise Professionals (REPs) Level Four qualification, allowing them to receive referrals from GPs and other health professionals.

Conclusion

There are a wealth of well-conducted studies which have demonstrated an association between regular exercise and lower risk of side effects after cancer, as well as reasonable prospective data for a lower relapse rates and better overall survival. However, as there are several overlapping lifestyle factors, which are difficult to investigate on their own, there remain some concerns that exercisers may do better in these studies because they are less likely to be over-weight, more likely to have better diets and to be non-smokers. Although the existing RCTs provide encouraging evidence that exercise intervention programmes are beneficial, further large RCTs are needed, particularly in terms of cost-effectiveness, before commissioner’s start investing more in this area.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ROBERT THOMAS, MRCP MD FRCR, CONSULTANT ONCOLOGIST, Bedford Hospital and Addenbrooke’s University Hospital, c/o The Primrose Research Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. United Kingdom. MEA HOLM, MSc, STUDENT c/o The Primrose Research Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. United Kingdom. ALI AL-ADHAMI, MBChB MACP, CLINICAL RESEARCH FELLOW, University of Buckingham and the Lister Hospital, Coreys Mill Lane, Stevenage, Hertfordshire. SG1 4AB. United Kingdom.
Corresponding Author Details: 
ROBERT THOMAS, The Primrose Oncology Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. UK
Corresponding Author Email: 
robert.thomas@bedfordhospital.nhs.uk
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Electroconvulsive Therapy (ECT): Important parameters which influence its effectiveness

Authors
Aadil Jan Shah, Ovais Wadoo, Javed Latoo
Article Citation and PDF Link
BJMP 2013;6(4):a634
Abstract / Summary
Abstract: 

Electroconvulsive therapy (ECT) is usually given to people with severe depression which has not responded to other forms of treatment such as anti-depressants. However, it is sometimes used for people with a diagnosis of bi-polar disorder or schizophrenia. It was originally developed in the 1930s and was used widely during the 1950s and 1960s for a variety of conditions. ECT consists of passing an electrical current through the brain to produce an epileptic fit – hence the name, electro-convulsive. The idea developed from the observation that, in the days before there was any kind of effective medication, some people with depression or schizophrenia, and who also had epilepsy, seemed to feel better after having a fit.

The mechanism of action of ECT is not fully known. ECT affects multiple central nervous system components, including hormones, neuropeptides, neurotropic factors, and neurotransmitters. The induction of a bilateral generalized seizure is required for both the beneficial and adverse effects of ECT. Certain parameters like seizure duration, electric stimuli, seizure threshold, ECT practice factors and medication can influence its efficacy or effectiveness. This study aims to review the evidence base of these parameters in detail.

Keywords: 
A review of literature regarding ECT was using search engines like MEDLINE, PsycInfo, and OVID using the key words “electroconvulsive therapy,” “seizure parameters,” “seizure duration,” “seizure threshold,” “stimulus dosing” and “effectiveness.”

Introduction

Electroconvulsive therapy (ECT) is an effective treatment for some individuals with severe neuropsychiatric illness. It is widely used to treat certain psychiatricdisorders, particularly major depression.1,2 ECT involves applying a brief electrical pulse to the scalp after the patients are administered muscle relaxants and general anaesthesia.3 This pulse excites the brain cells causing them to fire in unison and produce a seizure.

In 2003, the National Institute of Clinical Excellence (NICE) issued guidance on the use of ECT. Its use was recommended only to achieve rapid and short-term improvement of severe symptoms after an adequate trial of treatment options has proven ineffective and/or when the condition is considered to be potentially life-threatening in individuals with severe depressive illness, catatonia or a prolonged manic episode.4

The mechanism of action of ECT is not fully known. ECT affects multiple central nervous system components, including hormones, neuropeptides, neurotropic factors, and neurotransmitters. The induction of a bilateral generalized seizure is required for both the beneficial and adverse effects of ECT. Certain parameters like seizure duration, electric stimuli, seizure threshold, ECT practice factors and medication can influence its effectiveness. The degree to which electrical stimulation exceeds the seizure threshold, the positioning of electrodes on the head, pulse width, pulse frequency and seizure duration are all known to be important.5 This study aims to review the evidence base of these parameters in detail. The seizure duration and electric stimulus are the two critical parameters and are therefore the main focus of this review.

Literature Review

A review of literature regarding ECT was using search engines like MEDLINE, PsycInfo, and OVID using the key words “electroconvulsive therapy,” “seizure parameters,” “seizure duration,” “seizure threshold,” “stimulus dosing” and “effectiveness.”

Parameters Associated with Effectiveness of ECT

Seizure Duration Electrical Stimulus
Seizure Threshold
ECT Practice Factors
Endocrine Factors
Medication
Other Parameters

Relationship between Seizure Duration and Effectiveness of ECT

Very little is documented on clinical studies that correlate ECT effectiveness and seizure duration. There is evidence that supports the direct relationship of seizure duration and the effectiveness of ECT. It was thought that measuring the seizure duration and the knowledge of measuring such parameters can help explain its therapeutic effect.6 There has been research which suggests that motor seizures of less than 15 seconds in duration do not exhibit tonic-clonic phases and are ineffective in treatment.7 Some of the studies in past years found a direct relationship between total seizure duration during a course of treatment and patient response to ECT.8

A retrospective study on ward patients found that a positive clinical outcome from depressive symptoms has a direct relationship with accumulative seizure time in the course of therapy.8 However, the study was neither randomized nor controlled. Stimulus intensity, diagnosis, and concurrent medication parameters were not properly considered. Another study that supports the correlation found that 88% of patients with cumulative seizure time of 300 seconds and over had a favourable response. The data was retrospectively and prospectively collected in a university hospital. It was mentioned that data gathering was very difficult specifically with regard to the variable number of patients’ ECT sessions; the confounding effect of medication and the treatment of different patients using unilateral or bilateral.9

However other studies challenge these statements. A prospective study of a sample of depressed patients undergoing ECT, the seizure duration did not correlate with Hamilton Depression Rating Scale (HAM-D) scores after treatment. However, it was found that significant nonverbal memory loss of patients was correlated with seizure duration.10 The seizure duration does not directly influence the frequency of ECT, longer seizures do not equate to fewer ECT treatments. Studies using HAM-D scores do not support the idea that seizure duration is a variable correlated to efficacy.11 Short seizures during ECT for few patients are the result of a medical condition or drug treatment interference. On the other hand, patients who have been subjected to ECT treatment encounter shortened seizures.12

There are studies which show that the length of the cerebral seizure activity or the tonic–clonic convulsion is not related to clinical effectiveness.6,13 However, the treating psychiatrist should question whether, or not, generalised cerebral seizure activity had occurred if, at the first treatment, the convulsion lasted less than 15 seconds or the EEG recording showed seizure activity lasting less than 25 seconds.14 Such brief seizure activity might be the result of a focal or partial seizure, and therefore be of questionable therapeutic efficacy. It has been noted that there are patients who recover with ECT and yet display only short tonic–clonic convulsions. This may be more likely in elderly patients.

Most recent evidence mentions that the quality of cerebral seizure activity and the quality of the desired activity cannot simply be related to its length in time alone. It is recommended that the convulsion be timed from the end of electrical stimulation to the end of generalised, that is, bilateral, clonic activity. EEG monitoring can also be done but one needs to have good experience using this technique and sometimes artefacts can cause misinterpretation of the results.15

Relationship between Electric Stimulus and Effectiveness of ECT

ECT is administered by a constant-current, brief-pulse ECT machine that is able to deliver a wide range of electrical dose, that is, 25–50 mC up to 750–800 mC. It is recommended that new machines deliver a range of dose from 25 to 1000 mC.15 One of the important parameters in predicting clinical response is the degree to which the electrical stimulus exceeds the seizure threshold.16 The maintenance of adequate seizure duration on patients is a complicated issue. Elderly patients are also more susceptible to cognitive side effects than younger patients.17 Patients regularly treated with ECT have records of shorten seizure duration over time, and clinicians need to increase stimulus to maintain duration, which in the long run can lead to complications.18

Electroencephalography (EEG) Findings

Voltage Suppression Studies. Postical voltage suppression refers to the decrease in resting EEG voltage after seizure activity as compared with baseline. Proper excitation of seizures invoke voltage-suppressing neural mechanisms intended to terminate and further seizure activity. This suppression is considered as a lower baseline on the EEG post ictus.19 According to studies, the degree of suppression correlates with seizure generalization, therapeutic adequacy, and bilateral stimulation.20

EEG Waveform Features. Greater ictal EEG amplitude, intensity, and symmetry obtained with bilateral ECT are not common with longer seizures, but they are related to antidepressant outcome.21 Studies found that the immediate post stimulus and mid ictal EEG amplitudes correlated with seizure therapeutic adequacy in depression. The symmetry of waveforms at the midpoint on the EEG tracing was also predictive.20 It was also proven that seizure duration had no impact as an EEG measure of treatment adequacy.21

Seizure Charge. The calculated product of EEG voltage, seizure uniformity throughout the brain, and seizure duration was hypothesized to be a measure of treatment intensity and efficacy.21 The variables included in total seizure charge are not physiologically independent of one another, which means longer seizure duration will not guarantee better results.

Low-dose bilateralelectroconvulsive therapy has a powerful antidepressant effectbut low-dose right unilateral therapy is ineffective.22 Evidence shows that the efficacy of rightunilateral electroconvulsive therapy depends on the electricaldose.23,24 There is some research showing that forboth unilateral and bilateral ECT, a higherelectrical dose leads to a more rapid clinical response.7,17,23

Seizure Threshold and Electroconvulsive Therapy

The knowledge of the seizure threshold is a guide to the selection of the electrical stimulus dose for ECT. In theory, the seizure threshold is the lowest dose of electrical charge for each particular patient that is required to induce seizure.25 In clinical applications the seizure threshold depends on individual patient’s characteristics, treatment history, and other stimulus factors.26

The therapeutic effectiveness of ECT is partly dependent on the degree that the stimulus intensity exceeds the seizure threshold.27,28 This statement is true on unilateral non-dominant electrode placement (UL) and on relative stimulus intensity. On bilateral (BL) ECT, the therapeutic response frequency is dependent on higher relative stimulus intensity,28 whereas barely suprathreshold UL ECT has significantly reduced antidepressant potency in contrast to moderately suprathreshold UL ECT (150% above threshold).6 The clinical use of this can be applied after determining the seizure threshold at the first treatment.22,29 The desired relative stimulus intensity to be maintained during treatments is confounded by variable increase in seizure thresholds during treatment.28 This rise in the seizure threshold lessens the degree to which a fixed stimulus dosage exceeds the seizure threshold which can result in possible diminished treatment therapeutic potency.

The seizure threshold can be higher in the elderly population and this may increase the difficulty of eliciting effective seizures.29,30,31 The choice of anaesthetic agent and other age related factors can also affect the seizure threshold. Propofol can reduce the seizure duration and has a possible effect on the seizure threshold.32 The seizure threshold may sometimes rise during the course of therapy. The dose would usually rise pari passu with a rise in the seizure threshold to maintain the dosing strategy. The seizure threshold can increase about 80% in bilateral ECT and 40% in unilateral ECT over a course of treatment.6 Some studies found increases of only 25–40% for bilateral ECT.33

ECT Practice Factors and Seizure Duration

As discussed earlier, the success of ECT treatment can be related to the degree to which the electrical stimulus exceeds seizure threshold and not the absolute dose that determines clinical outcome, especially in unilateral patients.6 Right unilateral (RUL) treatment at variable dosage can produce seizures of equal duration to bilateral treatment. With low levels electrical stimulation, RUL patients showed only 17% improvement inHAM-D scores compared to 70% in the BL group, despite the same mean seizure duration.22

Positioning electrodes over the non-dominant hemisphere causes lesssevere cognitive side effects than bilateral placement.11,24 In spite of extensive research however, the relative efficacy of right unilateraland bilateral electroconvulsive therapy is controversial.2,34,35 There are studies which have found superior efficacy with bilateral therapy,22,36,37 and then there are other studies which have reported equivalent efficacy.38,39 Because ofthis uncertainty, the American Psychiatric Association TaskForce on Electroconvulsive Therapy recommended thatelectrode placement be determined on a case-by-case basis.2

Multiple ECT stimuli (MECT) is given to patients to achieve longer cumulative seizure durations. The clinical improvement in depression correlates to patients’ total seizure time in MECT. But there is no proven study on the benefits of increased seizure time from the increased number of stimuli administered.40

Endocrine Measures

Oxytocin. According to studies, the measurement of oxytocin released from posteriorpituitary has a direct relationship with HAM-D measured improvement in depression.41 The concentration of oxytocin-associated neurophysin (AON) serum was calculated before and after the patient’s treatment of ECT. The increase in AON positively affects HAM-D. This neurophysin response was evident on ECT treatment but does not relate to EEG-measured seizure duration.

Prolactin. The surge of prolactin released during ECT treatment can be an indicator of clinical improvement. Seizure duration is associated with a rise in prolactin.42 However, the relationship between the magnitude of prolactin release and benefits of ECT is yet to be established.24

Cortisol. Although several variables have been studied as a possible predictor for the efficacy of ECT but results regarding hypercortisolism have been inconsistent. There has been a study to evaluate the relation between pre-treatment cortisol levels and the efficacy of ECT in a population of drug-free inpatients with severe major depression. This study suggests that higher levels of post-dexamethasone salivary cortisol at 9 AM are predictive of ECT efficacy.43

Elevated glucocorticoids may increase the vulnerability of the brain to the adverse effects of repeated seizures.This hypothesis was tested in a study and it was found that, ECT treatments delivered over 2 weeks resulted in a significant improvement in mood and a decline in most measures of cognitive performance. Elevated basal cortisol was associated with a greater decline in performance of executive function, visuospatial processing speed, and verbal memory. It was concluded that elevated cortisol predicts a greater degree of ECT-induced cognitive impairment. 44

Medication

Concurrent medication. Concurrent therapy can be considered under two headings: general medication and psychotropic medication. Both can affect seizure threshold. Anticonvulsants, hypnotics and membrane stabilisers tend to raise the seizure threshold, while preparations containing theophyllines can have the opposite effect. Concurrent psychotropic medication can have a significant effect upon ECT. Benzodiazepines are anticonvulsant and should be avoided if possible, but it is important to remember that there are risks associated with their sudden withdrawal. Some authorities have suggested short-term reversal with flumazenil if their presence is considered to be a limiting factor in the success of ECT, but experience is limited.45,46 Tricyclics tend to be proconvulsant, but there is little evidence of any detrimental effect on ECT. Selective serotonin reuptake inhibitors (SSRIs) tend to reduce seizure threshold and may be associated with prolonged seizures. Monoamine oxidase inhibitors increase seizure threshold and it is essential that the anaesthetist is aware that the patient is taking this class of medication or has done so within the previous 2 weeks. Lithium reduces seizure threshold and serum levels should be checked regularly and kept within a moderate range (0.4–1 mmol/l). Selective inhibitors of the reuptake of noradrenaline in common with SSRIs, can reduce seizure threshold and also cause hypertension. Neuroleptics tend to be proconvulsant at low dosage but increase seizure thresholds at higher dosage.

In a retrospective study of 455 patients involving 5482 treatments differences in tolerability and clinical effectiveness were found between combination therapy (ECT administered together with neuroleptic medication) and ECT monotherapy.47 Seizure duration which was assessed by EEG was significantly longer in patients treated with combination therapy using neuroleptics with lower antipsychotic potency; whereas seizure duration assessed by EEG-monitoring-electromyograph (EMG) was shorter in combination treatments done with atypical substances. In a parallel study, of ECT monotherapy or combination therapy with antidepressants using the same patient group, seizure duration was unaffected by most antidepressants but SSRIs lengthened seizure activity.48 In addition this study found that therapeutic effectiveness was significantly enhanced in the patients receiving tricyclic antidepressants, the tetracyclic antidepressant mirtazapine or SSRIs.

There may also be a role for antidepressants in the prevention of relapse following ECT. A small double-blind placebo controlled study of the tricyclic antidepressant imipramine involving 27 depressive inpatients who had failed on pharmacotherapy prior to ECT showed that imipramine, when compared to placebo, resulted in a significant decrease in the risk of relapse of patients receiving ECT.49 This study is in broad agreement with an earlier randomized, double-blind, placebo-controlled trial using another tricyclic antidepressant nortriptyline, or combination therapy of nortriptyline with lithium in the prevention of post-ECT relapse in patients with unipolar major depression.50 In 29 patients receiving placebo the relapse rate during the 24 week duration of the trial was 86%; whilst in 27 patients receiving nortriptyline 60% relapsed; and 39% of the 28 patients receiving nortriptyline and lithium combination therapy relapsed during the time of the study.

Other parameters

The effectiveness of the treatment is influenced by many other underlying factors, specifically the conditions and factors relating to individual patients. This would include age, sex, physical health status, co morbidities etc. Thus, one should always consider other factors that might affect the efficacy of ECT. Two recent small Japanese studies have suggested that some cardiovascular and EEG parameters may act as markers to predict the therapeutic response of ECT in depression. Postictal systolic heart rate and blood pressure were found to be significant predictors of the therapeutic efficacy of ECT in a study of 24 patients with depression;51 with higher systolic heart rate and blood pressure being associated with more effective ECT.

Discussion

ECT is widely used to treat certain psychiatricdisorders, particularly major depression. Although ECT has been extensively used there is little published information on the effect of seizure parameters and the effectiveness of ECT. There is evidence that supports the direct relationship of seizure duration and the effectiveness of ECT but the latest research suggests that the length in time of the cerebral seizure activity or the tonic–clonic convulsion is not related to clinical effectiveness.10,11 The effectiveness of ECT is related to the quality of cerebral seizure activity and cannot simply be related to its length in time alone. One of the important parameters in predicting clinical response is the degree to which electrical stimulus exceeds the seizure threshold.

Past research has shown that a generalized seizureof adequate duration is necessary and sufficient for antidepressanteffectsand that the intensity of the electrical stimuluscontributes to decreased cognitive function, the principal sideeffect, but not to effectiveness.7 Different types of anaesthetics, or concurrent medications can affect the seizure parameters and its efficacy.52,53 Research shows that a generalized seizureof adequate duration is necessary and sufficient for antidepressanteffects1,7 and that the seizures of less than 15 seconds duration are ineffective. There are other studies which mention that seizure duration does not influence the effectiveness of the ECT.10,11

The Future

Clinicians need to continue to research this difficult area within psychiatry to enhance the evidence base and fill such gaps in this evidence as highlighted by the ECT Handbook.54 On-going research is needed into what is a proven treatment of depressive illness and this should include more in depth research into the relationship of the above discussed parameters with its effectiveness.

“If ECT is ever legislated against or falls into disuse, it will not be because it is an ineffective or dangerous treatment, it will be because of a failure to supervise and monitor it correctly”55 and such supervision includes future quality research by concerned clinicians. Current NICE guidelines have limited the use of ECT to individuals with severe depressive illness, catatonia or a prolonged or severe manic episode who have been unresponsive to other treatment options.In addition, intervention of ECT should be considered to be short term and NICE does not recommend using it as maintenance therapy.56 As research into ECT develops, the consequences may be an even more targeted approach to the use of ECT as therapy.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
AADIL JAN SHAH, MBBS, MSc, MRCPsych, Consultant Psychiatrist, Cheshire and Wirral Partnership NHS Foundation Trust, UK. OVAIS WADOO, MBBS, MSc, MRCPsych, Consultant Psychiatrist, Lancashire Care NHS Foundation Trust and honorary lecturer at John Moores University, Liverpool, UK. JAVED LATOO, MBBS, DPM, MRCPsych, Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust,UK.
Corresponding Author Details: 
AADIL JAN SHAH, Consultant Psychiatrist, Birkenhead Adult Mental Health Services and Adult ADHD, The Stein Centre, St Catherines Hospital Derby Road, Birkenhead, Wirral, CH42 0LQ.
Corresponding Author Email: 
aadilshah@gmail.com
References
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Biologics in Dermatology: A Brief Review

Authors
Iffat Hassan, Samia Aleem, Gousia Sheikh and Parvaiz Anwar
Article Citation and PDF Link
BJMP 2013;6(4):a629
Abstract / Summary
Abstract: 

With the advent of biologic therapy, the treatment of various systemic and cutaneous diseases, especially autoimmune diseases, has been revolutionized. Most of the treatment modalities available prior to biologics aimed at producing clinical improvement of the disease without targeting the actual causative factors. Biologics are protein molecules produced by recombinant DNA technology, which target the specific sites in the immune-pathogenesis pathway of the diseases. Because of the specific action on immune system, biologics are presumed to have lesser side effect profile compared to the traditional immune-suppressants. However, the use of biologics is still limited because of unknown long-term safety profile and various aspects of the biologics need to be thoroughly evaluated by conducting large scale studies worldwide. In this review we give a brief description of various biologic agents that are known till date.

Keywords: 
Biologics; proteins; autoimmune diseases.

INTRODUCTION

The US Food and Drug Administration (USFDA) considers the following as biologics: any therapeutic serum, toxin, antitoxin, vaccine, virus, blood, blood component or derivative, allergenic product, analogous product, or derivatives applicable to the prevention, treatment, or cure of injuries or disease of man1. However, generally, biologics refer to protein molecules therapeutically used in various diseases so as to target specific points in the inflammatory cascade of these disorders 2. Hope for an improved tolerability, convenience in usage and lasting remissions, combined with increased knowledge of immune-pathogenesis of various cutaneous diseases has lead to the introduction of biologics as alternative immune-modulating agents in the field of dermatology.

CLASSIFICATION

Biologics are generally divided into three major groups 3:

a) Monoclonal antibodies

b) Fusion antibody proteins

c) Recombinant human cytokines and growth factors

The main groups and the principal agents in each group are summarised in Box 1 and described below.

A) MONOCLONAL ANTIBODIES

Monoclonal antibodies target specific cell-surface receptors. In the early days of biologic therapy, purely murine monoclonal antibodies were used. However, due to the development of antimurine antibodies, which blocked their action, these could be given only for very short periods. The monoclonal antibodies used now have different amounts of murine sequences in the variable region. They may be categorised into three classes:

(a) chimeric antibodies comprising of 30% murine genes fused with human antibodies

(b) humanised antibodies, which have 10% murine sequences, and

(c) human antibodies, which are solely derived from human immunoglobulin genes 4.

Principal monoclonal antibodies with therapeutic relevance in Dermatology

The principal monoclonal antibodies known till date are enumerated in Box 1 and described briefly below.

Box 1: Classification of biologics
Monoclonal antibodies
    · Anti-TNFα: Infliximab, Adalimumab, Certolizumab, Golimumab
    · Anti-LFA1: Efalizumab
    · Anti-CD20: Rituximab
    · Anti-IL-12 and anti-IL-23 monoclonal antibody: Ustekinumab
    · Anti-CD2 antibody: Siplizumab
    · Anti-CD4 antibody: Orthoclone (OKTcdr4a)
    · Anti-CD25 antibodies: Basiliximab, Daclizumab
    · Anti-CD80r: Galiximab (IDEC 114)
    · Anti-IgE: Omalizumab
Fusion antibody proteins
    · Etanercept
    · Alefacept
    · Abatacept
    · Onercept
    · Denileukin Diftitox
Recombinant human cytokines and growth factors
  a) Interferons
    · Interferon α (IFNα)
    · Interferon γ (IFNγ)
    · Interleukin 1 Receptor antagonist (IL1Ra)
    · Interleukin 2 (IL-2)
    · Interleukin 4 (rhIL-4)
    · Interleukin 10 (rhIL-10)
    · Interleukin 11 (rhIL-11)
  b) Granulocyte macrophage colony stimulating factor (GM-CSF)
  c) Platelet derived growth factor (PDGF)

1. Infliximab

Infliximab (trade name Remicade) is a human-mouse monoclonal antibody that binds to and inhibits the activity of TNF-α, and also causes lysis of TNF-α producing cells5.

Important uses of Infliximab

Psoriasis: Infliximab is approved for the treatment of psoriatic arthritis and plaque psoriasis by FDA6, 7. Infliximab may also be of value in recalcitrant or unstable disease and in generalised pustular psoriasis. It is given as an IV (intravenous) infusion in doses of 5 or 10 mg/kg, over a period of 2 hours at weeks 0, 2, 6 and may be followed by repeat single infusions at 8-12 week intervals 8. In various controlled trials, improvement at 10 weeks has been noted in 87% of patients 7, 9.

Atopic dermatitis: Infliximab has also been evaluated in a study of atopic dermatitis 10. At 2 weeks, there was significant improvement in all patients. At 10, 14, and 30 weeks, variable response was seen.

Hidradenitis suppurativa: Long-term efficacy has also been evaluated in hidradenitis suppurativa. In one study, some patients had no evidence of recurrence after 2 years, while others relapsed within a mean of 8.5 months11.

2. Adalimumab

Adalimumab (Humira®) is a human IgG1 monoclonal antibody directed against TNF-α. Adalimumab is given in a dose of 40 mg subcutaneously (SC) every other week as self-injection 5, 12.

Important uses of Adalimumab

Psoriasis: Adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques 13. In a trial, patients with psoriatic arthritis received adalimumab every other week for 24 week14. It was well-tolerated and helped improve joint and skin manifestations significantly.

Hidradenitis suppurativa: An increasing number of reports in refractory hidradenitis supprativa have shown successful control with adalimumab 15, 16, 17.

3. Basiliximab

Successful treatment for severe psoriasis and generalised pustular psoriasis has been reported with basiliximab, an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody 18, 19.

4. Daclizumab

Daclizumab is a humanised monoclonal antibody thatbinds to the CD25 subunit of the IL-2 receptor onT-cells, thus blocking T-cell proliferation. It has been tried in recalcitrant psoriasis and HIV-associated psoriatic erythroderma with a mean reduction in PASI of 30% 20, 21 22.

5. Siplizumab

Siplizumab (Medi-507) is a humanisedmonoclonal antibody directed against CD2. It is designed to block stimulationby inhibiting the CD2–LFA-3 interaction. In earlyphase studies in psoriasis, significant response to therapy has been noted23.

6. Efalizumab

Efalizumab is a recombinant humanised monoclonal IgG1 antibody that binds to CD11a, a subunit of leukocyte function-associated antigen 1 (LFA-1) 24. It destabilises and decreases the trafficking of T-cells into dermal and epidermal tissues.

Important uses of Efalizumab

Psoriasis: Efalizumab was approved by the US FDA in October 2003 for the treatment of psoriasis5. It is currently the only biologic agent approved for continuous administration to adult patients24. The licensed dose of efalizumab is 1 mg/kg weekly as a subcutaneous self- administered injection for 12 weeks, following a first conditioning dose of 0.7 mg/kg 24.

Lichen planus: There is one case report of 3 months duration of treatment with efalizumab for lichen planus with resolution of skin lesions and pruritis 25.

7. Rituximab

Rituximab is a monoclonal humanised antibody directed again in the B cell-specific antigen CD20.

Important uses of Rituximab

Lymphoma: It has been used in patients with CD20-positive non-Hodgkin's lymphoma in a dosage of 375 mg/m2 for four infusions26.

SLE: In systemic lupus, dose escalation studies revealed no differences with respect to clinical outcome in patients who received either a single infusion of 100 mg/m2, a single infusion of 375 mg/m2, or four weekly infusions of 375 mg/m2 27.

Blistering diseases: For patients with blistering diseases, most patients receive the lymphoma dosage schedule. However, serious side effects were considerably higher.

There are reports of refractory pemphigus patients who received infusions of rituximab and had rapid resolution of lesions and a long lasting clinical remission 28, 29, 30.

8. Galiximab

Galiximab a humanised monoclonal antibody directedagainst CD80 and blocks its interaction with CD28 on the T cell, for T-cell stimulation 31. Clinicaldata for this drug are just beginning to emerge with 40% of patients achieving at least 50% reduction in PASI after receiving4 biweekly doses in a trial32, 33.

9. Ustekinumab

It is a fully human monoclonal antibody targeting IL-12 and IL-23, presently undergoing clinical trials for psoriasis and psoriatic arthropathy2, 34. In placebo-controlled studies, (PHOENIX 1) and (PHOENIX 2) have shown that ustekinumab could control plaque psoriasis with only four injections a year resulting in greater ease of use and more sustained relief 35, 36.

10. Certolizumab pegol

Certolizumab is the recombinant antibody Fab' fragment of a humanised TNF inhibitor monoclonal antibody. A study in chronic plaque psoriasis showed that certolizumab pegol, given subcutaneously every two weeks, over a period of 12 weeks shows significant improvement 37.

11. Golimumab

Golimumab, a fully human monoclonal antibody is at present undergoing Phase III clinical trials in psoriatic arthropathy 38.

12. Orthoclone or OkT4a

It is a humanised antihuman CD4 IgG4 monoclonal antibody preventing the recognition of the MHC-bound antigen by an appropriate T-cell receptor, hence T cells do not get activated 39. Several studies have found orthoclone to be effective in moderate to severe psoriasis 40, 41.

13. ABX-IL8

ABX-IL8 is a fully human monoclonalantibody designed to bind free IL-8, a key chemokine in psoriasis and deactivate it in theskin42, 43. In early trials, the drug has demonstrated good clinical responsein psoriasis 44, 45.

14. Omalizumab

Omalizumab is a recombinant, humanised, monoclonal antibody against immunoglobulin IgE. This agent acts as a neutralising antibody by binding IgE at the same site on IgE as its high-affinity receptor, FcεR I, thus inhibiting the biological effects before the generation of allergic symptoms 46. There are reports of the efficacy of omalizumab in chronic urticaria 47, cold urticaria 48 and atopic dermatitis 49.

15. Mepolizumab

Mepolizumab is a humanised monoclonal IgG antibody to the IL-5 molecule, which is essential for eosinophil growth and differentiation. Two weekly infusions showed significant clinical improvement in atopic dermatitisand clinical trials are underway for hyper-eosinophillic disorders 50, 51.

16. SMART Anti–IFN-γ

SMART anti–IFN- γ,a humanised monoclonal antibody, binds and inactivates IFN- γ, an important Th1 cytokinein psoriasis. Early phase studies are being performed at this time 52.

B) FUSION ANTIBODY PROTEINS

Fusion proteins, also known as chimeric proteins, are proteins which are created by the fusion of the receptor domain of a human protein with the constant region of human IgG. The resultant fusion protein binds specifically to a ligand or co-receptor 53. The most commonly used fusion proteins in dermatology are briefly described below and enumerated in Box 1.

1. Alefacept

Alefacept is a bivalent recombinant fusion protein composed of the first extracellular domain lymphocyte function antigen 3 (LFA-3), fused to the hinge domain of human IgG1. The LFA-3 portion of alefacept binds to CD2 receptors on T-cells, thereby blocking their natural interaction with LFA-3 on antigen presenting cells (APCs). The IgG1 portion of alefacept binds to FcγR receptor on natural killer cells to induce T-cell apoptosis 54.

Important uses of Alefacept

Psoriasis: The US FDA approved alefacept in January 2003 for treatment in adult patients with moderate to severe chronic plaque psoriasis. It is given by intramuscular or intravenous route with a dose of 10-15 mg IM weekly or 7.5 mg IV weekly and a 12 week course is recommended 5, 54. Two 12-week courses showed a75% or greater reduction in the PASI 55.

Alopecia areata: Case reports have shown that alefacept may be effective in the treatmentof AA56, 57.

Pyoderma gangrenosum: Alefacept has been used for pyoderma gangrenosum and improvement was shown in 25% of these patients 58.

Other Indications

Some of the off-label conditions where alefacept has been used with success are graft-versus-host disease (GVHD), lichen planus, alopecia areata, atopic dermatitis, mycosis fungoides,alopecia universalis, erosive lichen planus,Hailey-Hailey diseaseand hand dermatitis 58, 59, 60, 61, 62, 63.

2. Denileukin diftitox

Denileukin diftitox is a novel recombinant fusion protein consisting of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptors. It was tried in patients with recalcitrant psoriasis and the rate of improvement for treated patients was found to be significant 64.

3. Abatacept (Ctla4ig)

It is a fusion protein composed of the extracellular domain of CTLA4 and the Fc region of IgG4. It interferes with T-cell activation by competitively binding the B7.1 and B7.2 molecules on the surface of APC 65. In a study, patients with stable psoriasis vulgaris showed good improvement with IV infusion of abatacept 33. A second generation CTLA4Ig, Belatacept, is currently under Phase II clinical trial for allograft diseases 66.

4. Etanercept

Etanercept is a recombinant fully human dimeric fusion protein comprising of the human TNF-α p75 receptor and the Fc portion of human IgG1 molecule. It functions as a TNF inhibitor, thereby preventing interaction with its cell surface receptors on target cells and blocking its pro-inflammatory effects.

Important uses of Etanercept

Psoriasis: Etanercept (Enbrel®) is FDA approved for use as subcutaneous monotherapy in psoriasis. Several clinical trials have shown that it is effective67, 68, 69, 70. The adult dose is 50 mg/week, given subcutaneously for three months 5. The drug is also indicated for treatment of psoriatic arthritis 71, 72.

Hidradenitis supprivata:There is a study of etanercept in patients with severe hidradenitis with more than 50% score improvement12.

5. Onercept

Onercept is a recombinant human soluble p55 tumour necrosis factor binding protein under development for the potential treatment of psoriasis and psoriatic arthritis73.
C) RECOMBINANT HUMAN CYTOKINES AND GROWTH FACTORS

Cytokines are non-immunoglobulin proteins and glycoproteins produced by a wide variety of cells in the human body and released in response to any immune stimulus 74, 75. Recombinant cytokines or cytokine antagonists have been used as immunomodulators 76. The principal recombinant cytokines used in dermatology, enumerated in Box 1, are described below.

1. Interferons (IFNs)

IFNs, a family of related proteins, are produced by virus-infected leucocytes. They exhibit anti-proliferative, immune-modulatory and anti-neoplastic functions 77.

· Interferon α

Recombinant IFNα is given as a subcutaneous or intramuscular injection to treat verruca vulgaris 78 , condyloma acuminatum 79, cutaneous T cell lymphoma 80, Kaposi's sarcoma (AIDS related) 81, melanoma 82, basal cell carcinoma 83, squamous cell carcinoma 84, actinic keratosis 85, Behçet's disease 86, hemangiomas 87 and keloids 88.

The injections are usually given thrice weekly and the dose (depending on the condition being treated) varies from low-dose therapy for condyloma acuminatum to high-dose therapy for melanoma 89, 90. Of late, pegylated IFNα is being used for convenience, because it has a longer half-life and hence can be given once weekly 80.

· Interferon-γ

It is FDA approved for the treatment of chronic granulomatous disease 91 and has also been used in atopic dermatitis 92 and cutaneous T cell lymphoma 90.

2. Interleukin 1 receptor antagonist (IL1Ra, Anakinra)

Anakinra is the non-glycosylated form of human IL-1Ra and acts by blocking the functions of the naturally occurring IL-193. Good results have also been reported in Schnitzler's syndrome94, familial cold auto-inflammatory syndrome 95 and psoriatic arthropathy96. It is given by subcutaneous injection 100 mg once a day.

3. Interleukin 2

Recombinant IL-2 is an antitumour cytokine that has been used in cutaneous T cell lymphoma (CTCL) and metastatic melanoma 97. When given intravenously in high doses of 600,000-720,000 IU/kg in melanoma, IL-2 has produced a 15-20% overall response, with complete cure in 4-6% 98.

4. Interleukin 4 (rhIL-4)

In a dose-escalation study (0.5 to 5mg/kg given by subcutaneous injection thrice a week), IL-4 has been shown to cause improvement in psoriasis by inducing Th2 differentiation in human CD4 + T cells 99.

5. Interleukin 11 (rhIL-11, Oprelvekin)

It has also shown reasonably good results in the treatment of psoriasis at doses of 2.5 or 5mg/ kg, by subcutaneous injection 100.

6. Granulocyte macrophage colony stimulating factor (GM-CSF)

GM-CSF acts by stimulating stem cells to produce granulocytes, monocytes and macrophages 101. Recombinant human GM-CSF has been used to promote wound healing in ulcerated skin for example leg ulcers 102, 103, and for the treatment of melanoma 104 and Sezary syndrome 105.

7. Platelet derived growth factor (PDGF)

PDGF is a dimeric glycoprotein which regulates and promotes granulation tissue formation, re-epithelialisation and wound angiogenesis 106. Recombinant PDGF-BB topical gel (100ìg/g), applied once daily, has been approved by FDA for the treatment of diabetic foot ulcers 107, 108.

8. Recombinant Human IL-10

Recombinant Human IL-10 (Tenovil)can be given in subcutaneousinjections. Early phase clinical trials have shown thatrecombinant human IL-10 three times a week improved psoriasis 109, 110.

SIDE EFFECTS OF BIOLOGICS 5, 111, 112, 113

Some of the adverse effects of biologics are described below:

  • Allergic reaction and antibody formation: Mostly seen with TNF-α blockers.
  • Mild transient injection site reactions: Comprising of erythema, oedema and bruising, noted with etanercept in 10-20% of cases in the first month of therapy. Antibodies to etanercept may develop in 6% of patients.
  • Infusion reaction: Occurs during or within 1-2 hours of treatment and may affect up to 20% of all the patients treated with infliximab, rarely anaphylactic shock may occur.
  • Acute flu-like symptoms: Headache, chills, fever, nausea and myalgia may occur within 48 hours after administration of the first two doses of efalizumab and Interferon α.
  • Infections: Reactivation of tuberculosis may occur on treatment with anti-TNF-α agents and sepsis secondary to Listeria monocytogenes and Histoplasma capsulatum have been reported 113.
  • Malignancy: Patients previously treated with PUVA represent an at-risk group.
  • Demyelinating disease: Worsening of multiple sclerosis and demyelination reported with infliximab.
  • Thrombocytopenia: Occurs with efalizumab and warrants discontinuation of therapy.
  • Autoimmune haemolytic anemia: Occurs 4-6 months after the start of treatment with efalizumab.
  • Congestive cardiac failure: Worsening of congestive cardiac failure with TNF-α blockers is reported to occur.
  • Antinuclear antibodies and lupus-like syndrome: May develop during therapy with anti-TNF-α agents, but not associated with symptoms and signs of lupus in the majority.
  • Hepatitis: Reported following infliximab therapy, occurring from 2 weeks to more than a year after initiation of treatment. Treatment should be stopped in the event of jaundice and/ or marked elevations (>5 times the upper limit of normal) in liver enzymes.

PATIENT SCREENING FOR BIOLOGIC THERAPY 113, 114

All patients to be put on biologics should undergo a thorough evaluation including detailed clinical history, physical examination and relevant investigations with particular reference to known toxicity profile of the agent being considered. The investigations generally advised are113: full blood count, liver and renal function tests, screening for hepatitis and HIV infection, anti-nuclear antibodies, anti-ds DNA, urine analysis, chest X-ray and Tuberculin skin testing.

For efalizumab, haemogram (including platelet count) is recommended monthly for the first 3 months and then every 3 months. For TNF blockers, it is done at 3 months initially and repeated every 6 months.

Liver and renal function tests, serum electrolytes and urine analysis are done at 3 months initially and then every 6 months.

EXCLUSION CRITERIA/ CONTRAINDICATIONS

There are various contraindications for use of biologics, warranting their exclusion and precautions are to be exercised because of their immune-modulator properties. The main exclusion criteria are: active tuberculosis, severe congestive heart failure, patients having >200 treatments of PUVA (because of a risk of developing malignancies with anti- TNF agents), history of demyelinating disease or optic neuritis, hepatitis B and C positivity, HIV positivity, premalignant states, active infections and high risk states such as chronic leg ulcers, persistent or recurrent chest infections and indwelling urinary catheter infections, pregnancy and breast-feeding.

ASSESSMENT OF THE RESPONSE TO BIOLOGICS

Many scoring systems for assessing the severity of various dermatological diseases exist. These scoring systems and other indices can be used for assessment of response to the use of biologics. For example, for evaluation of improvement in psoriasis, PASI (psoriasis area and severity index) and DLQI (dermatology life quality index) are recommended at 3 months initially and then every 6 months 113. Reduction in baseline PASI score of >75% is the standard used by FDA to assess the efficacy of a new psoriasis agent 115. Similarly in atopic eczemas, improvement is monitored based on the Eczema Area and Severity Index, Pruritus Severity Assessment and DLQI. Reduction of the Eczema Area and Severity Index score by 50% is considered excellent, 30-49% moderate and <29% non-significant.

SUMMARY

To summarise, biologics represent the future of therapeutics, not only in dermatology but also in other fields of medicine. Among the various dermatological disorders where they are used, biologics have been most evaluated in psoriasis 116. However, the possibility of serious infections and the oncogenic potential combined with the high cost of the drugs limit their routine use at the present stage 117. Regular re-evaluation of efficacy and safety is essential if these agents are to be used to the maximum benefit of patients118.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Peerzada Sajad and Konchok Dorjay
Competing Interests: 
None declared
Details of Authors: 
IFFAT HASSAN, MD, Professor and Head, Department of Dermatology, STD and Leprosy, Govt.Medical College Srinagar (University of Kashmir), J & K, India; SAMIA ALEEM, MBBS, Resident, Department of Dermatology, STD and Leprosy, Govt.Medical College Srinagar (University of Kashmir), J & K, India; GOUSIA SHEIKH, MBBS, Resident, Department of Dermatology, STD and Leprosy, Govt.Medical College Srinagar (University of Kashmir), J & K, India; PARVAIZ ANWAR, MD, Senior Resident, Department of Dermatology, STD and Leprosy, Govt.Medical College Srinagar (University of Kashmir), J & K, India.
Corresponding Author Details: 
Professor IFFAT HASSAN, Head of Department of Dermatology, STD and Leprosy, Govt.Medical College Srinagar (University of Kashmir), J & K, India.
Corresponding Author Email: 
hassaniffat@gmail.com
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  115. Scheinfeld N. Adalimumab: A review of side effects. Exp Opin Drug Saf 2005; 4: 637-41.
  116. Thappa DM, Laxmisha C. Immunomodulators in the treatment of Psoriasis. Indian J Dermatol Venereol Leprol 2004; 70: 1-9.
  117. Lebowhl M, Clark LN. Recent advances in medical dermatology. Int J Dermatol 2007; 1: 197-202.
  118. Smith CH, Anstey AV, Barker JN, Burden AD, Chalmers RJ, Chandler DA, et al. British association of dermatologist guidelines for biological intervention for psoriasis 2009.Br J Dermatol 2009; 161: 987-1019.

Atopic Dermatitis for Family Physicians

Authors
Aly Khanbhai and Daljit Singh Sura
Article Citation and PDF Link
BJMP 2013;6(3):a626

Introduction

Atopic dermatitis (AD), also known as atopic eczema is a chronic, relapsing, inflammatory skin disease that can cause significant physical, psychological and social stress for patients and their families.1 This article focuses primarily on AD in adults. It is the most frequent inflammatory skin disease in the western world and is often characterized by chronic inflammation and pruritus interrupted by acute flares and bacterial infection.2,3 The majority of the care of AD is provided in primary care, with a minority of patients being referred to secondary care. There are currently extensive cost implications to the National Health Service (NHS) for both treating patients and for lost working days.4 AD can be a therapeutic challenge, especially in primary care, and there appears to be a great potential for improving the outcome and cost effectiveness of treatment in the community setting.4

Epidemiology and pathogenesis

AD typically begins in young infants or early childhood and subsides spontaneously by adolescence in approximately 90% of patients although it can persist into adulthood in about 10% of patients.5 The incidence of AD is generally considered to be increasing worldwide.6 AD affects both sexes equally, and in the United kingdom (UK) approximately 15-20% of school-aged children and 2-10% of adults will be affected by the condition at some stage.7

AD appears to result from a complex interplay between defects in skin barrier function, environmental agents, modified immune responses of the immune system to exogenous and endogenous factors, IgE-mediated mechanisms and other factors. However, the pathogenesis leading to the precise manifestation of AD is not completely understood.3,8

Diagnosis

There are no laboratory or diagnostic tests for AD. The diagnosis is based on visual assessment and clinical history. The UK diagnostic criteria (Table1) has been shown to be the most extensively validated for AD in comparison to the Hanifin and Rajka criteria, Schulz-Larsen criteria, Diepgen criteria, and Kang and Tian diagnostic criteria. Although several different diagnostic criteria have been developed they should mainly be used for research purposes as opposed to daily clinical management.4

Skin tests and laboratory investigations (specific IgE) may be helpful in the investigation of provocative factors such as food or environmental allergens. It is important to note that laboratory investigations should be interpreted in the context of the patient’s history.9

It is often difficult to differentiate AD from other skin conditions (e.g. seborrhoeic dermatitis, contact dermatitis, psoriasis, scabies). However, a family history of atopy and the clinical distribution of the lesions are helpful in making the diagnosis. Other conditions that need to be considered in the differential diagnosis of AD are metabolic and nutritional deficiencies, malignancies and immunodeficiency syndromes that present with skin manifestations.8

Table 1 – UK Working Party Diagnostic Criteria4

The patient must report an itchy skin condition (or parental report of scratching or rubbing in a child) in the last 12 months, plus three or more of the following:
  1. History of involvement of the skin creases (front of elbows, behind knees, fronts of ankles, around neck or around eyes)
  1. Personal history of asthma or hay fever (or history of atopic disease in first degree relative if child aged under four years)
  1. A history of generally dry skin in the last year
  1. Onset under the age of two years (not used if child aged under 4 years)
  1. Visible flexural dermatitis (including dermatitis affecting cheeks or forehead and outer aspects of limbs in children under four years)

Management

The management of AD should involve a combination that includes short-term treatment of flares and a long-term maintenance approach to prevent flares. For patients with mild to moderate AD, topical therapy may be sufficient to control the condition. Patients with more severe disease may require advanced therapy such phototherapy or systemic therapy.

Education

For optimal disease management, patients and/or their carers should be educated about the nature of AD, the need for continued adherence to prescribed treatment and about the appropriate use of topical therapies. Time spent educating patients and carers have been shown to have a positive effect on disease outcomes. Patients may also benefit from written information to reinforce learning.8

Emollients

Emollients soften the skin, aid in restoring the impaired barrier function, reduce itching, prevent moisture from leaving the skin and increase the efficacy of topical corticosteroids (TCS). They also replace the natural surface oils that are essential to preventing irritant materials, infection and allergy-inducing substances from entering the skin.4

Healthcare professionals should offer a range of emollients, and prescriptions should be reviewed frequently. To optimise adherence to emollient therapy, creams, lotions, and ointments, or a combination can be used depending on patient preference. Continued use of emollients during periods of disease quiescence can reduce the likelihood for exacerbations.10

When the treatment regimen involves both an emollient and TCS, there is no evidence on which to base the order of application. Patients should be advised to apply emollients liberally and frequently (at least 2-4 times a day). It is especially important to use emollients during or after bathing. The emollient should be applied in the general direction of growth of body hair in order to prevent accumulation at hair bases which might predispose to folliculitis. Emollients can become contaminated with bacteria and the use of pump dispensers minimises this risk. If the emollient is in a pot it should be removed with a clean spoon or spatula.4

Topical corticosteroid therapy (TCS)

TCS is considered first-line therapy for AD flares. Available preparations include ointments, creams, gels, lotions, liquids, and foams. Ointments and creams are generally the most effective in treating AD as they tend to be more moisturising.10 The least potent preparation required to control AD, particularly in sensitive areas, should be utilised. When possible the TCS should be stopped for short periods to reduce the risk of adverse events.8

TCS is categorised into four groups according to potency: mild, moderately potent, potent and very potent. The choice of TCS potency should be tailored to the age of the patient, the body region being treated, and the severity of inflammation. Patients should be advised to apply TCS once daily. If there is an inadequate response to once daily application, the frequency should be increased to twice daily.4 Once control has been achieved, twice weekly maintenance therapy with a TCS should be considered in patients with moderate to severe AD experiencing frequent relapses. The local adverse effects of TCS usage include skin thinning, bruising, perioral dermatitis, folliculitis, pruritus, allergic contact dermatitis and the spread of fungal infection. Patients being treated with intermittent courses of TCS should be reviewed regularly (depending on TCS potency and site of application) to determine response to therapy and assess skin for potentially reversible atrophic changes.4

Table 2 - The ‘fingertip unit’ (FTU) is a method of determining the amount of TCS to apply. It is described as “the amount of ointment expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin crease to the tip of the palmar aspect of the index finger.” The following table is a guide to the use of FTU in adults.4

Skin area FTU per dose
Face and neck 2.5
Torso and abdomen 7
Back and buttocks 7
Entire arm and hand 4
A hand and fingers (front and back) 1
Entire leg and foot 8

Topical calcineurin inhibitors (TCIs)

TCIs are non-steroidal immunomodulating agents licensed for the treatment of AD.4 TCIs work by inhibiting the phosphatase activity of calcineurin to block expression of cytokines and are thought to represent a more targeted way to limit inflammation and avoid many of the adverse effects of TCS. TCIs may be used either as monotherapy, as a combination or as sequential therapy. TCS are generally less expensive and more effective than TCIs although individual clinical situations will arise in which TCIs are preferred.10

Two TCIs are available: tacrolimus (0.03% and 0.1% ointments) and 1% pimecrolimus cream. The tacrolimus 0.03% and 0.1% ointments are both licensed for moderate to severe eczema and the 0.03% ointment is licensed for use in children aged two years and over. The 1% pimecrolimus cream is licensed for mild to moderate eczema in patients aged two years and over. The use of tacrolimus should be limited to doctors with a specialist interest and experience in treating AD.4

TCIs should not be used as first line treatment unless there is a specific reason to avoid the use of TCS.4 Given the high cost of TCIs, and the fact that their long-term safety is not fully known, they are generally reserved for patients with persistent disease or frequent flares that would require continuous TCS treatment. They are also of use in patients with severe disease in sensitive skin areas (e.g. around the eyes, face, neck and genitals) where systemic absorption and the risk of skin atrophy with TCS are of concern. Considering the possibility that the normal immunological response to infection may be suppressed, TCIs should not be applied to skin which appears actively infected.4, 8

Dressings and wet wrap treatment

Patients with non-infected moderate to severe AD can be advised to cover affected areas with dry wrap dressings to provide a physical barrier to scratching and improve the retention of emollients. Wet wrapping generally consists of two layers of bandage applied over topical preparations. The bottom layer is soaked in warm water, squeezed out and then put onto the skin over the topical preparation. The top layer is dry. Wet wraps can be worn under nightwear or ordinary clothes and used during the day or night. They are available in bandage form or as garments.4 Disadvantages include a high cost, inconvenience, a need for specialised training, and an increased potential for adverse effects from occluded corticosteroids (such as systemic absorption, atrophy, striae), and increased incidence of skin infection.10 There is currently insufficient consistent evidence on which to base a recommendation for wet wrap use in the primary care setting.4

Antimicrobial measures

Skin lesions of around 90% of patients with AD are colonised compared to less than 5% of individuals with healthy skin. Staphylococci are the main organisms isolated although other organisms such as streptococci may also cause infection. The routine swabbing of skin is not indicated although swabs of potential Staphylococcus aureus carriage sites should be considered in patients with recurrent infection. Oral antibiotics are not recommended in the routine treatment of non-infected AD but patients with clinically infected AD can be prescribed short term oral antibiotic treatment based on local/regional antibiotic sensitivities. However, first- or second-generation cephalosporins or penicillins for 7 to 10 days are usually effective in managing bacterial infection. Macrolides are less useful alternatives due to resistant patterns in patients with AD. Patients with AD are also prone to recurrent viral infections. Eczema herpeticum is a severe disseminated herpes infection that is a serious risk in patients with widespread AD and may be misdiagnosed as a bacterial infection. Patients with eczema herpeticum normally require systemic antiviral treatment4, 10.

Antihistamines

Although first-generation antihistamines do not directly affect the itching associated with AD, the sedative effects have been found to help improve sleep. Therefore, short-term bedtime use of sedating antihistamines should be considered in patients with AD where there is debilitating sleep disturbance. Daytime use of first generation antihistamines should be avoided given their sedative effects. Non-sedating antihistamines appear to have limited value in patients with AD but they may provide some benefit in patients with allergic triggers.4, 8

Dietary interventions

Although there is an association between IgE mediated food allergy and AD severity in infants, it is unclear whether hypersensitivity to food is a major factor in causing and maintaining AD. Dietary exclusion is not recommended for managing AD in patients without confirmed food allergy. The exclusion of foods during pregnancy and breast feeding to prevent the development of AD in infants is not recommended. Breast feeding for three months or more may help prevent the development of infant eczema where there is a family history of atopy. However, current UK guidelines state that weaning should start at six months.4

Table 3 - Guidance on when to refer to secondary care4

Eczema herpeticum (widespread herpes simplex) – emergency referral
Uncertainty concerning the diagnosis
Poor control of the condition or failure to respond to appropriate topical treatments
Psychological upset or sleep problems
Recurrent secondary infection

Other therapies

Systemic corticosteroids are usually reserved for the acute treatment of severe AD exacerbations. Prolonged use of oral steroids is associated with potentially serious adverse effects and their long-term use should be avoided. Furthermore, relapses are common following discontinuation of oral corticosteroid therapy.8

Ultraviolet (UV) phototherapy may also be beneficial for the treatment of AD in adults. In addition, systemic therapies are available and may be broadly classified into traditional medications (e.g. cyclosporine, azathrioprine, methotrexate) and biologic agents (targeted monoclonal antibodies). These options are available for severe, refractory AD. These therapeutic options should generally be reserved for unique situations and require consultation with a dermatologist. These therapeutic options are beyond the scope of this article.8

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ALY KHANBHAI, MB ChB, DRCOG, GP VTS ST2 Trainee'Queen's Hospital, Rom Valley Way, Romford, Essex, RM7 0AG, UK. DALJIT SINGH SURA, MBBS BSc DRCOG DFSRH MRCGP, General Practitioner North Street Medical Care / Lawns Medical Care, Romford, Essex, RM1 4QJ, UK.
Corresponding Author Details: 
Dr Aly Khanbhai MB ChB DRCOG Queen's Hospital, Rom Valley Way, Romford, Essex, United Kingdom RM7 0AG.
Corresponding Author Email: 
ali.dh.kh@gmail.com
References
References: 
  1. Gelbard CM, Hebert AA. New and emerging trends in the treatment of atopic dermatitis. Patient Preference and Adherence 2008:2 387–392
  2. Ong PY, Leung DYM. The Infectious Aspects of Atopic Dermatitis. Immunology and Allergy Clinics of North America 2010 August; 30(3): 309–321
  3. Novaka N, Leung DYM. Advances in Atopic dermatitis. Current Opinion in Immunology 2011 December; 23(6): 778–783
  4. SIGN. Scottish Intercollegiate Guidelines Network. Management of atopic eczema in primary care. A national clinical guideline. March 2011Scottish Intercollegiate Guidelines Network
  5. Park MK, Park KY, Li K, et al. The Short Stature in Atopic Dermatitis Patients: Are Atopic Children Really Small for Their Age? Annals of Dermatology Vol. 25, No. 1, 2013
  6. Furue M, Chiba T, Takeuchi S. Current status of atopic dermatitis in Japan.Asian Pacific Journal of Allergy and Immunology 2011; 1: 64-72
  7. Green C, Colquitt JL, Kirby J, et al. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation. Southampton, UK: Health Technology Assessment; 2004
  8. Watson W, Kapur S. Atopic dermatitis. Allergy, Asthma & Clinical Immunology 2011, 7(1):S4
  9. Bieber T. Atopic Dermatitis. Annals of dermatology 2010, Vol. 22, No. 2
  10. Walling HW, Swick BL. Update on the management of chronic eczema: new approaches and emerging treatment options. Clinical, Cosmetic and Investigational Dermatology. July 2010

Non-Pharmacological Management of Insomnia

Authors
Umesh Kumar Vyas
Article Citation and PDF Link
BJMP 2013;6(3):a623
Abstract / Summary
Abstract: 

Abstract: Insomnia is the most frequent sleep disorder. It is a symptom, and is defined as “chronic inability to obtain the amount of sleep needed for optimal functioning and well-being”. Untreated insomnia is associated with significant morbidity and mortality. Thorough assessment of insomnia is essential in choosing the most appropriate strategy for management. If a cause of insomnia is identified, initial treatment should be directed at specific factor. Since insomnia is a chronic condition, long-term and safe treatments are warranted. Non-pharmacologic options have been available for decades, but lack of physician awareness and training, difficulty in obtaining reimbursements and questions about efficacy have limited their use. These therapies offer the greatest potential for long term gains in preventing recurrence of insomnia. Pharmacological options are most useful for acute insomnia. They are commonly used but long term use of hypnotics can become complicated by drug tolerance, dependence or rebound insomnia. Non-pharmacological interventions produce reliable and durable clinical benefits in the treatment of primary insomnia, insomnia associated with medical or psychiatric conditions and insomnia in elders. Additional research is still needed to develop and validate treatment algorithms that would optimize outcomes and reduce morbidity. Author concludes that non-pharmacological therapies should always be a component in management of Insomnia. 

Key words: Insomnia 

Method: Pubmed.gov was searched by using pre-determined key word. 

Objectives: To provide an update of the evidence regarding the efficacy, effectiveness, durability and generalizability of psychological and behavioural interventions for persistent insomnia.

Keywords: 
Insomnia

Introduction:

Insomnia is chronic inability to obtain the amount of sleep needed for optimal functioning and well-being. Insomnia has received much attention in last few decades, since it has become a growing and complex problem in our society.Insomnia is defined as the chronic complaint of difficulty initiating or maintaining sleep, early awakening, and interrupting or non-restorative sleep. Furthermore, it must be accompanied by clinically significant impairment in day time function, for which there is no identifiable cause such as another sleep, psychiatric or medical disorder.1 

General Criteria for Insomnia:2

  1. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is non-restorative or poor in quality. In children, the sleep difficulty is often reported by the caretaker and may consist of observed bedtime resistance or inability to sleep inadequately.
  2. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.
  3. At least one of the following forms of daytime impairment related to the night-time sleep difficulty is reported by the patient:
  • Fatigue or malaise
  • Attention, concentration or memory impairment
  • Social or vocational dysfunction or poor school performance
  • Mood disturbance or irritability
  • Daytime sleepiness
  • Motivation, energy or initiative reduction
  • Proneness for errors, or accidents at work or while driving
  • Tension, headaches or GI symptoms in response to sleep loss
  • Concerns or worries about sleep 

Insomnia is prevalent condition in both the general population and in clinical practice, and it is associated with significant morbidity and mortality. It may present as the primary complaint or in association with physical or mental health problem. 

Classification:

Insomnia can be classified into two main etiologic groups:

  • Primary Insomnia: When identifiable etiologies for insomnia have been ruled out, a diagnosis of primary insomnia can be made.
  • Secondary Insomnia: Related to other medical disorders, mental disorders or related to known organic factors. 

Insomnia can be divided in to three types based on duration:

  • Less than one month called Acute or Transient insomnia.
  • One to six months called Sub-acute or Short-term insomnia.
  • More than six months called Chronic insomnia. 

Following types of Insomnia recognized in The International Classification of Sleep Disorders (ICSD) second edition, Diagnostic and Coding manual:2

  • Adjustment Insomnia (Acute Insomnia)
  • Psycho-physiological Insomnia
  • Paradoxical Insomnia
  • Idiopathic Insomnia
  • Insomnia Due to Mental Disorder
  • Inadequate Sleep Hygiene
  • Behavioural Insomnia of Childhood
  • Insomnia Due to Drug or Substance
  • Insomnia Due to Medical Condition
  • Insomnia Not Due to Substance or Known Physiological Condition, Unspecified (Nonorganic Insomnia, NOS)
  • Physiological (Organic) Insomnia, Unspecified 

Prevalence:

One third of adult population reports insomnia, 9 to 12% experience day time consequences and approximately 6% meet formal criteria for an insomnia diagnosis.3 Insomnia is more common among women, middle-aged and increases with age, shift workers and with medical or psychiatric disorders. 

Consequences:

Persistent insomnia can produce an important burden for individual and society, as evidenced by reduced quality of life, impaired daytime functioning and increased absenteeism at work, and higher health-care cost. Persistent insomnia is also associated with increased risks of depression and chronic use of hypnotics. 

Diagnosis of insomnia is based on subjective complaint of difficulties falling or staying asleep or non-restorative sleep that is associated with marked distress or significant daytime impairments. Several indicators such as intensity, frequency and duration, needs to be evaluated to assess severity of insomnia. 

Evaluation:

Insomnia is an important public-health problem that requires accurate diagnosis and effective treatment (Standard).4 Insomnia is a symptom of an underlying disorder or condition. The insomnia may be a problem directly related to the sleep-wake regulatory system and/or it might be associated with a comorbid psychiatric, behavioural, medical, or neurological condition.Insomnia is primarily diagnosed by clinical evaluation through a careful, detailed medical, psychiatric, and thorough sleep history (which includes assessment of sleep patterns and waking processes) (Standard).4 

Treatment options:

Pharmacotherapy is currently the most common treatment modality for insomnia,5 but long-term use of hypnotics in chronic insomnia can become complicated by drug tolerance, dependence or rebound insomnia. Since insomnia is a chronic condition, long-term and safe treatments are warranted. Non-pharmacological options provide longer lasting benefits. 

If a cause of insomnia is identified, initial treatment should be directed at the specific factor. If insomnia persists, non-pharmacologic and/or pharmacologic interventions should be instituted. Hypnotic agents are the treatment of choice for the management of acute or transient insomnia. The expected goal is to normalize the sleep pattern within a few days to weeks. Behavioural interventions are important aspect of the treatment of chronic primary insomnia. 

Classification of evidence (Table 1) is used to determine different level of recommendations (Table 2), which is available for behavioural therapies in management of insomnia. 

Table 1: AASM (American Academy of Sleep Medicine) Classification of Evidence (Based on Sackett system,6 the criteria for grading evidence level of each study)
Randomized well-designed trials with low alpha and beta error (Grade I) Randomized trials with high alpha and beta error (Grade II)
Non-randomized concurrently controlled studies (Grade III)
Non-randomized historically controlled studies (Grade IV)
Case series (Grade V)
(Alpha (Type I error) refers to the probability that the null hypothesis is rejected when in fact it is true (generally acceptable at 5% or less, or p<0.05). Beta (Type II error) refers to the probability that the null hypothesis is mistakenly accepted when in fact it is false (generally trials accept a beta error of 0.20). The estimation of Type II error is generally the result of a power analysis. The power analysis takes into account the variability and the effect size to determine if sample size is adequate to find a difference in means when it is present (Power generally acceptable at 80-90%).

 

Table 2: AASM Levels of Recommendations (The following are recommendations of the SPC (Standards of Practice Committee) approved by the Board of Directors of the AASM).7
Term Definition
Standard This is a generally accepted patient-care strategy, which reflects a high degree of clinical certainty. The term standard enerally implies the use of Level I evidence, which directly addresses the clinical issue, or overwhelming Level II evidence.
Guideline This is a patient-care strategy, which reflects a moderate degree of clinical certainty. The term guideline implies the use of Level II evidence or a consensus of Level III evidence.
Option This is patient-care strategy, which reflects uncertain clinical use. The term option implies either inconclusive or conflicting evidence or conflicting expert opinion.

Recommendations according to type of Insomnia:10, 11, 12 

For both, chronic primary insomnia and secondary insomnia, the standard psychological and behavioural interventions are effective and recommended.

Recommendations for specific therapies:

1. Stimulus control therapy

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

Objective is to train the insomnia patient by a set of instructions designed to re-associate the bed and bedroom with sleep and to re-establish a consistent sleep-wake schedule:

  • Go to bed only when sleepy;
  • Get out of bed when unable to sleep;
  • Use the bed/bedroom for sleep only (no reading, watching TV etc.);
  • Arise at the same time every morning;
  • No napping. 

2. Relaxation training

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

Aimed at reducing somatic tension (e.g. progressive muscle relaxation, autogenic training) or intrusive thoughts at bed time (e.g. imagery training, meditation) that interfere with sleep. 

3. Cognitive Behavioural Therapy (CBT) with or without relaxation therapy

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

CBT includes various combinations of both cognitive as well as behavioural interventions. The cognitive component is aimed at changing patient's beliefs and attitudes about insomnia. The behavioural component may include therapies such as stimulus control therapy, sleep restriction or relaxation training. Sleep hygiene education is often also included. 

4. Sleep Restriction

Effective and recommended therapy in chronic insomnia (Guideline) 

It involves curtailing the amount of time in bed to actual amount of time spent asleep. For example, if a patient reports sleeping an average of 6 hours per night, out of 8 hours spend in bed, the initial recommended sleep window (from lights out to final arising time) would restrict to 6 hours. Periodic adjustments to this sleep window are made contingent upon sleep efficiency, until optimal sleep duration is reached. Therapy creating mild sleep deprivation, and then lengthening sleep time as sleep efficiency improves. 

5. Multi-component therapy (without Cognitive therapy)

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

  • Combining stimulus control therapy, relaxation training, sleep hygiene education
  • Combining stimulus control therapy, sleep restriction therapy, sleep hygiene education
  • Combining sleep restriction therapy, stimulus control therapy 

6. Paradoxical intention

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

It involves instructing the patient to remain passively awake and avoid any effort (i.e. intention) to fall asleep. The goal is to eliminate performance anxiety, as it may inhibit sleep onset. This parameter is limited to sleep initiation insomnia. 

7. Biofeedback

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

It provides visual or auditory feedback to patients to help them control some physiological parameters (e.g. muscle tension) in order to seek reduction in somatic arousal. 

EEG Neurofeedback training: It is a self-regulation method that makes use of learning theory, more specifically, the paradigm of operant conditioning.8 While the EEG is measured; the patient receives instant feedback (visual and/or auditory) on the cortical activity of the brain. The goal of this treatment modality is to normalize the functioning of the brain by inhibiting and/or reinforcing specific frequency bands. 

Recommendations relevant to specific patient groups:

Psychological and behavioural interventions are effective and recommended in treatment of insomnia in older adults (Standard) and among chronic hypnotic users (Standard) 

Other mode of therapies:

Sleep Hygiene Education, Imagery training, Cognitive therapy. 

Insufficient evidence is available for sleep hygiene education, imagery therapy, and cognitive therapy to be an option as a single therapy. (No recommendation level) 

Sleep Hygiene Education: Please see table 3

Table 3: Sleep Hygiene Education:
1. Attempt to maintain a regular sleep-wake cycle
2. Obtain morning light exposure
3. Use the bedroom only for sleep and intimacy
4. Create a comfortable, quiet, dark and temperature-controlled bedroom environment
5. Develop a relaxing routine within an hour before bedtime
6. Exercise regularly, but not within a few hours of bed time
7. Avoid use of alcohol and other addicting substances
8. Avoid caffeine or nicotine, especially within a few hours of bedtime
9. Avoid empty stomach or heavy meals before bed time, a light snack may be of value
10. Avoid daytime napping, or if napping, be aware of the impact that napping has on nighttime sleep
11. Avoid disturbances at bedtime (e.g. disruptive noises, pets, family)
12. Avoid work, computers and emotional stress in the bedroom
13. Avoid keeping a clock close to the bed to prevent “clock watching”
14. Avoid excessive wakeful time in bed (>20 minutes)

Imagery therapy: It involves a visualization technique to focus on some pleasant or neutral images to block out unwanted thoughts before sleep. 

Cognitive therapy: Psychological methods aimed at challenging and changing misconceptions about sleep and faulty beliefs and attitudes about insomnia and its perceived daytime consequences. 

Limitations of non-pharmacological management:

  • Gains in sleep onset or total sleep time are not immediately attained.
  • Patient motivation and encouragement are required for success of management.
  • Non-pharmacological interventions are more expensive and time-consuming.
  • They require the availability of a skilled therapist. 

Results:

Psychological and behavioural therapies produce reliable changes in several sleep parameters of individuals with either primary insomnia or insomnia associated with medical and psychiatric disorders.10 A Meta-analysis indicates that in patients with primary insomnia, behavioural interventions produce improvements in sleep parameters (sleep onset latency, time awake after sleep onset (WASO), number of awakenings and total sleep time) in about 70 to 80% of patients.9 Behavioural interventions are more expensive, time-consuming and require the availability of a skilled therapist, but the benefits are long lasting.13 

Clinical Pearl:

  • Pharmacotherapy is currently the most common treatment modality for insomnia,5 but long-term use of hypnotics in chronic insomnia can become complicated by drug tolerance, dependence or rebound insomnia.
  • Psychological and behavioural therapies produce reliable changes in several sleep parameters of individuals with either primary insomnia or insomnia associated with medical and psychiatric disorders. 
  • Behavioural interventions are important aspect of the treatment of chronic primary insomnia; they should be used in every patient of Insomnia.
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None disclosed
Details of Authors: 
UMESH KUMAR VYAS, MD, FAASM, Regional Medical Director of Department of Behaviour Health, Chair of Department of Psychiatry and Psychology, Regional Medical Director of Sleep Disorders Centre, Mayo Clinic Health System, Mankato, MN, USA; Adjunct Clinical Assistant Professor, Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN, USA; Adjunct Assistant Professor of Psychiatry and Sleep Medicine, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, USA.
Corresponding Author Details: 
UMESH KUMAR VYAS, MD, FAASM, Regional Medical Director of Department of Behaviour Health, Chair of Department of Psychiatry and Psychology, Regional Medical Director of Sleep Disorders Centre, Mayo Clinic Health System, Mankato, MN, USA.
Corresponding Author Email: 
Vyas.Umesh@mayo.edu
References
References: 

1. Diagnostic and Statistical Manual of mental disorders, text revision. 4th edition, Washington, DC: American Psychiatric Association (APA); 2000.

2. The International Classification of Sleep Disorders (ICSD) - 2, Second edition, Diagnostic and Coding Manual, American Academy of Sleep Medicine (AASM); 2005

3. Ohayon M. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med rev 2002; 6:97-111.

4. Littner Michael, Hirshkowitz Max, Kramer Milton et al. Practice Parameters for using Polysomnography to Evaluate Insomnia: An Update. SLEEP 2003; 26(6):754-760

5. Kupfer DJ, Reynolds CF. Management of insomnia. N Engl J Med. 1997; 336:341-6.

6. Sackett D. Rules of evidence and clinical recommendation. Can J Cardiol 1993; 9:487-9

7. Eddy D, ed. A manual for assessing health practices and designing practice policies: the explicit approach. Philadelphia, PA: American College of Physicians, 1992

8. Othmer S, Othmer SF, Kaiser DA. EEG biofeedback: an emerging model for its global efficacy. In: Evans JR, Abarbanel A, editors. Introduction to quantitive EEG and neurofeedback. San Diego: Academic press; 1999. p. 3-27.

9. Morin CM, Culbert JP, Schwartz MS. Non-pharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994; 151:1172-80.

10. Morin CM, Bootzin RR, Buysse DJ et al. Psychological and behavioural treatment of insomnia: update of the recent evidence (1998-2004) Sleep 2006; 29(11):1398-1414.

11. Morgenthaler T, Kramer M, Alessi C et al. Practice parameters for the psychological and behavioural treatment of insomnia: an update. An American Academy of Sleep Medicine report SLEEP 2006; 29(11):1415-1419.

12. Chesson AL Jr., Anderson WM, Littner M, et al. Practice parameters for the non-pharmacologic treatment of chronic insomnia. SLEEP, vol 22, 8, 1999:1128-1133.

13. Hauri PJ. Insomnia. Clin Chest Med. 1998; 19:157-68.

The Next Pandemic - Tuberculosis: The Oldest Disease of Mankind Rising One More Time

Authors
Amer Saleem and Mohammed Azher
Article Citation and PDF Link
BJMP 2013;6(2):a615

Overview Of History

Mycobacterium tuberculosis was first isolated on 24th March 1882 by a German Physician Robert Koch, who received a Nobel Prize for this discovery in 1905 1. Tuberculosis is one of the oldest diseases in the history of mankind with evidence of tubercular decay found in some Egyptian mummies from 3000-2400 BC 2. The study of tuberculosis was also known as phthisiatry from phthisis, the Greek term for tuberculosis. Hippocrates identified phthisis as the most widespread disease of the time which involved the coughing up of blood, fever and was almost always fatal 3. Avicenna first identified that pulmonary TB was an infectious disease and developed the method of quarantine in order to limit the spread of disease 4 & 5. The disease was given the name of tuberculosis in 1839 by JL Schonlein 6.

Burden Of Disease

Tuberculosis (TB) is an infectious disease caused by various strains of mycobacteria; of which the commonest cause is Mycobacterium tuberculosis 7. The disease can affect any part of human body but commonly attacks the lungs. One third of the world’s current population has been infected by Mycobacterium tuberculosis and new infections occur at a rate of 1 per second 8. About 5-10% of these infections leads to active disease which, if left untreated, kills about 50% of its victims. TB affects approximately 8 million people worldwide and about 2 million people die of this disease annually. In the 19th century pandemic tuberculosis killed about 1/4th of the adult population of Europe 9. Nevertheless, these figures may be only the tip of the iceberg. Tuberculosis is again on the rise and main cause for the resurgence of TB is immunodeficiency as a result of HIV co-infection or, less commonly, immunosuppressive treatment such as chemotherapy or corticosteroids.

Introduction To Mycobacteria

Mycobacteria are aerobic and non-motile bacteria (with the exception of Mycobacterium marinum which is motile within macrophages) which are characteristically alcohol-acid fast 10. They are present in the environment widely in water and various food sources. They are usually considered to be Gram-positive bacteria, but they do not generally retain the crystal violet stain and are thus called Gram-positive acid-fast bacteria. These acid-fast bacilli (AFB) are straight or slightly curved rods 0.2-0.6 mm wide and 1-10 mm long. Mycobacteria are classified on the basis of growth & their ability to produce pigment.

On the basis of growth:

  • Rapid growing: Mycobacteria that forms colonies clearly visible to naked eye within 7 days on sub-cultures
  • Slowly growing: Mycobacteria that do not form colonies clearly visible to naked eye within 7 days on sub-culture

On the basis of pigmentation mycobacteria are divided into 3 groups:

  • Photochromogens (Group I): Produce non-pigmented colonies in dark and pigmented colonies when exposed to light and re-incubation e.g., M. kansasii, M. marinum etc
  • Scotochromogens (Group II): Produce deep yellow to orange colonies when grown in the presence of either light or darkness e.g., M. scrofulaceum, M. xenopi etc
  • Non-chromogens (Group III & IV): Non-pigmented in light and dark or only a pale yellow, buff or tan pigment that does not intensify after exposure to light e.g., M. tuberculosis, M. avium-intra-cellulare, M. ulcerans etc

For Clinical Purposes mycobacteria are divided into 3 main classes:

  • Mycobacterium tuberculosis complex: These are the mycobacteria which can cause TB and include M. tuberculosis, M. bovis, M. pinnipedii, M. africanum, M. microti and M. canetti.
  • Mycobacterium leprae causes leprosy, also known as Hansen’s disease.
  • Non-tuberculous mycobacteria (NTM) or environmental mycobacteria, atypical mycobacteria and mycobacteria other than tuberculosis (MOTT). These include all other mycobacteria which can cause pulmonary disease resembling tuberculosis, lymphadenitis, skin disease or disseminated disease. These include: Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium fortuitum and M. Kansasii which can cause both tuberculosis and leprosy in mammals.

Spread Of Tuberculosis

Today we know that TB is an airborne and highly infectious disease. A person becomes infected when he or she inhales Mycobacterium tuberculosis suspended in air as micro-droplets. Patients suffering from pulmonary TB who have detectable Mycobacterium tuberculosis in their sputum are known as smear positive cases of pulmonary TB. The bacterial load in sputum can be as high as 10,000,000 bacilli/mL. When such smear positive patients of pulmonary TB cough, sneeze or expectorate they produce micro-droplets of phlegm containing Mycobacterium tuberculosis (MTB). The size of these micro-droplets varies from 0.5 to 5mm in diameter. These micro-droplets can remain suspended in air up to 8 hours or even more (depending upon droplet size and environmental conditions including air flow). A single sneeze can produce up to 40,000 of these droplets 11. MTB cannot invade the mucous membranes of the respiratory tree and must reach the alveoli where it replicates. The size of the MTB-containing micro-droplet must be <1mm to be carried to the end of the bronchial tree otherwise it will be deposited on the walls of bronchial tree and cleared away by mucociliary action. Current knowledge asserts that even less than 10 bacteria may cause pulmonary infection 12 & 13. A sputum smear positive patient of TB, if left untreated, can cause infection in 10-15 new people each year.

Definition of TB contacts: People exposed to someone with infectious TB, generally including family members, roommates or housemates, close friends, coworkers, classmates, and others. They are a high priority group for latent-TB infection (LTBI) treatment as they are at high risk of being infected with TB.

Definition of close TB contacts: A person who had prolonged, frequent, or intense contact (i.e. >8 hours/day) with a person with sputum positive TB while he or she was infectious. They are more likely to become infected with TB than the contacts those who see the patient less often.

Pathogenesis

Once in the distal end of bronchial tree, MTB is engulfed by a macrophage in order to start replication within this host cell. Depending upon genetic factors, these macrophages can provide a variable environment for the replication of MTB. If this primary infection starts with a single mycobacteria and the initial host response is incapable of halting this process, within weeks or months there will be millions of tubercle bacilli within the body. MTB spreads in sequence from this primary site to the hilar-mediastinal lymph node initially. When seen on the X-ray, this primary focus of pulmonary infection is called a Gohn focus. It is generally located in the upper lobe or the apical segment of the lower lobe 7. The Gohn focus plus enlarged hilar-mediastinal node is called a Gohn complex. Tubercle bacilli enter the thoracic duct from the hilar-mediastinal lymph nodes, then by passing via the subclavian vein and right atrium, gain access to pulmonary and systemic circulation. As a result MTB can access, and subsequently infect, any organ of the body. Immunocompetent hosts can normally generate an effective immune response within 3-8 weeks, which tackles the primary Gohn focus and can cause involution of the lesions throughout the body. This immune response is a delayed type hypersensitivity reaction to the cell wall protein of bacilli and this is also responsible for positive tuberculin skin test, which appears 4-12 weeks after infection. The primary immune response is not however sufficient to sterilize the tissues and MTB can remain dormant in these foci. Latent foci may persist in the lungs or other organs of the body and are capable of producing disease reactivation which may be pulmonary or extra-pulmonary. In some cases where the initial host response is not capable of causing involution of the primary disease (such as infancy or an immunocompromised state) the infection proliferates and spreads, causing so-called “progressive primary disease”.

Mycobacterium bovis is a mycobacterium that causes tuberculosis in cattle but which can also infect humans. It can be transmitted from cattle to human by ingestion of infected milk and very rarely by inhalation of animal aerosol micro-droplets and by eating infected raw meat. The process of pasteurisation kills M. bovis and other bacteria in milk, meaning that infections in human are rare 14.

When To Suspect Tuberculosis

Primary Tuberculosis: Tuberculosis caused by infection with tubercle bacilli and characterized by the formation of a primary complex in the lungs consisting of a small peripheral pulmonary focus and hilar or para-tracheal lymph node involvement; it may cavitate and heal with scarring or progress. It is mainly seen in children but 10% cases of adults suffering from pulmonary TB have primary infection.

Reactivation Tuberculosis: Also known as chronic TB, post-primary disease, recrudescent TB, endogenous reinfection, and adult type progressive TB. It represents 90% of adult cases (in a non-HIV population), and is due to reactivation of dormant AFBs which are seeded at the time of the primary infection. The apical and posterior segments of the upper lobe and superior segment of the lower lobe of the lung are frequently involved.

Clinical Features: Symptoms and signs vary greatly as do radiological signs. A literature review showed that common signs and symptoms seen in TB infection were 15, 16, 17, 18:

  • Cough, which can be either productive or non-productive; it is often initially a dry cough which can later become productive.
  • Fever which seen in usually 70% of cases; generally it is low grade but could be as high as 390C, lasting for 14 to 21 days and in 98% cases is resolved completely by 10 weeks.
  • Night sweats which is usually seen in 50% of cases
  • Weight loss
  • Pleural effusion: 50% of the patients with pleuritic chest pain had pleural effusion
  • Chest pain: mainly pleuritic with some patients describing retrosternal and inter-scapular dull pain occasionally worsened by swallowing. This pain is believed to be due to enlarged bronchial/ mediastinal lymph nodes
  • Dyspnoea can be present in 33% of cases
  • Haemoptysis can be seen in 25%of cases
  • Fatigue
  • Arthralgia
  • Pharyngitis

Common radiological findings were as follows:

  • Hilar lymphadenopathy: can be seen as early as 1 week after the skin conversion and in almost all of cases within 2 months. It can be associated with right middle lobe collapse
  • Pleural effusion: typically within the first 3-4 months but can be seen as late as one year
  • Pulmonary infiltrates mainly in the upper zones and peri-hilar areas

How To Investigate 19

HIV testing should be done in all patients presenting with clinical features of tuberculosis

Active Pulmonary TB

  • CXR: Perform an X-ray chest PA view. If the appearance is suggestive of active tuberculosis perform further investigations
  • Sputum smear & culture for AFB: send at least 3 sputums for AFB smear and culture including at least one early morning sample. This ideally should be before starting treatment or within 7 days of starting treatment.
  • If clinical features and CXR are suggestive of active TB, do not wait for culture and sensitivity results, start the patient on the 4 drug initial treatment. This can be modified according to culture results later on.

Active Non-Respiratory TB

A tissue sample should be taken from the suspected non-respiratory site and sent for histological analysis, AFB smear and culture analysis. Common examples of non-respiratory tuberculosis are tuberculous lymphadenopathy, tuberculous meningitis and disseminated tuberculosis.

Physicians should think about CNS tuberculosis such as TB meningitis if a patient with risk factors (i.e., immigrants from endemic areas, positive history of close contact etc) presents with signs and symptoms such as headache, low grade fever, photophobia and/ or focal neurological signs. Lumbar puncture (LP) after a CT brain to rule out any contra-indication for LP may yield the diagnosis in these scenarios. An MRI brain is also very sensitive for picking up tuberculomas in such cases.

Latent TB

Offer Mantoux testing to the household contacts and close contacts of the person with active TB (aged 5 and older). If the Mantoux is positive or if results are unreliable, as can be the case with BCG-vaccinated persons consider interferon gamma testing (T-spot TB Test). If Mantoux is inconclusive, the patient should be referred to a TB specialist. A similar approach should be used for new entrant TB screening.

QuantiFERON-TB Gold (QFT-G) Test & QuantiFERON-TB Gold in Tube (QFT-GIT) Test

Both of these tests have replaced the QuantiFERON-TB (QFT) Test. It is an interferon gamma release assay (IGRA) and measures a component of cell-mediated immune reactivity to mycobacterium tuberculosis. In QFT-G test a blood sample is mixed with antigens (2 Mycobacterium TB protein) and a control. Mixtures are incubated for 16 to 24 hours and then the amount of interferon gamma is measured. If the patient is infected with mycobacterium TB, white blood cells will release interferon gamma when they come in contact with TB antigens. Clinical features, chest X-ray and sputum/ tissue smear and culture for AFB are needed to differentiate between active and latent TB.

Its advantages over tuberculous skin testing are:

  • This test requires a single patient visit to draw a sample
  • Results are available within 24 hours
  • Results are not dependent on reader
  • It is not affected by prior BCG vaccination

Its limitations/ disadvantages include:

  • The blood sample must be processed within 12 hours of collection (while white cells are still viable)
  • There is limited data for use of QFT-G in immune-compromised patients, children under 17 years of age and persons recently exposed to MTB
  • False positive results may occur with Mycobacterium szulgai, kansasii and marinum infection

QFT-GIT is a modification of QFT-G test. It consists of 3 blood collection tubes containing: 1) no antigen, 2) TB antigen, 3) mitogen. These tubes must be transferred to an incubator within 16 hours of blood collection. Interferon gamma detection is then carried out via ELISA. Its specificity varies from 96-99% and sensitivity is as high as 92% in individuals with active disease.

T-Spot TB Test

It is a type of ELISPOT assay, developed by the researchers at the University of Oxford in England. It counts the number of effector T-cells in the blood that produce gamma interferon so gives an overall measurement of antigen load on immune system. As it does not depend upon production of antibody or recoverable pathogen, it can be used to detect latent TB and it is much faster. In one study it was found that its sensitivity is 97.2% 20.

Treatment Of Tuberculosis (Caused By Mycobacterium Tuberculosis)

Active TB will kill 2 of every 3 people affected, if left untreated. Disseminated TB is 100% fatal if untreated. For the treatment of TB, drugs are used in combination and never singly. Patients require regular supervision of their therapy during treatment to monitor compliance and side effects of medications. Treatment of atypical mycobacterial infections should be under the care of specialized units as this needs special care and drug regimens are complicated. Drugs for treatment of TB are divided into 3 categories:

1st Line Drugs: 1stline anti-TB drugs are very effective against TB. There are 5 first line drugs. All have 3 letter and 1 letter standard abbreviations.

  • Rifampicin is RMP or R
  • Isoniazid is INH or H
  • Ethambutol is EMB or E
  • Pyrazinamide is PZA or Z
  • Streptomycin is STM or S

Using a single drug usually results in treatment failure and drug resistant strains 21. The frequency of Mycobacterium tuberculosis developing spontaneous mutations conferring resistance to an individual drug is well known: 1 in 107for EMB, 1 in 108 for STM & INH, 1 in 1010 for RMP 22. A patient with extensive pulmonary TB usually has 1012bacteria in his body and hence will have about 105 EMB-resistant bacteria, 104 STM-resistant bacteria, 104 INH resistant bacteria and 102 RMP resistant bacteria. Drug-resistant tuberculosis occurs when drug-resistant bacilli outgrow drug-susceptible bacilli. Mutations can produce bacilli resistant to any of the anti-tuberculosis drugs, although they occur more frequently for some drugs than others. The average mutation rate in M. tuberculosis for resistance to isoniazid is 2.56 x 10-8mutations per bacterium per generation; for rifampicin, 2.25 x 10-10; for ethambutol, 1.0 x 10-7; and for streptomycin, 2.95 x 10-8. The mutation rate for resistance to more than one drug is calculated by multiplying the rates for the individual drugs. For example, the mutation rate for resistance to both isoniazid and rifampicin is approximately 2.56 x 10-8 times 2.25 x 10-10, or 5.76 x 10-18. The expected ratio of resistant bacilli to susceptible bacilli in an unselected population of M. tuberculosis is about 1:106 each for isoniazid and streptomycin and 1:108 for rifampicin. Mutants resistant to both isoniazid and rifampicin should occur less than once in a population of 1014 bacilli. Pulmonary cavities contain about 107 to 109 bacilli; thus, they are likely to contain a small number of bacilli resistant to each of the anti-tuberculosis drugs but unlikely to contain bacilli resistant to two drugs simultaneously 23.

There are different regimens available for the treatment of TB. The initial 2 months of treatment (usually rifampicin based) is called Initial Phase or Intensive Phase Treatment which later leads to Continuation Phase Treatment. Initial intensive phase treatment is designed to kill actively growing bacteria. Drugs are listed using their single letter abbreviation and a prefix denotes the number of months a treatment has to be given and a subscript denotes intermittent dosage. For example; 2RHEZ/4RH3 = 2 months of initial phase treatment with Rifampicin, Isoniazid, Ethambutol, Pyrazinamide and 4 months continuation phase treatment with Rifampicin and Isoniazid given 3 times per week. If there is no subscript, it means the drugs are given daily.

Usual anti-TB regimens are:

  • 2RHEZ/4RH3 (in less endemic areas)
  • 2RHEZ/4RH (mostly practised, especially in non-endemic areas including UK); standard recommended regimen 24
  • 2RHEZ/7RH (in most endemic areas)
  • 2RHEZ/10RHE (in cases of disseminated, bone and CNS tuberculosis)

2nd Line Drugs 25 & 26: These are less effective than 1st line drugs, have more toxic side effects and are usually not available in most of the developing countries of the world. There are 6 classes of 2ndline anti-TB drugs:

  • Aminoglycosides: e.g., Amikacin (AMK) & Kanamycin (KM)
  • Polypeptides: e.g., Capreomycin, Viomycin
  • Fluoroquinolones: e.g., Ofloxacin, Ciprofloxacin (CIP), Levofloxacin, Moxifloxacin (MXF)
  • Thioamides: e.g., Ethionamide, Prothionamide
  • Cycloserine:
  • p-Aminosalicylic acid: (PAS or P)

3rd Line Drugs: These are drugs which may be useful, but are not on the WHO list of second line drugs. These are not as effective. 3rdline drugs include:

  • Rifabutin (this is an effective drug but is very expensive for developing countries, so it not included in WHO list). Occasionally this can be used for patients who are intolerant to or have bacterial resistance to Rifampicin.
  • Macrolides: Clarithromycin (CLR), Azithromycin
  • Linezolid: (LZD) not of proven efficacy
  • Thioacetazone (T)
  • Thioridazine
  • Arginine
  • Vitamin D
  • R207910: efficacy not proven

Indications of Steroids in the treatment of TB

Steroids should be used along with anti-TB drugs in following situations:

  • CNS TB (proven benefit)
  • TB pericarditis (proven benefit)
  • TB involving eye (definitely beneficial)
  • TB pleuritis (beneficial – 20-40mg tapered over 4-8 weeks)
  • Extremely advanced TB (beneficial)
  • TB in children (may be beneficial)
  • Miliary TB (beneficial)
  • Genitourinary TB (beneficial)
  • Laryngeal TB (may be beneficial – scanty evidence)
  • TB peritonitis (may be beneficial – scanty evidence)

Important Definitions / Terms 25, 27, 28, 29

New Case: A patient diagnosed as having TB who has never had anti-TB treatment before or had taken anti-TB treatment for less than 4 weeks.

Sputum Smear Positive Case of Pulmonary TB: A patient who has 2 out of 3 consecutive sputum samples positive for AFB.

Sputum Smear Negative Case of Pulmonary TB: A patient clinically and radiologically suspected to have pulmonary TB but with 3 consecutive sputum samples which are negative for AFB and is also culture negative for AFB.

Culture Positive Case of Pulmonary TB: A patient with 3 consecutive sputum smear samples which are negative for AFB but with at least 1 specimen positive for AFB in culture.

Short Course Therapy for TB: The short course therapy for treatment of TB includes 2RHEZ/4RH and also known as standard regimen. If PZA is not included in the regimen for treating TB, the course should be extended from 6 months to 9 months. If rifampicin is not included in treatment regimen then the length of course should be 18 months in total.

Treatment Failure: A TB patient is said to have treatment failure if they remain smear or culture positive while on treatment at the 5th month or if they were initially smear positive, became negative but then reverted to positive at the end of 5months of treatment. Another scenario is that of a patient who was initially smear negative but then becomes smear positive after 2 months of treatment. Important things to note are:

  • Never add a single drug to a failing anti-TB regimen
  • Most cases are due to non-compliance
  • There is a high chance of Mycobacterium developing resistance to anti-TB drugs

Relapse of TB: A patient is said to have a relapse of TB if they were treated and declared cured but is again smear or culture positive; with the same organism. If the patient gets an infection with a new MTB then they are deemed to be a new case. Because genetic analysis of the infecting MTB is required to determine if re-infection is with the same organism or a new one, it is difficult to accurately diagnose TB relapse.

TB Default Case: A TB patient who completed 1 month of anti-TB treatment, stopped the treatment, and then returns for TB treatment over 2 months after treatment was first initiated. If the patient returns within 2 months of initial treatment, then his/ her initial regimen should be continued.

Re-treatment Regimen: A patient should be a given re-treatment regimen when they relapse or are a TB default case. In highly endemic areas for TB, most authorities prefer an initial intensive phase with 5 drugs for 3 months (2 months RHEZS and 1 month RHEZ).

Chronic Case of TB: A patient is said to be a chronic case of TB, who remains sputum smear positive after 1 re-treatment course. Such patients invariably have drug resistant TB.

Extra-pulmonary TB: TB involving organs other than lungs is called extra-pulmonary TB. For the purpose of treatment and understanding, TB of the central nervous system is excluded from this classification.

Pulmonary TB: Tuberculosis involving lungs is called pulmonary TB.

Respiratory TB: TB involving lungs, pleural cavity, mediastinal lymph nodes or larynx.

CNS Tuberculosis: TB can involve the meninges, brain & spinal cord. It is called TB-meningitis, cerebritis & myelitis respectively. Standard treatment is for 12 months and steroids are mandatory. INH & PZA have 100% penetration into CSF.

Miliary Tuberculosis: This a complication of 1–3% of all TB cases. Tuberculosis involving 2 or more organs/ systems of the body is called disseminated TB or miliary TB. It is also called tuberculosis cutis acuta generalisata and tuberculosis cutis disseminate. It is a form of tuberculosis that is characterized by the wide dissemination and by the tiny size of the TB lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest X-ray of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including the lungs, liver, and spleen.

MDR-TB: Multi-drug Resistant TB (MDR-TB) is defined as TB caused by mycobacterium tuberculosis resistant to isoniazid and rifampicin. The diagnosis and appropriate treatment of MDR-TB is still a major challenge.

XDR-TB: Extensively-drug Resistant TB (XDR-TB) is defined as TB caused by mycobacterium tuberculosis resistant to isoniazid, rifampicin, quinolones and any 1 of 3 injectables: kanamycin, capreomycin or amikacin.

Treatment Categories of TB Patients:

There are four treatment categories of TB patients for details see table 1.

Table 1

Treatment Category Type of TB Patient
Category I New sputum smear +ve or 
Smear –ve pulmonary TB cases with extensive parenchymal involvement
New severe extra-pulmonary TB cases
Category II TB relapse cases
TB treatment failure cases
Category III Non-severe sputum smear –ve pulmonary TB
Non-severe extra-pulmonary TB
Category IV Chronic TB case

Directly Observed Treatment Short-course (DOTS):

In this programme a trained person observes the patient swallowing tablets for preferably the whole course of treatment or at least the initial 2 months of treatment. Daily or thrice weekly dosages are recommended but twice weekly dosages are not recommended because of the risk of omitting (by mistake or by chance) one dose. This would result in once weekly dose and it is not acceptable. WHO recommends the DOTS strategy in an attempt to control tuberculosis. There are 5 main points of action:

  • Government commitment to control TB
  • Diagnosis based on sputum smear microscopy tests done on patients who actively report TB symptoms
  • Direct observation short course chemotherapy treatment
  • Definite supply of drugs
  • Standardized reporting and recording of cases and treatment outcomes

DOTS-Plus:

WHO extended the DOTS programme in 1998 to include treatment of MDR-TB and this is called DOTS-Plus. It requires the capacity for drug susceptibility testing and provision of 2nd line anti-TB drugs with facilities for identification and drug sensitivities.

Latent TB Infection (LTBI):

A patient is said to have LTBI when he is infected with MTB but does not have any symptoms and signs suggestive of active TB and has a normal chest X-ray. Such patients are non-infectious but 10% of these persons go on to develop active TB in their life at a later stage. They have positive tuberculin skin test and positive Interferon Gamma Release Assay (IGRA) tests (e.g. T-SPOT.TB test, QuantiFERON-TB Gold &QuantiFERON-TB Gold-in tube tests). There are different regimens for treatment of LTBI, commonly used are the following:

  • 9H; 9 months INH (gold standard – only practised in USA)
  • 6H; 6 months INH
  • 3RH; 3 months INH + RMP (recommended in UK)

Common Causes Of Rising Burden Of Tuberculosis

  • The following are a few causes of rising burden of TB globally:
  • Non-compliance with medication
  • Presence of drug resistant strains of mycobacteria
  • Faulty regimens
  • Un-diagnosed cases
  • Under-diagnosed cases
  • Lack of newer, more effective anti TB medication.

Role Of Pcr In The Diagnosis Of Tuberculosis

There have been a number of studies regarding the role of PCR in the diagnosis of TB. They show that it has a high sensitivity and specificity but gold standard is still tissue smear and culture for AFB. In certain scenarios PCR of different tissue samples (pulmonary or extra-pulmonary) urine, CSF, sputum and blood can be useful and can also tell us about mycobacterial rifampicin resistance.

Role Of Physicians In Prevention & Control Of Tuberculosis In Relation To Airtravel 30

  • Inform all patients with infectious TB that they must not travel by air on a flight exceeding 8 hours until they have completed at least 2 weeks of adequate therapy.
  • Inform all patients with MDR-TB and XDR-TB that they must not travel by air until they are culture-negative.
  • Advise patients with TB who undertake unavoidable air travel of less than 8 hours’ duration to wear a surgical mask or to otherwise keep the nose and mouth covered when speaking or coughing during the flight. This recommendation should be applied on a case-by-case basis and only with the agreement of the airline(s) involved and the public health authorities at departure and arrival.
  • Inform relevant health authorities of the intention of a patient with infectious TB to travel against medical advice.
  • Inform relevant health authorities when a patient with infectious TB has a recent history of air travel (travel within 3 months).

Side Effects Of Medications Used For Treatment Of Tuberculosis 31, 32, 33, 34

Patients who are on treatment for TB should be monitored regularly for any signs of medication toxicity. This may include blood tests in addition to clinical examination. Common side effects of the routinely used 4 anti-TB medications (INH, rifampicin, Ethambutol & PZA) are as follows:

Hepatotoxicity: INH, PZA and rifampicin are known to cause liver toxicity. Ethambutol is a safer medication in patients with known liver problems. INH is contraindicated in patients with active hepatitis and end stage liver diseases. 20% patients can have an asymptomatic rise in AST concentration in the first 3 months of therapy. Symptoms of liver toxicity include anorexia, nausea, vomiting, dark urine, jaundice, fever, persistent fatigue, abdominal pain especially in the right upper quadrant. Routine base line LFTs are recommended prior to starting treatment. After that they should be repeated at least once a month and more frequently in those who are at risk of developing hepatotoxicity. Patients at increased risk of hepatotoxicity include:

  • HIV positive
  • Pregnant or post-partum (3 months after delivery)
  • History of or at risk of chronic liver disease (daily use of alcohol, IV drug users, hepatitis, liver cirrhosis)
  • Patients taking any other medication which have potential hepatotoxic side effects
  • The risk of hepatotoxicity increases with age (> 35 years old)

Suspect drug induced liver injury if there is AST/ ALT rise > 3 times base line with symptoms or > 5 times in the absence of symptoms, or disproportionate rise in ALP and total bilirubin. In such a situation:

  • Stop hepatotoxic anti-TB medications (INH, rifampicin and PZA) immediately
  • Admit the patient to hospital
  • Carry out serological tests for Hepatitis A, B,  and C (particularly in those who are at risk for hepatitis)
  • Look for other causes (hepatotoxic medications, high alcohol consumption)
  • In acutely ill smear or culture positive patients start liver friendly medications i.e. Ethambutol Quinolones, and Streptomycin, until the cause for hepatotoxicity is identified.
  • Re-challenge: Once LFTs are normal (or < two times the upper normal limit) start with Ethambutol and add INH 1st. If LFTs do not rise after 1 week add Rifampicin. Next add PZA if there is no rise in LFTs after 1 week of adding Rifampicin. If at any point LFTs increase or symptoms recur, stop the last added drug – as this is the culprit drug.

Gastro-intestinal (GI) upset: GI upset is quiet common with anti-TB medications and usually occur in the first few weeks of therapy. Symptoms usually are nausea, vomiting, anorexia, abdominal pain. In such a case recommend good hydration, change the timing of medication (advise to take with a light snack and at bed time) and also check LFTs for possible hepatitis. Aluminium salt containing antacids can reduce bioavailability of INH, so avoid them 1 hour before and 2 hours after INH administration.

Rash: All anti-TB medications can cause a skin rash. Management is based on severity:

  • Mild rash or itching: administer anti-histamines 30 minutes prior to anti-TB medications and continue with the therapy. If no improvement, add prednisolone 40mg/day and gradually taper down when the rash clears.
  • Petechial rash: Red pinpoint sized dots under the skin due to leakage from capillaries – suspect rifampicin hypersensitivity. Monitor LFTs and full blood count. If platelet count is below normal (base line), stop rifampicin and do not restart it.
  • Erythematous rash with fever: and/ or mucous membrane involvement; stop all anti-TB medications immediately and hospitalize the patient. Rule out anaphylaxis (angio-oedema, swollen tongue, throat, stridor, wheezing, flushed face, hypotension) and Stevens-Johnson Syndrome (systemic shedding of mucous membranes and fever). If situation does not permit to stop TB medication then try 3 new drugs i.e. aminoglycoside and 2 oral agents from second line. Once the rash has settled, can re-introduce first line TB medications one by one every 2-3 days, 1st rifampicin, then INH, then PZA and then Ethambutol. While re-introduction, monitor the signs and symptoms of rash, if rash recurs at any point remove the last agent added.

Peripheral neuropathy: signs and symptoms include numbness and tingling in feet and hands, increased sensitivity to touch and stabbing pain. INH can cause peripheral neuropathy. It is more common in malnourished people, diabetes, HIV, renal failure, alcoholism, pregnancy and in breast feeding women. Prevention is the key; prophylaxis is with Pyridoxine (vitamin B6) 10mg/ 100mg INH (normally 25 – 50mg) per week is used in high risk patients.

Optic neuritis: the main agent responsible for this is Ethambutol. It is dose related and gets more intense if treatment is continued. Signs and symptoms are difficulty in reading road signs, decreased red-green colour discrimination, blurring or vision, and colour blindness. These can be unilateral or bilateral. Ethambutol is not recommended in children <5 years of age as visual changes are difficult to monitor. Visual acuity and colour blindness tests are recommended at baseline and also on a monthly basis. Fluctuations of 1 or 2 lines on the Snellen chart  is considerable and Ethambutol must be stopped. More than 10% visual loss is considered significant.

Fatigue: INH can cause fatigue and in such situations patients should take the medication at bedtime. If it continues, check LFTs to look for hepatotoxicity.

Flu-like symptoms/joint aches and pains: These are usually seen with Rifampicin and treatment is symptomatic.

Drug-induced lupus: It is seen with INH and blood tests should be done to differentiate it from SLE. It can be managed with steroids while the patient is taking INH.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None Declared
Details of Authors: 
AMER SALEEM, BSc, MBBS, MCPS, FCPS, Specialist Registrar Chest Medicine, Bedford Hospital NHS Trust, Bedford, UK. MOHAMMED AZHER, MBBS, FRCP, Consultant in Chest Medicine, Bedford Hospital NHS Trust, Bedford, UK.
Corresponding Author Details: 
DR MOHAMMED AZHER,Consultant in Chest Medicine, Bedford Hospital NHS Trust, Bedford, UK.
Corresponding Author Email: 
m_azher@gmail.com
References
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  4. Y. A. Al-Sharrah. The Arab Tradition of Medical Education and its Relationship with the European Tradition. Prospects 33 (4), Springer.
  5. David W. Tschanz. Arab Roots of European Medicine. Heart Views 4 (2).
  6. Zur Pathogenie der Impetigines. Auszug aus einer brieflichen Mitteilung an den Herausgeber. [Müller’s] Archiv für Anatomie, Physiologie und wissenschaftliche Medicin. 1839, page 82.
  7. Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 516–522. ISBN 978-1-4160-2973-1.
  8. World Health Organization (WHO). Tuberculosis Fact sheet N°104 - Global and regional incidence. March 2006.
  9. Tuberculosis in Europe and North America, 1800–1922. The Harvard University Library, Open Collections Program: Contagion.
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  11. Cole E, Cook C. Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies. Am J Infect Control 26 (4): 453–64.
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  13. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 353 (9151): 444–9.
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  22. David HL. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Applied Microbiology 20 (5): 810–4.
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Risk of Development of Osteoporosis due to Depression in the Elderly Individuals: Review Article

Authors
Umesh Kumar Vyas
Article Citation and PDF Link
BJMP 2013;6(2):a612

Introduction:

Fifteen percent of elderly individuals report clinically significant depression due to variety of reasons. Osteoporosis is a disorder of bone metabolism which can be caused by multiple factors. The elder population has multiple risk factors for development of low Bone Mineral Density (BMD). Data supports that SSRI causes low BMD. There are numerous mediating processes, factors and causes that may contribute to relationship between depression and low BMD, therefore it has been suggested that depression may be an unrecognized risk factor for development of osteoporosis in this patient population.

Low BMD is a common condition among the elder population; prevalence of osteopenia and osteoporosis is expected to increase due to increasing elder population. Low BMD is associated with increased risk for debilitating fractures, particularly hip, vertebrae and distal forearm. There is a growing body of evidence that depression impact the risk for fractures in the older population.

Most studies support that depression is associated with increased risk for both low BMD and fractures. There are many risk factors for low BMD, but some are unalterable. Therefore it is crucial to identify modifiable risk factors to reduce the public health burden of osteopenia, osteoporosis and fractures, and complications associated with them.

Objective:

A literature review was performed to extract evidence and to evaluate risk of Osteoporosis in depression.

Educational Objectives:

At the conclusion of this article, the reviewer will be able to understand,

  1. The risk of development of osteoporosis,
  2. Need for close monitoring and early assessment of risk,
  3. Need for prophylactic treatment to avoid complications due to development of osteoporosis.

Method:

Pubmed.gov was searched by using pre-determined key word.

Key words:

“Depression AND Osteoporosis"

Background:

Osteoporosis was first recognized as a disorder of bone metabolism in 1947 by Albright. It is the most common degenerative disease in developed countries; it is characterized by low bone mineral density (BMD), causing bone fragility and increased fracture incidence. Over past quarter century, it has emerged as a major public health problem in the Western world, prevalence of osteopenia and osteoporosis is expected to increase dramatically in the next 50 years as the population pyramid shift toward old age. In United States alone, app 10 million individuals over age of 50 have osteoporosis. In addition, 33.6 million Americans in this age group have osteopenia (i.e. a decrease in bone mineral density [BMD] that precedes osteoporosis and its potential complications later in life). The estimated annual fracture rate due to an underlying bone disease is 1.5 million. These fractures lead to pain, skeletal mutilation, disability, loss of independence and increased mortality.1

Low BMD has been shown to be major risk factor for debilitating bone fractures, particularly of the hip, vertebrae and distal forearm.2 The established risk factors for osteoporosis include increasing age, female sex, oestrogen deficiency, glucocorticoid therapy and other medications, smoking, alcohol use, inactivity, and low calcium intake.3 Many prominent risk factors are unalterable, it is therefore crucial to identify modifiable risk factors in order to reduce the public health burden of osteopenia, osteoporosis and the fractures associated with them. In the USA, depression is a common disorder that affects 5 to 9% of women and 1 to 2% men.4 It ranks second only to hypertension as the most common chronic illness encountered in general medical practice.5 This disorder carries a considerable risk of death and is associated with a two to three fold increase in all-cause of non-suicide-related death.6 Fifteen percent of elderly individuals report clinically significant depression.

Definition of Osteopenia and Osteoporosis:

Osteopenia is a condition where bone mineral density is lower than normal, more specifically; it is defined as BMD T-Score between -1.0 and -2.5. It is considered to be precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis. Osteoporosis causes bones to become weak and brittle – so brittle that a fall or even mild stresses like bending over or coughing can cause a fracture.

Osteoporosis-related fractures most commonly occur in the hip, wrist or spine. Bone is a living tissue, which is constantly being absorbed and replaced. Osteoporosis occurs when the creation of new bone does not keep up with the removal of old bone. Osteoporosis affects men and women of all races, but White and Asian women especially those who are past menopause are at highest risk. Medications, dietary supplements and weight-bearing exercise can help strengthen bones.

Literature evidence:

Current evidence supports a bidirectional link between major depressive disorders (MDD), several other mood disorders, and various medical conditions such as osteoporosis and cardiovascular disease.7 A significant association was found between BMD and depressive symptoms after adjustment for osteoporosis risk factors. In Caucasians, depressive symptoms were associated with both osteoporotic and osteopenic levels of BMD.8 A meta-analysis reported BMD is lower in depressed than non-depressed subjects. The association between depression and BMD is stronger in women than men, and in premenopausal than postmenopausal women. Only women psychiatrically diagnosed for MDD display significantly low BMD; women diagnosed by self-rating questionnaires do not.9 Depression is a significant risk factor for fracture in older women.14 Numerous studies have examined association between antidepressant use (both SSRI and TCA) and fracture risk. The majority have found that use of these medications, regardless of class is associated with increased risk of fracture.10 Animal studies have also indicated that serotonin may influence bone mass, particularly during stages of bone growth.11, 12

Daily SSRI (Table 1) use in adults 50 years and older remained associated with a 2-fold increased risk of clinical fragility after adjustment for potential covariates. Depression and fragility fractures are common in this age group, and the elevated risk attributed to daily SSRI use may have important public health consequences.15 (Figure 1). SSRI may increase fracture risk because of their effect on bone physiology and on the risk of falling. Functional serotonin receptors and transporters have been localized to bone, while the administration of SSRI decreases bone mass and strength in growing mice. SSRI function by inhibiting the serotonin transporter. Functional serotonin transporters in osteoblasts, osteoclasts and osteocytes raises the possibility that serotonin transporters may play a role in bone metabolism and those medications that affect this transporter system may also affect bone metabolism. Use of SSRI is associated with an increased rate of bone loss at the hip in this cohort of older women; use of a TCA was not similarly associated with increased rates of hip bone loss in our cohort.16 In men, BMD was lower among those reporting current SSRI use, but not among user of other antidepressants.17 Meta-analysis proved that MDD is associated with low BMD and should therefore be considered a risk factor for osteoporosis. BMD in subjects with MDD was 4.7% lower at the AP spine, 3.5% lower at the total femur, and 7.3% lower at the femur neck as compared to healthy controls.18 NIH meta-analysis concluded MDD was associated with lower BMD at the AP spine, femoral neck and total femur. The deficits in BMD in subjects with depression are of clinical significance and likely to increase fracture risk over the lifetime of these subjects.18

Table 1: List of SSRI (Selective Serotonin Reuptake Inhibitor) and dosages range:

Generic Name Brand Name Dose range
Citalopram Celexa 10 to 40 mg
Escitalopram Lexapro 10 to 20 mg
Fluoxetine Prozac 20 to 80 mg
Fluvoxamine Luvox 50 to 300 mg
Paroxetine Paxil 10 to 40 mg
Sertraline Zoloft 50 to 200 mg

Figure 1: Fracture-free survival by Selective Serotonin Reuptake Inhibitors (SSRI) use

Potential mechanisms of bone loss in depression:

Depression is associated with alterations of the hypothalamic-pituitary-adrenal (HPA) axis at multiple levels, including altered secretion of hypothalamic corticotrophin-releasing hormone (CRH), as indicated by CRH levels in the cerebrospinal fluid, and change in the set point threshold for negative feedback; these changes generally result into hyper-cortisolism.

Pro-inflammatory cytokines are increased in depression and IL-6 is a potent activator of the osteoclast. Oestrogen deficiency in women and androgen deficiency in men may affect bone mass and there is at least theoretical evidence for decreased sexual hormones in both genders during the acute phases of depression. Serotonin transporter receptors are present on the osteoblast and use of antidepressants has been associated with more fractures. Commonly accepted life style risk factors for osteoporosis include smoking, inadequate calcium intake, excessive alcohol intake and physical inactivity. 

There are three pathophysiologic pathways leading to low BMD.13 (Figure 2):

  1. Inadequate acquisition of bone mass early in life
  2. Elevated resorption of bone mass later in life, and
  3. Inefficient bone formation during continuous bone remodelling

These pathways are interdependent and the relative importance of each mechanism changes over development and varies by sex.

Figure 2: Pathways linking depression, low bone mneral density and fracture. 13

Bottom line:

Current available evidence supports that there is increase of development of osteoporosis due to various factors, pathways and medications used in treatment of depression.

Conclusion:

Major depressive disorder is an important but still unrecognized risk factor for osteoporosis. Depression should be considered as an important risk factor for osteoporosis. Depression is associated with low BMD, with a substantially greater BMD decrease in depressed women and in cases of clinical depression. These patients need close monitoring, early assessment of risk and preventive measures to avoid complications. Premenopausal women with major depression should undergo DXA screening. Similar recommendation may be made for postmenopausal women with depression especially in the presence of one or more known risk factors for development of osteoporosis.

Once a diagnosis of osteoporosis is made in subjects with major depression, DXA measurements should be performed with a frequency based on the current WHO algorithm; this model takes into account the presence of other risk factors and age of the subjects.

Clinical Point:

Periodic BMD measurements and anti-osteoporotic prophylactic and curative measures are strongly advocated for these patients.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
UMESH KUMAR VYAS, M.D., Chair of Department of Psychiatry, Medical Director of In-Patient Behavioral Health Unit, Regional Medical Director of Sleep Disorders Center, Psychiatrist and Sleep Disorders Specialist, Mayo Clinic Health System, Mankato, MN, USA; Adjunct Clinical Assistant Professor, Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN, USA; Adjunct Assistant Professor of Psychiatry and Sleep Medicine, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, USA.
Corresponding Author Details: 
UMESH KUMAR VYAS, M.D., 1025 Marsh Street, P O Box 8673, Mankato, MN, 56002-8673, USA.
Corresponding Author Email: 
Vyas.umesh@mayo.edu
References
References: 
  1. US Department of Health and Human Services: Office of the Surgeon General: Bone Health and Osteoporosis: 2004; A Report of the Surgeon General. Available at http://www.surgeongeneral.gov/library/bonehealth/. Accessed December 1, 2008.
  2. Cummings SR, Black DM, Nevitt MC, et al. The study of osteoporotic fractures research group. Appendicular bone density and age predict hip fracture in women. JAMA, 1990; 263(5):665-668
  3. Ross PD. Osteoporosis. Frequency, consequences, and risk factors. Arch Intern Med, 1996; 156(13):1399-1411
  4. Robins LN, Helzer JE, Weissman MM, et al. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry, 1984; 41(10):949-958
  5. Wells KB, Stewart A, Hays RD et al. The functioning and well-being of depressed patients: results from the Medical Outcomes Study. JAMA, 1989; 262(7):914-919
  6. Zheng D, Macera CA, Croft JB et al. Major depression and all-cause mortality among white adults in the United States. Ann Epidemiol, 1997; 7(3):213-218
  7. Evans DL, Charney DS, Lewis L et al. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry, 2005; 58:175-189
  8. John Robbins, Calvin Hirsch, Rachel Whitmer et al. The association of bone mineral density and depression in an older population J Am Geriatric Soc, 2001; 49(6):732-736
  9. Itai A. Bab, Raz Yirmiya. Depression and bone mass Ann N Y Acad Sci, 2010; 1192:170-175
  10. Takkouche B. Montes-Martinez A, Gill S et al. Psychotropic medications and the risk of fracture: a meta-analysis. Drug safety, 2007; 30:171-184
  11. Bliziotes M, Gunness M, Eshleman A et al. The role of dopamine and serotonin in regulating bone mass and strength; studies on dopamine and serotonin transporter null mice. J Musculoskele Neuronal Interact, 2002; 2:291-295
  12. Warden S, Robling A, Sanders M et al. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology, 2005; 146:685-693
  13. B Mezuk, W. W. Eaton, S. H. Golden. Depression and osteoporosis: epidemiology and potential mediating pathways. International Osteoporosis Foundation and National Osteoporosis Foundation, 2007
  14. M A Whooley, K E Kip, J A Cauley et al. Depression, falls, and risk of fracture in older women, Arch Intern Med, 1999; 159:484-490
  15. J B Richards, A Papaioannou, J D Adachi et al. Effect of selective reuptake inhibitors of the risk of fracture. Arch Intern Med, 2007; 167:188-194
  16. S J Diem, T L Blackwell, K L Stone et al. Use of antidepressants and rates of hip bone loss in older women. Arch Intern Med, 2007; 167:1240-1245
  17. E M Haney, B K S Chan, S J Diem et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med, 2007; 167:1246-1251
  18. G. Cizza, S. Primma, M. Coyle et al. Depression and Osteoporosis: A research synthesis with Meta-analysis. Horm Metab Res, 2010; 42(7):467-482

Management of Painful Peripheral Diabetic Neuropathy

Authors
Namita Arora and G Niraj
Article Citation and PDF Link
BJMP 2013;6(1):a606
Abstract / Summary
Abstract: 
Diabetes Mellitus is an endocrine disorder which causes metabolic disturbance producing a state of hyperglycaemia. Hyperglycaemia adversely affects cardiovascular, renal, nervous and visual systems. The importance of good glycaemic control in these patients has been emphasised in literature to reduce the end organ damage. Diabetes can cause autonomic and peripheral neuropathy. The autonomic neuropathy can affect the cardiovascular, genitourinary and gastrointestinal systems. Peripheral neuropathy can cause acute and chronic sensorimotor neuropathy, which can cause significant morbidity in these patients affecting their daily activities and quality of life. It can be challenging to treat them because the pain can be resistant to the medication and the effective medication can be associated with adverse effects which the patients may find difficult to tolerate. It is very important to increase the dose of the drugs to their highest effective dose (within the therapeutic range of that drug) for each patient with a balance of the side effects caused by that drug in that patient. These patients often need more than one drug to provide adequate pain relief. There are guidelines and recommendations available to help the clinicians to use appropriate combination of available treatment options.

Epidemiology:

The WHO estimated that 171 million people had diabetes in the year 2000 and predicted this number to increase to 366 million in the year 2030. Given the increasing prevalence of obesity it is likely that these figures provide an underestimate of future diabetes prevalence1. Peripheral diabetic neuropathy (PDN) may be present in 60 to 65% diabetic patients, with 11% patients of diabetic neuropathy complaining of pain. The management of this condition can be particularly challenging as these patients may not get good response to the medications used for the treatment and the medications used are associated with side effects which the patients may find difficult to tolerate.

Pathophysiology:

Pathophysiology of PDN is complex and incompletely understood. Both peripheral and central processes contribute to the chronic neuropathic pain in diabetes.  Peripherally at the molecular level due to hyperglycaemia, glycosylated end products are generated, which deposit around the nerve fibres causing demyelination, axonal degeneration and reduction in nerve conduction velocity. Deposition of glycosylated end products around the capillary basement membrane causes basement membrane thickening and capillary endothelial damage, which in association with a hypercoaguable state causes peripheral arterial disease. The peripheral arterial disease leads to neuronal ischemia which worsens nerve damage. There also occurs depletion of NADPH by activation of NADPH oxidase causing increased oxidative stress and generation of oxidative free radicals which aggravate the nerve damage. Calcium and sodium channel dysfunction, changes in receptor expression are the other peripheral processes which cause further neuronal tissue injury. The nerve damage can cause neuronal hyperexcitability. Neurotropic factors are required for nerve regeneration. In diabetes there occurs a low level of both nerve growth factors and insulin-like growth factors resulting in impaired neuronal regeneration. This can lead to peripheral hyperexcitability. Central sensitization is cause by increased excitability at the synapse, which recruits several sub-threshold inputs and amplifies noxious and non-noxious stimuli. Loss of inhibitory interneurons, growth of non-damaged touch fibres into the territory of damaged pain pathways, increased concentration of neurotransmitters and wind up caused by NMDA receptors are responsible for central sensitization at the level of dorsal horn in the spinal cord2.

Clinical Presentation:

Chronic sensorimotor distal polyneuropathy is the most common type of diabetic neuropathy. Acute sensorimotor neuropathy is rare and is usually associated with diabetic ketoacidosis and acute neuritis caused by hyperglycaemia. Autonomic neuropathy is common and often under reported. It can affect cardiovascular, gastrointestinal and genitourinary system. The other presentations can be cranial neuropathies, thoraco-abdominal neuropathies or peripheral mononeuropathies involving median, ulnar, radial, femoral, lateral cutaneous nerve of the thigh or common peritoneal nerve.

The patients usually complain of one or more of the following symptoms. They can have a chronic continuous or intermittent pain described as burning, aching, crushing, cramping or gnawing pain. The pain can be associated with numbness. They can have brief abnormal stimulus evoked pain like allodynia or hyperalgesia. Some patients also complain of brief lancinating pains described as electrical or lightening pains which can be spontaneous or evoked. The symptoms typically start in the toes and feet and ascend in the lower limb over years and are worse at night. Diabetic distal polyneuropathy is typically described in glove and stocking distribution but the upper limb involvement is rare. On examination there can be paradoxically reduced sensation to light touch and pin prick in the area of pain. Examination can also show features of allodynia (pain caused by a stimulus that does not normally cause pain), hyperalgesia (pain of abnormal severity in response to a stimulus that normally produces pain), hyperpathia (painful reaction to a repetitive stimulus associated with increased threshold to pain), dysaesthesia (unpleasant abnormal sensation as numbness, pins and needles or burning), paraesthesia (abnormal sensation which is not unpleasant) or evoke electric shock like pains. There can be features of peripheral autonomic neuropathy including vasomotor changes like colour changes of feet which can be red, pale or cyanotic and temperature changes like warm or cold feet. With autonomic neuropathy there can also occur trophic changes which includes dry skin, callouses in pressure areas and abnormal hair and nail growth and sudomotor changes involving swollen feet with increased or decreased sweating. Mechanical allodynia is the most common type of allodynia, but there can be thermal allodynia described as cold or warmth allodynia. Patient often describes cold allodynia as the pain getting worse in cold weather and warmth allodynia can make the patient keep the effected limb cool by using fan or ice bags. There can be reduced joint position sense, reduced vibration sense, reduced temperature sensation and reduced ankle jerks.

Diagnosis:

The diagnosis of PDN can be made by clinical tests using pinprick, temperature and vibration perception (using a 128-Hz tuning fork). The feet should be examined for ulcers, calluses and deformities. Combinations of more than one test have >87% sensitivity in detecting PDN. Other forms of neuropathy, including chronic inflammatory demyelinating polyneuropathy, B12 deficiency, hypothyroidism and uraemia, occur more frequently in diabetes and should be ruled out. If required these patients should be referred to a neurologist for specialized examination and testing3.

Treatment Options:

US Food and Drug Administration has approved duloxetine in 2004 and pregabalin in 2005 for the treatment of painful DPN. Amitriptyline, nortriptyline and imipramine are not licenced for the treatment of neuropathic pain.

NICE clinical guidance on pharmacological management of neuropathic pain in adults in non-specialist settings as shown in Figure 1, recommends duloxetine as the first line treatment, which if contraindicated amitriptyline is suggested to be the first line. Second line treatment is amitriptyline or pregabalin. Pregabalin can be used alone or in combination with either amitriptyline or duloxetine, which if ineffective the patient should be referred to specialist pain services. While awaiting the referral tramadol can be started as the third line treatment. NICE also recommends that these patients should be reviewed to titrate the doses of the medication started, to assess the tolerability, adverse effects, pain reduction, improvement in daily activities, mood, quality of sleep and the overall improvement caused by the medication as reported by the patient4.

The Mayo clinic recommends5 the first tier of drugs for peripheral diabetic neuropathy are duloxetine, oxycodone CR, pregabalin and tricyclic antidepressants. The second tier of drugs iscarbamazepine, gabapentin, lamotrigine, tramadol and venlafaxine extended release. The topical agents suggested are capsaicin and lidocaine.

“Evidence Based guideline on treatment of Painful Diabetic Neuropathy”, was formulated by American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. A  systematic review of the literature between time period 1960 to 2008 was carried out. The review included the articles which looked at the efficacy of a given treatment either pharmacological or non-pharmacological to reduce pain and improve physical function and quality of life (QOL) in patients with PDN. They subsequently recommended that Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and quality of life6.

Non-pharmacological techniques:

Letícia et al. following their literature review on therapies used for PDN concluded that for non-pharmacological techniques like acupuncture, reiki, photic stimulation, electromagnetic stimulation of neural electrical stimulation, laser therapy, there is a lack of consensus about their effectiveness and there is scarce knowledge about them. They suggested new researches, including treatments for a longer period of time, with dosimetry control, and representative samples are necessary to discover the actual importance of these therapies for pain relief7.Spinal Cord Stimulators have however been shown to be effective and safe in severe resistant cases8,9.

Pharmacological Therapies:

Pregabalin: Pregabalin is a gamma aminobutyric acid analogue which binds to α2δ subunit of calcium channels and modulates them. Its starting dose is 150 mg/day with a maximum dose of 600 mg/day. As 98% of the drug is excreted unchanged in the urine, its dose is reduced in patients with renal impairment (creatinine clearance below 60 ml/min)10. A Cochrane Database Systematic Review in 2009 showed that Pregabalin was effective at daily doses of 300 mg, 450 mg and 600 mg, but a daily dose of 150 mg was generally ineffective. The NNT for at least 50% pain relief for 600 mg daily pregabalin dose compared with placebo was 5.0 (4.0 to 6.6) for PDN11.

Duloxetine: Duloxetine reduces the reuptake of serotonin and noradrenaline at the level of spinal cord, thereby potentiating the descending inhibitory pain pathways to reduce pain. It is started at a dose of 30 mg/day and its dose can be increased to 120mg/day10. Sultan et al. in their systematic review found that pain relief achieved with daily dose of 60 mg Duloxetine was comparable with daily dose of 120 mg of Duloxetine. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo was 5.8 as compared to NNT of 5.7 for daily dose of 120 mg of duloxetine. The side effects reported with Duloxetine were reduction in appetite, nausea, constipation and somnolence12. Systematic Reviews and cohort studies have shown that duloxetine provides overall savings in terms of better health outcomes and reduction in opioid use, in comparison to gabapentin and pregabalin, tricyclic antidepressants and venlafaxine, in pain caused by PDN13, 14.

Gabapetin: Gabapentin is structurally related to gamma-aminobutyric acid (GABA) but acts by binding to the alpha2-delta subunit of voltage-gated calcium channels and thereby reducing the transmission of neuronal signals. Gabapentin bioavailability is non-linear and it tends to decrease with increasing dose. Gabapentin is not bound to plasma proteins and has a high volume of distribution. It is eliminated unchanged by the kidneys so in elderly patients and in patients with impaired renal function, its dose must be reduced. Gabapentin can be started froma daily dose of 300 to 900 mg and the dose can be increased to a maximum daily dose of 3600 mg over 3 weeks period10.  Gabapentin provides good pain relief in about one third of patients when taken for neuropathic pain. Adverse events are frequent, but most of them are tolerable15.

Tricyclic Antidepressants (TCA): Amitriptyline and nortriptyline are the commonly used TCA for PDN. They may be used if there is no benefit from pregabalin or gabapentin and duloxetine. They may be used alone or in combination with pregabalin or gabapentin. In small RCTs, amitriptyline has been found to relieve pain better than placebo in patients with diabetic neuropathy10. Amitriptyline is a tricyclic antidepressant with marked anticholinergic and sedative properties. It increases the synaptic concentration of noradrenaline and serotonin in the CNS by inhibiting their re-uptake by the pre-synaptic neuronal membrane. For neuropathic pain it is started at 10-25 mg orally once daily at bed time initially and increased according to response to a maximum of 150 mg/day.

 TCA should be used with caution in patients with a history of epilepsy, cardiovascular disorders, deranged liver function, prostatic hypertrophy, history of urinary retention, blood dyscrasias, narrow-angle glaucoma or increased intra-ocular pressure. It’s other side-effects are agitation, confusion and postural hypotension in elderly patients10. Amitriptyline is the most studied TCA for DPN and has been compared with placebo, imipramine, and desipramine. Amitriptyline, when compared with placebo, reduced pain to a significant degree. Pain relief was evident as early as the second week of therapy, with greater pain relief noted at higher doses (at a mean dose of 90 mg). A decrease in pain was not associated with improvement in mood. A systematic review of the TCAs, including fewer than 200 patients, found no difference in efficacy between the agents16. Nortriptyline is associated with fewer adverse events than amitriptyline and therefore it should be preferred in elderly patients.

Opioids: The use of opioids in chronic neuropathic pain has been a topic of debate because of uncertainty about their effectiveness, the concerns about addiction problems, the loss of efficacy with their long term use due to development of tolerance with their long term use and the development of hyperalgesia associated with their use. Cochrane review of twenty-three trials of opiates was carried out. The short-term studies showed equivocal evidence, while the intermediate-term studies showed significant efficacy of opioids over placebo, in reducing the intensity of neuropathic pain. Adverse events of opioids were reported to be common but were not life threatening. The authors recommended the need for further randomized controlled trials to establish long-term efficacy, safety (including addiction potential) and effects on quality of life17.  In RCT Tramadol/Acetaminophen combination was shown to be associated with significantly greater improvement than placebo (p < or = 0.05) in reducing pain intensity, sleep interference and several measures of quality of life and mood18.  In another RCT, controlled release (CR) oxycodone was compared with placebo, CR oxycodone resulted in significantly lower mean daily pain, steady pain, brief pain, skin pain, total pain and disability. In this study the number needed to treat to obtain one patient with at least 50% pain relief is 2.619. Gabapentin and morphine combination in randomised controlled trial showed that the combination of the two drugs provided better analgesia at lower doses of each drug than either of the drugs used as a single agent20.

Capsaicin: Capsaicin is the active component of chilli peppers. Capsaicin works by releasing the pro-inflammatory mediators like substance P from the peripheral sensory nerve endings and thereby causes its depletion from the peripheral nerve. Pharmacological preparations of Capsaicin are available as 0.025% cream, 0.075% cream and 8% capsaicin patches10.  Repeated application of a low dose (0.075%) cream, or a single application of a high dose (8%) patch has been shown to provide a degree of pain relief in some patients with painful neuropathy. Common side effect includes local skin irritation which causes burning and stinging. It is often mild and transient but sometimes severe and not tolerated by the patients leading to withdrawal from treatment. Capsaicin rarely causes systemic adverse effects. Capsaicin can be used either alone or in combination with other treatment to provide useful pain relief in individuals with neuropathic pain21.

5% Lidocaine medicated plasters: A recent systematic review showed that 5% Lidocaine medicated plaster causes pain relief comparable to pain relief caused by amitriptyline, capsaicin, gabapentin and pregabalin in treatment of painful diabetic peripheral neuropathy. Lidocaine plaster being a topical agent may be associated with lesser clinically significant adverse events than the side effects of systemic agents. The need for further studies has been recommended by the reviewer as limited number and size of studies were included in the systematic review 22.

Conclusion:

The American Academy of Neurology, Mayo Clinic and NICE have both developed guidelines for treatment of peripheral diabetic neuropathic pain. There are several peripheral and central pathological mechanisms leading to the development of this condition and no single drug is available to target all these pathological mechanisms. Therefore often a combination of drugs is required for their management. Despite using a combination of medicines, managing these cases can be challenging. At the same time there is limited evidence on combination therapy in diabetic neuropathy and much work is required in this area. While using opioids for this condition the controversies over the use of opioids in non-malignant pain should be kept in mind and the advantages and disadvantages of using them should be discussed with the patients. Opioids should only be started with patient’s consensus. The treatment should be modified from the guidelines on an individual basis to achieve the optimal pain relief.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAMITA ARORA, FFPMRCA, FRCA, MD Anaesthesiology, Specialist Trainee 7, Cambridge University Hospitals NHS Foundation Trust, UK. G NIRAJ, FFPMRCA, FRCA, MD, Consultant in Anaesthesia & Pain Medicine, University Hospitals of Leicester NHS Trust, Honorary Clinical Lecturer Department of Health Sciences, University of Leicester, UK.
Corresponding Author Details: 
NAMITA ARORA, Specialist Trainee 7, Cambridge University Hospitals NHS Foundation Trust, UK.
Corresponding Author Email: 
namitaarora@hotmail.co.uk
References
References: 
  1. Wild S, Roglic G, Green A et al. Global prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53.
  2. Tavakoli M, Mojaddidi M, Fadavi H et al. Pathophysiology and treatment of painful diabetic neuropathy. Curr Pain Headache Rep. 2008;12(3):192-7.
  3. Boulton A, Vinik A, Arezzo J et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28(4):956-62.
  4. Tan T, Barry P, Reken S et al. Pharmacological management of neuropathic pain in non-specialist settings: summary of NICE guidance. BMJ. 2010;24;340:c1079.doi: 10.1136/bmj.c1079
  5. Argoff C, Backonja M, Belgrade M et al. Consensus Guidelines: treatment and planning options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 Suppl):S12-25.
  6. Bril V, England J, Franklin G et al. Evidence-based guideline: Treatment of painful diabetic neuropathy:  report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PMR. 2011;3(4): 345-52,352.e1-21. doi: 10.1016/j.pmrj.2011.03.008.
  7. Franco L, Ferreira Souza L, Costa Pessoa A et al. Nonpharmacologic therapies in diabetic neuropathic pain: a review. Acta Paul Enferm 2011;24(2):284-8.
  8. Tesfaye S, Watt J, Benbow S et al. Electric spinal cord stimulation for painful diabetic peripheral neuropathy. Lancet. 1996;21-28;348(9043):1698-701.
  9. Daousi C, Benbow S, MacFarlane I et al. Electrical spinal cord stimulation in the long term treatment of chronic painful diabetic neuropathy. Diabet Med. 2005; 22(4):393-8.
  10. http://www.medicines.org.uk/emc/
  11. Moore R, Straube S, Wiffen P et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;8;(3):CD007076. doi: 10.1002/14651858. CD007076.pub2
  12. Sultan A, Gaskell H, Derry S et al. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol. 2008;1;8:29. doi: 10.1186/1471-2377-8-29.
  13. Carlos F, Ramírez-Gámez J, Dueñas H et al. Economic evaluation of duloxetine as a first-line treatment for painful diabetic peripheral neuropathy in Mexico. J Med Econ. 2012;15(2):233-44.
  14. Wu N, Chen S, Hallett L et al. Opioid utilization and health-care costs among patients with  diabetic peripheral  neuropathic pain treated with duloxetine vs. other therapies. Pain Pract. 2011;11(1):48-56.
  15. Moore R, Wiffen P,  Derry S et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;16;(3):CD007938. doi:10.1002/14651858.CD007938.pub2
  16. McQuay H, Tramèr M, Nye B et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-27.
  17. Eisenberg E, McNicol E, Carr D. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;19;(3):CD006146.
  18. Freeman R, Raskin P, Hewitt D et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic neuropathy. Curr Med Res Opin. 2007;23(1):147-61.
  19. Watson C, Moulin D, Watt-Watson J et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1-2):71-8.
  20. Gilron I, Bailey J, Tu D et al. Morphine, Gabapentin, or their Combination for Neuropathic Pain. N Engl J Med. 2005;31;352(13):1324-34.
  21. Derry S, Lloyd R, Moore R et al. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009;7;(4):CD007393. doi: 10.1002/14651858.CD007393.pub2.
  22. Wolff R, Bala M, Westwood M et al. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): a systematic review. Swiss Med Wkly. 2010;29;140(21-22):297-306. doi: smw-12995.

Recent advances in the management of major obstetric haemorrhage

Authors
Rajashree Chavan and M Y Latoo
Article Citation and PDF Link
BJMP 2013;6(1):a604

Introduction

Major Obstetric haemorrhage (MOH) remains one of the leading causes of maternal mortality & morbidity worldwide. In the 2003-2005 report of the UK Confidential Enquiries into Maternal Deaths, haemorrhage was the third highest direct cause of maternal death (6.6 deaths/million maternities) with the rate similar to the previous triennium 1, 2. Postpartum haemorrhage (PPH) accounts for the majority of these deaths. This triennium, 2006-2008, unlike in previous reports there has been a change in the rankings of direct deaths by cause. Deaths from haemorrhage have dropped, to sixth place, following genital tract sepsis, preeclampsia, thromboembolism, amniotic fluid embolism and early pregnancy deaths 3. A well-defined multidisciplinary approach that aims to act quickly has probably been the key to successful management of MOH. In the developing world, several countries have maternal mortality rates in excess of 1000 women per 100,000 live births, and WHO statistics suggests that 25 % of maternal deaths are due to PPH, accounting for more than 100,000 maternal deaths per year 4.The blood loss may be notoriously difficult to assess in obstetric bleeds 5, 6. Bleeding may sometimes be concealed & presence of amniotic fluid makes accurate estimation challenging.

Definition

MOH is variably defined as blood loss from uterus or genital tract >1500 mls or a decrease in haemoglobin of >4 gm/dl or acute loss requiring transfusion of >4 units of blood. Blood loss may be:

1. Antepartum: Haemorrhage after 24th week gestation & before delivery; for example: placenta praevia, placental abruption, bleeding from vaginal or cervical lesions.

2. Postpartum: Haemorrhage after delivery

  • Primary PPH: Within 24 hours of delivery, which is >500 mls following vaginal delivery & > 1000mls following a caesarean section 7.
  • Secondary PPH: 24 hours to 6 weeks post-delivery; for example: Uterine atony, retained products of conception, genital tract trauma, uterine inversion, puerperal sepsis, uterine pathology such as fibroids 8.

PPH can be minor (500-1000 mls) or major (> 1000 mls). Major PPH could be divided to moderate (1000-2000 mls) or severe (>2000 mls).

Causes

Causes of PPH may be conveniently remembered using 4 T’s as a mnemonic:

  • Tone(Uterine atony)
  • Tissue (retained products)
  • Trauma( cervical & genital tract trauma during delivery)
  • Thrombosis (coagulation disorder)

Other Risk factors include:-Prolonged labour, multiple pregnancy, polyhydramnios, large baby, obesity, previous uterine atony & coagulopathy.

Prevention

The most significant intervention shown to reduce the incidence of PPH is the active management of the third stage of labour (see below).Other measures to prevent or reduce the impact of MOH include

  • Avoidance of prolonged labour
  • Minimal trauma during assisted vaginal delivery
  • Detection & treatment of anaemia during pregnancy
  • Identification of placenta praevia by antenatal ultrasound examination.
  • Where facilities exist, magnetic resonance imaging (MRI) may be a useful tool and assist in determining whether the placenta is accreta or percreta. Women with placenta accreta/percreta are at very high risk of major PPH. If placenta accreta or percreta is diagnosed antenatally, there should be consultant-led multidisciplinary planning for delivery 9.

Active management of the third stage

This represents a group of interventions including early clamping of the umbilical cord, controlled cord traction for placental delivery & prophylactic administration of uterotonic at delivery (e.g. oxytocin) 10. Active management of the third stage is associated with a lower incidence of PPH and need for blood transfusion 11. A longer acting oxytocin derivative, carbetocin, is licensed in the UK specifically for the indication of prevention of PPH in context of caesarean delivery. Randomised trials suggest that a single dose (100 mcg) of carbetocin is at least as effective as oxytocin by infusion 12, 13.

Management of MOH

Pregnant women are often young, healthy & have an increased blood volume of up to 20 % at term and therefore likely to compensate well to haemorrhage until the circulating blood volume is very low 14. MEOWS are a useful bedside tool for predicting morbidity. A validation study of the CEMACH recommended modified early obstetric warning system (MEOWS) in all obstetric inpatients to track maternal physiological parameters, and to aid early recognition and treatment of the acutely unwell parturient.  In addition, blood loss may sometimes be concealed and difficult to calculate. More commonly massive haemorrhage may be obvious; signs other than revealed haemorrhage include:

  • Tachycardia
  • Hypotension( BP may not drop until significant blood is lost)
  • Pallor
  • Oliguria
  • Cool peripheries
  • Lower abdominal pain

Management of anticipated MOH

On some occasions, cases at high risk of MOH can be predicted; e.g. caesarean section in a lady with a low lying placenta and previous uterine scar. These cases may be at a risk of placenta accreta and massive blood loss.

  • 2 large bore IV cannulae
  • Rapid infusion device or pressure bags in theatre
  • Blood warmer & warming blanket
  • Blood cross-matched & available
  • Consider preoperative invasive monitoring
  • Consider cell salvage if available (see below)
  • Consider interventional radiological procedures if available ( see below)

Management of unanticipated MOH

Management involves four components, all of which must be undertaken SIMULTANEOUSLY: communication, resuscitation, monitoring and investigation, arresting the bleeding 9, 15. Most maternity units in UK have CODE RED bleep system for alerting MOH.

Communication & teamwork:

Communication and teamwork are essential in cases of both anticipated & unanticipated maternal haemorrhage. This includes:

  • Call for help. Alert the midwife-in-charge, senior obstetrician & anaesthetist.
  • Alert Blood transfusion service & haematologist.
  • Alert portering service for transport of blood samples & collection of blood products
  • Check blood is available. In the UK 2-4 units of O-neg blood is kept on labour ward for emergency use.
  • Allocate roles to team members.
  • Ensure departmental guidelines exist for the management of MOH & regularly practice ‘fire drills’.
  • Alert one member of the team to record events, fluids, drugs and vital signs 9.
  • The use of standard form of words (such as ‘on going major obstetric haemorrhage’, ‘we need compatible blood now or group specific blood’) 9.

Goals of management:

  • Early identification of maternal bleed and institution of major haemorrhage drill
  • Rapid access to infusion of fluid in first instance with rapid availability & administration of blood.
  • Avoidance/limitation of complications of massive blood transfusion namely: acid/base disturbance, transfusion related acute lung injury (TRALI), hypocalcaemia, hyperkalaemia, hypothermia & thrombocytopenia.
  • Efficient team working & management decision making.

Resuscitation & immediate management:

  • ABC, 100% oxygen
  • 2 large bore cannulae & bloods for X-match
  • Fluid resuscitation; crystalloid/colloid 2000mls via rapid infuser or pressure bags e.g. Level 1 Rapid infuser ( can achieve >500mls/min warmed fluid flow)
  • Fluid therapy and blood product transfusion 9
  • Crystalloid Up to 2 litres Hartmann’s solution
  • Colloid up to 1–2 litres colloid until blood arrives
  • Blood Crossmatched
  • If crossmatched blood is still unavailable, give uncrossmatched group-specific blood OR give ‘O RhD negative’ blood
  • Fresh frozen plasma 4 units for every 6 units of red cells or prothrombin time/activated partial thromboplastin time > 1.5 x normal (12–15 ml/kg or total 1litres)
  • Platelets concentrates if platelet count < 50 x 109
  • Cryoprecipitate If fibrinogen < 1 g/l
  • Thromboelastography and rotational thromboelastometry coagulation tests: In most cases, medical and transfusion therapy is not based on the actual coagulation state because conventional laboratory test results are usually not available for 45 to 60 minutes. Thromboelastography and rotational thromboelastometry are point-of-care coagulation tests. A good correlation has been shown between thromboelastometric and conventional coagulation tests, and the use of these in massive bleeding in non-obstetric patients is widely practiced and it has been proven to be cost-effective.
  • A 2006 guideline from the British Committee for Standards in Haematology 1, 4summarizes the main therapeutic goals of management of massive blood loss is to maintain:
    • Haemoglobin > 8g/dl
    • Platelet count > 75 x 109/l
    • Prothrombin < 1.5 x mean control
    • activated prothrombin times < 1.5 x mean control
    • Fibrinogen > 1.0 g/l.
  • In addition, the Confidential Enquiry into Maternal and Child Health recommends that women with known risk factors for PPH should not be delivered in a hospital without a blood bank on site 1.
  • Transfer to theatre.
  • Non-surgical intervention for uterine atony.
  • Bimanual uterine compression (rubbing up the fundus) to stimulate contractions.
  • Ensure bladder is empty (Foley catheter, leave in place). ‘Rub up ‘the uterus
  • Syntocinon 5 units by slow intravenous injection (may have repeat dose).
  • Ergometrine 0.5 mg by slow iv/im injection (contraindicated in women with hypertension) 16.
  • Syntocinon infusion (40 units over 4 hours).
  • Carboprost 0.25 mg by intramuscular injection repeated at intervals of not less than 15 minutes to a maximum of 8 doses (contraindicated in women with asthma).
  • Direct intramyometrial injection of carboprost 0.5 mg im (Haemobate or Prostaglandin F2a) with responsibility of the administering clinician as it is not recommended for intramyometrial use. Can be repeated up to 5 doses (contraindicated in women with asthma, may cause bronchospasm, flushing & hypertension 17).
  • Misoprostol 1000 micrograms rectally.
  • If pharmacological measures fail to control the haemorrhage, initiate surgical haemostasis sooner than later.

Surgical treatment and other interventions

The most common cause of primary PPH is uterine atony. However, clinical examination must be undertaken to exclude other or additional causes:

  • Retained products (placenta, membranes, clots)
  • Vaginal/cervical lacerations or hematoma
  • Ruptured uterus
  • Broad ligament hematoma
  • Extra genital bleeding (for example, subcapsular liver rupture)
  • Uterine inversion.

Intrauterine balloon tamponade is an appropriate first line ‘surgical’ intervention for most women where uterine atony is the only or main cause of haemorrhage. If this fails to stop the bleeding, the following conservative surgical interventions may be attempted, depending on clinical circumstances and available expertise:                                                                               

  • Balloon tamponade (Bakri/Rusch balloon, Foley’s/condom catheter, Sengstaken-Blakemore tube 18-21
  • Haemostatic brace suturing (such as B-Lynch or modified compression sutures).
  • Bilateral ligation of uterine arteries.
  • Bilateral ligation of internal iliac (hypogastric) arteries.
  • Selective arterial embolisation or balloon occlusion radiologically.
  • Compression/ clamping aorta to buy time.
  • Uterine replacement if uterine inversion

It is recommended that a laminated diagram of the brace technique be kept in theatre. Resort to hysterectomy sooner rather than later (especially in cases of placenta accreta or uterine rupture). A second consultant clinician should be involved in the decision for hysterectomy.

Interventional Radiological techniques

Interventional techniques are gaining popularity if the facilities & expertise exist and are especially useful for the anticipated massive bleeds e.g. planned LSCS in a woman with anticipated placenta accrete. Though evidence of effectiveness is still limited, there are increasing case reports of its successful use. This suggests that prophylactic arterial catherisation (with a view to embolisation) could be considered where facilities permit until such time as further evidence becomes available 22-28.

  • Bilateral internal iliac artery balloons may be placed electively & inflated at C. section/ should bleed occur.
  • Selective pelvic artery (internal iliac arteries, anterior division of internal iliac or uterine artery) embolisation can be performed.
  • Complications appear rarely & include: haematoma, false aneurysms & lower limb ischemia.

Interventional radiology may be considered in cases of placenta praevia with accreta if intra-arterial balloons can be placed in the radiology department before the woman goes to theatre for caesarean section. Follow up studies of women who had undergone arterial embolisation for control of PPH suggest that the intervention does not impair subsequent menstruation and fertility 29, 30.

Intraoperative cell salvage in obstetrics (ICSO)

Cell salvage has now been used in numerous cases of obstetric bleeds and appear safe. Concerns relate to re-infusion of foetal cells which could theoretically cause haemolytic disease in future pregnancies and also the potential for amniotic fluid embolus. If cell salvage techniques are utilised, separate suction of amniotic fluid is recommended and a leukocyte depletion filter used during re-infusion of salvaged blood. Setting up cell salvage measures should not divert staff an attention from initial resuscitation.

Intraoperative cell salvage (the process whereby bloodshed during an operation is collected, filtered and washed to produce autologous red blood cells for transfusion to the patient) is commonly being used in cardiac, orthopaedic and vascular surgery with relative reduction of blood transfusion by 39% and absolute risk reduction by 23%, with cell salvage not appearing to impact adversely on clinical outcomes 31, 32. Although large prospective trials of cell salvage with auto transfusion in obstetrics are lacking, to date, no single serious complication leading to poor maternal outcome has been directly attributed to its use. Several bodies based on current evidence have endorsed cell salvage in obstetrics. Current evidence supports the use of cell salvage in obstetrics, which is likely to become increasingly commonplace, but more data are required concerning its clinical use 33. A National UK survey in 2007 showed that, in 2005–2006, 38% of all UK maternity units were using cell salvage and that 28% incorporated cell salvage into their massive haemorrhage guidelines 34. In particular, this survey showed that a lack of training was the main perceived barrier to its use: 48% of units specifically stated that their reason for not using cell salvage was lack of training and equipment, with fears about safety being expressed by only 10%. However, the potential difficulty is the effective removal of amniotic fluid and the degree of contamination with fetal red cells with potential maternal sensitization, intraoperative cell salvage may be a useful technique in women who refuse blood or blood products (Jehovah’s Witnesses guideline) 9 or those where massive blood loss is anticipated (placenta percreta or accreta). For women who are Rh-negative, to prevent sensitization, the standard dose of anti-D should be given and a Kleihauer test taken 1 hour after cell salvage has finished, to determine whether further anti-D is required 35.

Recombinant activated factor VII (rFVIIa)

Recombinant activated factor VII (rFVIIa) was developed for the treatment of haemophilia. Over the past decade, it has also been used to control bleeding in other circumstances. A 2007 review identified case reports of 65 women treated with rFVIIa for PPH 36.Although the case reports suggested that rFVIIa reduced bleeding, 30 of the 65 women underwent peripartum hysterectomy and particular caution is required in interpreting data from uncontrolled case reports. In the face of life-threatening PPH, and in consultation with a haematologist, rFVIIa may be used as an adjuvant to standard pharmacological and surgical treatments. A suggested dose is 90 micrograms/kg, which may be repeated in the absence of clinical response within 15–30 minutes 37. Although there is no clear evidence of thrombosis with the use of rFVIIa in obstetric practice, there have been case reports of thrombosis with the use in cardiac surgery 38-40. Women with PPH are particularly susceptible to defibrination (severe hypofibrinogenaemia) and this is particularly relevant to the most severe cases that will be considered for rFVIIa; rFVIIa will not work if there is no fibrinogen and effectiveness may also be suboptimal with severe thrombocytopenia (less than 20 x 109/l).Therefore, fibrinogen should be above 1g/l and platelets greater than 20 x 109/l before rFVIIa is given. If there is a suboptimal clinical response to rFVIIa, these should be checked and acted on (with cryoprecipitate, fibrinogen concentrate or platelet transfusion as appropriate) before a second dose is given 36-40.

Anaesthetic management 15:

  • GA with RSI is generally advocated if actively bleeding or coagulopathy.
  • Reduce dose of induction agent if severe on going bleeding.
  • Regional anaesthesia is relative contraindication but may be maintained if the patient has an epidural insitu & bleeding is controlled.
  • Alert Blood bank & haematologist.
  • Consider arterial line, central line and urinary catheter but only after definitive treatment has commenced. Their insertion must not delay resuscitation & fluid management.
  • Use fluid warmer & aim to keep the patient normothermic.
  • Regular monitoring of haemoglobin level and coagulation using near patient devices if available (e.g. Haemacue). FFP, platelets transfusion & cryoprecipitate may be necessary if coagulopathy develops. Liaise early with haematology department for optimal & timely product replacement.
  • Perioperative monitoring as per AAGBI guidelines.
  • Recording of parameters on a flow chart such as the modified obstetric early warning system charts.
  • Consider systemic haemostatic agents such as Aprotonin, Vit K, Tranexemic acid, Recombinant factor VII a (Novo seven R). Although evidence is conflicting, there is a consensus view that fibrinolytic inhibitors seldom, if ever, have a place in the management of obstetric haemorrhage 41, 42.
  • Postoperative management includes transfer to ITU/HDU.
  • Anticipate coagulopathy & treat clinically until coagulation results available.
  • It is also important that, once the bleeding is arrested and any coagulopathy is corrected, thromboprophylaxis is administered, as there is a high risk of thrombosis. Alternatively, pneumatic compression devices can be used, if thromboprophylaxis is contraindicated in cases of thrombocytopenia.

Conclusion

Globally, postpartum haemorrhage (PPH) is the leading cause of maternal morbidity and mortality. Major obstetric haemorrhage is managed by multidisciplinary approach. In the current treatment of severe PPH, first-line therapy includes transfusion of packed cells and fresh-frozen plasma in addition to uterotonic medical management and surgical interventions. In persistent PPH, tranexamic acid, fibrinogen, and coagulation factors are often administered. Secondary coagulopathy due to PPH or its treatment is often underestimated and therefore remains untreated, potentially causing progression to even more severe PPH. The most postnatal haemorrhage is due to uterine atony and can be temporarily controlled with firm bimanual pressure while waiting for definitive treatment.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RAJASHREE CHAVAN, MBBS, MD, DA, FRCA; Cambridge University Hospital Foundation Trust, UK. M Y LATOO, FRCA(London) Consultant Anaesthetist, Bedford Hospital, UK.
Corresponding Author Details: 
DR RAJASHREE CHAVAN, Cambridge University Hospital Foundation Trust, UK.
Corresponding Author Email: 
vidula77@doctors.net.uk
References
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  13. Dansereau J, JoshiAK, Helewa ME, DoranTA, Lange IR, Luther ER, et al. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after caesarean section. Am J Obstet Gynecol 1999; 180:670–6.
  14. de GrootAN.Prevention of postpartum haemorrhage.BaillieresClin Obstet Gynaecol 1995; 9:619–31.
  15. Anaesthesiology Clin 2008 march 26(1) 53-66
  16. McDonald SJ, Abbott JM, Higgins SP. Prophylactic ergometrineoxytocin versus oxytocin for the third stage of labour. Cochrane Database Syst Rev 2004 ;(1):CD000201.
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  18. Ikechebelu JI, Obi RA, Joe-Ikechebelu NN. The control of postpartum haemorrhage with intrauterine Foley catheter. J Obstet Gynecol 2005; 25:70–2.
  19. Bakri YN, Amri A, Abdul Jabbar F. Tamponade-balloon for obstetrical bleeding. Int J Gynaecol Obstet 2001; 74:139–42.
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  21. Condous GS, Arulkumaran S, Symonds I, Chapman R, Sinha A, Razvi K. The ‘tamponade test’ in the management of massive postpartum haemorrhage. Obstet Gynecol 2003; 101:767–72.
  22. Levine AB, Kuhlman K, Bonn J. Placenta accreta: comparison of cases managed with and without pelvic artery balloon catheters. J Matern Fetal Med 1999; 8:173–6.
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  24. Mitty HA, Sterling KM, Alvarez M, Gendler R. Obstetric haemorrhage: prophylactic and emergency arterial catheterization and embolotherapy.Radiology 1993; 188:183–7.
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Often overlooked neuropsychiatric syndromes in Parkinson’s disease

Authors
Javed Latoo, Minal Mistry, and Francis J Dunne
Article Citation and PDF Link
BJMP 2013;6(1):a603
Abstract / Summary
Abstract: 

Parkinson’s disease (PD) is a subcortical disorder that eventually spreads to the cortex. There is a wide variation in the global incidence and prevalence of PD. The disease usually presents in patients over the age of 65, although 5% of cases are under the age of 40 at the time of diagnosis. PD has a high prevalence of psychiatric co-morbidity. In this article, written with general neurologists and psychiatrists  in mind,  the main features and pathology of PD will be briefly outlined followed by a review of the epidemiology, aetiology, clinical features, and treatment of other often overlooked neuropsychiatric syndromes associated with PD. Close liaison between neurologists and psychiatrists is recommended in order to optimize treatment.

Introduction

The global epidemiology of PD varies widely which could be partly accounted for by differences in survival rates.1 One review paper examined the epidemiology of PD in Austria, the Czech Republic, France, Germany, Italy, The Netherlands, Portugal, Spain, Sweden and United Kingdom. It revealed that the prevalence rates range from 65.6 per 100,000 to 12,500 per 100,000 and annual incidence estimates ranged from 5 per 100,000 to 346 per 100,000.2 The wide variation in incidence and prevalence rates of PD across Europe could be due to environmental and genetic factors. Differences in methodologies for case ascertainment, diagnostic criteria, or age distributions of the study populations, could also account for the wide variations.2

Described by James Parkinson in 1817, PD is the second most common neurodegenerative disorder next to Alzheimer’s dementia. Depletion of dopaminergic neurones in the substantia nigra is the main pathology found in PD. Symptoms usually appear when dopamine levels are reduced by 50-80%.3 Noradrenergic, cholinergic and serotonergic pathways are also affected. Clinically PD is characterised by rigidity, tremor (cogwheel, lead pipe, and resting), akinesia, bradykinesia (poverty and slowness of movement), and postural instability (leading to frequent falls).4 These symptoms may also be accompanied by a range of non-motor symptoms other than well-known neuropsychiatric syndromes of depression, psychosis, and cognitive impairment.

In essence, a syndrome is a combination of signs and symptoms related to an underlying pathological process. PD may present with neuropsychiatric syndromes of depression, psychosis (usually affective in origin) and cognitive impairment.5 These syndromes are not under discussion here as readers are likely to be familiar with them. However, PD may also present with other neuropsychiatric syndromes and for the purpose of this article we have classified them into: 1) Anxiety disorders, 2) Apathy, 3) Involuntary emotional expression disorder, 4) Sleep disorders, and 5) Impulse control disorders.

Drugs used to treat PD themselves are associated with neuropsychiatric side effects. For example, dopamine agonists are well-known to cause sleep disturbance, dizziness (usually due to postural hypotension), hallucinations, hypersexuality, and compulsive gambling. Anticholinergics may cause confusion, hallucinations and impaired memory. Surgery also may cause adverse effects including depression, confusion and cognitive impairment.6 Table 1 illustrates the groups of drugs used in PD.

Table 1. Drugs used in Parkinson’s Disease
Group Drug
Dopamine receptor agonists Apomorphine, pramipexole, ropinirole, rotigotine
N-Methyl-D-aspartate (NMDA) receptor antagonist Amantadine hydrochloride
Levodopa Co-benedopa (levodopa/benzeraside), co-careldopa (levodopa/carbidopa)
Monoamine oxidase B inhibitors (MAO-B) Rasagiline, selegiline hydrochloride
Catechol-O-methyltransferase (COMT) inhibitors Entacapone, tolcapone
Antimuscarinic drugs Benztropine mesylate, orphenadrine, procyclidine, trihexyphenidyl

Overlooked neuropsychiatric syndromes in Parkinson’s disease

The prevalence of overlooked neuropsychiatric syndromes found in PD, summarised in Table 2, is generally less common than PD syndromes of depression (up to 50%),psychosis (up to 60%) and dementia (ultimately develops in 80%).7, 8, 9

Table 2. Overlooked neuropsychiatric syndromes found in Parkinson’s Disease.
Neuropsychiatric syndrome Prevalence
Anxiety disorders Up to 40%
Apathy 16-42%
Involuntary emotional expression disorder Up to 16.8%
Sleep disorders 60-98%
Impulse control disorders Up to 13.6%

Anxiety Disorders

Epidemiology

There is a wide range in the reporting of the prevalence of anxiety in patients with PD. Anxiety is significantly more prevalent in PD sufferers compared with age and sex matched non-sufferers. Prevalence is quite high with estimates indicating that up to 40% of PD patients suffer significant anxiety.10 However, clinicians’ recognition and awareness of anxiety in PD need to be raised because it is likely to be under-diagnosed and untreated.11, 12 Consequently the prevalence of anxiety may be even higher. Severity of anxiety is not correlated with severity of parkinsonian symptoms, duration of levodopa use, or current dose of levodopa.

Aetiology and risk factors

Anxiety is an understandable psychological response to the physical symptoms, to the neurochemical changes of the disease itself, or as a side effect of the various medications used to treat the condition.10 Sleep disturbances and cognitive impairment have been proposed as possible aetiological factors for anxiety in PD.11, 12 Depression in PD may manifest in two clinical phenotypes, one ‘anxious-depressed’ and the other ‘depressed’. However, a further large proportion of patients can have relatively isolated anxiety.13

Anxiety frequently precedes the development of motor symptoms, suggesting specific neurobiological processes are involved, not merely social and psychological reactions in learning to adapt to PD.14

Patients with postural instability and gait dysfunction have a higher incidence of anxiety compared with tremor-dominant patients. Younger-onset PD patients are also more likely to experience anxiety. The pathogenesis of anxiety involves noradrenergic, serotonin and dopamine neurotransmitters. GABAergic pathways may also be involved.14 Right hemisphere disturbances have also been implicated, particularly with panic disorder.Symptom variation in PD may be due to medication, as well as motor fluctuations.11 One study revealed that although the dose of levodopa was not associated with anxiety, the experience of dyskinesia or on-off fluctuations increased the risk of anxiety.12, 14, 15

Presentation and diagnosis

The commonest disorders found in PD are generalised anxiety, panic disorder, and social phobia. Anxiety contributes to the complexity of PD and lowers quality of life. 14, 15 The degree of comorbidity between anxiety and depression in PD patients is in excess of that found in patients without PD. While anxiety is significantly associated with depression, some patients show anxiety without depression.10

The main features of anxiety are inappropriate feelings of apprehension as well as mood, cognitive, and somatic changes. Some symptoms may be common to PD, such as autonomic symptoms, fatigue, muscle tension, insomnia and attention problems. Psychologically, anxiety in PD is understandable because being diagnosed with a chronic disease with no known cure and an inexorable course, would be difficult for anyone to contemplate. Motor signs and changes in appearance could explain social anxiety. However, the frequency of anxiety in PD seems to be higher than in other chronic diseases and unrelated to the severity of motor signs. Even in social phobia the phobic symptoms do not correlate with disease severity and are not restricted to performance situations. Furthermore, anxiety can precede motor signs by several years, suggesting that the neurobiological substrate of PD is responsible for anxiety at least in part.

Treatment

Treatment comprises the use of selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine and citalopram as well as other newer antidepressants - serotonin and noradrenaline reuptake inhibitor (SNRIs) for example, venlafaxine, cognitive behavioural therapy (CBT), exercise, the occasional use of atypical neuroleptics, and benzodiazepines.14 However, benzodiazepines have a tendency to cause sedation, unsteadiness of gait, and even confusion. Antidepressants are useful because they treat both anxiety and depression that often overlap: depression coexists with anxiety in 14% of cases.15 Low dose tricyclic antidepressants with minimal anticholinergic effects may be useful in those patients who do not respond to benzodiazepines.

Apathy

Epidemiology

Apathy, a state of lethargic indifference and loss of motivation, and fatigue are prominent non-motor symptom in PD with a prevalence of between 16-42%.16, 17 Fatigue is a sense of tiredness or exhaustion, due to mental or physical causes. Apathy and fatigue are important because they have significant repercussions for the quality of life in PD.18, 19 Apathy can exist without depression but, by definition, patients themselves do not complain of apathy, though are found to be unmotivated to engage in activities. Apathy and fatigue are often difficult to distinguish from low mood and daytime sleepiness, both of which are common to depression.

A four-year prospective longitudinal study of 79 patients found that 13.9% of those with PD had persistent apathy and 49.4% had developed apathy at follow up. The study showed apathy to be a frequent and persistent behavioural feature in PD with a high incidence and prevalence over time, and associated with neurotransmitter deficits.20

Aetiology and risk factors

The dorsolateral, medial and orbital frontal cortices, as well as subcortical structures such as the basal ganglia, thalamus and internal capsule are implicated in the pathogenesis of apathy.The independent risk factors for apathy are dementia at baseline, a more rapid decline in speech, and axial impairment (e.g. poor ability to turn in bed) during follow up.20, 21 A more recent study showed that male gender, higher depressive scores, and severe motor symptoms, were significantly associated with apathy, but not with greater cognitive impairment.22 It has been observed that deep brain stimulation (DBS) may contribute to the development of apathy23 but other studies show conflicting results.24

Presentation and diagnosis

There is a higher incidence of depression and dementia in PD patients with apathy.Therefore differential diagnosis between apathy and cognitive deficits and depression is essential because the therapeutic approaches are different.19, 20 It is equally important to differentiate between apathy and depression that are different clinical entitiesalthough both may coexist.The crucial difference is that people with apathy lack serious self-reproach or feelings of guilt. 21, 25 The Lille Apathy Rating Scale (LARS), administered as a structured interview, can be a useful tool to distinguish them both26 though further research is needed to differentiate the neurological and neurochemical basis for depression and apathy.

Treatment

Treatment options for apathy are limited. The use of methylphenidate, a stimulant drug related to amphetamine, has been suggested but evidence is scarce and side effects may outweigh its clinical benefit.27 Methylphenidate has been described as effective for both apathy and fatigue28 but more studies are necessary. Antidepressants are not effective, can cause unnecessary side effects and can even aggravate apathy, demonstrating that these syndromes are really independent.29 The association between cognition and apathy, along with the potential benefit of cholinesterase inhibitors on both cognition and apathy, suggests that cholinergic mechanisms take part in the pathophysiology of apathy.30, 31 ’Off-time’ refers to periods of the day when the medication is not working well, causing worsening symptoms of fatigue and apathy. ‘Wearing-off’ episodes may occur predictably and gradually, or they may emerge suddenly and unexpectedly. Wearing-off periods may be improved with appropriate changes in the medication regimen. This would mean optimizing dopaminergic agents or using a long-acting levodopa or a catechol-O-methyltransferase (COMT) inhibitor. Wearing off may be also better controlled by shortening the time between medication doses. In a study of 23 PD patients in both the 'on' and 'off' states compared to 28 controls, L-dopa had a positive effect on motivation suggesting striatofrontal loops are involved.32

Involuntary emotional expression disorder

Epidemiology

Involuntary emotional expression disorder (IEED) has been found to occur in 16.8% of PD patients, and in 15.3% if comorbid depressive disorder was excluded.33 However, other studies suggest that the symptoms of IEED are present in up 15% of PD patients but the actual IEED disorder occurs in half of these cases.34 This implies that IEED symptoms occur in PD but the condition of IEED is not present although this may depend on the criteria used for the diagnosis. If IEED does develop in PD it is particularly common in the later stages of PD and is likely to be distinct from depressive disorderwhich remains an important differential diagnosis.33, 35

Aetiology and risk factors

IEED can occur in neurological conditions such as stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorders, multiple system atrophy, corticobasal degeneration, and Alzheimer’s disease.35 Injury to the neurological pathways that control the expression of emotion have been implicated in its pathogenesis. Emotional expression involves various pathways within the frontal lobe, limbic system, brainstem and cerebellum, with disruption of regulatory and inhibitory mechanisms in this network implicated.36, 37

Presentation and diagnosis

IEED is described as sudden episodes of laughing or crying that may be spontaneous or disproportionate to the triggering stimuli.The emotional outbursts of IEED may involve laughter, crying or anger. The episodes all share common features in that they are involuntary, uncontrollable, and excessive, not sustained, and usually last from seconds to minutes. Outbursts are often stereotyped though single individuals may have episodes of both laughing and crying.IEED is also known as pseudobulbar affect, pathological laughter and crying, emotional lability, emotionalism, and emotional dysregulation.Despite the various terms used to describe the disorder, IEED is often missed and even sometimes mistaken for depression.33, 35 Symptoms of IEED are important because they are associated with an impairment of social and occupational functioning.38 It is hypothesized that neurological disease and injuries affect the excitatory action of glutamate, leading to excessive glutaminergic signalling and increased electrical activity in neurons. As glutamate is the primary excitatory neurotransmitter of the central nervous system, stabilizing or reducing glutaminergic activity could prove useful in the treatment of IEED.39

Treatment

Medication options include the use of SSRIs, tricyclic antidepressants (TCAs) for example, amitriptyline, and less frequently dopaminergic agents.A combination of dextromethorphan and quinidine has also been suggested. 35 38

Sleep disorders

Epidemiology

Sleep disorders have been known to affect 60-98% of patients with PD.40

Aetiology and risk factors

The aetiology of sleep disorders includes PD itself or other comorbid conditions such as depression, and cognitive impairment.41 Nocturnal pain from rigidity or dystonia, restless legs syndrome, and autonomic disturbance leading to nocturnal frequency and urgency, also contribute to insomnia. Degeneration of sleep regulatory centres in the brainstem and thalamocortical pathways, side effects of drugs, motor impairment, and incontinence may affect sleep. Sleep disorders may precede the onset of motor symptoms. Rapid Eye Movement (REM) sleep behaviour disorder (RBD), which occurs in almost a third of PD patients,is often associated with cognitive impairment and hallucinations. This disorder is directly related to the degenerative process of the pedunculopontine nucleus, the locus subceruleus and the retrorubral nucleus. A sudden onset of the disorder is almost always due to the introduction or the withdrawal of drugs, especially antidepressants. Curiously, parkinsonism can disappear during the RBD.42

Sleep fragmentation is the earliest and most common sleep disorder in PD, and gradually worsens as the disease progresses. Vivid dreaming, nightmares and night terrors are common and occur in up to 30% of patients using levodopa for long periods. Dream content is probably altered in PD and many patients vocalize during sleep. Vocalization may vary from incomprehensible sounds to detailed conversations, laughing, cursing or screaming. Excessive daytime sleepiness and 'sleep attacks' affect half of patients with PD and may precede disease onset. The causes are a combination of the disease process, the consequence of other sleep disorders and medication. A sudden onset of sleep during the day is a phenomenon in PD which resembles narcolepsy, and it is commonly associated with dopaminergic drugs. PD patients may be more prone to restless legs syndrome, periodic limb movements and obstructive sleep apnoea.

Sleep disorders in PD are seldom diagnosed and treated. Although an accurate diagnosis of a particular sleep disorder depends on polysomnography, sometimes the diagnosis can be based on clinical observation. Treatment is based on the correct diagnosis and underlying cause of the sleep disorder. Often it is difficult to decide whether excessive daytime sleepiness is cause or consequence of insomnia.43

Presentation and diagnosis

Sleep disorders may manifest as insomnia, excessive daytime sleepiness and sleepwalking.44, 45 Sudden attacks of sleepiness are known to occur during stimulating activities such as walking, eating, and even driving a car. These sudden sleep episodes can be associated with medication such as dopamine agonists and levodopa.46

RBD is characterised by the loss of the normal atonia during dreaming. In other words, patients act out their dreams as manifested by crying out, kicking or thrashing about during their sleep. RBD can predate the development of motor symptoms by several years and a longitudinal study of a cohort of 26 patients found an association between RBD and the later development of PD. 47

Treatment

Management involves the review of medication that may be contributing to the sleep disorder. Treatment of comorbid conditions such as depression and cognitive impairment is essential.

Sleep hygiene is the initial and basic measure applied to all patients. For instance, stimulating patients during the day can decrease the excessive naps and improve sleep at night, thus improving daytime sleepiness. Additional techniques include going to bed only when sleepy, exposure to natural and bright light during day, reduction of light and noise exposure at night as much as possible, and maintenance of a regular schedule.

Long-acting dopaminergic drugs might improve insomnia caused by worsening of motor symptoms at night. Clonazepam, a benzodiazepine, is efficacious and well tolerated by the majority of patients afflicted by RBD and should be considered as initial treatment.48 Antidepressants with a sedative effect might be helpful in cases of insomnia with comorbid depression or anxiety. Quetiapine, an antipsychotic which has sedative properties as a side effect, may be a safe and effective treatment for insomnia in PD because it has no untoward effects on motor function.49 Small clinical trials with Modafinil for excessive daytime sleepiness had controversial results. An additional remark concerning treatment of sleep disorder in PD is that sleep may provide a short-term benefit on motor symptoms.28, 43

Impulse control disorders

Epidemiology

A large multi-centre investigation (the DOMINION study) of 3,090 patients with PD revealed that impulse control disorder (ICD) was identified in 13.6% of PD patients; specifically, pathological gambling in 5%, compulsive sexual behaviour in 3.5%, compulsive buying in 5.7% and binge-eating disorder in 4.3%.50 The prevalence of ICD rises to 14% for patients taking dopamine agonists, compared with 0.7% for patients taking levodopa alone.51 It is not clear whether these ICD symptoms reflect a primary pathology of PD or whether dopaminergic medication is interacting with an underlying predisposition or vulnerability.52 Possible neurobiological explanation centres around dopamine-receptor binding profiles. Dopamine D2 and D1 receptors, abundant in the dorsal striatum, may mediate the motor effects of dopamine replacement therapies, whereas D3 receptors are abundant in the ventral striatum, a brain region associated with addictive behaviour and substance misuse disorders. Second generation non-ergot dopamine agonists (e.g. pramipexole and ropinirole) demonstrate relative selectivity for D3 receptors compared with D2 and D1 receptors.50

Aetiology and risk factors

Addiction to dopaminergic medication used in the treatment of PD may explain behaviours such as drug-seeking, gambling, and hypersexuality. The risk of pathological gambling increases if dopamine agonists are used in those with younger age of onset, higher novelty seeking traits, and a personal and family history of alcohol misuse.53

Presentation and diagnosis

In addition to the above PD patients with ICD may present with compulsive shopping, compulsive eating, and compulsive medication use, all of which can have potentially devastating psychosocial consequences because they are often hidden. Complex stereotyped repetitive behaviours (punding) may also be present.54Punding behaviour is stereotyped and purposeless and includes hoarding, shuffling papers, sorting labels, assembling and disassembling objects, to name a few.

Treatment

Stopping dopaminergic medication should be considered in the first instance. Further treatment options are limited but one double-blind crossover study demonstrated the use of amantadine in abolishing or reducing pathological gambling.55 In addition, one case report suggested the antipsychotic quetiapine to be effective in treating pathological gambling.56 Whether other treatments, such as DBS, are effective for these compulsive repetitive behaviours, remains to be seen.

Management of overlooked neuropsychiatric syndromes in PD

Because of the significant disability and impact on quality of life caused by overlooked neuropsychiatric symptoms in PD, it is important for neurologists and psychiatrists to recognise them and develop their clinical skills in order to be aware of their significance. Early detection is crucial. We have shown there is a limited range of treatment strategies available to guide the clinician in treatment choices. Because neuropsychiatric diagnoses in PD are different in phenomenology it is important to remember that treatment with 'psychiatric' drugs will often be insufficient and therefore more consideration should be given to 'antiparkinsonian' medications because the underlying pathology of PD is causing the various syndromes mentioned.

Table 3 provides an overview of the medical treatment of overlooked neuropsychiatric syndromes in PD, although it should be noted that overall very few studies document the effectiveness of the solutions proposed and more controlled studies are needed. Nonetheless, the reader should find the following useful.

Table 3. Summary of the medical treatment of overlooked neuropsychiatric syndromes in Parkinson’s Disease.
Psychiatric syndrome Treatment
Anxiety - Antidepressants - sertraline, citalopram, fluoxetine, venlafaxine- Others - antipsychotics, benzodiazepines
- Cognitive Behavioural Therapy
- Exercise
Apathy (diminished motivation) - Cholinesterase inhibitors
- Dopamine agonists
- Possible use of methylphenidate
Involuntary emotional expressive disorder - Antidepressants
- Dopaminergic agents.
- Possible combination of dextromethorphan and quinidine
Sleep disorders - Benzodiazepine - clonazepam
- Antipsychotic (sedating) – quetiapine
- Sleep hygiene
Impulse control disorders - Possible use of amantadine or quetiapine in pathological gambling
- Further research required

Conclusion and implications

The management of PD is often complicated because of the diverse factors underlying its aetiology. Dopaminergic, serotonergic, noradrenergic and cholinergic pathways are involved.57 Clinicians are generally competent in recognising the more common disorders such as depression, psychosis and cognitive impairment associated with PD though there is a tendency to focus too much on these at the expense of other nonmotor symptoms. Anxiety, apathy, involuntary emotional expression disorder, sleep disorders, and impulse control disorders cause significant disability and impact heavily on patients and carers.

Before introducing treatment for psychiatric complications it is essential to exclude causes such as antiparkinson’s medication, DBS (implicated in apathy), and underlying medical conditions. Once excluded or treated, subsequent management includes psychotropic pharmacotherapy but there are limited options. With no specific drug designed to treat the overlooked conditions, a wide range of medications (e.g. antidepressants, antipsychotics, benzodiazepines, dopaminergic agents, and psychostimulants) are available to manage the symptoms.

Neurologists and psychiatrists need to work together to manage these syndromes and they must be innovative in setting up joint research ventures into developing treatment options. Simple questionnaires may alert physicians when presenting symptoms are abstruse because many of the nonmotor symptoms predate the motor symptoms58 (the presymptomatic phase of stages 1-2 of Braak's classification system).59 60 For example, anosmia, constipation and other autonomic symptoms are not considered neuropsychiatric syndromes per se, but are some of the nonmotor problems associated with PD and may give clues that PD is developing.

Despite research highlighting the presence of these disorders in PD, they generally go unrecognised by clinicians, being less common, and therefore psychiatrists in old age and adult psychiatry as well as general neurologists may lack skills to recognise them. Besides, there are no clear treatment guidelines on how to manage the conditions.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAVED LATOO, Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Hollins Lane, Warrington WA2 8WA, UK. MINAL MISTRY, Consultant Psychiatrist, Southern Health NHS Foundation Trust, Hampshire, UK. FRANCIS J DUNNE, Consultant Psychiatrist and Honorary Senior Lecturer, North East London Foundation Trust (NELFT) United Kingdom, & University College London.
Corresponding Author Details: 
JAVED LATOO, Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Hollins Lane, Warrington WA2 8WA, UK.
Corresponding Author Email: 
javedlatoo@gmail.com
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Postural Orthostatic Tachycardia Syndrome (POTS): Evaluation and Management

Authors
Ronald Conner, Mujeeb Sheikh and Blair Grubb
Article Citation and PDF Link
BJMP 2012;5(4):a540
Abstract / Summary
Abbreviations: 
JHS - Joint hypermobility syndrome, POTS - Postural Orthostatic Tachycardia Syndrome, SSRI - serotonin reuptake inhibitor, SNRI - norepinephrine reuptake inhibitor, EPO - erythropoietin

Case Presentation

A 29 year-old woman had been well until 7 months previously when, after a viral syndrome, she developed palpitations, fatigue, and frequent episodes of light headedness and near syncope. On further questioning she notes exercise intolerance and dyspnea on exertion. She has stopped working as cashier. Her mother thinks she is having panic attacks and needs “something to calm her nerves.” ECG, echocardiogram, and endocrine evaluation are all normal. On physical examination, she displayed a postural heart rate increase of 35 beats per minute on standing, along with a 15mmHg fall in diastolic blood pressure.

Introduction

Disorders of the autonomic nervous system present unique challenges to the practicing clinician. These syndromes have a significant impact on quality of life, offer subtle diagnostic clues, and have a propensity to mimic other disease processes. For these reasons clinicians should have basic familiarity with the differentiating features of autonomic disorders. While much investigation has focused on Neurocardiogenic syncope, a distinct subgroup has emerged characterized by postural tachycardia and exercise intolerance. Postural orthostatic tachycardia syndrome (POTS) is the final common pathway of a heterogeneous group of underlying disorders that display similar clinical characteristics .1

The constellation of symptoms associated with POTS reflects underlying dysautonomia including palpitations, exercise intolerance, fatigue, lightheadedness, tremor, headache, nausea, near syncope, and syncope. Foremost amongst these is orthostatic intolerance. Besides being limited in the functional activities of daily living, increased sleep disturbances including excess daytime sleepiness, fatigue are also common and have been associated poor health-related quality of life. 2 We aim to discuss the clinical presentation, classification, evaluation and management of POTS.

Diagnosis

The current diagnostic criteria for POTS is the presence of orthostatic intolerance symptoms associated with a sustained heart rate increase of 30 beat per minute (bpm) or absolute rate exceeding 120 bpm within the first 10 minutes of standing or upright tilt in the absence of other chronic debilitating disorders, prolonged bed rest, or medications that impair vascular or autonomic tone. 3 Most patients will have orthostatic symptoms in the absence of orthostatic hypotension (a fall in BP >20/10 mmHg). A grading system for POTS has been developed (Table 1). This system focuses on the functional severity of orthostatic intolerance in a way similar to the NYHA heart classification.

The physical exam should be methodical and directed. Supine, sitting, and immediate standing heart rate and blood pressure should be recorded. Orthostatic tachycardia and acrocyanosis of the lower extremities may be the only physical signs in these patients. Standing and supine blood pressure measurements and baseline electrocardiogram are generally recommended. In patients with physical examination or clinical history suggestive of cardiovascular abnormalities, other diagnostic test including echocardiogram , stress test or coronary angiography may be indicated before a tilt test. In addition, other possible clinical disorders with similar clinical manifestations must be kept in mind and ruled out. Upright tilt test remains the diagnostic test of choice for POTS and other autonomic disorders. Implantable loop recorders, electrophysiological tests and Holter monitoring are not helpful in the evaluation of these disorders. Supine and upright serum catecholamine levels should be obtained if hyperadrenergic type is suspected. In the presence of gastrointestinal symptoms bowel motility studies may reflect the degree of involvement and help to tailor therapy. 4

Table 1 : The Grading of Orthostatic Intolerance*
Grade 0
Normal orthostatic tolerance
Grade 1
Orthostatic symptoms are infrequent or occur only under conditions of increased orthostatic stress
Subject is able to stand >15 minutes on most occasions
Subject typically has unrestricted activities of daily living
Grade II
Orthostatic symptoms are frequent, developing at least once a week
Orthostatic symptoms commonly develop with orthostatic stress
Subject is able to stand >5 minutes on most occasions
Some limitation in activities of daily living is typical
Grade III
Orthostatic symptoms develop on most occasions and are regularly unmasked by orthostatic stresses
Subject is able to stand for >1 minute on most occasions
Patient is seriously incapacitated, being bed or wheelchair bound because of orthostatic intolerance
Syncope / presyncope is common if patient attempts to stand
*Symptoms may vary with time and state of hydration and circumstances. Orthostatic stresses include prolonged standing, a meal, exertion, and head stress.

Classification and Clinical Features

POTS is a heterogeneous group of disorders resulting in a common clinical scenario. This syndrome is classified as being either primary or secondary. Primary POTS is idiopathic and not associated with other disease processes. Secondary POTS occurs in association with a known disease or disorder. Subtype classification affects management and is therefore essential.1,4 (Figure 1)

Partial dysautonomic (PD) POTS (also referred to as Neuropathic POTS) is the predominant form.1, 2 This is a mild peripheral autonomic neuropathy, characterized by inadequate peripheral vasculature constriction in the face of orthostatic challenge. Female predominance is seen with 5:1 female to male ratio. Presentation is commonly abrupt onset of symptoms after a febrile viral illness, pregnancy, immunization, sepsis, surgery, or trauma. The etiology of PD type POTS is postulated to be an autoimmune molecular antigen mimicry type pathogenesis. Serum autoantibodies to peripheral autonomic ganglion alpha-3 acetylcholine receptors may be positive in 10-15% of the cases. Anhidrosis of lower extremities is seen in more than 50% of these patients at quantitative sudomotor axon reflex testingDependent blood pooling when upright is greater than normal and heart rate and contractility increase as normal compensatory physiologic mechanisms to maintain cerebral perfusion. This autoregulatory response may initially be fully compensatory; however, peripheral venous pooling may increase with time and exceed this compensatory effect. Patients with PD type POTS become dependent on the skeletal muscle pump to augment their autoregulatory physiology. Ultimately, venous blood pooling increases beyond the body’s total ability to compensate and adequate blood pressure maintenance fails.

“Developmental” partial dysautonomic POTS is an adolescent subtype.6 The mean age of onset is 14 years. The clinical scenario is that of orthostatic intolerance following a period of very rapid growth. Symptoms are progressive and peak at a mean age of 16 years. Orthostatic intolerance may be severe, including severe headaches, and can be functionally disabling. Following their peak symptoms will slowly improve and resolve into young adulthood (19-24 years). Roughly 80% of patients with developmental PD POTS will experience complete resolution of symptoms. The etiology of this subtype is unclear and appears to be a transient period of autonomic imbalance occurring in rapidly growing adolescents.

Hyperadrenergic POTS is less common than the PD type ,7This form is characterized by a gradual onset with slowly progressive symptoms. Patients report experiencing tremor, anxiety, and cold clammy extremities with upright posture. 7 Many patients note increased urine output when upright. True migraine headaches may be seen in over half of patients.7 Gastrointestinal symptoms in the form of recurrent diarrhea were seen in 30% of the patients. In contrast to PD type of POTS, the hyperadrenergic form demonstrates elevated serum catecholamine levels with serum norepinephrine levels >600ng/ml. This may be a familial syndrome in some instances determined by a careful history. The etiology of hyperadrenergic POTS is felt to be genetic with a single point mutation resulting in a dysfunctional norepinephrine reuptake transporter protein present in the intrasynaptic cleft. The result is excessive norepinephrine serum spillover with sympathetic stimulation resulting in a relative hyperadrenergic state appearing similar to pheochromocytoma. 8

A connective tissue disorder has been an increasingly recognized etiology of secondary POTS 9 . Joint hypermobility syndrome (JHS) is an inherited condition characterized by joint hypermobility, connective tissue fragility, and soft velvety skin with variable hyperextensibility. The condition is associated with ecchymotic predisposition, premature varicose veins, diffuse muscle and joint pain, and orthostatic acrocyanosis. The etiology of POTS in JHS patients is thought to be due to abnormal vascular (venous) elastic connective tissue. During orthostatic stress and increased hydrostatic pressure these patients exhibit increased vessel distensibility and orthostatic intolerance. Excessive peripheral venous pooling and compensatory tachycardia follows. Up to 70% of JHS patients suffer from some degree of orthostatic intolerance. It is observed that adolescent PD POTS patients have features similar to JHS patients and further studies may determine the significance of this potential relationship 10.

Secondary POTS refers to a group of conditions which result in peripheral autonomic denervation with sparing of cardiac innervation. Most commonly, secondary POTS is associated with diabetes mellitus. Less commonly, this form may occur with heavy metal intoxication, multiple sclerosis, parkinsonism and chemotherapy, especially vinca alkaloids.11,12

Severe autonomic nervous system disorders may present as POTS. These may include pure autonomic failure or multiple system atrophy. Paraneoplastic syndrome associated with adenocarcinoma of the lung, breast, ovary, or pancreas may also present as POTS. These tumors produce auto-antibodies targeting the acetylcholine receptors in the autonomic ganglia in a manner similar to post-viral syndromes.

Figure 1. Subtypes of postural orthostatic tachycardia syndrome

Evaluation and Management

Treatment is generally individualized to each patient. Confounding pharmacology should be identified and stopped if possible (Table 2). The presence of secondary POTS should be considered. Underlying diagnoses causing or augmenting POTS should be identified and treated appropriately. Deconditioning is frequent seen in POTS patient and a deliberate aerobic reconditioning program should be a component of the treatment plan. 13 This is encouraged to begin promptly working up to a goal of 20-30 minutes of activity at least 3 times a week. Resistance training of the lower extremities is helpful to increase the efficacy of the skeletal muscle pump. Salt and water ingestion are the most common employed non-pharmacolgical therapeutic intervention for POTS. Although, the intravenous saline infusion has been associated with reduction in standing tachycardia, the effect on this intervention on the symptom reduction remains unknown 14 . In general, since low blood volume may exacerbate symptoms patients are encouraged to have liberal salt and water intake. Excluding hyperadrenergic POTS, daily fluid and sodium intake should be greater than 2 liters and 3-5 grams.

Table 2: Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance
Angiotensin-converting enzyme inhibitors
Alpha receptor blockers
Calcium channel blockers
Beta blockers
Phenothiazines
Tricyclic antidepressants
Bromocriptine
Ethanol
Opiates
Diuretics
Hydralazine
Ganglionic-blocking agents
Nitrates
Sildenafil citrate
Monoamine oxidase (MAO) inhibitors

The goal of pharmacotherapy in the treatment of POTS is to ameliorate the symptoms of POTS and thus maintain the functional capacity. Currently no drug is US FDA approved for the treatment of POTS. All pharmacology is inherently off-label. (Table 3).

Table 3: Therapeutic Options in POTS
Treatment Application Form Effective in Problems
Reconditioning Aerobic exercise 20 min 3 times / week PD, H If too vigorous may worsen symptoms
Hydration 2 liters PO/day PD Edema
Salt 2-4 grams/day PD Edema
Fludrocortisone 0.1-0.2 mg PO daily PD Hypokalemia, hypomagnesemia, edema
Midodrine 5-10 mg PO TID PD Nausea, scalp pruritus, supine hypertension
Methylphenidate 5-10 mg PO TID PD Anorexia, insomnia, dependency
Bupropion 150-300 mg XL daily PD, H Tremor, agitation, insomnia
SSRI-Escitalopram 10 mg PO Daily PD, H Tremor, agitation, sexual problems
Pyridostigmine 30-60 mg PO BID PD Nausea, diarrhea
Erythropoietin 10,000-20,000 IV SQ weekly PD Pain at injection site, expensive
Octreotide 50-200 ug SQ TID PD Nausea, diarrhea, gallstones
Clonidine 0.1-0.3 mg PO BID; 0.1-03 mg patch weekly H Dry mouth, blurred vision
Labetalol 100-200 mg PO BID H Fatigue
PD = partial dysautonomic; H = hyperadrenergic; POTS = postural tachycardia syndrome

Majority of the evidence for the use of different pharmacological agents in the management of POTS is based on some small randomised , observational and retrospective single center studies. In clinical practice most patients are treated with a single agent and second medication from different class with a different mechanism of action is added in case of treatment failure. Resistant cases are often treated with polypharmacy.

Fludrocortisone, a potent mineralocorticoid resulting in sodium retention, augmented fluid volume, and sensitized peripheral alpha adrenergic receptors. The effects are more pronounced in the younger population. Starting dose is 0.1-0.2 mg daily with a maximum dose of 0.4 mg. Common side effects include electrolyte imbalance and hypertension. In a study of 11 female POTS patients, fludricortisone alone or in combination with bisoprolol was associated with improvement in symptoms 15. Midodrine is an alpha -1 adrenoreceptor agonist and causes both arterial and venous vasoconstriction. It is commonly used as add on therapy and with starting dose at 5 mg orally three times a day. In our clinical experience we advise patients to take their first dose of midodrine 15 minutes prior to getting out of bed. An additional 5mg dose can be used for breakthrough symptoms. Midodrine is usually well tolerated with the most common complaints being nausea, “goose bumps,” and scalp pruritus. In a small study of 6 patients with POTS acute combination therapy of midodrine (10mg) with octreotide (0.9mcg/kg) was significantly associated with reduction in upright tachycardia and improved standing time.In another study of 53 children with POTS, midodrine was significantly associated with both higher clinical cure rate and reduced recurrence rate as compared to children treated with metoprolol or conventional therapy.

Patients may continue to be symptomatic despite dual-therapy as outlined above. In this population we add a serotonin reuptake inhibitor (SSRI) or norepinephrine reuptake inhibitor (SNRI). SSRI therapy has been found to be helpful in the prevention of neurocardiogenic syncope. However, SNRI therapy is more useful in the treatment of POTS. Usually, we use bupropion XL beginning with 150 mg orally daily titratable to 300 mg daily if necessary.

The most effective SSRI therapies combine serotonin and norepinephrine reuptake inhibition (venlafaxine and duloxetine). The agents are usually well tolerated with the most common side effects being gastrointestinal upset, tremor, sleep disturbance, and less commonly agitation and sexual dysfunction. Bupropion and SSRI therapy can be combined to achieve a similar effect.

Pyridostigmine is an acetylcholinesterase inhibitor that facilitates sympathetic and parasympathetic ganglionic neural transmission. In our single center experience of 203 patients of POTS treated with pyridostigmine; improved symptoms of orthostatic intolerance were seen in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to tolerate the drug. Fatigue (55%), palpitations (60%), presyncope (60%), and syncope (48%) were the most common symptoms that improved with pyridostigmine. Further, symptom reduction correlated with a statistically significant improvement in upright HR and diastolic blood pressure after treatment with pyridostigmine as compared to their baseline hemodynamic parameters (standing HR 94 ± 19 vs 82 ± 16, P < 0.003, standing diastolic blood pressure 71 ± 11 vs 74 ± 12, P < 0.02). Gastrointestinal problems were the most common adverse effects (n = 39, 19%) seen in our study. 18

Severely affected and refractory patients may benefit from erythropoietin (EPO) therapy. EPO increases red cell mass, central blood volume and augments response of blood vessels to the angiotensin-II and thus causes vasoconstriction. These effects are quite useful in the treatment of orthostatic disorders. Prior to initiation of EPO therapy obtain a complete blood count (CBC), total iron binding capacity, serum iron and ferritin levels. Hematocrit (HCT) levels must be monitored and should remain less than 50 on EPO. The starting dose is 10,000 units via subcutaneous injection once weekly. There is a 4-6 week delay between a given dose and the full clinical effect. The hematogenic and hemodynamic affects are independent but may occur simultaneously. A goal HCT of low to mid 40 will often result in optimum hemodynamic augmentation. Monitoring during EPO therapy should include monthly CBC to document HCT less than 50. EPO therapy may infrequently result in a “serum sickness” type reaction characterized by nausea, fever, chills, and general malaise. In another study of 39 patients (age 33 ± 12, 37 females) with resistant form of POTS, we reported sustained improvement in twenty-seven (71%) patients at mean follow-up of six month with EPO therapy. Eighty (21%) failed to respond to therapy while as 3 (8%) improved with therapy at 3months. Also, erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters.19 We reserve EPO therapy for patients that are refractory or intolerant of other forms of treatment because of its considerable expense and subcutaneous route of administration.

Beta blocker therapy such as metoprolol tartrate may be beneficial in adolescent type POTS patients. In a single center retrospective study of 121 patients with possible POTS, written survey at follow-up were used to evaluate response to therapy with beta-blockers and midodrine. 47 adolescents responded to survey (Walker Functional Disability Inventory Survey) and reported improvement with a β-blocker (100% vs 62%, P = 0.016) and more attributed their progress to medication (63.6% vs 36.4%, P = 0.011) than did those treated with midodrine 20 .In addition, beta-blocker therapy was associated with improved quality of life. Great caution should be taken in using beta-blocker therapy in a rare form of hyperadrenergic POTS secondary to the mast cell activation disorders. Octreotide is a somatostatin analogue with potent vasoconstrictive effects and is useful in the treatment of orthostatic disorders. In patients with resistant POTS, octreotide may be a useful as add on therapy. It is administered by subcutaneous injection 2-3 times daily. The stating dose is 50 ug and may be titrated up to 100-200 ug three times daily.

Agents that block the release or effect of norepinephrine (noradrenaline) are very effective for hyperadrenergic type POTS patients. We use clonidine starting at 0.1 mg orally twice daily and titrating up as needed. The patch form may be preferable to some patients and has the added benefit of providing a steady state drug release for one week. Labetalol, an alpha and beta receptor blocker, is also useful in this group of patients. Dosages of 100-400 mg orally twice daily are used. Methyldopa may have a role in highly selected patients with POTS. Symptom control may be improved with both the SSRI and SNRI classes of medications.

Inappropriate sinus tachycardia (IST) is an important confounding finding in suspected POTS patients. This syndrome is similar to hyperadrenergic type POTS. The clinical presentation may be similar with IST being more common in females. These disease states display and exaggerated response to isoproterenol infusion. It has been postulated that they may represent different states of the same pathologic process. A greater degree of orthostatic change in heart rate is seen in POTS patients. The supine rate rarely exceeds 100 bmp (IST will often be >100). Postural changes in serum norepinephrine levels are much more pronounced in POTS patients. It is important to differentiate POTS and IST. Radiofrequency ablation of the sinus node will rarely benefit hyperadrenergic POTS patients and will make PD POTS patients markedly worse.

Treatment of secondary POTS should focus primarily on the underlying disorder to the greatest extent possible. Diabetes mellitus or JHS related POTS are treated as PD POTS. Secondary POTS due to sarcoidosis or amyloidosis may benefit from steroid therapy. Secondary POTS that is paraneoplastic may completely resolve with treatment of the underlying malignancy but may also respond to pyridostigmine.

Patients suffering from POTS have a disease that affects many aspects of their life. They are often unable to take advantage of meaningful employment or education opportunities. The pervasive life change experienced often results in significant psychosocial disruption as they may be excluded from social norms and certain environments. Frequently, patients require psychologists, social workers, and lawyers to address these aspects of living with POTS. The treating physician is a prominent and central figure who is a beacon of hope for this population. A positive, caring, and nurturing attitude may be the best medicine and lead to a rewarding rapport where an otherwise challenging disease exists.

Prognosis

There is limited data on the prognosis of POTS patients. Recent short term follow-up studies have shown better prognosis in patients with POTS. 21 Roughly 50% of post-viral POTS patients make a meaningful recovery over about 2-5 years. Meaningful recovery may be defined as the absence of orthostatic symptoms and the ability to perform the activities of daily living with little or no restriction. Some patients experience a partial recovery and still others may demonstrate a progressive functional decline with time. As a general principle, a younger age of onset portends a better prognosis. A majority of patients tend to adopt different lifestyle modifications including increased fluid and salt intake to improve and reduce exacerbation of the POTS symptoms. In secondary POTS syndromes have a prognosis consistent with the underlying causative disorder.

Conclusion

Disruption of normal autonomic function may manifest as one of a heterogeneous group of clinical disorders collectively referred to as postural orthostatic tachycardia syndrome. Treatment is most successful when diligence has been taken to investigate the underlying disorder or POTS subtype and a comprehensive targeted treatment program is instituted with frequent follow up. Goals of care should focus on functional milestones and maintenance of function.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RONALD CONNER, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA. MUJEEB SHEIKH, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA. BLAIR GRUBB, MD, Professor of Medicine, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA.
Corresponding Author Details: 
Mujeeb Sheikh, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, Ohio, USA, 43614.
Corresponding Author Email: 
Mujeeb.sheikh@utoledo.edu
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  17.  Chen L, Wang L, Sun J, et al.Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. Circ J. 2011;75(4):927-31. Epub 2011 Feb 2.
  18. Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience. Pacing Clin Electrophysiol. 2011 Jun;34(6):750-5
  19. Kanjwal K, Saeed B, Karabin B, et al.Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Am J Ther. 2012 Mar;19(2):92-5.
  20. Lai CC, Fischer PR, Brands CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers.Pacing Clin Electrophysiol. 2009 Feb;32(2):234-8.
  21. Alexandra Sousa, Ana Lebreiro, Joa˜o Freitas, et al. Long-term follow-up of patients with postural tachycardia syndrome. Clin Auton Res (2012) 22:151–153

Over-the-counter and purchase-on-internet medications - Implications for psychiatry

Authors
Francis J Dunne, Mariam Omar, Nasser El-Hindy and Khalid Jaffar
Article Citation and PDF Link
BJMP 2012;5(4):a535

An unquestioning belief in the power and efficacy of nature's healing remedies and processes, the placebo effect, disappointment and  dissatisfaction with conventional medicines, outright rejection of orthodox treatments, convincing and persuasive  advertising, reinforcement from others with similar views, endorsement by influential celebrities, perceived hand-me-down wisdom, bogus pseudoscientific claims, uncritical journalism, scare-mongering, feelings of desperation for a 'cure', and anecdotal case studies or surveys masquerading as research, are among  the many reasons why patients and the public choose to alternative medicines either bought through local stores, pharmacies or on the internet. Over-the-counter drugs (OTCs)  or over-the internet remedies are taken either with or without conventional medicines by millions of people every year and while most are harmless and safe to use there are inherent dangers of additive effects and interference with prescribed medications.

Benefits for patients who use OTCs include the convenience and sometimes less costly outlay on prescription drugs (analgesics, for example). Preparations may vary in price, according to the pharmaceutical provider. Self-treatment of minor ailments should theoretically lead to less pressure on GPs. Unfortunately, some patients tend to self-medicate for long periods (for example, analgesics) without visiting their GP for a health check to monitor the condition(s) for which they are using the OTC remedy to begin with. There is also the incorrect but widespread belief that because a prescription is not necessary to obtain these drugs they must be much less harmful than prescription-only preparations. Medicines may be used inappropriately, such as paracetamol for insomnia, or aspirin for stomach aches. Very often no record of OTCs is documented in the patient's notes. The list of OTCs is too numerous to cover in any detail here and for practical reasons the authors will concentrate on common legal products which most people are familiar with.

What causes the adverse effects?

An understanding of drug interactions gained momentum through the study of metabolizing enzymes. Cytochrome P450 inhibition or induction is probably the main mechanism for the pharmacokinetic interactions of drugs. CYP450 enzymes are haemoproteins (like haemoglobin) which comprise many related though distinct enzymes referred to as CYP. Over 70 CYP gene families have been described so far and are further divided into families and subfamilies of which CYP1, CPY2 and CYP3, are involved in hepatic drug metabolism.1  Thus, CYP3A denotes a cytochrome P450 enzyme that is a member of family 3 and subfamily A. It is abundant in liver and intestine. In the liver CYP450s are found mainly in the smooth endoplasmic reticulum. Any inhibition of CYP enzymes may result in enhanced plasma and tissue concentration of drugs, leading to toxicity. Likewise, induction may result in reduced drug concentration leading to decreased drug efficacy and treatment failure. Tricyclic antidepressants are substrates of 2D6 (CYP450 2D6 in full), which inactivates them by hydroxylation. For example, if a tricyclic antidepressant is given concomitantly with the serotonin/ noradrenaline reuptake inhibitor venlafaxine, the levels of the tricyclic antidepressant will rise because venlafaxine inhibits CYP450 2D6 and therefore prevents the breakdown of the tricyclic compound. Similar effects can occur with paroxetine, duloxetine, fluoxetine and atomoxetine. However, in clinical practice only atomoxetine requires dosage reduction when given with a 2D6 inhibitor. 2

Diphenhydramine (a common ingredient in sleeping tablets) in therapeutic doses inhibits CYP45 2D6-mediated metabolism of venlafaxine in humans. Venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s 3 Of all the marketed drugs, about 60% are metabolized by the CYP450 system. The presence of the latter in red blood cells and hepatocytes contributes to the first-pass metabolism of drugs. This will have add-on effects when CYP450 inhibitors are simultaneously ingested. For example, grapefruit juice inhibits this enzyme system and therefore the bioavailability of drugs taken by mouth will increase causing a reduction in first-pass effect (presystemic metabolism).4

Common varieties of OTCs

Many commonly used OTC preparations (other than food supplements and analgesics) contain the ingredient dextromethorphan (related to codeine), used to treat coughs, colds and flu symptoms. Up to 125 different types of cold medicines contain dextromethorphan. It is an effective cough suppressant (antitussive) that works by raising the coughing threshold. It is not an analgesic. Cough syrups and tablet or capsule forms of medicine that contain dextromethorphan may lead to loss of coordination, dizziness and, nausea when used in high doses. Dextromethorphan is the d-isomer of the codeine analogue of levorphanol which mimics morphine. It is relatively nontoxic and its antitussive effects last for about 6 hours. It should be avoided when an MAO inhibitor is concomitantly given.

The generic term antihistamine refers in general to the H1 receptor antagonists used for inflammatory and allergic conditions. Sedation is a prominent feature of the H1 antagonist, diphenhydramine, used for allergies such as hay fever (short-term beneficial effect) and for symptomatic relief of the common cold. Guaifenesin, derived from the guaic tree, is a common ingredient found in cough expectorants. It is usually harmless though may cause problems in patients with compromised renal function. The mechanism of action, if any, is not known, save that it 'reduces viscosity’ of respiratory secretions.

OTCs believed to help weight loss, such as laxatives, diuretics and diet pills, are often purchased either for genuine health concerns or for misuse. All have serious and potentially fatal side effects if taken for a long time, particularly electrolyte disturbances.5  Where diet pills are concerned problems may emerge insidiously with a few pills, quickly escalating to addiction. The alkaloid eephedrine is the principal active ingredient in the herb ephedra or ma huang. It is a potentially dangerous stimulant (sympathomimetic amine) contained in diet pills. Among the many possible side effects of diet pills are of course excessive weight loss with its attendant problems, alopecia, insomnia, and anxiety.

Used daily by millions of people worldwide, coffee and tea contain the methylxanthines caffeine and theophylline which act mainly by antagonism at purine receptors and by inhibiting phosphodiesterase. The effect is akin to a beta-adrenoreceptor agonist action. Caffeine is naturally found in certain leaves, beans, and fruits of over 60 plants worldwide. Its bitterness acts as a deterrent to pests. It can also be produced synthetically. Other than coffee and tea, the most common sources in the diet are cocoa beans, cola, and energy drinks. Product labels are required to list caffeine in the ingredients. Caffeine consumption in excess of 250mg daily produces symptoms indistinguishable from anxiety, including nervousness, irritability, tremulousness, muscle twitching, sleep disturbance, tachycardia, tachypnoea, palpitations, ectopic beats, and diuresis. A withdrawal syndrome can also occur and is associated with headache and a general muzziness.  Caffeine may interfere with the effectiveness of drug treatment. For example, clozapine plasma levels can be raised, presumably through competitive inhibition of CYP1A2.6  In general terms, an average cup of brewed coffee contains 100mg caffeine per cup, Red Bull 80 mg/ 250ml per can, tea 45mg/ cup, instant coffee 60mg/ cup and filter coffee 120mg of caffeine per cup. Excess consumption of Red Bull may cause myopathy due to caffeine-mediated hypokalemia and rhabdomyolysis.7

Paracetamol (acetaminophen in the USA) is metabolized in the liver. It is probably the most common household analgesic and is present in a variety of preparations and is usually well tolerated. Drugs that increase the action of liver enzymes which metabolize it for example, carbamazepine, isoniazid, and rifampin, reduce the levels of paracetamol and decrease its action. Doses greater than recommended may result in liver damage and in overdose a potentially fatal hepatic necrosis can occur.

Not much is known about the contents of home medication cabinets (HMCs), the management of leftover medications, and the inclination of patients toward self-initiated treatment using non-prescription drugs. One cross-sectional study conducted in 72 Belgian community pharmacies revealed that the most frequently encountered categories of registered medicines were NAIDs, nasal decongestants, and drugs used for nausea. Despite their high prevalence, NSAIDs and non-opioid analgesics did not predominate (14%) among the most frequently used drugs: food supplements were used daily in 23.3% of households. Twenty-one per cent of the drugs were expired, 9% were not stored in the original container, and the package insert was missing for 18%. Self-medication, although generally acceptable in terms of indication and dosage, was commonly practiced, also with prescription drugs. Taking into account that younger people showed a significantly higher rate of self-medication, awareness of the risks of self-medication is warranted. 8

Relevance to Psychiatrists

Many psychiatric conditions are associated with excess alcohol use which complicates the picture when OTCs are used concurrently. Mixing alcohol with medication has the potential to cause nausea and vomiting, headaches, drowsiness, fainting, and loss of coordination. Because so many drugs can be bought without a prescription potential interactions with alcohol are often forgotten. Teenagers see OTCs as safer than illegal drugs and OTCs are sometimes taken to get a buzz or to help stay awake while studying. The home medicine cabinet allows quick access. Besides, parents will most likely have given an OTC preparation to their children for colds or other minor everyday ailments. Most drug education programmes however, focus primarily on illegal drugs, not OTC drugs and their potential for abuse.

Of some interest and importance to psychiatrists is the interaction when warfarin is combined with ginkgo (Ginkgo biloba) causing bleeding, a mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors. decreased bioavailability of digoxin  when combined with St John's wort, induction of mania in depressed patients who mix antidepressants and ginseng, exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine. Disulfiram which inhibits aldehyde dehydrogenase inhibits the metabolism of warfarin. Metronidazole causes an unpleasant disulfiram-like reaction when mixed with alcohol. Consumption of 6-8 glasses of grapefruit per day may raise levels of carbamazepine and pimozide. Grapefruit juice is thought to the metabolism of many drugs and inhibition can last a number of hours. 9 The St John's wort component, hyperforin, contributes to the induction of CYP3A4. St John's wort also enhances the metabolism of other CYP3A4 substrates including the protease inhibitors indinavir and nevirapine, oral contraceptives, and tricyclic antidepressants such as amitriptyline. Other herbal remedies with the potential to modulate cytochrome P450 activity include ginseng, garlic preparations, and liquorice. 10  Intake of St John's wort increases the expression of intestinal P-glycoprotein and the expression of CYP3A4 in the liver and intestine. The combined up-regulation in intestinal P-glycoprotein and hepatic and intestinal CYP3A4 impairs the absorption and stimulates the metabolism of cyclosporine, leading to subtherapeutic plasma levels.

The hormone melatonin plays a role in regulating the sleep-wake cycle but does not induce sleep per se.  It is easily available through the internet and over-the-counter in the USA and many people use it for jet lag. Melatonin has side effects including diarrhoea, abdominal pain, headaches, nightmares, morning hangover, nausea, mild depression and loss of libido. Melatonin is used for many other complaints including tinnitus, depression, chronic fatigue syndrome (CFS), fibromyalgia, migraine and other headaches. Valerian root, a medicinal herb has been known to cause liver damage and should be used with caution. It too is most commonly used for insomnia and frequently combined with hops, lemon balm, or other herbs.

Many complementary medicines prescribed for anxiolysis/sedation (e.g. kava kava, valerian, passion flower and chamomile) are GABAergic, GABA (formed from glutamate) being the major inhibitory mediator in the brain, though for some, such as hops, the mechanism of action remains unknown. As expected, all remedies can lead to drowsiness when taken in high doses and can potentiate the effect of synthetic sedatives.11  Kava has been taken off the market because of its hepatoxicity.

Although sufficient dietary fibre and water are effective for the treatment of constipation some patients fear they are building up 'toxins' if they do not have 'regular' bowel habits. Often constipation is caused by opiate analgesics which are widely available, and in many cases patients are using antidepressant/psychotropic medication concurrently. The tendency to misuse laxatives is commonly seen in anorexia nervosa though is not confine to that disorder. The osmotic laxative lactulose is a disaccharide of galactose and fructose and therefore care is needed where diabetic patients are concerned particularly if they are taking neuroleptic medications such as clozapine or olanzapine. Abdominal cramps and diarrhoea can occur with high doses. Laxatives have the potential to interfere with potassium levels, usually causing hypokalemia. 5

Ordinary foods and drinks may interfere with prescribed medications.12  Grapefruit juice reduces the metabolism of calcium channel antagonists. Vegetables such as broccoli, cabbage, and Brussels sprouts are putative cytochrome P450 inducers and are known sources of vitamin K. Red wine, ethanol and cigarette smoke are also believed to induce the cytochrome P450 system and have the potential to interfere with the metabolism and catabolism of many drugs. Smoking interferes with clozapine metabolism. When smokers are prescribed clozapine abrupt smoking cessation may lead to high plasma concentrations with potentially serious consequences. Clozapine plasma concentrations can rise 1.5 times in the 2–4 weeks following smoking cessation.13 and in some instances by 50–70% within 2–4 days. Where baseline plasma concentrations are higher, particularly over 1 mg/litre, the plasma concentration may rise dramatically owing to non-linear kinetics. If patients smoking more than 7–12 cigarettes per day while taking clozapine decide to quit, the dose may need to be reduced by 50%.14  Smoking also interferes with duloxetine levels due to an induction of CYP1A2 by hydrocarbons contained in tobacco smoke. It cannot be expected that patients would be aware of these facts, let alone understand the pharmacology of the multitude of chemicals contained in OTCs. 15

Availability does not mean harmless

Most people using OTCs are unaware of the potential for harm. Herbal remedies, for instance, with their attractive packaging, convey the impression of being beneficial merely because they contain 'earth minerals' and other 'natural ingredients:' therefore they must be beneficial for health, rather like eating vegetables or taking vitamins.10 There are numerous instances of drug interactions and many preparations may contain contaminants such as mercury, lead, and arsenic. One of the commonest ingredients in many lotions and potions is hydrocortisone, which if used liberally may cause skin atrophy. The most worrying aspect of OTCs is that they give hope to people with serious conditions which might be better treated with conventional medicines - multivitamins for cancer, mineral supplements for constipation, and so forth. With buzz words such as 'healing, energy, vitality, harmony, body balance, healthy living, total well-being, holistic', and 'traditional', targeting the sometimes gullible consumer, OTCs become very appealing. Others are taken in by the pseudoscientific jargon, 'healing powers, purifying the blood, eliminating toxins from the bowel', boosting one's immune system, and so forth. The outcome can be serious: for example, Chinese herbal medicines containing extracts from Aristolochia plants have been implicated in the high incidence of urinary tract cancer in Taiwan, a study has suggested 16  because aristolochic acid has a consistent pattern of inducing DNA damage.

Some patients may be coincidentally taking conventional, proven medicines yet attribute their improved health to the alternative remedy. Other beneficial factors which are often conveniently ignored include a change in diet, increased wellbeing through physical exercise, or going on holiday! There is of course, the natural remission of the illness, particularly with transient viral infections, or unexplained lower back pain, to cite two instances. 17

Some common problems

Although the dangers of the common analgesics are relatively well-known (paracetamol causing liver damage, gastrointestinal upset with ibuprofen), patients are often unaware of the potential for adverse effects with other preparations. Nor are they always aware that many compounds combine two analgesics, for example, paracetamol and aspirin, or paracetamol and ibuprofen. Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with renal clearance and may result in elevated lithium levels with resultant toxicity.18 Combined use of an antidepressant or sodium valproate with an OTC could lead to abnormal liver function tests attributed solely to the former agents and not the OTC. Even reading the label does not guarantee insight and understanding of what is on offer. Labels are carefully and handsomely packaged by advertisers to persuade people their product is better than conventional medicines.  Most consumers spend little time reading the labels about ordinary foodstuffs, never mind the chemical constituents of OTCs. In transplant patients, self-medication with St John's wort (hypericum perforatum) may lead to a drop in plasma levels of the immunosuppressant drug cyclosporine, causing tissue rejection. In the US, the Food and Drug Administration (FDA) with branches in other cities, including London (European Medicines Agency) approved a regulation in 1999 requiring that all OTC drug labels contain certain information such as ingredients, doses and warnings in a standardized format. This covers thousands of non-prescription products, including sunscreens. In the same way that people understand the nutritional value of foods, it is hoped that its efforts will help people use OTCs safely.

Sexual side effects are a frequent accompaniment of psychotropic drugs and patients are often bothered by impotence to such a degree they resort to surfing the internet to acquire sildenafil (Viagra) and the like. Such over-the-internet medicines are easy to acquire. Carbamazepine and St John's will decrease the level of sildenafil by competition with CYP3A4. Ketoconazole, the antifungal agent, works in a similar mechanism and may in increase the levels of citalopram. Metronidazole has a disulfiram-like reaction with alcohol.

There is also the problem of addiction with OTCs because of ease of access to opioid compounds. Patients often do not perceive them as having addictive potential. Preparations containing ephedrine or dextromethorphan can be abused. Ephedrine is still used as a nasal decongestant. As an indirectly-acting sympathomimetic amine it can react dangerously with monoamine oxidase inhibitors because of the increased amount of noradrenaline stored in noradrenergic neurones. Opioids may be crushed and the powder snorted or injected leading to euphoria or elation, followed by addiction when compulsive use takes over. Patients may be subject to mood swings making underlying psychiatric disorders and drug treatment difficult to manage. Opioids produce drowsiness, and depress respiration in high doses. The combination with sedative psychotropic medication such as mirtazapine, olanzapine or quetiapine could be deleterious especially where there is concomitant weight gain. Buspirone (a 5-HT1A receptor agonist used for anxiety) may interact with monoamine oxidase inhibitors (MAOIs), such as isocarboxazid, phenelzine, and tranylcypromine. Use of buspirone with these drugs can increase blood pressure. The combination of buspirone and trazodone may raise LFTs. The combination of buspirone and warfarin may accentuate the effects of warfarin and increase the risk of bleeding. Patients taking buspirone should not drink grapefruit juice, since even some time after a dose is taken, the amount of buspirone in the blood may be increased. Carbamazepine increases the metabolism of the pill reducing its effectiveness. The pill is more easy to acquire now (clinics and/or the Internet) and therefore unexpected pregnancies may occur in patients taking both. Cimetidine may increase the blood levels of sertraline by reducing its elimination by the liver. St John's wort interacts with the metabolism of the pill and this can result in unwanted pregnancies.

Overall OTCs are generally safe, though not where young children and pregnant women are concerned. Vitamins are safe unless taken in very high doses. Deficiency is rare in developed countries (apart from vitamin D) and therefore they are often taken unnecessarily 'to achieve balance' or for 'vitality and energy', and other eye-catching spurious claims. Glucosamine, an amino sugar, seems to be the most popular OTC dietary supplement for the treatment of osteoarthritis. It is naturally present in shellfish and in some fungi. Apart from occasional allergic reactions and mild gastrointestinal symptoms, it is generally innocuous, though conclusive evidence for its efficacy in osteoarthritis is lacking. Fish oil supplements usually come from mackerel, herring, tuna, halibut, salmon and cod. There is some evidence that omega-3-fatty acids contained in fish oils are beneficial for cardiovascular problems but more trials are needed. Side effects are minimal and include mild gastrointestinal upset. 19

Doctors' dilemma

Is there a solution? Probably not, though one way to increase consumers’ awareness of the dangers associated with OTCs could be to change their status to match that of drugs such as simvastatin—they would still be sold over the counter, but with a pharmacist’s supervision. The list of OTCs is rising leading to increased intake of phytochemicals in addition to the usual gamut of medicines used to treat upper respiratory infections. Potentially fatal interactions can occur with OTCs and traditional drugs. Providing better training for pharmacy staff, and restriction of the quantity sold per costumer, should also be considered, though with so many retail outfits selling these products this is probably unrealistic. Besides, many of these products are available on the shelves, not necessarily at the pharmacy counter.

The most common addictions are combinations of opioids with standard analgesics. The Internet is an easy source for prescription drugs, increasing their availability and eliminating the need to see a doctor. Is there an epidemic of prescription opiate use? It is difficult to tell. Effective prevention, public information, and treatment policies require sound epidemiological data about drug use to ensure policy-making is not distorted by stories of celebrity arrests and media-generated hysteria which tend to give that impression that use of illegal drugs is rife. The lack of knowledge about the ubiquitous presence of unknown ingredients in OTCs may be a source of concern in the future when even more become easily available.

It is difficult for doctors and other health care professionals to advise patients on the effectiveness and safety of OTCs. The numbers of well-designed studies available for review are limited, often conducted in a small number of healthy participants, and for short time periods only.20 A survey conducted by questionnaire in 238 follow-up UK rheumatology outpatients in three centers found nearly half (44%) had taken various herbal remedies or over-the-counter (OTC) preparations over the past 6 months. The most commonly used were: cod-liver oil, glucosamine, and/or chondroitin, and evening-primrose oil. Rheumatology outpatients have a particularly high risk of interactions with conventional medication because of polypharmacy and comorbidity. Gingko biloba, devil's claw, ginger, and garlic may have antiplatelet or anticoagulant effects and may exacerbate the gastrointestinal bleeding risk of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids. Echinacea (taken by 4%) may be hepatotoxic and could exacerbate the adverse effect of disease-modifying antirheumatic drugs (DMARDs). Most patients are unaware of the potentially harmful interactions.21

The authors carried out a small audit of consecutive outpatients and staff on a random basis seen in our unit. Of the 45 people who completed the questionnaire 70% affirmed use of OTCs, either presently or in the past. A high percentage (73%) had never been asked by their GP about these 'alternate medicines' and among health professionals 25% never enquired from patients about the use of OTCs. More than half (63%) were unaware of possible side effects before taking them and nearly 50% had not considered that the OTCs might interact with prescribed medication. As would be expected, the majority of users (84%) did not experience any side effects. Nonetheless 16% experienced unpleasant adverse effects such as tachycardia, nightmares, drowsiness, cough, constipation, and exacerbation of asthma. When asked who had recommended the preparation/s the response was generally, 'friends' or 'I knew about it myself'. When asked why they bought it over-the-counter, the response was 'just in case I need it', 'cheaper than prescription' 'it is a natural remedy' 'it's only Nurofen'. As with most surveys, the commonest preparations were analgesics, laxatives, glucosamine for arthritis, and decongestants. Others bought OTCs to promote good health because they are herbal and natural', for example, ginkgo biloba. In a separate random survey of 50 consecutive outpatients carried out by FJD and N El-H, some 40% were taking herbal remedies.

Conclusion

Medical care has become fragmented in recent years. The family doctor of old no longer acts as a gatekeeper to coordinate medications patients are prescribed. A gynaecologist may prescribe the pill to a patient and a walk-in clinic may prescribe an antibiotic to the same patient. How does a doctor inform the patient that antibiotics decrease the effectiveness of the pill if the doctor is unaware of the myriad of other supplements including OTC medications, a patient is taking? Although a patient should bear some responsibility, in reality he/she may not have the expertise to discern the complications and interactions of medications. Besides multiple use of preparations is more often a problem of older age groups who frequently have many health problems. The family pharmacist has also been lost to mail-order pharmacies and sometimes suspect internet web sites. Because of the increase in numbers of prescriptions and OTCs, doctors and pharmacists are using computer programs to establish what is safe and what is not.

Strategies to mitigate these problems could include more general enquiries about prescriptions, OTC, and herbal drug use at the initial examination. 22 Even though some patients may be aware of the potential for drug misuse, others are naive and do not realize the harm involved. Providing containers to enable patients to dispose of unused or unneeded prescriptions or OTC medications is another tactic. Treating the underlying causes (of pain, for example) more aggressively may obviate the need for   patients adding OTCs to their drug list. Practicing careful record keeping of prescription refills and tightening controls over prescription blanks are other practical measures. Where patients have become addicted to medications, programmes such as Narcotics Anonymous may help.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
FRANCIS J DUNNE, MARIAM OMAR, NASSER EL-HINDY, KHALID JAFFAR, Romford Community Recovery Team, UK.
Corresponding Author Details: 
FRANCIS J DUNNE, Romford Community Recovery Team, Victoria Centre, Pettits Lane, RM1 4HP.
Corresponding Author Email: 
dunnefrancis@googlemail.com
References
References: 
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  2. Stahl SM. Stahl's Essential Psychopharmacology. Neuroscientific Basis and Practical Application. 3rd ed. Cambridge University Press; 2008:603-09.
  3. Ball SE, Ahern D, Scatina J, Kao K. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2. Br J Clin Pharmacol. 1997; 43: 619-26.
  4. Lim GE, Li T, Buttar HS. Interactions of grapefruit juice and cardiovascular medications: a potential risk of toxicity. Exp Clin Cardiol. 2003; 8: 99-107.
  5. Dunne, FJ, Feeney S, Schipperheijn J. Selective 5-HT reuptake inhibiting antidepressants in general practice. Psychiatry in Practice. 1991; 10: 6-9. 
  6. Hägg S, Spigset O, Mjörndal T, Dahlqvist R. Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2000; 49: 59–63. 
  7. Ernest D, Chia M, Corallo CE. Profound hypokalaemia due to Nurofen plus and Red Bull misuse. Crit Care Res. 2010; 12: 109-110.
  8. De Bolle, L, Mehuys E, Adriaens E, Ramon JP, Van Borte L., Christiaens T. Home medication cabinets and self-medication: a source of potential health threats? Ann Pharmacother. 2008; 42: 572-579.
  9. Fugh-Berman A. Herb-drug interactions. Lancet. 2000: 355: 134-38.
  10. Dunne FJ. The Natural Health Service: natural does not mean safe. Advances in Psychiatric Treatment. 2009; 15: 49-56.
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  12. Bailey DG, Malcolm J, Arnold O, Spence D. Grapefruit juice-drug interactions. (1998) Br J Clin Pharmacol. 1998; 46:101-10.
  13. De Leon, J. Atypical antipsychotic dosing: the effect of smoking and caffeine. Psychiatric Services. 2004; 55: 491–93.
  14. Haslemo T, Eikeseth PH, Tanum L, Molden E, Refsum H. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006; 62:1049–53.
  15. Fric M, Pfulhmann B, Laux G, Riederer P, Distler G, Artmann S, Wohlschlager M, Liebmann M, Deckert J. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry. 2008; 151-55.
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  20. Cooper RJ. Over-the-counter medicine abuse -- a review of the literature. J Substance Use. 2011; 3:1-26
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Risk of Breast Cancer due to Hyperprolactinemia caused by Antipsychotics (Neuroleptics)

Authors
Umesh Vyas
Article Citation and PDF Link
BJMP 2012;5(4):a534
Abstract / Summary
Abstract: 

Breast cancer is the most common cancer in females, and is the second most common cause of death. There are several factors which increase a woman's risk for the development of breast cancer. Some reports suggest that neuroleptics and other dopamine antagonists increase the risk of breast cancer due to hyperprolactinemia. There are other reports which suggest that they may decrease the risk of cancer especially rectum, colon and prostate.  Additionally, there is evidence that patients with Parkinson's disease have lower rates of breast cancer and other types of malignancies.

Keywords: 
Hyperprolactinemia, Antipsychotics, Breast cancer

Introduction

Prolactin is a polypeptide hormone that is secreted by lactotrophs of the anterior pituitary gland. Prolactin secretion shows a circadian rhythm1, with highest levels occurring during the night and the nadir occurring during the afternoon and eveningThe best known function of prolactin is the stimulation and maintenance of lactation.

Normal basal levels of serum prolactin are approximately 20 to 40 ng/ml in women (depending on the phase of their menstrual cycle), and 15 ng/ml in men. However, these concentrations can also vary with ageHyperprolactinemia is diagnosed when serum prolactin concentrations are >20-25 ng/ml (400-500 mU/l) on two separate occasions3.

Hyperprolactinemia is the most common disorder of the hypothalamic-pituitary-gonadal (HPG) axis4 and can have physiological causes - pregnancy, nursing, sleep, stress, sexual intercourse or pathological causes - tumor called prolactinomaMultiple factors are involved in prolactin secretion (Figure 1). However, hyperprolactinemia is also a common side-effect of traditional antipsychotics (e.g. haloperidol) and is associated with the use of some newer second generation agents2, 6.

Figure 1: Factors involved in Prolactin secretion

The prevalence of hyperprolactinemia is low in the general population (0.4%), but it can be as high as 9 to 17 % in women with reproductive disordersThe disease occurs more frequently in women than in men, multiple signs and symptoms associated with hyperprolactinemia (Table 1).

Multiple variables affect probability of development of breast cancer (Table 2) and a number of important factors determine the risk for breast cancer, and the most important of these seem to be related to estrogen and possibly prolactin (Table 3).

Table 1: Signs and Symptoms of Hyperprolactinemia
  • Gynaecomastia
  • Galactorrhoea
  • Infertility
  • Menstrual irregularities: oligomenorrhoea, amenorrhoea
  • Sexual dysfunction: decreased libido, impaired arousal, impaired orgasm
  • Acne and hirsutism in women (due to relative androgen excess compared with low estrogen levels)
  • Behavioural effects
  • Decreased bone mineral density (BMD) which may lead to increased risk of osteoporosis.

 

Table 2: Probability of Developing Breast Cancer32
Risk of Breast cancer

Variables Increased Decreased
Age Older Younger
Socioeconomic status Higher Lower
Family history of breast cancer Present Absent
Racial Caucasian Oriental
Geographic America Asia
Marital status Single Married
Age at first pregnancy Older Younger
History of multiple pregnancies Present Absent
Age at menarche Younger Older
Age at natural menopause Older Younger
Artificial menopause Absent Present

 

Table 3: Epidemiology of breast cancer7
  • Age of menarche
  • Late pregnancy
  • Obesity
  • Caucasian females have slightly higher incidence
  • The highest incidence of breast cancer occurs after age 35, with 83% of the cases occurring after age 50 and only 1.5% under age 30
  • 1 in 11 women will develop breast cancer sometime during their lifetime
  • The highest incidence of breast cancer in the US is found in the northeastern part of the country
  • The women with previous cancer of one breast are at risk for cancer in the opposite breast
  • A woman whose natural menopause occurs before age 45 has only half the breast cancer risk of those whose menopause occurs after the age of 557.

Methods

Pubmed.gov searched by using keywords

Antipsychotics and Hyperprolactinemia

Hyperprolactinemia is caused by these agents by blocking D2 receptors on lactotrophs and thus preventing inhibition of prolactin secretion. Furthermore, it has been suggested that the degree of elevation of prolactin correlates with the degree of occupation of D2 receptors in excess of 50%8.

Most studies have shown that conventional antipsychotics are associated with a two to tenfold increase in prolactin levels9, 10. In general, second generation antipsychotics produce a lower increase in prolactin than conventional agentsAmong second generation antipsychotics associated with increased prolactin are amisulpride, zotepine and risperidone11, 12, 13.

Antipsychotic induced Hyperprolactinemiaand Breast cancer

Prolactin is known to increase the incidence of spontaneously occurring mammary tumors in mice14 and increase the growth of established carcinogen-induced mammary tumors in rats15.

Prolactin and other sex hormones such as, estradiol and progesteroneare important in normal mammary gland growth and developmentas well as lactation. Both animal and in vitro data suggestthat prolactin is involved in tumorigenesis by promotingcell proliferation, increasing cell motility,and improving tumor vascularization. Whereas prolactinand its receptor are found in normal and malignant tissues,concentrations of both are generally higher in malignant tissue16.

Several studies have linked hyperprolactinemia to an increased risk of breast cancer in women17, 18. Mechanisms that have been suggested to explain this possible action of prolactin include the increased synthesis and expression of prolactin receptors in malignant breast tissue and a prolactin-induced increase in DNA synthesis in breast cancer cells in vivo18.

One of the hypothesized roles of prolactin in the development of mammary tumors is to create mammary gland conditions favorable for the action of carcinogens through its stimulation of the rate of mammary gland DNA synthesis, a measure of the frequency of mammary gland cell division19.

Several epidemiological studies have investigated whether female psychiatric patients receiving treatment with antipsychotics have a higher incidence of breast cancer but results have been conflicting. However, the most recent and methodologically strong study, found that antipsychotic dopamine receptor antagonists conferred a small but significant risk of breast cancer. This study had a retrospective cohort design and compared women who were exposed to prolactin-raising antipsychotics with age-matched women who were not20.

Conversely, other studies have shown no correlation between hyperprolactinemia and breast cancer21, 22. Furthermore, as most breast cancers are thought to be fueled by estrogen23, and hyperprolactinemia causes estrogen deficiency24, it is perhaps surprising that hyperprolactinemia has been linked with an increased risk of breast cancer. Indeed, post-operative hyperprolactinemia in breast cancer patients has been shown to improve disease free and overall survivalObviously, more studies are necessary to define any possible links between hyperprolactinemia and breast cancer.

In view of these problems it would be of interest to go around the contentious issue of possible carcinogenic effects of dopamine antagonists using a classical condition of dopamine loss or attenuation as in Parkinson's disease (PD). Using computerized registers of death data of the National Center of Health Statistics for years 1991 through 1996, estimated 12,430,473 deaths of persons over forty, and extracted 144,364 cases with PDTellingly, PD patients showed a highly significant reduction of overall cancer incidence. PD resistance to breast cancer might conceivably be attributed to dopaminergic treatment antagonizing hyperprolactinemia26, 27, 28.

Another recent study showed that dopaminergic therapy inhibits angiogenesis thereby acting as an anti-tumor agent29.

Epidemiological studies of women who have received prolactin-releasing drugs such as reserpine and perphenazine have not disclosed increased risk30.

Antipsychotic induced Hyperprolactinemia and Other cancers

Antipsychotics have been hypothesized to account for the reduced cancer occurrence observed in patients with schizophrenia in a number of studies. This reduction has been found primarily in men in smoking-related cancers, and in prostate and rectal cancer.

In addition, a study found a reduced risk of rectal cancer in both men and women as well as indications of a reduced risk of colon and prostate cancer in this population-based cohort of neuroleptic users. Reassuringly, they observed no increased risk of breast cancer in female users31.

Comments and recommendations

  • Hyperprolactinemia results from treatment with any drug that disrupts dopaminergic function on the HPG axis and is not limited to the use of antipsychotics.
  • Management of supposed anti-psychotic associated hyperprolactinemia should exclude all other causes, involve regular monitoring of adverse effects and include a regular risk-benefit discussion with patient.
  • Switching the patient to prolactin-sparing antipsychotic (i.e. Aripiprazole, Olanzapine, Quetiapine or Clozapine) usually proves effective, though there is also a risk of relapse.
  • It seems prudent to avoid prescribing prolactin-raising antipsychotics in patients with past history or family history of breast cancer.
  • It is premature to mandate warning patients of an unknown and undemonstrated increase in the risk of developing breast cancer associated with neuroleptic treatment.
  • Before initiating antipsychotic treatment a careful examination of patient is necessary.
  • One should examine the patient for evidence of sexual adverse events, including menorrhagia, amenorrhoea, galactorrhoea and erectile/ejaculatory dysfunction. If evidence of any such effects is found, then the patient's prolactin level should be measured.
  • Patient history, physical examination, pregnancy test, thyroid function test, blood urea and creatinine level can help determine if other etiologies are responsible.
  • Presence of headache and visual field defects is suggestive of a sellar space-occupying lesion (MRI indicated), but the absence of these features does not exclude such pathology.
  • History of menstrual cycling (duration, amount and intervals of menstruation) as well as lactation and sexual functioning should be taken before antipsychotic medication is initiated.
  • Obtain a pretreatment prolactin level, which one can compare with subsequent samples if the patient develops symptoms associated with relatively modest hyperprolactinemia.
  • The risk-benefit ratio for treatment of antipsychotic-induced hyperprolactinemia needs to be assessed on an individual basis.
  • If there is doubt about the cause of the hyperprolactinemia, patient should be referred to an endocrinologist.

Current recommendation

A rise in prolactin concentration should not be of concern unless complications develop, and until such time no change in treatment is required.20

Conclusions

There is no definitive data suggesting increased risk of breast cancer available at this time, thus author concludes:

  • Further prospective studies are needed in this area, with large number of patients, before a more definitive answer can be provided.
  • Detection of existing mammary tumor by breast examination or studies (mammogram) is recommended prior to administration of neuroleptics.
  • Development of newer antipsychotic drugs that do not increase serum prolactin level may be indicated.

Strengths

  • Each article found by search term was reviewed
  • Data were extracted from each article to find answer of research question
  • Pubmed.gov is a huge database for search.

Limitations

  • This literature review has been conducted by a single author, thus bias on part of author cannot be ruled out
  • Author was limited by time to review articles available in other databases.
Key Points
  • Most studies report no increased risk of breast cancer associated with use of these medications.
  • Only one study reported a positive correlation between neuroleptic induced hyperprolactinemia and increased risk of breast cancer.
  • Other studies report inconclusive data.
  • At this time we do not have definitive data suggesting increased risk of breast cancer secondary to hyperprolactinemia caused by antipsychotics.
  • Further prospective studies are desirable.
  • Author concludes that thorough screening of patient should be best desirable before starting of antipsychotics to avoid any add-on risk.
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Umesh Vyas, MD, Medical Director of In-Patient Behavior Health Unit; Chair of Department of Psychiatry; Regional Medical Director of Sleep Disorders Center; Mayo Clinic Health System, Mankato, MN, USA; Adjunct Clinical Assistant Professor, Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN, USA; Adjunct Assistant Professor of Psychiatry and Sleep Medicine, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, USA.
Corresponding Author Details: 
Umesh Vyas, M.D., 1025 Marsh Street, P.O. Box 8673, Mankato, MN, 56002-8673
Corresponding Author Email: 
vyas.umesh@mayo.edu
References
References: 

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2. Hammar M. The effects of atypical antipsychotics on serum prolactin levels, Ann Clin Psychiatry 2002; 14:163-73

3. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999; 44:1085-90

4. Petty R G, Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999; 35 (Suppl): S67-73

5. Mah PM, Webster J, Hyperprolactinemia: etiology, diagnosis and management. Semin Reprod Med 2002; 20:365-73

6. Goodnick P J, Rodriguez L, Santana O. Antipsychotics: impact on prolactin levels. Expert Opin Pharmacother 2002; 3:1381-91

7. Marchant D J. Epidemiology of breast cancer. Clin Obstet Gynecol. 1982; 2: 387-92

8. Nordstrom A L, Farde L, Plasma Protein and central D2 receptor occupancy in antipsychotic drug-treated patients. J Clin Psychopharmacol 1998; 18:305-10

9. Meltzer H Y, Fang V S, The effect of neuroleptics on serum prolactin in schizophrenia patients. Arch Gen Psychiatry 1976; 33:279-86

10. Gruen Ph, Sachar E J, Langer G, Altman N, Leifer M, Frantz A, Halpern F S. Prolactin responses to neuroleptics in normal and schizophrenic subjects. Arch Gen Psychiatry 1978; 35: 108-16

11. Kleinberg D L, Davis J M, de Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999; 19:57-61

12. Schlosser R, Grunder G, Anghelescu I, Hillert A, Ewald-Grunder S, Hiemke C, Benkert O. Long-term effects of the substituted benzamide derivative amisulpride on baseline and stimulated prolactin levels. Neuropsychobiology 2002; 46:33-40

13. Fleischhacker WW, Unterweger B, Barnas C, Stuppack C, Hinterhuber H, Results of an open phase II study with zotepine – a new neuroleptic compound. Pharmacopsychiatry 1987; 20:64-6

14. Welsch C W, Nagasawa H. Prolactin and murine mammary tumorigenesis: a review. Cancer Res 1977; 37: 951-63

15. Pearson O H, Llerena O, Llerena L. Prolactin-dependent rat mammary cancer; a model for man? Trans Assoc Am Physicians 1969; 82: 225-38

16. Shelley S. Tworoger, A Heather Elissen et al, Plasma prolactin concentrations and risk of post menopausal breast cancer. Cancer Research 64, 6814-19, Sep, 2004

17. Halbreich U, Kinon BJ, Gilmore JA, et al. Elevated prolactin levels in patients with schizophrenia: mechanisms and related adverse effects. Psychoneuroendocrinology 2003; 28 (Supp I):53-67

18. Hankinson SE, Willett WC, Michaud DS, et al. FE. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl cancer Inst 1999; 91:629-34

19. Nagasawa H. Prolactin: its role in the development of mammary tumors. Med Hypotheses. 1979; 5: 1117-21

20. Wang P S, Walker A M, Tsuang M T, et al. Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry. 2002; 59 (12): 1147-54

21. Cohen A D, Cohan Y, Maislos M, Buskila D. Prolactin serum level in patients with breast cancer. Israel Med Assoc J 2000; 2:287-9

22. Mandala M, Lissoni P, Ferretti G, Rocca A, Torri V, Moro C, Curigliano G, Barni S. Postoperative hyperprolactinemia could predict longer disease-free and overall survival in node-negative breast cancer patients. Oncology 2002; 63:370-7

23. Travis RC, Key T J. Estrogen exposure and breast cancer risk. Breast Cancer R

24. Rosen C J, Kessenich C R, The pathophysiology and treatment of postmenopausal osteoporosis. An evidence-based approach to estrogen replacement therapy. Endocrinol Metab Clin North Am 1997; 26:295-311 es 2003; 5:239-47

25. Myslobodsky M, Lalonde F M, Hicks L. Are patients with Parkinson’s disease suicidal? J Geriatric Psychiatry Neurol 2001; 14:120-24

26. Kondo Y, Imai Y, Hojo H et al. Suppression of tumor-cell growth and mitogen response by aporhine alkaloids, dicentrine, glaucine, coryadine and apomorphine. J Pharmacobio-Dyn 1990; 13:426-431

27. Johnson D E, Ochieng J, Evans S L, The growth-inhibitory properties of a dopamine agonist on Mcf-7 cells. Anti-Cancer Drugs 1995; 6: 471-474

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29. Basu S, Nagy J A, Pal S et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001; 7:569-574

30. Lipsett M B. Hormones, medications and cancer. Cancer 1983; 51: 2426-9

31. Dalton S O. Cancer risk among users of neuroleptic medications: a population-based cohort study; British Journal of Cancer (2006) 95, 934-939

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Management of alopecia areata: an update

Authors
Imran Majid and Abid Keen
Article Citation and PDF Link
BJMP 2012;5(3):a530
Abstract / Summary
Abstract: 

Alopecia areata is a common, non-scarring, autoimmune disorder affecting any hair-bearing area. It is often psychologically devastating. This disorder occurs in both the sexes, in all age groups, and is characterized by the sudden appearance of circumscribed areas of hair loss on the scalp or other parts of the body. Various therapeutic approaches are presently available for managing alopecia areata including corticosteroids, contact sensitizers and immunosuppressants, but none have been shown to alter the course of the disease on a consistent basis.

Keywords: 
Alopecia areata, treatment, autoimmune, corticosteroids, recent advances, contact sensitizers

Introduction

Alopecia areata is a non-scarring autoimmune, inflammatory hair loss affecting the scalp and/or body. Although the etiopathogenesis of alopecia areata is still unknown, the most widely accepted hypothesis is that it is a T-cell mediated autoimmune condition that occurs in genetically predisposed individuals. The term ‘alopecia areata’ was first used for this disorder by Savages1.Alopecia areata has a reported incidence of 0.1-0.2%, with a life-time risk of 1.7%2-4. The disease can begin at any age, but the peak incidence is between 20 and 50 years of age5. Both the sexes are equally affected and there is no racial variation reportedClinically, alopecia areata may present as a single well demarcated patch of hair loss, multiple patches, or extensive hair loss in the form of total loss of scalp hair (alopecia totalis) or loss of entire scalp and body hair (alopecia universalis). Histopathologically, alopecia areata is characterized by an increase in the number of catagen and telogen follicles and the presence of perifollicular lymphocytic infiltrate around the anagen phase hair follicles. The condition is thought to be self-limited in majority of cases, but in some the disease has a progressive course and needs active treatment in the form of oral or topical therapeutic options. Progressive alopecia areata is associated with severe social and emotional impact.

Clinical features

Alopecia areata mostly presents as a sudden loss of hair in well demarcated localized areas. The lesion is usually a round or oval flat patch of alopecia with normal skin colour and texture involving the scalp or any other region of the body. The patch of alopecia may be isolated or there may be numerous patches. It usually has a distinctive border where normal hair demarcates the periphery of the lesion. In acute phases, the lesions can be slightly erythematous and oedematous.

The patches of alopecia areata are usually asymptomatic, although several patients may sometimes complain of local paraesthesia, pruritus or pain. The affected hairs undergo an abrupt conversion from anagen to telogen, clinically seen as localized shedding. Characteristic hairs, known as ‘exclamation point hairs’ may be seen within or around the areas of alopecia. The hairs are tapered towards the scalp end with thickening at the distal end. These hairs may also demonstrate deposition of melanin pigment in the distal extremity, also known as Wildy’s sign. Although not absolutely pathognomonic, it strongly suggests the diagnosis of alopecia areata. Hair pull test conducted at the periphery of the lesion may be positively correlated (six or more) with disease activity. In the chronic phases, the test is negative, since the hair is not plucked as easily as in the acute phases.

Another important clinical sign that can aid in the diagnosis is the presence of ‘cadaverous hair’. These are the hairs in which there occurs a fracture of the shaft inside the hair follicle, producing blackened points inside the follicular ostia resembling comedones. In alopecia areata, the hair loss progresses in a circumferential pattern. Often, distinct patches merge to form large patches. Upon regrowth, hairs will often initially lack pigment resulting in blonde or white hairs7.

Extrafollicular involvement in alopecia areata:

a) Nail changes: Nail changes are more frequent in children (12%) than in adults (3.3%)8.The prevalence of nail changes is greater in the more severe forms of alopecia areata such as alopecia universalis and alopecia totalisFinger nails are more commonly involved than the toe nails. Pitting is the most common finding. Other nail changes include koilonychias, onycholysis, onychomadesis, punctuate leukonychia, trachyonychia, Beau’s lines and red lunulae8-11.

b) Ocular changes: Various ocular changes have been reported to occur in alopecia areata. These include focal hypopigmentation of the retina12, lens opacities, posterior subcapsular cataracts13 decrease in visual acuity, Horner’s syndrome, heterochromia of the iris14, miosis and palpebral ptosis.

Treatment of alopecia areata

Treatment of alopecia areata is not mandatory in every affected patient because the condition is benign in majority and spontaneous remission is common. Treatment is mainly directed towards halting the disease activity as there is no evidence that the treatment modalities influence the ultimate natural course of the disease. Treatment modalities are usually tailored as per the extent of hair loss and the patient’s age. Addressing the impressive inflammatory process occurring in alopecia areata, corticosteroids have by far been the most commonly used treatment modality-16Few treatments have been subjected to randomized control trials and except for contact immunotherapy, there is a paucity of published data on their long term outcomes. Currently, new treatments targeting the immune system are being explored for the use in alopecia areata.

Topical treatments

Topical steroids

Intralesional steroid injections

Topical contact sensitizers

Anthralin

Minoxidil

Topical retinoids

Tacrolimus

Systemic treatments

Systemic corticosteroids

Sulfasalazine

Azathioprine

Methotrexate

Oral zinc sulphate

Photo-and photochemotherapy

PUVA

NBUVB

Excimer laser

Miscellaneous and Non-pharmacological treatment

Dermatography, wigs

Hypnotherapy etc

Topical treatment options

Topical corticosteroids:

Several topical corticosteroids with varying levels of efficacy have been used to treat alopecia areata. These include fluocinolone acetonide cream17, fluocinolone scalp gel, betamethasone valerate lotion18, clobetasol propionate ointment19, dexamethasone in a penetration-enhancing vehicle and halcinonide cream20. They are a good option in children because of their painless application and wide safety margin21. Topical corticosteroids are ineffective in alopecia totalis/universalisFolliculitis is a common side effect of corticosteroid treatment, appearing after a few weeks of treatment. Telangiectasia and local atrophy have also been reported. Treatment must be continued for a minimum of 3 months before regrowth can be expected and maintenance therapy often is sometimes necessary.

Intralesional corticosteroids:

Intralesional corticosteroids are widely used in the treatment of alopecia areata. In fact, they are the first-line treatment in localized conditions involving <50% of the scalp22. Hydrocortisone acetate (25mg/ml) and Triamcinolone acetonide (5-10mg/ml) are commonly used. Triamcinolone acetonide is administered usually in the concentration of 5mg/ml using a 0.5 inch long 30-gauge needle in multiple 0.1 ml injections approximately 1 cm apart22-23. The solution is injected in or just beneath the dermis and a maximum of 3 ml on the scalp in one visit is recommended23. Lower concentrations of 2.5mg/ml are used for eyebrows and face. Regrowth usually is seen within 4-6 weeks in responsive patients. Treatments are repeated every 3-6 weeks. Skin atrophy at the sites of injection is a common side effect, particularly if triamcinolone is used, but this usually resolves after a few months. Repeated injections at the same site or the use of higher concentrations of triamcinolone should be avoided as this may lead to prolonged skin atrophyPain limits the practicality of this treatment method in children who are less than 10 years of age. Severe cases of alopecia areata, alopecia totalis, alopecia universalis as well as rapidly progressive alopecia areata respond poorly to this form of treatment25.

Anthralin:

Dithranol (anthralin) or other irritants have been used in the treatment of alopecia areata. The exact mechanism of action is unknown, but is believed to be through immunosuppressant and anti-inflammatory properties with the generation of free radicals. It is used at concentrations ranging from 0.5 to 1 % for 20-30 minutes after which the scalp should be washed with shampoos in order to avoid excessive irritant effects. The applications are made initially every other day and later on daily. Adverse effects include pruritus, erythema, scaling, staining of treated skin and fabrics, folliculitis, and regional lymphadenopathy26-27. In an open study, 25% patients with severe alopecia areata were shown to respond positively to local applications of 0.5-1% anthralinMore placebo control studies are needed to justify the use of anthralin in alopecia areata.

Minoxidil:

Minoxidil appears to be effective in the treatment of alopecia areata. It’s mechanism of action has yet to be determined, but it is known to stimulate DNA synthesis in hair follicles and has a direct action on the proliferation and differentiation of the keratinocytes28. In one clinical study, hair growth was demonstrated in 38% and 81% of patients treated with 1% and 5% minoxidil respectively. Thus 5% minoxidil solution is usually recommended as a treatment option in alopecia areata. No more than 25 drops are applied twice per day regardless of the extent of the affected area. Initial regrowth can be seen within 3 months, but continued application is needed to achieve cosmetically acceptable regrowth. Minoxidil has also been studied in combination with anthralin29, topical betamethasone propionate30 and prednisolone31. Minoxidil is of little benefit to patients of severe alopecia areata, alopecia totalis or alopecia universalisThe possible side effects from minoxidil are allergic and irritant contact dermatitis and hypertrichosis which is usually reversible with the interruption of the treatment.

Topical immunotherapy:

Topical immunotherapy is the best documented treatment so far for severe and refractory cases of alopecia areata. Topical immunotherapy is defined as the induction and periodic elicitation of allergic contact dermatitis by applying a potent contact allergen33. In 1965, the alkylating agent triethyleneimino benzoquinone was the first topical sensitizer used to treat cutaneous disease, but it was abandoned on account of its mutagenic potential. Later nitrogen mustard, poison ivy, nickel, formalin, and primin were tried, mainly as topical immunotherapy, for alopecia areata and warts. Contact immunotherapy was introduced in 1976, by Rosenberge and Drake. Later, potent contact allergens namely dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DPCP) replaced the allergens that were used earlier33. DNCB is mutagenic against Salmonella tymphimurium in the Ames test and is no longer usedNeither SADBE, nor DPCP are mutagenic. DPCP is more stable in solution and is usually the agent of choice.

Mechanism of action: Topical immunotherapy acts by varied mechanisms of action. The most important mechanism is a decrease in CD4 to CD8 lymphocyte ratio which changes from 4:1 to 1:1 after contact immunotherapy. A decrease in the intra-bulbar CD6 lymphocytes and Langerhan cells is also noted. Happle et al, proposed the concept of ‘antigenic competition’, where an allergic reaction generates suppressor T cells that non-specifically inhibit the autoimmune reaction against a hair follicle constituent. Expression of class I and III MHC molecules, which are normally increased in areas affected by alopecia areata disappear after topical immunotherapy treatment34.A ‘cytokine inhibitor’ theory has also been postulated34.

Method of sensitization: The protocol for contact immunotherapy was first described by Happle et al in 1983 The scalp is the usual sensitization site. For the initial sensitization a cotton-tipped applicator saturated with 2% DPCP in acetone is applied to a small area. Patients are advised to avoid washing the area and protect it from sunlight for 48 hours. After 2 weeks 0.001% solution of DPCP is applied on the scalp and then the application of contact allergen is repeated weekly with increasing concentrations. The usual concentration of DPCP that ultimately causes mild contact eczema is 0.01-0.1% and this is repeated weekly till a response is seen. An eczematous response indicates that sensitization has taken place. Only 1-2% of the patients fail to sensitize. It is important to remember that DPCP is degraded by light and should thus be stored in the dark and the patient should also wear a wig or hat during the day after application of DPCP. DPCP immunotherapy has even been combined with oral fexofenadine treatment with good effect36.

Evaluation of efficacy: The clinical response after six months of treatment is rated as per the grading system proposed by Mcdonald Hull and Norris37:

Grade 1- Regrowth of vellus hair.

Grade 2- Regrowth of sparse pigmented terminal hair.

Grade 3- Regrowth of terminal hair with patches of alopecia.

Grade 4- Regrowth of terminal hair on scalp.

If no regrowth is observed within six months of treatment, the patient is considered to be a non-responder. Evaluation of plucked hair is done using light microscopy, for evaluation of anagen/telogen ratio.

A review of most of the published studies of contact immunotherapy concluded that 50-60% of patients achieve a worthwhile response but the range of response rates was very wide (9-87%)Patients with extensive hair loss are less likely to respond. Other reported poor prognostic factors include the presence of nail changes, early onset disease and a positive family history39.

Topical immunotherapy can lead to certain side effects such as persistent dermatitis, painfull cervical lymphadenopathy, generalized eczema, blistering, contact leukoderma, and urticarial reaction. Systemic manifestations such as fever, arthralgia and yellowish discoloration of hair are noted more often with DNCB.

In poor responders to DPCP, squaric acid dibutylester (SADBE) can be tried as a contact sensitizer. The method of application is the same as with DPCP but the applications are done once or twice weekly40.

Good care should be taken to avoid contact with the allergen by handlers, including pharmacy and nursing staff. Those applying the antigen should wear gloves and aprons. There is no available data on the safety of contact immunotherapy during pregnancy and it should not be used in pregnant women or in women intending to become pregnant.

Tacrolimus:

Tacrolimus is a topical calcineurin inhibitor that inhibits transcription following T-cell activation of several cytokines including IL-2, IFN-gamma and TNF-α. Yamamoto et al reported in their findings that tacrolimus stimulated hair growth in mice41, although subsequent studies have shown conflicting resultsRecently, Price et al reported an 11-patient study in which none of the patients had terminal hair growth in response to tacrolimus ointment 0.1 % applied twice daily for 24 weeks43.

Topical garlic

Garlic is a very commonly used home remedy in the treatment of alopecia areata in India and even in the rest of the world. One study analyzed the effect of a combination of topical garlic gel and betamethasone valerate ointment in alopecia areata in a double-blind study. The study found the combination useful in majority of the patients with a statistically significant difference between the treatment and control groups44.

Topical retinoids:

Among topical retinoids, tretinoin and bexarotene have been tried in alopecia areata with mixed results-46Irritation of the skin is a very common side effect and the efficacy is doubtful in the absence of double-blind randomized trials.

Prostaglandin analogs:

The propensity of certain prostaglandin analogues used as anti-glaucoma eye drops to cause hypertrichosis has been employed in the treatment of alopecia areata. These prostaglandin analogues include Latanoprost and Bimatoprost and they are used in the treatment of alopecia areata involving the eyelashes-48However, the results obtained with these drugs have not been really encouraging49.

Systemic treatments

Systemic treatments, as a rule, are used only in progressive forms of alopecia areata and going by the immune nature of the disease, majority of these treatment options are immunosuppressants or immunomodulators in nature.

Systemic corticosteroids:

The use of systemic corticosteroids for the treatment of alopecia areata is under much debate. Some authors support a beneficial role of systemic steroids on halting the progression of alopecia areata, but many others have had poor results with this form of therapy. The suggested dosages are 0.5-1mg/kg/day for adults and 0.1-1 mg/kg/day for children50. Treatment course ranges from 1-6 months, but prolonged courses should be avoided to prevent the side effects of corticosteroids. Side effects profile of corticosteroids in conjunction with the long-term treatment requirements and high relapse rates make systemic corticosteroids a more limited option. In addition to the daily oral administration of corticosteroids, there are several reports of high-dose pulsed corticosteroid treatments employing different oral and intravenous regimens51-53. Many of these regimens have been tried in alopecia areata with encouraging results but the majority of these studies have been non-blind open studies. One such pulsed administration employs a high dose oral corticosteroid on two consecutive days every week with a gap of 5 days between the two pulses. This modality of treatment is known as oral minipulse therapy (OMP) and it has been tried in many skin diseases in addition to alopecia areata like vitligo54-55 and lichen planusSome open label studies on corticosteroid OMP therapy have reported encouraging results in alopecia areata53.

Sulfasalazine:

Because of its immunomodulatory and immunosuppressive actions, sulfasalazine has shown good hair regrowth in the treatment of alopecia areata. The drug is administered orally usually as enteric coated tablets to minimize the gastrointestinal side effects. The treatment is started at a lower dose, usually in the range of 500 mg twice daily and then the dose is gradually increased to 1 g three times a dayAdverse effects include gastrointestinal distress, liver toxicity and haemotological side effects. Sulfasalazine helps in alopecia areata because it causes inhibition of T cell proliferation, and natural killer cell activity and also inhibits antibody production. It also inhibits the secretion of interleukin (IL)-2, IL-1, TNF- and IFN-gamma and even IL-667.

A number of clinical studies have documented a positive effect of sulfasalazine in alopecia areata. In one clinical study, 23% patients showed a really good response with satisfactory hair growth after sulfasalazine therapyOther studies have also shown a beneficial effect of this treatment option in resistant cases of alopecia areata66,69.

Azathioprine:

Azathioprine, being an immunosuppressive agent has also been tried in alopecia areata. The drug is used in many cutaneous disorders owing to its effect on circulating lymphocytes as well as Langerhan cells. In a limited study on 20 patients hair regrowth was demonstrated in about half of the patients with a dosage regimen of 2g/day70.

Cyclosporine:

This drug has proven effective in the treatment of alopecia areata because of its immunosuppressive and hypertrichotic properties. The side effect profile and high rate of recurrence render the drug a poor choice for the use in alopecia areata. So the drug is to be attempted only in severe forms of alopecia areata not responding to treatment71.

Methotrexate:

Methotrexate either alone or in combination with prednisolone has been used in the treatment of alopecia areata in various studies with variable success rates72.

Oral zinc sulphate

Serum zinc levels have been found to be lower in patients with alopecia areata than in control populationIn a study on 15 patients, hair regrowth was observed in 9 patients (67%) after oral zinc gluconate administration74.

Biological agents:

Tumour necrosis factor inhibitors such as Adalimumab, Infliximab and Etanercept have been tried in alopecia areata, but the results have not been encouraging-76Clinical trials conducted till now have failed to demonstrate the efficacy of any biological agent in alopecia areata.

Photo-and photochemotherapy

Photochemotherapy:

Several uncontrolled studies regarding PUVA therapy for the treatment of alopecia areata exist. All types of PUVA (oral PUVA, topical PUVA, local or whole body UVA irradiation) have been used with success rates of up to 60-65%57-59. The mechanism of action is considered to be the interference in the presentation of follicular antigens to T-lymphocytes by depletion of the Langerhan cells. The relapse rate following treatment is high, sometimes demanding repeated treatments for a prolonged period with implications for carcinogenic risks60. To mitigate the side effects of systemic psoralens, PUVA-turban therapy is used for alopecia areata involving the scalp. In this form of photochemotherapy, very dilute solutions of 8-methoxy psoralen are applied on the scalp by utilizing a cotton towel as a turban. The patient’s scalp is exposed to UVA after keeping the ‘turban’ in contact with the scalp for about 20 minutesThe efficacy of this form of PUVA therapy has been seen to be about 70%61.

Phototherapy

Although narrowband UVB is among the most effective treatment options in a number of immune mediated skin diseases, the same efficacy has not been found in alopecia areata. Properly designed randomized trials are needed to elucidate whether NBUVB has any role in the management of alopecia areata62-63.

Excimer laser and excimer light

Excimer laser and excimer light are two more recent additions to the phototherapeutic armamentarium for many skin and hair disorders. While the main use of these phototherapeutic modalities remains to be psoriasis and vitiligo, their immunomodulatory effect can be made use of in many other skin disorders. Some clinical studies have documented the efficacy of excimer laser and excimer light in alopecia areata64-65. In one such study, 41.5% patches were shown to respond to excimer laser therapy administered over 12 weeks64. Another study on childhood alopecia areata found regrowth in 60% lesions after a treatment period of 12 weeksThe treatment is well tolerated with erythema of the skin as the only adverse effect reported.

Miscellaneous therapies

Various non-conventional therapeutic agents have been used in alopecia areata with some degrees of success. These include fractional Er-Glass laser77, topical azelaic acid78, topical onion juice79, topical 5-fluorouracil ointment80 and photodynamic therapyThe efficacy and safety of these therapeutic agents need to be confirmed in large-scale, double-blind, placebo-controlled trials before they can be recommended for treatment of alopecia areata.

Non-pharmacological methods

Cosmetic treatments for patients with alopecia areata include the following:

a) Dermatography: It has been used to camouflage eyebrows of patients with alopecia areata. In this treatment tiny pigment dots of pigment are used on the skin on the region of the eyebrows to mask the underlying alopecia81.

b) Wigs or Hair pieces: These are useful for patients with extensive disease and allow them to carry on their usual social life.

Conclusion:

Alopecia areata is now regarded as an autoimmune disease involving the cellular immunity through the CD8 lymphocytes that act on follicular antigens. The pathogenesis of alopecia areata is being unravelled with various animal and human studies.

The localized forms often heal spontaneously or respond to simple treatments such as topical or intralesional corticosteroids. The severe forms have a reserved prognosis and are difficult to treat. In these cases the best results are achieved by topical immunotherapy technique.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
IMRAN MAJID, MD Dermatology and STD, Assistant Professor Dermatology, Govt Medical College, Srinagar, Kashmir, India. ABID KEEN, Postgraduate student Dermatology, Govt Medical College, Srinagar, Kashmir, India.
Corresponding Author Details: 
Dr IMRAN MAJID, CUTIS Skin and Laser Institute, Srinagar, Kashmir, India 190002.
Corresponding Author Email: 
imran54@yahoo.
References
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Integrative model of chronically activated immune-hormonal pathways important in the generation of fibromyalgia

Authors
Paul C. Breeding, Nancy C. Russell and Garth L. Nicolson
Article Citation and PDF Link
BJMP 2012;5(3):a524
Abstract / Summary
Abstract: 

Clinicians are often challenged by patients presenting with a syndrome of chronic and diffuse full body pain with long standing fatigue and a cluster of related symptoms.    Fibromyalgia has become the commonly accepted term for this syndrome.  Diagnosis is established through recognized subjective symptoms, such as tender points and other indicators of chronic full body pain and fatigue. Suspected triggers have included bacterial and viral infections, toxins, allergens, and emotional and physical trauma. Unknown causes limit the prescription of effective treatments; however, neuropathic pain and fatigue have been identified as key components so dual reuptake inhibitors and anti-convulsants have shown some effectiveness for some patients.  Based upon laboratory and clinical studies of the last decade, this article proposes a model for a subset of fibromyalgia patients who have prolonged immune activation with related oxidative and nitrogenous stress leading to multiple hormonal repression, disrupted collagen physiology, neuropathic pain and fatigue. This integrative model of fibromyalgia is based on chronic up-regulation of the immune system with subsequent hormonal, connective tissue and nervous system implications.

Introduction

Fibromyalgia (FM) is a challenging set of chronic, overlapping and debilitating syndromes with widespread pain, abnormal pain processing, sleep disturbance, fatigue and psychological distress.1 The American College of Rheumatology (ACR) 1990 diagnostic guidelines were based primarily on tender point examination findings at 11 of 18 potential tender points;2 however, lack of consistent application of these guidelines in clinical settings led the ACR in 2010 to develop new diagnostic criteria based on a Widespread Pain Index (WPI) and symptom severity (SS) scale with no requirement of a tender point examination.  Symptoms must have been present for at least three months with the absence of any other disorder that would otherwise explain the pain and other signs and symptoms.3

Type of pain and other symptoms vary widely in FM, complicating diagnosis and treatment.  A cross-sectional survey of 3,035 patients in Germany utilized cluster analysis to evaluate daily records of symptoms noted by patients on handheld computers. Five subgroups were described: four with pain evoked by thermal stimuli, spontaneous burning pain, pressure pain, and pressure pain combined with spontaneous pain; the fifth subgroup had moderate sensory disturbances, but greater sleep disturbances and the highest depression scores.4

Estimates of the prevalence of FM have varied based on case definitions and survey methods.  Using 1990 ACR guidelines, it was estimated to affect between 0.1 to 3.3% of populations in western countries and 2.0% in the United States. Greater prevalence occurs among females, with estimates ranging from 1.0 to 4.9%.1, 5  Reasons for the gender difference have not been determined.6-9 

Fibromyalgia Risk Factors

Identification of risk factors for FM has been complicated by the array of seemingly unrelated signs and symptoms. The United States Centers for Disease Control (CDC) notes  loose association with genetic predisposition,10 bacterial and viral infections, toxins, allergies, autoimmunity, obesity and both physical and emotional trauma.1, 11  

Chronic fatigue syndrome and infection

Although chronic fatigue syndrome (CFS) has been defined as a separate syndrome, up to 70% of patients with FM are also diagnosed with CFS and 35-70% of patients with CFS have also been diagnosed with FM.12   Thus studies of patients with CFS may have clinical relevance to FM. Several case controlled studies of CFS and one of CFS/FM have been associated with chronic bacterial infections due to Chlamydia (Chlamydophila p.), Mycoplasma, Brucella, and Borrelia.12-18  The most prevalent chronic infection found has been that of the various Mycoplasmaspecies.15-23 

Mycoplasmas are commonly found in the mucosa of the oral cavity, intestinal and urogenital tracts, but risk of systemic illness occurs with invasion into the blood vascular system and subsequent colonization of organs and other tissues.15-23  Mycoplasmal infections have been identified in 52 – 70% of CFS patients compared with 5 to 10% of healthy subjects in North America15-17, 19-22 and Europe (Belgium)23.  For example, the odds ratio (OR) of finding Mycoplasma species in CFS was 13.8 (95% CL 5.8-32.9,  p< 0.001) in North America.17  A review by Endresen12 concluded that mycoplasmal blood infection could be detected in about 50% of patients with CFS and/or FM.  A CDC case-control study attempted to replicate these findings based on the hypothesis that intracellular bacteria would leave some evidence of cellular debris in cell-free plasma samples.  Results were that the healthy subjects actually had evidence of more bacteria although the difference was not significant. The authors noted the complexity and limitations of this type of analysis and also postulated that since the CFS patients were years past the onset of illness, they might have previously cleared the triggering agent.24  However, most studies found Mycoplasma DNA in intracellular but not extracellular compartments in CFS patients, and this could explain the discrepancy.15-23  Other studies have found that 10.8% of CFS patients were positive for Brucella species (OR=8.2, 95% CL 1-66, p<0.01)16 and 8% werepositive for  Chlamydia pn. (OR= 8.6; 95% CL 1-71.1,p< 0.01)17.

The presence of multiple co-infections may be an especially critical factor associated with either initiation or progression of CFS.  Multiple infections have been found in about one-half of Mycoplasma-positive CFS patients (OR = 18.0, 95% CL 8.5-37.9, p< 0.001), compared with single infections in the few control subjects with any evidence of infection.17 A  North American study identified chronic infections in 142 of  200 patients (71%) with 22% of all patients having multiple mycoplasmal infections while just 12 of the 100 control subjects (12%) had infections (p<0.01) and none had multiple infections.15 Similarly, a European study reported chronic mycoplasmal infections in 68.6% of CFS and 5.6% of controls.  Multiple infections were found in 17.2% of the CFS patients compared with none in the controls (p<0.001).23 Multiple co-infections were also associated with significantly increased severity of symptoms (p<0.01).15, 23 

Viral infections associated with CFS have included Epstein Barr virus, human herpes virus-6, cytomegalovirus, enteroviruses and several other viruses.15, 25, 26

Despite indications of single or multiple bacterial and/or viral infections in most patients with CFS, antibiotic or antiviral treatments have yielded inconsistent results.27  Slow growing intracellular bacteria are relatively insensitive to most antibiotics and have inactive phases when they would be completely insensitive to any antibiotics.28 23   Some treatments may actually have resolved the infections, but not the immune pathways that may remain in an activated state capable of producing symptoms. 

Fibromyalgia and infection

Bacterial infections associated with FM as a separate syndrome have included small intestinal bacterial overgrowth (SIBO)29, 30 and helicobacter pylori (HP)31.   Utilizing the lactulose hydrogen breath test (LHBT), investigators found SIBO in 100% of 42 patients with FM.   They noted that 30-75% of patients with FM have also been found to have irritable bowel syndrome (IBS).29, 30  A confounding factor is that medications prescribed for FM often have gastrointestinal side effects.29  HP diagnosed by positive immunoglobulin gamma (IgG) serum antibody was significantly higher in women with FM (44/65 or 67.7%) compared with controls (18/41 or 43.9%) (p=0.025) in Turkey31.

Viral infections associated with FM have included hepatitis C, in which two studies found an association,32-34 and two studies found no association.35, 36 Associations with FM have also been found with hepatitis B, 37 human immunodeficiency virus (HIV)38, 39 and human T cell lymphotropic virus type I (HTLV-1).40

Fibromyalgia and non-infectious associations

Non-infectious triggers associated with FM have included toxins, allergens, and physical or emotional trauma. These triggers may not have been strictly “non-infectious” as allergens and toxins may also be produced by infections, and physical or emotional trauma may lead to the reactivation of previously controlled infections. Respondents to an internet survey of people with FM (n=2,596) also identified triggers as chronic stress (41.9%), emotional trauma (31.3%), acute illness (26.7%) and accidents (motor vehicle 16.1%, non-motor vehicle 17.1%).41 Physical trauma associated with FM has included cervical spine injuries as well as motor vehicle and other accidents.42-44 

Fibromyalgia and autoimmunity

Three studies have found thyroid autoantibodies to be in greater percentages in subjects with FM compared with controls, in spite of normal thyroid hormone levels.  One study reported autoantibodies in 41% of FM patients versus 15% of controls.45  The second study reported 16% in FM versus 7.3% in controls, p<0.01.46 The third study reported 34.4% in FM versus 18.8% in controls (p=0.025)47 and OR =3.87, 95% CL  1.54-10.13.48  This could also have been the result of thyroiditis, because infections like Mycoplasma are often found in thyroiditis patients.15

Autoantibodies to serotonin were identified in 74% of 50 patients with FM compared with 6% of 32 healthy (blood donor) controls. Notably, serotonin levels were normal in 90% of the FM patients indicating serotonin receptor involvement.49

Fibromyalgia and Metabolic Syndrome

Metabolic Syndrome consisting of abdominal obesity, high triglycerides, high blood pressure, elevated fasting glucose and decreased high-density lipids, was associated with FM in a U.S. study in which  cases were 5.6 times as likely to have Metabolic Syndrome as controls (C2MH = 3.84, p = .047, 95% CL 1.25 – 24.74).50 

Fibromyalgia and emotional trauma

Although emotional trauma has been acknowledged as a contributing factor, most studies of CFS/FM have used recognized tests such as Beck’s Depression Index, Beck’s Anxiety Index and Minnesota Multi Personality Index (MMPI) to exclude potential subjects with actual psychiatric illnesses.51, 52

Psychological and physiological subsets of fibromyalgia 

A Wisconsin cross sectional survey of 107 women with confirmed diagnoses of FM used validated psychological and physiological measures followed by cluster analysis. Four distinct subsets were identified: (I) history of childhood maltreatment and hypocortisolism with the most pain and disability; (II) “physiological dysregulation” described as “distinctive on nearly every biological index measured” with high levels of pain, fatigue and disability; (III) normal biomarkers with intermediate pain severity and higher global functioning; and (IV) psychological well-being with less disability and pain.53

The “physiological dysregulation” of FM subset II  consisted of the highest antinuclear antibody (ANA) titers (t=4.06, p=0.001), highest total cholesterol levels (t=3.96, p<0.001), larger body mass index (BMI) values t=2.21, p<0.04), lowest Natural Killer (NK) cell numbers (t=3.95, p<0.001), lowest growth hormone (t=3.20, p<0.002), and lowest testosterone levels (t=3.80, p<0.001).  Trends were also indicated toward the highest erythrocyte sedimentation rate (ESR) (t=2.02, p=0.056), lowest creatinine clearance (t=1.85, p=0.067) and lowest cortisol (t=2.78, p<0.007).53

Proposed Model of Fibromyalgia

The authors’ proposed model of FM develops a rationale for the “physiological dysregulation” indicated in subset II of the Wisconsin study.  In this model, various triggers are followed by prolonged immune activation with subsequent multiple hormonal repression, disrupted collagen physiology and neuropathic pain.

 Activation of immune response pathways

Innate immune responses begin with anatomical barriers, such as the epithelium and mucosal layers of the gastrointestinal, urogenital and respiratory tracts, and physiological barriers, such as the low pH of stomach acid and hydrolytic enzymes in bodily secretions. 54 Breeching of these barriers activates cell-mediated immunity launched by leucocytes with pattern recognition receptors: neutrophils, macrophages and dendritic cells (DCs).54 Insufficient or damaged anatomical or physiological barriers would necessarily keep this cell mediated level of innate defense in a constant state of alert and activity.

In contrast to the innate immune response, adaptive immunity has highly specific recognition and response activities resulting in lasting changes produced by leukocytes known as lymphocytes.   B lymphocytes (B cells) secrete plasma cells producing antibodies to specific pathogens. T lymphocytes (T cells), the other major cells of adaptive immunity, can be either cytotoxic (Tc) or helper cells (Th).  Tc cells produce progeny that are toxic to non-self peptides and Th lymphocytes secrete small proteins (cytokines) that mediate signaling between leukocytes and other cell types.  All types of lymphocytes retain memory so that subsequent invasions provoke faster and more rapid differentiation into effector cells. 54, 55  Some Th cells respond to intracellular pathogens (Th1) and some to extracellular pathogens (Th2).  A third type (Th17) appears to respond to certain bacterial and fungal infections, tumor cells and are also involved in autoimmune diseases.56  

In the presence of environmental stressors, cells may release stress proteins to alert the organism to potentially damaging conditions. These proteins can bind to peptides and other proteins to facilitate surveillance of both the intracellular and extracellular protein environment.  One form of stress proteins, heat shock proteins (HSP), can mimic the effects of inflammation and can be microbicidal.52, 57

One of the earliest responses to intracellular viral or bacterial infections involves production of three types of interferon (IFNa, IFNb and IFNg).  Any of these can initiate a series of metabolic events in uninfected host cells that produce an antiviral or anti-bacterial state.58, 59 When IFN-γ targets genes in uninfected cells, the targeted genes become microbicidal by encoding enzymes generating oxygen (O2) and nitric oxide (NO) radicals.58  Activation of O2 or NO radicals triggers another cascade involving IL-6, IL-1b, the cytokine Tumor Necrosis Factor-a (TNF-a) and the transcription nuclear factor kB (IKKb-NF-kB).  NF-kB can be activated by a variety of inflammatory stimuli, such as cytokines, growth factors, hormones, oncogenes, viruses and their products, bacteria and fungi and their products, eukaryotic parasites, oxidative and chemical stresses, therapeutic and recreational drugs, additional chemical agents, natural products, and physical and psychological stresses.60 Activation of NF-kB releases its subunits; the p50 subunit has been associated with autoimmunity and the RelA/p65 unit with transcriptional activity involving cell adhesion molecules, cytokines, hematopoietic growth factors, acute phase proteins, transcription factors and viral genes.61  The authors propose that chronic infection or other stress would be a sustaining trigger of an immune cascade that includes NF-kB and resultant cell signaling processes that drive many of the symptoms of fibromyalgia.

The cytokine interleukin-6 (IL-6) can either activate or repress NF-kB through a switching mechanism involving IL-1ra and Interleukin 1b(IL-1b).   IL-6 first activates Interleukin 1b  (IL-1b), which then activates TNF-a, leading to the subsequent activation of NF-kB. 62, 63 Specifically, the release of the RelA/p65 subunit of activated  NF-kB switches on an inhibitory signaling protein gene (Smad 7) that blocks phosphorylation of Transforming Growth Factor Beta (TGF-b) resulting in the repression of multiple genes.  Alternatively, IL-6 activates IL-1ra, which allows TGF-b to phosphorylate and induce the expression of activating signaling protein genes Smad2 and Smad3, resulting in the full expression of multiple genes.61  

NF-kB plays a key role in the development and maintenance of intra- (Th1) and inter- (Th2) cellular immunity through the regulation of developing B and T lymphocytes. The p50 dimer of NF-kB has been shown to block B Cell Receptor (BCR) editing in macrophages, resulting in loss of recognition and tolerance of host cells (autoimmunity). T cells that are strongly auto-reactive are normally eliminated in the thymus, but weakly reactive ones are allowed to survive to be subsequently regulated by regulatory T-cells and macrophages.  Acquired defects in peripheral T-regulatory cells may mean failure to recognize and eliminate weakly reactive ones.54, 64  The IL-17 cytokine associated with autoimmunity can activate NF-kB through a pathway that does not require TNF-a.56 NF-kB activity can also be activated or repressed by the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (c AMP) in the early phases (3 days) of nerve injury through its main effector enzyme, protein kinase A (PKA).65, 66  PKA decreases during later stages as the enzyme protein kinase C (PKC) increases.  PKC then plays important roles in several cell type specific signal transduction cascades.67 An isoform of PKC within primary afferent nociceptive nerve fibers signals through IL-1b and prostaglandins E2 (PGE2) as demonstrated in animal studies.68  This process has been called “hyperalgesic priming,” and it has been described as responsible for the switch from acute to long-lasting hypersensitivity to inflammatory cytokines.69

Figure 1 depicts key immune pathways leading to expression or repression of multiple genes proposed to be important in FM and neuropathic pain.

Fibromyalgia and immune - hormonal interactions

Reciprocity exists between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis through its production of glucocorticoid signal transduction cascades. 63, 70, 71. Hormones such as cortisol (hydrocortisone) produced by the adrenal cortex, affect metabolism of glucose, fat and protein.72  The glucocorticoid receptor (GR), a member of the steroid/thyroid/retinoid super family of nuclear receptors is expressed in “virtually all cells”.  When the GR in the cytoplasm binds a glucocorticoid, it migrates to the nucleus where it modulates gene transcription resulting in either expression or repression of TNF-a, IL-1bβ and the NF-kB p65/Rel A subunit.  However, the RelA/p65 protein can also repress the Glucocorticoid Receptor. 63, 70, 71, 73

Growth hormone (GH), an activator of NF-kB,74  is usually secreted by the anterior pituitary, but changes found in FM may be hypothalamic in origin.  GH is needed for normal childhood growth and adult recovery from physical stresses.75  Although low levels of GH were found in subset II of the Wisconsin study, 53 functional deficiency may be expressed as low insulin-like growth factor 1 (IGF-1) combined with elevated GH, suggesting GH resistance.76, 77   Defective GH response to exercise has been associated with increased pain and elevated levels of IL-1b, IL-6, and IL-8.77, 78

The hormones serotonin and norepinephrine modulate the movement of pain signals within the brain.  Serotonin has been found to suppress inflammatory cytokine generation by human monocytes through inhibition of the NF-kB cytokine pathway in vitro;79 however, NF-kB promotion of antibodies can repress serotonin.49  Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), such as duloxetine and milnacipran, are key treatment options for fibromyalgia and have been approved of by the U.S. Food and Drug Administration (FDA).80, 81  Although serotonin has been best measured in cerebral spinal fluid (CSF), recently improved methods of collection were utilized  (using rats and in 18 women) that yielded a high degree of correlation (r=0.97) between CSF and plasma, platelet, and urine measurements.82

NF-kB activation has also been documented to interfere with thyroid hormone action through impairment of Triiodothyronine (T3) gene expression in hepatic cells. 83  However, T3 administration has induced oxidative stress and activated NF-kB in rats.84 

Metabolic Syndrome, a confounding factor in Fibromyalgia

Leptin and insulin hormones interact to regulate appetite and energy metabolism.  Leptin, produced by adipose cells, circulates in the blood eventually crossing the blood-brain barrier to bond with a network of receptors within the hypothalamus.   Insulin, produced by beta cells in the pancreas, similarly crosses the blood brain barrier to interact with its own network of hypothalamic receptors.  Leptin and its receptors share structural and functional similarities to long-chain helical cytokines, such as IL-6, and it has been suggested that leptin be classified as a cytokine.85-89

Metabolic syndrome can be a confounding factor in FM due to peripheral accumulation of fatty acids, acylglycerols and lipid intermediates in liver, bone, skeletal muscle and endothelial cells.  This promotes oxidative endoplasmic reticulum (ER) stress and the activation of inflammatory pathways involving PKC and hypothalamic NF-kB, leading to central insulin and leptin repression.85-87, 89-91   Hyperinsulinemia further stimulates adipose cells to secrete and attract cytokines such as TNFa and IL-6 that trigger NF-kB in a positive feedback loop, which can be complicated by chronic over nutrition that increases the generation of reactive oxygen intermediates and monocyte chemoattractant protein-1 (MCP-1).87, 89  When exposed to a chronic high fat diet, hypothalamic NF-kB was activated two fold in normal mice and six times in mice with the obese (OB) gene.89

Fibromyalgia and indicators of immune-hormonal activity

Although most components of either innate or adaptive cell mediated immune responses exist for only fractions of seconds, some of their effects and products can be detected long after in the skin, muscle, blood, saliva or sweat92, 93.  

One component,  nitric oxide (NO),  can suppress bacteria; however, endothelial damage causes dysfunction with impaired release of NO and loss of its protective properties.86 The enzyme transaldolase acts as a counterbalance by limiting NO damage to normal cells.  Thus, high levels of transaldolase indicate elevated reactive oxygen species, reactive nitrogen species (ROS/RNS) and cellular stress. The “exclusive and significant over-expression of transaldolase” in the saliva samples of 22 women with FM compared with 26 healthy controls (77.3% sensitivity and 84.6% specificity, p<0.0001; 3 times greater than controls; p=0.02) was “the most relevant observation”; although there was no correlation between transaldolase expression and the severity of FM symptoms.92  

High levels of NO have been associated with high levels of insulin, and insulin itself is a vasodilator that, in turn, can stimulate NO production.  Beta cells of the pancreas are quite susceptible to ROS/NOS damage .86 When free radical damage of beta cells reaches critical mass, insulin production plummets with an associated decline in NO levels.  Thus, patients with FM who have high NO levels would likely be suffering from associated metabolic syndrome, and patients with low NO levels would likely be suffering from Type II diabetes.85, 88 

Figure 2 illustrates the relationship of NF-kB to various hormone systems.

Fibromyalgia and immune-hormonal influences on connective tissue

Inflammation of muscles, tendons, and/or fascia is generally followed by proliferative and remodeling phases of healing initiated by fibroblasts which lay down an extracellular matrix (ECM) composed of collagen and elastin fibers. “Fibroblasts respond to mechanical strain by altering shape and alignment, undergoing hyperplasia and secreting inflammatory cytokines including IL-6.”  The extra cellular matrix is initially laid down in a disorganized pattern that is subsequently matured and aligned. Chronic and excessive mechanical tension from postural imbalance, hormonal disruption or other factors may interfere with collagen maturation. 94  Remodeling of the extracellular matrix and collagen deposition around terminal nerve fibers may be compressive and contribute to neuropathic pain.95

Oxidative stress in muscles accelerates the generation of advanced glucose (glycation) end products (AGEs).  AGE-mediated cross-linked proteins have decreased solubility and are highly resistant to proteolytic digestion.  Interaction of AGEs with their receptors leads to activation of NF-kB resulting in an increased expression of cytokines, chemokines, growth factors, and adhesion molecules.96 97   

Two AGE products have been reported at significantly elevated levels in the serum of patients with FM: N-carboxymethyllysine (CML) (2386.56 ± 73.48 pmol/mL; CL 61.36-2611.76 versus controls 2121.97 ± 459.41 pmol/mL; CL 2020.39-2223.560; p<0.05)96 and pentosidine (mean 190 ± 120 SD and median 164 versus controls mean 128 ± 37 SD and median 124; p<0.05)97  Comparison of muscle biopsies showed “clear differences in the intensity and distribution of the immunohistochemical staining”. CML was seen primarily in the interstitial tissue between the muscle fibers where collagens were localized and in the endothelium of small vessels of patients.  Activated NF-kB was seen in cells of the interstitial tissue especially around the vessels of patients, but almost no activated NF-kB was seen in the control biopsies. AGE activation of NF-kB has been shown to be significantly more prolonged than the activation of NF-kB by cytokines.96 97 

Fibromyalgia, the nervous system and pain

Sensory transmission in humans occurs through three primary afferentnerve fiber types: heavily myelinated mechanical afferent pathways (A Beta fibers) that transmit non-noxious tactile sensations, small-diameter myelinated fibers (A Delta fibers) that transmit sharp pain, and small diameter unmyelinated fibers (C fibers) that transmit dull aching pain.  The heavily myelinated non-pain fiber type has been shown to sprout axons that terminate on pain lamina in the posterior horn of the spinal cord resulting in the conversion of mechanical stimuli to pain.  Within the brain, sensitization of the N-methyl D-aspartate (NMDA) receptors can amplify pain signals between the thalamus and the sensory cortex.67, 98 

Chronic damage or excitation of nociceptive afferent fibers from compressive collagen deposition may develop into spontaneous (ectopic) firing oscillating at frequencies sufficient to initiate cross (ephaptic) excitation of sympathetic and sensory fibers (myelinated A-delta and non-myelinated C fibers) within the dorsal root ganglia (DRG) of the central nervous system.98 Normally, the DRG has little sympathetic innervation, but trauma can trigger sympathetic sprouting that forms basket-like structures within the DRG. Neurotrophins, in particular nerve growth factor (NGF), play an important role in sympathetic fiber sprouting of sensory ganglia in murine models. DRG can be reservoirs for latent viral infections such as Herpes Zoster, HIV and enteroviruses.  In addition, the Borrelia species has been identified in a non-human primate model of Lyme disease.  NGF also facilitates expression of Substance P (SP), a peptide neurotransmitter involved in the induction of the IL-6 - NF-kB pathway 60, 99, 100 and in the transmission of neuropathic pain.101, 102  SP has been found to be elevated in the cerebrospinal fluid of patients with FM in comparison to normal values,103 and control subjects.104

Summary and Conclusions

Chronic unresolved infection, trauma, and/or emotional stresses that trigger immune pathways with subsequent chronic hormonal and nervous system responses is proposed to perpetuate chronic neuropathic pain. Figure 3 provides a summary model of immune-hormonal contributions to neuropathic pain in fibromyalgia.

The ACR criteria and severity scales have defined fibromyalgia and The Wisconsin study has identified psychological and physiological subsets that are critical steps in its characterization.   This type of testing could be further strengthened through the use of specific biomarkers.  Potential markers of FM status include the RelA/p65 and p50 subunits of NF-kB, which are currently the focus of several clinical trials of other chronic painful conditions.  Additional potential markers include: IL-6, IL-1b, TNF-a, PKC, transaldolase, CML, pentosidine and NGF.   Substance P has been previously identified as a marker of pain, but is problematic as a marker for FM, since it has only been measured in the CSF.    The search for markers that are truly specific to FM may continue to be a difficult task  due to their overlap with other metabolic conditions, such as CFS, metabolic syndrome, type II diabetes, and IBS.  Nonetheless, these markers remain important as they can indicate oxidative stress, cytokine activation, hormonal dysregulation and neuropathic pain.  These potential FM markers need to be evaluated in clinical trials where they can be measured over time and correlated with patient symptoms. 

Currently, family and general medical practice physicians are uniquely positioned to establish the FM diagnosis, determine subsets of FM patients, investigate potential triggers of chronic immune activation, advise patients, prescribe medications and refer patients to appropriate specialists or pain centers.  Establishment of the FM diagnosis requires use of the ACR Widespread Pain Index (WPI) and symptom severity (SS) scale, but no longer requires the tender point examination. 3 

Determination of FM subsets can be accomplished using the approach used in  the Wisconsin cross sectional survey.53  Investigation of potential triggers of chronic immune activation needs to include sources of underlying infection, unresolved physical or emotional trauma, toxins and food sensitivities.  These investigations may be accomplished through careful interviewing and well-designed questionnaires. Advising the patient should acknowledge the reality of their pain and other symptoms and provide rational approaches to resolution of those symptoms. Prescribing of medications needs to be sensitive to current and previous patient experience with medications, in addition to following current guidelines for stabilizing FM symptoms.  Referral to appropriate specialists and centers would include those with expertise in physical medicine, psychology and nutrition.  Physical medicine can address pain and functional deficits; psychology can address underlying emotional issues and trauma; and nutrition can focus on resolution of chronic inflammation, oxidative stress, and intestinal dysbiosis.

Where do we go from here for additional FM treatment options?  Immune modulators have been used successfully in other painful conditions, such as rheumatoid arthritis.  Immune modulators acting on the IL-6 - NF-kB cascade have considerable potential for FM, but only after ruling out or successfully treating any underlying infections.  Numerous pharmaceutical blockers of NF-kB exist, but most are associated with serious side effects.  Natural products may provide additional options as some are able to mediate pathways leading to NF-kB without the same side effects.105  Medications that elevate individual hormone levels have been included in accepted treatment protocols in the case of serotonin and norepinephrine.  However, elevations of other hormones, such as cortisol and thyroid hormones, are under investigation and remain controversial.  Elevation of individual hormones may be problematic because of the number of different hormones influenced by the IL-6 - NF-kB pathway. 

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Paul Breeding proposed the initial model and wrote early drafts of the paper. Nancy Russell assisted in subsequent literature reviews and the writing of subsequent versions of the manuscript. Garth Nicolson contributed most of the section on infectious triggers and both critiqued and added to remaining parts of the manuscript.
Competing Interests: 
None declared
Details of Authors: 
GARTH L. NICOLSON, PhD President, Institute for Molecular Medicine, Department of Molecular Pathology, The Institute for Molecular Medicine, California, USA. PAUL C. BREEDING, DC Rehabilitation Specialist, The Institute for Molecular Medicine, California, USA. NANCY C. RUSSELL, DrPH Consultant, The Institute for Molecular Medicine, California, USA.
Corresponding Author Details: 
GARTH L. NICOLSON, PhD President, Institute for Molecular Medicine, Department of Molecular Pathology, The Institute for Molecular Medicine, P. O. Box 9355, S. Laguna Beach, CA 92652, USA. website: www.immed.org
Corresponding Author Email: 
gnicolson@immed.org
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REM Behavior Disorder (RBD) as an Early Marker for Development of Neurodegenerative Diseases

Authors
Umesh Vyas and Rose Franco
Article Citation and PDF Link
BJMP 2012;5(1):a506
Abstract / Summary
Abstract: 

REM behavior disorder (RBD) is a parasomnia characterized by emergence of purposeful complex motor activity with an enactment of dream related activities. This condition is associated with vivid often violent dreams. In normal adults during REM, diffuse hypotonia of muscles occur and on polysomnography the limb and chin electromyographic (EMG) channels demonstrate a low voltage or even flat signal. In RBD, the EMG demonstrating intermittent loss of electromyographic atoniais one of the criteria for diagnosis. Diagnostic polysomnographyrequire capturing the complex dream behaviors on video and electroencephalography monitoring confirms that the behavior originated out of REM sleep. RBD can be either idiopathic or symptomatic of various underlying conditions and may in fact be a prodromal symptom of neurodegenerative disease. It can present acutely which is almost always induced by medications; or develop gradually over months to years. More than half of those with RBD will eventually exhibit signs and symptoms of a degenerative neurologic disorder. A Polysomnogram (PSG) is necessary to diagnose RBD, showing absence of REM sleep atonia and related abnormal behavior.

Keywords: 
REM sleep; REM Behavior Disorder; Neurodegenerative diseases; Parkinson’s disease; Polysomnogram

Introduction

Normal sleep is divided into Non-REM and REM. REM occurs every 90-120 minutes during adult sleep throughout the night with each period of REM progressing in length such that the REM periods in the early morning hours are the longest and may last from 30-60 minutes. Overall, REM accounts for 20-25% of the sleep time but is weighted toward the second half of the night. During REM sleep with polysomnography monitoring one observes a low voltage mixed frequency amplitude EEG and low voltage EMG in the chin associated with intermittent bursts of rapid eye movements. During the periods of REM breathing becomes irregular, blood pressure rises and the heart rate also increases due to excess adrenergic activity. The brain is highly active during REM and the electrical activity recorded in the brain by EEG during REM sleep is similar to that of wakefulness.

Parasomnias are undesirable, unexpected, abnormal behavioral phenomena that occur during sleep. There are three broad categories in parasomnias. They are 

  1. Disorders of Arousal (from Non-REM sleep)
  2. Parasomnias usually associated with REM sleep, and
  3. Other parasomnias which also includes secondary type of parasomnias.

RBD is the only parasomnia which requires polysomnographic testing as part of the essential diagnostic criteria.

Definition of RBD

“RBD is characterized by the intermittent loss of REM sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation” (ICSD-2).1 These motor phenomena may be complex and highly integrated and often are associated with emotionally charged utterances and physically violent or vigorous activities. RBD was first recognized and described by Schenck CH et al. in 1986.2 This diagnosis was first incorporated in the International Classification of Sleep Disorders (ICSD) in 1990. (American Academy of Sleep Medicine)

A defining feature of normal REM sleep is active paralysis of all somatic musculature (sparing the diaphragm to permit ventilation). This result in diffuse hypotonia of the skeletal muscles inhibiting the enactment of dreams associated with REM sleep. In RBD there is an intermittent loss of muscle atonia during REM sleep that can be objectively measured with EMG as intense phasic motor activity (figure 1 and 2).


Figure 1


Figure 2

This loss of inhibition often precedes the complex motor behaviors during REM sleep. Additionally, RBD patients will report that their dream content is often very violent or vigorous dream enacting behaviors include talking, yelling, punching, kicking, sitting, jumping from bed, arm flailing and grabbing etc. and most often the sufferer will upon waking from the dream immediately report a clear memory of the dream which coincides very well with the high amplitude violent defensive activity witnessed. This complex motor activity may result in a serious injury to the dreamer or bed partner that then prompts the evaluation.

Prevalence

The Prevalence of RBD is about 0.5% in general population.1, 3 RBD preferentially affect elderly men (in 6th and 7th decade) with ratio of women to men being 1 to 9.4 The mean age of disease onset is 60.9 years and at diagnosis is 64.4 years.5 RBD was reported in an 18 year old female with Juvenile Parkinson disease,6 so age and gender are not absolute criteria.

In Parkinson disease (PD) the reported prevalence ranges from 13-50%,7, 14-19 LewyBody Dementia (DLB) 95%,8 and Multiple System Atrophy (MSA) 90 %.9 The presence of RBD is a major diagnostic criterion for MSA. RBD has been reported in Juvenile Parkinson disease, and pure autonomic failure10-12 all neurodegenerative disorders are synucleinopathies.13

Physiology

The neurons of locus coeruleus, raphe nuclei, tuberomammillary nucleus, pedunculopontine nucleus, laterodorsal tegmental area and the perifornical area are firing at a high rate, and cause arousal by activating the cerebral cortex. During REM sleep, the aforementioned excitatory areas fall silent with the exception of the pedunculopontine nucleus and laterodorsal tegmental areas. These regions project to the thalamus and activate the cortex during REM sleep. This cortical activation is associated with dreaming in REM. Descending excitatory fibers from the pedunculopontine nucleus and laterodorsal tegmental area innervate the medial medulla, which then sends inhibitory projections to motor neurons producing the skeletal muscle atonia of REM sleep.20-21

There are two distinct neural systems which collaborate in the “paralysis” of normal REM sleep, one is mediated through the active inhibition by neurons in the nucleus reticularis magnocellularis in the medulla via the ventrolateral reticulospinal tract synapsing on the spinal motor neurons and the other system suppresses locomotor activity and is located in pontine region.22

Pathophysiology

REM sleep contains two types of variables, tonic (occurring throughout the REM period), and phasic (occurring intermittently during a REM period). Tonic elements include desynchronized EEG and somatic muscle atonia (sparing the diaphragm). Phasic elements include rapid eye movements, middle ear muscle activity and extremity twitches. The tonic electromyogram suppression of REM sleep is the result of active inhibition of motor activity originating in the perilocus coeruleus region and terminating in the anterior horn cells via the medullary reticularis magnocellularis nucleus.

In RBD, the observed motor activity may result from either impairment of tonic REM muscle atonia or from increase phasic locomotor drive during REM sleep. One mechanism by which RBD results is the disruption in neurotransmission in the brainstem, particularly at the level of the pedunculopontine nucleus.23Pathogenetically, reduced striatal dopaminergic mediation has been found24-25 in those with RBD. Neuroimaging studies support dopaminergic abnormalities.

Types of RBD

 

RBD can be categorized based on severity:

  1. Mild RBD occurring less than once per month,
  2. Moderate RBD occurring more than once per month but less than once per week, associated with physical discomfort to the patient or bed partner, and
  3. Severe RBD occurring more than once per week, associated with physical injury to patient or bed partner.

RBD can be categorized based on duration:

  1. Acute presenting with one month or less,
  2. Subacute with more than one month but less than 6 months,
  3. Chronic with 6 months or more of symptoms prior to presentation.

Acute RBD: In 55 - 60% of patients with RBD the cause is unknown, but in 40 - 45% the RBD is secondary to another condition. Acute onset RBD is almost always induced or exacerbated by medications (especially Tri-Cyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, Mono-Amine Oxidase Inhibitors, Serotonin Norepinephrine Reuptake Inhibitors,26 Mirtazapine, Selegiline, and Biperiden) or during withdrawal of alcohol, barbiturates, benzodiazepine or meprobamate. Selegiline may trigger RBD in patients with Parkinson disease. Cholinergic treatment of Alzheimer’s disease may trigger RBD.

Chronic RBD: The chronic form of RBD was initially thought to be idiopathic; however long term follow up has shown that many eventually exhibit signs and symptoms of a degenerative neurologic disorder. One recent retrospective study of 44 consecutive patients diagnosed with idiopathic RBD demonstrated that 45% (20 patients) subsequently developed a neurodegenerative disorder, most commonly Parkinson disease (PD) or Lewy body dementia, after a mean of 11.5 years from reported symptoms onset and 5.1 years after RBD diagnosis.27

The relationship between RBD and PD is complex and not all persons with RBD develop PD. In one study of 29 men presenting with RBD followed prospectively, the incidence of PD was 38% at 5 years and 65% after 12 years.7, 28, 29 Contrast this with the prevalence of the condition in multiple system atrophy, where RBD is one of the primary symptoms occurring in 90% of cases.9 In cases of RBD, it is absolutely necessary not only to exclude any underlying neurodegenerative disease process but also to monitor for the development of one over time in follow up visits.

Clinical manifestations

Sufferers of RBD usually present to the doctor with complaints of sleep related injury or fear of injury as a result of dramatic violent, potentially dangerous motor activity during sleep. 96% of patients reporting harm to themselves or their bed partner. Behaviors during dreaming described include talking, yelling, swearing, grabbing, punching, kicking, jumping or running out of the bed. One clinical clue of the source of the sleep related injury is the timing of the behaviors. Because RBD occurs during REM sleep, it typically appears at least 90 minutes after falling asleep and is most often noted during the second half of the night when REM sleep is more abundant.

One fourth of subjects who develop RBD have prodromal symptoms several years prior to the diagnosis. These symptoms may consist of twitching during REM sleep but may also include other types of simple motor movements and sleep talking or yelling.30-31 Day time somnolence and fatigue are rare because gross sleep architecture and the sleep-wake cycle remain largely normal.

RBD in other neurological disorders and Narcolepsy:

RBD has also been reported in other neurologic diseases such as Multiple Sclerosis, vascular encephalopathies, ischemic brain stem lesions, brain stem tumors, Guillain-Barre syndrome, mitochondrial encephalopathy, normal pressure hydrocephalus, subdural hemorrhage, and Tourette’s syndrome. In most of these there is likely a lesion affecting the primary regulatory centers for REM atonia.

RBD is particularly frequent in Narcolepsy. One study found 36% pts with Narcolepsy had symptoms suggestive of RBD. Unlike idiopathic RBD, women with narcolepsy are as likely to have RBD as men, and the mean age was found to be 41 years.32 While the mechanism allowing for RBD is not understood in this population, narcolepsy is considered a disorder of REM state disassociation. Cataplexy is paralysis of skeletal muscles in the setting of wakefulness and often is triggered by strong emotions such as humor. In narcoleptics who regularly experienced cataplexy, 68% reported RBD symptoms, compared to 14% of those who never or rarely experienced cataplexy.32-33 There is evidence of a profound loss of hypocretin in the hypothalamus of the narcoleptics with cataplexy and this may be a link that needs further investigation in the understanding of the mechanism of RBD in Narcolepsy with cataplexy. It is prudent to follow Narcoleptics and questioned about symptoms of RBD and treated accordingly, especially those with cataplexy and other associated symptoms.

Diagnostic criteria for REM Behavior Disorder(ICSD-2: ICD-9 code: 327.42)1

A. Presence of REM sleep without Atonia: the EMG finding of excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental or (upper or lower) limb EMG twitching (figure 1 and 2).

B. At least one of the following is present:

i. Sleep related injurious, potentially injurious, or disruptive behaviors by history

ii. Abnormal REM sleep behaviors documented during polysomnographic monitoring

C. Absence of EEG epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder.

D. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder.

Differential diagnosis

Several sleep disorders causing behaviors in sleep can be considered in the differential diagnosis, such as sleep walking (somnambulism), sleep terrors, nocturnal seizures, nightmares, psychogenic dissociative states, post-traumatic stress disorder, nocturnal panic disorder, delirium and malingering. RBD may be triggered by sleep apnea and has been described as triggered by nocturnal gastroesophageal reflux disease.

Evaluation and Diagnosis

  • Detailed history of the sleep wake complaints
  • Information from a bed partner is most valuable
  • Thorough medical, neurological, and psychiatric history and examination
  • Screening for alcohol and substance use
  • Review of all medications
  • PSG (mandatory): The polysomnographic study should be more extensive, with an expanded EEG montage, monitors for movements of all four extremities, continuous technologist observation and continuous video recording with good sound and visual quality to allow capture of any sleep related behaviors
  • Multiple Sleep Latency Test (MSLT): Only recommended in the setting of suspected coexisting Narcolepsy
  • Brain imaging (CT or MRI) is mandatory if there is suspicion of underlying neurodegenerative disease.

Management

RBD may have legal consequences or can be associated with substantial relationship strain; therefore accurate diagnosis and adequate treatment is important, which includes non-pharmacological and pharmacological management.

Non-pharmacological management: Acute form appears to be self-limited following discontinuation of the offending medication or completion of withdrawal treatment. For chronic forms, protective measures during sleep are warranted to minimize the risks for injury to patient and bed partner. These patients are at fall risk due to physical limitations and use of medications. Protective measure such as removing bed stands, bedposts, low dressers and applying heavy curtains to windows. In extreme cases, placing the mattress on the floor to prevent falls from the bed has been successful.

Pharmacological management: Clonazepam is highly effective in treatment and it is the drug of choice. A very low dose will resolve symptoms in 87 to 90% of patients.4, 5, 7-34 Recommended treatment is 0.5 mg Clonazepam 30 minutes prior to bed time and for more than 90% of patients this dose remains effective without tachyphylaxis. In the setting of breakthrough symptoms the dose can be slowly titrated up to 2.0 mg. The mechanism of action is not well understood but clonazepam appears to decrease REM sleep phasic activity but has no effect on REM sleep atonia.35

Melatonin is also effective and can be used as monotherapy or in conjunction with clonazepam. The suggested dose is 3 to 12 mg at bed time. Pramipexole may also be effective36-38 and suggested for use when clonazepam is contraindicated or ineffective. It is interesting to note that during holidays from the drug, the RBD can take several weeks to recur. Management of patients with concomitant disorder like narcolepsy, depression, dementia, Parkinson disease and Parkinsonism can be very challenging, because medications such as SSRIs, selegiline and cholinergic medications used to treat these disorders, can cause or exacerbate RBD. RBD associated with Narcolepsy, clonazepam is usually added in management and it is fairly effective.

Follow-up

Because RBD may occur in association with neurodegenerative disorder, it is important to consult a neurologist for every patient with RBD as early as possible, especially to diagnose and provide care plan for neurodegenerative disorder, which includes but not limited to early diagnosis and management, regular follow up, optimization of management to provide better quality of life and address medico-legal issues.

Prognosis

In acute and idiopathic chronic RBD, the prognosis with treatment is excellent. In the secondary chronic form, prognosis parallels that of the underlying neurologic disorder. Treatment of RBD should be continued indefinitely, as violent behaviors and nightmares promptly reoccur with discontinuation of medication in almost all patients.

Conclusions

RBD and neurodegenerative diseases are closely interconnected. RBD often antedates the development of a neurodegenerative disorder; diagnosis of idiopathic RBD portends a risk of greater than 45% for future development of a clinically defined neurodegenerative disease. Once identified, close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative diseases. Treatment for RBD is available and effective for the vast majority of cases.

Key Points

  • Early diagnosis of RBD is of paramount importance
  • Polysomnogram is an essential diagnostic element
  • Effective treatment is available
  • Early treatment is essential in preventing injuries to patient and bed partner
  • Apparent idiopathic form may precede development of Neurodegenerative disorder by decades
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
UMESH VYAS, MD, Chair of Department of Psychiatry, Medical Director of Behavioral Health Unit and Medical Director of Sleep Disorders Center, Psychiatrist and Sleep Disorders Specialist, Mayo Clinic Health System, Mankato, MN, USA. ROSE FRANCO, MD Sleep Medicine Fellowship Director and Associate Professor in Medicine and Otolaryngology, Pulmonologist and Sleep Disorders Specialist, Medical College of Wisconsin, Milwaukee, WI, USA.
Corresponding Author Details: 
UMESH VYAS, MD, Chair of Department of Psychiatry, Medical Director of Behavioral Health Unit and Medical Director of Sleep Disorders Center, Psychiatrist and Sleep Disorders Specialist, Mayo Clinic Health System, Mankato, MN, USA.
Corresponding Author Email: 
Vyas.umesh@mayo.edu
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36. Boeve BF, Silber MH, Ferman JT. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4: 281-284.
37. Fantini ML, Gagnon JF, Filipini D, et al. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003, 61: 1418-1420.
38. Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behavior disorder. Sleep Med 2006, 7: 418-423.

Management of Drooling of saliva

Authors
Ganesh Bavikatte, Poh Lin Sit and Ali Hassoon
Article Citation and PDF Link
BJMP 2012;5(1):a507
Abstract / Summary
Abstract: 

Drooling, also known as ptyalism or sialorrhea can be defined as salivary incontinence or the involuntary spillage of saliva over the lower lip. Drooling could be caused by excessive production of saliva, inability to retain saliva within the mouth, or problems with swallowing. Drooling can lead to functional and clinical consequences for patients, families, and caregivers. Physical and psychosocial complication includes maceration of skin around the mouth, secondary bacterial infection, bad odour, dehydration and social stigmatisation. People with drooling problems are also at increased risk of inhaling saliva, food, or fluids into the lungs especially when body's normal reflex mechanisms, such as gagging and coughing are also impaired. Successful management of sialorrhea can alleviate the associated hygienic problems, improve appearance, enhance self-esteem, and significantly reduce the nursing care time of these sufferers.Chronic drooling can be difficult to manage; this article gives overview of the causes, effects and management of drooling of saliva in general practice.

Saliva is the watery and usually frothy substance produced in and secreted from the three paired major salivary (parotid, submandibular and sublingual) glands and several hundred minor salivary glands, composed mostly of water, but also includes electrolytes, mucus, antibacterial compounds, and various enzymes. Healthy persons are estimated to produce 0.75 to 1.5 liters of saliva per day. At least 90% of the daily salivary production comes from the major salivary glands while the minor salivary glands produce about 10%. On stimulation (olfactory, tactile or gustatory), salivary flow increases five fold, with the parotid glands providing the preponderance of saliva.1

Saliva is a major protector of the tissues and organs of the mouth. In its absence both the hard and soft tissues of the oral cavity may be severely damaged, with an increase in ulceration, infections, such as candidiasis, and dental decay. Saliva is composed of serous part (alpha amylase) and a mucus component, which acts as a lubricant. It is saturated with calcium and phosphate and is necessary for maintaining healthy teeth. The bicarbonate content of saliva enables it to buffer and produce the condition necessary for the digestion of plaque which holds acids in contact with the teeth. Moreover, saliva helps with bolus formation and lubricates the throat for the easy passage of food. The organic and inorganic components of salivary secretion have got a protective potential. They act as barrier to irritants and a means of removing cellular and bacterial debris. Saliva contains various components involved in defence against bacterial and viral invasion, including mucins, lipids, secretory immunoglobulins, lysozymes, lactoferrin, salivary peroxidise, and myeloperoxidase. Salivary pH is about 6-7, favouring digestive action of salivary enzyme, alpha amylase, devoted to starch digestion.


Image -1. (Source of this image- http://www.entdoctor.co.nz)

Salivary glands are innervated by the parasympathetic and sympathetic nervous system. Parasympathetic postganglionic cholinergic nerve fibers supply cells of both the secretory end-piece and ducts and stimulate the rate of salivary secretion, inducing the formation of large amounts of a low-protein, serous saliva. Sympathetic stimulation promotes saliva flow through muscle contractions at salivary ducts. In this regard both parasympathetic and sympathetic stimuli result in an increase in salivary gland secretions. The sympathetic nervous system also affects salivary gland secretions indirectly by innervating the blood vessels that supply the glands.

Table 1: Functions of saliva

Digestion and swallowing
Initial process of food digestion
Lubrication of mouth, teeth, tongue and food boluses
Tasting food
Amylase- digestion of starch
Disinfectant and protective role
Effective cleaning agent
Oral homeostasis
Protect teeth decay, dental health and oral odour
Bacteriostatic and bacteriocidal properties
Regulate oral pH
Speaking
Lubricates tongue and oral cavity

Drooling (also known as driveling, ptyalism, sialorrhea, or slobbering) is when saliva flows outside the mouth, defined as “saliva beyond the margin of the lip”. This condition is normal in infants but usually stops by 15 to 18 months of age. Sialorrhea after four years of age generally is considered to be pathologic. The prevalence of drooling of saliva in the chronic neurological patients is high, with impairment of social integration and difficulties to perform oral motor activities during eating and speech, with repercussion in quality of lifeDrooling occurs in about one in two patients affected with motor neuron disease and one in five needs continuous saliva elimination7, its prevalence is about 70% in Parkinson disease8, and between 10 to 80% in patients with cerebral palsy9.

Pathophysiology

Pathophysiology of drooling is multifactorial. It is generally caused by conditions resulting in

  1. Excess production of saliva- due to local or systemic causes (table 2)
  2. Inability to retain saliva within the mouth- poor head control, constant open mouth, poor lip control, disorganized tongue mobility, decreased tactile sensation, macroglossia, dental malocclusion, nasal obstruction.
  3. Problems with swallowing- resulting in excess pooling of saliva in the anterior portion of the oral cavity e.g. lack of awareness of the build-up of saliva in the mouth, infrequent swallowing, and inefficient swallowing.

Drooling is mainly due to neurological disturbance and less frequently to hyper salivation.Under normal circumstances, persons are able to compensate for increased salivation by swallowing. However, sensory dysfunction may decrease a person’s ability to recognize drooling and anatomic or motor dysfunction of swallowing may impede the ability to manage increased secretion.

Table 2 Aetiology of hypersalivation

Physiological
Pregnancy
Local causes
Oral inflammation- teething
Infection –oral cavity infection, dental caries, tonsillitis, peritonsilar abscess
Systemic
Toxin exposure- pesticides, mercury, capsaicin, snake poisoning
Medication –tranquilizers, anticonvulsants, anticholinesterases, lithium
Neuromuscular –cerebral palsy, Parkinson’s disease, motor neuron disease, bulbar/ pseudobulbar palsy, Stroke
Infection- rabies
Gastric- gastroesophageal reflux

Depending on duration of drooling, it can be classified as acute e.g. during infections (epiglottitis, peritonsilar abscess) or chronicneurological causes.

Symptoms

Drooling of saliva can affect patient and/or their carers quality of life and it is important to assess the rate and severity of symptoms and its impact on their life.

Table 3 Effect of untreated Drooling of saliva

Physical Psychological
Perioral chapping (skin cracking)
Maceration with secondary infection
Dehydration
Foul odour
Aspiration/ pneumonia
Speech disturbance
Interference with feeding
Isolation
Barriers to education (damage to books or electronic devices)
Increased dependency and level/intensity of care
Damage to electronic devices
Decreased self esteem
Difficult social interaction

Assessment

Assessment of the severity of drooling and its impact on quality of life for the patient and their carers help to establish a prognosis and to decide the therapeutic regimen. A variety of subjective and objective methods for assessment of sialorrhoea have been described3.

History (from patient and carers)

Establish possible cause, severity, complications and possibility of improvement, age and mental status of patient, chronicity of problems, associated neurological conditions, timing, provoking factors, estimation of quantity of saliva – use of bibs, clothing changing required/ day and impact on the day today life (patient/carer)

Physical examination

Evaluate level of alertness, emotional state, hydration status, hunger, head posture

Examination of oral cavity- sores on the lip or chin, dental problems, tongue control, swallowing ability, nasal airway obstruction, decreased intraoral sensitivity, assessment of health status of teeth, gum, oral mucosa, tonsils, anatomical closure of oral cavity, tongue size and movement, jaw stability. Assessment of swallowing

Assess severity and frequency of drooling (as per table 4)

Investigation

  • Lateral neck x ray (in peritonsilar abscess)
  • Ultrasound to diagnose local abscess
  • Barium swallow to diagnose swallowing difficulties
  • Audiogram- to rule out conductive deafness associated with oropharyngeal conditions
  • Salivary gland scan- to determine functional status

Table 4 : System for assessment of frequency and severity of drooling

Drooling severity Points
Dry (never drools) 1
Mild (wet lips only) 2
Moderate (wet lips and chins) 3
Severe (clothing becomes damp) 4
Profuse (clothing, hands, tray, object become wet) 5
 
Frequency Points
Never drools 1
Occasionally drools 2
Frequency drools 3
Constantly drools 4
Other methods of assessing salivary production and drooling

1) 1- 10 visual analogue scale (where 1 is best possible and 10 is worst possible situation)

2) Counting number of standard sized paper handkerchiefs used during the day

3) Measure saliva collected in cups strapped to chin

4) Inserting pieces of gauze with a known weight into oral cavity for a specific period of time and then re-measuring weight and calculating the difference between the dry and wet weights.

5) Salivary gland scintigraphy / technetium scanning

6) Salivary duct canulation 12 and measuring saliva production.

Management

Drooling of saliva, a challenging condition, is better managed with a multidisciplinary team approach. The team includes primary care physician, speech therapist, occupational therapist, dentist, orthodontist, otolaryngologist, paediatrician and neurologist. After initial assessment, a management plan can be made with the patient. The person/ carer should understand the goal of treating drooling is a reduction in excessive salivary flow, while maintaining a moist and healthy oral cavity. Avoidance of xerostomia (dry mouth) is important.

There are two main approaches

  1. Non invasive modalities e.g. oral motor therapy, pharmacological therapy
  2. Invasive modalities e.g. surgery and radiotherapy

No single approach is totally effective and treatment is usually a combination of these techniques. The first step in management of drooling is correction of reversible causes. Less invasive and reversible methods, namely oral motor therapy and medication are usually implemented before surgery is undertaken5

Non invasive modalities

Positioningprior to implementation of any therapy, it is essential to look at the position of the patient. When seated, a person should be fully supported and comfortable. Good posture with proper trunk and head control provides the basis for improving oral control of drooling and swallowing.

Eating and drinking skills-drooling can be exacerbated by pooreating skills. Special attention and developing better techniques in lip closure, tongue movement and swallowing may lead to improvements of some extent. Acidic fruits and alcohol stimulate further saliva production, so avoiding them will help to control drooling10

Oral facial facilitation - this technique will help to improve oral motor control, sensory awareness and frequency of swallowing.Scott and staios et al 18 noted improvement in drooling in patients with both hyper and hypo tonic muscles using this technique. This includes different techniques normally undertaken by speech therapist, which improves muscle tone and saliva control. Most studies show short term benefit with little benefit in long run. This technique can be practiced easily, with no side effects and can be ceased if no benefits noted.
 

a) Icing – effect usually last up to 5-30 minutes. Improves tone, swallow reflex.

b) Brushing- as effect can be seen up to 20- 30 minutes, suggested to undertake before meals.

c) Vibration- improves tone in high tone muscles

d) Manipulation – like tapping, stroking, patting, firm pressure directly to muscles using fingertips known to improve oral awareness.

e) Oral motor sensory exercise - includes lip and tongue exercises.

Speech therapy-speech therapy should be started early to obtain good results. The goal is to improve jaw stability and closure, to increase tongue mobility, strength and positioning, to improve lip closure (especially during swallowing) and to decrease nasal regurgitation during swallowing.

Behaviour therapy-this uses a combination of cueing, overcorrection, and positive and negative reinforcement to help drooling. Suggested behaviours, like swallowing and mouth wiping are encouraged, whereas open mouth and thumb sucking are discouraged. Behavior modification is useful to achieve (1) increased awareness of the mouth and its functions, (2) increased frequency of swallowing, (3) increased swallowing skills. This can be done by family members and friends. Although there is no randomized controlled trial done, over 17 articles published in last 25 years, show promising results and improved quality of life. No reported side effects make behavioural interventions an initial option compared to surgery, botulinum toxin or pharmaceutical management. Behaviour interventions are useful prior and after medical management such as botulinum toxin or surgery.

Oral prosthetic device- variety of prosthetic devices can be beneficial, e.g. chin cup and dental appliances, to achieve mandibular stability, better lip closure, tongue position and swallowing. Cooperation and comfort of the patient is essential for better results.

Pharmacological methods

Systematic review of anticholinergic drugs, show Benztropine, Glycopyrrolate, and Benzhexol Hydrochloride, as being effective in the treatment of drooling. But these drugs have adverse side-effects and none of the drugs been identified as superior.

Hyoscine- The effect of oral anticholinergic drugs has been limited in the treatment of drooling. Transdermal scopolamine (1.5 mg/2.5 cm2) offers advantages. One single application is considered to render a stable serum concentration for 3 days. Transdermal scopolamine has been shown to be very useful in the management of drooling, particularly in patients with neurological or neuropsychiatric disturbances or severe developmental disordersIt releases scopolamine through the skin into the bloodstream.

Glycopyrrolatestudies have shown 70-90% response rates but with a high side effect rate. Approximately 30-35% of patients choose to discontinue due to unacceptable side effects such as excessive dry mouth, urinary retention, decreased sweating, skin flushing, irritability and behavior changes. A study on 38 patients with drooling due to neurological deficits had shown up to a 90% response rateMier et al21 reported Glycopyrrolate to be effective in the control of excessive sialorrhea in children with developmental disabilities. Approximately 20% of children given glycopyrrolate may experience substantial adverse effects, enough to require discontinuation of medication.

Antimuscarinic drugs, such as benzhexol, have also been used, but limited due to their troublesome side effects.

Antireflux Medication: The role of antireflux medication (Ranitidine & Cisapride) in patients with gastro esophageal reflux due to esophageal dysmotility and lower esophageal tone did not show any benefits in a study 21.

Modafinil - One case study noticed decreased drooling in two clients who were using the drug for other reasons, but no further studies have been done.

Alternate medications: (Papaya and Grape seed extract) – Mentioned in literature as being used to dry secretions but no research in to their efficacy has been conducted.

Botulinum toxin It was in 1822 that a German poet and physician, Justinus Kerner, discovered that patients who suffered from botulism complained of severe dryness of mouth which suggested that the toxin causing botulism could be used to treat hypersalivation. However, it was only in the past few years that botulinum toxin type A (BTx-A)has been used for this purpose. BTx-A binds selectively to cholinergic nerve terminals and rapidly attaches to acceptor molecules at the presynaptic nerve surface. This inhibits release of acetylcholine from vesicles, resulting in reduced function of parasympathetic controlled exocrine glands. The blockade though reversible is temporary as new nerve terminals sprout to create new neural connections. Studies have shown that injection of botulinum toxin to parotid and submandibular glands, successfully subsided the symptoms of drooling 30,31. Although there is wide variation in recommended dosage, most studies suggest that about 30- 40 units of BTx-A injected into the parotid and submandibular glands are enough for the symptoms to subside The injection is usually given under ultrasound guidance to avoid damage to underlying vasculature/ nerves. The main side effects from this form of treatment are dysphagia, due to diffusion into nearby bulbar muscles, weak mastication, parotid gland infection, damage to the facial nerve/artery and dental caries.

Patients with neurological disorders who received BTX-A injections showed a statistically significant effect from BTX-A at 1 month post injection, compared with control, this significance was maintained at 6 months. Intrasalivary gland BTX-A was shown to have a greater effect than scopolamine.

The effects of BTx-A are time limited and this varies between individuals.

Invasive modalities

Surgerycan be performed to remove salivary glands, (most surgical procedures focused on parotid and submandibular glands). ligate or reroute salivary gland ducts, or interrupt parasympathetic nerve supply to glands. Wilke, a Canadian plastic surgeon, was the first to propose and carry out parotid duct relocation to the tonsillar fossae to manage drooling in patients with cerebral palsy. One of the best studied procedures, with a large number of patients and long term follow up data, is submandibular duct relocation 32, 33.

Intraductal laser photocoagulation of the bilateral parotid ducts has been developed as a less invasive means of surgical therapy. Early reports have shown some impressive results34.

Overall surgery reducedsalivary flow and drooling can be significantly improved often with immediate results – 3 studies noted that 80 – 89% of participants had an improvement in their control of their saliva. Two studies discussed changes in quality of life. One of these found that 80% of those who participated improved across a number of different measures including receiving affection from others and opportunities for communication and interaction. Most evidence regarding surgical outcomesof sialorrhea management is low quality and heterogeneous. Despitethis, most patients experience a subjective improvement followingsurgical treatment 36.

Radiotherapy - to major salivary glands in doses of 6000 rad or more is effective Side effects which include xerostomia, mucositis, dental caries, osteoradionecrosis, may limit its use.

Key messages
  • Chronic drooling can pose difficulty in management
  • Early involvement of Multidisciplinary team is the key.
  • Combination of approach works better
  • Always start with noninvasive, reversible, least destructive approach
  • Surgical and destructive methods should be reserved as the last resort.

 

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Ganesh Bavikatte, MBBS, MD (Medicine), MRCP(UK), MRCP(London), Speciality Registrar Rehabilitation Medicine, Manchester, UK. Poh Lin Sit, MBBch, Staff Grade in Rehabilitation Medicine, Central Manchester University Hospitals, Manchester, UK. Ali Hassoon, MB ChB, FRCP (London), Consultant Physician Rehabilitation Medicine, Central Manchester NHS Trust, Manchester, UK.
Corresponding Author Details: 
Ganesh Bavikatte, MBBS, MD (Medicine), MRCP(UK), MRCP(London, Speciality Registrar Rehabilitation Medicine, 9 averhill, worsley, Manchester, M281ZN.
Corresponding Author Email: 
ganeshbavikatte@ukdoctor.org
References
References: 

 

1. Stuchell RN, Mandel ID. Salivary gland dysfunction and swallowing disorders. Otolayngol Clin North Am 1988;21:649-61.2. Costanzo, L. Text book of Physiology, 3rd edition. Saunders Elsevier. ISBN 10:1-4160-2320-8.3. Sochaniwskyj AE. Drool Quantification: noninvasive technique. Arch Phys Med Rehabil 1982;63:605-74. Neil G. Hockstein, Daniel S. Samadi, Kristin Gendron, Steven D. Handler, Am Fam Physician 2004;69:2628-345. Louise Cummings, Text book of Clinical Linguistics, edin univ press, page 95-99, 2008 6. Hilary Johnson, Amanda Scott, Text book on A practical approach to saliva control page31, 86.7. Giles R, Naummann M, Werner E, Riemann M, Beck I, Puls I, Reinners C, Toyka KV. Injection of botulinum toxin A in to salivary glands improve sialorrhoea in amyotropic lateral sclerosis. J Neurol Neurosurg Psychiatry 200;69:121-38. Jongerius PH, Rotteveel JJ, Van Limbeck J, Gabreels FJM, Van Ilulst KBS, Van Den Ilogen FJA. Botulinum toxin effect on salivary flow rate in children with cerebral palsy. Neurology 2004;63:1371-59. Boothwell JE, Clarke K, Dooley JM, Gordon KE, Anderson R, Wood Camfied CS,  Camfield PR.  Botulinum toxin A as a treatment for excessive drooling in children. Paediatr Neurology 2002; 27(1):18-2210. Johnson H, Scott A. 1993; Book on  practical approach to saliva control and communication; 199311. Scully C, Limeres J, Gleeson M, Tomás I, Diz P. Drooling, J Oral Pathol Med. 2009 Apr;38(4):321-7. Epub 2009 Feb 23.12. Suskind DL, Tilton A. Clinical study of botulinum toxin- A in the treatment of sialorrhoea in children with cerebral palsy. Laryngoscope 2002. 112:73-81.13. Crysdale WS, McCann C, Roske L. Saliva control issues in the neurologically challenged: a 30 year experience in team management. Int J Paedatr Otolarynol: 2006; 70: 519-52714. Sullivan PB, Lambert B, Rose M. Prevalence and severity of feeding and nutritional problems in children with neurological impairment: Oxford Feeding study. Dev Med Child Neuol 2000;42:674-68015. Meningaud JP, Pitak-Arnnop P, Chikhani L, Bertrand JC. Drooling of saliva: A Review of the etiology and management options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(1):48-57.16. Hockstein NG, Samadi DS, Gendron K, Handler SD, Sialorrhoea: a management Challenge, Am Fam Physician 2004; 69:2628-2634.17. Jongerius PH, Van Tiel P, Van Limbeek J, A systematic review for evidence of efficacy of anticholinergic drugs to treat drooling. Arch Dis Child 2003; 88: 911-91418. Scott, A., & Staios, G. (1993). Oral-facial facilitation. In J. Hilary & A. Scott (Eds.), A practical approach to saliva control (pp. 32-42). San Antonio, TX: Communication Skill Builders.19. Potulska A, Friedman A. Controlling sialorrhoea: a review of available treatment options. Expert Opin Pharmacother. 2005 Aug;6(9):1551-4.20. Mato Montero A, Limeres Posse J, Tomás Carmona I, Fernández Feijoo J, Diz Dios P.Med Oral Patol Oral Cir Bucal. 2008 Jan 1;13(1):E27-30.21. Mier RJ, Bachrach SJ, Lakin RC, Barker T, Childs J, Moran M. Treatment of sialorrhea with glycopyrrolate: A double-blind, dose-ranging study. Arch Pediatr Adolesc Med. 2000 Dec;154(12):1214-8.22. Blasco P.A. Glycopyrrolate treatment of chronic drooling. Archives of paediatric adolescent medicine, vol 150, sept 1996:932-935. 23. Heine R.G. Effect of antireflux medication on salivary drooling in children with cerebral palsy. Developmental medicine and child neurology, 1996, vol 38, 1030-36.24.  Blasco P.A. (2002) Management of drooling: 10 years after the consortium on drooling, 1990. Dev. Med. Child Neurol. 44, 778–78125. Camp-Bruno J.A., Winsberg B.G., Green-Parsons A.R. (1989) Efficacy of benztropine therapy for drooling. Dev. Med. Child Neurol. 31, 309–31926. Lloyd Faulconbridge R.V., Tranter R.M., Moffat V. Review of management of drooling problems in neurologically impaired children: A review of methods and results over 6 years at Chailey Heritage clinical services. Clin. Otolaryngol. Allied Sci. (2001) 26, 76–8127. Porta M., Gamba M., Bertacchi G. et al. (2001) Treatment of sialorrhoea with ultrasound guided botulinum toxin type A injection in patients with neurological disorders. J. Neurol. Neurosurg. Psychiatry 70, 538–54028. Jongerius P.H., van den Hoogen F.J., van Limbeek J. et al. (2004) Effect of botulinum toxin in the treatment of drooling: A controlled clinical trial. Pediatrics 114, 620–62729. Diamant H, Kumlien A. A treatment for drooling in children with cerebral palsy. J Laryngol Otol. 1974;88(1):61-64.30. Peter Misra. Botulinum toxin as a treatment for drooling of saliva. ACNR; nov/dec 2002: v2 n2 11-12.31. Dayse Manrique, application of botulinum toxin to reduce the saliva in patients with amyotropic lateral sclerosis; Rev Bras Otorrinolaringol; sept-oct 2005, v.71, n.5, 566-6932. Borg M, Hirst, the role of radiation therapy in the management of sialorrhea international journal of radiation oncology, biology and physics; 1998 jul: 1113-933. Crysdale W.S. Management of drooling in individuals with neurodisability: a surgical experience. Developmental medicine and child neurology. 2001(43) 379- 383.34. O’Dwyer T.P. the surgical management of drooling- a 15 year follow up. Clinical Otolaryngology. 1997(22) 284-287.35. Chang C. Intraductal laser photocoagulation of the bilateral parotid ducts for reduction of drooling in patients with cerebral palsy. Plastic and reconstructive Surgery. 2001(107) 907- 913.36. Jeremy Reed, MD, MPH; Carolyn K. Mans, MD; Scott E. Brietzke, MD, MPH Surgical Management of Drooling A Meta-analysis. Arch Otolaryngol Head Neck Surg. 2009;135(9):924-931.

Benzodiazepines Revisited

Authors
Tauseef Mehdi
Article Citation and PDF Link
BJMP 2012;5(1):a501
Abstract / Summary
Abstract: 

Up to 1 million people in the UK are currently long-term prescribed benzodiazepine users.1 Surveys of general practices show that there are over 180 long-term prescribed users per general practice.2 Despite repeated recommendations to limit benzodiazepines to short-term use (2–4 weeks), doctors in the UK and worldwide are still prescribing them for months or years. Dependence upon prescribed benzodiazepines is now recognised as a major clinical problem and the National Performance Assessment Framework for the NHS makes it a national priority to reduce this within each health board area. Junior doctors who have recently graduated from medical school are commonly placed in rotations where they have to manage patients on benzodiazepine prescriptions.  It is necessary for doctors in general to be aware of the essentials of benzodiazepines not only for the adequate management of patients on chronic benzodiazepine prescriptions, but also for responsible prescription of this drug when it is appropriate.

­­­­History of benzodiazepines

The advent of benzodiazepines in the late fifties was met with great excitement by the practicing physicians around the world. Their range of actions – sedative/hypnotic, anxiolytic, anticonvulsant and muscle relaxant – combined with low toxicity and alleged lack of dependence potential seemed to make them ideal medications for many common conditions. The drugs were prescribed long term, often for many years, for complaints such as anxiety, depression, insomnia and ordinary life stressors. They began to replace barbiturates; drugs known to be dangerous in overdose, which tended to cause addiction and were associated with troublesome side-effects. Previous compounds including opium, alcohol, chloral and bromides were similarly burdened.

The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The compound showed very strong sedative, anticonvulsant and muscle relaxant effects when submitted for a standard battery of animal tests. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam was marketed by Hoffmann–La Roche under the brand name Valium in 1963.

The benefits of benzodiazepines and the apparent lack of discouraging factors led an alarming rise of benzodiazepine prescriptions. In the late 1970s benzodiazepines became the most commonly prescribed of all drugs in the world.1 In1980, Tyrer reported that each day about 40 billion doses of benzodiazepine drugs are consumed throughout the world.3 This figure is staggering by any standards. However, towards the end of the 1970s, awareness begin to grow that benzodiazepines were being unnecessarily over-prescribed and it was noticed that certain patients might become dependent on benzodiazepines after chronic use.4 In particular, patients found it difficult to stop taking benzodiazepines because of withdrawal reactions and many complained that they had become ‘addicted’. Several investigations showed quite unequivocally that benzodiazepines could produce pharmacological dependence in therapeutic dosage.5-9

In 1988, the Committee of Safety of Medicines reacted to the concerns by spelling out emphatic guidelines about the use of benzodiazepines drugs. For anxiety and insomnia, benzodiazepines are indicated for short term relief (two to four weeks) only if the condition is severe, disabling and subjecting the individual to extreme distress.10

Tolerance and dependence

Tolerance is a phenomenon that develops with many chronically used drugs. The body responds to the continued presence of the drug with a series of adjustments that tend to overcome the drug effects. In the case of benzodiazepines, compensatory changes occur in the GABA and benzodiazepine receptors which become less responsive, so that the inhibitory actions of the GABA and benzodiazepines are decreased. As a result, the original dose of the drug has progressively less effect and a higher dose is required to obtain the original effect.

Dependence is understood to be the inability to control intake of a substance to which one is addicted. It encompasses a range of features initially described in connection with alcohol abuse, now recognised as a syndrome (see box 1) associated with a range of substances.

Dependence has two components: psychological dependence, which is the subjective feeling of loss of control, cravings and preoccupation with obtaining the substance; and physiological dependence, which is the physical consequences of withdrawal and is specific to each drug. For some drugs (e.g. alcohol) both psychological and physiological dependence occur; for others (e.g. LSD) there are no marked features of physiological dependence.


Box 1: Dependence Syndrome*

 

Three or more of the following manifestations should have occurred together for at least one month or if persisting for periods of less than one month then they have occurred together repeatedly within a twelve month period.

  1. A strong desire or sense of compulsion to take the substance.
  2. Impaired capacity to control substance-taking behaviour in terms of onset, termination or level of use, as evidenced by: the substance being often taken in larger amounts or over a longer period than intended, or any unsuccessful effort or persistent desire to cut down or control substance use.
  3. A physiological withdrawal state (see F1x.3 and F1x.4) when substance use is reduced or ceased, as evidenced by the characteristic withdrawal syndrome for the substance, or use of the same (or closely related) substance with the intention of relieving or avoiding withdrawal symptoms.
  4. Evidence of tolerance to the effects of the substance, such that there is a need for markedly increased amounts of the substance to achieve intoxication or desired effect, or that there is a markedly diminished effect with continued use of the same amount of the substance.
  5. Preoccupation with substance use, as manifested by: important alternative pleasures or interests being given up or reduced because of substance use; or a great deal of time being spent in activities necessary to obtain the substance, take the substance, or recover from its effects.
  6. Persisting with substance use despite clear evidence of harmful consequences, as evidenced by continued use when the person was actually aware of, or could be expected to have been aware of the nature and extent of harm.

* ICD 10 Classification of Mental and Behaviour disorder, online version 2007.

Withdrawal syndrome and discontinuation syndrome

Any drug consumed regularly and heavily can be associated with withdrawal phenomenon on stopping. Clinically significant withdrawal phenomena occur in dependence to alcohol, benzodiazepines, opiates and are occasionally seen in cannabis, cocaine and amphetamine use. In general, drugs with a short half-life will give rise to more rapid but more transient withdrawal.

Discontinuation syndrome is a common phenomenon and occurs with all classes of antidepressants. It is only experienced when one tries to discontinue its use. The most common symptoms are dizziness, vertigo, gait instability, nausea, fatigue, headaches, anxiety and insomnia. Less commonly shock-like sensations, paraesthesia, visual disturbances, diarrhoea and flu-like symptoms have been reported. Symptoms usually begin 2-5 days after SSRI discontinuation or dose reduction. The duration is variable (one to several weeks) and ranges from mild to moderate intensity in most patients, to extremely distressing in a small number. Tapering antidepressants at the end of treatment, rather than abrupt stoppage, is recommended as standard practice by several authorities and treatment guidelines11-13.

The terms ‘antidepressant withdrawal syndrome’ and ‘antidepressant discontinuation syndrome’ are used interchangeably in the literature. ‘Discontinuation’ is preferred as it does not imply that antidepressants are addictive or cause a dependence syndrome. The occurrence of withdrawal symptoms does not in itself indicate that a drug causes dependence as defined in ICD 10 (World Health Organisation 1992)14 and DSM –IV (American Psychiatric Association, 1994)15.

Understanding how benzodiazepines work and their effects

For the first 15 years after the introduction of benzodiazepines, no clear picture emerged as to how these drugs might exert their psychotropic effects. The great breakthrough in our understanding in the mechanism of action of benzodiazepines came in the mid 1970s when biologists at Hoffman-La Roche demonstrated that benzodiazepines exert their psychotropic effects by potentiating GABA neurotransmission.16

GABA, Gamma-Amino butyric acid, is the most important inhibitory neurotransmitter in the mammalian brain representing about 30% of all synapses in the whole brain. GABAergic neurones mediate pre-synaptic inhibition by depressing the release of neurotransmitter at excitatory input synapse, and post-synaptic inhibition by depressing synaptic excitation of the principal neuron. When benzodiazepines react at their receptor site, which is actually situated on the GABA receptor, the combination acts as a booster to the actions of GABA making the neuron more resistant to excitation. Several studies showed that benzodiazepines were able to facilitate both types of inhibition, indicating that the effects of the benzodiazepines were in fact due to an interaction with the GABAergic transmission process17-19­.

Various subtypes of benzodiazepine receptors have slightly different actions. Alpha 1 is responsible for sedative effects. Alpha 2 exerts anxiolytics effects. Alpha 1, Alpha 2 and Alpha 5 are responsible for anticonvulsant effects. As a consequence of the enhancement of GABA’s inhibitory activity caused by benzodiazepines, the brain’s output of excitatory neurotransmitters including norepinephrine, serotonin, dopamine and acetylcholine is reduced.

The studies on the receptor binding of benzodiazepines and the subsequent changes that occur in the central nervous system have provided us with an adequate explanation for some or all of the actions of benzodiazepines, which are listed in Box 2.


Box 2: Four principle biological properties of benzodiazepines

 

  1. Anxiolytic and behavioural inhibition – The anxiolytic effect is seen in animals as an increase of those behavioural responses that are suppressed experimentally by punishment or which are absent because of innate aversion20-23.
  2. Anticonvulsant – Benzodiazepines are most potent against chemically induced epileptiform activities. At higher doses most, but not all, benzodiazepines also prevent seizures induced by electric shock24.
  3. Sedative/hypnotic – These effects of benzodiazepines are most easily observed as a decrease of spontaneous locomotor activity in rodents placed in an observation chamber. Benzodiazepines will shorten sleep latency (amount of time taken to fall asleep after the lights have been switched off) which can be demonstrated by electroencephalogram25.
  4. Muscle relaxant - Common tests on rodents show that benzodiazepines impair performance at motor performance tasks for example the rodent’s ability to balance on a rotating drum. The cat shows marked ataxia at after relatively low doses25.

What are benzodiazepines used for?

Sleep disorders

The benzodiazepines are used widely in the treatment of sleep disorders and many have been developed and licensed for this purpose. They are mainly known as hypnotic drugs (sleeping pills) because insomnia is the main target use. Certain factors are important in determining the choice of the hypnotic drug. Ideally, the hypnotic should be effective at inducing sleep in the individual, and should enhance objective and subjective elements of sleep. It should have a fast onset with minimal side effects and the absence of withdrawal symptoms.

The early benzodiazepine hypnotics were drugs such as nitrazepam and flurazepam. After their introduction, it was found that they had half-lives of more than a day, and individuals suffered undesirable effects such as sedation, ataxia or amnesia during the day. This was problematic especially for those individuals who needed to drive or operate machinery. Another consequence was of falls with subsequent hip fractures in the elderly population because, due to slower metabolism, they accumulated raised plasma levels of the drug. For these reasons, benzodiazepines with shorter half lives were developed so that plasma levels fall below the functional threshold concentration by the next morning.

The first of the shorter half-life benzodiazepine hypnotics to be introduced were temazepam and triazolam. Temazepam has a half-life of 5 hours and is commonly used in primary, secondary and tertiary settings for insomnia. A possible drawback of very short half-life hypnotics is rebound insomnia. This is a state of worsening sleep which commonly follows discontinuation of a regularly used hypnotic.

An important point to note is that although the subjective efficacies of benzodiazepines are widely reported, the use of polysomnography (a sleep study that involves recording a variety of physiological measures including electroencephalograph, electro-oculogram and electromyogram) has shown that sleep architecture in individuals with insomnia is not normalised by benzodiazepines. The increase in sleep duration can be accounted for by an increase in the time spent in stage 2 of sleep, while the amount of time spent in slow-wave sleep (deep) and REM (rapid eye movement) is actually decreased26.

Anxiety disorders

It can be argued that the benzodiazepines are probably the most efficacious and best tolerated pharmacological treatments of anxiety. Numerous studies, many of them conducted under stringent double-blind conditions, have consistently shown that benzodiazepines produce significantly more improvement than placebo in both somatic and emotional manifestations of anxiety27-29.

Before the introduction of benzodiazepines, anxiety disorders were treated either with the barbiturates or related drugs such as meprobomate and glutethimide. These agents were highly likely to be abused and led to a great deal of dependence. Moreover, they were toxic in overdose and fatalities were high in populations using them. The improved efficacy and safety profile of benzodiazepines, aided by intense campaigns to restrict use of barbiturate-type drugs, meant they rapidly became the first choice drugs for anxiety within a few years of them being introduced.

Much clinical practice and opinion suggests that benzodiazepine can be used as first-line treatment for acute anxiety episodes as long as CSM guidelines are adhered to. For more intractable conditions such as established social phobia, generalised anxiety disorder and panic disorder, they should probably be reserved for adjunctive or second-line agents.

In contrast to the treatment of sleep disorders, it is important to achieve a constant level of receptor occupation to maintain anxiolysis throughout the day. So for anxiety, compounds with longer elimination half-lives are preferred, whereas for sleep induction, short half-life drugs are favoured. The principal benzodiazepines used as anxiolytics include diazepam, chlordiazepoxide, clonazepam, lorazepam, alprazolam and oxazepam.

The use of benzodiazepines as first-line agents for anxiety has been on the decline since the 1990s. There are changing cultural and medical attitudes to the prescription of drugs for the treatment of anxiety disorders as a result of growing evidence that psychological approaches are also effective. The risks of dependence and withdrawal difficulties are problematic in a significant number of patients. Another issue is the abuse of benzodiazepines by drug addicts and diversion of legitimate supplies on to the black market. There is competition from other agents (buspirone, tricyclic antidepressants, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors) which have a different side-effect profile and are free from dependence/withdrawal problems.

Seizure Disorders

The anti-convulsant effects of benzodiazepines find their greatest clinical use in the acute control of seizures. Diazepam, clonazepam and lorazepam have all been used in the treatment of status epilepticus.

Status epilepticus is a life-threatening condition in which the brain is in a state of continuous seizure activity which can result in impaired respiration, hypoxic brain damage and brain scarring. It is a medical emergency that requires quick and effective intervention.

  1. Diazepam was reported to be effective for the treatment of status-epilepticus in the mid-1960s 30-32 and is still widely considered to be the drug of choice for the initial control of seizures. Given intravenously, diazepam has a rapid onset of clinical activity achieving cessation of the seizure within 5 minutes of injection in 80% of the patients in one studyWhere facilities for resuscitation are not immediately available; diazepam can be administered as a rectal solution.
  2. Although intravenous diazepam is effective for status epilepticus, it is associated with a high risk of thrombophlebitis which is why BNF suggests use of intravenous lorazepam. Lorazepam is also highly activeIts onset of action is rapid but because of its slower rate of tissue distribution, its anticonvulsant activity is prolonged compared to diazepam35,36.
  3. Gestaut et al (1971) showed that clonazepam was an even more potent anti-convulsant than diazepam in the treatment of status epilepticusIt can be administered via the buccal mucosa (an advantage in children) and can also be given as a suppository.
  4. Benzodiazepines are undoubtedly potent anti-convulsants on acute administration but their use in long-term treatment of epilepsy is limited by the development of tolerance to the anti-convulsant effects and by side-effects such as sedation and psychomotor slowing,39They are usually considered as an adjunct to standard drugs where these have failed to give acceptable control.

Table 1: Pharmacokinetic profile of common benzodiazepines and their licensed indications

Long-acting TMax (hrs) T1/2 (hrs) Licensed indications11
Chlordiazepoxide42 2 7-14 Short-term use in anxiety, adjunct to acute alcohol withdrawal
Diazepam42 0.5-2 32-47 Short term use in anxiety, adjunct to acute alcohol withdrawal, insomnia, status epilepticus, muscle spasm, peri-operative use.
Clonazepam43 2.5 23.5 all forms of epilepsy, myoclonus, status epilepticus
Intermediate-acting      
Temazepam42 1 5-8 Insomnia; peri-operative use.
Nitrazepam, Flurazepam*42 1-3 16-48 Short-term use for insomnia
Loprazolam, Lormetazepam42 1-3 8-10 Short-term use for insomnia
Short-actingα      
Lorazepam42 1-1.5 10-20 Short term use in anxiety or insomnia; status epilepticus; peri-operative use.
Oxazepam42 2.2-3 5-15 Short term use in anxiety
Midazolam43 0.6 2.4 Sedation with amnesia, sedation in intensive care, induction of anaesthesia.
Alprazolam42 1.2-1.7 10-12 Short term use in Anxiety

Tmax: time to peak plasma concentration
T1/2: half-life
*Nitrazepam and flurazepam have prolonged action and may give rise to residual effects on the following day. Temazepam, Loprazolam and Lormetazepam act for a shorter time and have little or no hangover effect.
α Short-acting compounds preferred in hepatic impairment but carry a greater risk of withdrawal symptoms.

Other uses

Alcohol detoxification – Benzodiazepines have become the standard pharmacological treatment for alcohol withdrawal. In acute alcohol detoxification, long acting benzodiazepines, such as diazepam or chlordiazepoxide are more appropriate than shorter acting agents like lorazepam or temazepam. The two principal reasons for this are 1) former drugs provide stable plasma concentrations over several hours which is necessary to maintain control over central nervous system excitability, and 2) There is a higher risk of addiction with short-acting drugs in this patient population.

  1. In alcohol dependent patients with hepatic impairment, oxazepam or lorazepam is more suitable as they are not eliminated by hepatic oxidation through the Cytochrome P450 system. Cytochrome p450 (CYPs) is a collective generic term use to describe a superfamily of membrane bound heme-thiolate proteins of critical importance in the oxidative and reductive metabolism of both endogenous and foreign compounds. CYPs are the major enzymes in drug metabolism accounting for 75% of the total metabolismMany of the CYPs in humans are found in the liver and the gastrointestinal tract. After the acute detoxification is over, many patients enter rehabilitation programmes aimed at maintaining abstinence in the community. There is no evidence that use of benzodiazepines is useful in reducing alcohol craving or facilitating abstinence.

Anaesthesia – The psychotropic effects of benzodiazepines make them appropriate for use as anaesthetic agents or as adjuncts to anaesthesia. Muscle relaxation, sedation and retrograde amnesia are sought after properties in anaesthetic agents. Midazolam is used as a sedative agent in patients undergoing minor invasive practices considered as traumatic, such as dental treatment or endoscopy.41

Muscle relaxants – The muscle relaxant properties of benzodiazepines are an indication for their use in some neurological disturbances for symptomatic relief of muscle spasms and spasticity.

Assessment and management of patients with chronic benzodiazepine dependence

Because of the adverse effects, lack of efficacy and socioeconomic costs of continued benzodiazepine use, long-term users have for many years been advised to withdraw if possible or at least to reduce dosage.10,44 Echoing the CSM advice, the Mental Health National Service Framework (NSF), which was published in 1999, recommended that benzodiazepines should be used for no more than two to four weeks for severe and disabling anxiety. The Mental Health NSF called upon health authorities to implement systems for monitoring and reviewing prescribing of benzodiazepines within local clinical audit programmes. Primary Care Trusts (PCTs) should ensure that this recommendation is still being implemented45.

In primary care, early detection and intervention are the main principles of assessment. The initial assessment should

· Establish the pattern of benzodiazepine usage: onset, duration, which benzodiazepine/s, dosage history, current regime and any periods of abstinence.

· Check for evidence of benzodiazepine dependence (see box 3).

· If benzodiazepine dependence is present, determine the type of benzodiazepine.

· Detail any history of previous severe withdrawal (including history of seizures).

· Establish the level of motivation to change.

Dependence on benzodiazepines often indicates psychosocial problems in a person. Benzodiazepines are increasingly used in conjunction with other substance of abuse to enhance the effects obtained from opiates, and to alleviate withdrawal symptoms of other drugs of abuse such as cocaine, amphetamines or alcohol. The patient needs to have an individualised and a comprehensive assessment of their physical and mental health needs and any co-morbid use of other drugs and alcohol. Stable psychological health and personal circumstances are desirable features for successful withdrawal from benzodiazepines. Certain patients will be unsuitable for withdrawal, e.g. those patients experiencing a current crisis or having an illness for which the drug is required at the current time. Referral to specialist teams may be appropriate for some, e.g. if the patient is also dependent on other drugs or alcohol, if there is co-existing physical or psychiatric morbidity or if there is a history of drug withdrawal seizures. In some circumstances, it may be more appropriate to wait until other problems are resolved or improved.


Box 3 – Benzodiazepine Withdrawal Symptoms46

 

Psychological symptoms – excitability, sleep disturbances, increased anxiety, panic attacks, agoraphobia, social phobia, perceptual distortions, depersonalisation, derealisation, hallucinations, misperceptions, depression, obsessions, paranoid thoughts, rage, aggression, irritability, poor memory and concentration, intrusive memories and craving (rare).

Physical symptoms – Headache, pain, stiffness, tingling, numbness, altered sensation, weakness, fatigue, influenza-like symptoms, muscles twitches, jerks, tics, “electric shocks”, tremor, dizziness, light-headedness, poor balance, visual problems, tinnitus, hypersensitivity to stimuli, gastrointestinal symptoms, appetite change, dry mouth, metallic taste, unusual smell, flushing, sweating, palpitations, over breathing, urinary difficulties, skin rashes, itching, fits (rare).

This list is probably not inclusive. Not all patients get all the symptoms. Different individuals get a different combination of symptoms.

Management of benzodiazepine withdrawal

  1. Withdrawal of the benzodiazepine drug can be managed in primary care if the patients in consideration are willing, committed and compliant. Clinicians should seek opportunities to explore the possibilities of benzodiazepine withdrawal with patients on long-term prescriptions. Interested patients could benefit from a separate appointment to discuss the risks and benefits of short and long term benzodiazepine treatment47. Information about benzodiazepines and withdrawal schedules could be offered in printed form. One simple intervention that has been shown to be effective in reducing benzodiazepine use in long-term users is the sending of a GP letter to targeted patients. The letter discussed the problems associated with long-term benzodiazepine use and invited patients to try and reduce their use and eventually stopAdequate social support, being able to attend regular reviews and no previous history of complicated drug withdrawal is desirable for successful benzodiazepine withdrawal.
  2. Switching to diazepam: This is recommended for some people commencing a withdrawal schedule. Diazepam is preferred because it possesses a long half-life, thus avoiding sharp fluctuations in plasma level. It is also available in variable strengths and formulations. This facilitates stepwise dose substitution from other benzodiazepines and allows for small incremental reductions in dosage. The National Health Service Clinical Knowledge Summaries recommend switching to diazepam for people using short acting benzodiazepines such as alprazolam and lorazepam, for preparations that do not allow for small reductions in dose (that is alprazolam, flurazepam, loprazolam and lormetazepam) and for some complex patients who may experience difficulty withdrawing directly from temazepam and nitrazepam due to a high degree of dependencySee table 2 for approximate dose conversions of benzodiazepines when switching to diazepam.

Gradual Dosage Reduction: It is generally recommended that the dosage should be tapered gradually in long-term benzodiazepine users such as a 5-10% reduction every 1-2 weeks1,49. Abrupt withdrawal, especially from high doses, can precipitate convulsions, acute psychotic or confusional states and panic reactions. As mentioned earlier, benzodiazepines’ enhancement of GABA’s inhibitory activity reduces the brain’s output of excitatory neurotransmitter such as norepinephrine, serotonin, dopamine and acetylcholine. The abrupt withdrawal of benzodiazepines may be accompanied by uncontrolled release of dopamine, serotonin and other neurotransmitters which are linked to hallucinatory experiences similar to those in psychotic disorders46.

  1. The rate of withdrawal should be tailored to the patient's individual needs and should take into account such factors as lifestyle, personality, environmental stressors, reasons for taking benzodiazepines and the amount of support available. Various authors suggest optimal times of between 6-8 weeks to a few months for the duration of withdrawal, but some patients may take a year or more,50A personalised approach, empowering the patient by letting them guide their own reduction rate is likely to result in better outcomes.

Table 2: Approximate equivalent doses of benzodiazepines1

Benzodiazepine Approximate equivalent dosage (mg)a
Alprazolam 0.5
Chlordiazepoxide 25
Clonazepam 0.5
Diazepam 10
Flunitrazepam 1
Flurazepam 15-30
Loprazolam 1
Lorazepam 1
Lormetazepam 1
Nitrazepam 10
Oxazepam 20
Temazepam 20

aClinical potency for hypnotic or anxiolytic effects may vary between individuals; equivalent doses are approximate.

Patients may develop numerous symptoms of anxiety despite careful dose reductions. Simple reassurance and encouragement should suffice in most cases however, in a minority who are experiencing significant distress, formal psychological support should be available. Cognitive therapy, behavioural approaches including relaxation techniques and breathing exercises for anxiety management as well as other therapies such as massage and yoga may alleviate difficulties during withdrawal. Psychoeducation around withdrawal symptoms should be offered and a referral to a support organisation or group is helpful.

Resources

Summary

Although prescriptions of benzodiazepines have declined substantially since 1988, there is an ongoing challenge within all sectors of the NHS to prevent benzodiazepine dependence. This can be achieved by adhering to official recommendations to limit prescriptions to 2-4 weeks, or for brief courses or occasional usage. All health authorities should have clinical audit programmes reviewing and monitoring prescribing rates for benzodiazepines. Through this, increased awareness of CSM guidelines amongst all health care professionals should aid in more appropriate prescriptions and subsequent monitoring that is required to prevent unnecessary prescriptions. Patients on long-term prescriptions should be offered the opportunity for controlled withdrawal and the relevant psychological and social support.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
TAUSEEF MEHDI, MBBS, MRCPsych. Specialty Registrar in Psychiatry, Wells Unit, Regional Secure Unit. West London Mental Health Trust, Uxbridge Road, Southall Middlesex. UB1 3EU.
Corresponding Author Details: 
TAUSEEF MEHDI, MBBS, MRCPsych. Specialty Registrar in Psychiatry, Wells Unit, Regional Secure Unit. West London Mental Health Trust, Uxbridge Road, Southall Middlesex. UB1 3EU.
Corresponding Author Email: 
tauseefmehdi@doctors.net.uk
References
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2)      Ashton, C H: All Party Action Group on Tranquilliser addiction. London: House of Commons, November 7, 2006.

3)      Tyrer P. Dependence on benzodiazepines. Brit J Psychiat. 1980; 137: 576-577

4)      Lader M. Benzodiazepines – the opium of the masses. Neuroscience 1978;3:159-165

5)      Pevnick JS, Jasinski DR, Haertzen CA. Abrupt withdrawal from therapeutically administered diazepam. Arch Gen Psychiatry. 1978; 35:995-8.

6)      Winokur A, Rickels K, Greenblatt DJ, Snyder PJ, Schatz NJ. Withdrawal reaction from long term, low dosage, administration of diazepam. Arch Gen Psychiatry 1980; 37:101-5.

7)      Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet 1981; i: 520-2.

8)      Petursson H, Lader MH. Withdrawal from long-term benzodiazepine treatment. Br Med J 1981; 283:643-5.

9)      Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after chronic therapy. Lancet 1983; i: 1402-6.

10)  Committee on Safety of Medicines . Benzodiazepines, dependence and withdrawal symptoms. 1988; Current Problems 21.

11)  British National Formulary. 2009: British Medical Association/Royal Pharmaceutical Society of Great Britain. BMJ Publishing Group & RPS Publishing.

12)  Drug and Therapeutics Bulletin. Withdrawing patients from antidepressants. Drug and Therapeutics Bulletin, 1999; 37(July), 49–52

13)  Anderson, I. M., Nutt, D. J. & Deakin J. F. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology, 2000; 14, 3–20.

14)  World Health Organization (1992) The ICD–10 Classification of Mental and Behavioural Disorders.World Health Organization.

15)  American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders(4th edn) (DSM–IV). APA.

16)  Polc P, Mohler H, Haefely W. The effects of diazepam on spinal cord activities: possible sites and mechanisms of action. NS Arch Pharmacol 1988;34: 124-128.

17)  Polc P, Haefely W. Effects of two benzodiazepines, phenobarbitone and baclofen on synaptic transmission in the cat cuneate nucleus. Naunyn Schmiedebergs Arch Pharmacol. 1976;294(2):121–131.

18)  Wolf P, Haas HL. Effects of diazepines and barbiturates on hippocampal recurrent inhibition. NS Arch Pharmacol 1977; 299: 211-218.

19)  Raab W, Gummit RJ. Anticonvulsant action of diazepam: Increase of cortical post-synaptic inhibition. Epilepsia 1977; 18:117-120

20)  Cook, L & Davidson, A. B. In The Benzodiazepines (eds S. Garattini, E. Mussini, L 0.Randall). New York: Raven Press, 1973; pp 327-45.

21)  Dantzer, R. Behavioural effects of benzodiazepines: a review. Biobehavioural Reviews, 1977;1,71-86.

22)  Haefely,W.E.Behavioural and neuropharmacological aspects of drugs used in anxiety and related states. In Psychopharmacology: A Generation of Progress (eds M. A. Upton, A. Di Mascio, K. F. Killam). New York: Raven Press, 1978; pp 1359-74.

23)  Cooper SJ. Benzodiazepines, barbiturates and drinking, In: Cooper SJ ed. Theory in psychopharmacology. London: Academic Press 1983; 2:115-148.

24)  Raabe, W. & Gumnit, R. J. Anticonvulsant action of diazepam: increase of cortical postsynaptic inhibition. Epilepsia, 1977; 18, 11720.

25)  Haefely, W.E. Central Actions of Benzodiazepines: General Introduction. Brit.J.Psychiat, 1978; 133,231-238

26)  Wheatley, D. Effects of drugs on sleep. In Psychopharmacology of sleep. Wheatley D, ed. New York: Raven Press, 1981; 153-176.

27)  Lader, M. The present status of benzodiazepines and psychiatry and medicine. Drug Res 1980; 30:910-913.

28)  Rickels, K. Use of anti-anxiety drugs and anxious outpatients. Psychopharmacology 1978; 58:1-17.

29)  Greenblatt, D.J & Shader RI: Benzodiazepines in Clinical Practice. New York, Raven Press, 1974.

30)  Gestaut H, Naquet R, Poire R, et al: Treatment of status-epilepticus with diazepam (Valium). Epilepsia 1965; 6:167-182.

31)  Lombroso CT: Treatment of status epilepticus with diazepam. Neurology 1966; 16:629-634.

32)  Prensky AL, Roff MC, Moore MJ, et al: Intravenous diazepam in the treatment of prolonged seizure activity. N Engl J Med 1967; 276:779-784.

33)  Delgado-Escueta AV, Westertain C, Treiman DM, et al: Current concepts in neurology: management of status epilepticus. N Engl J Med 1982; 306:1337-1340.

34)  Leppick IE, Derivian AT, Homan RW, Walker J, Ramsay E and Patrick B. Double blind study of lorazepam and diazepam in status epilepticus. J. Am. Med. Assoc. 249, 1452-4.

35)  Walker JE, Homan RW, Vasko MR, et al: Lorazepam in status epilepticus. Ann Neurol 1979; 6:207-213.

36)  Griffith PA, Karp HR: Lorazepam in therapy for status epilepticus. Ann Neurol. 1980; 7:493.

37)  Gestaut H, Coujon J, Poire R et al: Treatment of status epilepticus with a new benzodiazepine more active than diazepam. Epilepsia 1971; 12:197-214.

38)  Eadie MJ. Anti-convulsant drugs: an update. Drugs 1984; 27, 328-63.

39)  Robertson MM. Current status of the 1,4- and 1,5-benzodiazepines in the treatment of epilepsy: the place of clobazam. Epilepsia 1986; 27 (Suppl. 1), 27-41.

40)  Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chem. Res. Toxicol.2008; 21 (1): 70–83.

41)  Whitwam JG, Al-Khudhairi D, McCloy RF. Comparison of midazolam and diazepam in doses of comparable potency during gastroscopy. Br J Anaesth 1983; 55:773-777.

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43)  I.Hindmarch, G.Beaumont, S.Brandon, B.E.Leanord: Benzodiazepines:Current Concepts. 1st Edition. Sussex, England. John Wiley and Sons Ltd. 1990; 66-77.

44)  CMO’s Update 37. Benzodiazepines warning. Department of Health; January 2004. p. 4.

45)  National Service Framework for Mental Health. London: Department of Health; 1999. Available from: www.dh.gov.uk.

46)  Prof H Aston: Benzodiazepines: How they work and how to withdraw aka “The Ashton Manual”. 2002; Ch 3 Table1. http://www.benzo.org.uk/manual/bzcha03.htm

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49)http://www.cks.nhs.uk/benzodiazepine_and_z_drug_withdrawal/management/scenario_benzodiazepine_and_z_drug_withdrawal/managing_someone_who_wants_to_stop.

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Latest diagnosis and management of diverticulitis

Authors
Stephen O’Neill, Phillip Ross, Philip McGarry and Satheesh Yalamarthi
Article Citation and PDF Link
BJMP 2011;4(4):a443
Abstract / Summary
Abstract: 

Diverticular disease is extremely common especially amongst the elderly. It mainly presents as sigmoid diverticulitis but there is potential for serious complications. In the acute setting Computed Tomography is the gold standard investigation and helps classify the stage. Evidence to support outpatient treatment of uncomplicated diverticulitis is appearing however hospital admission and treatment with intravenous antibiotics is often required and is highly effective. The decision to proceed with elective surgery is judged on an individual basis with a long-term conservative approach suitable for most. For elective surgery there is evidence to advocate a laparoscopic approach. In Hinchey stage III or IV disease, laparotomy followed by either a Hartmann’s procedure or ideally, a resection followed by primary anastomosis may be required. Radiologically guided drainage of an abscess is an established alternative and laparoscopic lavage is another less invasive option that has emerged. Following successful acute medical management, colonoscopy is usually performed several weeks after resolution to rule out other colonic pathology. 

Keywords: 
Diverticulitis, Diagnosis, Management, Surgery

Introduction

A colonic diverticulum is defined as a sac-like protrusion of mucosa through the muscular component of the colonic wall1. The terms “diverticulosis” and “diverticular disease” are used to express the presence of diverticula without associated inflammation. While the term “diverticulitis” indicates there is inflammation of a diverticulum or diverticula, which is commonly accompanied by either microscopic or macroscopic perforation2.

In the developed world, diverticular disease of the colon is widespread and in those aged over 65 years of age it is present in greater than 65%3. The incidence increases dramatically with time and while only 5% of the western population are affected in the fifth decade this rises steeply  to over 50% by the eight decade and 60% in the ninth 4.

Although diverticulosis is extremely common, complications requiring surgery only occur in 1% of patients overall 5 and 10% of those admitted to hospital as an emergency for treatment6. Despite this, there is a substantial healthcare burden inflicted by diverticular disease and within the United States alone it accounts for 312,000 hospital admissions, 1.5 million days of inpatient treatment and a total estimated cost of 2.6 billion dollars per annum 7.

The aetiology of the diverticulosis is poorly understood but it is probably a multi-factorial process involving dietary habits (specifically low fibre intake) as well as changes in colonic pressure, motility and wall structure that are associated with ageing8. The pathogenesis of diverticulitis is also uncertain, however stasis or obstruction in a narrow necked diverticulum leading to overgrowth of pathogens and local tissue ischemia is thought likely 2.

This review will discuss the common presentations, investigations and current treatment strategies utilised in the management of acute diverticulitis and its complications as well as providing an up to date synopsis of existing recommendations for follow up and prevention. 

Symptoms and Signs

In Western nations, diverticula are most commonly situated in the left colon9 and 99% of patients will have some element of sigmoid involvement10. Therefore patients commonly present with sigmoid diverticulitis that typically displays features of left iliac fossa pain and fever with raised inflammatory markers (see below). Physical exam will disclose left lower quadrant peritonism for simple disease, but in complicated cases physical examination findings may reveal a palpable abdominal mass, evidence of fistulas or obstruction, or widespread peritonitis11.

In cases of complicated diverticulosis, a stricture may lead to obstructive symptoms with complaints of nausea, vomiting and distension being present. If a fistula has developed, a history of recurrent urinary tract infection, pneumaturia and faecaluria may also be elicited12. In a female with a previous history of hysterectomy suspicion will be further raised as colovesical and colovaginal fistulas are rare in females with their uterus in place. If a patient reports passing stools per vagina, insertion of a vaginal speculum and inspection may confirm this latter diagnosis12.

Differential diagnosis

The differential diagnosis for diverticulitis and its complications is extensive and includes irritable bowel syndrome, inflammatory bowel disease, ischaemic or infective colitis, pelvic inflammatory disease and malignancy. It is obviously most imperative to exclude the latter differential 4, particularly in the case of a stricture that is impassable on colonoscopy, as many of these specimens following resection (32% in one series13) will transpire to be adenocarcinoma4. It should also be noted that sigmoid diverticulitis may also masquerade as acute appendicitis if the colon is long and redundant or otherwise situated within the abdomen or pelvis such that the inflamed segment lies in the suprapubic region, right iliac fossa or McBurney’s point2.

Complications

Although diverticulosis is present in nearly two thirds of the elderly population, the vast majority of patients will remain entirely asymptomatic. Even so, an estimated 20% of those affected will manifest symptomatology, mainly as diverticulitis, but  potentially with further complications of perforation, abscesses, fistulas, and obstruction, as well as bleeding per rectum6.

The European Association for Endoscopic Surgeons (EAES) developed a classification scheme based upon the severity of diverticulitis, which broadly classifies patients into either simple symptomatic or complicated disease (Table 1)14. Where an abscess or perforation develops the Hinchey classification is used as a staging tool and can provide prognostic information on the likely outcome (Table 2)15.

Table 1 - European Association for Endoscopic Surgeons classification system for diverticulitis 14

Grade of disease Clinical explanation of grade Clinical state of the patient
I Symptomatic uncomplicated disease Pyrexia, abdominal pain, CT findings consistent with diverticulitis
II Recurrent symptomatic disease Recurrence of Grade I
III Complicated disease Bleeding, abscess formation, phlegmon, colonic perforation, purulent and faecal peritonitis, stricturing, fistula and obstruction

Table 2 – Hinchey classification of perforated diverticulitis 15

Hinchey stage Features of disease Risk of death71
Stage I* Diverticulitis with a pericolic abscess 5%
Stage II** Diverticulitis with a distant abscess (this may be retroperitoneal or pelvic) 5%
Stage III Purulent peritonitis 13%
Stage IV Faecal peritonitis 43%

* Stage I has been divided into Ia Phlegmon and Ib confined pericolic abscess in later modifications38 72
** Stage II has been divided into IIa abscesses amenable to percutaneous drainage and IIb complex abscess with or without fistula in later modifications14 73

Perforation is probably the most feared complication and the annual prevalence of perforated diverticulitis within a northern European population is currently thought to stand at 3.8 per 100,000 of the population, which is a figure that is increasing16. Despite this only 1-2% of patients who attend for urgent assessment and treatment will have a gross perforation2 but for 80% this will be their first presentation so a high index of suspicion is still required17.

Blood investigations

In clinical practice, inflammatory markers, commonly the White Blood Cell (WBC) count and C-Reactive Protein (CRP) level, are frequently employed to assist in diagnosing diverticulitis and its complications. In a recent retrospective study, a White Blood Cell (WBC) count >10,000/μL was present in 62% of patients with Computed Tomography (CT) confirmed diverticulitis and the presence of leukocytosis was significantly more common in patients with diverticulitis and associated perforation than without (86% v 65%, p=0.01)18.

CRP has also been shown to be of considerable benefit in the diagnosis of acute left sided colonic diverticulitis 19. A recently established diagnostic nomogram with a reported accuracy of 86%  that was developed to improve the clinical diagnosis of diverticulitis includes an elevated CRP >50mg/l as well other variables including  age, previous episodes, aggravation of pain on movement, absence of vomiting and localization of symptoms and tenderness in the left iliac fossa19.

In addition, it has been demonstrated that in acute sigmoid diverticulitis a CRP below 50mg/l is unlikely to correlate with an associated perforation (negative predictive value 79%) while a CRP above 200mg/l is an indicator that the patient may have a perforation (positive predictive value 69%)20. In this latter study, CRP also had the highest diagnostic accuracy in diagnosing perforation in acute sigmoid diverticulitis across a range of parameters assessed that included WBC count as well as less commonly used tests like bilirubin and alkaline phosphatase20.

Imaging investigations

In the acute phase of diverticulitis the extent of the extramural component of inflammation is more important than the degree of the intramural inflammation and as such CT associated with the use of intravenous and oral contrast and, in ideal conditions, rectal contrast is the gold standard means of investigation21.

CT can accurately identify extra-luminal complications such as an abscess, phlegmon, adjacent organ involvement, or fistula, as well as recognising other alternative diagnoses such as appendicitis, pelvic inflammatory disease, tubo-ovarian abscess or inflammatory bowel disease22.

The two most frequent signs of diverticulitis on CT are bowel wall thickening (96%) and fat stranding (95%) (Figure 1) with less common but highly specific signs including fascial thickening (50%), free fluid (45%), and the presence of inflamed diverticula (43%) 23. Specifically, abscess formation (Figure 2a and b) and extracolonic air or contrast (Figure 3a and b) are findings that are known to predict severity as summarised in the CT classification system developed by Ambrosetti et al 24.


Figure 1 -
Sigmoid diverticulitis: sigmoid colon with multiple diverticula, significant mural thickening (arrow) and pericolic fat stranding (circles)


Figure 2a -
Sigmoid diverticulitis with abscess formation: sigmoid colon displaying diverticulosis mural thickening, and pericolic fat stranding (arrow). Adjacent low attenuation, septated collection (circle) representing abscess formation.


Figure 2b -
Sigmoid diverticulitis with abscess formation: sigmoid colon displaying mural thickening, diverticulosis and pericolic fat stranding (arrow). Adjacent low attenuation, septated collection (circle) representing abscess formation, with adhesion noted to adjacent small bowel loops.


Figure 3a -
Perforated sigmoid diverticulitis: sigmoid colon displaying diverticulosis and mural thickening (arrow) with adjacent collection of intra-abdominal free air and adjacent inflammatory fat stranding (circle), representing active diverticulitis with perforation.


Figure 3b -
Perforated sigmoid diverticulitis: sigmoid colon displaying diverticulosis, mural thickening and pericolic inflammatory fat stranding (arrow) with adjacent collection of intra-abdominal free air and adjacent inflammatory fat stranding (circle), again representative of active diverticulitis with perforation.

However despite CT having a reported sensitivity of 97%, specificity of 98%, and global accuracy of 98%25, a misdiagnosis of diverticulitis in cancer patients is relatively common and occurs in 5% of cases21. Therefore investigation of the colonic lumen by endoscopic means or barium enema after the acute attack is mandatory4 but avoided in the initial stages for fear of perforation and exacerbation of the disease2.

In expert hands ultrasound is the next best alternative investigation with a reported sensitivity of 94%26. It has been supported by a recent systematic review27 as well as current practice guidance4 and in critically ill patients it avoids the use of intravenous and intra-luminal contrast21. However it is rarely used in practice as it is operator dependent21 and for it to be accurately utilised it requires a highly skilled/trained individual to be available at all times28.

The other practical alternative  to CT is a hydro-soluble contrast enema, however this investigation is significantly inferior both in terms of sensitivity (98 v 92%, p<0.01) and evaluation of the severity of inflammation (26 v 9%, p<0.02)29. While Magnetic resonance imaging (MRI) has a good sensitivity of 94% and a specificity of 87%30, in the acute setting it may be impractical both in terms of examination time and patient co-operation21. Finally, laparoscopy can also be helpful for diagnostic purposes but again in practical terms, with the increasing availability of cross-sectional imaging, it is rarely required for this purpose4.

Outpatient treatment

Evidence for successful and economical outpatient treatment of uncomplicated diverticulitis is beginning to emerge. In a prospective study of 70 patients classified on the basis of an ultrasound examination as having mild-to-moderate acute colonic diverticulitis (as defined by either limited inflammation within a diverticulum extending up to an abscess < 2 cm in diameter), 68 patients were successfully treated with oral antibiotics with an initial liquid diet and this led to a cost saving on inpatient treatment of 80%31.

In a further retrospective analysis, among a cohort of patients who were referred for outpatient treatment it was found that such treatment was effective for 94% of patients, with women and those with free fluid on CT scan appearing to be at higher risk for treatment failure32.

In reality the prospect of outpatient treatment in uncomplicated cases of acute diverticulitis is determined largely by access to the necessary investigative tools for accurate diagnosis and staging of disease, the general fitness of the patient, their ability to maintain adequate oral intake, the possibility of further outpatient review, patient compliance with medications, satisfactory social support and ability to plan for endoscopic follow up21.

In broad terms, if symptoms are not severe and the patient has no significant co-morbidities and is compliant with medical treatment, then a course of broad spectrum antibiotics can be administered orally on an outpatient basis and the patient followed up at subsequent outpatient clinics. However if the patient is systemically unwell, elderly, has significant co-morbidities or there are any other concerns it is safer to arrange for a hospital admission and treatment with intravenous antibiotics12.

Conservative inpatient treatment

Simple diverticulitis requiring hospital admission is usually treated by rehydration, symptomatic relief and intravenous antibiotics. Most patients with uncomplicated disease respond well to medical treatment and generally experience significant improvement in their abdominal pain, temperature and inflammatory markers within two days of initiation of antibiotic treatment33. If this is not the case or there is clinical concern a repeat CT is advocated and operative intervention or percutaneous drainage considered (see below)2.

It should be noted at this stage while the use of broad spectrum antibiotics in acute uncomplicated diverticulitis is supported by guidelines34 there is no actual evidence mandating the routine use of antibiotics in mild uncomplicated diverticulitis35 and in some European countries it is not routine36.

High-quality evidence regarding the most effective type of antibiotic is also lacking35. However anaerobic bacteria (usually bacteroides, clostridium, fusobacterium and peptostreptococcus) are the most commonly cultured organisms with gram-negative aerobes, especially Escherichia coli, and facultative gram-positives, such as streptococci, often grown as well37. Therefore coverage against both Gram-negative and anaerobic bacteria is widely advocated2 21 38.

If combination antibiotics are selected, Metronidazole provides excellent anaerobic cover with less risk of clostridium difficle infection than alternatives4. However use of single agent may be more cost effective39. Local protocols are likely to influence selection but the patient may be safely switched from intravenous to oral therapy when they can tolerate a diet and oral medicines22 as intravenous antibiotics are not felt to be vastly superior40. Seven to ten days of antibiotic therapy is an acceptable treatment period22 however evidence is emerging to support shorter courses41.

Elective surgery 

In a recent position statement from the Association of Coloproctology of Great Britain and Ireland (ASCPGBI) it was concluded that the majority of patients, whether young or old, presenting with acute diverticulitis could be managed with a conservative, medical approach in the longer term. Previous blanket recommendations for elective resection e.g. following two acute episodes of diverticulitis14 were challenged in this statement and it was proposed that the decision on elective resection should be made on an individual basis4. The traditional practice of waiting for a period of 4-6 weeks after a diverticulitis attack before performing an elective operation was not disputed12.

Surgery in the elective setting can be by either an open or laparoscopic technique with a recent randomised trial identifying a 27% reduction in major morbidity42 along with less pain, improved quality of life and shorter hospitalization at the cost of a longer operating time with the laparoscopic approach43. In expert centres conversion rates as low as 2.8% and median hospitals stays of 4 days can be achieved44 and individual case reports of resections using single laparoscopic port access have also emerged45.  However if a laparoscopic resection is considered, it is currently recommended that patients should be treated after full recovery from the acute episode of inflammation as there is evidence to suggest lower complication and conversion rates can be achieved4.

The principles for both approaches are the same. A colorectal anastomosis is a predictor of lower recurrence rates after elective sigmoid resection for uncomplicated diverticulitis46. Therefore it is recommended that the distal resection margin is taken onto the rectum as opposed to the distal sigmoid and the splenic flexure is fully mobilised to facilitate this4, however in the case of a long redundant left colon this may not be necessary12. The proximal resection margin is less clear but should be made onto soft compliant bowel4 34. Often it is possible to identify the ureters intra-operatively however, there may be cases of complicated diverticulitis in which the extent and degree of inflammatory changes warrant the use of pre-operatively placed ureteric stents to help aid their identification and avoid injury12.

Emergency surgery for complicated diverticulitis

The indications for emergency operative intervention in acute diverticulitis include the presence of generalised peritonitis, uncontained visceral perforation, gross uncontrollable sepsis, a large undrainable or inaccessible abscess, bowel obstruction and lack of improvement or clinical deterioration with initial medical management 2.

Historically, perforated diverticulitis was treated with a three-stage procedure consisting of faecal diversion with a stoma, resection of the diseased segment of bowel, followed by takedown of the stoma and restoration of intestinal continuity. This then shifted to performing a Hartmann’s procedure which includes a primary resection of the diseased segment and end colostomy followed by subsequent colostomy reversal at a second operation11. In this case reconstruction generally involves a second laparotomy because although laparoscopic reconstruction is effective, it is infrequently performed47-48. As a result reversal is often permanently deferred. 

In selected cases the ideal therapeutic option in colonic perforation is a one-stage procedure with resection followed by primary anastomosis, which adds the benefits of being a definitive treatment with the avoidance of the morbidity and mortality associated with a stoma and its reversal49. A protective ileostomy after resection and primary anastomosis is viewed as a valid additional step in patients at high risk of an anastomotic leak (immunosuppression, American Society of Anaesthesiologists (ASA) grade IV, faecal peritonitis)21 but a Hartmann’s procedure may also be selected.

Particularly in cases where there is a stricture causing obstruction and significant faecal loading, a resection in conjunction with on-table colonic lavage and primary anastomosis may be used. This technique has also been described as facilitating a primary anastomosis in the case of a perforation50.  However in certain patients with obstruction depending on the viability of the proximal colon a subtotal colectomy with ileorectal anastomosis may be required12 and because small-bowel obstruction may also occur, especially in the presence of a large diverticular abscess, this may also warrant further treatment2.

The use of endoscopic colonic stenting as a treatment of acute obstruction of the large bowel secondary to colonic cancer has been well documented in the literature either as a definitive procedure or as a bridge to surgery and can effectively decompresses the obstructed colon in 90% of cases51.  However the use of stents in benign disease is less well documented , with it used mainly as a bridge to surgery52 and because is associated with a higher incidence of complications in acute diverticular disease53 it cannot as yet be recommended.

Laparoscopic surgery in the emergency setting

There have been a number of recent reports of laparoscopic lavage with or without the placement of an intra-abdominal drain for patients with acute diverticulitis and perforation, with the reported advantages including the avoidance of an acute resection and the possibility of a stoma 4. The evidence that has been produced thus far to support its case is highly promising.

A recent systematic review of laparoscopic lavage for perforated colonic diverticulitis identified two prospective cohort studies, nine retrospective case series and two case reports with 231patients and the vast majority of patients (77%) had Hinchey grade III purulent peritonitis. Laparoscopic peritoneal lavage successfully controlled abdominal and systemic sepsis in 95.7% of patients, mortality was 1.7%, morbidity 10.4% and only four (1.7%) patients received a colostomy54.

In the largest series in the literature to date, Myers et al reported 100 patients with perforated diverticulitis and generalised peritonitis. Eight patients with Hinchey IV disease required conversion to an open procedure, with the overall mortality being 4% and recurrence rates only 2% over a median time period of 36 months55.

Percutaneous therapy

The appropriate management of diverticular abscesses is a matter of some debate. However according to the American Society of Colon and Rectal Surgeons (ASCRS) radiologically guided percutaneous drainage is usually the most appropriate treatment for patients with a large diverticular abscess as it avoids the need for emergency surgery and possibility of a colostomy34.

When the abscess diameter is over 5 cm, percutaneous CT guided drainage, in combination with antibiotics, is the standard treatment and offers rapid improvement in symptoms in over 90% of cases, albeit with a high recurrence rate in more severe cases38 and higher likelihood of surgery being needed in those involving the pelvis56.

In practical terms diverticular abscesses less than 3 cm in diameter usually cannot be successfully drained, as the diameter of the pigtail of most drainage catheters will be a similar dimension28. Also for smaller abscesses21, especially those less than 2cm resolution usually occurs with the use intravenous antibiotics alone34. However if a drain is sited it is advisable that before it is removed, resolution of the abscess should be confirmed and a potential bowel fistula excluded by a further contrast study28.

Finally, diverticular disease of the colon is also a relatively common cause of acute lower gastrointestinal bleeding and is in fact the diagnosis in 23% of cases57. This usually settles with conservative management but if the bleeding is profuse angiography and endovascular intervention may be helpful, with surgery very rarely required for this indication4.

Follow up

Following successful medical management of an acute episode of diverticulitis, colonoscopy, flexible sigmoidoscopy or barium enema should be performed several weeks after the resolution of symptoms to confirm the diagnosis and rule out other colonic pathology such as malignancy, inflammatory bowel disease, or ischemia22.

Following surgery there is reported to be a high incidence of the order of 25% for recurrent symptoms, which is put down to the diagnostic overlap that exists with irritable bowel syndrome58. However any suspicion of recurrent diverticulitis following surgical resection should be confirmed by CT scan after which antibiotic treatment should be initiated, as for a case of primary uncomplicated disease12. If this is excluded the high incidence (17.6%) of symptomatic anastomotic stenosis after elective laparoscopic sigmoidectomy should be borne in mind with the possibility of endoscopic dilatation considered if applicable59.

Summary points
  • CT scan is the gold standard means of investigation for acute diverticulitis and helps classify the stage of disease.
  • Evidence to support outpatient treatment of uncomplicated diverticulitis is beginning to appear, however hospital admission and treatment with broad spectrum intravenous antibiotics is often required and is highly effective.
  • The decision to proceed with elective surgery is judged on an individual basis and there is evidence gathering to advocate a laparoscopic approach.
  • In Hinchey stage III or IV disease, emergency laparotomy followed by either a Hartmann’s procedure or ideally in selected patients a resection followed by primary anastomosis may be required.
  • In certain cases percutaneous radiologically guided drainage of abscesses is an established alternative to open surgery with laparoscopic lavage another less invasive and highly promising option.

Lifestyle modifications and prevention

Following treatment weight loss, rationalisation of certain medications and exercise are recommended as obesity is significantly associated with an increased incidence of both diverticular bleeding and diverticulitis60, as are non-steroidal anti-inflammatory drugs and paracetamol61, with physical activity significantly associated with a reduction in the risk of complications62.

Whilst dietary fibre, particularly cellulose63, is recommended22 the evidence that supports these recommendations is not particularly strong64. However foodstuffs such as nuts, seeds, popcorn and corn that are usually discouraged have no evidence to support the theory that they may lead to increased complications65.

Small studies without control groups suggest that probiotics may have a positive effect on the recurrence of symptomatic diverticular disease66-67. Long term administration of the non-absorbable antibiotic Rifaxamin has also been used with reported success68 as has the anti-inflammatory mesalazine69.  However none of these medications have a strong evidence base and as a result are not in routine use70.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
S O’NEILL, Surgical Registrar MB BCh BAO (dist) MSc (dist) MRCSEd Department of Colorectal Surgery, Queen Margaret Hospital, Dunfermline. P ROSS, Medical Student, Queens University, Belfast. P MCGARRY, Radiology Registrar MB BCh BAO (dist), Department of Radiology, Altnagelvin Hospital, Londonderry. S YALAMARTHI, Consultant Surgeon MS FRCS, Department of Colorectal Surgery, Queen Margaret Hospital, Dunfermline
Corresponding Author Details: 
Mr STEPHEN O’NEILL, 6 Dean Park Mews, Edinburgh EH4 1EF.
Corresponding Author Email: 
stephenoneill@doctors.org.uk
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63. Aldoori W, Ryan-Harshman M. Preventing diverticular disease. Review of recent evidence on high-fibre diets. Can Fam Physician 2002;48:1632-7.

64. Unlu C, Daniels L, Vrouenraets BCet al. A systematic review of high-fibre dietary therapy in diverticular disease. Int J Colorectal Dis 2011.

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Recent Advances In Management Of Pre-Eclampsia

Authors
Pallab Rudra, Sonela Basak, Dilip Patil and M Y Latoo
Article Citation and PDF Link
BJMP 2011;4(3):a433

Pre-eclampsia is a multisystem disorder of pregnancy that forms an integral part of the spectrum known as hypertensive diseases of pregnancy. The National High Blood Pressure Education Program (NHBPEP) Working Group1classifies hypertensive diseases in pregnancy into 4 groups:

1)     Gestational hypertension 

·       New onset hypertension in pregnancy presenting after 20 weeks

·       No proteinuria

·       BP returns to normal less than 12 weeks postpartum

·       Final diagnosis made only postpartum                                                                                                                                                            

2)     Chronic hypertension

·       BP >140/90 mm Hg before pregnancy or diagnosed before 20 weeks gestation not attributable to gestational trophoblastic disease
or

·       Hypertension first diagnosed after 20 weeks gestation but persistent after 12 weeks postpartum.

3)     Pre-eclampsia/eclampsia

·       BP > 140/90 mm Hg after 20 weeks gestation in a women with previously normal blood pressure

·       Proteinuria (>0.3 gm urine protein in 24 hr). 

·       Eclampsia is defined as seizures that cannot be attributed to other causes in a woman with pre-eclampsia

4)     Superimposed pre-eclampsia (on chronic hypertension)

·       New onset proteinuria (>300 mg/24 hr) in a woman with hypertension but no proteinuria before 20 weeks gestation

·       A sudden increase in proteinuria or blood pressure, or platelet count less than 100,000 in women with hypertension and proteinuria before 20 weeks gestation

Epidemiology

Pregnancy induced hypertension complicates about 10% of pregnancies, but there is a widespread geographic variation in its incidence.The incidence is higher in developing countries. The highest reported rate of pre-eclampsia is 7.1% (deliveries) from Zimbabwe2, while the incidence is as low as 0.81% (deliveries) in Colombia3. In UK, the incidence of severe pre-eclampsia is 5/1000 maternities4, while the incidence of eclampsia is 4.9/10,000 maternities5. The incidence of severe pre-eclampsia in European countries ranges from 2/1000 (deliveries) in Norway to 6.4/1000 (deliveries) in Belgium and Hungary6.

The 8th Confidential Enquiry into maternal and child heath7 revealed pre-eclampsia and eclampsia as the second leading cause of direct maternal death, thereby contributing to a maternal death rate of 0.83 / 100,000 maternities.

Worldwide studies show that mortality from pre-eclampsia can be as high as 0.4%, while that in eclampsia varies from 6.1% in developing countries to 1.8% in UK 5, 8-9.

Estimates of maternal mortality from the developing countries (in Asia, Africa, Latin America and the Caribbean) suggest that 10-15% of maternal deaths are associated with hypertension in pregnancy, while eclampsia is associated with 10% maternal mortality10.

Severe pre-eclampsia is also associated with significant maternal morbidity, including eclamptic seizures, intracerebral haemorrhage, pulmonary oedema due to capillary leak or heart failure, acute renal failure, liver dysfunction, and coagulation abnormalities.

Fetal complications include abruptio placentae, intrauterine growth restriction, premature delivery, and intrauterine fetal death. The incidence of stillbirths and neonatal deaths in mothers who suffered eclampsia was 22.2/1000 and 34.1/1000, respectively, in the UK with a higher incidence in developing countries5.

More than half a million women die each year from pregnancy related causes across the globe. The Millennium Development Goals have placed maternal health as a basic human right, one that is integral to the core of the fight against poverty and inequality. The high incidence of pre-eclampsia and its complications makes its prevention and effective management important. The following article attempts to outline the pathophysiology and management of pre-eclampsia.

Aetiology & Risk factors

Pre-eclampsia is commonly referred as the “disease of theories” making its prevention and management an ongoing challenge worldwide. Although the aetiology is still largely unknown, there are a few hypotheses regarding the pathophysiology and prediction of pre-eclampsia.

It has been postulated that pre-eclampsia may be autoimmune in nature. Seminal-vesicle-derived transforming growth factor 1 (TGF-1) initiates a post mating inflammatory reaction, which is a type 2 immune response towards paternal antigens resulting in maternal-fetal (paternal) immune maladaptation11. This idea originates from epidemiological studies demonstrating the protective effect of long-term sperm exposure and is supported by the fact that frequency of pre-eclampsia is higher in nulliparous women or multiparous women with a new partner, teenagers, women who conceive after donor insemination or oocyte donation, and women with autoimmune conditions.

Another potential mechanism responsible for pathogenesis of pre-eclampsia is placental hypoperfusion which in turn releases various factors that trigger endothelial activation / dysfunction. Nitric oxide, disordered endothelin metabolism, thromboxane/prostaglandin imbalance, cellular fibronectin, inflammatory cytokines (TNF-α, IL-6, IL-1α, and IL-1β) and otherfactors such as lipid peroxides and reactive oxygen intermediateshave all been implicated in mediating the endothelial cell injury12. This is well-supported by the fact that pre-eclampsia commonly occurs in pre-existing metabolic (diabetes, hypercholesterolemia), renal, vascular disorders (hypertension) and connective tissue disorders that result in poor placental circulation. In cases of multiple gestation or increased placental mass, it is not surprising for the placenta to become underperfused.

However, majority of the pre-eclamptic women do not suffer from any underlying medical conditions. In these women, lack of placental cytotrophoblastic invasion of uterine spiral arterioles and arrest of arteriolar remodelling results from failure of pseudo-vascularisation of the invasive cytotrophoblasts13. Deregulation of angiogenesis-related gene products such as vascular endothelial growth factor (VEGF), angiopoietin and ephrin family proteins, placental growth factor (PlGF) and their receptors have been implicated in this process14.Shallow placentation leads to reduced placental perfusion and subsequent ischaemia. 

Obese (BMI ≥30 Kg/m2) women are at higher risk for pre-eclampsia compared to lean women (odds ratio = 3.3). The exact mechanism is not completely understood but possible explanations are: increased stress due to the hyperdynamic circulation associated with obesity; dyslipidaemia or increased cytokine-mediated oxidative stress; and direct haemodynamic effects of hyperinsulinaemia15 (increased sympathetic activity and increased tubular sodium resorption).

 On the other hand, smoking actually decreases a woman’s risk of pre-eclampsia. Inhibition of thromboxane A2production by nicotine might explain the decreased risk. However, the adverse effects of smoking on pregnancy significantly outweigh any beneficial effects16.

Epidemiological and clinical risk factors for pre-eclampsia are classified as maternal, paternal, and/or pregnancy-specific2, 17 (Table 1, below).

Table 1: Pre-eclampsia Risk Factors

Maternal Considerations

Inherent

Ø  Age < 20 or 35–40 years

Ø  Nulliparity

Ø  Afro-Caribbean origin

Ø  Prior or family history of PE or cardiovascular disease

Ø  Woman born small for gestational age

Medical conditions

Ø  Obesity

Ø  Chronic hypertension

Ø  Chronic renal disease

Ø  Diabetes mellitus (insulin resistance, type 1, and gestational)

Ø  Antiphospholipid antibody syndrome

Ø  Connective tissue diseases

Ø  Thrombophilia

Ø  Stress

Pregnancy specific

Ø  Multiple gestation

Ø  Oocyte donation

Ø  New partner

Ø  Urinary tract infection

Ø  Congenital conditions affecting the fetus

Ø  Hydatidiform mole

Ø  Hydrops fetalis

Ø  Structural anomalies

Paternal Considerations

Ø  Limited sperm exposure

Ø  Barrier contraception

Ø  First-time father

Ø  Donor insemination

Ø  Partner who fathered a pre-eclamptic pregnancy in another woman

 

What exactly happens in Pre-eclampsia?

The triad of physiological derangements in pre-eclampsia include
1. Vasospasm
2. Plasma volume contraction
3. Local or disseminated intravascular coagulation.

Although the cause of pre-eclampsia is unknown, we have already discussed that the placenta is largely implicated. The sequence of events starts with vasospasm caused by increased production or sensitivity to vasoconstrictors (angiotensin II, serotonin and endothelin) and/or decreased production or sensitivity to vasodilators (prostacyclin and nitric oxide). This is followed by plasma volume contraction, increased capillary permeability and, in severe cases, low plasma oncotic pressures. Redistribution of fluid occurs from the intravascular to interstitial fluid spaces causing peripheral tissue oedema. Along with this, intravascular coagulation may occur due to platelet activation, thrombocytopenia and, often, reduced production of anti-thrombin III.

The net effect is organ hypoperfusion. Commonly affected systems are kidney (manifested by reduced GFR, proteinuria, hyperuricaemia and occasionally oliguria), liver (manifested by elevated transaminases with or without epigastric and right upper quadrant pain), and the brain (manifested by headaches, transient visual disturbances due to occipital lobe ischaemia and rarely convulsions, i.e. eclampsia). This leads to increased maternal morbidity.

 Placental insufficiency resulting from uterine hypoperfusion is characterised by intrauterine fetal growth retardation and less commonly placental abruption or fetal death. Preterm delivery, low birth weight, respiratory distress syndrome, and admission to the neonatal intensive care lead to increased perinatal morbidity.

In spite of major advances in understanding the pathophysiology of the disease in recent years, interventions to prevent hypertensive disorders in pregnancy have had disappointing results, hence early detection, continued surveillance and timely intervention still remains the key towards decreasing the inherent maternal and fetal morbidity and mortality associated with severe pre-eclampsia and eclampsia.

Prevention of pre-eclampsia

Till date there is no well-established measure for prevention of pre-eclampsia in the general population. Calcium is clearly of benefit amongst high risk women in communities where low dietary calcium intake is prevalent. A Cochrane systematic review in 2010 concludes that calcium supplementation approximately halves the risk of pre-eclampsia, reduces the risk of preterm birth and the rare occurrence of the composite outcome 'death or serious morbidity18.

Low dose aspirin (antiplatelet agent) therapyefficiently reduces the development of pre-eclampsia in women with abnormal uterine artery Doppler studies. If started in early gestation (< 16 weeks), it also causes a significant reduction in the incidence of severe pre-eclampsia, gestational hypertension and IUGR19.

Some studies have suggested that prophylactic use of antioxidants (vitamin C, E) may be beneficial as well but this is not routinely recommended20 in practice.

Evidence is also lacking to support lifestyle preventative interventions for pre-eclampsia, such as rest, exercise and reduced dietary salt intake.

The pre-eclampsia community guideline (PRECOG)

This has been developed for screening and detection of onset of pre-eclampsia in the community21. It includes:

  • Initial risk assessment at community booking using pre-determined criteria, to identify factors that predispose women to pre-eclampsia in a given pregnancy. Following this, women are offered referral before 20 weeks gestation for specialist input to their antenatal care plan if they have been identified as high risk: this may be for clarification of risk, necessary investigations, advice on early intervention or pharmacological treatment.
  • Systematic community assessment for onset of pre-eclampsia from 20 weeks gestation. The frequency of assessment is determined by the likelihood of developing pre-eclampsia. Women with no risk factors for pre-eclampsia are offered assessments at weeks 16, 28, 34, 36, 38, 40, and 41 weeks.Women with one risk factor for developing pre-eclampsia (excluding previous pre-eclampsia, multiple pregnancy and underlying medical conditions like hypertension, renal disease, diabetes, antiphospholipid syndrome)  are reviewed in the community at least once every three weeks before 32 weeks, and then at least once every two weeks, until delivery.  At every visit, recommendation is to look for presence of any signs or symptoms like new hypertension, new proteinuria, headache/visual disturbance, or both, epigastric pain/vomiting, or both, reduced fetal movements, small for gestational age infant. In the presence of two such, they are referred for early specialist input, individual assessment, and discussion of obstetric risk.
  • Recommendations have been made within the scope of this guideline for improving accuracy inblood pressure measurement, increasing reliability of proteinuria test with dipstick and community assessment of fetal growth and well being which provide the parameters for referral. Referral is made forstep-up assessment in hospital day unit within 24/48 hoursor admission in accordance with set criteria. All pregnant women are also made aware that pre-eclampsia may develop between antenatal assessments, and they could self-refer at any time.
  • It is recognised that all women benefit from a continuity of care in the community and need midwifery or GP care as part of their individual antenatal care plan, whatever be their obstetric risk.

Management of Pre-eclampsia

Antenatal Care

These patients should be under consultant led care with multidisciplinary input from the anaesthetic and neonatal teams as necessary.

Women with risk factors for developing pre-eclampsia may be considered for uterine artery doppler velocimetry at 20-24 weeks to look for increased impedance to flow (resistance index >95th centile or early diastolic notch), which is predictive of developing pre-eclampsia or IUGR in late gestation, however the specificity and sensitivity varies widely between different studies22-25.

At diagnosis of pre-eclampsia, the best practice is to offer initial hospital admission for assessment and formulation of follow-up care. Assessment of proteinuria should be done by automated reagent strip reading device. Visual assessment of the dipstick is not recommended nowadays because of high error rates26-28. If the automated reagent strip reading of urine yields a result of 1+ or more, this should be followed up with a spot urinary protein:creatinine ratio or a 24 hour urine collection to quantify the proteinuria. Significant proteinuria is diagnosed if the urinary protein:creatinine ratio is more than 30mg/mmol or the validated 24 hr urine sample has more than 300 mg of protein. Baseline blood investigations should include full blood count, liver function (bilirubin and transaminases), electrolytes and kidney function tests. Antihypertensive medications may need to be commenced with the aim of maintaining the systolic blood pressure below 150 mm Hg, and the diastolic pressure between 80 - 100 mm Hg. Labetalol is the first line treatment. However, in patients in whom labetalol cannot be used (e.g. in patients with bronchial asthma), alternatives include nifedipine (contraindicated before 20 weeks of gestation), methyldopa, atenolol and metoprolol. 4-6 hourly blood pressure, daily assessment of proteinuria, along with haematological and biochemical monitoring are also carried out. Inpatient management is required till the blood pressure stabilises.

Following discharge blood pressure can be checked in the community or in antenatal day assessment 2-3 times a week depending on clinical circumstances. Quantification of urinary protein is not necessary after the initial assessment, however, blood tests for full blood count, liver and kidney functions need to be repeated at least twice weekly (thrice weekly if the hypertension is moderate or severe). There is often a rise in serum uric acid level, which has been associated with poor maternal and fetal outcome29, 30. However, there is no evidence to use serum uric acid levels for clinical management.

Fetal monitoring:

Ultrasound assessment of fetal growth and amniotic fluid volume along with umbilical artery doppler velocimetry needs to be done at initial diagnosis of pre-eclampsia to exclude IUGR and then every 2 weeks if the pregnancy is managed conservatively and the results remain normal CTG monitoring is commonly done at diagnosis, along with the ultrasound assessment. If normal, further CTG should be performed weekly unless otherwise clinically indicated.

Delivery

In pre-eclampsia with mild or moderate hypertension, women may be delivered between 34 and 37 weeks of gestation, depending on maternal and fetal condition, presence of risk factors and availability of neonatal intensive care facilities. If severe pre-eclampsia develops, refractory to treatment or fetal wellbeing delivery may need to be done earlier.

Pre-eclampsia is considered to be severe in case of

1)       Severe hypertension with proteinuria or

2)       Mild / moderate hypertension and proteinuria with one or more of the following signs / symptoms:

Ø  Severe headache , not responding to medications

Ø  Visual disturbance (blurring or flashing of light)

Ø  Severe pain in upper abdomen or vomiting

Ø  Papillo-oedema

Ø  Signs of clonus (³ 3 beats)

Ø  Liver tenderness

Ø  HELLP syndrome

Ø  Decrease in platelet count to less than 100 x 109 per litre

Ø  Abnormal liver enzymes (ALT or ASTrising to above 70 iu/litre).

 

HELLP syndrome

HELLP Syndrome (haemolysis, elevated liver enzyme, low platelets) is a form of severe pre-eclampsia that is associated with high maternal and perinatal morbidity and mortality and may be present without hypertension or, in some occasions, without proteinuria.

A diagnosis of HELLP syndrome is made after confirmation of haemolysis, either by blood film microscopy showing fragmented red cells or increased serum LDH level. An AST or ALT level of above 70 iu/l is significant while a level more than 150 iu/l is associated with increased morbidity to the mother, though neither of them are independent risk factors for increased maternal morbidity 31.  A low platelet count (less than 100 x 10 6 /ml) supports the diagnosis. 

There is some evidence to suggest that the severity of pre-eclampsia differs according to the time of onset. More severe form occurs with the onset of pre-eclampsia prior to 34 weeks of gestation. This form is associated with abnormal uterine artery blood flow, IUGR and adverse maternal and fetal outcomes32-33.

There may be some difference in the pathophysiology of these two disease types. The early onset disease may be associated with placental abnormalities, while the late onset one is more linked to maternal constitutional factors such as increased BMI34

In severe pre-eclampsia, delivery is appropriate anytime beyond 34 weeks of gestation following corticosteroid administration to achieve fetal lung maturity. Delivery before 34 weeks is only indicated in maternal/fetal compromise or hypertension refractory to treatment35-37. Prolonging pregnancy at early gestation may improve the perinatal outcome but has to be carefully balanced against maternal wellbeing. If conservative management is planned, ultrasound assessment of fetal growth, amniotic fluid volume and umbilical artery doppler flow should be done at admission, and thereafter, every two weeks. In case of normal ultrasound findings, weekly CTG monitoring should suffice, unless clinically indicated otherwise (for e.g. reduced fetal movement, vaginal loss, abdominal pain or deterioration of maternal condition).

Eclampsia

Generalised tonic-clonic seizures, with or without raised blood pressure and proteinuria, occurring during or after pregnancy with no other identifiable cause is classified as eclampsia. The cause is usually multi-factorial including cerebral vasoconstriction, ischaemia, vasogenic oedema, or other pathology. Although it is more likely to occur in women with severe rather than mild pre-eclampsia, there is no convincing test for predicting the onset of eclampsia. Convulsions may occur antepartum (38-53%), intrapartum (18-36%), or postpartum (11-44%)38. Women with a history of previous eclampsia are at increased risk of eclampsia (1-2%) and pre-eclampsia (22-35%) in subsequent pregnancies39.

Intrapartum Care

During labour, hourly blood pressure monitoring in women with mild or moderate hypertension, and continuously in severe hypertension is ideal. Antenatal hypertensive treatment should be continued, with the aim of maintaining the systolic blood pressure below 150 mm Hg, and the diastolic pressure between 80-100 mmHg. If oral medications fail to control the blood pressure, then intravenous anti-hypertensives are indicated to prevent the known risk of vascular damage due to uncontrolled hypertension.

Hydralazine, a peripheral arteriolar vasodilator, has been widely used as the first-line treatment for acute hypertension in pregnancy, in the past.It is administered as bolus doses (5-10 mg) intravenously, every 20 minutes to a maximum dose of 30 mg, with careful monitoring of blood pressure. The side effects include headache, nausea, and vomiting. Importantly, hydralazine may result in maternal hypotension, which may subsequently cause fetal distress. Preloading with 500 ml of crystalloid fluid before or with the first dose of intravenous hydralazine may avoid this40. Labetalol is another antihypertensive that can be given intravenously, either as bolus doses or as an infusion to manage severe hypertension. It is commonly used as the first line drug in many centers in UK. However, it is not suitable for patients with bronchial asthma. Nifedipine may also be used orally to control blood pressure (sublingual administration is not recommended).However, it can interact with magnesium sulphate to produce profound muscle weakness, maternal hypotension and fetal distress41-43. Recent evidence suggests labetalol and nifedipine as better alternatives than hydralazine40. In all cases, the blood pressure should be monitored closely, along with fetal monitoring, as sudden decrease in maternal blood pressure will reduce the utero-placental blood flow, resulting in fetal distress.

Magnesium sulphate isthe agent of choice for treatment of eclampsia. It is also used in women with severe pre-eclampsia for prophylaxis of eclampsia andis usually commenced once delivery decision is made or in immediate postpartum period.  In women with less severe disease the decision will depend on individual case assessment. Evidence shows that magnesium sulphate more than halves the risk of eclamptic seizures44.It has also been shown to reduce maternal morbidity related to pneumonia, mechanical ventilation and intensive care45.However, there is little evidence to suggest that it decreases the risk of stillbirth or neonatal death.Magnesium sulphate is usually continued for 24 hours following delivery or 24 hours after the last seizure, whichever is the later, unless there is a clinical reason to do otherwise. This is based on the findings of the Collaborative Eclampsia Trial, 1995. However, recent evidence suggests that magnesium infusion may be stopped earlier (12 hours postpartum), especially when used in conjunction with other clinical parameters46, 47. Regular assessment of the urine output, deep tendon reflexes, respiratory rate, oxygen saturation and serum concentration is done as long as magnesium sulphate is continued to avoid toxicity. Features of magnesium toxicity include suppression/loss of patellar reflexes, drowsiness and respiratory depression. Intravenous calcium gluconate is used for reversal of magnesium toxicity.

Fluid restriction is the usual practice, unless there is associated maternal haemorrhage, to reduce the chance of fluid overload and pulmonary oedema. As per NICE guidelines, total fluids should be limited to 80 ml/hour in women with severe pre-eclampsia. Strict intake-output chart should be maintained. The regime of fluid restriction should continue until postpartum diuresis commences.

The mode of delivery should be individualised taking into account the gestation, presentation, cervical favourability for induction of labour and well-being of the fetus. Vaginal delivery is generally preferable but in case of extreme prematurity or fetal compromise, caesarean section is more likely.

Haematological and biochemical monitoring needs to be continued in labour and is dictated by the patient condition and need for analgesia/anaesthesia. For those on magnesium sulphate, bloods must be repeated every 6 hours.

Anaesthetic management

The anaesthetic management in pre-eclamptic patients is important, and should start with a detailed pre-anaesthetic assessment. Appropriate history and physical examination are important. Pre-eclamptic patients are at increased risk of oedema of the pharyngolarynx and assessment of airway is vital48-49. Clinical assessment of the cardiopulmonary and fluid status is required, along with laboratory investigations including renal biochemistry and coagulation status.An appropriate understanding of the obstetric interventions such as antihypertensive medications, and magnesium sulphate infusion is required.

Anaesthetic management should include appropriate monitoring, and should include NIBP, pulse oximetry and urine output. Invasive blood pressure monitoring (arterial line) is indicated in patients with poorly controlled blood pressure, or when NIBP is difficult to obtain (e.g. in the obese patients).

Pulmonary oedema is a rare but serious complication of severe pre-eclampsia, which can lead to increased maternal mortality (10%) and perinatal mortality as high as 50%50. Central venous pressure monitoring is indicated in patients with pulmonary oedema, poor urine output or when difficulty in fluid management is anticipated in the peripartum period. Pulmonary arterial catheters are rarely needed. Non-invasive monitoring of cardiac output may be required in patients with difficult fluid management or coexisting cardiac problems.

The safety of regional anaesthesia in pre-eclamptic patients is now well established51. Lumbar epidural may be used for labour analgesia in women with pre-eclampsia if the mothers opt for it. Early epidural should be considered as it helps to diminish the hypertensive responses to pain. Platelet count >75x109/L in the absence of other coagulation abnormalities is not associated with increased likelihood of regional anaesthetic complications in the setting of pre-eclampsia52. The presence of a functioning epidural catheter allows the epidural block to be titrated for LSCS if indicated. If central neuraxial block is contraindicated, then intravenous opioids may be used for labour analgesia53-54. Few studies have mentioned the successful use of remifentanil PCA in these patients55.Regional blockade is currently the preferred mode of anaesthesia for caesarean section. It has long been argued that while titrated epidural blocks are safe, single shot spinal or CSE techniques may produce profound hypotension. However, multiple studies have demonstrated the safety of spinal and CSE in pre-eclamptic patients for LSCS with no adverse effects on mother or fetus56-58. In fact the incidence of hypotension in pre-eclamptic patients following regional anaesthesia is less than that in healthy patients, and is successfully managed by intravenous boluses of ephedrine or phenylephrine59-60.Doses of local anaesthetics in regional anaesthesia remain the same in pre-eclamptic patients as in normal healthy parturients.

Though regional anaesthesia is preferred for LSCS, a general anaesthesia may still be needed if regional anaesthesia is contraindicated (e.g. coagulopathy as in HELLP syndrome), and in emergency situations where the baby has to be delivered as early as possible. General anaesthesia increases the risk of hypertension during induction and emergence, loss of airway due to pharyngolaryngeal oedema, aspiration and transient neonatal depression. Extreme care is to be undertaken to obtund the hypertensive response during induction-intubation, as this has been a significant past cause of maternal mortality61. Several agents (alfentanil, fentanyl, remifentanil, magnesium sulphate, intravenous lignocaine and esmolol) have been suggested for induction, and clinicians should use familiar ones. All opioids rapidly cross the placenta and increase the risk of neonatal depression, and appropriate facilities for neonatal resuscitation must be available. Remifentanil has the advantage as it is rapidly metabolised by the neonate, and any respiratory depression is usually brief62- 63.Maintenance of anaesthesia is done by inhalational anaesthetic agents. Isoflurane is considered to be a good choice, because of its vasodilating properties. Vigilance is also required during emergence from anaesthesia, to prevent hypertension, as well as aspiration.

Anaesthetists must also be aware of the potential drug interactions of agents commonly used in pre-eclampsia. Magnesium sulphate and calcium channel blockers may potentiate the action of muscle relaxants and appropriate monitoring is vital.

Post delivery analgesia

This is maintained by simple analgesics like paracetamol. Non-steroidal anti-inflammatory agents have been used; however, caution must be exercised due to their effect on cyclo-oxygenase pathway, especially those with renal insufficiency and coagulopathy. A few case reports of significant increase in blood pressure in postpartum women have been reported following their use64. Patient controlled analgesia with opioids has been used widely, and is considered to be a safe option.

Use of oxytocic agents

Syntocinon is the drug of choice. Ergometrine should be avoided because of its propensity to cause hypertension. Synthetic prostaglandins such as Carboprost (15 methyl PGF 2 alpha) may be given with caution after considering the risk-benefit ratio, especially because it can aggravate hypertension.

Use of thromboprophylaxis

This should be considered in all patients with pre-eclampsia.

Table 2: Management strategies for chronic hypertension and gestational hypertension

 

Preconception

Antenatal

Delivery

Postpartum

Further follow-up

Chronic Hypertension

Optimise antihypertensives, change ACE inhibitors, diet and lifestyle modification

Continue treatment to maintain BP <150/100. Offer uterine artery dopplers to detect risk of developing pre-eclampsia/IUGR

At 37 weeks, if BP is controlled.

Aim to maintain BP <140/90 with antihypertensives

Medical review at 6-8 weeks

Gestational Hypertension

Assessment of risk factors

Hospital admission if severe hypertension. Antihypertensive if BP > 150/100. Test for proteinuria at each visit, blood tests as indicated

At 37 weeks, if BP <160/110, with/without antihypertensives

Titrate antihypertensives to keep BP <140/90

Medical review at 6-8 weeks, or earlier if need to continue antihypertensives

Pre-eclampsia

Assessment of risk factors.

Hospital admission at diagnosis. Antihypertensives to be started if BP>150/100. Regular blood investigations (2-3/week)

Delivery between 34-37 weeks, depending on maternal/ foetal condition

Initial monitoring as inpatient, to be discharged to the community when BP <149/99 with/without treatment and blood results are stable

Medical review at 2 weeks, if continuing antihypertensives. Otherwise at 6-8 weeks

Postpartum Care

Following childbirth, mobilisation of the extravascular fluid occurs increasing the intravascular volume, and consequently increasing the blood pressure. This fluid shift also increases the risk of pulmonary oedema, cerebral oedema and eclampsia.

Most of the existing guidance focuses on management of blood pressure and its associated problems in the antenatal and intrapartum period but the postpartum phase can often be poorly looked after 65. Regular blood pressure monitoring at an interval of 4-6 hours should be done as an inpatient initially and blood platelet count, transaminases and creatinine should be measured to note any changing trends. The aim is to maintain blood pressure <160/110mmHg, thereby preventing cerebral injury from occurring. In order to achieve this, beta-blockers, calcium-channel blockers and ACE inhibitors can be used in a stepwise manner. Use of methyldopa is usually avoided as it has the potential to cause depression and psychosis in postpartum period. Women are discharged to the community care if they are asymptomatic, blood pressure, with or without treatment, is 149/99 mmHg or lower and blood test results are stable or improving. Blood pressure isthen checked daily/alternate days in the community till 2 weeks postpartum. Antihypertensives should continue till blood pressure falls below 130/80 mm of Hg and the dose adjustments need to be made by the GP. If blood pressure becomes uncontrolled, then women would require urgent referral to the hospital.

In most cases, the hypertension and/or proteinuria resolve within six weeks postpartum. Any women whohad pre-eclampsia complicating their pregnancy, needs to have blood pressure and urine protein checked at 6-8 week postnatal visit at the GP surgery. If still requiring antihypertensive treatment at that stage or persistent proteinuria further assessment is warranted to find out cause for raised blood pressure if any and also identify and advise on risk factors for cardiovascular disease and lifestyle changes.

For all these women preconception counselling should be offered for subsequent pregnancies especially if risk factors are identified so that potentially preventative strategies can be initiated.

Table 2  outlines briefly the management strategies for mothers with chronic hypertension and gestational hypertension. However, a detailed discussion is outside the scope of this article.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
PALLAB RUDRA, Specialist Registrar (Anaesthetics), Addenbrookes Hospital, Cambridge. SONELA BASAK MBBS, MD, MRCOG, Speciality Registrar (Obstetrics & Gynaecology) Bedford Hospital, Bedford. DILIP PATIL MRCOG, Consultant (Obstetrics & Gynaecology) Bedford Hospital, Bedford. M YAKUB LATOO MBBS, FRCA, Consultant (Anaesthesia & Intensive Care) Bedford Hospital, Bedford.
Corresponding Author Details: 
DR PALLAB RUDRA, Specialist Registrar (Anaesthetics), Addenbrookes Hospital, Cambridge
Corresponding Author Email: 
pallabrudra@yahoo.co.in
References
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22. Magee LA, Ornstein MP,  von Dadelszen P. Management of hypertension in pregnancy. BMJ 1999; 318 : 1332.

23. Bower S, Schuchter K, Campbell S. Doppler ultrasound screening as part of routine antenatal scanning: prediction of pre-eclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1993;100:989–94

24. Harrington K, Cooper D, Lees C, Hecher K, Campbell S. Doppler ultrasound of the                   uterine arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small-for-gestational-age baby. Ultrasound Obstet Gynecol 1996;7:182–8

25. Roncaglia N, Crippa I, Locatelli A, Cameroni I, Orsenigo F, Vergani P, Ghidini A. Prediction of superimposed pre-eclampsia using uterine artery Doppler velocimetry in women with chronic hypertension. Prenat Diagn. 2008 ;28:710-4

26. Waugh J, Bell SC,Kilby M,Seed P,Blackwell C,Shennan AH, et al. Optimal bedside urinalysis for the detection of proteinuria in hypertensive proteinuria: a study of diagnostic accuracy? BJOG 2005:112:412–17.

27. Waugh JJ, Clark TJ, Divakaran TG, Khan KS, Kilby MD. Accuracy of urinalysis dipstick techniques in predicting significant proteinuria in pregnancy. Obstet Gynecol 2004;103:769–77.

28. Phelan LK, Brown MA, Davis GK, Mangos G.A prospective study of the impact of automated dipstick urinalysis on the diagnosis of pre-eclampsia. Hypertens Pregnancy 2004;23: 135–42.

29. Martin JN Jr,May WL, Magann EF,Terrone DA, Rinehart BK, Blake PG. Early risk assessment of severe pre-eclampsia: admission battery of symptoms and laboratory tests to predict likelihood of subsequent significant maternal morbidity. Am J Obstet Gynecol 1999;180:1407–14.

30. Redman CW, Bonnar J. Plasma urate changes in preeclampsia.Br Med J 1978;i(6125):1484–5.

31. Martin JN Jr,May WL, Magann EF, Terrone DA, Rinehart BK, Blake PG. Early risk assessment of severe pre-eclampsia: admission battery of symptoms and laboratory tests to predict likelihood of subsequent significant maternal morbidity. Am J Obstet Gynecol 1999;180:1407–14.

32. Sibai BM, Caritis S, Hauth J. What we have learned about preeclampsia.Semin Perinatol. 2003; 27:239–246.

33. Lindheimer MD, Taler SJ, Cunningham FG. Hypertension in pregnancy. J Am Soc Hypertens.2008; 2:484–494.

34. Valensise H, Vasapollo B, Gagliardi G, Novelli GP. Early and late pre-eclampsia: Two different maternal hemodynamic states in the latent phase of the disease. Hypertension. 2008;52:873–880.

35. Rath W, Fischer T. The diagnosis and treatment of hypertensive disorders of pregnancy: New findings for the antenatal and inpatient care. Dtsch Arztebl Int. 2009;106(45):733–738.

36. Sibai BM, Barton JR. Expectant management of severe pre-eclampsia remote from term: Patient selection, treatment, and delivery indications. Am J Obstet Gynecol. 2007;196(6):514.e1–e9.

37. Chammas MF, Nguyen TM, Li MA, et al. Expectant management of severe pre-eclampsia: Is intrauterine growth restriction an indication for immediate delivery? Am J Obstet Gynecol. 2000;183(4):853–858.

38. Turner JA.  Diagnosis and management of pre-eclampsia: an update. Int J Womens Health. 2010 ;2:327-37.

39. Sibai BM. Diagnosis, prevention and management of eclampsia. Obstet Gynecol. 2005 105:402–410

40. Magee LA, Cham C, Waterman EJ, et al. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ.  2003; 327:955-60. 

41. Waisman GD, Mayorga LM, Camera MI, Vignolo CA, Martinotti A. Magnesium plus nifedipine: Potentiation of hypotensive effect in pre-eclampsia. Am J Obstet Gynecol 1988; 159: 308-309

42. Ben-Ami M, Giladi Y, Shaley E. The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. Br J Obstet Gynaecol 1994; 101: 262-263

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51. Dyer RA, Piercy JL, Reed AR. The role of the anaesthetist in the management of the pre-eclamptic patient. Curr Opin Anaesthesiol. 2007;20:168-74.

52. Sharma SK, Philip J, Whitten CW, Padakandha UB & Landers DF 1999, ‘Assessment of changes in coagulation in parturients with pre-eclampsia using thromboelastography’, Anesthesiology; 90: 385-90.

53. Head BB, Owen J, Vincent RD, Shih G, Chestnut DH & Hauth JC .A randomized trial of intrapartum analgesia in women with severe pre-eclampsia, Obstet Gynecol. 2002; 99:  452-7.

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55. El-Kerdawy H, Farouk A. Labor analgesia in pre-eclampsia: remifentanil patient controlled intravenous analgesia versus epidural analgesia. Middle East J Anesthesiol. 2010; 20: 539 -45.

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Diagnosis and Management of Stable COPD

Authors
Katerina M Achilleos and Duncan J Powrie
Article Citation and PDF Link
BJMP 2011;4(3):a427

Chronic obstructive pulmonary disease (COPD) is a debilitating condition resulting in significant morbidity and mortality. It is the fifth leading cause of death in the UK 1, estimated to be the third by 2020 2.

Definition:

  1. COPD is a preventable and treatable disease with some extra-pulmonary effects that may contribute to the severity in individual patients Its pulmonary component is characterised by airflow limitation that is progressive and not fully reversible. There is an abnormal inflammatory response of the lung to noxious gases and particles, most commonly cigarette smoke 3.
  2. Airflow obstruction is defined as post-bronchodilator FEV1/FVC ratio (where FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity) of less than 0.7 If FEV1 is ≥ 80% predicted, a diagnosis of COPD should only be made in the presence of respiratory symptoms 4.

Incidence/ Prevalence:

Within the UK it is estimated that 3 million people are affected with COPD 4. However, only 900,000 are diagnosed -4An estimated two million people who have COPD remain undiagnosed 4.

Causes:

90% of cases are smoking related 4, particularly those with >20 pack year smoking histories 5. Environmental and occupational factors can also play a role, including exposure to biomass fuels such as: coal, straw, animal dung, wood and crop residue which are used to cook in some countries and heat poorly ventilated homes COPD occurs in 10-20% of smokers, suggesting there is an element of genetic susceptibility 2-3, 5.

Diagnosis:

To make a diagnosis of COPD an obstructive deficit must be demonstrated on spirometry in patients over the age of 35 years with risk factors (mainly smoking) and signs and symptoms of the disease 4.

Signs and Symptoms:

  1. Progressive dyspnoea on exertion
  2. Chronic cough
  3. Chronic sputum production
  4. Wheeze
  5. Frequency of exacerbations – particularly during winter months 4
  6. Functional status – bearing in mind gradual progression of disability, effort intolerance and fatigue.
  7. Features suggestive of Cor pulmonale 5:
    1. Peripheral oedema
    2. Elevated jugular venous pressure
    3. Hepatomegaly
    4. Right ventricular heave
    5. Tricuspid regurgitation

Investigations/ Tests to consider:

  1. Post-bronchodilator Spirometry – essential in confirming the diagnosis of COPD.
    1. Demonstrating an obstructive picture.
    2. FEV1 is used to assess the progression and severity of COPD, but correlates poorly with the degree of dyspnoea 3-6. (Table 1)
  1. Pulmonary functions tests – Markers suggesting the presence of emphysema include:
    1. Reduced TLCO and KCO due to a reduced surface area for gaseous exchange 5.
    2. Raised Total lung capacity, residual volume and functional residual capacity due to air trapping 5.
  1. Chest radiograph – Is not required for the diagnosis, but is recommended to exclude other conditions such as interstitial lung disease, pleural effusions or pneumothorax. It may demonstrate features of the condition, such as 3, 5:
    1. Hyperinflated lung fields
    2. Flattened diaphragms
    3. Bullous changes, particularly at the apices
  1. BODE index prognostic indicator – This is grading system shown to be better than FEV1 at predicting the risk of hospitalisation and death in patients with COPD. Patients are scored between 0 and 10, with higher scores having an increased risk of death. It encompasses 3, 5-7: (Table 2)
    1. BMI
    2. Airflow Obstruction – taking into account the FEV1
    3. Dyspnoea – in accordance with the Medical Research Council (MRC) scale 5.
    4. Exercise capacity – measured by the distance walked in 6 minutes. (Table 3)

Table 1. Severity of airflow obstruction 4

Stage Severity post-bronchodilator FEV1 (%) Predicted Comments
1 Mild ≥ 80% Only diagnosed in the presence of symptoms
2 Moderate 50- 79% Managed within the community
3 Severe 30-49% TLCO usually Low
Hospitalization may be needed only with exacerbations
4 Very Severe <30% Or FEV1 <50% with respiratory failure

Table 2. BODE Index 3, 5-8

  1 2 3  
FEV1 Predicted (%) ≥ 65 50- 64 36- 49 ≤ 35
Distance walked in 6 minutes (meters) ≥ 350 250- 349 150- 249 ≤ 149
MRC dyspnoea scale 0-1 2 3 4
BMI ≥ 21 ≤ 21    

Table 3. Medical research council (MRC) Dyspnoea scale 5, 8

1 Dyspnoeic only on strenuous activity
2 Dyspnoeic on walking up a slight incline or when hurrying
3 Walks slower than contemporaries on the flat, or has to stop for breath, or has to stop for breath when walking at own pace
4 Stops for breath on walking 100m or after a few minutes on walking on the flat
5 Breathless on minimal exertion e.g. dressing/ undressing. To breathless to leave the house

Differential Diagnosis:

  1. Asthma – the most important differential diagnosis to consider.
    1. This is steroid and bronchodilator responsive
    2. Indicative of reversible airway obstruction.
    3. It is not associated with smoking.
    4. Patients with asthma may exhibit 3, 9: chronic non-productive cough, variability in breathlessness, diurnal /day-to-day variation, nocturnal wheeze and dyspnoea
    5. However both conditions may coexist creating diagnostic uncertainty.
  1. Alpha1 antitrypsin deficiency is an autosomal dominant condition associated with an increased risk of developing emphysema at an early age 3, 5, 9.
    1. It can occur in non-smokers
    2. Can be asymptomatic and thus under-diagnosed with an estimated 1 in 2000-5000 individuals being affected 5.
    3. The disease is worse in smokers
    4. COPD can develop in patients < 35years of age
    5. It is associated with liver cirrhosis.
    6. All patients with COPD should be screened.
    7. Emphasis should be made to avoid smoking, including passive smoking.
  1. Other conditions to consider include:
    1. Bronchiectasis
    2. Interstitial lung disease
    3. Cardiac failure.

Treatment:

Goals of management include:

  1. Early and accurate diagnosis
  2. Improve symptoms and quality of life
  3. Reduce the number of exacerbations
  4. Improve mortality

Non-pharmacological management:

  1. Smoking cessation – an accurate smoking history should be obtained, including the number of pack years smoked. All current smokers with COPD should be encouraged to stop at every opportunity, and offered smoking cessation advice. Advising the patient alone will help a certain proportion to stop, whilst referral to smoking cessation services has been shown to further increase in quit rates. There are a range of nicotine and other pharmacological therapies available such as Bupropion (Zyban®) and Varenicline (Champix®) 3-4, 7, 8.
  2. Vaccinations – A once off Pneumococcal and annual Influenza vaccine should be offered.
  3. Pulmonary rehabilitation – Should be offered to patients who have had a recent exacerbation requiring hospitalisation and those that have an MRC score of ≥ 3, but are still able to mobilise and thus have the potential for further rehabilitation. It is not suitable for those patients that are immobile or limited in their mobility due to symptoms of unstable angina or a recent cardiac event. Benefits are seen in terms of reduced hospital admission, improved quality of life and exercise tolerance Commitment to the programme should be relayed to the patient, and each programme should be tailored to their individual needs. This usually includes 3-5:
    1. Disease education – which can improve the ability to manage their illness.
    2. Exercise – tailored programmes to prevent de-conditioning and improve functional exercise capacity, dyspnoea and quality of life 4. This includes strength and endurance training of upper limbs and respiratory muscles Benefits may be seen even after 6 months.
    3. Physiotherapy – to teach active cycle breathing techniques or to use positive expiratory pressure masks in patients with excessive sputum production.
    4. Nutritional support – in the form of supplementation or dietician advice in patients with a suboptimal BMI. A low BMI is associated with increased mortality as it is associated with poor exercise capacity, reduced diaphragmatic mass and impaired pulmonary status. Alternatively, weight loss is recommended in patients who are in the obese range.
    5. Psychological – Assessment for support at home, introduction of patients to day centres, assessing for features of depression and anxiety, and aiding in the obtainment of a car disability badges may require referral to occupational therapy and social services.
  1. Travel advice – Patients who are planning air travel and have FEV1 <50%, Sa02 < 93%, or are on long term oxygen therapy (LTOT) should undergo formal assessment -4Patients with bullous disease should be informed that they are at increased risk of pneumothorax during high altitude flights 4.

Pharmacological management:

  1. Bronchodilators – Provide long term benefit in reducing dyspnoea. This is not reflected in improvements in FEV1 as it may not show reversibility 4.
    1. Start with an inhaled SABA (short-acting beta2-agonist) or a SAMA (short-acting muscarinic antagonist) on an as required basis for symptomatic relief. If symptoms remain despite regular SABA therapy (i.e. four times a day), then treatment will need to be stepped up.
    2. If symptoms persist or if the patient is having recurrent exacerbations add in a LABA (long-acting beta2 agonist) or a LAMA (long acting muscarinic antagonist).
    3. If symptoms continue, add in a LAMA if already on a LABA (or vice versa).
    4. If FEV1 <50% add in an inhaled corticosteroid (ICS). This can be offered as a combination inhaler.

Inhaled therapy should offer sufficient bronchodilator response. A spacer can be used for those with poor technique. Nebulisers are reserved for patients who demonstrate respiratory distress despite maximal inhaled therapy, and for those that show an improvement in symptoms or exertional capacity 4.

Diagram 1: Summary of step-by-step management 4

  1. Corticosteroids – A short course of oral steroids may be used during exacerbations. A maintenance course however is not recommended Any patients on long term steroids should be weaned off.
  2. Mucolytic agents – May be considered in patients with a chronic cough who have difficulty expectorating. They should only be continued if symptomatic benefit is evident, otherwise they can be stopped. There is no evidence to show that they reduce the exacerbation frequency.
  3. Theophylline – Should only be offered in people that are unable to use inhaled therapy or after trials of SA and LA bronchodilators 4. The same generic brand should be prescribed as individual brands will have different efficacy. It is usually used as an adjunct to beta2-agonists and muscarinic antagonists. Interactions with macrolides and fluroquinolones and other drugs are also common, and as such the theophylline dose should be reduced if interactions are known. Caution should be taken in prescribing theophylline in the polypharmacy patient 3, 5. Little evidence has been shown to support theophylline usage in COPD (compared to asthma), however it is used for its anti-inflammatory effects As such levels are only performed if toxicity is suspected and should not be adjusted if in the sub-therapeutic range.
  4. Oxygen therapy – Patients should be assessed for long-term oxygen therapy (LTOT) if they exhibit 4:
    1. Severe airflow obstruction
    2. Features of Cor pulmonale
    3. Hypoxaemia (Sa02 ≤ 90%)
    4. Cyanosis
    5. Polycythaemia

Patients with stable COPD who are receiving maximum medical therapy are assessed by measuring arterial blood gases taken on two separate occasions at least 3 weeks apart. To meet the criteria patients must have 4:

  1. A Pa02 < 7.3 kPa when stable, or
  2. A Pa02 >7.3 but < 8.0 kPa when stable and:
    1. Pulmonary hypertension or
    2. Peripheral oedema or
    3. Secondary polycythaemia or
    4. Nocturnal hypoxaemia

LTOT should be used for a minimum of 15L per day, including during sleep 3-4.

Patients who continue to smoke should be made aware of the serious risk of facial injuries due to the highly flammable nature of oxygen.

When to refer:

Referrals for specialist advice or specialist investigations may be appropriate at any stage of the disease.

Other possible reasons for referral 4

§ Diagnostic uncertainty § Suspected severe COPD
§ Onset of Cor pulmonale § Rapid decline in FEV1
§ Assessment for LTOT, home nebulisers or oral corticosteroid therapy § Symptoms that do not correlate to lung function deficit
§ Pulmonary rehabilitation assessment § Frequent infective exacerbations
§ Family history of alpha-1-antitrypsin deficiency § Haemoptysis
§ Onset of symptoms < 40 years § Bullous lung disease
§ Assessment for lung volume reduction surgery/ lung transplantation § Dysfunctional breathing

Follow-up:

Patients with stable mild-moderate COPD should be reviewed by their general practitioner at least once a year and those with severe COPD twice yearly.

At each visit 4:

  1. An opportunity should be taken to ask about their current smoking status and the desire to stop.
  2. Assessment of adequate control of symptom: dyspnoea, exercise tolerance and the estimated number of exacerbations per year.
  3. Assessment of inhaler technique.
  4. To assess the effects/side effects of each drug treatment.
  5. The need for pulmonary rehabilitation.

For those patients with very severe airflow obstruction (FEV1 < 30%), the above still remains, in addition to the assessment of 4:

  1. Features of Cor pulmonale
  2. Nutritional status
  3. The need for LTOT
  4. Signs of depression
  5. The need for occupational therapy and social services input
  6. Referral to specialist and their services
  7. Measurements of:
    1. FEV1 and FVC
    2. BMI
    3. MRC dyspnoea scale
    4. Sa02 via pulse oximetry

Those patients requiring long term non-invasive ventilation will be reviewed by a specialist on a regular basis.

Patient Information:

§ www.patient.co.uk/health/Chronic-Obstructive-Pulmonary-Disease.htm
§ www.lunguk.org/you-and-your-lungs/conditions-and-diseases/copd
§ http://smokefree.nhs.uk/ways-to-quit

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
KATERINA M ACHILLEOS, MBBS BSc (Hons), Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY DUNCAN J POWRIE, MB ChB, Consultant Respiratory Physician, Heart and chest clinic, Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY
Corresponding Author Details: 
KATERINA M ACHILLEOS, ST1 Respiratory Medicine, Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY
Corresponding Author Email: 
katerina.achilleos@southend.nhs.uk
References
References: 

1.      National statistics (2006) Health Statistics Quarterly 29.

2.      European Respiratory society (2003) European White Lung Book.

3.      Global Strategy for Diagnosis, Management, and Prevention of COPD.  Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2010.

4.      Chronic obstructive pulmonary disease. Management of chronic obstructive pulmonary disease in adults in primary and secondary care. NICE guidelines 2010.

5.      Chapman S, Robinson G, Straddling J, West S. Oxford handbook of  respiratory medicine, 2e, Oxford university press, 2009

6.      Celli BR.  Update on the management of COPD. Chest 2008;133:1451-1462.

7.      Celli BR, et al. The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. NEJM 2004; 350: 1005-12.

8.      Todd DC et al. Approach to chronic obstructive pulmonary disease in primary care. Can Fam Physician 2008; 54:706-11.

9.      Celli BR, MacNee W et al. Standards for the diagnosis and treatment of patients with COPD. A summary of the ATS/ESR position paper.Eur Respir J 2004; 23: 932–946

10.  Barnes PJ. Theophylline for COPD. Thorax 2006; 61: 742-743.

Response Predictors in ECT: A discussion about Seizure Threshold

Authors
Madhavan Seshadri and Nadeem Z Mazi-Kotwal
Article Citation and PDF Link
BJMP 2011;4(2):a424
Abstract / Summary
Abstract: 

Electroconvulsive Therapy (ECT) has been in use since 1938 and remains one of the most important and controversial treatments. The National Institute of Clinical Excellence in UK specifically recommends considering ECT as an option in treatment of severe depression (when life threatening and a rapid response is needed or when other treatments have failed), moderate depression (not responding to multiple treatments), catatonia and a prolonged and severe manic episode. For ECT to have a therapeutic response, it is now recognised that a generalised tonic-clonic seizure is essential. The degree by which the stimulus intensity exceeds the seizure threshold is an important determinant of both therapeutic effectiveness and cognitive side effects. This article attempts to discuss the significance of estimating the seizure threshold and the practical ways of lowering it, to reduce the side effects during the course of the treatment.

Abbreviations: 
ECT: Electroconvulsive Therapy
Keywords: 
ECT, Electroconvulsive Therapy, Seizure Threshold

Introduction

The use of convulsive therapy for psychiatric conditions evolved after its first use by Meduna using camphor in 1934, and by 1938, Cerletti and Bini had documented the use of electricity to induce convulsions and therapeutic benefit. The technique has been extensively modified by the addition of muscle relaxants and general anaesthesia. Electroconvulsive Therapy is now an important and effective treatment option for certain severe neuropsychiatric disorders.

Most developments and changes in the practice of ECT have been driven to reduce the adverse effects and not by the need to make it more efficacious. The aim is to induce a generalised tonic-clonic seizure with a sufficient dose to maximise efficacy but not too high to reduce cognitive side effects. The newer brief-pulse, constant-current, square-wave machines are more efficient in inducing seizure than the older sine-wave, constant-voltage machines.

Between January and March 2002, there were nearly 12800 ECT administrations in England to 2300 individuals 1. The National Institute of Clinical Excellence currently recommends that ECT is only used to achieve rapid and short term improvement of severe symptoms after an adequate trial of other treatment options have proved inefficient and/or when the condition is life threatening as in people with severe depression, catatonia or prolonged/severe manic episode2. The newer guidelines on depression suggest that ECT be considered as a treatment option in moderate depression when it has failed to respond to multiple treatments15. It has been noted from the observation of the users experiences that the cognitive impairment often outweighed their perception of any benefit after ECT treatment.

It has been recognised that the induction of a generalised tonic-clonic seizure is necessary to achieve a therapeutic response and a number of studies demonstrate superiority of ECT over Sham ECT. It is also noted that administration of an electrical stimulus that fails to induce a seizure and immediate termination of a seizure after induction does not result in clinical improvement. Stimulus which just about produces a generalised tonic-clonic seizure may not ensure therapeutic potency, but the degree to which the stimulus intensity exceeds the Seizure Threshold is an important determinant of the therapeutic effectiveness. Unfortunately, this also corresponds to the cognitive side effects3.

Seizure Threshold

Seizure Threshold is empherically defined as the minimal electrical dose that induces generalised tonic clonic seizure activity. Boylan et alfound that greater that 40% of individuals had an initial seizure threshold of less than 50mC with unilateral electrode placement4 and Scott and Dykes and Sakheim concluded that for bilateral ECT, this was around 7%5,9.

Standard fixed doses continue to be used in UK, and this can result in a dose which is several times the seizure threshold, contributing to acute and long term cognitive side effects without any additional benefits of clinical efficacy. It is also associated with a greater risk of missed or partial seizures that have no therapeutic effect.

 

 

There is a great deal of variability between seizure thresholds in different individuals. Many factors influence it and Box 1 summarises them. Seizure threshold is generally higher in older men than younger women. Electrolyte imbalances, particularly, hyponatremia and hypocalcaemia can lower the seizure threshold. It is important for the clinician to consider these before starting the course of ECT.

 

 

Box 1: Factors influencing Seizure Threshold

  • Individual characteristics

Increases with age

Higher in men

Increases with increase in skull density

Higher for bilateral electrode placement

Electrolyte imbalances

  • Seizure Threshold increases during course of ECT
  • Medication increasing Seizure Threshold

Anticonvulsants, Benzodiazepines, Hypnotics, Anti-arrhythmics

  • Medication decreasing Seizure Threshold

Antidepressants, Antipsychotic, Lithium, Theophylline

  • Anaesthetic Induction agent

Increased: Propofol & Barbiturates

Decreased/minimal effect: Methohexital, Etomidate, Ketamine

  • Machine characteristics

Brief-pulse, constant-current, square-wave output better

Initiation of a course of Electroconvulsive Therapy treatment should routinely involve the estimation of the seizure threshold by gradual dose titration (Stimulus dosing) and then treatment by using the supra threshold doses. Once seizure threshold is determined a dose of 1.5 to 2 times the seizure threshold for bilateral ECT and at least 2.5 to 3 times the seizure threshold for unilateral ECT may provide the best balance of clinical efficacy and cognitive side effects3. This is supposed to be a better practice compared to the fixed dose method used to initiate the ECT treatment.6

Missed Seizure

An adequate electrical dose will manifest as generalised tonic, followed by clonic activity of skeletal muscle, accompanied by a typical seizure pattern on EEG. The absence of both is deemed a missed seizure7.Pippard’s audit of ECT practice showed that in nearly 22% of ECT treatments, there was either no seizure or a brief seizure.

Box 2: Causes for Missed Seizure

  • Low stimulus intensity
  • Excess impedance
  • Premature stimulus termination
  • Excess Anaesthetic Agent
  • Increase of seizure threshold by ECT
  • Other factors increasing seizure threshold

The causes of Missed Seizures are summarised in Box 2. Missed seizures may be due to faulty technique leading to insufficient stimulus intensity, excess impedance or premature stimulus termination. Individual patient factors such as electrolyte imbalances, particularly dehydration and hypercarbia can lead to missed seizures. A common reason for raised seizure threshold is the administration of high dose of anaesthetic induction agent 5. Propofol, the most commonly used agent for ECT increases seizure threshold and also decreases the seizure duration. Use of alternatives like Methohexital, Etomidate or Ketamine may be successful as they either have minimal or no effect on seizure threshold and may increase the seizure duration.

During the course of treatment seizure threshold usually rises and this may lead to missed seizures. In addition to delaying the improvement, missed seizures cause more irritability and restlessness10. By measuring the seizure duration during the course of ECT missed seizure could be anticipated and appropriate steps can be taken. Some of the effects of a missed seizure are listed in Box 3.

Box 3: Consequences of Missed Seizure

  • Anxiety
  • Headache
  • Confusion
  • Lethargy
  • Tiredness 

A missed seizure should prompt monitoring and correction of electrolyte imbalance if any. Seizure activity during the ECT procedure is affected by medication as well. Administration of seizure threshold increasing drugs should be reviewed and where possible stopped or reduced. If the treatment is for depression, consider using tricyclic drugs which lower the seizure threshold and augment ECT.

The maximum dose deliverable by the ECT machines is restricted in some countries and this may be inadequate due to very high seizure threshold in a few individuals. The US Food and Drug Administration restrict the maximum output of ECT machines to 576 millicoulombs compared to the Royal College of Psychiatrists which has recommendeda maximum output charge of 1200millicoulombs8. While higher electric doses may be able to induce generalised seizure activity, the cognitive side effects are also increased11. Therefore attempts must be made to decrease the seizure threshold to minimise these side effects.

Seizure Threshold Lowering Techniques

The aim of ECT treatment is to induce a generalised seizure activity; failure to do so makes the treatment session ineffective and of no therapeutic benefit. If a patient does not have generalised tonic-clonic seizure after a stimulus it is important to wait for at least 20 seconds after a non-seizure and at least 45 seconds after a partial/focal seizure prior to restimulating. Using appropriate techniques to avoid like low stimulus intensity, inappropriate application of electrodes, premature stimulus termination, etc are important6.

Charter and Simpson established the use of hyperventilation immediately before the application of the electrical stimulus and it has been shown to enhance seizure duration12. Sleep deprivation safely reduces the seizure threshold and also increases the seizure duration13. Caffeine prolongs the seizure duration, but has no effect on the seizure threshold14.

Conclusions

ECT remains the most maligned and misunderstood of psychiatric treatments. Whilst it has no doubt, successfully saved many lives and provided relief from the abyss of depression, proving its efficacy, the thrust of recent developments have been towards minimising the side effects. Adequate training and supervision of trainee psychiatrists will be essential to raise the standards of ECT administration techniques and skills.

Being aware of the significance of seizure threshold and ways to lower it, as an alternative to electric dose increase may address to some extent, the concerns about cognitive difficulties.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MADHAVAN SESHADRI MBBS, DPM, MRCPsych, ST4 Registrar in General Adult Psychiatry, South Essex Partnership NHS Trust, Weller Wing, Kempston Road, Bedford, UK NADEEM MAZI-KOTWAL, MBBS, MRCPsych, Consultant in Old Age Psychiatry, South Essex Partnership NHS Trust, Weller Wing, Kempston Road, Bedford, UK
Corresponding Author Details: 
MADHAVAN SESHADRI, ST4 Registrar in General Adult Psychiatry, Weller Wing, Kempston Road, Bedford, UK, MK42 9DJ
Corresponding Author Email: 
seshmadhavan@doctors.org.uk
References
References: 

1. England. Department of Health. Electro Convulsive Therapy: Survey covering the period from January 2002 to March 2002, p1: 2003

2. Guidance on the use of Electroconvulsive therapy (ECT): National Institute for Health and Clinical Excellence; 2003 Apr. p5: Technology appraisal 59.

3. Sackeim H A., Prudic J., et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of ECT. NEJM. 1993; 328: 839-846. 

4. Boylan L S, Haskett R F, et al. Determinants of seizure threshold in ECT, benzodiazepine use, anaesthetic dosage, and other factors. Journal of ECT. 2000;16:3-18.

5. Sackeim H A, Devanand D P, Prudic J. Stimulus intensity, seizure threshold and seizure duration: impact on the efficacy and safety of ECT. Psychiatric Clinics of North America, 1991;14: 803-843.

6. Scott A I F Editor, The ECT Handbook, second edition; The third Report of the Royal College of Psychiatrists’ Special Committee on ECT. CR128, 2004.

7. Pippard J. Audit of electroconvulsive treatment in two National Health Service regions. British Journal of Psychiatry. 1992;160: 621–637.

8. Lisanby  Sarah H.; Devanand  D P ; Nobler Mitchell S.; Prudic Joan; Mullen Linda; Sackeim Harold A. Exceptionally High Seizure threshold: ECT device limitations. Convulsive Therapy, 1996; 12, 156-164.

9. Scott A I F & Dykes S. Initial seizure threshold in the clinical practice of bilateral electroconvulsive therapy in Edinburgh, Scotland. Journal of ECT, 1999; 15: 118–124

10. Scott A I F & Boddy H. The effect of repeated bilateral electroconvulsive therapy on seizure threshold. Journal of ECT. 2000;16: 244–251.

11. Weiner R D, Rogers H J, Davidson J R, et al (1986) Effects of stimulus parameters on cognitive side effects. Annals of the New York Academy of Sciences. 1986: 462, 315–325.

12. Chater S N, & Simpson K H., Effect of passive hyperventilation on seizure duration in patients undergoing ECT. British Journal of Anaesthesia. 1988: 60: 70–73.

13. Gilabert E; Rojo E, Vallejo J. Augmentation of Electroconvulsive Therapy Seizures with Sleep Deprivation. Journal of ECT. 2004; 20: 242-247

14. McCall W V, Reid S, Rosenquist P, Kiesow-Webb N. A reappraisal of the role of caffeine in ECT. American Journal of Psychiatry. 1993; 150: 1543–1545.

15. Depression: The Management and Treatment of Depression in Adults: National Institute of Clinical Excellance, Clinical Guideline 90 (CG90), May 2010

Oesophageal dysfunction and disease in obesity

Authors
Zakir K Mohamed and Stephen E Attwood
Article Citation and PDF Link
BJMP 2011;4(2):a417
Abstract / Summary
Abstract: 

Patients with morbid obesity suffer a wide range of symptoms that relate to their oesophagus and stomach. It is rather paradoxical that patients who are overweight suffer the symptoms of difficulty in swallowing, pain during eating or pain after eating, because the symptoms of difficulty eating do not translate into weight reduction.  There are a range of underlying causes that include gastro-oesophageal reflux disease, dysmotility in the oesophagus, peptic ulceration and the nature and pattern of dietary intake.  In addition the surgical treatments used for morbid obesity cause similar symptoms from gastric bands leading to dysphagia or reflux from being too tight or from erosion into the stomach, from balloons being displaced and bypass complications.  Serious oesophageal conditions occur more frequently in patients with obesity such as Barrett’s oesophagus and Adenocarcinoma of the oesophagus.   This article reviews the literature to highlight the range of potential problems from oesophageal symptoms and disease and how they can be managed in the context of morbid obesity. 

Keywords: 
Obesity, Reflux, GORD, Bariatric, Balloon, Gastric band, Gastric Bypass, Dysphagia, Sleeve gastrectomy, Vertical gastric banding

 

Introduction

Patients with morbid obesity suffer a wide range of symptoms that relate to their oesophagus and stomach. It is rather paradoxical that patients who are overweight suffer the symptoms of difficulty in swallowing, pain during eating or pain after eating because the symptoms of eating difficulty do not translate into weight reduction. There are a range of underlying causes that include gastro-oesophageal reflux disease, dysmotility in the oesophagus, peptic ulceration and the nature and pattern of dietary intake.  The pathophysiology of gastro-oesophageal reflux disease and of dysphagia will be considered. The detrimental effects of the treatments of balloons, gastric bands and gastric bypass will be described and options for management discussed.  The serious complications of adenocarcinoma and its premalignant precursor, Barrett’s oesophagus will be reviewed.

Gastro-oesophageal reflux disease (GORD)

GORD is highly prevalent in obese people with increasing BMI a risk factor for developing the disease. The relation between GORD and obesity has been studied for decades and there have been conflicting results. A person with BMI of ³30 kg/m2   is 3 times more likely to suffer from heartburn and acid regurgitation 1.

Though the mechanism of this is poorly understood, a number of epidemiological studies have proven this association. Since recently, more evidence has emerged in favour of a positive association 2. In 2000, Lagergren et al, based on a population based interview study on 820 Swedish, concluded that GOR symptoms occurred independent of BMI 3. His claim was supported by two previous studies, one of which used oesophageal pH measure and other assessed the impact of weight loss on symptom relief 4, 5. A contrary view has emerged since this, with large number of western studies showing a positive association 1, 2, 6-12. This, however, has not been the case with Asian and Afro-Caribbean population. In a large population study with various ethnicities, a strongly positive association was found between BMI and GOR symptoms in white population. This was not the case in Asian and black population 13, a view re-iterated by another study from Iran 14. The overall incidence of GORD is high in western world between 10% and 20%, compared to 5% in Asia 6.

The mechanism of GORD in obesity is very poorly understood. Various theories have been postulated and the evidence for each is discussed below, including the theory that the patho-physiology of reflux in the morbidly obesity could differ from others and might require a different therapeutic approach 9

Increased intra-abdominal pressure as a cause of reflux

Increasing intra-abdominal pressure has been hypothesised to be the cause for reflux symptoms. Increasing BMI has been shown to increase intra-gastric pressure and pressure study in a prospective cohort has shown 10% increase in intra-gastric pressure with rise in each unit of BMI 15. A pH and manometry study in general population with GORD showed a higher pressure gradients across the Oesophago-gastric junction than that in controls both before and during transient lower oesophageal sphincter relaxation. This phenomenon is thought to be caused by increased intra-gastric pressure, supporting the above theory 16.

Lower oesophageal sphincter dysfunction as a cause

Kuper et al showed a dysfunction of LOS and altered oesophageal motility even in asymptomatic patients with morbid obesity using pH and manometry study (BMI >40 kg/m2) 17and Wu et al showed an abnormal post-prandial LOS with prolonged transient lower oesophageal relaxation 18, 19.These findings were re-iterated by ayazi et al, showing obese patients to be more than twice as likely to have a mechanically defective LOS 20.   However, another study back in 1987 had shown a similar LOS pressure in normal weight and obese patients, though the gastro-oesophageal pressure gradient to LOS pressure ratio was high in obese 21.

Diet

The amount or composition of dietary intake and its relation to GORD has been studied. There is some evidence that volume, fat content and a high-caloric diet increases the oesophageal acid exposure time, giving rise to symptoms 22-24. This would suggest an improvement of symptoms with reduction of these in the diet. More studies have shown an improvement in reflux symptoms with improved diet 25-29. But, there is no convincing evidence to implicate the role of diet in reflux symptoms of obese patients.

Hiatus hernia

The incidence of hiatus hernia is over 50% in morbid obesity 30. Hiatus has been shown to be predicted by intra-gastric pressure, gastro-oesophageal presssure gradient and BMI. BMI has in turn been shown to predict the former two. This confirms a positive association between BMI and presence of hiatus hernia 31. High BMI is more likely to have oesophago-gastric junction disruption, leading to hiatal hernia and an augmented gastro-oesophageal pressure gradient, providing a perfect scenario for reflux to occur 32. The incidence of defective LES was twice as much in obese patients with hiatus hernia, compared to obese without it 20. Hiatus hernia thus plays a role in the obese patients and the subsequent development of GORD 33.

Poor mobility and mental state

There is no evidence to support the theory of reflux symptoms secondary to poor mobility and depression in the morbidly obese patients.

Treatment of GORD in obesity

Medical therapy

Medical therapy with a PPI remains the first line of treatment of GORD symptoms in obesity as in patients with a normal BMI. No guidelines are available for dose adjustments in the obese patients 34. They continue to receive the standard therapy, adjusted to the severity of disease and symptoms.

Endoluminal therapy

Endoluminal therapy was introduced recently as treatment alternative for GORD and has shown promising results. This looked a safe option for use in obese patients. However, published results have shown high rate of post-operative PPI requirement in the obese patients 35. Further evidence has to emerge before this option can be recommended for use in the obese patients.

Balloon

Intra-gastric balloon therapy has been an established temporary procedure for weight loss. GORD symptoms in obese tends to improve with weight loss, but as studies have shown, a balloon insertion tended to worsen symptoms 36, 37. Balloon is hence not considered an option for treatment of obesity with patients with reflux symptoms.

Gastric band

Gastric banding provides a sufficient anti-reflux barrier in most of the obese patients with GORD. Abnormal manometric findings like increased LES (lower oesophageal sphincter) residual pressure and peristaltic wave duration are frequently encountered after banding. The clinical significances of these manometric abnormalities are not clear 38. The oesophageal stasis caused by the band could explain the reflux in patients during longer follow up. Though, the reflux from the distal stomach is prevented by the gastric band, formation of a proximal pouch predisposes to stasis and reflux. This is more common in patients with preoperatively defective oesophageal motility. The studies suggesting a good GORD symptom control following banding had shorter follow up, explaining the results 39, 40. Hence it could be concluded that gastric banding may aggravate GORD symptoms and cause oesophageal dilatation, especially in patients with pre-operative motility defects. Routine pre-operative testing should be done and alternative bariatric surgical procedures such as Roux-en-Y gastric bypass considered in these patients   41-43.

Sleeve Gastrectomy (Vertical gastric banding)

Gastrectomy reduces weight, but not gastro-oesophageal acid reflux. Although this procedure has been shown to have anti-reflux properties 44, it has fallen to disrepute in terms of relieving the reflux symptoms, especially with the superior results of RYGB 45-48. A number of these cases requiring revision, due to reflux symptoms, have been reported 49-51.

Gastric Bypass Vs Anti-reflux surgery

Though laparoscopic fundoplication is the standard operation for GORD, gastric bypass has been shown to improve the reflux symptoms in the morbidly obese, apart from reducing their weight and obesity related co-morbid conditions such as diabetes mellitus, hypertension etc. Patterson et al. showed an equivalent symptomatic improvement and objective DeMeester score improvement with Laparoscopic Nissen fundoplication and laparoscopic gastric bypass. The LES (lower oesophageal sphincter) pressure was also noted to improve, following bypass 52. This was in light of an earlier report of 31% recurrence rate of reflux symptoms following laparoscopic Nissen’s in obese patients 53. Hence, morbidly obese patients with GORD should be offered laparoscopic gastric bypass as a surgical option 27, 30, 54-59.

The improvement in GORD symptoms after gastric bypass is related to the way that the operation staples off the distal 90% or more of the stomach body and antrum, removing any possibility that acid generated in this part of the stomach can reach the oesophagus.  The parietal cell mass within the small gastric pouch that is left attached to the oesophagus, the complete elimination of duodeno-gastric reflux owing to a long Roux limb, and decrease in intra-abdominal pressure with weight loss all contribute to an almost total reflux control in all patients. The overall complications secondary to this procedure were lower than in laparoscopic fundoplication 54. It is also the procedure of choice for previous other weight-loss surgery, when reflux symptoms develop 49-51. Thus, a bariatric team prior to surgical intervention should review obese patients with GORD symptoms.

Dysphagia in obesity

Dysphagia in obesity is often related to the interventions used to treat obesity, though it can be primary in nature.

Various modalities of interventions available in obesity have been discussed above. Intra-gastric balloon therapy can be complicated by its displacement into the distal stomach, precipitating dysphagia and outlet obstruction. Gastric bands can be overfilled, causing this problem, and a slipped band or a band eroding through the stomach wall can also lead to dysphagia 60-64. There has been no report of gastric bypass resulting in dysphagia, in the literature.

It is our understanding that patients with obesity may present with primary oesophageal dysmotility. Although there is little published literature on this issue, it is our hypothesis that fatty infiltration of the oesophageal wall and myenteric plexus may result in a poor amplitude peristaltic contraction.

Other oesophageal conditions associated with obesity

Barrett’s Oesophagus

This is characterised by the replacement of the normal squamous epithelium of the lower oesophagus by a specialised metaplastic columnar epithelium. Barrett’s oesophagus is a known risk factor for oesophageal adenocarcinoma, with a 30 to 125 times increased risk compared to general population 65. Risk factors leading to Barrett’s have been poorly understood, though GORD is widely believed to be the main risk factor 66-68. Since several studies have found an association between obesity and GORD 1, 2, 6-12, and obesity as a risk factor for Barrett's have gained momentum in the recent year. Abdominal obesity or waist circumference has been shown to be more associated with Barrett’s than BMI 69.

A recent systematic review showed a statistically significant relation between increasing BMI and Barrett’s 70. However, two older systematic reviews had found a rather week relation between these two, showing a need for further well designed studies 71, 72. To mention a few studies, Jacobson et al showed a positive relation between BMI and Barrett’s in women, independent of GORD, though the waist circumference was not found to have any association 73and Stein at al., found a positive relation between BMI and Barrett’s in war veterans 74. Abdominal obesity or circumference appears to be more influential in the incidence of Barrett’s oesophagus in another study 75. There is however, little evidence to suggest an increased progression of Barrett’s to neoplasia in obesity 69

Obesity is a modifiable risk factor and if proven to be a risk for Barrett’s and subsequent neoplasia, resources can be directed at modifying this, as there is evidence to suggest the regression Barrett’s with weight loss 69. Barrett’s have been shown to regress with weight loss following gastric bypass and hence this has been recommended as bariatric procedure of choice in the morbidly obese with Barrett’s 76-79. A precise endoscopic evaluation before bariatric surgery with continuing postsurgical surveillance in patients with known Barrett's oesophagitis, and early evaluation in patients who develop new symptoms of GERD after bariatric surgery is suggested 80, 81

Adenocarcinoma of oesophagus

The incidence of oesophageal adenocarcinoma has increased about 400% during the past three decades, the most rapid rate of increase of any cancer in the United States 82-84. The association between high BMI and oesophageal adenocarcinoma is strong and well established, though the mechanism of this is still unclear. The risk is higher with increasing BMI, especially in men 85-94. Obesity has also been shown to play a role in adenocarcinomas with a family history 95. The incidence of adenocarcinoma of the cardia of stomach has not been so strongly related to BMI 96, 97. Squamous cell carcinoma of oesophagus has not shown any association to obesity either 85, 93, 94, 98, 99. Few studies have negated the association of obesity with oesophageal adenocarcinoma, but many were due to the fact that they included oesophageal and proximal stomach together 96. The majority of these cancers arise from a background of premalignant Barrett’s oesophagus, though less than 10% of the patients with oesophageal adenocarcinoma were known to have Barrett’s oesophagus previously. Presently there is no evidence that strongly supports any specific strategy to screen a subgroup of the population at risk for Barrett’s oesophagus and adenocarcinoma of the oesophagus 100.

A number of studies have also looked at the mechanism or pathway of this metaplasia-dysplasia-adenocarcinoma sequence.  Visceral adiposity rather than BMI is thought to have a greater role in chronic inflammation and subsequent neoplasia. It has a clear association with Barrett’s as above. Increasing abdominal girth increases the risk of adenocarcinoma and it has been shown for Barrett’s 98. Visceral fat is hypothesised as a major producer of interleukin-6, adinopectin, leptin and other adipokines that may be associated with the development of various gastro-intestinal cancers 101-103. More specifically, insulin-like growth factor has been implicated in the pathogenesis of adenocarcinoma in the obese 104. Oesophago-gastric tumours after bariatric surgery, has been reported, though rare. This condition, when occurs, requires the close collaboration of the bariatric team to achieve a successful oncological result, due to the altered anatomy like the blood supply to the gastric pouch and excluded stomach 105.

Conclusion

Obesity is associated with oesophageal disease, benign and malignant, and both the effects of obesity and the effects of it’s treatment can aggravate oesophageal symptoms. The management of reflux and of dysphagia in obese patients requires a broad understanding of these issues.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Z K MOHAMED, MRCSEd, Specialist Registrar, North Tyneside Hospital, Rake Lane, North Shields NE29 8NH S E ATTWOOD, FRCS. Consultant Upper GI Surgeon, North Tyneside Hospital Rake Lane North Shields NE29 8NH
Corresponding Author Details: 
S E ATTWOOD, FRCS, Consultant Upper GI Surgeon, North Tyneside Hospital Rake Lane North Shields NE29 8NH
Corresponding Author Email: 
Stephen.Attwood@northumbria-healthcare.nhs.uk
References
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57. Merrouche M, Sabate JM, Jouet P, Harnois F, Scaringi S, Coffin B, et al. Gastro-esophageal reflux and esophageal motility disorders in morbidly obese patients before and after bariatric surgery. Obes Surg 2007;17(7):894-900.

58. Clements RH, Gonzalez QH, Foster A, Richards WO, McDowell J, Bondora A, et al. Gastrointestinal symptoms are more intense in morbidly obese patients and are improved with laparoscopic Roux-en-Y gastric bypass. Obes Surg 2003;13(4):610-4.

59. Frezza EE, Ikramuddin S, Gourash W, Rakitt T, Kingston A, Luketich J, et al. Symptomatic improvement in gastroesophageal reflux disease (GERD) following laparoscopic Roux-en-Y gastric bypass. Surg Endosc 2002;16(7):1027-31.

60. Bernante P, Francini Pesenti F, Toniato A, Zangrandi F, Pomerri F, Pelizzo MR. Obstructive symptoms associated with the 9.75-cm Lap-Band in the first 24 hours using the pars flaccida approach. Obes Surg 2005;15(3):357-60.

61. Lucchese M, Alessio F, Valeri A, Cantelli G, Venneri F, Borrelli D. Adjustable silicone gastric banding: complications in a personal series. Obes Surg 1998;8(2):207-9.

62. Patel SM, Shapiro K, Abdo Z, Ferzli GS. Obstructive symptoms associated with the Lap-Band in the first 24 hours. Surg Endosc 2004;18(1):51-5.

63. Pinsk I, Dukhno O, Levy I, Ovnat A. Gastric outlet obstruction caused by total band erosion. Obes Surg 2004;14(9):1277-9.

64. Srikanth MS, Oh KH, Keskey T, Rumbaut R, Fox SR, Fox ER, et al. Critical extreme anterior slippage (paragastric Richter's hernia) of the stomach after laparoscopic adjustable gastric banding: early recognition and prevention of gastric strangulation. Obes Surg 2005;15(2):207-15; discussion 215.

65. Wild CP, Hardie LJ. Reflux, Barrett's oesophagus and adenocarcinoma: burning questions. Nat Rev Cancer 2003;3(9):676-84.

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68. Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett's esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol 2001;33(4):306-9.

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71. Seidel D, Muangpaisan W, Hiro H, Mathew A, Lyratzopoulos G. The association between body mass index and Barrett's esophagus: a systematic review. Dis Esophagus 2009;22(7):564-70.

72. Cook MB, Greenwood DC, Hardie LJ, Wild CP, Forman D. A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus. Am J Gastroenterol 2008;103(2):292-300.

73. Jacobson BC, Chan AT, Giovannucci EL, Fuchs CS. Body mass index and Barrett's oesophagus in women. Gut 2009;58(11):1460-6.

74. Stein DJ, El-Serag HB, Kuczynski J, Kramer JR, Sampliner RE. The association of body mass index with Barrett's oesophagus. Aliment Pharmacol Ther 2005;22(10):1005-10.

75. Edelstein ZR, Farrow DC, Bronner MP, Rosen SN, Vaughan TL. Central adiposity and risk of Barrett's esophagus. Gastroenterology 2007;133(2):403-11.

76. Csendes A, Burgos AM, Smok G, Burdiles P, Henriquez A. Effect of gastric bypass on Barrett's esophagus and intestinal metaplasia of the cardia in patients with morbid obesity. J Gastrointest Surg 2006;10(2):259-64.

77. Houghton SG, Romero Y, Sarr MG. Effect of Roux-en-Y gastric bypass in obese patients with Barrett's esophagus: attempts to eliminate duodenogastric reflux. Surg Obes Relat Dis 2008;4(1):1-4; discussion 4-5.

78. Cobey F, Oelschlager B. Complete regression of Barrett's esophagus after Roux-en-Y gastric bypass. Obes Surg 2005;15(5):710-2.

79. Chang CG, Perez E. Case reports--resolution of Barrett's disease and esophageal epithelial atypia after gastric bypass and LAP-BAND. Obes Surg 2009;19(11):1597-8.

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81. Varela JE. Barrett's esophagus: a late complication of laparoscopic adjustable gastric banding. Obes Surg;20(2):244-6.

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83. Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999;26(5 Suppl 15):2-8.

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Eating Disorders in Children and Adolescents

Authors
Fayyaz Khan and Uttom Chowdhury
Article Citation and PDF Link
BJMP 2011;4(1):a405

Eating disorders are defined as those disorders in which there is excessive concern with the control of body weight and shape, accompanied by grossly inadequate, irregular or chaotic food intake. It is widely accepted that eating disorders occur in young adults and adolescents, however, a number of reports have described series of young patients with eating disorders aged from eight years upwards.1,2The range of disorders in children includes selective eating, food avoidance emotional disorder, functional dysphagia and pervasive refusal syndrome.  

ANOREXIA NERVOSA.

The DSM IV diagnostic criteria for anorexia nervosa are as follows:

  1. Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g weight loss leading to maintenance of body weight less than 85% of expected; or failure to make weight gain during growth period).
  2. Intense fear of gaining weight or becoming fat, even though underweight.
  3. Disturbance in the way one’s body weight and shape is experienced, undue influence of body weight or shape on self evaluation, or denial of the seriousness of current low body weight.
  4. Absence of at least three consecutive menstrual cycles

Subtypes:

Restricting Type: During the current episode of anorexia nervosa, the person has not regularly indulged in binge eating or purging behaviour.

Binge-Eating/Purging Type: During the current episode of anorexia nervosa, the person has regularly indulged in binge eating or purging behaviour.3                       

The above criteria are intended primarily for use with older patients and do not adequately address the problems of anorexia nervosa in children. For example, criterion D in DSM IV applies only to post-menarcheal females and states that there should be an “absence of at least three consecutive menstrual cycles”. This is clearly inapplicable in this age group, where the majority are premenarcheal. Equally unhelpful is the statement that weight should be maintained at less than 85% of that expected, for expected weight can only be calculated on the basis of height and age. Yet growth may also be impaired because of poor nutrition, so further adjustments have to be made. For these reasons, the Eating Disorders Team at Great Ormond Street Hospital for Sick Children in London, U.K, developed a more practical diagnostic criterion for early onset anorexia nervosa.4The current criteria is as follows:

Great Ormond Street diagnostic criteria for early-onset Anorexia Nervosa:

  1. Determined weight loss (e.g. food avoidance, self-induced vomiting, excessive exercising and abuse of laxatives).
  2. Abnormal cognitions regarding weight and/or shape.
  3. Morbid preoccupation with weight and/or shape.5

Weight loss: Since children should be growing, static weight may be regarded as equivalent to weight loss in adults. Weight loss is a real cause for concern in children, since they have lower total body-fat deposits and therefore do not have much fat to lose. One measurement for weight loss uses the Tanner-Whitehouse Standards6 where 100% represents the desired weight for a child’s sex, age and height, and 80% or less is classed as ‘wasting’.

Food avoidance: Children with anorexia nervosa give a variety of reasons for refusing food, the most common of which appears to be a fear of becoming obese. Other reasons include feelings of nausea or fullness, abdominal pain, appetite loss and difficulty swallowing. 7

Self-induced vomiting: Fosson et al (1987) reported that at least 40% of the 48 children included in their study of early-onset anorexia nervosa were known to be vomiting at presentation.

Excessive exercising: This is not uncommon in children with anorexia nervosa. Daily exercise workouts may be a feature in these children’s lives. Sometimes exercise may be carried out in secret in the privacy of the bedroom or bathroom.

Laxative abuse: This is not as common as in adult populations partly because children have less access or opportunity to obtain laxatives, but nevertheless, it still occurs.

Abnormal cognitions regarding weight and/or shape: The main beliefs are centred around body image and its distortion, although it must be acknowledged that body image is difficult to assess reliably. Many children with anorexia nervosa will report that they consider themselves fat even when severely underweight, which is similar to the clinical observation seen in adult patients with the same condition.

Preoccupation with weight: Children with anorexia nervosa tend to be preoccupied by their own body weight and are often experts at calorie counting. This preoccupation is closely related to fear of fatness.

Physical Aspects

The majority of physical changes in anorexia nervosa are predominantly related to the effects of starvation and dehydration. This includes slow pulse rate, low blood pressure and poor circulation leading to cold hands and feet. Often there is excess fine hair especially on the back, known as ‘lanugo’. Teeth may be pitted, eroded and decayed from gastric acid during vomiting.

A wide range of biochemical changes have been described in anorexia nervosa, although there is little information specifically relating to children. These include low haemoglobin and white cell count, low levels of potassium and chloride, raised liver enzymes such as alanine transaminase and alkaline phosphatase, and low levels of plasma zinc and serum iron.

A number of endocrine changes appear in anorexia nervosa and evidence suggests that this is due to the secondary effects of starvation. Changes include increased cortisol, growth hormone and cholecystokinin, and decreased luteinizing hormone, follicle stimulating hormone, oestrogen, triodothyronine and thyroid stimulating hormone.

BULIMIA NERVOSA

The DSM IV diagnostic criteria for bulimia nervosa is as follows 8 :    

  1. Recurrent episodes of binge eating e.g, eating large amounts of food in two hours, and a sense of lack of control during the episode.
  2. Regular use of methods of weight control:
  3. vomiting
  4. laxatives
  5. diuretics
  6. fasting or strict diet
  7. vigorous exercise.
  8. Minimum average of two binges a week in three months.
  9. Self-evaluation is influenced by body weight or shape.
  10. The disturbance does not occur exclusively during episodes of anorexia nervosa.

Sub-types:

Purging Type: During the current episode of bulimia nervosa, the person regularly engages in self-induced vomiting or laxative misuse, diuretics or enemas.

Non-purging Type: During the current episode of bulimia nervosa, the person has used other inappropriate compensating behaviours such as fasting or excessive exercise, but not regularly used purging behaviour. 2

Self-induced vomiting can lead to complications such as fluid and electrolyte disturbance and gastro-intestinal bleeding. Other physical complications include dental erosions, enlargement of the salivary glands, and muscle weakness.

OTHER EATING DISORDERS IN CHILDREN

Food Avoidance Emotional Disorder

This term was first introduced by Higgs et al (1989)9, to describe a group of underweight children presenting with inadequate food intake and emotional disturbance who did not meet the criteria for anorexia nervosa.

The operational definition we use has evolved from Higgs and colleagues original description together with clinical experience and is as follows:

  1. Food avoidance not accounted for by primary affective disorder.
  2. Weight loss.
  3. Mood disturbance not meeting criteria for primary affective disorder.
  4. No abnormal cognitions regarding weight or shape.
  5. No morbid preoccupation regarding weight or shape.
  6. No organic brain disease or psychosis.

Selective Eating

Selective eaters are a group of children who present with very restricted eating habits in terms of the range of foods they will accept. Characteristics include:

  1. Have eaten a narrow range of foods for at least 2 years.
  2. Unwillingness to try new foods.
  3. No abnormal cognitions regarding weight or shape.
  4. No fear of choking or vomiting.
  5. Weight may be low, normal or high.

Pervasive Refusal Syndrome

This term was first described by Lask et al (1991).10 The main features are:

  1. Profound refusal to eat, drink, walk, talk or self-care.
  2. Determined resistance to efforts to help.

Initially these children present with features fairly typical of anorexia nervosa, but the food avoidance is gradually followed by a more generalised avoidance with a marked fear response.

Functional Dysphagia

Children with this condition generally present with complaints of difficulty or pain on swallowing. Features include:

  1. Food avoidance.
  2. Fear of swallowing, choking or vomiting.
  3. No abnormal cognitions regarding weight or shape.
  4. No morbid preoccupation regarding weight or shape.
  5. No organic brain disease or psychosis.

For more information on the above eating disorders in children see Lask & Bryant-Waugh (1999).5

INCIDENCE AND PREVALENCE

For a number of reasons, the incidence and prevalence of childhood-onset anorexia are not known. There have been no epidemiological studies which have focussed specifically on this age group and the strict diagnostic criteria used in wider epidemiological studies may lead to a substantial underestimate of the true incidence. 2 However studies in adolescent populations estimate the prevalence to be in the order of 0.1-0.2% 11, 12 and it is likely to be even lower in children. Although debatable, an increase in actual referral rate of anorexia nervosa in children has been reported.2 Gender distribution: Five to ten percent of cases of anorexia nervosa in the adolescent and young adult population occur in males.13 However, in children, studies have reported that between 19 and 30% of children with anorexia nervosa have been boys.7,9,14,15

At present, there is little epidemiological information on the other eating disorders in children.

MANAGEMENT AND INTERVENTIONS16

Initial assessment

Comprehensive assessment should include physical, psychological and social components. Those with low to moderate risk should be managed as an outpatient. Those who are severely emaciated, with serious risk of self harm, with severe deterioration or with poor response to treatment are deemed high risk and should be considered for inpatient treatment or urgent referral to specialist services.

Anorexia nervosa – outpatient care

Psychological interventions

Psychological interventions are the key element in the management of anorexia.

The delivery of psychological interventions should be accompanied by regular monitoring of a patient’s physical state including weight and specific indicators of increased medical risk.

• When delivering psychological treatment consider, in conjunction with the patient:

– Cognitive analytical therapy (CAT)

– Cognitive behaviour therapy (CBT)

– Interpersonal psychotherapy (IPT)

– Focal psychodynamic therapy

– Family interventions focused explicitly on eating disorders

• Focus of treatment should be on weight gain, healthy eating, and reducing other symptoms related to eating disorders.

• Dietary counselling should not be provided as the sole treatment for anorexia nervosa.

Medication

Pharmacological interventions have a very limited evidence base for the treatment of anorexia nervosa.

• Medication is not effective as sole or primary treatment; caution should be exercised in its use for comorbid conditions such as depression or obsessive–compulsive disorder, as these may resolve with weight gain alone

• Avoid using drugs that affect the heart such as antipsychotics, tricyclic antidepressants, some antibiotics and some antihistamines.

Anorexia nervosa – inpatient care

•Body Mass Index (BMI) is a measure of weight in relation to height. Normal BMI range is 18.5-24.9. BMI below 17 is a concern and GPs should consider referral to specialist services. However, BMI below 15 is serious and inpatient care should be considered.

• Consider inpatient treatment for patients with high or moderate physical risk, who have not improved with appropriate outpatient treatment or have significant risk of suicide or severe self-harm.

• Admit to setting that can provide the skilled implementation of refeeding with careful physical monitoring (particularly in the first few days of refeeding) and in combination with psychosocial interventions

• Consider increased risk of self-harm and suicide at times of transition for patients with anorexia nervosa, especially that of the binge–purging sub-type.

Psychological treatment

• Psychological treatment is a key element of an inpatient stay, but evidence for what kind of treatment or approach to treatment is effective, is limited.

• A structured symptom-focused treatment regimen with the expectation of weight gain should be provided, with careful monitoring of the physical status during refeeding.

• Provide psychological treatment with a focus on both eating behaviour and attitudes to weight and shape, and wider psychosocial issues with the expectation of weight gain

• Do not use rigid behaviour modification programmes.

Feeding against the will of the patient

• Feeding against the will of the patient should be an intervention of last resort in care and should only be done in the context of the Mental Health Act 1983 or Children Act 1989.

Post-hospitalisation treatment in adults

• Following discharge, extend the duration of psychological treatment over that normally provided to those who have not been hospitalised, typically for at least 12 months.

• Offer outpatient psychological treatment that focuses on both eating behaviour and attitudes to weight and shape, and on wider psychosocial issues, with regular monitoring of both physical and psychological risk.

Anorexia nervosa –physical management

Anorexia nervosa carries considerable risk of serious physical morbidity. Awareness of the risk, careful monitoring and, where appropriate, close liaison with an experienced physician, are important in the management of the physical complications of anorexia nervosa.

Managing weight gain

• Aim for an average weekly weight gain of 0.5–1 kg in inpatient settings and 0.5 kg in outpatient settings. This requires about 3500 to 7000 extra calories a week

• Provide regular physical monitoring and consider multivitamin/multimineral supplementation in oral form for both inpatients and outpatients.

• Total parenteral nutrition should not be used unless there is significant gastrointestinal dysfunction.

Managing risk

• Inform patients and their carers if the risk to their physical health is high

• Involve a physician or paediatrician with expertise in the treatment of medically at-risk patients for all individuals who are at risk medically.

• Consider more intensive prenatal care for pregnant women to ensure adequate prenatal nutrition and fetal development.

• Oestrogen administration should not be used to treat bone-density problems in children and adolescents as this may lead to premature fusion of the epiphyses.

• Healthcare professionals should advise people with eating disorders and osteoporosis or related bone disorders to refrain from physical activity that significantly increases the likelihood of falls.

Additional considerations for children and adolescents

The involvement of families and other carers is particularly important.

The right to confidentiality of children and adolescents with eating disorders should be respected.

Family members, including siblings, should normally be included in the treatment of children and adolescents with eating disorders. Interventions may include sharing of information, advice on behavioural management and facilitating communication.

Anorexia nervosa

• Family interventions that directly address the eating disorders should be offered to children and adolescents with anorexia nervosa.

• Offer children and adolescents individual appointments with a health professional separate from those with their family members or carers.

• For children and adolescents, once a healthy weight is reached, ensure increased energy and necessary nutrients are available in the diet to support growth and development.

• Involve carers of children and adolescents in any dietary education or meal planning.

Inpatient care of children and adolescents with anorexia nervosa

• Inpatient care of children and adolescents should be within age-appropriate facilities (with the potential for separate children and adolescent services), which have the capacity to provide appropriate educational and related activities. They should also balance the need for treatment and urgent weight restoration with the educational and social needs of the young person.

• Consider using the Mental Health Act 1983 or the right of those with parental responsibility to override the young person’s refusal to receive treatment that is deemed essential.

• Seek legal advice and consider proceedings under the Children Act 1989 if the patient and those with parental responsibility refuse treatment where treatment is deemed essential.

Bulimia nervosa

Following the initial assessment consider:

• As a possible first step, an evidence-based self-help programme – direct encouragement and support to patients undertaking such a programme may improve outcomes. This may be sufficient treatment for a limited subset of patients.

Psychological treatment should form the key element of treatment, so consider:

For adolescents: Cognitive behavioural therapy for bulimia nervosa (CBT-BN) adapted as needed to suit their age, circumstances and level of development.

Where there has been no response to CBT or it has been declined: other psychological treatments,particularly interpersonalpsychotherapy (IPT). (Note: patients should be informed that IPT takes 8–12 months to achieve results comparable with CBT-BN).

Medication may have a role

• Consider a trial of an antidepressant drug as an alternative or additional first step to using an evidence-based self-help programme.

• In terms of tolerability and reduction of symptoms, SSRIs (specifically fluoxetine) are the drug of first choice for the treatment of bulimia nervosa.

• The effective dose of fluoxetine may be higher than for depression.

• Beneficial effects will be rapidly apparent and are likely to reduce the frequency of binge eating and purging, but the long-term effects are unknown.

• No drugs, other than antidepressants, are recommended for the treatment of bulimia nervosa.

Physical management

• Assess fluid and electrolyte balance where vomiting is frequent or there is frequent use of laxatives.

• If electrolyte balance is disturbed, consider behavioural management as the first option

• If supplementation is required, use oral rather than intravenous preparations.

Bulimia nervosa – inpatient or day care

• Consider inpatient treatment for patients with risk of suicide or severe self-harm.

• Admit patients to a setting with experience of managing this disorder.

PROGNOSIS 17

If untreated, anorexia nervosa carries high mortality rates of

10-15%. If treated, one third have full recovery, one third partial recovery and one third have chronic problems. Poor prognostic factors for anorexia nervosa include: chronic illness, late age of onset, bulimic features such as vomiting and purging, anxiety when eating with others, excessive weight loss, poor childhood social adjustment, poor parental relationships and male sex.

Prognosis for Bulimia nervosa is generally good, unless there are significant issues of low self esteem or evidence of severe personality disorder.

USEFUL RESOURCES

National Eating Disorder Association
Tel: 0800 931 2237
Website: www.nationaleatingdisorders.org
 
Royal College of Psychiatrists
17 Belgrave Square
London SW1X 8PG
Tel: 0171 235 2351
Website:www.rcpsych.ac.uk

 

Acknowledgements / Conflicts / Author Details
Competing Interests: 
<p> None declared</p>
Details of Authors: 
<p> Dr. Fayyaz Khan, MBBS, CT3 in Psychiatry. South Essex Partnership Trust.<br /> Dr. Uttom Chowdhury, MRCPsych, Consultant Child and Adolescent Psychiatry. South Essex Partnership Trust.</p>
Corresponding Author Details: 
<p> Dr. Fayyaz Khan, MBBS, CT3 in Psychiatry. South Essex Partnership Trust</p>
Corresponding Author Email: 
fayyaz.khan@sept.nhs.uk
References
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