Dec

INTRODUCTION

The concept of burnout has been used to describe emotional and psychological stress among healthcare workers in response to work-related stressors¹. Maslach et al² have defined burnout as a triad of characteristics: emotional exhaustion, depersonalisation (such as objectifying and treating patients indifferently) and lack of feelings of personal accomplishment. Since high time-pressure, high job- stress and excessive workload with poor support are among significant factors that contribute to burnout, physicians are at a greater risk of suffering from it as compared to the general population³.

Burnout affects approx. half of the doctors in the U.S. and in Western Europe working across multiple specialties including in family medicine and internal medicine^4,5. Likewise, burnout is universally prevalent among healthcare workers from low and middle-income countries⁶.

Psychiatry presents specific range of stressors not encountered concurrently in other medical specialties, such as treating chronically ill patients, potentially difficult therapeutic relationships, threat of patient suicide/self-harm and stigma associated with this field of medicine⁷. Therefore, it is not surprising to discover that approx. 37% of psychiatric trainees working across 22 countries suffered from severe burnout⁸.

The COVID-19 pandemic resulted in a national lockdown in the U.K. with travel restrictions and unprecedented pressure on an already stretched healthcare system. Healthcare workers were, therefore, faced with extraordinary difficulties including increased working hours, heavy workload, staff shortages and lack of resources. A recent systematic review showed that a startling 40% of medical workers experienced acute stress disorder following COVID-19 pandemic, with burnout prevalent among 29% of them⁹.

During to the pandemic, there has been a huge increase in the pressure on mental health related admissions to hospitals¹⁰. A number of causative stressors may have instigated further strain on mental health workers, including bereavement, unemployment, and isolation, resulting in increased psychological morbidity¹¹. Under such circumstances, ensuring the wellbeing of healthcare workers is of paramount importance to maintain a resilient healthcare system. However, limited research has been carried out so far on the effects of pandemics on psychiatrists and other frontline healthcare workers.

Following two surges of COVID-19 pandemic, we proposed to ascertain the frequency of burnout among doctors working in a large mental health trust in Southeast England, with a secondary aim of exploring possible contributory factors.

METHODOLOGY

We carried out a cross-sectional survey of all doctors working in a county-wide mental health Trust in England. Using the NHS Mail, a link to complete the online survey was sent to all doctors working at different experience levels and across a number of psychiatric specialties.

The survey was based on The Maslach Burnout Inventory¹², which is considered to be a gold standard in assessing burnout among healthcare workforce. It consists of 22 questions, divided into domains that assess emotional exhaustion, depersonalisation and personal accomplishment based on a 7-point scale, ranging from “never” to “every day”. Scores for these domains range from 0 to 54, 0 to 30, and 0 to 48, respectively. High scores on the EE (≥ 30) and DP (≥ 12) subscales or a low score on the PA subscale (≤ 30) were considered highly suggestive of burnout symptoms.

The anonymised survey contained questions related to demographics, 22 questions as derived from the Maslach Burnout Inventory, and 14 other questions exploring specific work-related stressors regarding the COVID-19 pandemic. Responses to the questions were analysed and categorised into themes to allow further analysis and discussion.

RESULTS

Our response rate was 42% as 106 out of 254 doctors filled the questionnaire. Not all participants answered all questions, and response numbers for each question are indicated where applicable in the respective tables. There was an even distribution between trainees and consultants, but less representation from speciality doctors, which was expected due to their fewer numbers. Where gender was equally split, we found that age was relatively evenly distributed in our sample.

Figure 1: Participant demographics

Regarding the Maslach Burnout Inventory questions, higher aggregates in emotional exhaustion and depersonalisation subscales indicate higher chance of burnout. When comparing these two subscales, the levels of emotional exhaustion were higher than that of depersonalisation. Conversely, in the personal accomplishment subscale, more common occurrences indicate a lower chance of burnout.

Table 1: Maslach Burnout Inventory Results

In other quantitative questions, all respondents reported that their screen time had increased during the pandemic. A majority reported it to be by more than 2 hours/week, and 71% registered an increase of more than 4 hours/week. Despite this, there appears to be no increase in their home-working that could account for this difference.

The results of the remaining questions reflected a poorer work experience. The strongest evidence was for a feeling that mask wearing had affected rapport with patients. Other more common experiences included poor outcomes for patients during the pandemic, with decreased staffing levels, increased workload, and delayed treatments.

Table 2: Other Question Responses – Quantitative only

DISCUSSION

Our study provides a snapshot of difficulties encountered by different grades of psychiatrists, while working in a large English county, during the COVID-19 pandemic. We found a burnout rate of 44.2%, which is higher than 36.7% observed by Jovanović et al⁸ among those working in other countries before the pandemic. Since a higher prevalence is also documented in other recent studies¹³, it is reasonable to assume that the higher rate of burnout is due to increased work-related stressors during the COVID-19 pandemic. These stressors could be linked to the newly introduced guidelines, which involved social distancing, high staff sickness and redeployment.

In the personal accomplishment subset of our study, highest number of doctors experienced burnout, possibly suggesting a link to the COVID-19 pandemic. Unfortunately, we do not have a pre-COVID pandemic survey for the sake of comparison, which could have confirmed causality with greater certainty.

71% of our cohort reported an increase of more than 4 hours of computer screen time a week, which was not due to increased amount of working from home. Various factors could explain this finding including the introduction of remote medical consultations, online multidisciplinary team meetings and teaching/training. Virtual consultations may provide an alternative to face-to-face assessments, but complications such as difficulty in discussing sensitive topics and demonstrating empathy could influence therapeutic relationship, medical errors, and screen fatigue resulting in increased levels of burnout^{14, 15}.

A compromised professional identity and reduced job satisfaction are considered among significant predictors of job burnout^{16, 17}. It is, therefore, reasonable to question whether the increased screen time and reduced patient contact could have impacted the professional identity of our cohort and their job satisfaction. This could also provide possible explanation for our cohort scoring highly for low personal accomplishment. However, one study that examined burnout in medical residents, who had used virtual telemedicine to replace outpatient clinics, found that the burnout actually decreased with increased use of virtual consultations¹⁸. Therefore, more consideration and research needs to be conducted on telemedicine practices in different medical subspecialties and their impact on medical professionals’ working lives.

Burnout is associated with an increase in clinical errors and may manifest in irritability, fatigue, and reduced cognitive functioning that ultimately result in a reduction in quality of patient care^12,19. Medical errors on the other hand cost the National Health Service (NHS) £3.3 billion in litigation costs and additional bed days due to both systemic and individual factors²⁰. Overall, 41% of our cohort were dissatisfied with remote consultations and the care provided to their patients during the pandemic. The reported difficulties with providing good patient care primarily consisted of poorer quality of and reduced patient interaction, patients being unable to engage with services and delayed treatments.

Wearing face masks could affect both verbal and non-verbal communication that in turn hinder the therapeutic relationship, as previous research has shown that patient engagement, understanding and treatment success are influenced by a clinician’s facial expressions²¹. Poorer patient outcomes found in our study could partly be due to the difficulties experienced during the pandemic as approx. 62% of our cohort felt that face masks affected their rapport with patients. Other factors that could have contributed to these poorer outcomes include redeployment of staff due to NHS pressures and reduced services. Further work is, however, needed to ascertain the associated casual pathway.

During the height of pandemic, carrying out frenetic clinical work with limited resources and little respite, coupled with the loss of loved ones and colleagues, could have undoubtedly impacted the mental health of medical workforce including psychiatrists. On the other hand, the pandemic may have also heightened the sense of vocation for some doctors. It is, therefore, difficult to assess the lasting effects of burnout until the pandemic is finally over and we resume normal therapeutic practices, in both clinical and personal settings.

Introduction

Lung carcinoma the most common malignancy worldwide, presents as a metastatic disease in majority of the cases. The most frequent sites of distant metastases are liver, adrenal glands, bones, and brain. Skeletal muscle metastasis is an unusual presentation of lung adenocarcinoma.

Case report

A fifty three year old male patient, labourer by occupation, beedi smoker for twenty five years, admitted to tertiary care hospital with pain and swelling over left arm, cough and expectoration for the past two months, accompanied with significant weight loss. There was no evidence of chest pain or haemoptysis. On local examination there was hard swelling over extensor compartment of left upper limb with mild tenderness, no loss of sensation and mild restriction of range of movements on flexion at elbow. Respiratory and other systemic examination was within normal results. Plain CT of thorax defined multilobulated lesion in right perihilar location in right middle lobe (Figure 1).

Figure 1: CT of Thorax: Well defined multi-lobulated lesion in right perihilar location in right middle lobe measuring 2.9 x 2.4 cm.

USG of left arm showed an irregular heterogenous soft tissue lesion noted within the triceps muscle with few areas of intra-lesional necrosis, MRI of left arm showed lobulated lesion in posteromedial aspect of mid and distal arm, involving triceps muscle, medial aspect of brachialis, encasing brachial artery, veins and median nerve (Figure 2).

Figure 2: MRI of Left arm: Well defined irregular lobulated enhancing T1 hypo intense, T2 and T2 flair hyperintense lesion in the posteromedial aspect of mid and distal arm.

PET scan showed enhancing nodular soft tissue lesion noted in middle lobe of right lung, 2.9 x 2.4 centimetres. Biopsy revealed metastatic adenocarcinoma. For further studies Immunophenotyping was done which showed negative for EGFR and ALK. Patient was treated with palliative RT, Pem-Carbo f/b Pemtrexed maintenance and recently 3# of Gemcitabine. The patient died of metastasis to brain within eight weeks of diagnosis.

Discussion

Lung carcinoma is a leading cause of cancer-related mortality. The most common sites of distant metastasis in lung carcinoma are brain, bones, the liver, and the adrenal gland¹. The most common tumours that cause skeletal muscle metastasis are tumours originating from thyroid, oesophagus, stomach, pancreas, colon, rectum, bladder, breast, ovary, and prostateand skeletal muscle metastasis of lung carcinoma was first reported by Fisher ER². Willis RA reported four skeletal muscle metastases in their autopsy series composed of 500 lung carcinoma patients³. Skeletal muscle metastasis is a rare occurrence for any tumour with a reported incidence lees than one percent^4-5. The most common sites of muscle metastasis are thigh muscles, iliopsoas, and paraspinous muscles⁶.

The mechanism of skeletal muscle metastasis is unclear. Despite its rich vascular blood supply and a large mass in the body, it is resistant to haematogenous metastases. Organs that are frequently metastasized, including liver, lung, and bone have rich capillary networks and blood supply. As a result of the muscle metabolism, substances such as lactic acid, free oxygen radicals, and low pH in the environment constitute an infertile medium for proliferating tumour cells. In addition, mechanical insults due to contractions, high tissue pressure, and widely alternating blood flow are also against the survival of tumour cells⁷.

There are several hypotheses proposed for skeletal muscle metastasis in lung carcinoma. The most widely accepted hypothesis is the haematogenous route. In this hypothesis, it is believed that tumour cells are formed through tumour embolism. Some authors suggested that skeletal muscle metastases might originate from abnormal lymph nodes found in the muscle. In a study by Bocchino M et al. 1754 lung carcinoma patients treated between 2007 and 2012 were analyzed and forty six (2.6%) had skeletal muscle metastasis⁸. Despite the variations between different studies in terms of the association between histological subtypes and skeletal muscle metastasis, forty patients in that study (87%) had non small cell lung carcinoma and six had (13%) small cell lung carcinoma. Among non small cell lung carcinoma patients, twenty four (60%) had adenocarcinoma. The most common initial manifestation of skeletal muscle metastasis is a pain. Pain can be accompanied by extremity swelling. The case presented herein also applied with pain and swelling. Diagnostic methods for skeletal muscle metastasis are not specific. Direct films usually show only soft tissue shadows. MRI usually reveals hypointense signal in T1 and hyperintense signal in T2. MRI is preferred to distinguish soft tissue metastasis from an abscess, sarcoma, and other conditions⁹, similarly; our patient had hypointense signal on T1 and the hyperintense signal on T2 series. The optimum treatment and prognosis of skeletal muscle metastasis from lung cancer is unclear. Depending on the clinical characteristics, treatment options include observation, surgery, chemotherapy and radiotherapy.

Conclusion

Lung carcinoma with skeletal muscle metastasis should be considered as a potential differential diagnosis in patients presenting with an intramuscular mass.

Acknowledgements

Authors acknowledge the immense co-operation received by the patient and the help received from the scholars whose articles are cited and included in references of this case report. The authors also acknowledge the authors/editors/publishers of all those articles, journals and books from where the literature for this case report has been reviewed and discussed.

Introduction

There have been continuing initiatives to transform and improve the National Health Service (NHS) in recent years. Mental health services in England have similarly shown evolution with regards to service provision. There has been a shift away from the perceived “medicalisation” of treatment, with traditional long-stay institutions replaced with more targeted and personalised care in the community.¹ Furthermore, community services themselves have seen much remodelling over the years including decommissioning and integration, as well as increased involvement in outreach and early intervention teams.²

Mental health services are sometimes perceived as relatively well funded from outside but, as with most healthcare sectors, compared to the population requiring this service, these resources are inadequate to support the growing demand. This has been the case for some time, but it has become more evident with a significant reduction in funding observed since 2010/11.¹ In addition, constant governmental pressures to meet key performance targets, as well as unachievable expectations from the public, have further stretched an already resource-depleted mental health service.

The implementation of new National policies³ was supposed to be a shift from large psychiatric hospitals to smaller specialist community centres with a promised reduction in the demand placed on inpatient services. In England, a peak number of 150,000 inpatient psychiatric beds was reported in 1955; this has since rapidly declined to 22,300 in 2012. Between 2010/11 and 2013/14, a further rapid reduction of 7% of all beds available was seen.⁴

Despite the promise of changes in service delivery within mental health to mitigate the continued reduction in the number of inpatient beds, demand for inpatient beds has not in fact reduced nationally.¹ The recommended level of occupancy, for example, is 85% but 119 wards surveyed⁵ were operating at 91%, with some at 138% level of occupancy. The occupancy levels of over 100% usually occurred when long-stay inpatients were discharged home on short-term leave and their beds got filled during their absence.⁴ Where numbers of inpatient beds fail to meet the demands, or waiting list for their first assessment or review grows, the inadequacy lends these facilities to issues with regard to providing high quality and safe patient care. Examples of this may include inappropriate use of the Mental Health Act for detention of patients as a means of securing an inpatient bed,⁵ incomplete assessments of people detained in places of safety due to time or space constraints,⁶ and an increase in violent incidents on overcrowded inpatient wards.⁷

What is a Crisis Resolution and Home Treatment Team (CRHTT)?

In the late 1980s and 1990s, community mental health teams provided acute crisis support. This posed a number of issues including that these teams usually operated during normal working hours of 9am-5pm (Monday to Friday) and were not always available to provide support to patients in a crisis, and did not have the desired impact of reducing the number of acute admissions.⁸ This gap in service provision inspired the experimentation with and subsequent development of intensive home treatment services, some of which showed evidence of reduced hospital admissions, and holistic-working often preferred by families who were happy to have their loved ones receive the required support in the home environment.⁹ Over the last two decades, with remodelling of services, increased investment, NHS funding rising from £49 billion in 2000 to £122 billion in 2016, and a migration of mental health professionals, CRHTTs were established and are now available in every mental health trust across the United Kingdom (UK).¹⁰

CRHTT is a team of mental health professionals including psychiatrists, community psychiatric nurses, social workers and support workers, who provide rapid and intensive support at home during a mental health crisis.¹¹ They are a 24-hour service operating seven days a week, and acting as the “gatekeeper” for acute services accepting referrals from various sources including inpatient, community, liaison and from outside the Trust for providing support to patients experiencing crises. These teams risk-assess patients and determine whether they require inpatient or home treatment. In the latter case, CRHTTs provide intensive home treatment by offering up to 2-3 visits a day as well as 24/7 phone support. These teams are also involved in facilitating early discharges from hospitals; in cases where patients are past the initial acute crisis, but may need further input prior to discharge to community mental health teams for longer term support.⁸

Definition of diagnosis and second opinion.

A second opinion is defined as “advice from a second expert (such as a doctor/psychiatrist) to make sure advice from the first such expert is correct” whilst diagnosis is defined as “the art or act of identifying a disease from its signs and symptoms”.¹² Due to increased pressure on inpatient facilities and remodelling of community services, there has been a huge increase in the number of referrals made to CRHTTs. Between 2011/12 and 2013/14, it has been noted that referrals to CRHTTs increased by 16%.¹³ Reduction in inpatient beds and high workloads within community services often result in the formulation of arbitrary diagnoses and treatment plans. With increased pressures on other mental health services, the role of CRHTTs has begun to evolve. In addition to the previously discussed functions, CRHTTs appear to be becoming second opinion services by default enabled by the psychiatrists working in these teams.

We organised a project to establish whether a typical CRHTT is fulfilling the criteria of being a diagnostic or second opinion service provider.

Method

We examined 100 consecutively accepted referrals to a CRHTT from 1^st December 2016. The patients were divided into three groups: those being discharged/referred from hospital (HR), those referred from the community (CR), and those who were not open to secondary mental health services at the time of referral (NR). The age range and gender of the groups were noted. Thereafter, the NR group was excluded from analysis for the obvious reason that the CRHTT was not providing a second opinion in their case. The HR and CR groups were further reduced by excluding patients who were not seen by a CRHTT psychiatrist. The remaining patients in both groups were scrutinised regarding a change in medication; this was also recorded for the previous and next care occasions. The likelihood of medication change at the next treatment event was analysed to establish whether it was affected by the previous event. The numbers of patients with CRHTT diagnosis change were also recorded for both groups.

Results

Figure 1: Project Flowchart

Figure 2: Group Demographics

There was little difference in age between the three groups (average ages were: CR=37.8, HR=39.0, NR=36.0). There was a lower proportion of men in the CR group than were present in the HR and NR groups (36% as against 48% and 47%). Whether a psychiatrist saw a patient appeared to be related to both the referral source and the length of CRHTT stay. Most (n=16, 76%) patients in the hospital-referred group (HR) were not seen by a psychiatrist while most (n=24, 67%) of those referred from the community (CR) did receive such an outcome. No community-referred patient was seen by a psychiatrist if they were with the CRHTT for less than a week. These short-stay patients accounted for 7 out of the 12 community-referred patients who were not seen. This suggests that a psychiatric assessment should be scheduled more quickly after community referrals so as to offer patients a more comprehensive service.

Psychiatric assessment led to changed diagnoses for 28% (8/29) of patients. This figure was 40% (2/5) for the HR group and 25% (6/24) for the CR group.

Medications were changed for 69% (20/29) of patients seen by a psychiatrist. In the subgroups; 60% (3/5) of HR psychiatric assessments resulted in a change of medication while 71% (17/24) of CR psychiatric assessments led to medication changes.

The chi-square statistic was used to evaluate whether a recent medication change, during the inpatient stay or at the most recent outpatient appointment, made the CRHTT less likely to adjust medication. This indicated that there was no relationship between the two events. A similar analysis indicated that the likelihood of a medication change at the patient’s next community appointment was increased by seeing a CRHTT psychiatrist but unrelated to whether that assessment had resulted in a change of medication.

Discussion

We have demonstrated in this study that a typical CRHTT is providing a diagnostic and second opinion service. Changes in medication were more than twice as frequent as changes in diagnosis – this is perhaps unsurprising as diagnostic changes would be likely to require a different prescription.

Most community referrals were actively evaluated in terms of both diagnosis and treatment. This is a significant change to the original function of the CRHTT where a psychiatric assessment was not a standard aspect of care when very few of the original CRHTTs included a psychiatrist. This may also reflect the current pressures on community teams, which are frequently short-staffed, leading to more competition for the available clinic appointments. Consequently, patients may not have seen a psychiatrist for some time and their requirements may have changed. It is, however, also known¹ that community patients who have not been reviewed recently or who have a long wait before their first assessment are more likely to present in crisis.

The diagnostic and second opinion function of the CRHTT is more prevalent when patients have been referred by the community team (67% reviewed, 47% medication changed) rather than on discharge from hospital (24% reviewed, 14% medication changed). This appears to largely reflect the fact that relatively few discharges were seen by the CRHTT psychiatrist because these patients had just received a full consultant-led discharge treatment plan. This may be another example of community service pressures leading to patient crises and thus engagement with alternative services – in this case inpatient care may be offering a second opinion service. The current separation of community and inpatient services will augment this effect as previously the patient would have been more likely to receive continuous care from the same consultant. This is an interesting view of current service configuration. The reduced continuity of care is often seen as a disadvantage but it does present an opportunity for a fresh evaluation of a patient’s diagnosis and medication by a different psychiatrist.

Longer lengths of stay with the CRHTT made psychiatric assessments more likely. It was particularly clear that discharge within a week made a psychiatric review unlikely. The proportion of community-referrals seen by a CRHTT psychiatrist could be increased to 83% if patients were to be seen within 24 hours. This figure is derived from the assumption that psychiatrists would then see the same proportion of both long and short stay patients. The residue would include those patients who refuse to engage with such an appointment.

It is interesting that chi-square statistical analysis suggests that the only influence on prescription change at the next appointment is whether the patient was seen by a CRHTT psychiatrist. It is not related to whether or not the CRHTT psychiatrist changed the medication. It is difficult to see why this should be the case unless the community psychiatrists consider the patients’ needs in more detail or are tempted to regain control after the referral to another psychiatrist.

In conclusion, the addition of psychiatric care to CRHTTs may be a valuable adjunct to the current pressures on community teams. The current trend to separate community, inpatient and CRHTT care is often cited as a disadvantage due to reduced continuity of care for patients. This project has drawn attention to the fact that it also offers opportunities for new teams to re-evaluate both diagnosis and treatment which offers patients the advantage of an internal second-opinion service. This advantage could be offered to more community-referred patients, albeit with more resources, by ensuring that they are assessed by the CRHTT psychiatrist within 24 hours.

Limitations

This is a small study conducted in a single CRHTT. It does, however, offer an indication of the evolving role of the CRHTT and its relationship to other services.

My countryside

home is where the heart is

at its gladdest and lightest,

like a hot air balloon

floating gently over

emerald green fields

and golden dirt tracks.

My rustic

home is where the heart is

far from health services,

far from those specialists –

like cardiologists –

who can stop diseases in

their concrete-covered tracks.

My bucolic

home is where the heart is

more likely to fail –

liable to stop beating

earlier than all those

hearts that thump out their

rhythms in the city.

My rural

home is where the heart is

woven into the patterned fabric

of a vibrant community,

whose median age

keeps rising and rising

as fond memories fade.

My countryside

home is where the heart is

destined to be

till its last beat.

Introduction

In the UK, all newly graduated doctors spend their first two years of work rotating between different specialities, usually spending four months in each placement, before applying for speciality training. This period is called the Foundation Programme.

In January 2016, the Royal College of Psychiatrists published its first ever strategy on Broadening the Foundation Programme to address the need to improve the psychiatric training experience for foundation doctors. The strategy’s aim is to “ensure the delivery of a high-quality training experience in all psychiatry foundation placements”.¹

Over the last few years, the number of Foundation training posts in psychiatry in England and Wales has significantly increased. Health Education England aims that all Foundation doctors should rotate through a community or an integrated placement (psychiatry is considered as a community placement) from August 2017.²

As such, the College highlights the need to provide a supervised and well-structured psychiatric training experience for Foundation doctors. This aims not only to improve recruitment into psychiatry but also to ensure doctors have a good working knowledge and understanding of psychiatry and psychiatric services, no matter what career they pursue.

Mentoring provides an additional support and therefore can be helpful to improve the placement of Foundation doctors in psychiatry.

We implemented an ambitious mentoring scheme in Norfolk and Suffolk NHS Foundation Trust (the seventh largest mental health trust in the UK). The paper describes its essential component together with a brief review of the literature on mentoring in clinical settings, focusing on Foundation placements.

Why is mentoring is needed for Foundation doctors in psychiatry?

The literature on mentoring for medical professionals draws attention to the idea that it is beneficial to all doctors at all stages of their career to experience mentoring in some form or another. However, mentoring is of particular importance to doctors moving to a new job or organisation ³, thus making it highly relevant to Foundation trainees.

For newcomers, most of the mentoring support will focus on helping them settle into their new role, becoming familiar with, and developing an understanding of the expectations of their employers.⁴

Evidence shows that the quality of care in any organisation can be improved when clinical leaders support time for activities such as reflection, coaching and mentoring ⁵.

Most Foundation doctors will lack experience in psychiatry and will need a substantial amount of guidance from their supervisors and their teams.⁶ Research has shown that the transition from student to doctor is a difficult one and can be associated with significant levels of emotional stress.⁷

Foundation doctors find psychiatric assessments physically and emotionally challenging. They feel they lack the specialist knowledge and skills to deal with complex patients, especially concerning self-harm, personality and eating disorders. Dealing with such complex diagnostic categories requires knowledge, skill, understanding as well as physical and emotional robustness. Due to the relative lack of focus on such topics in most undergraduate medical training, a comprehensive support in psychiatric placements is essential.

Psychiatry is very different from other specialities in the way services are configured and delivered: junior doctors may face isolation as psychiatric units are typically spread across a wide geographical area and often lack a centralised meeting place for junior doctors (e.g. a doctors’ mess). In addition, they may find themselves the lone practitioner when on call, which can be daunting for many.

Clinical and Educational supervision is provided to Foundation doctors in similar ways to other rotations. However, the consultants delivering this essential support often focus only on clinical issues related to knowledge and skills. Furthermore, it is easy to see that the best guides to new trainees regarding the idiosyncrasies of the speciality and its services are likely to be trainees who have spent some time in those services and are more able to detect the specific stresses new doctors may experience and may find difficult to articulate.

Furthermore, mentoring fosters a productive peer-to-peer relationship. The learning needs of the Foundation doctor can be considered alongside their personal and professional interests and lifestyle. Questions can be posed in a non-judgmental forum, without fear of being ridiculed or condemned. The fundamentals of on-call systems, clinical cases and management options can all be considered at a level appropriate to their junior grade. Tips for examination success and information about essential courses and core texts can be shared. Job choices and research opportunities can be discussed. Day to day difficulties and mismatches between expectation and reality can be identified and possibly overcome. Where this is not possible next steps can be identified, and clinical and educational supervisors can be drawn in for higher level support. The benefits of the scheme are broad.

Finally, although mentoring is different from role-modelling (teaching by example and learning by imitation), it has been shown toserve some of the same aims of role-modelling, including enhancing problem-solving abilities of the mentee, improving professional attitudes, showing responsibility and integrity, and supporting career development. ⁸

What is mentoring?

Mentoring can mean different things to different people. There are various definitions which can create confusion between mentoring and other formal structures of support such as supervision, coaching, consultation, befriending or friend systems and even counselling. However, mentoring is none of the above but at the same time a combination of them.

The Standing Committee on Postgraduate Medical and Dental Education (UK) defined mentoring as ‘The process whereby an experienced, highly regarded, empathetic individual (the mentor) guides another individual (the mentee) in the development and re-examination of their ideas, learning, and personal and professional development”.⁹

The term “mentoring” takes us back to Greek mythology: Mentor was a person: he was the friend of Odysseus who was asked to look after Odysseus’ son Telemachus when Odysseus was fighting in the Trojan Wars. The name Mentor was later used to describe a trusted person, a supporter, or a counsellor.¹⁰

Mentoring as a professional developmental tool became popular in the private sector organisations in the USA during the 1970s and was introduced to the area of health during the 1990s ¹¹. Since then, it has been widely used in various organisations.

Aims of mentoring

Mentoring has the advantage of being a flexible supporting tool, unlike other structured processes (e.g., clinical supervision or coaching) where the goals are set clearly from the start of the relationship between the supervisor and supervisee. The aims of mentorship are summarised in Table 1.

Types of mentoring

Buddeberg-Fischer and Herta ¹¹ discussed various types of mentoring based on the numbers of mentors and mentees and their professional status or grade:

1. One to one mentoring (between a mentor and a mentee).
2. Group mentoring (one mentor and a small group of mentees)
3. Multiple-mentor experience model (more than one mentor assigned to a group of mentees).
4. Peer-mentoring (the mentor and mentee are equal in experience and grade): This mentoring is used mainly for personal development and improving interpersonal relationships. Mentor and mentee roles can be reversed. Also, called ‘co-mentoring’.

Distance or e-mentoring is becoming more popular, and it has the advantages of being “fast, focused, and typically centred on developmental needs”. ¹²

Structured vs. flexible mentoring

Evidence suggests that providing mentorship through a rigid and structured process can be counterproductive. ¹³ Mentors and mentees usually work in different locations, making it difficult for both to have a set of pre-planned meetings and topics for discussions.

Another advantage of the flexibility of mentoring is that it does not follow a “tick box” exercise but encourages informal discussions and exploration of whatever comes to mind during meetings. Doubtless, having some structure to the overall mentoring process is important as it ensures that the mentoring session doesn’t become an informal befriending or friend support system. Table 2 sets out the main benefits of mentoring.

Table 2-Benefits of mentoring. Developed from Mentoring – Chartered Institute of Personnel and Development (CIPD) Factsheet. Revised February 2009 ¹⁴. Available from: https://www.shef.ac.uk/polopoly_fs/1.110468!/file/cipd_mentoring_factsheet.pdf

Are there any Disadvantages of mentoring?

There is extensive literature on the benefits of mentoring, but is there any harm associated with it?

As with any intervention, it does carry some potentially adverse effects. Mentoring can be perceived to “infantilise” junior employees rather than empowering them ¹⁰. This perception is probably more common among employees who see themselves as senior or very competent and think of themselves as able to adapt to change very quickly.

Mentoring might hinder creativity in new employees and inhibit them from thinking “outside the box” as it might re-enforce the message that ‘this is how we do things here’. ¹⁰

Clashes of personalities or other interpersonal factors could lead to a troubled mentor-mentee relationship and cause distress to both parties. Hence, plans must be put in place in any formal mentoring scheme to ensure an amicable ending to this relationship. Multiple mentor allocation mentioned earlier could also prevent such interpersonal problems and help to tackle them early on.

Furthermore, some mentees may feel uncomfortable with the influence or authority of the mentor, and this may hinder the progress of the mentoring relationship. ¹³ This is particularly relevant when the mentor is also involved in the formal assessment of the performance of the mentee (e.g. being the line manager or supervisor) or when a mentee who lacks self-confidence is paired with an overconfident mentor.

Good mentors avoid common pitfalls in the mentoring process, such as a patronising attitude, breaches of confidentiality and offering direct advice to the mentees. Instead, they encourage the mentee to reflect and come up with their answers. ¹⁵

Finally, mentoring can be perceived as an additional demand on doctors during their training, and some may feel that they are forced to provide it or receive it during placement. However, it must be remembered that mentoring should always be voluntary and flexible to meet the individual’s needs and not an additional ‘box to tick’ or a portfolio enrichment exercise.

The Mentoring Scheme for Foundation Doctors in Psychiatry Norfolk:

The scheme started in December 2015 and initially ran as a pilot in Norfolk with the support of all stakeholders. The mentoring scheme coordinator (YH) contacted twelve Foundation doctors by email, welcoming them to the Trust and inviting them to participate. The welcome email contained information about mentoring, including the benefits it may offer.

The voluntary nature of this scheme was highlighted so that the doctors didn’t feel they were being pressured to be enrolled.

Of the 12 doctors invited, five took up this opportunity. Uptake has remained constant over the consequent cohorts of Foundation doctors for many reasons. Those deciding not to enrol in this scheme explained that they felt happy with the support provided by their clinical supervisors. However, some doctors asked for a mentor halfway through their placement when they felt that they needed additional support. In these instances, a mentor was allocated to them as soon as possible.

Mentors were core and higher trainees already involved in supporting more junior psychiatric trainees through informal mentoring. Their experience meant there was no need for formal training. However, reading material was circulated to them to highlight the roles and responsibilities of mentors and what to do if any problem arose during mentoring. Monthly mentors’ meetings were very helpful to discuss issues arising in mentoring and offer peer to peer support.

Also, there were regular meetings and discussions between the mentoring coordinator, the Director of Medical Education, and Medical Director of the Trust to resolve any issues facing the Foundation doctors and provide feedback to improve the Psychiatric placement.

During the first meeting, the mentors and mentees agreed on the aims of mentoring drawing up a list of objectives that the Foundation doctor would like to achieve by the end of the placement. Following this initial meeting, there should have been once monthly face to face meetings throughout the placement. The mentor and mentee agreed on the most convenient means of communication (e.g. using text messages, emails, etc.) outside scheduled meetings.

All mentors kept a record of the mentoring meetings, with the mentoring coordinator informed about these meetings. Issues discussed were confidential and not shared with the coordinator or supervisors unless the mentee gave specific consent.

At the end of the mentoring scheme, the coordinator collected feedback from mentees and mentors using a structured questionnaire that was designed by the coordinator using SurveyMonkey® website. The feedback highlighted the positive aspects of mentoring as well as areas for improvement.

End of mentoring survey

Mentors reported that acting as a mentor without being involved in clinical supervision allowed them to offer objective advice and support in a way that would have been harder if they were directly involved in the workplace. One Foundation doctor experienced bullying from another member of the team who was a locum doctor. The mentor supported the Foundation doctor, and the issue was addressed and resolved promptly. There was a significant risk that they would have been left isolated and unsupported during this time if the mentor scheme had not been in place.

The topics discussed were varied, and this suggested that mentoring was not limited to a aspect of the job (see Table 3)

Mentees reported that they found mentoring useful and supportive of learning and development. This was especially important in a speciality that they had little experience of as an undergraduate. With a mentor in Psychiatry, the Foundation doctors reported that they could identify areas of development, including leadership and teaching opportunities for Foundation doctors.

Overall, mentoring was shown to be a useful tool to improving Foundation doctors’ experience in Psychiatry by offering extra support during placement in a challenging medical speciality.

Table 4 summarises the areas of development suggested by the mentors and mentees.

Limitations

Feedback from mentors and mentees showed an overall satisfaction with the scheme, but it was not possible to measure such satisfaction quantitatively, this was expected from an approach which is willfully kept outside the realm of performance management.

According to the literature on mentoring, most mentoring schemes lack a clear structure, as well as a clear evaluation process of its short and long terms, benefits ¹¹.In our scheme, we addressed this by continually monitoring the mentoring process and collecting feedback from mentees and mentors. Another limitation involves training the mentor himself and finding the time in a highly pressurised and heavy workload environment.

There are many questions that the literature on mentoring is yet to answer. For example, what are the long-term benefits of mentoring? Would our Foundation doctors who received mentoring be more successful professionally and personally compared to their peers who decided not to participate? These questions remain unanswered as our pilot was not set up to address this general shortcoming of current knowledge and understanding.

Conclusions and recommendations

Mentoring provides a focused opportunity to target the wider needs of the trainee. Not only could this encourage Foundation doctors to pursue a career in Psychiatry, but it also provides the space for them to learn how to incorporate psychiatric skills into whatever speciality they choose to pursue.

As a new doctor in a novel environment, being expected, welcomed, and gently guided into the job is invaluable. With the hindsight of our training experiences (good and bad), junior doctors are ideally placed to support more junior colleagues at all levels.

There is a need to develop links with other mentoring schemes to exchange experiences and learn lessons from others. Research has shown the importance of supporting mentors in their roles through regular meetings where mentors learn from each other. ¹³

In our experience, the mentoring scheme worked both alongside and separately to clinical and educational supervision and the opportunity for reflective practice offered in Balint groups. Mentoring added another level of support for the Foundation doctors, which was deemed beneficial by those participating.

We recommend more research is required to determine whether mentoring will increase recruitment to psychiatry. Organisations responsible for the training of doctors should support formal mentoring schemes and supervisors should ensure that mentors and mentees have protected time in their timetable due to the benefits of the mentoring experience to the doctors and the employing organisations.

Finally, funding should be available to support training of mentors in their workplace and aim to develop their skills in helping their mentees. Many private organisations offer mentoring training packages (including classroom and online training) for competitive prices. These courses provide useful resources to mentors and may help to increase the motivation of mentors to continue their participations in mentoring.

Appendix:

How does mentoring work? A simple three stage model:

Figure 1- The three stage model of mentoring. Developed from Alred et al (1998). Alred, G., Gravey, B. and Smith, R, 1998, Mentoring pocketbook. Alresford: Management Pocketbooks.

One of the unique characteristics of mentoring is that it is a partnership between two individuals (mentor and mentee) where both contribute to its growth and sustainability. It is based on trust, eagerness to learn and mutual respect. ¹⁶

Alred et al (1998) ⁴ described a model of mentorship with three stages: exploration, developing new understanding and then action planning (Figure 1). Both the mentors and mentee have certain roles and responsibilities in each stage and it is only through their collaborative work that the benefits of mentoring can be obtained.

The stage of exploration is characterised by the building of a relationship between the mentor and the mentee. Trust, confidence and rapport start to develop and hopefully grow throughout the mentoring process. Methods such as active listening, asking open questions, and negotiating an agenda are essential to facilitate this growth.

The second stage is where new understanding develops, is characterised by showing support to the mentee, demonstrating skills in giving constructive feedback and challenging negative and unhelpful cognitions.

Key methods employed in this stage include recognition of the strengths and weaknesses of the mentee, giving them information, sharing experience and establishing priorities for the mentee to work on.

In the third and last stage of the mentoring, action planning, the mentee takes the lead in negotiating and agreeing on the action plan, examining their options and developing more independent thinking and decision-making abilities.

A good mentor should help the mentee to gain confidence and knowledge over time. In order to achieve this, the mentor helps the mentee to develop new ways of thinking and improve their problem-solving abilities.

Monitoring the progress and evaluating the outcomes of the mentoring process is essential to ensure that the mentoring relationship is going in the right direction.

Acknowledgement

We would like to thank Dr Stephen Jones (Consultant CAMHS and former Training Programme Director), Dr Trevor Broughton (Consultant Forensic Psychiatrist, Director of Medical Education), Dr Bohdan Solomka (Medical Director) from Norfolk and Suffolk NHS Foundation Trust for their unlimited support for the mentoring scheme.

We also would like to thank Dr Calum Ross (Foundation Training Programme Director-FY1) and Mr Am Rai (Foundation Training Programme Director -FY2), Norfolk and Norwich University Hospital for their support in implementing this scheme. Dr Srinaveen Abkari (Specialist Registrar, Norfolk, and Suffolk NHS Foundation Trust) is one of our mentors who also contributed useful ideas to the development of this paper.

Finally, we would like to thanks all our mentors who provided the support for the Foundation, without their efforts, this scheme would not have succeeded.

Introduction

Metastatic bone disease is a relatively common event in the advanced stages of many malignancies.¹ Bone-modifying agents decrease the incidence of skeletal-related events (SREs) such as spinal cord compression and bone fracture, as well as the need for skeletal radiotherapy or surgery.²

Bone modifying agents such as intravenous bisphosphonates (IV BPs) (e.g. pamidronate and zoledronic acid) and denosumab are approved for prevention of SREs. IV BPs are primarily used and effective in the treatment and management of cancer related conditions such as multiple myeloma (MM), and breast cancer with skeletal metastases, because they reduce bone pain, hypercalcemia, and the risk of pathologic fractures.³

Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor, represents a breakthrough in the treatment of osteoporosis, MM, and bone metastases. The Food and Drug Administration (FDA) approved it in 2010 for the prevention of SREs in patients with bone metastases and in 2011 for the prevention of endocrine-therapy induced bone loss in patients taking aromatase inhibitors for breast cancer and in patients with non-metastatic prostate cancer.

Three international, randomised, double-blind, double-dummy phase III studies have evaluated denosumab versus zoledronic acid for the treatment of SREs in breast and prostate cancers, and in combined solid tumours and MM. Denosumab’s superior efficacy over zoledronic acid was demonstrated in the studies of patients with advanced breast or prostate cancer, as well as in a pre-specified integrated analysis of all patients enrolled across the three studies.⁴

In the 2014 position paper of the American Association of Oral and Maxillofacial Surgeons (AAOMS), the nomenclature “bisphosphonate-related osteonecrosis of the jaw” changed to “medication related osteonecrosis of the jaw” (MRONJ). MRONJ is defined as cases in which all of the following 3 characteristics are present⁵:

• current or previous treatment with antiresorptive or antiangiogenic agents
• exposed bone or bone that can be probed through an intraoral or extra-oral fistula in the maxillofacial region that has persisted for longer than 8 weeks
• no history of radiation therapy to the jaws or obvious metastatic disease to the jaws

Other terminologies used previously include “denosumab related osteonecrosis of the jaw” (DRONJ), and “antiresorptive agent-induced ONJ” (ARONJ).

The aetiopathogenesis of MRONJ related to denosumab therapy remains enigmatic, and hypotheses have focused on reduced bony turnover, infection, toxicity of the soft tissue, and antiangiogenesis. The epidemiology also remains unclear, and reported incidence varies widely.⁶ Overall, it is estimated that bone necrosis can develop in about 0.7-1.9% of patients with malignancy who are given high-potency IV BPs (such as zoledronic acid), and in 0.01–0.1% of those with osteoporosis who take low-potency oral BPs (such as alendronate). Data relevant to denosumab given subcutaneously in patients with metastatic cancer and osteoporosis seem to replicate those when IV high-potency BPs are administered.⁷ The risk of osteonecrosis of the jaw (ONJ) is higher in patients exposed to concomitant antiagiogenic medication. The individuals’ risk of ONJ is further determined by factors such as the potency of agent, cumulative dosage or duration of antiresorptive treatment, route of administration, comorbidities and local factors such as periodontal disease.^8,9 Oral hygiene plays a significant role with evidence supporting a strong correlation between bacteria associated with periodontal disease and MRONJ.¹⁰

MRONJ typically manifests as painful and often infected areas of necrotic bone, which subsequently may lead to severe chronic pain and facial disfigurement. This adversely affects the ability to eat, speak and lowers the quality of life. Adverse events related to RANKL inhibitors are usually considered to be infrequent and low in occurrence. Unfortunately from our recent clinical experience at Sheffield Teaching Hospitals' Trust, there have been several new cases presented in a very short period of time. In this paper we present a case series of MRONJ related to denosumab therapy since adverse events of denosumab in the mandible or maxilla have received relatively little attention.

The aim of this article is to highlight the elevated risk of MRONJ in patients receiving denosumab treatment and educate all health care providers involved in the management of such patients. Furthermore, the mechanisms of denosumab, comparison with bisphosphonates and the reported management strategies are reviewed.

Mechanism of Denosumab

Denosumab is an antiresorptive agent that exists as a human IgG2 monoclonal antibody and inhibits the binding of the receptor activator of nuclear factor kappa-B ligand (RANKL) to RANK (Receptor Activator of Nuclear Factor kappa-B). The binding normally signals the proliferation of osteoclasts, as RANK is expressed on the surface of osteoclasts and their precursors, whereas its ligand, RANKL, is a membrane bound protein expressed by bone marrow stromal cells, osteoblasts and T-lymphocytes. The activation of RANK is integral to the function of osteoclasts. Osteoprotegerin binds to membrane bound RANKL on osteoblast which in turns decreases the osteoclastic activity and in theory negatively effects bone turnover. Denosumab acts similarly to osteoprotegerin but has a higher affinity for RANKL.^11-13

Denosumab follows nonlinear, dose-dependent pharmacokinetics. The bioavailability of one subcutaneous denosumab injection is 61% and serum concentrations are detected within 1 hour. Maximum serum concentrations occur in 5-21 days and cessation of osteoclast activity occurs within six hours of the subcutaneous injection. The normal function is restored approximately six to nine months later, whilst bone turnover returns to normal shortly after this.¹⁴ Based upon monoclonal antibody pharmacokinetics, denosumab is most likely cleared by the reticuloendothelial system with minimal renal filtration and excretion thus avoiding nephrotoxicity. Its elimination half-life is 32 days, and it does not incorporate into bone.¹⁵

It is currently marketed as Prolia® and Xgeva®, approved by FDA. Prolia® is administered subcutaneously every six months and has shown to reduce the incidence of new vertebral, non-vertebral, and hip fractures in osteoporotic patients.^16,17 Xgeva® is also effective in reducing SRE related to metastatic bone disease from solid tumours when administered intravenously on a monthly basis.^17,18

RANKL Inhibitors and BPs Pharmacokinetics

There are fundamental differences between denosumab and BPs with regard to their mode of action. Denosumab is an antibody and acts extracellularly whereas BPs act intracellularly. As such, BPs must be present in the circulation and available for reuptake into bone for prolonged periods to function.¹⁹ There is not any evidence of drug recycling with RANKL inhibitors, and therefore it is suggested that their adverse effects can be reversible with discontinuation, in fact leading to a transient rebound phenomenon, which can be restored, with subsequent treatment.^14,20 On the other hand, recycling of BPs in the circulation system has been proposed as a reason for the long duration of action even after cessation which can be up to 12 years.

The US FDA-approved manufacturer’s package insert for both zolendronate and pamidronate states that “there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ in patients who require dental procedures during therapy and that clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment”. The package insert for denosumab does not address the issue of treatment continuation in patients who develop MRONJ to date.

Denosumab is a circulating protein capable of distributing throughout extravascular space. It is expected to reach all sites within bone including intracortical sites unlike with BPs. BPs have strong affinity for hydroxyapatite and bone mineral which limits their even distribution throughout the skeleton, particularly to sites deep within the bone.^19,21 This can explain the more profound inhibition of bone remodelling with denosumab than that seen with BPs.

Case Series

Case 1

A 55 year-old lady referred to a dedicated Oral Surgery nerve injury clinic for an opinion and management of her left sided inferior alveolar nerve (IAN) paraesthesia. The patient presented with a history of numbness in the left sided inferior alveolar nerve distribution following removal of the left mandibular second premolar (LL5) in July 2014. She was asymptomatic until she had the LL5 removed and since had suffered with constant pain and numbness. A year later, she had removal of the left mandibular first molar (LL6) and gave a history of recurrent infections and excruciating pain in her mandible over the past two months. On presentation she had an obvious submental swelling and left sided IAN anaesthesia.

Medically she was diagnosed with breast cancer in 2011, for which she underwent wide local excision followed by chemotherapy. She then was placed on unknown clinical trial that we identified at the time to be denosumab trial, following liaison with the Oncology team. She is currently receiving intravenous denosumab every three months.

Clinical examination revealed a grossly mobile anterior mandible with widespread bony necrosis and associated osteomyelitis. Sensory testing revealed complete anaesthesia in the left sided IAN distribution secondary to MRONJ.

An OPG (Orthopantogram) and CBCT (Cone-Beam Computerised Tomography) revealed an extensive patchy area of ill-defined bone loss in the anterior mandible extending posteriorly to the premolar/molar areas bilaterally (Fig 1).

Figure 1 A) OPG showing non-healing sockets in the left mandible with extensive bony destruction together with periosteal reaction extending to the right mandible as shown by the arrows.

Rather interestingly, the bony destruction was evident bilaterally with the patient only having had extraction of teeth in the left mandible (Fig 1). This could be the case of spontaneous ONJ in the right mandible or an extensive ONJ arising from simple extractions on the left side.

Figure 2 3D reconstruction of the CBCT image demonstrating extensive bony destruction involving the lower border of anterior mandible in keeping with a spreading chronic bony infection and clinical presentation of submental swelling as showing by arrows.

Case 2

A 66-year-old female referred by her general medical practitioner (GMP) with a 3-month history of delayed healing following a tooth extraction in the left posterior mandible. She had moderate to severe discomfort and reported multiple previous infections and purulent discharge from the area, which treated with multiple courses of antibiotics. In addition, she reported discomfort from the root treated right mandibular first and second premolar teeth (LR4 and LR5).

Medically she was diagnosed with breast cancer over 10 years ago for which she underwent resection followed by chemotherapy. Three years ago, she diagnosed with metastatic deposits and therefore has been receiving intravenous denosumab every six weeks since then. Other medications include steroids, chemotherapy agents, antihypertensives and analgesics. She did not receive any radiotherapy or BPs treatment in the past.

Clinical presentation revealed a heavily restored dentition with chronic generalised periodontal disease. There was evidence of widespread bone loss clinically and radiographically. The slow healing socket in the left mandible was visible but did not have any exposed bone (Fig 3). The lower right first and second premolar teeth (LR4 and LR5) were clinically and radiographically sound.

Figure 3. Non-healing socket in the left posterior mandible with no evidence of exposed bone or suppuration as showing by white arrow. Gingiva recession (black arrows) is evident in the LL6 and LL5 teeth in keeping with chronic periodontal disease.

Figure 4 Coronal sections of CBCT A and B showing multiple lytic areas within the inferior cortex of the mandible and incomplete healing of the extraction sockets.

On follow-up appointments, the patient suffered multiple repeated infections in the right and left posterior mandible and due to deteriorating periodontal disease, the LR4, LR5, LR6 were extracted by her own general dental practitioner (GDP) due to severe mobility. All three extraction sockets failed to heal (Fig 5) leading to an extensive area of exposed bone in the right mandible, extending from the lower right first premolar (LR4) to lower left first molar (LL6) region. Conservative management was embarked which included antibiotics, chlorhexidine mouthwash and routine oral hygiene appointments. Selective sharp bone trimming and three sequestrectomies were undertaken. At the same time, liaison with the patient’s oncologist resulted in cessation of the denosumab therapy and complete resolution of her oral symptoms.

Figure 5 Clinical picture of exposed necrotic bone (white arrows) following simple extractions of periodontally involved teeth.

Case 3

A 76-year-old lady referred to the Oral Surgery department by her GDP with a 3-month history of a non-healing lower left first premolar (LL4) socket. The patient was treated with two courses of antibiotics prior to referral which provided only temporary relief to her symptoms.

Medically she was diagnosed with breast cancer 10 years ago and recently commenced intravenous denosumab for metastatic disease. She also receives hormone therapy and palliative radiotherapy to the spine.

On clinical examination, there was a partially healed LL4 socket with a rather granulomatous appearance. There was no clinical evidence of suppuration or bony exposure. Radiographs confirmed the absence of bony infill in the socket. Local debridement and biopsy of the granulomatous tissue was performed to exclude any metastatic disease. Biopsy report confirmed the presence of inflammation tissue.

Figure 6 CBCT scan; A and B sagittal views, C axial view and D 3D reconstruction. Extensive periosteal reaction extending from the midline of the mandible to the left molar region is evident in keeping with chronic osteomyelitis secondary to MRONJ.

Liaison with the microbiologist suggested a long-term antibiotic course to arrest osteomyelitis. Further liaison with the oncology team, resulted in denosumab being stopped for 4 months. On subsequent review appointments, patient’s symptoms improved however, there is now an area of exposed bone in the LL4 region as shown in Fig 7.

Figure 7 Clinical photo illustrating exposed bone (white arrow) in the LL4 region without evidence of local infection.

Case 4

A 65-year-old lady referred to the Oral Surgery department by her GDP with a history of a sore upper mouth and jaw underneath the dentures which is unable to wear.

Medically she was diagnosed with disseminated breast malignancy including bone metastases 3 years ago and for that, she is on exemestane and IV Denosumab monthly.

Clinical examination revealed multiple draining sinuses in the anterior maxilla. There was a partially healed LL4 socket with a rather granulomatous appearance and tenderness on palpation. There was neither discharge from the area nor any exposed bone. Radiographs confirmed the absence of bony infill in the LL4 socket. Local debridement and biopsy of the granulomatous tissue was performed to exclude any potential malignancy and it was confirmed as inflammation tissue.

Figure 8 CBCT scan; A axial view, B and C 3D reconstruction. A 25mm fragment of right anterior maxilla is beginning to sequestrate. This extends from the anterior margin of the right maxillary sinus approximately to the position of the upper left lateral incisor, crossing the midline. The sequestrated fragment involves the lateral margin of the nasal cavity. There is bilateral moderate mucosal thickening in the maxillary sinuses. Extensive periosteal reaction extending from the midline of the mandible to the left molar region is evident in keeping with chronic osteomyelitis secondary to MRONJ.

Table 1 Summary of cases

Discussion

ONJ associated with antiresorptive therapy deserves distinction from other causes and diseases/medications associated with the development of osteonecrosis of the jaw. AAOMS recently published stage specific treatment recommendation for MORNJ.²² The various stages and suggested stage-specific treatment strategies are not evidence-based, and in particular, stage 0 disease is not universally accepted. AAOMS recommendations echoed those stated in previous years for BRONJ, namely supporting conservative therapy, with aggressive surgery offered only to symptomatic patients. In contrast, the MRONJ guideline report from the German Dental and the German Oral and Maxillofacial Associations refrains from recommending therapy at least for certain stages of the disease. This might be attributed to the pitfalls of current MRONJ criteria. Furthermore, due to poor guidelines specifically related to RANKL inhibitors, no agreement exists on a universally acceptable therapy strategy of such cases.

Management strategies are largely based on expert opinion rather than experimental data. It includes prevention, conservative and surgical modalities. Prevention of the condition is the gold standard. It is highly recommended all patients have a comprehensive dental examination and preventive dentistry (pre-emptive extraction of unsalvageable teeth and optimised periodontal health) before commencing antiresorptive therapy.^23,24 Oral hygiene should be kept meticulous during the course of therapy as periodontal disease and associated bacteria claim to be implicated in this condition and also observed in these cases.

The success rate of conservative treatment regimens range from less than 20% ^25,26 to above 50%^27,28 although some cases become chronic and develop complications.²⁹

Microbial cultures from areas of exposed bone are not always helpful since normal oral microbes are isolated. However, when there is extensive soft tissue involvement, microbial cultures may help to define comorbid oral infections, which may guide the selection of an appropriate antibiotic regimen.³⁰

Regardless of the stage of disease, areas of necrotic bone that are a source of chronic soft tissue irritation and loose bony sequestra should be removed or recontoured so that soft tissue healing can be optimised. This is in line with our clinical experience. The extraction of symptomatic teeth within exposed, necrotic bone should be considered as it appears unlikely that extraction will worsen the established necrotic process. Otherwise, surgical resection of necrotic bone should generally be reserved for refractory or advanced cases.³¹ Resection may occasionally result in even larger areas of exposed and painful infected bone.³²

A recently published MISSION study⁷ reported that the AAOMS system misclassified/ underestimated the severity of the disease at a rate of about 1 in 3, in particular in patients suffering from MRONJ stage 1 and 2. The authors conclude that these findings may explain why the treatment of stage 3 ONJ, namely surgery with success rate over 85%^33,34, has been deemed to be more predictable and therefore yields more favourable outcomes than the treatment of stages 1 and 2.³⁵

Denosumab is characterised by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. This is in line with our findings since cessation of denosumab in two cases helped to improve their symptoms significantly.

MRONJ has been reported to occur after a mean administration period of 39.3 months and 35 infusions in oncology patients.²³ It is interesting that all published cases of denosumab-related ONJ occurred early after commencement of therapy, independent of the number of previous administrations.^36,37 In our experience, all patients developed MRONJ within the first 3 months of teeth extractions; well ahead of the reported period and number of administrations of denosumab.

Furthermore, all four cases have had extensive lytic lesions developed following removal of a single tooth. The common radiographic findings in all cases include:

• non-healing extraction socket
• areas of focal and diffuse sclerosis
• thickened lamina dura
• early sequestrum formation
• reactive periosteal bone
• osteolysis of cortical and spongious bone

These findings, although common in MRONJ cases, have had extensive bony involvement and rapid progression of ONJ, demonstrating a far more aggressive nature of the disease compared to that seen with BPs.

In our experience, not all patients are adequately informed of the risks and adverse events of denosumab therapy. This highlights the importance of educating patients and inter-professional communication regarding the prevention and best management of MRONJ cases. In one of the cases, the lack of patient education concerning denosumab side effects and the failure of inter-professional communication had a detrimental effect on the patient’s overall management and subsequently patient’s oral health.

Table 2 Important Points

Conclusion

We present our experience with denosumab-related ONJ from Sheffield Teaching Hospital’s NHS Trust. This case series should contribute to the existing sparse clinical literature on this topic. The pathogenesis, treatment and outcome of ONJ are complex and multifactorial. Patients treated with denosumab may be more prone to developing ONJ even without a precipitating dental event. ONJ may have a more aggressive profile and develop significantly earlier in patients receiving denosumab. Prevention of ONJ still remains the most important goal, and this is most directly accomplished by avoiding invasive dental procedures and establishing inter-professional communication.

Introduction

Postgraduate medical training should equip trainees with the skills, knowledge and attributes for independent practice¹. They need to be equipped with the skills to become lifelong learners and continually develop their abilities throughout their careers by learning from colleagues, mentors, patients and disease. The challenge for clinical teaching is how to provide an optimal learning environment in which trainees can achieve their competencies for practice within a defined training rotation; both the limitations in the number of hours within a working week and the balance between learning and service commitments all can negatively impact on the educational experience of trainees². Moreover, trainees need to balance their own development of skills, knowledge and attributes for independent practice against the requirement to provide high quality and safe healthcare³. The appropriate level of supervision must be provided to trainees performing any patient interaction and this is gauged by the trainer-trainee relationship, regular assessment and feedback. The clinical workload of a trainee needs to be finely balanced between overstretching them with tasks outside their competencies and being left with all the routine and menial tasks⁴. Thus whilst trainees should work within their competencies, they must be given the opportunities to expand their repertoire of skills, which may result in errors (and potentially patient harm) – supervision should limit these errors, which should be reflected on to provide a learning opportunity within a ‘no-blame’ culture⁵. As a trainee gains competence of their necessary skills, the amount of supervision required can be stepped down, until distant supervision (i.e. advice via a telephone) may be all that is required.

An understanding of how each learning environment within the hospital setting can be maximized may enhance the learning opportunities conferred upon trainees. Both technical skills and the professional attributes of being a clinician can be learnt in clinical and non-clinical environments. These learning environments will be explored in the subsections below.

Bedside Teaching and Ward Rounds

Bedside teaching is a stalwart of medical education, allowing clinical history and examination to be performed under guidance, in an appropriate setting and with relevant clues (observation charts, oxygen, etc.) present. This patient-trainee interaction provides an opportunity to develop professionalism and communication, and can also be the source of training of diagnostic techniques ranging from venesection and cannulation to more invasive techniques (e.g., pleural aspiration, drainage of ascitic fluid)¹.

Presentation of patients during ward rounds allows a professional conversation between trainees and trainers to occur, which justifies their role in management and provides an insight into understanding and thought processes⁶. The multidisciplinary nature of rounds creates a community of practice⁷, allowing social learning to occur, and an opportunity to voice differing perspectives on patient care³. In order to maximize these learning opportunities, learning objectives can be discussed prior to commencement and reflection undertaken once they it has been completed⁶. Teaching rounds should be carried out when the ward is quiet, at a suitable pace, with regular questioning and opportunities for trainees to ‘lead’ the process⁸. Factors that hinder this educational process include time pressures, patients not being available, and the availability of trainees⁸.

Outpatient Clinics

Outpatients provides a mixture of new and follow-up patients that enables a trainee to learn management of patients in an ambulatory setting. Trainees may be in the same room as their supervisor (learning the basics of the consultation), or can practice semi-autonomously as their experience increases (with discussion with their supervisor as required); they must select an appropriate investigation and treatment plan, with a time frame for review, once the investigation or intervention has been performed³. Outpatient teaching is more highly valued by trainees and students compared to ward based tuition⁹. Factors that hinder this educational opportunity include room availability, time constraints, staffing levels and attitudes to teaching⁹.

Operating Theatre and Interventional Suites

Invasive procedures should be performed by adequately trained (or supervised) personal in the relevant area of the hospital (e.g. endoscopy, interventional radiology suites, theatre), with the necessary equipment and monitoring for the technique to be performed. Even before patients enter these environments, trainees have an opportunity to review the patient and their relevant investigations, discuss the procedure with the patient and obtain consent for the intervention¹. Trainees can learn a wide spectrum of skills within these environments including both technical (both procedural related and anesthetic related) and non-technical skills, including Human Factors, anatomy, identification of instruments, aseptic technique, effective hand-washing and donning of surgical gowns¹⁰. Teaching invasive procedures represents a dichotomy for clinicians, not only do trainees need to gain exposure and experience in the relevant technique, but patients need to be prevented from undue harm. Prior to undertaking an intervention, trainees should be familiar with the relevant anatomy and physiology of the system they are about to operate upon, will have watched the procedure being performed and may have learnt the basics of the procedure in a simulated setting.

Trainees must to be able to self-reflect on their own skills and record of the number of procedures they have performed (which can act as a proxy for ability) to ensure that the correct level of supervision is provided alongside an intervention of suitable difficulty. Trainers need to be sure that their trainees have the necessary skills and knowledge to perform a technique, with experience often being gained in a stepwise reflecting both the difficulty of intervention and the gaining of skills, competence and confidence by the trainee¹¹. This skills acquisition should be accompanied by regular discussion and feedback to maximise learning opportunities; when no supervision is available, trainees should consider video-recording the procedure as this allows reflection and review at a later date. A video diary can also be used as a portfolio of a trainee’s repertoire from beginner to expert during their training rotation. The challenge for trainees is to achieve competence in the relevant invasive technique within their training rotation; the number of interventions required to gain competence will vary between each trainee and technique¹¹.

Handover

Handover allows the care of patients to be transferred from one group of individuals to another on a temporary or permanent basis. Handover confers an opportunity to present a clinical synopsis of patients with key information to ensure continuity of care and patient safety is maintained³. Most handovers are trainee led which provides an opportunity for peer learning to occur, checking comprehension and sharing interesting cases or tips for practice¹². Handovers should be considered to be a high risk procedure, as communication errors can result in vital information being omitted; as such the process should be undertaken in suitable environment away from distractions, in a structured written and oral manner supported by an electronic format¹². A further review at the patient’s bedside can be performed if required, which can highlight high risk patients.

Multidisciplinary Team Meetings

Multidisciplinary team (MDT) meetings are small formal meetings focused on all aspects of a patient’s care that involve a wide range of medical personal, nursing staff and allied health care professionals¹. Meetings ensure that evidence-based guidelines are followed, and help to streamline management, removing unnecessary delays in treatment and improving cost effectiveness. MDTs represent a Community of Practice⁷ allowing social learning to occur as each individual can share their relevant expertise; MDTs enable best practice to be shared and help break down barriers between different specialties.  Trainees can learn from the didactic teaching that occurs within the MDT (in relation to clinical details, investigation and management), but can also contribute to the meetings and practice their presentation skills.

Morbidity and Mortality Meetings

Morbidity and Mortality (M&M) meetings can help ascribe accountability and be used to highlight improvements in patient safety. They provide an opportunity for professional education, especially if the discussion can be held within a no-blame culture, and the meeting can voice discrepancies in how to manage patients, especially in ambiguous situations¹³. Trainees may be tasked with presenting a case and the potential learning aspects associated with patient care.

Grand Rounds/Formal Teaching

Grand rounds are traditional formal teaching opportunities that typically revolve around a case, whereby salient findings are presented prior to a discussion of management. These meetings allow opportunities for trainees to present cases and learn management, but their educational benefit may be decreasing as they are being replaced with lectures with limited clinical relevance¹⁴. However “audience apathy, deteriorating decorum and shrinking attendance” have diminished these learning opportunities¹⁴. Targeted teaching and the establishment of learning objectives for trainees can improve the educational content and the provision of feedback to the speakers can also enhance these meetings.

Journal Club

Journal clubs confer an opportunity for current scientific research and developments to be presented, critiqued and discussed by trainees. These clubs confer an opportunity to appraise the current literature and how that can be translated into evidence based patient care¹⁵. Journal clubs tend to be both voluntary and occur outside of working hours, resulting in highly motivated groups of participants whom are protected from interruptions.

eLearning and mLearning

Electronic learning (eLearning) and multimedia learning (mLearning) enable trainees to work informally, away from desks and computers, and at their own pace through a series of educational modules. Any intervention that engages trainees and promotes learning should be encouraged and these online learning platforms can be combined traditional learning resources should be promoted to ensure that all aspects of the curriculum are covered. mLearning in particular  can be ‘dipped into’ allowing the learner optimal flexibility of how and when they want to use it. elearning can be referred to during point-of-care patient interactions when a trainee is unsure of how to proceed with patient management¹. These increasingly important and under-utilized resources should be supported by educational institutions that support both undergraduate and post graduate trainees. By developing a virtual learning environment, individual tailored learning programs can be created that allow a trainee to develop and control their own online learning¹⁶.

Simulation

Simulation is becoming increasingly important for medical training. , anything can be simulated from learning clinical skills to human factors training, for both individuals and teams, focused on patient care and current medical practice in both the undergraduate and postgraduate setting. The availability of simulators coupled with competency based training and a decreased amount of training within the workplace has led to an increase use of this teaching format¹. In addition, trainees need to understand how to use certain pieces of equipment prior to employing them on patients and this familiarity can only be gained in a simulated setting. Simulation can either occur within the workplace (allowing point-of-care simulation to see how teams react in a situation) or on formal taught courses; it can be low-technology and cheap (e.g., tying surgical knots on the back of a chair), but can also be high-fidelity and expensive (e.g., a virtual reality training simulator for laparoscopic operations), or use animal or cadaveric tissue. Simulation that increases trainee’s familiarity with certain techniques is likely to improve their clinical performance, decreasing potential patient harm and shorten the time taken for trainees to achieve competence¹. A simulation should be completed with feedback from the supervisor to ensure that trainees gain the most from the session and clarify any facts or concerns about the simulation; a video recording of the session can also enable participants to reflect on their performance in a manner that is almost impossible in everyday clinical practice.

Introduction

The NHS is supplied with approximately 300 000 NG tubes per year¹. There are approximately 800-1000 incidents reported to the NPSA every year related to the insertion and use of NG tubes. Difficulties are often encountered with their insertion, especially in the setting of general anaesthesia. Whilst stridor and injury related to the use of NG tubes has been previously reported^2,3, it has been related to prolonged siting. We describe a case acute stridor occurring in the recovery room due to direct trauma of the airway upon NG tube insertion.

Case report

A 61-year-old male presented with clinical symptoms of bowel obstruction. His medical history included atrial fibrillation (AF) treated with flecainide, and a 30-pack year smoking history. He was previously independent with a World Health Organisation performance status of 0. After CT confirmation of bowel obstruction, he was scheduled for an emergency laparotomy. A predicted P-Possum 30 day mortality was calculated at over 10%. He required no organ support pre-operatively, although his AF was poorly controlled. He had a low thoracic epidural sited awake, followed by induction of general anaesthesia with a rapid sequence induction. An arterial line, a central venous line, and an NG tube were inserted once anaesthetised. The NG tube was documented as difficult to site, and there were several attempts at a blind insertion via the oral and nasal route, before successfully inserting under direct vision using a laryngoscope.

The operative finding was that of an unresectable caecal tumour, and a defunctioning loop colostomy was formed. The total duration was 150 minutes. Following peripheral nerve stimulation and administration of 2mg/kg Sugammadex, he was woken, extubated and escorted to recovery.

Within minutes of being in the recovery area, he was acutely stridulous. Emergency assistance was called, and after assessment he was given nebulized adrenaline (1mg diluted in 4mls 0.9% saline), and 200mg of intravenous hydrocortisone. The nasogastric tube was removed, and his breathing was then supported with CPAP via a Mapleson C circuit and 100% oxygen. Direct examination of his airway, and indirect nasendoscopy with a Storz fibre-optic scope were performed. Significant bruising of his soft palate was seen, in addition to bruising and oedema of the soft tissues around the arytenoid cartilages with a small haematoma within the valleculae [Figure 1]. After approximately twenty minutes his stridor settled.

He was transferred to a level 2 high dependency unit later that day. He did not suffer from any further airway compromise, and his symptoms completely resolved.

Discussion

The insertion of an NG tube, whilst often deemed low risk, may result in life threatening consequences⁴. There even exists a “NG tube syndrome” ⁵, the pathophysiological mechanism of which is thought to be paresis of the posterior cricoarytenoid muscles secondary to ulceration and infection over the posterior lamina of the cricoid. There is no doubt that insertion of an NG tube in the anaesthetised patient can prove to be difficult, with a failure rate of up to 50% on first pass⁶, with repeated attempts at insertion being required. However, this case highlights the need for a controlled and ordered approach to managing the difficulties that can be encountered. Medical training incorporates NG insertion as a basic skill within the curriculum, but this affords new anaesthetic trainees little help with the anaesthetised and intubated patient.

There are several techniques described to insert NG tubes in anaesthetised, intubated patients⁷. There is evidence to suggest that modified techniques such as a reverse Sellick’s manoeuvre or neck flexion with lateral pressure are better than blind insertion in the neutral position. In the right hands, insertion under direct vision can overcome most difficulties, but is again not without risk.

We feel it is important to remember that NG insertion can cause patient harm, and potentially lead to life threatening consequences. Whatever the approach or technique that is chosen, having a logical and ordered approach is paramount. Using suitable alternative methods for insertion, or abandoning the procedure, as opposed to blindly continuing to repeat the same unsuccessful method must be key for success, as would be the case for approaching any clinical encounter.

Published with the written consent of the patient.

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.

It all began when she was sixteen.

She started getting, increasingly,

Worried about her weight.

All day she dreamt of getting slim, getting lean.

Her days revolved around counting calories.

She made every effort to avoid fattening food, 

To survive on soup, toasts, coffee and berries.

Her fear of being judged, fat and ugly, was overwhelming.

Her life revolved around specific chores

Of excessive exercises, 

Of inducing vomiting, of taking 

Laxatives. All hidden from her family and friends.

Like a tree in the winter, bereft 

Of life, bereft of glow, she lost 

Her every feature, every playfulness,

That made her beautiful, that made her desirable.

She was slowly withering, like crops 

In a drought, until her family 

Alarmed her to see a doctor. A timely 

Intervention, timely support, raised

The hopes of a new dawn

The hopes of her recovery.

Case history

A 46 year-old man presented to the Emergency department with chest pain and collapse, associated with loss of consciousness lasting several minutes. He had no significant past medical history and he had no risk factors for coronary artery disease. However, he did note a similar episode of collapse and loss of consciousness one year prior for which he did not seek medical attention. There was no known family history of heart disease or sudden death.

On examination he was haemodynamically stable with a blood pressure of 130/80 mmHg and heart rate of 85 beats per minute. Jugular venous pressure was measured at 2cm above the sternal angle and heart sounds were normal with no added sounds. His oxygen saturation was 98% on air and chest was clear to auscultation. Chest X-Ray demonstrated clear lung fields and laboratory investigations, including electrolytes and cardiac troponin T were within normal limits. Echocardiography showed a structurally normal heart. Figure 1 shows his 12-lead electrocardiogram (ECG) on admission.

Figure 1 – 12 lead ECG on admission

Questions

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

2. What life-threatening arrhythmias can arise from this condition?

3. What is the pathophysiology of this condition?

4. How is the diagnosis of this condition made?

5. What treatment options are available for patients with this condition?

Answers

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

Short answer

Brugada syndrome

Long answer

The ECG shows coved Type 1 ST segment elevation in keeping with a diagnosis of Brugada syndrome.

First described in 1992, Brugada syndrome is a primary cardiac electrical disease or channelopathy that is accompanied a structurally normal heart and carries an association with sudden cardiac death¹.

Presentation often occurs in the third or fourth decades of life, with a male preponderance of 8:1, however sudden cardiac death due to Brugada syndrome has also been seen in patients at the extremes of age. It is estimated that it accounts for up to 20% of all sudden cardiac deaths in patients without structural heart disease, ischaemia or electrolyte abnormalities². It is most commonly seen in south-east Asia, especially Thailand, where its incidence is around 1%, and is much less common in western countries¹.

2. What life-threatening arrhythmias can arise from this condition?

Short answer

Brugada syndrome is associated with increased risk of ventricular tachycardia (VT), often polymorphic, and ventricular fibrillation (VF).

Long answer

Brugada syndrome often manifests clinically in the form of syncope or sudden cardiac death. It is most commonly associated with polymorphic VT and VF, which may or may not terminate spontaneously. There are a large proportion of patients with Brugada syndrome who never experience any symptoms and indeed, may not ever even be identified as having the condition, unless they are found to have incidental ECG abnormalities as part of routine medical testing or are under investigation for another problem³.

3. What is the pathophysiology of this condition?

Short answer

Brugada syndrome is understood as a genetic cardiac channelopathy, a disorder produced by the dysfunction of a cardiac ion channel participating in the action potential which can result in electrical change favouring the development of arrhythmias. Inheritance of the condition occurs via an autosomal dominant mode of transmission with incomplete penetrance⁴.

Long answer

Brugada syndrome is a genetic disorder, with a loss-of-function mutation of the SCN5A gene implicated in about 30% of sufferers. This gene codes for the α-subunit of the cardiac sodium channel. Other mutations of sodium and calcium channels have also been found. In inherited cases, the gene is passed in an autosomal dominant fashion, though sporadic mutations are also seen.

There is increased susceptibility to ventricular arrhythmias, because of altered depolarisation within the right ventricle. In SCN5A mutations, the defect in sodium channels leads to decrease in the sodium current and a shortening of the cardiac action potential by blunting phase 0 depolarisation. Potassium channels are also affected, with an increased number of transient outward potassium channel currents. This imbalance in the myocytes between sodium and potassium concentrations means the overall effect is to shorten the refractory period, making the myocytes more prone to re-entrant circuits, leading to the development of VT and degeneration to VF^2,5.

4. How is the diagnosis of this condition made?

Short answer

Brugada syndrome is characterised by electrocardiographic changes demonstrating coved ST segment elevation in the right precordial leads.

Long answer

Electrocardiographic abnormalities constitute the hallmark of Brugada syndrome. There are three different ECG patterns and in all three types, the ECG shows ≥2mm J point (junction between the termination of QRS complex and beginning of ST segment) elevation and a characteristically shaped ST segment in the right precordial leads⁶.

Type I has a ‘coved’ pattern ST segment elevation ≥2mm, with a descending terminal portion in at least one right precordial lead.

Type II has a ‘saddle-back’ ST segment elevation ≥1mm and has a high elevation in its initial portion.

Type III has either coved or saddleback ST elevation but is less accentuated than types I or II (<1mm).

Although all the 3 patterns can be present in patients with Brugada syndrome, only the presence of a type-1 ECG pattern defines the diagnosis of the condition^2,7. The patterns for type II or III are not diagnostic, and carrying out a Class I anti-arrythmic drug (AAD) test to confirm the diagnosis is recommended. This can be done with AADs such as ajmaline, flecainide or procainamide, though currently ajmaline is preferred due to its higher sensitivity in revealing Brugada type ECG changes¹.

It is worth noting that the resting ECG changes associated with Brugada syndrome (in particular type I) are often transient, and therefore, in someone in whom the diagnosis is suspected, an AAD test may be indicated even if there are no resting spontaneous ECG abnormalities evident⁶.

Differential diagnoses of Brugada syndrome must be approached with care as ST segment elevation is associated with a wide variety of benign and malignant pathophysiologic conditions³.

5. What treatment options are available for patients with this condition?

Short answer

Currently, the implantable cardioverter defibrillator is the only proven effective treatment in the prevention of sudden cardiac death.

Long answer

Management of Brugada syndrome is focused on risk stratification of patients to prevent arrhythmic death in high risk individuals. ICD implantation can prevent sudden cardiac death in these groups¹. Newer devices are now also being used, including the subcutaneous ICD which is implanted in a subcutaneous pocket and does not require any endovascular leads in the heart or access to the central venous circulation⁸.

Pharmacological options are focused on rebalancing the ion channel current active during the early phases of the epicardial action potential in the right ventricle^3,9. Some studies have evaluated the role of quinidine in the treatment of Brugada syndrome and found it to be effective in preventing polymorphic VT and VF in this condition¹⁰. Quinidine has also been proposed as an alternative to ICD implantation in children and infants too young to receive an ICD^11,12.

Data relative to the use of cryosurgical treatments or ablation therapy in Brugada syndrome are very limited at this point in time³.

Patient outcome

The patient underwent successful implantation of a subcutaneous cardioverter defibrillator. Figure 2 and Figure 3 show chest radiographs of the leadless device.

Figure 2 – Chest radiograph (PA view) showing the implanted subcutaneous ICD

Figure 3 – Chest radiograph (lateral view) showing the implanted subcutaneous ICD

INTRODUCTION

Surgery and anaesthesia have traditionally been viewed as expensive, resource-intensive and requiring highly specialized training.¹ This misconception has led to surgery and anaesthesia taking a back seat to public health, maternal and child health, and infectious diseases in global health.² Surgery has also been termed the “neglected stepchild of global health.³These concepts have changed rapidly since it has been found that surgical diseases contribute about 11% to Disability Adjusted Life Years⁴ and therefore would benefit from preventive and public health strategies necessary to achieve the Millennium Development Goals. The realization of the huge public health burden of surgical diseases in low and medium income countries (LMICs), and the fact that surgical services and treatment could be made cost effective, led World Health Organization (WHO) to launch the Global Initiative for Emergency and Essential Surgical Care (GIEESC) in 2005.⁵

The GIEESC is a global forum whose goal is to promote collaboration among diverse groups of stakeholders to strengthen the delivery of surgical services at the primary referral level in LMICs.⁵ Improvements in surgical services at the primary referral level in LMICs will equally require the provision of safe and effective anaesthesia. The provision of safe and effective anaesthesia will need adequately trained human resources and essential health technologies. The surgical and anaesthesia service capacity have generally been very low in sub-Saharan Africa (SSA) as evidenced through surveys conducted in Ethiopia,⁶ Gambia,^7,8 Ghana,^9,10 Liberia,^8,11 Malawi,¹² Nigeria,¹³ Sierra Leone,^8,14 Rwanda,^15,16 Tanzania,^8,17 and Uganda.¹⁸ The survey from Nigeria was conducted among rural private hospitals and was administered to attending members in a conference of the Association of Rural Surgical Practitioners of Nigeria.¹³ This was done using the Personnel, Procedures, Equipment and Supplies (PIPES) survey tool developed by the non-governmental organization Surgeons Overseas (SOS).¹³ This is a tool developed to assess surgical capacity through the workforce, infrastructure, skill, equipment, and supplies of health facilities in LMICs.¹³ The other indicated surveys done in SSA used a comprehensive survey tool designed by the Harvard Humanitarian Initiative. This tool was adapted from the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care as part of an international initiative to assess surgical and anaesthesia capacity in LMICs.

The present survey used a rapid assessment tool known as the Lifebox Hospital Initial Needs Assessment questionnaire with another structured questionnaire to assess anaesthesia services in public hospitals in the Cross River State (CRS) of Nigeria. Lifebox (www.lifebox.org) is a non-profit organization saving lives by improving the safety and quality of surgical care in low-resource countries.¹⁹ Since 2001, Lifebox has trained more than 2000 anaesthesia providers, and more than 4200 pulse oximeters have been supplied to more than 70 low-resource countries thereby closing the operating room pulse oximetry gap in about 15 countries.¹⁹ This organization is supported by the World Federation of Societies of Anaesthesiologists (WFSA), Association of Anaesthetists of Great Britain and Ireland, Harvard School of Public Health and the Brigham and Women’s Hospital in Boston, United States of America.¹⁹ This survey was primarily aimed at the secondary health care facilities which are owned and managed by the CRS Ministry of Health (MOH). This survey audit will identify the anaesthesia providers in CRS, their level of training and retraining as well as equipment available for providing safe anaesthesia and monitoring patients in the peri-operative period. The data will also identify baseline information and gaps in anaesthesia and surgical capacity as a first step for the CRS MOH initiative to improve surgical and anaesthesia services. This information is a stepping-stone for national and international assistance since CRS is a relatively poor state in the Nigerian Federation.

Country and State overview

Nigeria is the most populous African country, located in the West African sub-region with a population of more than 160 million people.²⁰ It is a Federal Republic with 36 states and a Federal Capital Territory. It is politically sub-divided into six geo-political zones: North-Central, North-Eastern, North-Western, South-Eastern, South-South and South-Western. There are 774 Local Government Areas (LGAs) where more than 60% of the population reside. The health care system is divided into three levels: primary, secondary and tertiary. There are public and private health facilities operating at all levels. The primary healthcare facilities (health centres) are managed by the Local Government, the secondary healthcare facilities (general hospitals) are managed by the State Government, while the tertiary facilities (University Teaching Hospitals and Federal Medical Centres) are managed by the Federal Government. Health indicators for Nigeria are among the worst in the world despite the fact that Nigeria is the sixth largest exporter of crude oil. The United Nations Human Development Index ranked Nigeria 156 out of 187 countries.²¹ In particular, Nigeria is one of the five countries contributing more than 50% to the global maternal mortality ratio²² and one of the countries with the highest physician’s and nurse’s emigration to developed countries.²³ Physicians and nurses who remain in Nigeria predominantly practice in urban cities leaving the LGAs, most of them rural with severe shortages in health manpower.

CRS, with approximately 3.2 million population and 20156 square kilometres, is located in the South-South geo-political zone.²⁴ The state has boundaries with the Republic of Cameroon in the East, Benue State in the North, Ebonyi State in the North West and Akwa-Ibom State in the South.²⁴ It is divided into 18 LGAs with 18 general hospitals and 613 primary health centres. There is only one tertiary health facility, the University of Calabar Teaching Hospital (UCTH) located in Calabar, the capital city, which provides specialist care to the entire population. Being a tourism state, the importance of safe anaesthesia as a component of safe surgery cannot be overemphasized.

Physician-anaesthetist, nurse-anaesthetist and surgery training programs in Nigeria

Physicians are trained to be specialist anaesthetists or surgeons in a four-year training program leading to the Fellowship in Anaesthesia (FMCA) or Surgery (FMCS) of the National Postgraduate Medical College of Nigeria (NPMCN) or the Fellowship in Anaesthesia or Surgery (FWACS) of the West African College of Surgeons (WACS). This is after a six-year medical education program in the university leading to the Bachelor of Medicine and Bachelor of Surgery degree, one-year rotatory internship, and one-year of compulsory National Youth Service. Most Fellows, after completion (average time of completion is 7-8 years), work in University Teaching Hospitals and Federal Medical Centres, all located in urban cities. Another training program for doctors designed for primary and secondary healthcare is the Diploma in Anaesthesia (D.A) of the Universities or WACS, which is a 12-month training program. There is no short training program in Surgery.

Nurses are trained as nurse-anaesthetists after 18 months of training in a post-basic nursing program. The basic nursing training program is three-years of training in general nursing, after completing six years of secondary school education. There are now few university degree programs leading to the Bachelor’s degree in Nursing Science (BSN) from the universities. All these nursing training programs lead to certification by the Nursing and Midwifery Council of Nigeria.

Rural-urban practice

Physician-anaesthetists (Fellows and Diplomates), nurse-anaesthetists and consultant surgeons are all concentrated in urban hospitals leaving the rural areas and urban slums with a critical shortage of anaesthetic and surgical workforce. Therefore the majority of the surgical and anaesthetic procedures in rural areas in Nigeria are carried out by government-employed medical officers with almost all anaesthesia being provided by nurse-anaesthetists. In some very remote districts, Community Health Extension Workers (CHEWs) and Community Health Aids with little or no formal training in providing surgical care, are the only health workers available to provide some form of surgical care. The Association of Rural Surgical Practitioners of Nigeria (ARSPON) has been making some effort to address this workforce gap in rural areas by providing short on-the job training for medical officers to enable them to provide safe and affordable surgery to the rural population.¹³ The concept of surgical task-shifting to “non-physician clinicians” to address this rural-urban surgical workforce disparity, as is being officially done in other LMICs of SSA²⁵ is not acceptable in Nigeria.

METHODOLOGY

A standardized questionnaire, the Lifebox Hospital Initial Needs Assessment Survey (Appendix 1) and another structured questionnaire (Appendix 2) was distributed to all 18 general hospitals (secondary health facilities) in CRS. All the general hospitals, which are the first referral hospitals in the districts, perform surgery. The site visit was conducted in April/May 2014. Permission to conduct the site visit was given by the CRS Honorable Commissioner for Health. The hospital surveys did not involve face-to-face interviews with the medical superintendents, hospital matrons or anaesthesia providers. The questionnaires were to be completed by the anaesthesia providers and medical superintendents in each of the hospitals visited. Each completed questionnaire was to be sent to the office of the Honorable Commissioner for Health at the MOH headquarters in Calabar, the capital city. The results are presented in frequency tables and charts.

RESULTS

A total of 16 well-completed questionnaires were received from 18 general hospitals/secondary healthcare facilities visited (88.9 % response rate). Averages of 3 - 53 surgeries are performed monthly in each of the hospitals (Table 1). The common procedures performed include: herniorrhaphy, appendicectomy, caesarean section, myomectomy, prostatectomy and exploratory laparotomy (Table 1). There are no practicing physician anaesthesiologists or surgeons employed by the State MOH except for one visiting consultant anaesthesiologist and five visiting consultant surgeons from the University of Calabar Teaching Hospital (UCTH), at the General Hospital, Calabar, which is located in the capital city of the State (Table 1). There are 13 nurse-anaesthetists distributed unevenly in the 16 hospitals (Table 1). There are no clinical officers cadres in the Nigerian healthcare system. Apart from the nurse-anaesthetists at the General Hospital in Calabar and Dr Lawrence Henshaw Memorial Hospital, also in Calabar, the other nurse-anaesthetists have had no refresher course or in-service training in the past two years. In the 16 general hospitals, the commonest anaesthetic technique used is Total Intravenous Anaesthesia (TIVA) with Ketamine (Table 1).

Table 1 : Summary of audit of anaesthesia services in the 16 district hospitals in Cross River State, April/May2014

GA: General Anaesthesia. ETT: Endotracheal Intubation. C/S: Caesarean Section. CSE: Combined Spinal and Epidural anaesthesia.

Basic anaesthetic equipment such as anaesthetic machines, oxygen cylinders, suction machines, and pulse oximeters were lacking in most of the hospitals visited (Box 1).

The WHO Surgical Safety Checklist Information was administered to the hospitals management team at the Districts Hospital (Box 2). This shows that all the surgical teams had never used the WHO checklist, never received training, and the checklist was not available in the operating rooms, although all surgical personnel would like to receive training on the WHO checklist and pulse oximetry

DISCUSSION

This survey aimed to provide a quick assessment of anaesthesia and surgical services in public hospitals in CRS of Nigeria. The data shows gross and significant shortages in anaesthesia and surgical providers in all 16 general hospitals. There were no consultant anaesthetists, diplomate anaesthetists or consultant surgeons employed in the CRS MOH. There were only 13 nurse-anaesthetists working in the 16 general hospitals, and one visiting consultant anaesthetist and five visiting consultant surgeons at the General Hospital, Calabar, the capital city. In six of the hospitals, there were no nurse-anaesthetists providing care for the surgical procedures being conducted. As it has been reported from the many surveys in SSA.^{6, 18, 26} most of the procedures in all the hospitals are being done by generalist medical doctors and general nurses, many without any postgraduate training in surgery and anaesthesia.

The gross inadequacy of the anaesthetic workforce in this survey represents what is found in many of the 778 LGAs (Districts) in the Federal Republic of Nigeria. This is because many of the LGAs are rural and studies have indicated the general difficulties of most health workers seeking jobs in rural hospitals. The lack of specialist anaesthetists in peripheral hospitals in most of Nigerian Districts therefore requires a re-direction of the training programs for doctors in Nigeria with greater emphasis on the shorter training program design for primary and secondary healthcare levels. Inaddition, annual refresher courses should be made mandatory for nurse-anaesthetists especially for those practicing in rural areas.

A recent review of the met and unmet needs of surgical disease in rural SSA, where district and rural hospitals are the main providers of care, shows a very huge burden.²⁷ An important finding is the discrepancy between surgical care needs and provision.²⁷ Since the majority of the population in SSA reside in rural areas, there is the need to strengthen the surgical services at this level. This is the first of the four recommendations of the Bellagio Essential Surgery Group.²⁸ Many of the surveys using the WHO Situational Analysis Tool have described the lack of capacity in many district hospitals to meet the local surgical and anaesthesia needs.^6-18 One study, using pulse oximeter availability as a measure of operating room resources, showed that between 58.4% and 78.4% of operating rooms in West Africa, East Africa and Central SSA do not have pulse oximeters.²⁹ This finding was also clearly shown by our own rapid survey and assessment. Three important factors have been responsible for these findings. These are lack of resources, lack of manpower and the need for training.²⁷ The need for training to improve the quality of the surgical and anaesthesia providers at the district hospitals is the third recommendation of the Bellagio Essential Surgery Group.²⁸

Training programs and improvement of the facilities at the District Hospital has been shown to increase the number of operations performed.²⁷Also, the presence of a visiting consultant anaesthetist in the District Hospital has been shown to increase the scope of anaesthesia services during the visiting period.³⁰ The visit left more knowledgeable local staff in the care of their patients especially in peri-operative care.³⁰ The need for developing countries in SSA, particularly in Nigeria, to concentrate more on shorter training programs in surgery and anaesthesia at their current level of development has been advocated.^31,32 This has been shown by Sani et al where a 12-month training program for General Practitioners in district hospitals in Niger significantly reduced the number of referrals to the regional and specialist hospital.³³ In many other SSA countries, where gross shortages of medical manpower exist, surgical task shifting has been championed and research has shown that these are cost effective interventions.^{25, 34} This is, however, not acceptable in Nigeria which is Africa’s most populous country with very poor health indicators.

There are some limitations to this study. Firstly, it was a snapshot of anaesthesia and surgical services which did not highlight in detail the eight key areas of surgical and anaesthesia care, as in other surveys. These key areas include: access and availability of hospital services, human resources, physical infrastructures (including availability of water and electricity), surgical and anaesthetic procedures, surgical and anaesthesia outcome, essential equipment availability, NGO and international organizations providing care, and access to essential pharmaceuticals. Secondly, this assessment did not include the only public tertiary hospital in the State and private hospitals. Lastly, this was an initial assessment in preparation for a more detailed survey based on the WHO guidelines when research funds are received.

CONCLUSION AND RECOMMENDATIONS

Therehas been a paradigm shift in global public health and the concept of primary healthcare which has resulted in increased awareness of the importance and contributions of surgical disease to the overall burden of disease especially in LMICs. This rapid survey of anaesthesia services in CRS, one of the 36 states in Nigeria, will serve as a window to inform other Nigerian State governments of the need to increase surgical and anaesthesia capacity and funding in their development agenda. It is therefore recommended that visiting consultant’s services to all the general hospitals in an organized and planned fashion should be highly encouraged. All the anaesthesia caregivers should attend refresher courses at least once every two years. These courses can be arranged locally, or sponsorship provided for attendance of relevant courses by Anaesthesia Trainers within and outside the State. Basic anaesthesia equipment and guidelines as recommended by the Nigerian Society of Anaesthetists (Box 3) must be available and followed to enhance patient safety. It is also recommended that the government should give incentives to medical and nursing staff working in rural areas so that there will be a reversal of the rural- urban shift. The Lifebox global oximetry project is interested in making high quality, low-cost pulse oximeters available in every operating room. Therefore, every secondary care facility in the country should take advantage of this laudable program.

Global Health can be defined as “an area for study, research, and practice that places a priority on improving health and achieving health equity for all people worldwide”. ¹ Article 25 of the 1948 Universal Declaration of Human Rights declares that, “everyone has the right to a standard of living adequate for the health of himself and of his family”. ² Unfortunately, the health disparity between high-income and low-income countries, as well as between individuals within a country, often makes this impossible, leaving many people living in unhealthy settings without sufficient access to care.  

The field of global health is concerned with the health of populations worldwide, focusing on issues that typically have global, political, and economic significance. These health issues usually transcend national boundaries and are best solved through international collaboration. ³ Global health initiatives aim to improve the health and wellbeing of impoverished, vulnerable, and underserved people worldwide. ¹ These initiatives include poverty reduction strategies, disease prevention measures (for HIV/AIDS, malaria, and tuberculosis, for instance), efforts to improve nutrition and food security, policy to raise environmental standards and living conditions, and the promotion of gender equality.  

In 2001, the Commission of the World Health Organization (WHO) recommended to fund global health with 0.1% of GDP. ⁴

The average expenditure per capita for health in low-income countries is estimated at $ 20 per year while that of Western countries is estimated at $ 947. The target to be reached to help out the most disadvantaged countries is $ 44-60 per capita, which would ensure the populations of the poorest countries with the access to essential health services. Directing the 0.1% of the GDP of developed Western countries to the aids for global health would mean closing the gap to reach the target base of $ 44-60 that would allow the saving of 8 million lives a year. ⁴

Despite the good intentions, there is still a marked disparity between the current spending levels and the commitments made by developed countries in a context in which, among other things, the percentage of aid for global health has been in decline for almost all donor countries.

Activists claim that only 10 per cent of global health research is devoted to conditions that account for 90 per cent of the global disease burden – the so-called ‘10/90 Gap’. ⁵ They argue that virtually all diseases prevalent in low income countries are ‘neglected’ and that the pharmaceutical industry has invested almost nothing in research and development for these diseases.

In fact, the WHO acknowledges that there are only three diseases that are genuinely ‘neglected’: African trypanosomiasis, leishmaniosis and Chagas disease. ⁶

A large proportion of illnesses in low-income countries are entirely avoidable or treatable with existing medicines or interventions. Most of the disease burden in low-income countries finds its roots in the consequences of poverty, such as poor nutrition, indoor air pollution and lack of access to proper sanitation and health education. The WHO estimates that diseases associated with poverty account for 45 per cent of the disease burden in the poorest countries. ⁷ However, nearly all of these deaths are either treatable with existing medicines or preventable in the first place.

If treatments exist for the majority of poor countries’ health problems, why then do mortality rates remain so high? Any discussion of this question must address the problem of access to essential medicines, which remains an intractable political and economic problem. According to the WHO, an estimated 30 per cent of the world population lacks regular access to existing drugs, with this figure rising to over 50 per cent in the poorest parts of Africa and Asia. ⁸ And even if drugs are available, weak drug regulation may mean that they are substandard or counterfeit.

Within these populations, it is the poorest socioeconomic groups that disproportionately suffer from a lack of access to existing medicines. ⁹ The implications of this failure of public health policy on global mortality are profound – according to one study, over 10 million children die unnecessarily each year, almost all in low-income or poor areas of middle income countries, mostly from a short list of preventable diseases such as diarrhoea, measles, malaria and causes related to malnutrition. ¹⁰

Many governments fail their populations in this respect by imposing punitive tariffs and taxes on medicines, and by skewing their spending priorities in favour of defence over health. The governments of poor countries hinder the creation of wealth, imposing obstacles in the way of owning and transferring property, imposing unnecessary regulatory barriers on entrepreneurs and businesses, and restricting trade through extortionate tariffs. It is these and other political failures that have left poor populations without the necessary resources to access the medicines that could so easily transform their quality of life.

In conclusion, it appears more and more urgent and necessary to decide where to direct our efforts and investment in research, without prejudice, analyzing all the possible strategies for tackling global health issues, including those standing beyond the current economic paradigm based on the market.

Introduction

Adiponectin, first reported in 1995 by Scherer et al, is a novel and important member of the adipokine family.¹ It is a collagen-like protein that is exclusively synthesised in white adipose tissue and is the gene product of adipose most abundant gene transcript 1 (apM1).

Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues in both humans and animals. Various studies have reported a protective effect of plasma adiponectinagainst type 2 Diabetes Mellitus (T2DM) ^2-6. Adiponectin is also inversely associated with traditional cardiovascular risk factors, such as total and low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and is positively related to high-density lipoprotein cholesterol (HDL-C).⁷ Recent studies suggest that it may have anti-atherogenic and anti-inflammatory properties .^8-10 A few researchers who studied the combined effects of these findings reported inverse correlation between plasma adiponectin and risk of coronary heart disease.^11-15

Recent epidemiological studies have shown that association of adiponectin with insulin resistance and cardiovascular risk factors vary with ethnicity. Mente et al studied the ethnic variations in adiponectin concentrations and insulin resistance and found that South Asians and aboriginal people display a greater increase in insulin resistance with decreasing levels of adiponectin compared to Chinese and Europeans .¹⁶ However, a similar study involving Asian Indian teenagers showed that adiponectin did not correlate directly with measures of insulin sensitivity, overweight, and other cardio-metabolic variables .¹⁷ Similar studies in adults are not available.

The present study was done to assess the association between plasma adiponectin levels and coronary event in patients with diabetes. Also the relation between plasma adiponectin level and various cardiovascular risk factors were studied in patients with diabetes with and without acute coronary event.

Subjects and Methods:

The prospective study was conducted at a tertiary care centre in Bangalore, India from January 2008 to December 2009. The study was approved by the institution ethics committee. Three groups of patients, age and sex matched, were included in the study. The first group included 30consecutive T2DM patients admitted with a diagnosis of myocardial infarction (MI) at the study centre. While the second consisted of patients with T2DM without MI, the third group were patients without diabetes without any history of acute coronary event. MI was diagnosed as per World Health Organization’s criteria.¹⁸ Patients aged less than 18 years were not included in the study. Patients with diabetes with chronic kidney disease or receiving Thiazolidinediones were also excluded from the study as it would alter plasma adiponectin levels.

Fasting Blood Glucose (FBG), Post-Prandial Blood Glucose (PPBG), Glycated Hemoglobin (HbA_1C), Fasting Lipid Profile, Baseline Electrocardiogram and Plasma Adiponectin were done for all the study subjects. In addition, Coronary Angiogram was done for patients with diabetes with MI to confirm Coronary Artery Disease (CAD) and treadmill tests were done for patients with diabetes without MI to exclude underlying CAD.

FBG and PPBG, serum total cholesterol and serum triglycerides were estimated using enzymatic kit method (Vital Diagnostics, Mumbai, India); and serum HDL-C (Bayer Diagnostics, Baroda, India) using a semi-auto-analyser.

Plasma Adiponectin levels was estimated using Human Total Adiponectin/Acrp30 Quantikine ELISA Kit (R&D Systems Inc., India). This assay employs the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for the Adiponectin globular domain has been pre-coated onto a microplate. Standards and samples are pipetted into the wells and any Adiponectin present is bound by the immobilised antibody. After washing away any unbound substances, an enzyme-linked monoclonal antibody specific for the Adiponectin globular domain is added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution is added to the wells and colour develops in proportion to the amount of Adiponectin bound in the initial step. The colour development is stopped and the intensity of the colour is measured.

Statistical Analysis

Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) for Windows 16.0 (SPSS Inc., Chicago, USA). The results for each parameter (numbers and percentages) for discrete data and average (mean + standard deviation) for continuous data are presented in tables and figures using Microsoft office 2007 software package.

Two-way Analysis of Variance (ANOVA) was performed for plasma adiponectin in patients with diabetes with MI, patients with diabetes without MI and controls as the grouping factor. Two tailed ‘P’ values less than 0.05 were considered significant. Spearman correlation was performed to analyse the association between plasma adiponectin, BMI, FBG, PPBG, HbA_1C, serum triglycerides, HDL-C and LDL-C.

Results

The following results are expressed as mean± standard deviation. The mean age of the study subjects in the three groups-patients with diabetes with MI, patients with diabetes without MI and Controls- was 58.00±8.77 years, 57.17±9.34 years and 54.20±7.28 years respectively. The descriptive statistics of the various parameters under study is given in table 1.

Patients with diabetes with MI had significantly lower plasma adiponectin levels (6.11±1.82) when compared to patients with diabetes without MI (9.47±1.55) which in turn was lower than normal subjects (17.82±1.30) (P<.001) . Plasma adiponectin was significantly correlated with BMI (r=-.31), FBG (r=-.61), HbA_1C (r=-.63) and triglycerides (r=-.54) (all P<.001). We did not find any significant correlation between plasma adiponectin levels and HDL-C (Table 2).

Table 1: Descriptive statistics of various parameters under study

Table 1: Patients with diabetes with MI had significantly lower plasma adiponectin when compared to patients with diabetes without MI which in turn was lower than in normal subjects

Table 2: Spearman correlation between adiponectin and body mass index, blood lipids, HbA_1C, fasting and post-prandial glucose levels

** Correlation is significant at the 0.01 level (2-tailed); * Correlation is significant at the 0.05 level (2-tailed); (BMI- Body Mass Index, FBG- Fasting Blood Glucose, HDL- High Density Lipoprotein, LDL-Low Density Lipoprotein, HBA1C- Glycated Haemoglobin, TG- Serum Triglycerides); Plasma adiponectin was significantly correlated with BMI, FBG, HbA_1C and triglycerides (all P<.001). The correlation between plasma adiponectin levels and HDL-C was not statistically significant.

Discussion

In the present study, we found decreased plasma adiponectin concentrationsin the patients with diabetes which was further lower in patients with an acute coronary event indicating that it may be a predictor of macroangiopathy. Hotta et al found similar results in their study and proposed that accumulation of adiponectinin atherosclerotic vascular walls may accelerate its half-lifein plasma, resulting in the reduction of the plasma concentrationof adiponectin in subjects with CAD .¹⁹ Ouchi et al studied the molecular basis of link between adiponectin and vascular disease and found that adiponectinmodulates endothelial inflammatory response and that the measurementof plasma adiponectin levels may be helpful in assessment ofCAD risk. ²⁰ Large scale prospective experimental research is needed to clarify these theories.

The relation between plasma adiponectin and the various known metabolic risk factors were on par with the world literature, except for HDL-C. Koenig et al reported an additive effect of HDL-C and adiponectin on CAD risk prediction. ²¹ In their joint analyses, the highest risk for T2DM as well as acute coronary events was observed in men with low adiponectin in combination with low HDL-C levels. In the present study, the mean HDL-C levels were lower in patients with diabetes with MI compared to patients with diabetes without MI. However, we did not find any significant correlation between plasma adiponectin levels and HDL-C in the present study. Similar findings were obtained by Schulze et al indicating that although plasma adiponectin has been established to be correlated with insulin resistance, CAD and metabolic disease, the interrelation between these is far more complex.

The molecular mechanisms by which adiponectin exerts its multiple functions and whether its actions are receptor mediated still remain a mystery. Is the primary activity of adiponectin antiatherosclerotic, or is it principally a modulator of lipid metabolism and regulator of insulin sensitivity, or is it all of the above? The answers to these and other intriguing questions will undoubtedly provide additional insight into the metabolic roles of this new adipocyte hormone.

Conclusion

The present study and the recent evidence suggest that cross-talk between inflammatory signalling pathways and insulin signalling pathways may result in insulin resistance and endothelial dysfunction that synergise to predispose to cardiovascular disorders. Large scale prospective studies are needed to examine the ability of increase in adiponectin levels and insulin sensitivity to improve primary end points including incidence of diabetes and outcomes of cardiovascular events.

Introduction

Organ transplantation is an effective therapy for end-stage organ failure and is widely practiced around the world. According to World Health Organization (WHO), kidney transplants are carried out in 91 countries. Around 66,000 kidney donations, 21,000 liver donations and 6000 heart transplants were performed globally in 2005. ¹ In India the rate of organ donation is only 0.16 per million populations, compared to America's 26 and Spain's 35.² The shortage of organ is virtually a universal problem. Though many efforts were undertaken by the government to motivate the public towards donation of organs, the rate of organ donors has not paralleled the growing waiting list³,⁴, ⁵ and inadequate organ donation in India remains a major limiting factor for transplantation. There are several factors which could facilitate and hinder the general public to donate a organ. Identifying these factors could help in planning effective strategies to combat the problem. Hence the present study was conducted with the aim to explore the general publics perceived barriers and facilitating factors of organ donation.

Materials and methods

The present study was a cross sectional, exploratory survey conducted among the general public of Puducherry U.T, India. 400 eligible subjects who fulfilled the following criteria were included a) Subjects aged 18 and above, and b) who understand either the local language Tamil or English. Subjects with intellectual, psychiatric and emotional disturbances that could affect the reliability of their responses were excluded from the study. The population registry in the primary health centers of the selected community area was used as a sample frame to select subjects randomly. Every eligible subject was explained about the purpose of the study and signed a written consent form. Formal ethical clearance was obtained from the institute ethics committee before actual data collection procedure.

Preparation of the questionnaire

An extensive literature review was carried out to understand the possible barriers and facilitators reported in the past. Reported barrier and facilitating factors in the literature were included in constructing the questionnaire, including specific cultural and religious oriented items specific to Indians. Subject’s intention to donate the organ was assessed using a single dichotomous question (yes or no). For assessing the barriers and facilitators related to organ donation a questionnaire with a total of 18 items (9 items each) was prepared in the form of closed ended question i.e. yes or no. Along with closed ended questions, an open ended question i.e. any other? was also included for obtaining an extended response apart from the framed questions. As knowledge is an important factor which could serve both as a barrier and facilitator for organ donation, 8 items related to knowledge were also included as a part of the questionnaire. Knowledge items of the questionnaire were evaluated by assigning a score of 1 for each correct response with a maximum possible score of 8. Interpretation of the knowledge component was also done by categorizing the knowledge as follows - Below 50% of the total score - Inadequate knowledge, 51 – 75% - Moderately adequate knowledge, above 75% - Adequate knowledge, for ease of understanding. The draft tool was validated for its content by 10 experts from the field of surgery, medicine, nursing, anthropology and psychology for its appropriateness. After appropriate modification the content validity index for the tool was calculated and it was found to be highly valid (0.98). The reliability of the tool was estimated by a test re-test reliability method among 10 subjects with an interval of 2 weeks from the first and second time of administration of the questionnaire. It was found to be highly reliable with reliability coefficient of 0.91. A face to face interview method was used to collect data from each subject. Collected data was analyzed using SPSS for windows version 14 (SPSS Inc., Chicago, Il, USA) with appropriate descriptive and inferential statistics. A probability value of < 0.05 was set as the level of significance

Results

Basic Demographic details

Of the total 400 subjects enrolled the majority were male (56%), between the age group of 31-40 years (48%), and followed Hinduism (68%) at the time of interview. Most of the subjects were literate (70%) with education up to high school and resided in a rural area (53%).

Knowledge regarding organ donation

The mean knowledge score of the subjects regarding organ donation was 4.74 1.45 score which ranged from a minimum score of 1 to a maximum score of 8. Most subjects responded correctly to questions related to organ matching (85.3%) and consent procedure (84.7%). Details of different aspects of knowledge regarding organ donation of the subjects can be found in Table 1. When subjects were asked about the source of information regarding organ donation, 51.3% of the subjects reported that they gained knowledge through television, 23% from health personnel, and 12% from friends and 7% through books and internet (Figure1). Whilecategorizing knowledge scores the majority of the subjects (38.6%) had inadequate knowledge, 50.6% had moderate knowledge and only 10.6% had adequate knowledge regarding organ donation.

Intention to donate organs: Barriers and Facilitators

Of the total 400 subjects interviewed 69.75% of the subjects reported that they wish to donate their organs, whereas the remaining 30.25% reported that they will not donate their organs either during their life or after their death. Subsequently the factors for barriers and facilitators were also analyzed using the pretested questionnaire. The most common barriers perceived by the subjects related to organ donation were as follows, ‘family opposition’ (82.8%), ‘complicated organ donation procedure’ (69%), ‘fear that donation affects their future’ (58.36%), and ‘misuse of organs’ (55.2%). More information about barriers is detailed in Table 2.The most important facilitating factors of organ donation as reported by the subjects were ‘thought of saving someone’s life’ (95.9%), ‘feeling of improved sense of humanity’ (95%), ‘to save the life of a close relative’, ‘thought that their organ live after their death (92.6%) and ‘being a role model for others’ (77.7%). More details of facilitating factor can be seen in Table 3

While associating the subject’s intention to donate organs with demographic variables like age, gender, residence, education, religion, marital status, type of family and knowledge; only educational level had a significant association with the subject’s intention to donate organ. Specifically graduate people are more likely to report intention to donate organ their organs than others (p<0.001).

Figure 1: Distribution of source of information regarding organ donation among the subjects.


Table 1: Item wise distribution of different aspects of knowledge regarding organ donation (n=400)

Table 2: Perceived Barriers towards organ donation (n=121)

Table 3: Perceived Facilitators towards organ donation (n=279)

Discussion

The current study was conducted with the aim to explore the general publics intention towards organ donation and to identify the perceived barriers and facilitators. The present study revealed that 69.7% of the subjects have an intention to donate their organs either during their life or after their death, which is similar to the finding of Chung et al⁶ and Shahbazian H et al⁷. Similar to the previous studies⁸ the current study also confirmed a positive association between public intentions to donate their organ with their educational status. Though many studies in the past reported attitudes⁹,¹⁰ of public towards organ donation, the present study was the first of its kind to analyze specifically the barriers and facilitators of organ donation among the general public, this adds strength to this study. The most common barrier reported in the present study was ‘opposition form family in donating their organs’; these findings were similar to a previous study.⁶ Illegal organ donation and misuse of organ is a major problem in India for the low organ donation rate among public¹¹, this fact was reflected even in the current study as 55.2% of the subjects reported misuse of an organ as barrier to organ donation. The most important facilitating factors of organ donation reported in the present study was ‘thought of saving someone’s life’ (95.9%), ‘feeling of improved sense of humanity’ (95%), ‘to save the life of a close relative’ (92.9%), these finding were similar to the findings of Neelam et al conducted in India¹². The majority of the respondents in this study reported "lack of information" about organ donation and transplantation. These findings are comparable with those reported from previous studies, which all indicate the importance of public education about the importance of organ donation¹³,¹⁴,¹⁵,¹⁶. Our study identified that the principle respondents' source of information about organ donation was the television (TV). The contribution of other sources of information in providing respondents with knowledge about organ donation was minimal. Generally, studies had shown the importance of visual media in increasing the awareness of the public about organ donation. ¹⁷,¹⁸

Conclusion

Better knowledge may ultimately translate into the act of donation. Effective measures should be taken to educate people with relevant information with the involvement of media, doctors and religious scholars.

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

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 antidepressanteffects^1,7 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.

Introduction

Bortezomib is a reversible proteasome inhibitor, currently approved by US FDA for use in multiple myeloma and mantle cell lymphoma. It has been shown to cause new onset and exacerbation of underlying congestive cardiac failure (CHF) in some case reports. Although the exact mechanism of bortezomib induced congestive cardiac failure is unknown, studies have shown dysregulation of ubiquitin proteasome system (UPS) in human cardiac tissues in end stage heart failure^1-3. Furthermore, a study in rats has shown reduced left ventricular contractility after bortezomib administration, which was attributed to reduced ATP synthesis in mitochondria of cardiac myocytes⁴. Our case demonstrates new onset severe reversible left ventricular systolic dysfunction after 4 cycles of bortezomib in a 58 year old female with multiple myeloma. It highlights the importance of monitoring cardiac function in patients receiving bortezomib.

Case Report

A 58 year old female with past medical history of well controlled hypertension presented with severe low back pain, anorexia and unintentional weight loss of around 20 pounds over a period of 3 months in medical clinic. On evaluation of her routine laboratory tests, she was found to have haemoglobin of 6.5 g/dl, haematocrit of 19.9%, white blood cell (WBC) count of 3.9 x 10³/cc, red blood cell (RBC) count of 2.18 x 10⁶/cc and platelet count of 1.52 x 10⁵/cc. Her blood urea nitrogen and creatinine was 10 mg/dl and 0.7 mg/dl respectively and corrected calcium level was 10g/dl. On liver function test, her total protein was 12.4 g/dl and albumin level was 2.8 g/dl. X-ray of lumbosacral spine revealed a compression fracture at the level of T12and L2 vertebra. Bone survey confirmed diffuse osteopenia, severe collapse of the body of T12 and partial collapse of L2 and L3. Due to the presence of severe anaemia and compression fractures, multiple myeloma was suspected. Urine protein electrophoresis showed two monoclonal protein bands with concentration of 46.8% and 4.8% and urine immunofixation showed two intact monoclonal IgA-Kappa immunoglobulin bands. Beta-2 microglobulin level was 5.49. Bone marrow aspiration and biopsy confirmed the diagnosis of multiple myeloma. Patient was staged as IIIA according to Durie-Salmon staging system.

Subsequently, patient was planned to be treated with eight cycles of bortezomib and dexamethasone, with bortezomib being given on day 1, 4, 8 and 11 of each cycle at a dose of 1.3 mg/m² body surface area. Prior to initiation of chemotherapy, she received radiotherapy to spine as well. However, after completing the fourth cycle of bortezomib/dexamethasone, she was admitted to the hospital with generalized weakness, nausea and vomiting. Chest X ray revealed possible right lower lobe infiltrate or effusion along with increased bronchovascular markings and she was treated with antibiotics for suspected community acquired pneumonia. However, an echocardiogram was obtained due to bilateral crackles on physical exam and increased bronchovascular markings on chest X ray, which revealed dilation of left ventricle with left ventricular ejection fraction of 30-35%, diffuse hypo kinesis of left ventricle, mild mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I). Left ventricular septal and posterior wall thickness was 0.8 cm. Infiltrative Cardiomyopathy in the setting of multiple myeloma was unlikely due to the absence of bi-atrial enlargement, pericardial effusion and thick bright myocardium on echocardiogram. Cardiology consultation was sought and their impression was new onset left ventricular dysfunction due to bortezomib therapy.

Patient did not receive any further cycles of chemotherapy due to cardiotoxicity and was on optimal medical management for heart failure with lisinopril, carvedilol and isosorbide dinitrate. An echocardiogram was repeated four months after discontinuation of bortezomib, which revealed normal left ventricular contractility with global left ventricular ejection fraction of 55% and trace mitral regurgitation.

Currently, at 2 year follow up, her echocardiogram shows global left ventricular ejection fraction of 65%, trace mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I).

Discussion and Review of Literature

Botezomib is a novel proteasome inhibitor which acts by inducing bcl-2 phosphorylation and cleavage, resulting in G2-M cell cycle phase arrest and apoptosis⁵. US Food and Drug Administration (FDA) have approved bortezomib for use in multiple myeloma and mantle cell lymphoma. The common adverse effects of bortezomib observed in clinical trials and post marketing surveillance include thrombocytopenia, neutropenia, hypotension, asthenia, peripheral neuropathy and nausea. US package insert for bortezomib states that acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction and it is recommended to closely monitor patients with risk factor for, or existing heart disease.

The role of ubiquitin proteasome system (UPS) in heart failure has been studied extensively in recent years. Two studies by Hein et al and Weekes et al in 2003 have shown presence of increased amount of ubiquitinated proteins and substrates in cardiac tissues of heart failure patients, indicating reduced activity of UPS in end stage heart failure^1-3. Another study has shown impaired proteasome activity in hypertrophic and dilated cardiomyopathy likely secondary to post translational modification of proteasome⁶.However, in early stage heart failure, there is increased activity of UPS, resulting in remodelling and high cardiac output². Bortezomib, by inhibiting UPS, would lead to accumulation of ubiquitinated proteins in cardiac myocytes, similar to that seen in end stage heart failure. A study in rats exposed to bortezomib alone showed development of left ventricular systolic dysfunction by echocardiography and reduced synthesis of ATP was observed in the mitochondria of cardiac myocytes⁴. However, the exact mechanism of bortezomib induced systolic dysfunction in humans is not clear.

There have been a few reported cases of bortezomib induced congestive cardiac failure in literature (Table 1). The amount of bortezomib administered before development of symptoms of heart failure was 20.8 mg/m² in four patients, 3 mg/m² in one patient and 10.4mg/m² in one patient. Three of them have received prior anthracycline based chemotherapy. Complete reversibility of heart failure after discontinuation of bortezomib was documented only in two cases by follow up echocardiograms and brain natriuretic peptide levels^{7, 8}. The patient described in our index case had well controlled hypertension and no additional cardiac risk factors at baseline. She developed non-specific symptoms, including weakness, nausea and vomiting after the fourth cycle of chemotherapy and was admitted to the hospital for community acquired pneumonia. However, an echocardiogram was obtained due to pulmonary congestion, which uncovered the diagnosis of left ventricular systolic failure. The two echocardiograms obtained at a follow up of 4 months and 2 years showed gradual improvement in ejection fraction to 55% and 65% respectively from 15% after chemotherapy with bortezomib.

We did a review of major clinical trials of bortezomib in patients with multiple myeloma, Waldenstrom’s macroglobulinemia and plasma cell leukaemia (Table 2) to investigate the incidence of congestive cardiac failure reported after administration of bortezomib. In APEX trial, the incidence of congestive cardiac failure was 2% in both bortezomib and high dose dexamethasone group ¹¹. In a study on melphalan refractory multiple myeloma by Hjorth et al, 3 cases of congestive cardiac failure was reported in bortezomib-dexamethasone group and 2 cases were reported in thalidomide-dexamethasone group¹². Another study evaluating the safety of prolonged therapy with bortezomib by Berenson et al reported 1 case of cardiomegaly and 1 case of pulmonary edema¹³. However, further studies are needed to specifically evaluate the incidence of congestive cardiac failure with bortezomib therapy.

In summary, our case and review highlights the importance of maintaining a high level of suspicion for development of congestive cardiac failure after therapy with bortezomib. Given the widespread use of bortezomib and new generation proteasome inhibitors in multiple myeloma, there might be increased incidence of new onset and exacerbation of underlying congestive cardiac failure in future. Currently, there is no guideline for routine evaluation and monitoring of cardiac function in all patients during the course of bortezomib therapy. Furthermore, it is unclear whether the severity of congestive cardiac failure is proportional to the cumulative dosage of bortezomib administration and also, if there is any correlation between onsets of congestive cardiac failure with the timing of bortezomib therapy. Further studies are required in future to address these issues.

Table 1: Review of cases of bortezomib induced congestive cardiac failure reported so far.

*NK: Not Known; **EF: Ejection Fraction

Table 2: Review of cases of congestive cardiac failure reported in clinical trials with bortezomib in multiple myeloma, Waldenström’s Macroglobulinemia and plasma cell leukaemia.
 

Conclusion

CHF is an infrequent but serious adverse effect of bortezomib. Cardiac function should be closely monitored in patients receiving bortezomib, as case reports have shown that these patients might present with non-specific symptoms like weakness and fatigue. Further studies are required to establish the frequency and mode of monitoring of cardiac function during and after bortezomib therapy.

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.

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 FDA^{6, 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/m^{2 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 trial^{32, 33}.

9. Ustekinumab

It is a fully human monoclonal antibody targeting IL-12 and IL-23, presently undergoing clinical trials for psoriasis and psoriatic arthropathy^{2, 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 theskin^{42, 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 AA^{56, 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 effective^{67, 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.

Introduction:

Colorectal cancer (CRC) is the third most common cancer in men and women worldwide (1) and a leading cause of cancer related deaths (2). 5FU synthesized in 1957 by Heidelberger (3) is the mainstay in all current standard regimens for CRC (4). Chemotherapy induced hepatic toxicity in 5FU based regimens can be an acute or delayed outcome (5, 6); whereas steatosis is a hallmark of 5FU induced hepatic toxicity (7). Chemotherapy induced nephrotoxicity (8) is also an area of concern for oncologists. The antimetabolite 5FU is often linked with kidney damage (9). Therapeutic outcomes and toxicity of 5FU differs markedly in different doses, combinations, schedules of administration and routes of administration. Leucovorin (LV) incorporated in 5FU based regimen enhances the cytotoxicity of 5FU. In this study we opt to report abnormalities in hepatic enzymes and renal biomarkers biochemically assessed in the serum after alternate cycles of treatment in CRC patients subjected to 5FU/LV based chemotherapy.

Methods:

The study was designed in the Department of Pharmacology, University of Karachia and conducted in a leading cancer hospital in Pakistan. Following institutional authorisation, informed consent was obtained from patients being admitted during 2008-2011. The inclusion criteria was maintained on the following grounds:

1. Histologically confirmed advanced colorectal carcinoma
2. Adequate blood count before therapy
3. Age 20-80 years
4. ECOG score of < 3
5. Serum bilirubin < 5× normal
6. Serum creatinine < 135µmol/liter
7. Serum transaminases < ×2.5 normal

Twenty three patients (median age 59 years) who underwent surgery were included in the study. All the patients had measureable disease at CT scan, ultrasonography or clinical examination. Patient’s characteristics are shown in Table 1. Seventeen patients were treated with the adjuvant bimonthly regimen of 5FU/LV - high dose Folinic acid (de Gramont Regimen); whereas, six patients were treated with adjuvant monthly regimen of 5FU/LV –low dose Folinic acid(Mayo Clinic Regimen) as follows.

5Fluorouracil/ Leucovorin (de Gramont’s regimen)

5Fluorouracil: 400mg/m² IV followed by 600mg/m² CIV for 22 hours on day 1-2.
Leucovorin: 600 mg/m² IV as 2 hours infusion before 5FU on day 1-2.
Cycle repeated after 2 weeks.

5Fluorouracil/ Leucovorin (Mayo clinic regimen)

5Fluorouracil: 425mg/m² IV on day 1-5.
Leucovorin: 20 mg/m² IV before 5FU on day 1-5.
Cycle repeated after 4-5 weeks.

Premedication with oral phenothiazines, 5HT₃RA and 10-20 mg of dexamethasone was given.

The blood samples were collected before the initiation of the therapy and after each alternate cycle of treatment. The blood was drawn when the patient was rested and comfortable from the antecubital vein under minimal tourniquet pressure. The blood drawn was sampled and collected into vacutainers (BD). The biochemical profile of the pretreatment and subsequent treatment was comparatively assessed. SGOT, SGPT, bilirubin and alkaline phosphatase levels were measured after each cycle of treatment or on the clinical presentation of any hepatic adverse effect notified by the physician or oncologist and the levels were compared to the pretreatment values. The serum creatinine levels and BUN was measured before the start of chemotherapy and after each alternate cycle of treatment up to six times in each patient.

Table 1 Patient characteristics