Internal Medicine

Twelfth nerve palsy in Sjogren’s syndrome

Authors
Youssef Kort, Nahed Kessentini, Naziha Khammassi & Heykel Abdelhedi
Article Citation and PDF Link
BJMP 2016;9(4):a933
Abstract / Summary
Abstract: 

We report the case of a 62-year-old patient suffering from a sicca syndrome for 6 years. The diagnosis of a primary Sjögren’s syndrome was made according to the European American study group criteria. Her mouth examination showed a fissured, smooth and left deviated tongue without evidence of atrophy or fasciculation. Neurological examination confirmed the deficit of the right XII cranial nerve and excluded other cranial nerves involvements. Cranial nerve palsy (especially optic neuritis and trigeminal palsy) is a possible neurological manifestation of Sjögren’s syndrome. However, hypoglossal involvement is very uncommon and only two cases have been described in English literature. 

Keywords: 
Cranial nerve palsy, sjogren syndrome

Background

Sjögren’s syndrome (SS) is an autoimmune exocrinopathy characterised by a lymphoplasmacytic infiltration of the exocrine glands. Both xerophthalmia and xerostomia are the most common manifestations of the disease. However serious organ damage such as, pulmonary and neurological involvement, can occur. The prevalence of neurological manifestations of SS varies between 0% and 70% (average 20%), which is largely dominated by peripheral neuropathies¹. The cranial nerve involvement, especially when it is isolated, represents a rare facet of the peripheral neuropathy.

Observation

We report the case of a 62-year-old patient with no medical history, referred to the internal medicine department with a 6 years history of dry mouth and xerophthalmia. No other complaints were reported.

The mouth examination showed a fissured, smooth and left deviated tongue without evidence of atrophy or fasciculation (figure 1). The rest of the oropharyngeal examination was unremarkable with no angina or cervical lymphadenopathy. Neurological examination confirmed a deficit of the right XII cranial nerve and excluded other cranial nerve involvements, sensibility or motility deficit. A specialised ophthalmologic examination was performed and showed a bilateral superficial punctuate keratitis.

The search for antinuclear antibodies by indirect immunofluorescence was positive at the titre of 1/1280 (speckled) corresponding to Anti-SSA and Anti-SSB antibodies. Cryoglobulinemia search was negative.

The rest of the laboratory investigations (blood cell count, liver and renal function tests, thyroid balance and inflammation markers) were normal.

A labial salivary gland biopsy was performed and its histological examination showed a lymphoid cell cluster of more than 50 cells/ 4 mm² corresponding to a focus score 1.

Brain MRI was normal - no damage in the brain stem was seen. Electromyography was normal.

The diagnosis of SS was made according to the presence of five out of six criteria according to the European American study group. The diagnosis of primary SS was retained due to the lack of clinical or biological argues for an associated autoimmune disease. A symptomatic treatment of Sicca syndrome was prescribed but no specific therapy has been initiated for the hypoglossal nerve attempt because of its asymptomatic nature.

Discussion

In the case of our patient, the tongue deviation was discovered at physical examination and was totally asymptomatic. In other cases, the twelfth nerve palsy could be responsible for swallowing difficulties, and in advanced stages for a lingual or hemi lingual amyotrophy. The spectrum of its aetiologies is numerous. In a large case series of 100 patients, malignant tumors (about half of cases), neurological causes (16 %) and post-traumatic palsy (12% of cases) were the three most popular aetiologies². Other conditions could be associated with twelfth nerve palsy, such as, infections², vascular injury³ and non-invasive oxygen therapy⁴. Paroxysmal idiopathic hypoglossal nerve palsy has also been described⁵. Our patient had Sicca syndrome which was related to SS according to 5 criteria of the European American study group: it was a subjective sensation of dry mouth and dry eyes associated to a bilateral punctuated keratitis, a focus score > 1 at the histological examination of the salivary gland biopsy and positive anti-SSA and anti-SSB⁶.

SS is an autoimmune disease that often presents as dry eyes and dry mouth due to lacrimal and salivary gland involvement. It can be primitive or associated to other autoimmune diseases such as, Hashimoto’s Thyroiditis, Rheumatoid Arthritis or Systemic Lupus Erythematosus. Wide varieties of neurological complications are characteristic features of SS which occurs most frequently in the primary form. Peripheral neuropathy is the most frequent neurological manifestation. Its most common presentation is a symmetrical sensorimotor or pure sensory neuropathy of hands and feet. Sensitive neuropathy, small fiber neuropathy, multiple mononeuropathy and polyradiculoneuropathy have also been described¹. Cranial nerve involvement is rare. In a review of the literature, Colaci M found 267 patients suffering from SS with different types of cranial neuritis during their clinical history. The discovery of cranial neuritis was contemporary to SS diagnosis in 40% of the patients, as in the case of our patient.

Optic neuritis and trigeminal nerve injury were the most frequent attempts and represent respectively 46.4% and 38% of all cranial nerve palsies. All cranial nerves palsies have been described except the eleventh⁷. Involvement of the twelfth cranial nerve is very rare and only two cases have been described⁸′ ⁹. In these two cases, it was associated with an involvement of other cranial nerves (table 1). To the best of our knowledge, this is the first report of an isolated and permanent involvement of the twelfth cranial nerve in a patient with primary SS. Many mechanisms were proposed to explain the cranial nerve involvement in SS. Clinicopathological observations of Mori K⁸ suggest that an isolated trigeminal nerve attempt could be explained by an immune-mediated neuron death in the sensory gasser ganglion. Whereas, other cranial nerve involvements which are frequently associated together could be explained by a multiple mononeuropathy resulting from a vasculitis⁸.

Further clinical observations will be necessary to determine the exact mechanisms of such neurological involvement.

Table 1: Review of the literature regarding SS patients with hypoglossal nerve injury

  Number of patients Age Nerves

involved

Treatment Evolution
Mori/2005 [8] 1 No data V, VII, IX, X, XII No data Paroxysmal
Ashraf/2009 [9] 1 47 V–IX–XII No data Paroxysmal
Our patient 1 62 XII None Permanent

Figure 1: Smooth and left deviated tongue

Conclusion

In front of cranial nerves neuritis, we should actively search for sicca syndrome, sometimes not spontaneously reported by patients. Examination of the mouth can be instructive and should not be omitted in the diagnosis and monitoring of Sjögren’s syndrome.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
YOUSSEF KORT, Doctor, Razi Hospital, Tunisia. NAHED KESSENTINI, Doctor, Razi Hospital, Tunisia. NAZIHA KHAMMASSI, Doctor, Razi Hospital, Tunisia. HEYKEL ABDELHEDI, Doctor, Razi Hospital, Tunisia.
Corresponding Author Details: 
YOUSSEF KORT; Razi hospital, 2010, Tunisia
Corresponding Author Email: 
y_kort@yahoo.fr
References
References: 
  1. Carvajal Alegria G, Guellec D, Devauchelle-Pensec V, Saraux A. Is there specific neurological disorders of primary Sjögren's? Joint Bone Spine. 2015 Mar;82(2):86-9.
  2. Keane JR. Twelfth-nerve palsy. Analysis of 100 cases. Arch Neurol. 1996 Jun;53(6):561-6.
  3. Mahadevappa K, Chacko T, Nair AK. Unilateral Hypoglossal Nerve Palsy Due to Vertebral Artery. Clin Med Res. 2012 Aug;10(3):127-30.
  4. Weissman O, Weissman O, Farber N et al. Hypoglossal nerve paralysis in a burn patient following mechanical ventilation. Ann Burns Fire Disasters. 2013 Jun 30;26(2):86-9.
  5. Ibarra V, Jaureguiberry A, Moretta G, Lazzarini G, Ceruzzi R, Reich E. Idiopathic and unilateral  hypoglossal  nerve palsy. Medicina . 2015;75(3):173-4.
  6. Vitali C,  Bombardieri S, Jonsson R et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Annals Rheumatology Disease. 2002;61(6): 554–58.
  7. Colaci M, Cassone G, Manfredi A, Sebastiani M, Giuggioli D, Ferri C. Neurologic Complications Associated with Sjögren’s Disease: Case Reports and Modern Pathogenic Dilemma. Hindawi Publishing Corporation, Case Reports in Neurological Medicine. Case Rep Neurol Med.; 2014: 590292.
  8. Mori K, Iijima M, Koike H et Al. The wide spectrum of clinical manifestations in Sjogren's syndrome-associated neuropathy. Brain. 2005; 128:2518-34.
  9. Ashraf VV, Bhasi R, Kumar RP, Girija AS. Primary Sjogren’s syndrome manifesting as multiple cranial neuropathies: MRI findings. Annals of Indian Academy of Neurology.2009; 12(2):124–126.

A Registry Comparison of ESC and NICE guidelines 95 in the assessment of stable angina in a UK district hospital

Authors
Jessica Ball, Andrew Cai, A Pineau-Mitchell, Katie Brown, Benjamin Coope and Kuno Budack
Article Citation and PDF Link
BJMP 2016;9(3):a925
Abstract / Summary
Abstract: 

Background: National Institute for Clinical Excellence (NICE) and European Society of Cardiology (ESC) have developed guidance and risk-stratification tables to assist physicians in assessing the pre-test probability of coronary artery disease (CAD) in patients with stable chest pain. We hypothesised that NICE clinical guideline 95 overestimates prevalence of CAD and that using ESC guidelines instead may enable more targeted, cost-effective use of investigations.

Methods and results: Clinic records of 1968 patients who attended Tunbridge Wells Hospital’s Rapid Access Chest Pain Clinic between July 2005 and December 2012 were reviewed. A comparison was made between the pre-test probability of CAD in these patients and the actual incidence of CAD.

In patient groups where NICE guidelines’ pre-test probability of CAD was 61–90%, 31-60%, 10-29% and <10%, actual incidence of CAD was 31% (95% CI 27.6 – 34.5), 4.4% (3.0–6.5), 2.5% (1.2-5.0) and 0.28% (0.1–1.6) respectively.

Where ESC guidelines pre-test probability of CAD was >85%, 66-85%, 15-65% and <15%, actual incidence of CAD was 73.4% (63.7–82.7), 58.5% (51.1–65.5), 6.4% (5.3–7.8) and 0.76% (0.2–2.7) respectively.

Conclusion: Strict adherence to NICE guidelines overestimates the pre-test probability of CAD in our cohort. ESC guidelines offer a more conservative estimate and their use may reduce the number of coronary angiograms performed, resulting in more cost-effective practice. £322,545.88 was spent on investigations when hypothetically applying ESC guidelines to our cohort, compared with £943,865.22 spent when applying NICE guidelines. However, strict use of ESC guidelines may risk missing other diagnoses of chest pain.

Abbreviations: 
NICE - national institute for clinical excellence, ESC - European Society of Cardiology, CAD - coronary artery disease, RACPC - rapid access chest pain clinic
Keywords: 
angina pectoris, coronary artery disease, chest pain, risk, pre-test probability

Introduction

Chest pain accounts for 1% of all GP consultations, but in only 8%-18% of cases is it an indicator of underlying ischemic heart disease.1 Given the potential diagnostic uncertainty associated with chest pain at initial presentation, specialist evaluation of patients in a Rapid Access Chest Pain Clinic (RACPC) is of value and represents an important process in the evaluation of symptoms. These clinics were established with the aim of providing rapid outpatient assessment of patients with suspected cardiac disease in order to permit earlier provision of appropriate treatment and investigations where required.

Stable chest pain typically presents as angina, a triad of dull central chest pain, brought on with exertion and relieved by rest or GTN spray. The aetiology is usually stable atherosclerotic plaque disease which is associated with low mortality and can be treated with oral anti-anginals, as demonstrated by meta-analyses and the landmark COURAGE study. 2, 3

NICE Clinical Guideline 95 (NICE CG95) suggests that choice of initial investigation for stable chest pain should be guided by a patient’s pre-test probability of having CAD. Calculations of the pre-test probability take into consideration a patient’s age, gender, cardiac risk factors and symptoms. Patients are defined as high risk of cardiac disease if they have diabetes, smoke or have hyperlipidaemia (total cholesterol >6.47mmol/litre). Patients with none of the above are considered low risk. Symptoms are defined as “typical angina” if the pain is: 1) constricting discomfort in the front of the chest or in the neck, shoulders, jaw or arms; 2) is precipitated by physical exertion and 3) is relieved by rest or GTN spray within approximately five minutes. Pain is defined as “atypical angina” if only two of the above criteria are met and defined as “non-anginal” if one or none of the above criteria are met.

NICE pre-test probabilities of CAD (Table 1), are based on a version of Diamond and Forrester’s pre-test probabilities published in 1979, modified using data from Duke’s cohort study, published in 1993.4, 5, 6 Recent studies suggest that these NICE pre-test probabilities may overestimate the prevalence of CAD in a primary care population and may risk over investigating patients.7, 8 In addition to having financial implications, this may cause patients undue anxiety and unnecessarily put them at risk of complications.

Table 1: NICE Clinical Guideline 95 pre-test probabilities table.

Each cell represents the percentage risk of each group of patients having CAD, based on their typicality of symptoms, gender, age and cardiac risk factors (lo, low and hi, high)4

ESC guidelines utilise an updated, validated model of the Diamond-Forrester model by Genders et al. to create pre test probabilities of CAD (Table 2), based on patient’s age, gender and typicality of symptoms. 9, 10

Table 2: ESC guidelines clinical pre-test probabilities in patients with stable chest pain symptoms 

Each cell represents likelihood of each group of patients having CAD, based on typicality of symptoms, age and gender.9

We hypothesised that strict adherence to NICE guidelines results in over-estimation of the pre-test probability of CAD and therefore over-investigation of patients presenting with stable chest pain. ESC guidelines may offer more accurate pre-test probabilities of CAD and allow a more targeted and cost-effective use of investigations.

Methodology

Clinic records of all patients who attended the RACPC at Tunbridge Wells Hospital between July 2005 and December 2012 were reviewed. This service is run by a cardiology specialist. Patient demographics, cardiac risk factors and information regarding the nature of patient symptoms were collected prospectively and completed at the time of the patient’s RACPC appointment. Results of cardiac investigations were collected from paper and computerised records, and included diagnoses of significant CAD made following invasive coronary angiogram. These results were compared with patients’ pre-test probabilities of CAD calculated using both NICE and the ESC’s calculation methods. Outcome and readmissions were obtained from electronic records from the Maidstone and Tunbridge Wells NHS Trust computer records retrospectively.

Results

Study population

A total of 1968 records were reviewed. 59% (n = 1162) of patients were male and 41% (n = 806) were female. Their mean age was 60 years. At initial assessment, 69.8% patients (n=1373) had non-anginal chest pain, 19.5% (n=383) had atypical angina and 10.8% (n=212) had typical angina, based on the NICE guideline definitions of chest pain.

97.2% (n= 1912) patients underwent further investigation; 15% (n=256) of these were subsequently diagnosed as having significant CAD, accounting for their symptoms. The 2.8% (n=56) of patients who did not undergo investigation either chose not to, were unable to, were lost to follow up, or were diagnosed as having a non-cardiac cause of their symptoms at the initial RACPC appointment.

NICE CG95 pre test probabilities compared against cohort data

Table 3: NICE guidelines 95 pre test probabilities compared against cohort data

Each cell represents the proportion (%) of cohort patients from each group who were diagnosed with CAD. We have colour-coded cells to represent the NICE estimated pre-test probability of CAD in each group. Red cells represent 61-90+% probability, pink cells represents 30-60% probability, blue cells represent 10-29% probability and white cells represents <10% probability of CAD according to NICE Guidelines. “ – “ marks a cell where pre-test probabilities of CAD could not be calculated for cohort patients.

Table 4: A comparison of NICE pre-test probabilities and cohort patient data.

The risk of CAD as predicted by NICE guidelines 95 on the left compared with the actual number of cohort patients in each category and the proportion of those patients diagnosed with significant CAD.

The average discrepancy between the pre-test probability and actual incidence of CAD in cohort patients was 28% (range 20% - 88%). In 48% of cells in the NICE CG95 pre-test probability table (Table 1) the pre-test probability of CAD was overestimated by 30% or more (Table 3). A marked discrepancy between pre-test probability and actual incidence of CAD was found between “high risk” and “very low risk” patients. On average, high risk patients had an overestimated pre-test probability of 34.3 – 40.9% per cell compared with low risk patients whose pre-test probability was only overestimated by 6.5% (Table 3).

The cells highlighted in dark red in table 3 represent high risk patients whose pre-test probability was of 61-90+%, according to NICE CG95. In our cohort, only 31.2% (n=214, 95% CI 27.6-34.5) of high risk patients in this category were diagnosed with CAD. On average, actual incidence of CAD compared with pre-test probability was overestimated by 34.4% – 40.9% in each cell.

The pink cells in table 3 represent medium risk patients with a pre-test probability of CAD of 30-60%, according to NICE CG95. In our cohort, only 4.4% (n=24, 95% CI 3.0 – 6.5) of medium risk patients had a positive angiogram (Table 4). The average overestimate of actual incidence against pre-test probability was 35.9%.

The cells highlighted in blue in table 3 represent low risk patients with a pre-test probability of CAD of 10-29%, according to NICE CG95. In our cohort, only 2.5% (n=7, 95% CI 1.2 – 5.0) of low risk patients were diagnosed with CAD (Table 4). On average, the pre-test probability of CAD exceeded the found incidence of CAD by 18.6% (Table 3).

The white cells in table 3 represent very low risk patients with pre-test probability of CAD <10% according to NICE CG95. In our cohort, only 0.28% (n= 1, 95% CI 0.1 – 1.6) of patients were diagnosed with CAD. Average overestimation in this group was 6.5% in each cell.

ESC guidelines pre test probabilities compared against cohort data

Table 5: A comparison of ESC pre-test probabilities with cohort patient data.

Each cell shows the proportion (%) of cohort patients from each group diagnosed with CAD. Each cell is colour coded to correspond with the ESC estimated pre-test probability. Dark red cells represent >85% probability, pale pink cells represent 66-85% probability, pale blue cells represent 15-65% probability and white cells represent <15% probability.

Table 6: A comparison of ESC pre-test probabilities and cohort patient data

The risk of CAD as predicted by ESC guidelines on the left compared with the actual number of cohort patients in each category and the proportion of those patients diagnosed with significant CAD.

The average discrepancy between pre-test probability of CAD, according to the ESC’s risk stratification table, and actual incidence of CAD in cohort patients was 20.7%. In 28% of cells, the pre-test probability of CAD exceeded the found incidence of CAD by 30% or more (Table 5).

The cells highlighted in dark red in table 5 represent very high risk patients with a pre-test probability of CAD greater than 85%, according to ESC guidelines (Table 5). 73.4% (n= 58, 95% CI 63.7 – 82.7) of cohort patients in this high-risk category were diagnosed with CAD (Table 6). On average, incidence of CAD in each cell has been overestimated by 13% in this category.

The cells highlighted in pale pink in table 5 represent high risk patients, with a pre-test probability of CAD of 66-85%, according to ESC guidelines. 58.5% (n=103, 95% CI 51.1 – 65.5) of cohort patients in this high-medium risk category were diagnosed with CAD (Table 6). On average, the pre-test probability of CAD exceeded the found incidence of CAD in each cell by 17.7% (Table 5).

The cells highlighted in pale blue in table 5 represent medium risk patients with a pre-test probability of CAD of 15-65%, according to ESC guidelines. 6.4% (n=93, CI 5.3 –7.8) of cohort patients in this risk category were diagnosed with CAD (Table 6). On average, the pre-test probability of CAD exceeded the found incidence of CAD by 24.1%in each cell (Table 5).

The cells highlighted in white in table 5 represent patients whose pre-test probability of CAD was less than 15% according to ESC guidelines. Only 0.76% (n=2, 95% CI 0.2 –2.7) of cohort patients in this risk category were diagnosed with CAD (Table 6). On average, pre-test probability of CAD exceeded found incidence of CAD in each cell by 6.2% (Table 5).

Discussion

Only 15% of a total of 1968 patients referred to RACPC were diagnosed with significant CAD. The majority (70%) of referred patients had “non-anginal” chest pain and low pre-test probabilities of CAD, reflecting the importance ascribed by General Practitioners of ruling out ischemic heart disease as the underlying cause for chest pain, even in low risk patients. This may not be surprising given the large media attention to heart disease and sustained campaigns for early warning signs of heart attack in the British media. It is therefore of great public interest for cardiac disease to be identified.

NICE CG95 pre test probabilities compared against cohort data

Comparing cohort data to the pre-test probabilities of CAD outlined in NICE CG95, NICE have overestimated the number of patients likely to have CAD in the majority of groups. Strict adherence to NICE CG95 therefore carries the risk of over-investigating patients. NICE recommend CT calcium scoring as the first line investigation for patients with a low (10-29%) pre-test probability of CAD. 284 patients fall into this category and only 7 patients were shown to have CAD. This means that 40.5 patients need to be treated in order to identify 1 positive patient (NNT= 40.5).

In patients with a medium (30-60%) pre-test probability of CAD, NICE recommends functional imaging as the first line diagnostic investigation. In our cohort 544 patients would undergo functional imaging, but only 24 of these patients would be diagnosed with CAD, NNT=22.7.

Finally, in patient groups with a high (61-90%) pre-test probability of CAD, NICE recommends invasive coronary angiography as the first line diagnostic investigation. In our cohort of 1968 patients, 691 patients had a high pre-test probability of CAD, and 214 had significant coronary artery disease on angiography, NNT= 3.2.

Although invasive coronary angiography is considered the gold standard investigation for diagnosing CAD, and permits simultaneous therapeutic intervention, the procedure is not without risk, particularly in elderly patients and those with renal impairment.11 Furthermore, invasive angiography is expensive and is costed by the East Kent Hospitals University NHS Foundation Trust at £1166.02 per procedure (private correspondence).

NICE CG95 offers no guidance on managing patients who have a <10% pre-test probability of CAD. 347 of our cohort patients fell into this very low risk category and only 1 was diagnosed with CAD. Therefore, NICE CG95, if strictly adhered to, would have missed one diagnosis of CAD in our patient cohort.

ESC pre test probabilities compared against cohort data

ESC guidelines tend to offer more conservative estimates of pre-test probability of CAD compared with NICE guidelines. Using the ESC’s risk stratification table, almost all patients, except those with over 85% pre-test probability and those with less than 15% pre test probability, would be investigated for chest pain. This is due to their claim that non-invasive, image-based diagnostic methods for CAD have typical sensitivities and specificities of around 85%, so that roughly 15% of these investigations could be yielding false results. Hence, due to these inaccuracies, in patients with pre-test probabilities of CAD below 15% or above 85%, ESC state that performing no test at all could provide fewer incorrect diagnoses.9

In our patient cohort, 79 patients had very high (>85%) pre-test probability of CAD, but only 58 patients (73%) were diagnosed with CAD. For this patient risk group, ESC guidelines suggest that further investigation may not be necessary and that a diagnosis of CAD may be assumed. Thus, applying ESC guidelines to our cohort could result in 21 patients being incorrectly diagnosed with stable angina, and more serious causes of chest pain, for example pulmonary emboli or gastric ulceration, may be missed. However, in practice, it is likely that many patients in this very high pre-test probability category would have undergone angiography, because patients who have "severe symptoms" or who are clinically thought to have "high risk coronary anatomy" should be offered an invasive angiography with or without pressure wire studies. The vagueness of the guidelines allows interventionists to interpret this in the clinical context.

In ESC guidelines, invasive coronary angiography is not specifically recommended as a first line investigation for stable angina, regardless of the pre-test probability of CAD. In patients with a high (66-85%) pre-test probability of CAD, ESC guidelines recommend non-invasive functional imaging first line. Of the 176 patients who fell into this category, only 102 (58.0%) patients were ultimately diagnosed with CAD.

In patients with medium (15-65%) pre-test probability of CAD, ESC guidelines advise exercise ECG testing (or non-invasive imaging for ischemia if local expertise is available) as first line diagnostic investigations. Of the 1451 patients which fell into this category, only 93 were diagnosed with CAD, NNT= 15.6. Fortunately, exercise ECG testing would not expose the patient to potentially harmful radiation or medication, but their poor diagnostic power may result in the need for further investigations, despite a negative result.

In patients with low risk of CAD (<15%) ESC guidelines suggest making an assumption that the patient does not have CAD and advocates conducting no further investigations. In our cohort, 263 patients fell into this low risk category, two (0.8%) of which were diagnosed with CAD.

The ESC guidelines appear to have higher specificity than the NICE guidelines, and only two patients would have been missed had ESC guidelines been adhered to, compared to one patient missed if NICE guidance was used. Thus, although highly sensitive, ESC guidelines when applied to our cohort have lower sensitivity than NICE guidelines.

Comparison of number of investigations

Following ESC guidance for our cohort of patients would have resulted in fewer diagnostic invasive angiograms being performed than if NICE guidance had been followed. ESC guidance only recommends invasive angiography if first line, non-invasive investigations generate positive results. Overall, however, ESC guidance would result in a greater number of overall investigations being performed.

In total, NICE advises that all 691 of our high risk cohort patients should undergo invasive angiography as a first line investigation. 544 with medium risk should undergo functional testing first and 24 of these patients (assuming an angiogram would follow a positive result) would go on to have invasive angiography. 284 low risk patients should undergo CT calcium scoring first, of which 7 would go on to have functional imaging and angiography if the above logic is followed. This generates a total of 1557 investigations; 722 angiograms, 551 functional imaging investigations and 284 cardiac CT scans.

In comparison, using ESC guidance, 176 of our high risk patients would have functional imaging investigations, 103 patients with positive results would then undergo invasive angiography. 1451 patients would receive exercise ECGs, of which 93 with positive results would undergo functional imaging and invasive angiography. This generates a total of 1916 investigations; 196 angiograms, 269 functional imaging investigations and 1451 exercise ECGs.

If we assume that stress echocardiograms are used as “functional imaging” we can estimate costs for our cohort when applying each set of guidelines. Costs for each investigation are supplied by East Kent Hospitals University NHS Foundation Trust and are as follows: Outpatient elective coronary angiograms are costed at £1,166.02; stress echocardiograms are costed at £132.30; exercise ECGs at £40.26 and CTs of one area at £102.47 (private correspondence). If we were to apply NICE guidelines to our cohort, £841,866.44 would be spent on angiograms, £72,897.30 would be spent on stress echocardiograms and £29,101.48 on CT scans. This is a total of £943,865.22 on investigations.

If we were to apply ESC guidelines to our cohort, £228,539.92 would be spent on coronary angiograms, £35,588.7 would be spent on stress echocardiography and £58,417.26 would be spent on exercise ECGs. A total of £322,545.88 would be spent on investigations. Overall, this is £621,319.34 cheaper than applying NICE guidelines.

Limitations of study

This study is based on data from a single site and may not be nationally representative. The final diagnosis was made clinically by an experienced interventional cardiologist, which introduces subjectivity and the risk of interpreter bias. Not all patients underwent the gold standard of invasive coronary angiography to demonstrate the presence of CAD. However, all patients were seen and fully assessed by a cardiologist and 97% underwent investigations if deemed necessary.This study has all the limitations of a registry study. In addition, costs for investigations may vary throughout the country, and indeed the world, with varying expertise available.

Conclusion

In conclusion, strict adherence to NICE CG95 over-estimates the pre-test probability of CAD in our local population group. This is consistent with previous studies conducted in South London where there is a larger Afro-Caribbean population, as well as with studies conducted in the North of England.8,9 Adherence to ESC guidelines in place of NICE guidelines may enable a more targeted and cost-effective use of investigations. Strict application of the ESC guidelines to the study cohort would have resulted in investigations costing an estimated £322,545.88, compared to £943,865.22 if NICE guidelines were applied. However, conducting fewer investigations carries greater risk of misdiagnosis, and using ESC guidelines in isolation introduces the possibility of assuming CAD in patients without conducting investigations to confirm this.

It is advisable that local cardiology departments audit their stable chest pain guidelines to ensure that the interpretation of pre-test probabilities is in keeping with the local population. Unfortunately there is no ideal policy and local protocols should reflect the local population.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ANDREW CAI, Department of Cardiology, Kings College Hospital, Denmark Hill, London SE5 9RS, UK. JESSICA BALL, St Thomas' Hospital, Westminster Bridge Rd, London SE1 7EH, UK. ANTONINE PINEAU-MICTHELL, Tunbridge Wells hospital, Tonbridge Road, Tunbridge Wells, Kent TN2 4QJ, UK. KATIE BROWN, Tunbridge Wells hospital, Tonbridge Road, Tunbridge Wells, Kent TN2 4QJ, UK. BNEJAMIN COOPER, Tunbridge Wells hospital, Tonbridge Road, Tunbridge Wells, Kent TN2 4QJ, UK. KUNO BUDACK, Tunbridge Wells hospital, Tonbridge Road, Tunbridge Wells, Kent TN2 4QJ, UK.
Corresponding Author Details: 
JESSICA BALL, St Thomas' Hospital, Westminster Bridge Rd, London SE1 7EH, UK.
Corresponding Author Email: 
jb8511@my.bristol.ac.uk
References
References: 
  1. Ruigomez A, Rodriguez LA, Wallander MA, et al. Chest pain in general practice: incidence, comorbidity and mortality. Family Practice. 2006;23(2):167-74
  2. Boden WE, O'Rourke RA, Teo KK, et aland the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503–1516
  3. Stergiopoulos K, Boden WE, Hartigan P, et al.  Percutaneous Coronary Intervention Outcomes in Patients With Stable Obstructive Coronary Artery Disease and Myocardial Ischemia - A Collaborative Meta-analysis of Contemporary Randomized Clinical Trials JAMA Intern Med. 2014;174(2):232-240
  4. National institute for health and care excellence. NICE guideline CG95. Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. London: NICE 2010. Available from:http://guidance.nice.org.uk/CG95 (accessed December 2014)
  5. Diamond GA and Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. New England Journal of medicine 1979; 300: 1350-8
  6. Pryor DB, Shaw L, McCants CB, et al. Value of the history and physical in identifying patients at increased risk for coronary artery disease. Annals of Internal Medicine 1993: 118(2): 81–90)
  7. Khan J, Harrison R, Schnaar C, et al. Do NICE tables overestimate the prevalence of significant CAD? Br J Cardio 2014;21:75
  8. Cucukcu A, Murra I and Anderson S. What’s the risk? Assessment of patients with stable chest pain Echo Res Pract 2015;2(2):41-48
  9. Montalescot G, Sechtem U, Achenbach S, et al. European Society of Cardiology. ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery disease of the European Society of Cardiology European Heart Journal 2013; 34: 2949–3003
  10. Genders TS,Steyerberg EW, Alkadhi H, et al. A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension. EurHeart J 2011;32:1316–1330
  11. Tavakol M, Ashraf S and Brener SJ. Risks and Complications of Coronary Angiography: A comprehensive review. Global journal of health science 2012; 4(1): 65 - 93

Musculoskeletal training in Rheumatology - What the trainees think

Authors
Kavitha Nadesalingam, Eleana Ntatsaki, Dobrina Hull & Rod Hughes
Article Citation and PDF Link
BJMP 2016;9(2):a917
Abstract / Summary
Abstract: 

One in four adults are affected by longstanding musculoskeletal (MSK) problems, which are responsible for up to 30% of GP consultations. With a move towards providing rheumatology services in the community there is need for rheumatology trainees to become competent in diagnosing and managing MSK conditions. Rheumatology trainees have expressed the anecdotal view that training in MSK is compromised, partly due to the reduction of referrals of MSK conditions to secondary care and partly due to the focus on more complex inflammatory conditions.

A survey was carried out on behalf of the Rheumatology Specialist Advisory Committee, to assess rheumatology trainees’ confidence and ability in dealing with MSK conditions during, and on recent completion of training. The survey was sent to the rheumatology trainee representative of each LETB, to be disseminated to rheumatology trainees in their region. 77 responses from a total of an estimated 223 trainees were received. 20 of these surveys were incomplete, with not all questions being answered. Responses from trainees across all career grades from ST3 to 2 years post Certificate of Completion of Training were received.

92% thought MSK medicine to be an important part of rheumatology training; 64% had managed patients with soft tissue pathology on a daily basis; 30% felt they managed MSK conditions on a weekly basis; 32% of trainees felt they were not yet confident in diagnosing and distinguishing between different types of soft tissue pathologies; 16% felt they were lacking in competency for their level of training in managing MSK pathologies as outlined in the JRCPTB 2010 rheumatology curriculum; the majority of trainees felt they were either partially competent in all, or some areas, satisfactory for their level of training; 67% felt their training in injection techniques had been at least ‘adequate’. Exposure to, and experience with MSK medicine in current jobs and throughout training ranged from poor to excellent.

Within this limited survey, the views of 77 trainees have shown that training in MSK could be improved at all levels. Although trainees felt they were lacking confidence in dealing with certain areas of MSK medicine, when competencies were mapped out to the rheumatology curriculum, trainees felt they were achieving appropriate competency for their level of training. Trainees were keen to have further MSK training specifically in sports medicine. Free text comments for ways to improve skills repeatedly mentioned shadowing physiotherapists and exposure to more teaching and supervision focusing on examination techniques.

With changes in the nature and geography of rheumatology services we feel these aspects of training should not be overlooked to ensure trainees are equipped to deal independently with MSK conditions by completion of training.

Abbreviations: 
MSK - musculoskeletal
Keywords: 
Musculoskeletal medicine, rheumatology training, medical education and training

One in four adults are affected by musculoskeletal (MSK) problems, which account for up to 30% of General Practice (GP) consultations in the United Kingdom..1 Some GPs have direct access to community MSK services, but when not available, referrals are made to secondary care departments such as rheumatology. MSK training involves the skills that a rheumatologist needs to achieve competencies in the diagnosis and treatment of soft tissue rheumatism as opposed to inflammatory rheumatic joint disease.

It has been reported that junior doctors in the United Kingdom fail to routinely screen for MSK conditions on admission onto general medical or surgical wards2 which may be reflective of training issues. It was in our anecdotal opinion that MSK training at higher specialist training was being compromised as well. Within the United Kingdom doctors in training typically begin work as a first year rheumatology trainee four years after graduation from medical school following completion of both a two year foundation programme (encompassing a generic training programme which forms the bridge between medical school and specialist/general practice training) and a two year Core Medical Training programme, (involving 2 years of training, undertaking between four and six rotations in different medical specialties). At the time of writing, higher specialty training, such as in rheumatology, began at the level of Specialist Trainee 3 (ST3) and was either a four year training programme or a 5 year training programme if trainees were dually accrediting in general medicine.3 Higher specialist training involves rotating through different rheumatology departments within each Local Education Training Board (LETB).

In our opinion, the basic MSK skill set is essential to the training of a competent rheumatologist and trainees gain overall MSK competencies within routine clinical practice as they rotate through different hospitals during training. However, in some training programmes, there is very little MSK training opportunities, as MSK centres operating in the community in the United Kingdom, mean that these patient groups are not being treated in training hospitals. Faculty in these centres are competent to train, but training opportunities in MSK centres are reduced.

Rheumatology registrars in-training have expressed the anecdotal view that MSK training may be compromised, partly due to the reduction of referrals to secondary care and partly due to the inevitable focus on training in the more complex inflammatory conditions.

Rheumatology trainees in the UK were surveyed in 2015 on behalf of the Rheumatology Specialist Advisory Committee to assess confidence and ability in dealing with MSK conditions during and on recent completion of training. The survey was disseminated to rheumatology trainees via the trainee representative from each LETB.

77 responses were received across 15 LETBs from a total of an estimated 223 trainees. 20 of these surveys were incomplete, with not all questions being answered but those questions answered were considered in the results of this survey. Responses from trainees across all career grades from ST3 (1st year of specialist training) to 2 years post Certificate of Completion of Training were received.

58 out of 63 doctors (92%) thought MSK medicine to be an important part of rheumatology training. Free text comments recognised that MSK conditions were frequently referred to rheumatology and differentiating between inflammatory and non-inflammatory pain is important.

Only 41 out of 64 doctors (64%) felt they managed patients with soft tissue pathology on a daily basis and 20 out of 63 (32%), felt they were not yet confident in diagnosing and distinguishing between different types of soft tissue pathologies.

Exposure to, and experience with MSK medicine in current jobs and throughout training ranged from poor to excellent.

Only 9 out of 58 trainees (16%) felt they were lacking in competency for their level of training in managing the MSK pathologies outlined in the Joint Royal Colleges of Physicians Training Board (JRCPTB) 2010 rheumatology curriculum. The majority of trainees felt they were either partially competent in all, or some areas, satisfactory for their level of training.

Interestingly, only 39 out of 58 trainees (67%) felt their training in injection techniques had been at least ‘adequate’. Some trainees mentioned they had been self-taught in some injection procedures and training had been limited in certain soft tissue injections (most commonly plantar fasciitis, tendon sheath and elbow enthesis injections).

This survey has limitations in that the numbers of trainees surveyed were small. However, our total response number considering the usual poor response rate for online surveys is reasonable. Our survey was not validated and it is likely that there will be an element of selection bias in the responses received.

However, one of the strengths of our survey is the ability to review responses by seniority. We analysed further the confidence rating according to training level grade and we looked into two main subgroups, the more junior trainees (ST3 and ST4s) and the more senior trainees (ST6 and ST7). As expected the more junior cohort rated their confidence slightly lower compared to the more experienced group. Within the junior group (n=17) only 41% suggested they felt confident for their level of training when generically asked about their general diagnostic skills on MSK, which improved to 59% when this question was mapped to the curriculum. In the senior group of ST6 and ST7 (n=25), the confidence levels were significantly higher (80% felt confident appropriate to their level of training) and there was no change in confidence levels when skills were mapped to the curriculum. (Table 1). This may reflect the natural increase in experience and exposure to MSK medicine with progression in training, but also the better understanding of the curriculum requirements by the more senior trainees.Only one fully completed survey was received from a rheumatologist post Certificate of Completion of Training making this subgroup too small for further analysis.

Table 1:

 

(n)

Q6) Confidence in dealing with MSK

% Q6

Q9) Confidence mapped to curriculum

% Q9

ST3 and ST4- junior

17

7

0.41

10

0.59

ST6 and ST7- senior

25

20

0.8

20

0.8

Q6) How confident do you feel in diagnosing and distinguishing between different types of soft tissue pathologies/MSK in your daily practice? Q9) Do you feel competent in diagnosing and managing the above MSK pathologies outlined in the 2010 rheumatology curriculum?

Within this limited survey, the views of 77 trainees have shown that training in MSK could be improved for rheumatologists in training at all levels. Although trainees felt they were lacking confidence in dealing with certain areas of MSK medicine, when competencies were mapped out to the rheumatology curriculum, trainees felt they were achieving appropriate competency for their level of training although this was not assessed objectively.

The trainees’ perception of the level of competency needed in dealing with MSK conditions seemed to overestimate the requirement of the 2010 rheumatology curriculum. In clinical practice, trainees may feel they encounter different MSK pathologies, which they are being expected to manage which are not being given sufficient emphasis within their curriculum. Further questioning in this area may conceivably lead to adjustments within the curriculum and the training programmes.

In particular, to improve training in MSK medicine, rheumatology trainees valued teaching from physiotherapists and being able to attend specialist sports medicine clinics. Trainees who had ‘independently’ taken time to gain experience in this way felt that their training had benefitted. To support trainees in achieving these competencies it may be worthwhile adding a prerequisite in the Annual Review of Career Progression (ARCP) process (a formal method in UK medical training by which a trainee’s progression through their training programme is monitored and recorded) to ensure dedicated time is set aside for this aspect of MSK rheumatology training. Completion in a range of direct assessments such as Clinical Evaluation Exercises (miniCEX), and DOPs (Directly Observed Procedures) may ensure competency in this aspect of rheumatology training as well as secure confidence in dealing with MSK conditions and soft tissue pathology.

With changes in the nature and geography of rheumatology specialist services we feel these aspects of rheumatology training should not be overlooked so trainees are equipped to deal with MSK conditions independently by their completion of training.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Dr KAVITHA NADESALINGAM, MBChB, MRCP (Rheumatology), Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, LS7 4SA, UK. ELEANA NTATSAKI Norfolk and Norwich University Hospital, Department of Rheumatology, Colney Lane, Norwich, NR4 7UY, UK. DOBRINA HULL, Queen ELizabeth Hospital, Rheumatology, Stadium Road, Wooliwch, London SE18, UK. ROD HUGHES, Ashford and St Peter's Hospital Trust, Rheumatology, St Peters Hospital Guildford Road, Chertsey, KT16 OPZ, UK.
Corresponding Author Details: 
KAVITHA NADESALINGAM, Chapel Allerton Hospital, Chapeltown Road, Chapel allerton, Leeds, LS7 4SA, UK.
Corresponding Author Email: 
kavitha_nades@hotmail.com
References
References: 
  1. Expert opinions in rheumatology. Issue 2. The Primary Care Rheumatology Society Guide to Commissioning in Musculoskeletal Services. September 2011 (cited 1st June 2016). Available from https://www.pcrsociety.org/downloads/resources/exp-op-rheumatology-issue-2.pdf
  2. Sirisena D, Begum H, Selvarajah M, Chakravarty K. Musculoskeletal examination - an ignored aspect. Why are we still failing the patients? Clinical Rheumatology 2011; 30(3):403-7
  3. Joint Royal Colleges of Physicians Training Board. Recruitment (cited 1st June 2016). Available from https://www.jrcptb.org.uk/recruitment

Tuberculosis presenting as Costochondritis: a rare case report and brief review of literature

Authors
Manzoor Ahmad Wani, Naveed Nazir Shah, Syed Quibtiya Khursheed, Khurshid Ahmad Dar, and Asma Bashir
Article Citation and PDF Link
BJMP 2016;9(2):a913
Abstract / Summary
Abstract: 

Mycobacterium tuberculosis can affect almost any part of the body. Although tuberculosis of the bones is well known, tuberculosis involving the cartilages is rarely described. We report a 30 year male, who presented with insidious onset pain and swelling of the right lower parasternal area which on evaluation was diagnosed as tubercular infection of costochondral junction. The patient had no evidence of tuberculosis anywhere else in the body. Thoracic wall tuberculosis is rare and primary tubercular costochondritis has been very rarely reported in the literature.

Abbreviations: 
ESR - Erythrocyte Sedimentation Rate, ECG - Electrocardiogram, AFB - =Acid Fast Bacilli CT=Computed Tomography FNAC=Fine needle aspiration Cytology
Keywords: 
Mycobacterium tuberculosis

Introduction

Tuberculosis is an important and major infectious disease worldwide, especially in developing countries with an estimated global case fatality rate of 13% in 2007. The World Health Organization estimated that there were 13.7 million prevalent cases of TB infection worldwide, with each year bringing about 9.27 million new cases, 44% of which are new smear-positive cases1. Musculoskeletal tuberculosis is rare, chest wall tuberculosis is rarer and involvement of costochondral junction is among the rarest forms of tuberculosis. Tubercular costochondritis usually presents with insidious onset non-specific pain and swelling, resulting in delay in the diagnosis. Diagnosis is usually made by typical radiological findings and microbiological and histological evidence of tuberculosis. Treatment consists of antitubercular therapy with or without surgery.

Case report

30 year male, smoker, from low socio economic status presented with history of low grade fever, malaise and anorexia which began gradually two months back. For about one month he had pain in right side of chest just adjacent to lower part of sternum. The pain had started insidiously, gradually worsened with time, and was dull and aching in character. Pain was localized to the right lower parasternal area, occasionally radiating to the back. The pain was aggravated by physical activity and deep inspiration and was relieved to some extent by ordinary anti- inflammatory medications. There was significant history of pulmonary tuberculosis in the patient’s sister 1 year ago. There was no history of cough, haemoptysis, fever with chills or history of tuberculosis in the past.

On general physical examination, the patient was weak and febrile. On local examination, there was a bulge in the right lower parasternal area, corresponding to the right 9th costochondral junction. On palpation, there was severe tenderness in the same area. There was no peripheral lymphadenopathy and abdomen was soft and non-tender with no organomegaly. Chest examination was unremarkable. The rest of the examination was normal.

In terms of investigations, the chest radiograph, ECG, haemogram, kidney function tests and liver function tests were normal. ESR was high (34), Mantoux test was positive(15mm). Sputum for AFB was negative. Axial CT chest demonstrates expansion of the left 9th costal cartilage with soft tissue thickening on both the inner and outer aspect of the cartilage (Fig.1). FNAC (Fine Needle Aspiration Cytology) of the costochondral junction revealed Mycobacterium tuberculosis and on culture and histopathology of aspirated material revealed tubercular granuloma (Fig.2). A final diagnosis of tubercular costochondritis was made and the patient was treated with anti tubercular drugs for 9 months. Patient's symptoms improved after 2 weeks of treatment and swelling and tenderness subsided. Post treatment axial CT demonstrated complete resolution of soft tissue abnormality previously seen around the costal cartilage (Fig.3).


Figure 1: CT chest showing evidence of costochondritis.


Figure 2: Typical tubercular granuloma with central caseous necrosis on histopathology.


Figure 3: Post ATT CT showing complete resolution of costochondritis.

Discussion

Tuberculosis is very common infectious disease in developing countries like India, resulting in significant morbidity and mortality. Musculoskeletal tuberculosis is relatively uncommon and accounts for 1 to 2% of all the tuberculosis patients2,3 and accounts for about 10% of all extrapulmonary TB infections4. Tuberculosis of the chest wall constitutes 1 to 5% of all cases of musculoskeletal TB5,6. TB abscesses of the chest wall are usually seen at the margins of the sternum and along the rib shafts, and can also involve the costochondral junctions, costovertebral joints and the vertebrae7. In one study8, on the basis of the part of the rib involved, the roentgenographic findings for patients with rib tuberculosis was divided into four categories: Costovertebral (35%), Costochondral (13%),Shaft (61%), and Multiple cystic bone. TB of the thoracic wall is usually caused by reactivation of some latent foci of primary tuberculosis formed during hematogenous or lymphatic dissemination but direct extension from contiguous mediastinal lymph nodes can also occur9. In developing countries such as ours, tuberculosis is endemic and all the rare forms of the disease have been described, but in developed countries, resurgence of tuberculosis due to HIV may be responsible for atypical presentations .

Thoracic wall tuberculosis mostly presents insidiously with pain and swelling, but the diagnosis of chest wall TB is often delayed due to lack of specific symptoms and signs and gradual course10. Approximately less than 50% of chest wall TB patients may have active pulmonary TB11,12. Imaging techniques like X-Rays and CT scan play an important role in diagnosis and follow up of these patients. According to a study done by Vijay YB et al13, radiological signs may not be present initially at the time of presentation with symptoms, abscesses or sinuses may be present much before the imaging modalities detect them. Computed tomography (CT) scan is more valuable for localization and detection of bone destruction and soft tissue abnormalities. Atasoy et al demonstrated the role of Magnetic Resonance Imaging (MRI) for early detection of marrow and soft tissue involvement in sternal tuberculosis due to high contrast resolution of MRI14.Diagnosis is usually confirmed by finding acid fast bacilli (AFB) and positive AFB cultures of bone (positive in up to 75% of cases), and caseous necrosis and granuloma on histopathology11.

Complications of thoracic wall tuberculosis include secondary infection, fistula formation, spontaneous fractures of the sternum, compression or erosion of the large blood vessels, compression of the trachea and migration of tuberculosis abscess into the mediastinum, pleural cavity or subcutaneous tissues as discharging sinus. Chest wall TB needs to be differentiated from benign and malignant tumors [chondroma, osteochondroma, fibrous dysplasia, lipoid granuloma, chondrosarcoma, myeloma multiplex]11, metastatic carcinoma, lymphoma or other kinds of infection15,16.

The treatment of choice of chest wall TB is still not clear. Whether antitubercular therapy alone or surgical debridement (or excision based on lesion extension) combined with antitubercular therapy should be done needs further studies. But the general rule is if there are any complications, surgery is the treatment of choice followed by antitubercular therapy. We conclude that the diagnosis of thoracic wall tuberculosis is a challenge for physicians and is suspected by gradual onset clinical features and confirmed by microbiology, histopathology and radiography findings. Early diagnosis and treatment are important to prevent complications caused by bone and joint destruction.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MANZOOR AHMAD WANI, DM resident, Department of Gastroenterology, SKIMS, Srinagar, India. NAVEED NAZIR SHAH, Assistant professor, Chest Diseases Hospital, Government Medical College, Srinagar, India. SYED QUIBTIYA KHURSHEED, Registrar, Department of General Surgery, Government Medical College, Srinagar, India. KHURSHID AHMAD DAR, Lecturer, Chest diseases hospital, Government Medical College, Srinagar, India. ASMA BASHIR, PhD scholar, Kashmir University, Srinagar, India.
Corresponding Author Details: 
MANZOOR AHMAD WANI, MBBS, MD, DM resident, Department of Gastroenterology, SKIMS, Srinagar, India.
Corresponding Author Email: 
drmanzoorahmadwani@gmail.com
References
References: 
  1. World Health Organization Global tuberculosis control – epidemiology, strategy, financing: WHO Report 2009. http://www.who.int/tb/publications/global_report/2009/en/index.html.
  2. Garcia S, Combalia A, Serra A, Segur JM, Ramon R. Unusual locations of osteoarticular tuberculosis. Arch Orthop Trauma Surg 1997; 116:321-3.
  3. Chang DS, Rafii M, McGuinness G, Jagirdar JS. Primary multifocal tuberculous osteomyelitis with involvement of the ribs. Skeletal Radiol 1998; 27:641-5.
  4. Reider HL, Snider DE Jr, Cauten GM: Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 1990, 141:347-351. 
  5. Gayler BW, Donner MW. Radiographic changes of the ribs. Am J Med Sci 1967; 253:586-619.
  6. Mathlouthi A, Ben M'Rad S, Merai S, Friaa T, Mestiri I, Ben Miled K et al. Tuberculosis of the thoracic wall. Presentation of 4 personal cases and review of the literature. Rev Pneumol Clin 1998; 54:182-6.
  7. Morris BS, Varma R, Garg A, Awasthi M, Maheshwari M. Multifocal musculoskeletal tuberculosis in children: appearances on computed tomography. Skeletal Radiol 2002; 31:1-8.
  8. Tatelman M, Drouillard EJP. Tuberculosis of the ribs. Am J Roentgenol 1953;70:923-35. 
  9. Iwata Y, Ishimatsu A, Hamada M, Emori M, Ikedo Y, Wakamatsu K, et al. A case of cervical and mediastinal lymph nodes tuberculosis, tuberculous pleurisy, spinal caries and cold abscess in the anterior chest wall. Kekkaku 2004;79:453-7. 
  10. Newton P, Sharp J, Barnes KL: Bone and joint tuberculosis in greater Manchester 1969-1979. Ann Rheum Dis 1982, 41:1-6. 
  11. Agrawal V, Joshi MK, Jain BK, Mohanty D, Gupta A: Tuberculotic osteomyelitis of rib-a surgical entity. Interact Cardiovasc Thorac Surg 2008, 7:1028-1030
  12. Asnis DS, Niegowska A: Tuberculosis of the rib. Clin Infect Dis 1997, 24:1018-1019. 
  13. Vijay YB, Vinod A, Umesh S, Anubhav G. Primary tuberculous sternal osteomyelitis: a clinical rarity. Asian Cardiovasc Thorac Ann 2009;17:310-2. 
  14. Atasoy C, Oztekin PS, Ozdemir N, Sak SD, Erden I, Akyar S. CT and MRI in tuberculous sternal osteomyelitis: a case report. Clin Imaging 2002;26:112-5. 
  15. Chang GH, Kim SK, Lee WY: Diagnostic issues in tuberculosis of the ribs with a review of 12 surgically proven cases. Respirology 2009, 4:249-253.
  16. Ormerod LP, Grundy M, Rahman MA: Multiple tuberculosis bone lesions simulating metastatic disease. Tubercle 1989, 70:305-307.

Ventilator-associated pneumonia: A review of the clinically relevant challenges in diagnosis and prevention

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

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

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

INTRODUCTION

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

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

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

PATHOGENESIS

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

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

COMMON CAUSES

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

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

DIAGNOSIS

Clinical Diagnosis

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

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

Radiologic Diagnosis

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

Microbiologic Diagnosis

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

Blood cultures

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

Quantitative cultures of airway specimens

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

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

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

Table 1: CDC Algorithm for VAP diagnosis30

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

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

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

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

rinse for oropharyngeal colonization

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

STRATEGIES FOR VAP PREVENTION

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

Non-Pharmacologic Strategies

Staff Education in the Intensive Care Unit

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

Hand Hygiene

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

Impact of patient position

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

Kinetic Beds

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

Artificial Airway Management

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

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

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

Mechanical Ventilation Management

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

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

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

Pharmacologic Strategies

Modulation of Oropharyngeal Colonization

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

Selective Decontamination of the Digestive Tract

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

Stress Ulcer Prophylaxis

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

Ventilator sedation protocol

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

Antibiotic Policy and Infection Control

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

VAP prevention in low resource/developing countries

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

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

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

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

Bundle approach to prevention of VAP

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

CONCLUSION

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

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

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NIL
Competing Interests: 
None declared
Details of Authors: 
VARUN GOEL MD Microbiology, AIIMS, New Delhi, India; SAVITA GUPTA MD Anaesthesia, LNJP, New Delhi, India; TARUN GOEL MRCP, HOLY FAMILY HOSPITAL, New Delhi, India.
Corresponding Author Details: 
Dr Varun Goel, Senior Resident, Clinical Microbiology division, Department of Laboratory Medicine, AIIMS, New Delhi-110029.
Corresponding Author Email: 
drvarun21@gmail.com
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Comparing the use of traditional sites and alternative sites puncture for determination of blood glucose by glucometer

Authors
Crisafulli Cristiano, Massimo Catanuso, Carmelo Di Gregorio, Adriana Di Gregorio, Gaetano Profeta and Antonino Di Guardo
Article Citation and PDF Link
BJMP 2015;8(4):a835
Abstract / Summary
Abstract: 

Self-monitoring of blood glucose (SMBG) is important in evaluating the efficacy of prescribed anti-hyperglycaemic therapies and can help the patient better understand the importance of achieving glycaemic control. Pain related to puncture of the fingertip, needed for determination of blood glucose, can notably reduce compliance of patients using self-monitoring devices. The use of glycated haemoglobin, while providing a measure of glycaemic control over the past 2-3 months, is an average of pre- and post-prandial glycaemia and does not take into account glycaemic variability, which is an important cardiovascular risk factor that can be assessed by SMBG. The search for sites as an alternative to the fingertip that are associated with less pain and good reproducibility and accuracy of blood glucose measurements is an area of growing interest. The present study enrolled 5 general practitioners and 70 patients with diabetes and without diabetes-related or neurological/vascular complications that could alter pain perception. Traditional and periungual puncture sites were assessed. In contrast to the fingertip, no pain was perceived at the alternative site, while there was no significant difference in the values of blood glucose obtained using traditional and alternative sites. 

Abbreviations: 
SMBG - Auto Monitoring Glycaemic, HbA1c - Haemoglobin glycated, VAS - Visual Analogue Scale

The increasing collaboration between diabetologists and general practitioners (GPs) (e.g. the IGEA project) has resulted in the GP taking a more relevant role in management of patients with diabetes. Just as measurement of arterial blood pressure has become an important tool in follow-up of patients with hypertension by the GP, SMBG has become a valuable tool to evaluate glycaemic control. In particular, self-monitoring of both blood pressure and glycaemia are important to assess the efficacy of prescribed therapies, and can help the patient to better understand the importance of control of blood pressure and blood glucose.

Several instruments for measurement of blood pressure have been validated by important medical societies involved in hypertension, and much effort has been given to compliance and patient comfort. However, less attention has been dedicated to glucometers. In particular, little consideration has been given to patient compliance, and SMBG is often perceived as an agonising experience. Moreover, hourly pre-visit glucose curves for glycaemic control, even if important, do not have the same value as a standard control over 2 to 3 months between visits. In addition, after an initial period of "enthusiasm" the fear and hassle of pricking oneself and the unpleasant feeling of pain often cause the patient to abandon SMBG.

A literature search on PubMed using the term “self-measurement of blood glucose (SMBG) and pain” retrieved only two publications, demonstrating a general lack of interest of the medical community. However, SMBG can be of important diagnostic-therapeutic value. Pain related to skin pricks on the fingertip, needed for determination of glucometric blood glucose, can significantly reduce compliance to SMBG, thus depriving the physician of a useful tool for monitoring the efficacy of anti-hyperglycaemic therapy and glycaemic control. Moreover, HbA1c has clear limitations, even if it provides a good idea of glycaemic control over the past 2-3 months, as it is a mean value of pre- and post-prandial blood glucose. It does not, therefore, measure glycaemic variability, which is an important cardiovascular risk factor. Thus, more research is needed into puncture sites as an alternative to the fingertip that are associated with less pain, which could favour greater use of SMBG.

Another problem of significant importance concerns the reproducibility and accuracy of blood glucose measurements. In the traditional method, blood samples for self-monitoring are taken from the fingertip of any finger using a lancing device with a semi-rigid prick (Figs. 1 and 2). The large blood vessels in the derma of the fingertip (Fig. 3) are lanced, and a drop of blood is obtained for the glucometer. All lances are optimised to prick the skin at a depth greater than 0.5 mm with a variability of ± 0.2 mm (Fig. 4).


Figure 1. The fingertip as a traditional site of puncture using a lancet.


Figure 2. Traditional method for self-monitoring of blood glucose.


Figure 3. Vascularisation of derma.


Figure 4. Traditional lancet.

Unfortunately, by pricking the fingertip at this depth, numerous tactile corpuscles in the dermis are also touched, causing the unpleasant sensation of pain. In a recent study by Koschinsky1 on around 1000 patients with type 1 (T1D) and type 2 diabetes (T2D), about one-half (51%) referred that they normally pricked themselves on the side of the fingertip because it is less painful. However, almost one-third (31%) used the centre of the fingertip, which is the site associated with the most pain. Other sites of puncture on the fingers are used much less frequently (5%), while 12% used other places on the body. It is also interesting to see how many times patients reused the lancet: 10% once, 19% for 2-4 times, 22% for 5-7 times, 25% for 8-10 times and 21% for more than 11 times. Pricking oneself 2 several times daily for years is not only troublesome for patients, but also leads to the formation of scars and callouses, and reduces fingertip perception and tactile sensitivity. Notwithstanding, alternative sites of puncture such as the arm, forearm and abdomen have not been evaluated in a systemic manner.

The objective of the present study is to compare alternative sites of puncture using a new semi-rigid lancet and determine if blood glucose values are similar to those obtained using traditional methods. A new puncture site was chosen, namely the area proximal to the nail bed of each finger. The sensation associated with puncture (with or without pain) was used to compare the two groups. Pain was assessed with a visual analogue scale (VAS). Blood glucose was measured in the morning after 12 hours of fasting.

Materials and methods

The present study enrolled 5 general practitioners and 70 patients with diabetes and without diabetes-related (micro-albuminuria, retinopathy, arterial disease of the lower limbs) complications. In addition, patients with diabetic neuropathy or neurological/vascular complications that could alter pain perception were excluded. The study population was composed of 20 women and 50 men with a mean age of 47.8 ± 15.3 years and a mean duration of diabetes of 11.4 ± 10.3 years; 34.3% had T1D and 65.7% had T2D. The study was carried out according to the standards of Good Clinical Practice and the Declaration of Helsinki. All patients provided signed informed consent for participation.

Semi-rigid lancets were provided by Terumo Corporation (Tokyo, Japan) and consisted in a 23-gauge needle that was remodelled to permit less painful puncture than a traditional lancet (Fig. 5). Punctures (nominal penetration from 0.2 to 0.6 mm) were made at a depth variation of ± 0.13 mm. In addition, a novel puncture site was used, namely the area proximal to the nail bed of each finger (Figs. 6-8). In this area of the finger, blood flow is abundant and it is easy to obtain a blood sample. Moreover, the area has fewer tactile and pain receptors than the fingertip, and thus when lanced less pain is produced.

Six fingers were used in a random fashion to evaluate puncture of the anterior part of the finger, the periungual zone and the lateral area of the fingertip (depth 0.2-0.6 mm), and compared to fingertip puncture at a depth of 0.6 mm. The sensation provoked by puncture (with or without pain) was used to compare groups. Pain was evaluated using a VAS ranging from ‘no pain’ to ‘worst pain imaginable’. The VAS is a unidimensional tool that quantifies the subjective sensation such as pain felt by the patient and considers physical, psychological and spiritual variables without distinguishing the impact of the different components.


Figure 5. New lancet


Figure 6. Proximal lateral area of the nail bed as a new site of puncture.


Figure 7. Method of lancing.


Figure 8. Site of lancing

Blood glucose was measured in the morning after 12 hours of fasting. The Fine Touch glucometer used was provided by Terumo Corporation (Tokyo, Japan). Statistical analysis was carried out using Fisher’s two-sided test. Differences in blood glucose with the two methods were analysed using Wilcoxon matched pairs signed ranks test. A P value <0.05 was considered statistically significant.

Results

Pain was not perceived in 90% and 94.28% of subjects punctured in the lateral area of the fingertip at a depth of 0.2 and 0.3 mm, respectively. At a depth of 0.4 mm, 67.14% of subjects did not perceive pain, while at 0.5 mm and 0.6 mm, 47.14% and 17.14% of subjects did not feel pain, respectively. There was no significant difference in pain considering punctures at 0.2 or 0.3 mm, while significant differences were seen between 0.2 and 0.4 mm (p <0.05), 0.5 mm (p <0.001) and 0.6 mm (p <0.001). All subjects who performed puncture in the central zone of the fingertip referred a painful sensation.

Using a periungual puncture site, pain was not referred by any subject, although a bothersome sensation was noted by some. The same results were obtained for all fingers used. Blood glucose levels obtained using traditional and alternative puncture sites were highly similar with no significant differences between groups (134.18 mg/dl ± 5.15 vs. 135.18 mg/dl ± 5.71 mg/dl; p = 0.5957).

Discussion

The present study evaluated the use of alternative puncture sites that are associated with less pain. These encouraging results undoubtedly warrant further investigation in a larger cohort, but nonetheless suggest that compliance with SMBG can be optimised. The use of the area close to the nail bed allowed high quality blood samples to be obtained for measurement of blood glucose, with an accuracy that was the same as that seen using the fingertip. The design of the lancet used herein was also associated with a lower perception of pain, which is composed of a hypodermic needle in a rigid casing that prevents accidental needle sticks both before and after use. Thanks to the needle point that was made using a triple-bevel cut, epidermal penetration is less traumatic and as a consequence less painful. This further favours rapid recovery of tactile function of patients with T2D. This allows the use of a larger transversal section using a puncture with less depth, and less involvement of nerves present in skin. In addition, the characteristics of the novel lancing device (Fine Touch, Terumo Corporation, Tokyo, Japan) allows adjusting the depth of puncture to the characteristics of each patient (e.g. in children, adolescents and adults).

The depth of penetration of the lancet can be varied from 0.3 to 1.8 mm with a self-incorporated selector; the maximum deviation of the lancing device in terms of depth is approximately 0.1 mm. Due to the possibility to select a minimal depth of only 0.3 mm, it can be used at alternative sites that allow a reduction in the frequency of samples taken from the fingertip. In theory, compared to traditional lancets, this would allow less perception of pain even at traditional sites as well as at periungual zones, and it was our intention to compare the different types of lancets to reinforce this idea. No puncture-related complications were reported, and another fundamental aspect that is not reported in other studies comparing traditional and alternative puncture sites is that no differences in blood glucose were observed.

In conclusion, it is our belief that a new type of finger lancet that decreases or eliminates pain associated with lancing merits additional consideration. Further studies are warranted on larger patient cohorts to confirm the present results. If validated, this would enable patients with diabetes - especially those who need to take several daily blood glucose samples - to perform SMBG with greater peace of mind and less distress.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
CRISAFULLI CRISTIANO, MASSIMO CATANUSO, CARMELO DI GREGORIO, ADRIANA DI GREGORIO, GAETANO PROFETA, ANTONINO DI GUARDO - Italian College of General Practitioners, Via del Pignoncino 9/11, Florence, Italy.
Corresponding Author Details: 
CRISTIANO CRISAFULLI, Via Livorno, 1 - 95127, Catania, Italy.
Corresponding Author Email: 
cricrisa@tin.it
References
References: 
  1. Koschinsky T1, Jungheim K, Heinemann L. Glucose sensors and the alternate site testing-like phenomenon: relationship between rapid blood glucose changes and glucose sensor signals Diabetes Technol Ther. 2003;5(5):829-42
  2. Heinemann L. Finger Pricking and Pain: A Never Ending Story J Diabetes Sci Technol Vol 2, Issue 5, September 2008 p. 919-921

Tumefactive Multiple Sclerosis Masquerading as Cancer

Authors
Kamran Khan, Susan E. Wozniak, JoAnn Coleman
Article Citation and PDF Link
BJMP 2015;8(4):a832
Abstract / Summary
Abstract: 

Tumefactive Multiple Sclerosis (MS) is a rare variant of MS that is extremely difficult to diagnose. It can resemble malignancy and perplex the clinician until all diagnostic tests are exhausted. A brain biopsy is not required to treat for the disease, as it is in CNS malignancy. Newer diagnostic tests are available that allow diagnosis to be attained and treated presumptively. Presented is a case of a 48-year-old female that mimicked metastatic malignancy. We were able to use surveillance MRI and CSF analysis to diagnose our patient.

Abbreviations: 
ECG- Electrocardiogram, CSF- Cerebrospinal Fluid, CN- Cranial Nerve, V/Q- Ventilaion/Perfusion, CA- Cancer Antigen, AFP- Alpha Feto Protein,
Keywords: 
Tumefactive Multiple Sclerosis, MS, Demyelinating lesion

Introduction

Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States and 2.5 million worldwide.1 There are rare variants of this disease that can profoundly delay diagnosis and treatment. Examples of such variants include: Tumefactive MS, Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, Marburg’s MS and Balo Concentric Sclerosis.2 These variants have a uniquely aggressive presentation and do not exhibit classic MS features.2 Classic MS features include relapsing and remitting sensory and motor impairments, optic neuritis and pain. These aggressive variants are more likely to present with symptoms similar to neoplasm such as motor impairments and seizures. When dealing with these aggressive MS variants diagnostic options include Magnetic Resonance Imaging (MRI), Single Photon Emission Computed Tomography (SPECT) scan, MR spectroscopy and Cerebrospinal Fluid (CSF) analysis.3

Invasive tests such as brain biopsy are not warranted unless absolutely necessary. In MS, a biopsy must not be completed in order to confirm a diagnosis. However, to confirm a diagnosis of cancer a biopsy is required.

We present a rare case of Tumefactive MS that exhibited a clinical picture identical to brain metastasis. This was diagnosed with surveillance MRI and CSF analysis in the absence of a brain biopsy.

Case presentation

A 48-year-old African American female was brought in by emergency medical services after falling with a brief loss of consciousness. Associated symptoms included dull chest pain, diaphoresis and shortness of breath. While in the emergency department she also developed nausea, vomiting and dizziness. The patient reported no similar previous episodes and denied precipitating events. There was nothing else to note on review of systems. The past medical history included hypertension with no previous surgeries and family history included breast cancer of the mother diagnosed at age 47. The patient denied tobacco, alcohol and intravenous drug use. She noted an allergy to iodine.

On physical examination the patient was afebrile, normotensive and tachycardic with an oxygen saturation of 89% on room air. She was alert and oriented but pale and diaphoretic with mild left sided chest pain. Cardiac examination revealed a normal rhythm tachycardia and no murmurs were heard. Her neurological examination showed a normal mental status, normal cognition/comprehension and that Cranial Nerves II-XII were intact.

Laboratory findings included haemoglobin of 9.8 g/dL, 30.8% haematocrit and potassium of 3.3 mmol/L. Electrolytes were otherwise normal. Cardiac workup showed a normal ECG and slightly elevated cardiac enzymes of 0.319 ng/mL.

Given the patients tachycardia and desaturation, a stat Ventilation-perfusion (V/Q) scan was completed (patient had an iodine allergy). The V/Q scan revealed a perfusion defect suggesting pulmonary embolism (PE) as the cause of symptoms. Subsequently the patient was placed on appropriate anticoagulation.

Head CT (computed tomography) showed a left centrum semiovale round hypodense lesion measuring 1.4 cm, a left basal ganglia round hypodense lesion measuring 1.0 cm and a left occipital lobe round hypodense lesion measuring approximately 1.0 cm (Figure 1). No midline shift was seen. MRI showed multiple hypointense T1/hyperintense T2 nonenhancing lesions, mainly within the left cerebrum (Figure 2 A-F). The three largest lesions within the left posterior centrum semiovale (2A), left globus pallidus (2B) and left posterior corona radiata adjacent to the occipital horn (2C) measured 1.5 cm, 1.0 cm and 1.0 cm respectively. Perilesional vasogenic oedema was seen in all except the basal ganglia lesion. There were bilateral cerebral scattered foci of hyperintense FLAIR/T2 signals (D-F). The imaging suggested a differential diagnosis which included metastasis, infection or primary CNS malignancy.

Further work up in search for possible malignancy was completed. Skin map revealed no concerning nevi. Mammogram showed no tumor. CT of the abdomen and pelvis revealed a 2.6 cm indeterminate hypodense lesion in the left lobe of the liver (Figure 3A) along with an enlarged fibroid uterus (17x 7 x 14 cm). Liver biopsy was considered but a repeat MRI and ultrasound showed the lesion to be cystic, so this was deferred following surgical oncology recommendations (Figure 3B). For the hypertrophic uterus found on imaging, gynecology felt no further workup was necessary as they attributed the findings to a fibroid uterus.

Tumor markers CA 27-29, CA 19-9, CA 125 and AFP were all sent and came back negative. Initial lumbar puncture with CSF analysis was not completed secondary to possible complications that could be incurred while on necessary PE anticoagulation.

Due to a non-focal neurological examination, she was discharged on Levetiracetam 500 mg for seizure prophylaxis and Dexamethasone 4 mg for perilesional oedema. Over subsequent months the patient did well without headaches, vision changes or seizure like activity. On subsequent visits to the clinic, she had no evidence of focal neurological deficits except for mild bilateral symmetric hyperreflexia. Given that the metastatic work up remained negative, we considered obtaining a baseline Positron emission tomography (PET) scan to ensure we were not missing any possible metastasis.

She subsequently went back to work full-time and reported no symptoms. Repeat MRI of the head (Figure 4 A-C) showed predominantly T1 hypointense and T2 hyperintense (A-B) lesions with significant decrease in size from MRI done three months ago. These lesions demonstrated no enhancement to incomplete ring enhancement, with diminished vasogenic oedema (A). These findings suggested an inflammatory demyelinating process so a lumbar puncture was obtained after anticoagulation was held. CSF analysis was done using Isoelectric Focusing (IEF) and immunoblotting methodology. This revealed a normal myelin basic protein but with eight oligoclonal bands restricted to the CSF. These findings solidified the suspicion of Tumefactive MS.


Figure 1. Head CT without contrast: left centrum semiovale round hypodense lesions measures 1.4 cm with perilesional vasogenic edema


Figure 2. MRI of brain showing axial T1-weighted (A-C) hypodense lesions of the left centrum semiovale(A), left basal ganglia(B) and left occipital lobe(C). Axial T2-weighted (D-F) views show multiple hyperdense lesions corresponding to the same locations. Perilesional vasogenic edema is seen.


Figure 3A. Thorax CT without contrast. 2.6 cm left lobe liver lesion.


Figure 3B. MRI of abdomen showing coronal T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE) hyperdense lesion. A mildly enlarged liver measuring 18.7 cm in craniocaudal span. Simple 2.8 x2.4 cm cyct in the medial segment of left lobe.


Figure 4. MRI of brain (3 month after initial scans) showing axial T-2 weighted (A-B) hyperdense lesions of the left centrum semiovale(A) and left basal ganglia(B). There is irregular peripheral enhancement. Considerable decrease in size is seen from previous MRI (Figure 2). Left posterior centrum semiovale, left globus pallidus and left occipital lobe lesion measure 1.3 cm, <1 cm and <1 cm respectively. Vasogenic edema is diminished in comparison to previous study.

Discussion

Tumefactive MS lesions are defined as solitary demyelinating plaques greater than 2 cm.5 Lesions are difficult to distinguish between primary or metastatic given similarity of imaging features.5 Imaging features suggestive of Tumefactive MS include incomplete ring enhancement, absence of mass effect and absence of cortical involvement.6 7 Kim describes that CT hypoattenuation of magnetic resonance enhancing lesions was found to be highly specific for distinguishing Tumefactive MS lesions from CNS cancer pathology.6 It has been shown that SPECT using I-IMP is useful for diagnosing CNS malignancy.3 This is because there would be increased uptake in comparison to the MS lesions - implying increased metabolic activity.3 However this study has its limitations in diagnosis. In a few isolated cases I-IMP was found in greater quantities in MS tumor-like lesions.3

The imaging studies for this patient established a concern for metastasis, infection or primary malignancy. Extensive cancer workup was completed as previously discussed. Since all tumor markers were negative a baseline PET scan was considered however, was not done secondary to insurance denial. Due to the asymptomatic presentation of her disease, a primary differential diagnosis of brain metastasis and anticoagulation therapy for PE, a CSF analysis was not considered until much later. We were able to use surveillance MRI and CSF analysis to see some resolution of these lesions and confirm the diagnosis. Brain biopsy was never warranted but in unique symptomatic cases it may have been.6

The cornerstone of diagnosing MS is the demonstration of lesions in both time and space - termed the McDonald Criteria.8 The revised criteria allow a diagnosis of MS, “possible MS” or “not MS”.8 This is what made the diagnosis of our patient difficult, as no clinical symptoms or attacks were evident. It was demonstrated that over the course of three months the lesions seen on MRI evolved. From the size of 1.5 cm, 1.0 cm and 1.0 cm they became 1.3 cm, <1.0 cm and <1.0 cm respectively (Figure 2, Figure 4). This was likely the effects of steroids that the patient was on due to her vasogenic oedema. Here an evolution in time and space is demonstrated which excluded brain metastasis and infection. This brings into discussion the diagnostic value of surveillance MRI, which in our case was helpful and appropriate as the patient did not have clinical symptoms.

Conclusion

The diagnosis of Tumefactive MS can be extremely difficult and time consuming. As seen in our case, it can mimic other conditions. Our patient was able to be diagnosed with MRI surveillance and CSF analysis. The definitive diagnostic test for MS is a brain biopsy but this is not preferred due to the invasiveness of the procedure. With the advent of newer diagnostic tests such as SPECT, MR Spectroscopy, surveillance MRI and CSF analysis, diagnosis can be attained and treated presumptively.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We would like to acknowledge Dashartha Harsewak MD for interpreting radiological scans, Musarat Shareeff MD for valuable guidance and Anna Lucia Giannone for input on figure design.
Competing Interests: 
None declared
Details of Authors: 
KAMRAN KHAN, Medical Student, Sinai Hospital, Baltimore, MD, USA. SUSAN E. WOZNIAK, MD, MBA, General Surgery Resident, Sinai Hospital, Baltimore, MD, USA. JOANN COLEMAN DNP, ANP, ACNP, AOCN, Acute Care Nurse Practitioner & Clinical Program Coordinator, Sinai Center for Geriatric Surgery, Baltimore, MD, USA.
Corresponding Author Details: 
KAMRAN KHAN, Sinai Hospital, Baltimore, MD, USA.
Corresponding Author Email: 
kamkmd92@gmail.com
References
References: 
  1. Hersh CM, Fox RJ. Multiple Sclerosis [Internet]. Clevelandclinicmeded.com. 2014 [cited June 2015] Available from:  http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/
  2. Hamed SA. Variant of multiple sclerosis with dementia and tumefactive demyelinating brain lesions. World J clin cases. 2015 June 16; 3(6): 525-532
  3. Sagiuchi T, Oka H, Utsuki S. Increased accumulations of N-isopropyl-p-[123I]- iodoamphetamine related to tumefactive multiple sclerosis. Annals of Nuclear Medicine Vol. 2005;19,No. 7;603-606,
  4. Yamada S, Yamada MS, Nakaguchi H. Tumefactive multiple sclerosis requiring emergent biopsy and histological investigation to confirm the diagnosis: a case report. Journal of Medical Case Reports. 2012;6:104
  5. Fallah A, Banglawala S. Ebrahim S. Tumefactive demyelinating lesions: a diagnostic challenge. Can J Surg. 2010;53, No. 1
  6. Jitawatanarat P, Tingpej B, Deringer P. Tumefactive Multiple sclerosis. BJMP.  2011;4(2):a419
  7. Kim DS, Na DG, Kim KH. Distinguishing tumefactive demyelinating lesions from glioma or central nervous system lymphoma: added value of unenhanced CT compared with conventional contrast-enhanced MR imaging. Radiology. 2009 May;251(2):467-75.
  8. McDonald WI, Compston A, Edan G. Recommended diagnostic criteria for multiple sclerosis: guidelines from the   International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001 Jul;50(1):121-7.

Acute reversible cardiomyopathy due to methamphetamine overdose

Authors
Ashok Raj Devkota, Alix Dufrense and Premraj Parajuli
Article Citation and PDF Link
BJMP 2015;8(4):a830
Abstract / Summary
Abstract: 

Methamphetamine abuse is associated with various cardiac complications like acute coronary syndrome, cardiomyopathy and sudden cardiac death. We report a case of patient who presented with cardiomyopathy and acute heart failure due to intravenous methamphetamine abuse. His cardiac function recovered fully after medical management. 

Abbreviations: 
EKG: Electrocardiogram, ECHO: Echocardiogram, CT: Computed tomography, LVEDP: Left ventricular end diastolic pressure
Keywords: 
Methamphetamine, cardiomyopathy, heart failure

Introduction

Methamphetamine and related compounds are the most widely abused drugs in the world after cannabis 1. Methamphetamine is a synthetic stimulant which acts both on central and peripheral nervous system. It causes the release and blocks the reuptake of dopamine, norepinephrine, epinephrine and serotonin in neuronal synapse. Methamphetamine can be smoked, snorted, injected or ingested orally. Methamphetamine is more potent, and its effects last longer than cocaine 2, 3.

Methamphetamine intoxication causes various systemic complications like sympathetic over activity, agitation, seizure, stroke, rhabdomyolysis and cardiovascular collapse. Acute cardiac complications of methamphetamine like chest pain, hypertension, arrhythmias, aortic dissection, acute coronary syndrome, cardiomyopathy, and sudden cardiac death have been reported 4, 5. Chronic methamphetamine use is associated with coronary artery disease, chronic hypertension and cardiomyopathy 6.

Here we present a case of methamphetamine overdose, which presented with cardiomyopathy and severe systolic heart failure whose cardiac function was normalized after treatment.

Case presentation

A 38-year-old male presented with shortness of breath, chest tightness and sweating which started after he used intravenous crystal meth the day before presentation. He was an active poly substance abuser and used different drugs like marijuana, alprazolam, amphetamine, cocaine, percocet (oxycodone and acetaminophen) and clonazepam regularly. He was on methadone maintenance program as well. The patient did not have any cardiac problem in the past. He had a seizure disorder but he was not on medication. He had an episode of a seizure after methamphetamine use. His review of system was otherwise unremarkable.

On presentation he was tachycardic, his pulse was 128/min and his temperature was 98 degree Fahrenheit. He had bilateral diffuse crackles on lung bases. Troponin I was high 4.23 ng/ml (reference 0.01-0.05 ng/ml) and BNP was high 657 pg/ml (reference 0-100pg/ml). His electrolytes, renal function, liver function and creatinine kinase were normal. Urine toxicology was positive for opiate, methadone, amphetamine, benzodiazepine, cocaine and cannabinoid. Electrocardiogram showed sinus tachycardia at rate 130/min and QTc was prolonged at 488ms (Figure 1).


Figure 1 - Electrocardiogram: Sinus tachycardia at 130/min with prolonged QTc

Subsequently the patient became tachypnoeic and hypoxic, was intubated, put on a mechanical ventilator, and sedated with versed, fentanyl and propofol. Arterial blood showed respiratory acidosis and hypoxia. The patient was in cardiogenic shock and dopamine drip was started and intravenous Lasix was given. A subsequent chest X-ray showed newly developed pulmonary congestion. Echocardiogram showed left ventricular dilatation with diffuse hypokinesis and depressed systolic function. The left atrium was dilated. He had moderate diastolic dysfunction, mild mitral regurgitation and tricuspid regurgitation with a pulmonary artery pressure of 38mmHg. There was global left ventricular function was reduced and ejection fraction was 25-30%. His CT head was negative for an infarct or hemorrhage. He was managed in the cardiac care unit and responded very well to treatment. He became haemodynamically stable and dopamine was discontinued; aspirin, clopidogrel and carvedilol were started. The patient gradually improved and was extubated. Cardiac catheterization showed normal coronaries and normal left ventricular function. LVEDP was 18mmHg. His repeat echocardiogram one week later showed normal left ventricular systolic and diastolic function with an ejection fraction of 70%. The patient was discharged to drug rehab after eight days of treatment.

Discussion

This patient used intravenous crystal meth after which his problem started, so the most likely culprit was methamphetamine. Although he used multiple drugs including cocaine and amphetamine, which have acute and chronic effects on the heart, his cardiac function was normal before. Different mechanisms for cardiac injury due to methamphetamine have been proposed which include catecholamine excess, coronary vasospasm and ischaemia, increase in reactive oxygen species, mitochondrial injury, changes in myocardial metabolism, and direct toxic effects 3.Methamphetamine use is known to cause acute and chronic cardiomyopathy and the reversal of cardiac failure has been documented after discontinuing the drug. In one case report, a patient with chronic methamphetamine-associated cardiomyopathy did not demonstrate late gadolinium enhancement, consistent with an absence of significant fibrosis, and had left ventricular function recovered with 6 months of medical therapy and decreased drug abuse 7. Another case of a female 42 year old methamphetamine user who had transient left ventricular dysfunction and wall motion abnormalities and an index ventriculogram showed apical ballooning consistent with Takotsubo cardiomyopathy; her left ventricular function significantly improved after 3 days of medical treatment 8. In our patient, acute cardiomyopathy resolved quickly with intensive medical management. It is not clear how long it takes for cardiomyopathy to revert to normal after discontinuing the drug, or at what stage cardiac damage is irreversible. Many patients who use methamphetamine also ingest other drugs as well. It is unclear to what extent the use of multiple drugs play synergistic role in the cardiac complications that occur. Among patients who present with cardiomyopathy and cardiogenic shock, the usage of drugs like methamphetamine and co-ingestion of other drugs should be considered. Further study is needed to recommend treatment for methamphetamine and related drugs induced cardiomyopathy.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ASHOK RAJ DEVKOTA, MD, Resident, Department of Internal medicine, Interfaith medical Center, Brooklyn, NY. ALIX DUFRENSE, MD, Chair, Department of Cardiology, Interfaith Medical Center, Brooklyn, NY. PREMRAJ PARAJULI, MD, Resident, Department of Medicine, Interfaith Medical Center, Brooklyn, NY.
Corresponding Author Details: 
ASHOK RAJ DEVKOTA, MD, Resident, Department of Internal medicine, Interfaith medical Center, 1545 Atlantic Ave, Brooklyn, NY 11213.
Corresponding Author Email: 
ashokdevkota@hotmail.com
References
References: 
  1. World Drug Report 2012  8/21/2014; Available from: http://www.unodc.org/documents/data-and-analysis/WDR2012/WDR_2012_web_small.pdf.
  2. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. 2011; Available from: http://samhsa.gov/data/2k13/DAWN2k11ED/DAWN2k11ED.htm#3.2.
  3. Won, S., et al., Methamphetamine-associated cardiomyopathy. Clin Cardiol, 2013. 36: p. 737-42.
  4. Hawley, L.A., et al., Cardiac complications of adult methamphetamine exposures. J Emerg Med, 2013. 45: p. 821-7.
  5. Yeo, K.K., et al., The association of methamphetamine use and cardiomyopathy in young patients. Am J Med, 2007. 120: p. 165-71.
  6. Kaye, S., et al., Methamphetamine and cardiovascular pathology: a review of the evidence. Addiction, 2007. 102: p. 1204-11.
  7. Lopez, J.E., et al., Recovery of methamphetamine associated cardiomyopathy predicted by late gadolinium enhanced cardiovascular magnetic resonance. J Cardiovasc Magn Reson, 2009. 11: p. 46.
  8. Srikanth, S., R. Barua, and J. Ambrose, Methamphetamine-associated acute left ventricular dysfunction: a variant of stress-induced cardiomyopathy. Cardiology, 2008. 109: p. 188-92.

Acute Oesophageal Necrosis: A Case Report and Review Of The Literature

Authors
Sabina Beg and David Rowlands
Article Citation and PDF Link
BJMP 2015;8(3):a829
Abstract / Summary
Abstract: 

Here we present a case of Acute Oesophageal Necrosis, a rare but increasingly recognised endoscopic finding. At gastroscopy distal necrosis of the oesophagus is observed. This condition is associated with a poor prognosis and therefore diagnosis should prompt aggressive correction of abnormal physiology.

Abbreviations: 
AON - Acute Oesophageal Necrosis

CASE

A 79 year old lady presented to the accident and emergency department with severe abdominal pain. On admission she was hypotensive and hypothermic. Blood tests demonstrated raised inflammatory markers and white count, but were otherwise unremarkable. A CT scan revealed no abnormalities. She was treated with intravenous fluids and empirical antibiotics.

She had multiple co-morbidities, including ischaemic heart disease, hypertension and chronic kidney disease.


Figure 1 – Upper Oesophagus


Figure 2 – Distal Oesophagus


Figure 3 - Gastro-eosophageal Junction


Figure 4 – Stomach (in retroflexion)


Figure 5 - Duodenum

Three days into her admission she had a single episode of hematemesis and a gastroscopy was arranged. Endoscopic features were as per figures 1- 5. Histology taken at the time showed necrotic tissue with evidence of candidiasis. Her treatment was optimised with a two-week course of fluconazole with the dose adjusted for her renal function and parenteral nutrition, with good clinical response. She was discharged after a two week hospital admission. A repeat gastroscopy 10 weeks later showed complete resolution of endoscopic features with no evidence of perforation or stricture formation.

DISCUSSION

The images seen at endoscopy demonstrate a region of oesophageal ulceration progressing to a diffuse, circumferential, black discoloration of the distal esophageal mucosa, with an abrupt transition to normal mucosa at the gastro-esophageal junction (Figs. 1-3). These endoscopic features, in the absence of a history of ingestion of caustic substances, are diagnostic of Acute Oesophageal Necrosis (AON), also known as ‘Black Oesophagus’. Whilst histology confirming necrosis is not necessary to make the diagnosis, it is confirmatory.

AON was first described in 1990 by Goldberg et al, since which over one hundred cases have been reported in the literature1. Population studies have suggested the incidence of this condition to be between 0.08% and 0.2%, although interestingly one post-mortem series of 1000 patients failed to reveal any cases2-4. There is a male preponderance, with an incidence four times greater than that for women and a peak incidence during the sixth decade of life5, 6.

The aetiology of this condition is not entirely clear; however case reports to date suggest that this is almost exclusively observed in those who are systemically unwell, usually in the context of multi-organ dysfunction5-7. It has been postulated that necrosis most commonly occurs as a consequence of hypo-perfusion caused by a low flow state in those with underlying vascular disease. This is likely to account for the predilection for the distal third of the esophagus, which is relatively less vascular5. Individual cases have occurred in association with bacterial, viral and fungal infections, whilst malnutrition, malignancy and immune-compromise appear to be important factors3, 5, 6.

The most common indication for the gastroscopy that makes the diagnosis of AON is hematemesis and melena, accounting for over 75% of cases6. It is therefore likely that AON is significantly under reported as endoscopy is often precluded in those who are clinically unstable. Further it is not clear whether hematemesis is a universal symptom of this condition; it is conceivable that AON may go undiagnosed in those in whom this is not a feature.

Whilst AON has no specific treatment, its presence is indicative of significant systemic compromise and predicts a poor prognosis. This diagnosis should alert physicians that close monitoring and aggressive treatment is required to optimise patient outcomes. There is no clear role for the use of anti-acid therapy, however this is commonly used in management due to patient symptoms, which usually includes hematemesis. Similarly, candidiasis may occur in conjunction with AON, whilst it is not thought to be causative, treatment is considered prudent given the poor prognosis associated with this condition.

For those that recover from their acute systemic insult the prognosis appears to be good. The long-term sequale of this condition includes oesophageal stenosis due to structuring. Evaluation with a repeat gastroscopy if therefore indicated if dysphagia develops.

CONCLUSION

The clinical course of AEN is variable, with an associated mortality of 32%5. The severity of the underlying clinical condition appears to be the most important factor in determining prognosis. There is no specific treatment for AON. The current body of experience suggests aggressive management of abnormal physiology optimises outcomes5, 6. Antibiotics, antifungals and nutritional support should be considered on an individual basis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SABINA BEG, BSC MBBS MRCP, North East Hertfordshire Trust, UK. DAVID ROWLANDS MBBS FRCP, North East Hertfordshire Trust, UK.
Corresponding Author Details: 
SABINA BEG, Lister Hospital, North East Hertfordshire NHS trust, Correy Mill lane, Hertfordshire, SG1.
Corresponding Author Email: 
sabina.beg@nhs.net
References
References: 
  1. Goldenberg SP, Wain SL, Marignani P. Acute necrotizing esophagitis. Gastroenterology 1990; 98: 493 – 6.
  2. Ben Soussan E, Savoye G, Hochain P, e t al. Acute esophageal necrosis: a 1-year prospective study. Gastrointest Endosc 2002; 56: 213 – 17.
  3. Augusto F, Fernandes V, Cremers MI, e t al. A cute necrotizing esophagitis: a large retrospective case series. Endoscopy 2004; 36: 411 – 15.
  4. Postlethwait RW, Musser AW. Changes in the esophagus in 1,000 autopsy specimens. J Thorac Cardiovasc Surg. 1974; 68:953–956.
  5. Gurvits GE. Black esophagus: acute esophageal necrosis syndrome. World J Gastroenterol 2010; 16: 3219 – 25.
  6. Grudell AB, Mueller PS, Viggiano TR. Black esophagus: report of six cases and review of the literature, 1963-2003. Dis Esophagus. 2006;19(2):105-10
  7. Gurvits GE, S hapsis A, Lau N, e t al. Acute esophageal necrosis: a rare syndrome. J Gastroenterol 2007; 42: 29 – 38.

 

Do thalidomides have a role in the treatment of multiple sclerosis?

Authors
G.V. Sherbet
Article Citation and PDF Link
BJMP 2015;8(3):a828
Abstract / Summary
Abstract: 

Angiogenesis is pivotal component of many normal biological programmes as well as of pathogenetic processes involved in tumour growth and progression and of inflammatory and autoimmune diseases such as multiple sclerosis (MS), a demyelinating disease of the CNS. Many angiogenic factors are expressed in MS and in the animal model of MS known as experimental autoimmune encephalomyelitis. Inhibition of angiogenesis by suppressing these angiogenic effectors or inhibiting the elements of angiogenic signalling might provide a viable way to target therapy to manage MS. The focus of this article is on the ability of thalidomide and its analogues to inhibit angiogenic signalling systems. Thalidomide is a highly toxic drug but its analogues, lenalidomide and pomalidomide, show reduced toxicity and greater efficacy of growth suppression and inhibition of angiogenesis. The thalidomides are highly efficient suppressors of canonical and non-canonical angiogenic signalling by PI3K (phosphoinositide-3 kinase)/Akt, NF (nuclear factor)-κB and mTOR (mammalian target of rapamycin). Here a postulate is presented that the perceived potential synergy between the thalidomides and modulators of angiogenic signalling might deliver benefits of thalidomides more effectively and at lower dosages compatible with greater safety of administration.

Keywords: 
Multiple sclerosis; angiogenesis signalling; thalidomides

Angiogenesis is an integral process in biological programmes of embryonic development, tissue damage and regeneration, tumour growth and progression and pathogenesis of inflammatory and autoimmune diseases. MS (multiple sclerosis) is a demyelinating disease of the CNS (central nervous system). Angiogenesis has been a consistent feature of demyelinating plaques of MS1-3. Many inducers of angiogenesis are expressed in these plaques. They are also closely associated with the animal model of MS viz. EAE (experimental autoimmune encephalomyelitis)4 (Table 1). This has led to the suggestion that inhibition of angiogenesis by suppressing these effectors or inhibiting the elements of angiogenic signalling pathways might provide a viable way to target therapy to manage MS.

Table 1. Angiogenic mediators of MS

Angiogenic agent/mediator
Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2)
Nitric oxide (NO) and NOS (NO synthase)
Transforming growth factor-β (TGF-β)
Basic fibroblast growth factor (bFGF) ↓
Matrix metalloproteinases (MMP)
Hepatocyte growth factor (HGF)

[Note: Inhibitory effects of thalidomides were described by Sherbet4; D’Amato et al.6; Kenyon et al.7; Lu et al.8]

Multiple sclerosis is an autoimmune inflammatory condition and so immunomodulators have been used in treatment. It is recognised that aberrant activation of the immune system and the associated network of its regulation are important events in the pathogenesis of the disease. This is the rationale for using immunomodulatory agents in disease control. Among immunomodulators of note are Fingolimod which prevents infiltration of auto-destructive lymphocytes into the CSF, Teriflunomide which reduces lymphocyte infiltration of the CNS, axonal loss and inflammatory demyelination, and dimethyl fumarate, which modulates the immune system by many mechanisms. Furthermore, much attention has been devoted to the immunomodulatory properties of MSCs (mesenchymal stem cells) 4,5. Thalidomides are also capable of modulating the function of key element of the immune system related to the pathogenesis of MS, but this brief article is intended to emphasise the potential of thalidomide and its analogues as potent inhibitors of angiogenesis and the latent possibility of their use as a therapeutic agent in the control of MS.

Thalidomide was introduced over four decades ago to treat respiratory infections and to combat morning sickness in pregnant women. It was withdrawn when it was found to be highly teratogenic. The teratogenic effects are a result of the binding of thalidomide to cereblon, a protein found in both embryonic and adult tissues. Cereblon is required for normal morphogenesis. It is inactivated by binding to thalidomide and this leads to teratogenesis9. Thalidomide possesses immunomodulatory, anti-inflammatory, anti-angiogenesis and cell proliferation inhibitory properties and this has suggested its use in the treatment of cancer5. Analogues of thalidomide, viz. lenalidomide and pomalidomide, have been synthesised and these possess reduced toxicity and greater efficacy10, 11. Recently, many studies have elucidated the signalling pathways which thalidomides inhibit and thereby suppress cell proliferation, promote apoptosis and inhibit angiogenesis. These have led to the suggestion of combining the modulators of these signalling pathways to synergise with thalidomides to deliver the suppressor effects with enhanced efficacy and at lower concentrations thus reducing the side effects5 (Figure 1).

Most of the work on the efficacy of thalidomide and the analogues has been carried out in preclinical models. Quite understandably, in the clinical setting very little effort is seen to check whether thalidomide or the analogues provide any beneficial effects in MS or neuro-inflammation. Clinically orientated investigations so far relate mainly to multiple myeloma and some other forms of haematological malignancies but not solid tumours5. Any perceived beneficial effects are probably outweighed by the side effects. We need to expend more effort and design and develop new analogues with reduced toxicity. In this context one should emphasise that pre-clinical exploration of the potential synergy between the thalidomides and the acknowledged modulators of the signalling pathways would be worthwhile. This might enable the delivery of benefits more effectively and at lower dosages. It is needless to say that safety of drug administration is of paramount importance.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
G.V. SHERBET, DSc, FRSC, FRCPath, Institute for Molecular Medicine, Huntington Beach CA, USA and University of Newcastle upon Tyne UK.
Corresponding Author Details: 
G.V. SHERBET, Institute for Molecular Medicine, Huntington Beach CA, USA and University of Newcastle upon Tyne UK.
Corresponding Author Email: 
gsherbet@immed.org
References
References: 
  1. Holley, JE., Newcombe, J., Whatmore, JL, Gutowski NJ. Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci Lett 2010; 47: 65-70.
  2. Lengfeld, J., Cutforth, T., Agalliu, D. The role of angiogenesis in the pathology of multiple sclerosis. Vasc cell 2014; 6: 23-9.
  3. Girolamo, F., Coppola, C., Ribatti, D., Trojano M. Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol Commun 2014; 2: 84.
  4. Sherbet, GV. Molecular approach to targeted therapy for multiple sclerosis (submitted). (2015).
  5. Sherbet, GV. Therapeutic potential of thalidomide and its analogues in the treatment of cancer. Anticancer Res 2015; in press.
  6. D’Amato, RJ., Loughnan, MS., Flynn, E., Folkman, J. Thalidomide is an inhibitor of angiogenesis, Proc. Natl. Acad. Sci. USA  1994: 91: 4082–4085.
  7. Kenyon, BM., Browne, F., D’Amato, RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization, Exp Eye Res 1997; 64: 971–978.
  8. Lu, L., Payvandi, F., Wu, L., Zhang, LH., Hariri, RJ., Man HW. et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009; 77: 78-86.
  9. Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y. et al, Identification of a primary target of thalidomide teratogenicity, Science 2010; 327: 1345-1350.
  10. Botting, J. The history of thalidomide, Drug News Perspect. 2002; 15: 604-611.
  11. Bartlett, JB., Dredge, K., Dalgleish, AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents, Nature Rev Cancer 2004; 4: 314-322.

Generalized Lymphadenopathy : an unusual presentation of syphilis

Authors
Naziha Khammassi, Asma Gargoura, Haykel Abdelhedi, Youssef Kort, Manel Mabrouk and Ouahida Cherif
Article Citation and PDF Link
BJMP 2015;8(3):a827
Abstract / Summary
Abstract: 

This report describes a case of secondary syphilis represented by generalized lymphadenopathy . Histopathological analysis of biopsy specimen revealed the presence of a well-developed epithelioid granuloma  including  central  areas of caseous necrosis . As granuloma formation can be seen in numerous diseases, additional clinical and laboratory  diagnoses are necessary aids in the diagnosis of the granuloma aetiology .In this case  granulomatous lesion with caseous necrosis was highly suggestive of tuberculosis , but the identification by Ziehl-Neelsen staining was negative.However,  the   serologic tests of syphilis (VDRL and TPHA)  confirmed the diagnosis of syphilis. As illustrated by this case, syphilis should also be considered as a possible cause of generalized lymphadenopathy. Awareness by the clinician of such a presentation would make it easy to diagnose syphilis at an earlier stage.

Keywords: 
Syphilis; Granuloma; Diagnosis; Lymphadenopathy; Caseous necrosis.

Introduction

As syphilis is a notable clinical and pathological imitator, its diagnosis remains challenging. Physicians should be vigilant to suspect syphilis in cases of non-specific signs, such as lymphadenopathies, even in patients with no apparent risk for sexually transmitted infections or a history of primary syphilis.

Case Report

We report the case of a seventy-year old woman with a medical history of arterial hypertension. She had neither smoked cigarettes nor drunk alcohol and she had no significant medical family history. The patient presented with a history of swelling in the left axilla of one year duration. The swelling gradually increased in size and was painless. There was a history of occasional low-grade fever and weight loss, but no cough or night sweats.

On initial examination, the patient was thin with generalised lymphadenopathy: she had an axillary adenopathy that measured 4 cm in diameter in the right axilla and one measuring 3 cm in the left axilla. She also had two cervical lymph nodes that were less significant, and one enlarged right inguinal lymph node of about 3 cm in diameter. The existing lymph nodes were painless, mobile, mildly tender and smooth. Otherwise, breasts, limbs and other regions were essentially normal. No skin rash or suspect lesions were noticed. All her family members were well, with no contributory medical history, and none of them had similar symptoms.

A complete blood count revealed a white blood cell count of 5300/l (neutrophils 40%, eosinophils 19%, lymphocytes 30%, monocytes 10%), and a C-reactive protein of 14 mg/l. The remaining results of her full blood count, electrolytes, liver enzymes, lactate dehydrogenase and urine analysis were within normal limits. Calcium and phosphate levels were normal in both blood and urine analyses. Both human immunodeficiency virus screening and the serological tests for hepatitis B and C were negative. Mantoux test did not show any indurations. Smear and culture of the sputum were negative. Her chest x-ray and abdominal ultrasound were normal.

A CT scan of the patient’s neck and chest showed a marked anterior mediastinal mass of about 50 mm diameter with multiple calcifications. Several small lymph nodes were also noticed in the cervical and axillary areas. An axillary lymph node biopsy was performed. Histopathological examination of the biopsy specimen revealed a granulomatous lesion with epithelioid and multinucleated giant cells (Fig.1) associated with calcifications and central areas of caseous necrosis (Fig.2), which were highly suggestive of tuberculosis.

Fig 1: Epithelioid granuloma with giant cell

Fig 2: Eosinophilic granuloma with acellular caseous necrosis

According to these clinical and pathological findings, the most common granulomatous diseases are mycobacterial diseases such as tuberculosis, hence why the diagnosis of tuberculous lymphadenitis was highly suspected, and the patient was given anti-TB drugs. However, other differential diagnoses were considered, including bacterial infections like syphilis or actinomycosis, protozoal infections such as toxoplasmosis, and miscellaneous diseases such as sarcoidosis, Crohn's disease and Wegener's granulomatosis. To distinguish disease processes and make a definitive diagnosis, further investigations, such as special stains, culture methods and serologic tests, were indicated.

Additional histological stains, including Ziehl-Nielsen, were performed and returned negative, excluding the diagnosis of tuberculosis. In the meantime, the serological tests showed a positive venereal disease research laboratory test (VDRL: 1/8) and Treponema Pallidum haemagglutination assay (TPHA: 1/350). As a result, the diagnosis of secondary syphilis was confirmed and tuberculosis treatment was ceased.

The patient received intramuscular injections of 2.4 million units of benzathine penicillin every three weeks. Additional clinical and laboratory examinations were performed for both the patient and her family. She did not present with any manifestations of cardiovascular or neurological syphilis. Her husband’s VDRL and TPHA tests were negative. After a nine-month follow-up, the patient had no clinical or laboratory evidence of syphilis.

Discussion

Syphilis is predominantly a sexually-transmitted disease with both local and systemic manifestations. The causative organism is the spirochete Treponema Pallidum (TP) which was first demonstrated on the 17th of May 1905 1.

Syphilis has many non-specific signs and symptoms that may be overlooked by the physician, because in some cases it may simply be indistinguishable from other more common diseases. In fact, syphilis can share clinical manifestations with other treponemal and non-treponemal diseases, and it may be asymptomatic in some stages. Unfortunately, undiagnosed and untreated syphilis may lead to life-threatening complications such as hepatitis, stroke and neurological damage 2. Therefore its clinical diagnosis must be supported by laboratory tests.

Several older methods can be used to confirm syphilis diagnosis such as direct identification of TP by dark-field microscopy or direct fluorescent antibody tests, but such tests are not practical in a routine clinical setting and these methods can only be performed on lesion exudate or tissue 3.

As a consequence, the diagnosis in most patients is based on serological tests. Guidelines from the United States of America (USA) and Europe recommend a combination of two tests: the first one is a non treponemal (cardiolipin, reaginic) test, essentially Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR); and the second is a treponemal test, essentially TP haemagglutination assay (TPHA), TP particle agglutination, or the fluorescent treponemal antibody absorption (FTA-abs) test 3,4.

In our patient, the most significant clinical finding was lymphadenopathy. This case presented diagnostic difficulties because of its clinical and histopathological resemblance to other pathological conditions. In fact, the presence of generalised lymphadenopathy and the finding of granulomatous lesions with epithelioid cells in the biopsy were highly suggestive of tuberculosis. As a matter of fact, tuberculosis tops the list of aetiological causes of granulomatous infections5. Worldwide it is considered the leading cause of contagious disease leading to approximately 1.4 million deaths per year 6. Its prevalence is still extremely high in certain populations especially in low-and middle-income countries such as Tunisia where the disease is endemic.

Tuberculosis is caused by Mycobacterium tuberculosis (M. tuberculosis) and M. bovis, an acid and alcohol fast organism 7,8. Histopathology is characterized by the presence of epitheloid granuloma with Langerhans giant cells and central caseous necrosis 7.

Lymphadenitis is the most common extra-pulmonary manifestation of tuberculosis but its diagnosis is difficult, often requiring biopsy. In such granulomatous disease, and in cases of persisting doubts, it is necessary to identify the specific etiological agent by further investigations such as special stains, culture methods and molecular techniques like polymerase chain reaction (PCR) and serological tests, as in the case of syphilis.

In the case of tuberculosis infection, demonstration of the mycobacteria can be done with Ziehl-Neelsen staining or by immunofluorescence using auramine-rhodamine. Mycobacterial culture and detection of mycobacterial DNA using PCR are also used 7,9. Since the growth of mycobacterium in culture requires a long time, additional histological stain with Ziehl-Nielsen was performed, but returned negative in the case of our patient. As a consequence, the diagnosis of tuberculosis was excluded and syphilis was considered as a definitive diagnosis.

Conclusion

Granulomatous lesions can be seen in numerous diseases. A definitive diagnosis cannot be made on the basis of the history and physical examination alone, confirmatory testing should be performed in order to identify the specific etiologic agent correctly. Diagnosis of the disease in the initial stages would be beneficial not only to allow the patients to receive early treatment, but also to prevent the spread of the disease to others.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAZIHA KHAMMASSI, ASMA GARGOURA, HAYKEL ABDELHEDI, YOUSSEF KORT, MANEL MABROUK and OUAHIDA CHERIF, Department of Internal Medicine, Razi Hospital, 2010- Manouba, Tunisia.
Corresponding Author Details: 
NAZIHA KHAMMASSI, Doctor, Department of Internal Medicine, Razi Hospital, 2010- Manouba, Tunisia.
Corresponding Author Email: 
naziha.khammassi@rns.tn
References
References: 
  1. Schaudinn F, Hoffmann E, Vorläufiger Bericht über das Vorkommen von Spirochaeten in syphilitischen Krankheitsprodukten und bei Papillomen, Arbeit Kaiser-Klin.  Gesundheits 1905; 22: 527.
  2. Markle W, Conti T, Kad M. Sexually transmitted diseases. Prim Care. 2013; 40(3):557-87.
  3. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55: 997.
  4. Carol R. Emerson. Syphilis: A Review of the Diagnosis and Treatment. The Open Infectious Diseases Journal, 2009, 3, 143-147.
  5. Kumar SN, Prasad TS, Narayan PA, Muruganandhan J. Granuloma with langerhans giant cells: An overview. J Oral Maxillofacial Pathol. 2013; 17:420-3.
  6. World Health Organisation. Global tuberculosis report, WHO Library Cataloguing-in-Publication Data. Switzerland. 2012. p. 3 [chapter 1].
  7. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. AM J Respir Crit Care Med. 2000; 161(4 Pt 1):1376-95.
  8. Hernandez-Pando R, Bornstein QL, Aguilar Leon D, Orozco EH, Madrigal VK, Martinez Cordero E. Inflammatory cytokine production by immunological and foreign body multinucleated giant cells. Immunology. 2000; 100:352–8.
  9. Baek CH, Kim SI, Ko YH, Chu KC. Polymerase chain reaction detection of Mycobacterium tuberculosis from fine-needle aspirate for the diagnosis of cervical tuberculous lymphadenitis. Laryngoscope. 2000 Jan;110(1):30-4.

Hypertensive Crises – the Acute Take

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

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

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

Keywords: 
hypertension crisis emergency acute

Introduction

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

The What

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

The Why

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

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

The Who

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

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

The When

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

Evaluation

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

Present…

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

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


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

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

…and Past

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

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

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

Examination

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

Parameters

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

Physical

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

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

Investigation

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


Figure 2. Investigations in hypertensive crises

Bedside

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

Laboratory

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

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

Imaging

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

Treatment

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


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

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

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

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

Outcome

There…

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

…And Back Again

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

Key Points

Definition

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

Symptomatology

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

Investigations

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

Management

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

 

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

                            

Medical Pain - A Forgotten Cousin, or Lost Cause?

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

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

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

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

Introduction

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

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

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

Predictability & On-Call Skills

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

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

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

A Surgical Predilection?

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

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

Community Confounders

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

Chronicity

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

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

Fear of Pain

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

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

Conclusion

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

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ANDREW GRECH, M.D. (MELIT.), Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Details: 
ANDREW GRECH, Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Email: 
andrew-kristian.grech@gov.mt
References
References: 
  1. Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd Edition. IASP Press; 1994. Available at: http://www.iasp-pain.org/files/Content/ContentFolders/Publications2/FreeBooks/Classification-of-Chronic-Pain.pdf.
  2. Dix P. Pain on medical wards in a district general hospital. Br. J. Anaesth. 2004;92(2):235-237. doi:10.1093/bja/aeh052.
  3. Atkinson VJ, Almahdi B. A prospective audit project into the adequacy of pain assessment in the medical and surgical wards in a North London District General Hospital. Br. J. Pain 2013;8(2):78-83. doi:10.1177/2049463713510288.
  4. Siow S, Lim C, Cheng N, Zaslawski C, Wiltshire J. What Do The Junior Doctors Know About Pain Management And Opioids Use??: An Australian Study. J Geriatr. Palliat. Care 2014;2(2):9. Available at: http://www.avensonline.org/wp-content/uploads/2014/09/JGPC-2373-1133-02-0008.pdf.
  5. Australia and New Zealand College of Anaesthetists. Designing a Curriculum for Knowledge/skills in Pain Medicine in Postgraduate Years 1 and 2 (PGY 1 and 2).; 2011. Available at: http://www.fpm.anzca.edu.au
  6. Chang SH, Maney KM, Mehta V, Langford RM. Pain assessment and management in medical wards: an area of unmet need. Postgrad. Med. J. 2010;86(1015):279-84. doi:10.1136/pgmj.2008.076497.
  7. Cooper RJ. Over-the-counter medicine abuse - a review of the literature. J. Subst. Use 2013;18(2):82-107. doi:10.3109/14659891.2011.615002.
  8. Freburger JK, Holmes GM, Agans RP, et al. The rising prevalence of chronic low back pain. Arch. Intern. Med. 2009;169(3):251-8. doi:10.1001/archinternmed.2008.543.
  9. Carod-Artal FJ. Tackling chronic migraine: current perspectives. J. Pain Res. 2014;7:185. doi:10.2147/JPR.S61819.
  10. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur. J. Pain 2006;10(4):287-333. doi:10.1016/j.ejpain.2005.06.009.
  11. Turk DC, Robinson JP, Burwinkle T. Prevalence of fear of pain and activity in patients with fibromyalgia syndrome. J. Pain 2004;5(9):483-90. doi:10.1016/j.jpain.2004.08.002.
  12. Olsen Y, Daumit GL. Chronic pain and narcotics: a dilemma for primary care. J. Gen. Intern. Med. 2002;17(3):238-40. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1495025&tool=pmcentrez&rendertype=abstract. Accessed April 18, 2015.
  13. Blake S, Ruel B, Seamark C, Seamark D. Experiences of patients requiring strong opioid drugs for chronic non-cancer pain: a patient-initiated study. Br. J. Gen. Pract. 2007;57(535):101-8. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2034169&tool=pmcentrez&rendertype=abstract. Accessed April 18, 2015.
  14. Collett BJ. Chronic opioid therapy for non-cancer pain. Br. J. Anaesth. 2001;87(1):133-143. doi:10.1093/bja/87.1.133. 

EYE: “A clue to diagnosis”

Authors
K V K S N Murthy, Madhura Prasad, Mithra Prasad and V G Mohan Prasad
Article Citation and PDF Link
BJMP 2015;8(2):a817

A 38 year male presented to our centre with a two-month  history of jaundice. Past medical & family history was insignificant. Clinical examination revealed a icterus and greenish brown ring in both eyes (Figure 1). Laboratory investigations revealed a mild thrombocytopenia (platelet count-1.2 lakh/mm3) and a prolonged prothrombin time. Liver function tests showed elevated serum levels of alanine aminotransferase & aspartate aminotransferase. Serology for hepatotropic viruses was negative. Serum ceruloplasmin was 9.8 mg/dl (reference range 20-60mg/dl) and 24 hour urinary copper was elevated.


Figure 1

What is the eye finding?

  1. Arcus Senilis
  2. Pterygium
  3. Kayser Fleischer ring
  4. Phlycten

Correct Answer:

3. Kayser Fleischer ring

Discussion:

Wilson’s disease is a consequence of defective biliary excretion of copper. This leads to its accumulation in the liver and brain 1. It is due to mutations of the ATP7B gene on chromosome 13, which codes for a membrane-bound copper transporting ATPase 2.

Kayser-Fleischer ring is an outcome of abnormal copper deposition in the membrane in the limbus of cornea. Slit-lamp examination by an experienced observer is required to identify a K-F ring. The colour may range from greenish gold to brown. When well developed, a K-F ring may be readily visible to the naked eye. K-F ring is observed in most individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations. They are not entirely specific for Wilson’s disease, since they may also be found in patients with chronic cholestatic diseases.

Clinical presentation is variable and patients presenting with chronic hepatitis, cirrhosis & at times acute liver cell failure. The most common presenting neurologic feature is asymmetric tremor. The characteristic tremor is coarse, irregular proximal tremulousness with a “wing beating” appearance.

Typically, the combination of K-F rings and a low serum ceruloplasmin (<0.1 g/L) level is sufficient to establish a diagnosis of Wilson’s disease 3.  However delayed diagnosis in patients with neuropsychiatric presentations is frequent and was in one case as long as 12 years 4.Our patient was treated with a none copper diet, oral zinc and d pencillamine. His liver functions became normal over 6 months of treatment and without progression of liver disease.

Arcus Senilis is a grey band of apacity near the sclero-corneal margin, commonly found in the elderly and associated with hypercholesterolemia. Pterygium is a benign wedge shaped fibrovascular growth of conjunctiva that extends onto the cornea. Phylecten is consequence of allergic response of the conjunctive & corneal epithelium usually associated with tuberculosis, staphylococcus protein and moraxella.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
K V K S N MURTHY, MBBS, MD, (DM Gastroenterology), Registrar, Department of Gastroenterology, VGM Hospital & Institute of Gastroenterology, Coimbatore , India. MADHURA PRASAD, MBBS, MD Internal Medicine, DNB Gastroenterology, VGM Hospital & Institute of Gastroenterology, Coimbatore , India. MITHRA PRASAD, MBBS, MD Internal Medicine, VGM Hospital & Institute of Gastroenterology, Coimbatore , India. V G MOHAN PRASAD, MBBS, MD, DM Gastroenterology, MIASL, FCCP, FAGE, Chairman, VGM Hospital & Institute of Gastroenterology, Coimbatore , India.
Corresponding Author Details: 
Dr. K V K S N Murthy, MBBS, MD, (DM Gastroenterology), Registrar, Department of Gastroenterology, VGM Hospital & Institute of Gastroenterology, Coimbatore , India.
Corresponding Author Email: 
vamsikiran9@gmail.com
References
References: 
  1. Gitlin JD. Wilson disease. Gastroenterology 2003;125:1868–1877.
  2. Tao TY, Gitlin JD. Hepatic copper metabolism: insights from genetic disease. Hepatology   2003;37:1241–1247.
  3. EASL Clinical Practice Guidelines: Wilson’s disease. Journal of Hepatology 2012 vol. 56; pg 671–685.
  4. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical Presentation, diagnosis and long-term outcome of Wilson disease – a cohort study. Gut 2007;56:115–120.

Malignant Syphilis as an Initial Presentation of Underlying HIV Infection: A Case report

Authors
Ashok R Devkota, Rabindra Ghimire, Mirela Sam and Oo Aung
Article Citation and PDF Link
BJMP 2015;8(2):a816
Abstract / Summary
Abstract: 

There is a higher rate of HIV coinfection among men who have sex with men (MSM) infected with syphilis. HIV positive patients present more often with secondary syphilis and disease course is more aggressive. Here we present a patient, with diffuse papulo-nodular and ulcerative skin lesion and newly diagnosed human immunodeficiency virus. Biopsy of skin lesions confirmed the diagnosis of malignant syphilis, supported by serology results and he responded very well to doxycycline. It is important to recognize and diagnose malignant syphilis early and institute appropriate treatment as complete cure can be achieved.

Keywords: 
Malignant syphilis, human immunodeficiency virus (HIV), MSM

Introduction

The rate of primary and secondary syphilis reported in the United States is gradually increasing. Reported cases of syphilis decreased during the 1990s, were lowest in 2000, after which it gradually increased annually during 2001-20091. In a recent report published by CDC, primary and secondary syphilis rates have increased among men of all ages, races and ethnicities, largely among MSM, from 5.1 cases per 100,000 population in 2005 to 9.8 in 2013. Rates of 50%–70% HIV coinfection among MSM infected with primary and secondary syphilis have been reported2.  Syphilis and the behaviours associated with acquiring it, increase the likelihood of acquiring and transmitting HIV. Although the incidence of HIV has remained stable, the incidence of syphilis has been increasing disproportionately possibly due to adaptive behaviour like serosorting among HIV concordant couples and oral sex that decrease transmission of HIV but not syphilis3

Syphilis may manifest differently in patients with HIV. HIV positive patients present more often with secondary syphilis and the disease course is more aggressive4. Malignant syphilis also known as lues maligna or ulceronodular syphilis is a severe form of secondary syphilis and is more common among HIV infected persons5. Although HIV patients present with varied clinical symptoms, it is uncommon to present with florid secondary syphilitic skin lesions. Here we present a case report of a patient, who presented with diffuse ulceronodular skin lesions, whose serology and skin biopsy confirmed syphilis and was subsequently found to have HIV. 

Case report

A 20-year-old African American man was admitted to Interfaith Medical Center with a generalised body rash for a month. He noticed a rash on his chest, which in few days spread centrifugally to his whole body, face and arms, including palms and soles. The rash was non-pruritic, painless, progressive in size and gradually oozed and crusted (Figure 1a). Besides significant unintentional weight loss of 26 pounds in the last two months, he did not report any other systemic complaints. He denied any travel or unwell contacts. He is a homosexual man and has had two male sexual partners in the last two years; one of them was treated for syphilis two years ago. He denied smoking, alcohol or drug use.


Figure 1a - Skin lesions reveal papulosquamous nodular and ulcerative changes in upper limbs

On admission, he was afebrile with normal vital signs.  His physical examination revealed widespread papulonodular and ulcerated lesions on his whole body including the scalp and oral mucosa, and measured up to 2-3 cm. Skin lesions were prominent on his face, some with sero-purulent discharge and some covered with crusts and scabs, which would bleed on removal of crusts and scabs. No skin lesions were noted in genital area. Besides bilateral enlarged axillary lymph nodes, nosignificant lymphadenopathy was noted. Other systemic examinations were within normal limits.

His full blood count showed microcytic hypochromic anaemia with a mean corpuscular volume of 77.2 fL (normal reference range, 80-100 fL) and thrombocytosis with platelets of 546 per microliter (reference range, 130-400 per microliter). Renal and hepatic function tests were normal.  He tested positive for HIV using serum enzyme linked immunosorbent assay (ELISA), rapid plasma reagin was 1:128 (reference range, nonreactive), fluorescent treponemal antibody absorption test was reactive (reference range, nonreactive) and neurosyphilis was ruled out with negative spinal fluid studies.  Hepatitis B and Cserologieswere negative. Nucleic acid amplification test of the urine sample was negative for Neisseria gonorrhea and Chlamydia trachomatis. The patient was treated with doxycycline100 mg every 12 hours for secondary syphilis as he was allergic to penicillin.

The patient developed chills, fever, sweating, tachycardia and hypotension 18 hours after treatment with doxycycline. A Jarisch-Herxheimer reaction was suspected, which was managed with observation, intravenous hydration and a single dose of methylprednisone. Despite being on antibiotics, he had intermittent fever for two weeks, possibly related to the syphilis and its treatment. Further investigations included blood and urine culture, chest x-ray, CT scan of the head, chest, abdomen and pelvis and a gallium scan, which were unremarkable. Brucella IgM antibody, Q fever phase I and II antibodies, coccidioides antibody, histoplasma urine antigen,  cryptococcal antigen and blood culture for acid fast bacilliwere all negative. His EBVserologies suggested past infection and CMV serologies for IgG and IgM were positive. Wound culture taken from the purulent skin lesions grew methicillin sensitive Staphylococcus aureus (MSSA)which was treated with antibiotics. His HIV-1 RNA was 1050118 (reference range, <20) and CD4 was 276 cells per microlitre (reference range, 317-1868 cells per microlitre), CD4 was 17.4% (reference range, 25.7-62.8%) and CD4:CD8 ratio was 0.32 (reference range, 0.20-3.50). Skin biopsy from the left forearm lesion showed lichenoid lymphohistiocytic infiltrate with plasma cells (Figure 1b). Immunochemical stain was positive for spirochetes, which confirmed secondary syphilitic skin lesions (Figure 1c). After three weeks of doxycycline therapy, significant clinical improvement in the skin lesions were noted.  The skin lesions healed well with hyperpigmentation.  Combination anti-retroviral therapy was initiated upon discharge and on follow-up a month later, the skin lesions had resolved and the RPR titre was 1:32; showing a four-fold reduction. 


Figure 1b - A lymphocyhistiocytic infiltrate was present in the dermis and extended around blood vessels.


Figure 1c - Immunohistochemical stain showing delicate and spiral shaped spirochaetes, highly specific and sensitive of Treponema pallidum

Discussion

Skin lesions of secondary syphilis in patients with HIV may have varied appearance that mimic other diseases like cutaneous lymphomas, mycobacterial infections, bacillary angiomatosis, fungal infections or Kaposi’s sarcoma6.  Detail workup was done in our patient and systemic fungal and bacterial infections were ruled out. He had secondary infection of the skin lesions due to MSSA and was treated with doxycycline. Skin biopsy confirmed secondary syphilitic skin lesions. Histology showed abundant plasma cells and lymphocytesandtreponomes were demonstrated in the special immuno-histochemical stains.  Fisher’s diagnostic criteria for lues maligna include strongly positive RPR titre, a severe Jarisch-Herxheimer reaction, characteristic gross and microscopic morphology and rapid resolution of the lesions with antibiotics7.  Our patient had all of these features. Because of variable presentation of skin lesions and increased rate of false negative serological tests due to prozone phenomenon in patients with HIV, alternative diagnostic techniques like biopsy of skin lesions and special stains should be performed8,9.  The relative paucity of spirochetes in the biopsy of skin lesions makes the demonstration of microorganisms difficult. Yanagishawa et al were able to find 6 published cases of pathologically confirmed malignant syphilis with the demonstration of spirochetes10. Treatment of secondary syphilis in HIV infected patient is the same as that of HIV non infected patients. Benzathine penicillin is first line therapy and doxycycline is an alternative drug for penicillin allergic patients11. A severe Jarish-Herxheimer reaction occurred in our patient, which might not be observed in some cases with HIV and syphilis due to concurrent immunosuppression10. Experience from case reports have shown that malignant syphilitic skin lesions respond very well to antibiotics regardless of CD4 count12. With the increasing incidence of syphilis in HIV infected patients, it is important to recognise and diagnose malignant syphilis early and institute appropriate treatment as complete cure can be achieved.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We acknowledge our pathologist Dr Shamah Iqbal, MD for providing the histopathology and immunostain photographs.
Competing Interests: 
None declared
Details of Authors: 
ASHOK R DEVAKOTA, MBBS, MD: Internal Medicine Resident, Interfaith Medical Center, Brooklyn, NY, USA. RABINDRA GHIMIRE, MBBS, MD: Infectious Disease Fellow, The Dr. James J. Rahal, Jr. Division of Infectious Diseases, New York Hospital Queens, NY, USA. MIRELA SAM, MD: Attending and Chief-Infectious Diseases, Interfaith Medical Center, Brooklyn, NY, USA. OO AUNG, MD: Internal Medicine Resident, Interfaith Medical Center, Brooklyn, NY, USA.
Corresponding Author Details: 
drrabindraghimire@gmail.com
Corresponding Author Email: 
drrabindraghimire@gmail.com
References
References: 
  1. Division of STD prevention. Sexually Transmitted Disease Surveillance. C.D.C, 2012.  Jan 2014:2.
  2. Patton, M.E., et al. Primary and secondary syphilis--United States, 2005-2013. MMWR Morb Mortal Wkly Rep, 2014;63(18):402-6.
  3. Mayer, K.H. and M.J. Mimiaga. Resurgent syphilis in the United States: urgent need to address an evolving epidemic. Ann Intern Med, 2011; 155(3):192-3.
  4. Lynn, W.A. and S. Lightman. Syphilis and HIV: a dangerous combination. Lancet Infect Dis, 2004;4(7):456-66.
  5. Zetola, N.M., et al. Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection. Mayo Clin Proc, 2007; 82(9):1091-102.
  6. Yayli, S., et al. Late secondary syphilis with nodular lesions mimicking Kaposi sarcoma in a patient with human immunodeficiency virus. Int J Dermatol, 2014;53(1):  e71-3.
  7. Fisher, D.A., L.W. Chang, and D.L. Tuffanelli. Lues maligna. Presentation of a cas and a review of the literature. Arch Dermatol, 1969; 99(1):70-3.
  8. Pialoux, G., et al. Effect of HIV infection on the course of syphilis. AIDS Rev, 2008;10(2):85-92.
  9. Tucker, J.D., et al., Lues maligna in early HIV infection case report and review of the literature. Sex Transm Dis, 2009;36(8):512-4.
  10. Yanagisawa, N., et al. Pathologically confirmed malignant syphilis in an HIV-infected patient. Intern Med, 2011;50(20):2423-6.
  11. Zetola, N.M. and J.D. Klausner, Syphilis and HIV infection: an update. Clin Infect Dis, 2007;44(9):1222-8.
  12. Rallis, E. and V. Paparizos, Malignant syphilis as the first manifestation of HIV infection. Infect Dis Rep, 2012;4(1): e15.

Phytochemicals in cancer prevention and management?

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

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

Keywords: 
Cancer, diet, phytochemicals, polyphenols

Introduction

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

Classification

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

Table.1 Classification of phytochemicals with notable food rich sources

Polyphenols

1. Flavonoids

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

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

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

o Flavanones: naringenin, hesperitin (citrus fruit)

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

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

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

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

2. Phenolic acids

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

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

3. Other non-flavonoid polyphenols

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

o Curcuminoids: curcumin (turmeric)

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

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

Terpenoids

1. Carotenoid terpenoids

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

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

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

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

o Astaxanthin (salmon, shrimp, krill, crab)

2. Non-carotenoid terpenoids

o Saponins (chickpeas, soya beans)

o Limonene (the rind of citrus fruits)

o Perillyl Alcohol (cherries, caraway seeds, mint)

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

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

o Ginkgolide and bilobalide (Ginkgo biloba)

Thiols

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

o Allylic sulfides: allicin and S-allyl cysteine (garlic, leeks, onions)

o Indoles: Indole-3-carbinol (broccoli, Brussel sprouts)

Other phytochemicals

o Betaines found in beetroot

o Chlorophylls found in green leafy vegetables

o Capsaicin found in chilli

o Peperine in black peppers

Table. 2 learning points

Higher intake of phytochemical-rich foods such as colourful fruit, vegetables, herbs, pulses, spices and teas is associated with a lower risk of cancer and relapse after treatments.

Their anti-oxidant properties help to protect our DNA from ingested or environmental carcinogens.

Phytochemicals, particularly polyphenols have direct anti-cancer mechanism of action via inflammation, modulation of cellular and signalling events involved in growth, invasion and metastasis.

Concentrating element of foods such as minerals, vitamins and phytoestrogenic polyphenols to potentially boost their health effects have largely been unsuccessful in preventing cancer in clinical trials.

Whole food phytochemical-rich supplements have demonstrated significant benefits in phase II and well conducted RCT and their true potential is been evaluated in ongoing studies.

Clinical evidence for cancer prevention.

Although not all, many studies have linked a higher intake of phytochemical-rich foods, such as vegetables, fruit, legumes, nuts, herbs and spices, with a lower incidence of cancer as highlighted in the latest comprehensive review from the World Cancer Research Fund and other systemic reviews2,3.

More specifically, certain elements of food have been addressed within a number of cohort studies. Carotenoids found in leafy green vegetables and carrots have been linked with a lower risk of breast cancer in a recent meta-analysis demonstrated7 and a lower risk of ovarian and pancreatic cancers, especially among smokers in either questionnaire or serum-based studies8, 9, 10. Higher intake of cruciferous vegetables such as cabbage, cauliflower, Brussel sprouts, radishes and broccoli have been associated with a lower prostate cancer risk11, as have foods rich in isoflavones such as pulses and soy products12, lycopene rich colourful fruits and tomatoes13. Foods with abundant levels of flavonoids such as onions, rich in quercetin, have been shown to reduce the incidence of numerous cancers particularly those arising from the lung, especially amoung smokers14, 15. The anthoxanthins, in dark chocolate, have been reported to lower the risk of colon cancer16 and higher green tea intake lowers the risk of breast, prostate, ovarian and oesophageal cancer, again particularly among smokers and alcoholics17, 18. Finally, coffee consumption has been shown to reduce the risk of non-melanomatous skin cancers and melanoma, even after removing other factors such as ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake and smoking history19,20.

Clinical evidence for a benefit after cancer

The benefits of healthy foods do not stop after a diagnosis, especially if combined with other healthy lifestyle habits. For example, breast cancer survivors who regularly consumed more than the government recommended five portions of fruit and vegetables a day, had a third lower breast cancer recurrence risk if combined with regular physical activity21. In another study, women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, cruciferous vegetables and soya, were reported to have the lowest risk of death22. Likewise, a lignan and polyphenol rich diet was associated with a lower colorectal cancer relapse rate23.

The large Shanghai Breast Cancer Survival Study demonstrated that women with the highest intake of the phytoestrogenic polyphenols isoflavones and flavanone found in soya and other beans, had a 29% lower risk of relapse and death24. Similar findings were seen for green tea after breast25 and colorectal cancer23. Green tea also decreased the abnormal white cell count in 30% of patients with chronic leukaemia and reduced the levels of several markers of proliferation, as well as serum Prostate Specific Antigen (PSA) among men with prostate cancer26. A slowing of PSA progression has similarly been observed in other dietary studies, most notably the randomised trial involving a plant-based diet together with other lifestyle changes27 and a phase II study of pomegranate juice28.

Another cancer influenced by nutrition is skin cancer, as highlighted by a study of individuals who have been treated for basal cell carcinoma or squamous cell carcinoma, and who have a high risk of further lesions due to their on-going solar damage. Those who consumed the highest levels of lutein and zeaxanthin-rich foods, such as leafy green vegetables, had the lowest levels of new cancer formation29.

A number of other studies evaluating the impact of phytochemicals are underway, the largest and probably most comprehensive is the UK’s DietCompLyf prospective trial involving 3159 women treated for breast cancer30.

What are the likely anti-cancer mechanisms of phytochemicals?

The precise biochemical mechanisms through which phytochemicals exert their anti-cancer effects are still being explored, as their actions are wide-ranging and complex but significant advances have been made of late in the understanding the mode of action. The most quoted cancer prevention mechanism is via their antioxidant activity, elicited either through direct free radical absorption or through induction of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione via a variety of molecular mechanisms31, 32. One of these mechanisms is activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes31, 32. Phytochemicals, particularly the thiol class such as sulforaphane,have also been shown to inhibit the conver­sion of procarcinogens to their electrophilic, DNA damaging, chemicals32,33.

A number studies involving known, common carcinogens have highlighted the antioxidant properties of phytochemicals. A good example of their protective effect was an experiment involving the known house-hold carcinogen triclocarban, commonly found in detergents and cleaning agents. Healthy cells exposed to triclocarban tend to mutate into pre-malignant cells, however, the amount and rate of carcinogenesiswas significantly reduced byadding curcumin to the petri dish culture feeds34. In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to have improved SOD activity and higher urinary concentration of these polyphenols35. Rats exposed to cigarette smoke given indole-3-carbinol, a phytochemical rich in cruciferous vegetables, had a lower lung cancer rate than those not given idole-3-carbinol36. Subjects eating a meal of onions, which increased their serum levels of quercetin, demonstrated decreased levels of oxidative metabolites including 8-hydroxydeoxyguanosine (8-OHdG) a marker of DNA damage and repair1618, 37. Quercetin supplementation has also been shown to improving mitochondrial dysfunctions induced by the toxin 3-nitropropionic acid38. A clinical study in Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, and found a similar effect on urinary markers of DNA damage39. Finally, marinating meat in rosemary and thyme, has been reported to reduced the serum levels of carcinogenic heterocyclic amines (HCA) by 87% compared to subjects who eat the meat unseasoned40.

Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inflammation. It is now well established that inappropriate inflammation is intimately involved in the cancer process, particularly in the promotion and progression stages of cancer. Inflammation is closely associated with oxidative stress and activation of NF-kappa B family of transcription fac­tors. These factors regulate more than 150 genes involved in mechanisms of cell survival and these target genes are not just pro-inflammatory but also oncogenic. Numerous phytochemicals have been shown to inhibit NF-kappa B signalling, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid and caffeic acid phenethyl ester and the phytochemicals within bilberries31,41.

More recently, it has been reported mainly from laboratory studies that phytochemicals have an affect on several cancer process through modulation of cellular and signalling events involved in growth, invasion and metastasis32. Pomegranate, for example, rich in the polyphenol ellagic acid, has been shown to directly inhibit cell growth and induce apoptosis in androgen sensitive and aggressive human prostate cancer cells42. Pomegranate extract has also been reported to inhibit processes involved in cancer metastasis in a study involving oestrogen sensitive and resistant breast cancer cell lines, showing increased markers of cell adhesion and migration in cancer but not normal cells43. In another study it inhibited a chemokine that attracts breast cancer cells to the bone44. Curcumin slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells45, 46, 47, 48. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells49. Curcumin has been shown to modulate miRNA expression in breast cancer cells leading to a reduced expression of Bcl-250 and stabilisation of tumour suppressor gene in colorectal cancer cell lines52. Green tea, rich in epigallocatechin gallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis26, 52, 53. It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis50, 54. Resveratrol has demonstrated epigenetic regulatory properties which influence regulate proliferation, cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor46. Caffeic acid and phenethyl ester, as well as inhibiting NF-κB signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo47. Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition which is a basic biological process related to cancer initiation and development47.

Finally some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism. Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells, yet at the same time blocking the binding of more harmful oestrogens, including those produced endogenously39. This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavones and flavanones-rich foods had a lower risk of death24. In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels. This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer.

Can concentrating foods into supplements enhance their anti-cancer effect?

If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with poor diets or further enhance the benefits in those whoes diets are already adequate. People living with and beyond cancer (PLWBC) are certainly attracted to the potential health benefits of food supplements, as over 65% report regular intake5,6. There are two main categories of supplements commercially available: the first involves chemicals extracted from food, or made synthetically, such as minerals and vitamins; the second involves purifying and concentrating whole foods:

Vitamins and mineral supplements: The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals. Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse57. The SU.VI.MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium and zinc, or a placebo, and found no reduction in mortality or cancer-specific mortality overall58, although a further analysis in men found a reduction in the risk of prostate cancer. The authors postulated that this difference between the sexes was related to French men having a lower baseline micro-nutrient status59. A major trial of selenium and vitamin supplements in a poor region of China, demonstrated reduced risks of oesophageal cancer; at the time this population was known to have widespread micro-nutrient deficiencies60.

Unfortunately, most other studies of vitamin, minerals and other extracted nutrients have shown no benefit, or have actually shown an increased risk of cancer. For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer61. The Health Professionals Follow-up study (HPFS) which followed the lifestyle habits of 51,529 male professionals for over 15 years found that men who took very high doses of zinc (>100mg/day), or took it for long durations were more than twice as likely to develop advanced prostate cancer compared with controls62. The randomised SELECT study demonstrated an increased prostate cancer incidence with vitamin E and selenium supplementation63. A further analysis of the HPFS found that of the 4,459 men who had developed prostate cancer, those who took selenium supplementation of ≥ 140 μg/d after diagnosis were associated with a 2.60-fold greater risk of prostate cancer mortality64.

The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed that men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation, and that those with high levels had a higher risk, particularly in smokers65. This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer66. These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency67, which is rarely routinely detected unless individuals have self funded micro-nutrient analysis (cancernet.co.uk).

Whole food supplements: More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies. Despite some initial encouragement from smaller evaluations, studies of extracted lycopene or genistein given on their own in more scientifically robust analyses have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy68, 69, 70 neither were there links with the reduction in the risks of breast cancer with regular intake5. Of more concern, a randomised study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation (25.8 g twice a day) added to laboratory tumour cells caused them to proliferate faster (Increased K67 expression) and overexpress the tumorigenic growth factor receptor FGFR271. This supports the notion that phytoestrogen foods are healthy, but concentrating them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements has shown any detrimental effects on cancer outcomes and some have beneficially influenced progression rates. For example, a study carried out at John Hopkins involving pomegranate seed extract, found that men taking the supplements had a reduction in PSA progression rate72. A study conducted at the Mayo Clinic found that green tea concentrate decreased the abnormal white cell count in 30% of patients with chronic leukaemia, and a small study from Louisiana University reported that green tea concentrate significantly reduced levels of several cancer-promoting growth factors as well as PSA levels in participants26. In the Vitamins and Lifestyle (VITAL) cohort study, a regular intake of grapeseed extract was shown to be linked with a lower risk of prostate cancer70, and another small RCT found that a dietary supplement containing isoflavones, plus other phytochemicals and anti-oxidants delayed PSA progression73. Interestingly one of the most popular supplements, Saw Palmetto, despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation74. Likewise, another popular supplement, lycopene, despite similar suggestions from smaller non-randomised trials68, 69, demonstrated no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts was the National Cancer Research Network adopted Pomi-T study75. This study combined four different food types (pomegranate, green tea, broccoli and turmeric) in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical. It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse, following initial radical interventions.

The results, presented as an oral presentation at the American Society of Clinical Oncology Conference (ASCO), Chicago, showed a statistically significant, 63% reduction in the median PSA progression rate compared to placebo in both men on active surveillance and experiencing a PSA relapse post-treatment. A further analysis of MRI images, demonstrated the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect75. It was well tolerated, apart from some mild loosening of the bowels in 10% of men, and there was no effect on testosterone levels. At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis and erectile dysfunction75.

A number of other RCT’s involving whole food phytochemical-rich supplement have demonstrated benefits for some of the distressing symptoms common after cancer treatments, such as fatigue76 and urinary infections77. There are currently over ten, on-going studies registered with the National Institute of Health. In the UK, the Institute of Preventative Medicine has plans to include the Pomi-T supplement into the next national prostate cancer prevention study. This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study, co-ordinated by the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer. In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer.

Conclusion

There is increasingly convincing evidence to show that plant phytochemicals, particularly polyphenols have significant benefits for humans. Not only do they improve our daily lives by helping our food taste, smell and look appetising, they also reduce our risk of cancer and help people living with and beyond treatments. Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical-rich diets, along side other lifestyle factors, largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as ASCO. Going a step further and concentrating these foods, or extracted elements of these foods, into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects, but have their pitfalls. Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects. No study has reported detrimental effects of whole, non-phytoestrogenic food supplements and some have reported significant advantages. Despite these potential benefits and reports that over 60% of patients living with and beyond cancer take nutritional supplements, oncologists have been reluctant to discuss their pros and cons due to a lack of RCTs from academic institutions55, 56. Hopefully this trend will change, particularly following the success of the Pomi-T study75 and ongoing studies registered with the National Cancer Institute.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. ELIZABETH BUTLER, MSc Dip ION. Body Soul Nutrition, Level 2, 25 Petersham Road, Richmond, Surrey, UK. FABIO MACCHI, M.Sc. Head of Scientific & Clinical Development, Helsinn Healthcare S.A. PO Box 357 6915 Lugano/Pambio-Noranco, Switzerland. MADELEINE WILLIAMS, BA(Hons) PgDip. Research Manager, The Primrose Oncology Unit, Bedford Hospital, Bedford, UK.
Corresponding Author Details: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. MK42 9DJ.
Corresponding Author Email: 
rt@cancernet.co.uk
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Phenobarbital induced Pellagra

Authors
Youssef kort, Naziha Khamassi, Heykel Abdelhedi and Ouahida Cherif
Article Citation and PDF Link
BJMP 2015;8(2):a814
Abstract / Summary
Abstract: 

Background: Pellagra is a nutritional disorder due to an insufficiency in vitamin B3 also called vitamin PP for “pellagra preventing” vitamin. The disease was characterized by the “3D” consisting in dermatitis, dementia and diarrhea. The insufficiency can be due to drug use as anti epileptics. We describe a case of Phenobarbital-induced pellagra.
Observation: We report here a 61 years old woman who developed pellagra after a 45 years use of Phenobarbital. The diagnosis was suspected by the association of dermatological, neurological and gastro intestinal signs. It was confirmed by the good response to the niacin treatment and Phenobarbital discontinuation.
Conclusion: Pellagra should be considered in patients taking anti epileptic drugs because of its very good prognosis if treated and fatal issue if misdiagnosis.

Keywords: 
Pellagra, Phenobarbital, epilepsy

Introduction

Pellagra is a nutritional disorder due to an insufficiency in vitamin B3 also called vitamin PP (‘Pellagra preventing’). The disease was characterized by the following ‘3 D’s’: ‘Dermatitis’, ‘Dementia’ and ‘Diarrhoea’. When it is misdiagnosed, it can lead to the fourth ‘D’ which is ‘Death’.1 It was very common in past centuries, particularly in populations that had an exclusively maize diet. Nowadays, this diet problem is rare in developed countries, so the disease is less frequent. However, many recent studies suggest that the disease has not been eradicated and can be under-diagnosed. Alcohol, drugs and malabsorption seem to be the new aetiologies of the disease. So, it is important to recognize the ‘3 D’s’ triad in such situations to avoid fatalities.

Observation

A 61-year-old patient presented to the Internal Medicine Department with an 8-month history of deterioration in her general state. She had a medical history of Epilepsy treated by Phenobarbital since she was 16.

Review of systems revealed gastrointestinal symptomatology consisting of intermittent diarrhoea (6-7 watery stools a day without blood), dysphagia and diffuse abdominal pain. The patient also reported a skin photosensitive eruption affecting her hands and feet.

Physical examination showed a listless patient with a low Body Mass Index (17 kg/m²).

On dermatological examination, symmetric, well-defined, brown-coloured and scaly eruption was observed on the dorsa of her feet (Picture 1) and hands (Picture 2). The mucous examination showed a commissural Cheilitis and Glossitis.


Picture 1:
Brown well-defined patches on feet.


Picture 2:
Brown pigmentation and scales of hands.


Picture 3:
Hands aspect after treatment.

The nervous system examination revealed a pyramidal and cerebellar syndrome. The response to neurocognitive tests was altered suggesting Dementia.

The rest of physical examination was normal. In particular, there were neither peripheral lymph nodes, nor spleen or liver enlargements, nor abdominal mass.

The laboratory tests (glucose, calcaemia, creatinine, liver function tests, urine analysis, haemoglobin, hematocrit, sedimentation rate, C-reactive protein and protein electrophoresis) were within normal limits.

Oesogastroduodenal endoscopy was normal. The cranial, thoracic and abdominal CT scans were normal.

The diagnosis of Pellagra was made on dermatological, abdominal and neurological signs. The patient was treated by Niacin (1000 mg/day) and multivitamin complex. Phenobarbital was discontinued and switched to Clobazam. The patient’s symptoms started to improve quickly. Ten days after the treatment began the skin lesions (Picture 3) and gastrointestinal signs completely disappeared.

Discussion

Pellagra was diagnosed clinically in our patient based on the skin aspects. The skin lesions have been described since 1771 by Frapolli whose name was given to the disease: Pellagra which means rough skin in Italian.1 The typical lesions consist of a brown pigmentation and scales with a photosensitive distribution and well-defined borders as seen in our patient. The face, the neck and the dorsa of the hands are the preferential locations.2 The skin lesions are not always found, and cases of Pellagra Sine Pellagra have been described.3 The extra-cutaneous manifestations are less specific, but their association with pellagrous skin lesions are sufficient to reach a diagnosis. The neurological involvement is classically a Dementia syndrome, but ‘Pellagrous Encephalopathy’ can also consist of delirium, insomnia, depression, cerebellar and extrapyramidal syndrome.4 The gastrointestinal signs are non-specific; they can be Glossitis, dysphagia, nausea, vomiting and abdominal pain. An intractable diarrhoea may occur in advanced stages of disease and can quickly lead to death.5

In 1929, Goldberger attributed such clinical manifestations to a Niacin (vitamin B3 or PP) deficiency. Niacin is a precursor for two important coenzymes namely ‘Nicotinamide Adenine Dinucleotide (NAD)’ and ‘NAD-Phosphate’ which are essential for many oxidative reactions. This probably explains why Pellagra affects tissues with a high rate of cell turnover such as the skin and digestive tract.4

Niacin can be directly absorbed by the gastrointestinal tract or synthesized from Tryptophan.

Primary Pellagra occurs when the diet is deficient in Niacin or Tryptophan as in poor populations with an exclusive maize diet (which contain Niacin but in an indigestible form).

Despite sufficient dietary Niacin, Secondary Pellagra may be caused by a problem in Niacin absorption or metabolism. Many causes of Secondary Pellagra were identified as alcohol, intestinal malabsorption, carcinoid tumours, Hartnup’s Syndrome, Anorexia Nervosa and drugs (Table 1).5 Our patient did not consume alcohol and had no biological signs of malabsorption, but she was taking Phenobarbital for about 45 years. In the English literature, we found only two cases of Phenobarbital-induced Pellagra, and with a fatality in one case.6, 7 The underlying mechanism of Pellagra caused by Phenobarbital, or other antiepileptic drugs, is an alteration in Niacinamide synthesis due to an enzymatic induction.5

Table 1: List of drugs predisposing to Pellagra.

Predisposing Drugs
Antituberculosis agents:
Isoniazid
Pyrazinamide
Antiepileptic drugs:
Hydantoins
Ethionamide
Phenobarbital
Diazepam
Chemotherapy and immunosuppressive drugs
6-Mercaptopurine
5-Fluorouracil
Chlorambucil
Azathioprine
Chloramphenicol

The treatment is first based on correction of predisposing factors. In our patient, it consisted of using another antiepileptic drug instead of Phenobarbital. Second-line treatment is a vitamin therapy based on Niacin. There is no consensus on the doses, form and duration of the treatment, but the minimal dose is 300 mg of Niacin/day. A multivitamin complex containing other B-vitamins is often necessary because of the frequency of other deficits in such patients.2 With treatment, the skin lesions and gastrointestinal symptoms generally disappear within a few hours or days, as in the case of our patient, and it is a good argument for a retrospective diagnosis of pellagra.1 Testing for Niacin levels or urinary metabolites is not frequently available and it’s not necessary for the diagnosis.

Conclusion

We described a typical case of Pellagra in which the ‘3 D’s’ were present. In such a case, we should begin the treatment before the results of the laboratory investigations are known. The improvement of all symptoms within a few days is sufficient to confirm the diagnosis. However, the ‘3 D’s’ triad is not always present, and the clinician should consider the diagnosis in face of unexplained abdominal or neurological signs in certain patient groups.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
YOUSSEF KORT, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. NAZIHA KHAMMASSI, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. HEYKEL ABDELHEDI, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. OUAHIDA CHERIF, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia.
Corresponding Author Details: 
YOUSSEF KORT, Razi hospital, cité les orangers 2010, Tunis, Tunisia.
Corresponding Author Email: 
y_kort@yahoo.fr
References
References: 
  1.  Sayyidou S. Pellagra: a non-eradicated old disease. Clin Pract. 2014; 28; 4(1): 637.
  2. Pitche PT. Pellagra. Sante. 2005; 15(3): 205-208.
  3. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: Clinical and pathological study of 20 necropsy cases. Journal of Neurology Neurosurgery and Psychiatry. 1981; 44(3): 209-215.
  4. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract. 2012; 7: 12.
  5. Piqué-Duran E, Pérez-Cejudo JA, Cameselle D, Palacios-Llopis S, García-Vázquez O. Pellagra: A clinical, histolopathological and epidemiological study of 7 cases. Actas Dermosifiliogr. 2012; 103: 51-58.
  6. Stadler R, Orfanos CE, Immel C. Drug induced pellagra. Hautarzt. 33(5): 276-280.
  7. Pancar Yuksel E, Sen S, Aydin F and al. Phenobarbital-induced pellagra resulted in death. Cutan Ocul Toxicol. 2014; 33(1): 76-78. 

Familial dilated cardiomyopathy linked with hearing loss in brothers: case report

Authors
Jing Lin, Jianhong Tao, Guangre Xu and Li Cai
Article Citation and PDF Link
BJMP 2015;8(2):a812
Abstract / Summary
Abstract: 

Dilated cardiomyopathy (DCM) is the third leading cause of severe heart failure and the most common cause of heart transplantation. Many cases (25–30%) of DCM are familial, indicating a genetic contribution to the etiology. The diagnosis of Familial dilated cardiomyopathy (FDC) is clinically based on the clinical manifestation, with at least two affected members from the same family. More than 30 genes associated with FDC have been identified, but still theses explain only a minority of the etiology of FDC. Here we present a strange case of FDC accompanied by hearing loss and rapid progressive course. The manifestations of FDC in this family was really rare and it is anticipated that more susceptibility genes may be discovered.

Keywords: 
familial dilated cardiomyopathy; hearing loss; rapid progressive course

Introduction

Dilated cardiomyopathy (DCM) is a cardiac muscle disease, characterized by dilatation and impaired contraction of the left ventricle or both ventricles, and leads to progressive heart failure and sudden or heart failure-related death [1]. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis [2]. Although the pathogenesis of this disease has been extensively studied for decades, it remains ambiguous. Currently, myocarditis, immunological abnormalities, toxic myocardial damage, and persistent cardio-tropic viral infection are all assumed to be causes of DCM [3]. Dilated cardiomyopathy occurring in families, or the familial dilated cardiomyopathy (FDC) may occur in 25% to 35% of DCM cases, implicating a genetic contribution to the etiology [4-7].  More than 30 susceptibility genes have been shown to be associated with an increased risk of developing a DCM. Here we report three strange cases of FDC accompanied by hearing loss and rapid progressive course in brothers from Sichuan Province of China. The presentation of the family was really rare and it is anticipated that more susceptibility genes may be discovered.

Case report

The patient was a boy from Sichuan Province, and had lost his hearing when he was five years old. At the age of eight, the boy presented with cough and acute onset breathlessness. On examination, he had blood pressure (BP) of 90/60mmHg, heart rate (HR) 105/min, raised jugular venous pressure (JVP), crackles over the lung bases and a pansystolic murmur at the apex. A huge cardiomegaly was seen on chest X-ray (CXR), and the cardiothoracic ratio (CT ratio) was 0.721. ECG revealed primary atrioventricular block and left ventricular hypertrophy (LVH). Echocardiography (Echo) showed enlargement of both ventricles of the heart, a decreased left ventricular ejection fraction (LVEF), and severe mitral regurgitation (MR). The patient was treated in line with congestive cardiac failure (CCF). However, he died three months after the acute onset of breathlessness.

Surprisingly, the progression was nearly the same as two of his older brothers. Both of them also lost hearings at the age of five. Then presented with acute onset breathlessness and they were diagnosed with DCM aged seven to eight years. They also died three months later after the acute onset of breathlessness. Because of the terrible experience of his older brothers, the boys’ parents took him to hospital every year to be examined. ECG and Echo images were normal 6 months before the onset of breathlessness. Moreover, the boy had no symptoms 1 month before his presentation.

Discussion

The definition of FDC is clinically based on manifestation with at least two affected members from the same family [5]. The most common mode of inheritance is the autosomal dominant type, while X-linked, autosomal recessive and mitochondrial forms are less common [8, 9]. Although most people affected die in early adulthood, the age of onset, rate of progression, disease complications, as well as overall prognosis and outcome vary within families [5, 10]. Nevertheless, the age of onsets in this family were similar and with a rapid progressive course. All of the sons in the family suffered from DCM as well as hearing loss. The manifestation of the brothers haven’t been reported before. We traced back three generations of this family finding no other affected members.  As all the patients were male, we speculated that the possible mode of inheritance in this family is X-linked. Regrettably, the parents had no daughters and we were not able to investigate the possible association between gender and FDC of this kind. Because of the rapid progressive course, we hypothesize that autoimmune abnormalities might be the pathogenic factors for this disease, but we do not have any solid evidence yet. Fortunately, we were able to get the blood samples from the patient and the relatives. Further studies are needed to explore new susceptibility genes as well as the molecular mechanisms that are involved in the disease.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JING LIN, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. JIANHONG TAO, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. GUANGRE XU, Department of digestive internal medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. LI CAI, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China.
Corresponding Author Details: 
LI CAI, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610041, PR China.
Corresponding Author Email: 
582301352@qq.com
References
References: 
  1. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841-842.
  2. Osterziel KJ, Hassfeld S, Geier C, Perrot A: [Familial dilated cardiomyopathy]. Herz 2005;30:529-534.
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  4. Ghosh N, Haddad H: Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol 2011;26:155-164.
  5. Pasotti M, Repetto A, Pisani A, Arbustini E: [Genetic diagnosis of familial dilated cardiomyopathy]. Ital Heart J Suppl 2002;3:386-393.
  6. Burkett EL, Hershberger RE: Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005;45:969-981.
  7. Hershberger RE, Siegfried JD: Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2011;57:1641-1649.
  8. Martins E, Cardoso JS, Abreu-Lima C: Familial dilated cardiomyopathy. Rev Port Cardiol 2002;21:1487-1503.
  9. Zheng DD, Yang JH, Tao Q, Geng M, Lin J, Yang XJ, Song JP, Li HX, Han LH, Jiang WP: Mutations in the beta-myosin heavy chain gene in southern Chinese families with hypertrophic cardiomyopathy. J Int Med Res 2010;38:810-820.
  10. Serio A, Narula N, Kodama T, Favalli V, Arbustini E: Familial dilated cardiomyopathy. Clinical and genetic characteristics. Herz 2012;37:822-829.

Homeopathy: In God we trust, all others must bring data.

Authors
Nasseer A Masoodi MD, MBA, FACP
Article Citation and PDF Link
BJMP 2015;8(1):a809
Abstract / Summary
Keywords: 
Homeopathy, effectiveness, science based medicine

Effectiveness of homeopathic remedies continues to be a question of concern for public, policy makers and the other involved stakeholders. A recent systematic review of studies by Australian National Health and Medical Research Council (NHMRC) 1 heightened further the concerns about the perception of effectiveness of homeopathic treatments in general. After an exhaustive review, the authors found no good quality, or well-designed studies with adequate sample size to support claims made by homeopathic practitioners. They concluded that the homeopathic remedies are no better than a placebo. Authors of the report cited concerns about the designs of the most of the studies especially the ones that showed any beneficial effect. Authors noted that such studies either had smaller sample sizes, were conducted poorly and/or were insufficiently powered to detect a statistically significant outcome. NHMRC concluded that there is no evidence from systematic reviews regarding the effectiveness of homeopathy as a treatment for any clinical condition in humans. The NHMRC identified “claiming benefits for human health not based on evidence”1 as a major health issue in Australia.

NHRMC’s report comes as no surprise as many other exhaustive reviews had failed to show any objective benefits of such remedies. Authors of a 2009-10 UK report titled as Evidence Check 2: Homeopathy2, reached to a similar conclusion. They questioned the lack of homeopathic treatment trials and cited that there is plenty of evidence showing that it is not efficacious. Their conclusion was no different from NHRMC’s and proposed that “systematic reviews and meta-analyses conclusively demonstrate that homeopathic products perform no better than placebo”2. They further recommended stopping any public funding of Homeopathic remedies in UK. Although a Swiss report3 argued otherwise claiming that homeopathy is a “valuable addition to the conventional medical landscape”3; however its methodology was considered to be flawed, biased, misinterpreting and discrediting the current science based study methodologies4.

The homeopathic notion of successive dilution of its products in water increasing the potency of the final product and “like cures like” doesn’t only defy any science based medicine logic, it is also in contrast to other alternative systems of medicine. The paucity of good-quality studies of sufficient size that examine the effectiveness of homeopathy as a treatment for any clinical condition in humans does no favors to this notion either. As cited by many reports referenced above, the available evidence is not compelling and fails to demonstrate that homeopathy is an effective treatment for any of the reported clinical conditions in humans. In spite of these significant concerns about the legitimacy and efficacy of homeopathy, the industry continues to benefit from public’s increasingly favorable attitudes toward homeopathy. The National Institutes of Health5 in the United States, reports that there is little evidence to support homeopathy as an effective treatment for any specific condition however millions of American adults and thousands of children use homeopathy. Even in UK6 where there is no legal regulation of homeopathic practitioners, The National Institute of Health and Care Excellence (NICE)-that advises the NHS on proper use of treatments, doesn’t recommend that homeopathy should be used in the treatment of any health condition. However homeopathy has seen a significant increase in its market share not only in UK but many other European countries too7.

With its market share in USA and rest of the world markets reaching in billions of dollars with yearly incremental increase, its claims for its remedial effects albeit lacking any generally acceptable evidence, raises concern that a vulnerable person may choose an ineffective remedy that may actually worsen their clinical status. There is a clash between patient autonomy and informed consent in decision making by a vulnerable patient about the appropriateness of homeopathic remedies. The ethical and policy debate on the appropriate balance between public’s access to different remedies (autonomy) and government institutional duty of public’s protection from potentially harmful or ineffective medicines is a delicate balance.  An objective and thorough evaluation of homeopathic remedies is needed however how to decide what is an objective and accurate way to assess homeopathic research continues to be the bone of contention. Although from a science based medicine perspective, homeopathic remedies have no scientific explanation, its advocates3, 4 don’t agree that it has to fall or go through same process of research methodology for its effectiveness as do allopathic remedies. Though it is a valid logic that reasoning directly from data that is gathered by controlled structure, as is true of science based trials in allopathy, is not always accurate as it’s with many biases and confounders, however the statistical testing helps to get beyond mere correlation to cause-and-effect and eliminate most of these concerns. These trials also help to formulate conclusions that can be further validated or refuted by gathering real world data. The mainstream science considers the homeopathic notion of ultra-dilutions, particle leaving imprint of itself on water, and “likes cures like” to be scientifically implausible. Even though this notion of scientists may be considered as a bias towards evaluating any homeopathic remedy, the public health institutions have an ethical obligation to educate public especially the vulnerable ones, not to substitute a proven and effective treatment for the ones whose effectiveness has not been scientifically proven.

As the saying goes, “change the rule and you will get a new number”, the onus is on homeopathic advocates not only to design trials, gather data, and publish papers but also to collect real world data to further study the impact of treatments on outcomes. The real world data can further help to understand the effects of treatments on patient outcomes that was not generated from a clinical trial. It is also an obligation of the homeopathic practitioners and organizations to seek to create standards of medical treatment, that are objective, replicable, and that will be made broadly available to physicians, researchers, parents, policy makers, and others who want to improve the care of individuals. As recommended by many exhaustive reviews1,2, these studies should recruit larger samples of patients, utilize methodologies that eliminate the bias, better discoverable record keeping for proper reporting and follow up, an objective analysis of outcomes data and how they were measured, and better discussion of potential confounders or biases. Besides they have to adequately and accurately report study details including treatment regimens, length of follow up, outcomes studied and the clinical and statistical significance of results. 

Going by the logic of famous words attributed to the noted statistician and management scientist, W Edwards Deming, “In God we trust; all others must bring data,” the ball is in their court.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NASSEER A MASOODI, MD, MBA,FACP, Senior Consultant, Department of Medicine, Hamad Medical Corporation, Qatar.
Corresponding Author Details: 
Dr Nasseer A Masoodi, Senior Consultant, Department of Medicine, Hamad Medical Corporation, Qatar.
Corresponding Author Email: 
haadin@yahoo.com
References
References: 
  1. Effectiveness of Homeopathy for Clinical Conditions: Evaluation of the Evidence. Overview Report. Prepared for the NHMRC Homeopathy Working Committee, October 2013. Available at http://www.nhmrc.gov.au/_files_nhmrc/file/your_health/complementary_medicines/nhmrc_homeopathy_overview_report_october_2013_140407.pdf, accessed on April 04, 2015. 
  2. House of Commons Science and Technology Committee. Evidence check 2: Homeopathy. 2009. Available at: http://www.publications.parliament.uk/pa/cm200910/cmselect/cmsctech/45/45.pdf, accessed on April 04, 2015.
  3. Bornhöft G, Matthiessen P, Eds (2012). Homeopathy in Healthcare: Effectiveness, Appropriateness, Safety, Costs: An HTA report on homeopathy as part of the Swiss Complementary Medicine Evaluation Programme. Springer-Verlag, New York. 
  4. Shaw D (2012). The Swiss report on homeopathy: a case study of research misconduct. Swiss Med Wkly 142:w13594.
  5. Homeopathy: An Introduction. Available at https://nccih.nih.gov/health/homeopathy, accessed on April 04, 2015.
  6. Homeopathy: Overview. Available at http://www.nhs.uk/Conditions/Homeopathy/Pages/Introduction.aspx, accessed on April 04, 2015.
  7. Homeopathy- a healthcare choice for everyone. Available at http://www.britishhomeopathic.org/what-is-homeopathy/facts/the-growing-demand-for-homeopathy/, accessed on April 2015.

Chest pain and syncope in a middle-aged man

Authors
Deacon Zhao Jun Lee, Karan Saraf and Paul Sheridan
Article Citation and PDF Link
BJMP 2014;7(4):a735
Abstract / Summary
Abstract: 

A 46 year old man presented to the Emergency Department with chest pain and collapse with loss of consciousness. The history, examination and investigation findings are detailed below followed by five questions surrounding the pathophysiology, diagnosis and management of the condition.

Keywords: 
Brugada syndrome, channelopathy, sudden cardiac death, ventricular tachycardia, ventricular fibrillation, risk stratification, internal cardioverter defibrillator

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 VF2,5.

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 condition2,7. 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 ventricle3,9. 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 ICD11,12.

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

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DEACON ZHAO JUN LEE, MBCHB MRCP, Sheffield Teaching Hospitals, UK. KARAN SARAF, MBCHB, Sheffield Teaching Hospitals, UK. PAUL SHERIDAN, MBCHB MRCP PhD, Sheffield Teaching Hospitals, UK.
Corresponding Author Details: 
DEACON ZHAO JUN LEE, Sheffield Teaching Hospitals, Northern General Hospital, Herries Road, Sheffield, S5 7AU.
Corresponding Author Email: 
deacon.lee.04@aberdeen.ac.uk
References
References: 
  1. Boussy T, Sarkozy A, Chierchia GB et al. The Brugada Syndrome: Facts and Controversies. Herz 2007;32:192-200
  2.  Antzelevitch C, Brugada P, Borggrefe M et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-70
  3. Antzelevitch C. Brugada Syndrome. PACE 2006;29:1130-59
  4. Benito B, Brugada R, Brugada J et al. Brugada Syndrome. Progress in Cardiovascular Diseases 2006;51(1):1-22
  5. Herbert E, Chahine M. Clinical aspects and physiopathology of Brugada Syndrome: a review of current concepts. Can J Physiol Pharmacol 2006;84:795-802
  6. Richter S, Sarkozy A, Chierchia GB et al. Variability of the diagnostic coved-type ECG during long-term follow-up of patients with Brugada syndrome and primary prophylactic ICD implantation. Eur Heart J 2006,27:Suppl 1:AB88662
  7. Wilde AAM, Antzelevitch C, Borggrefe M et al. Proposed diagnostic criteria for the Brugada syndrome. Eur Heart J 2002;23:1648-1654
  8. Weiss R, Knight BP, Gold MR et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944-953
  9. Márquez MF, Salica G, Hermosillo AG et al. Ionic basis of pharmacological therapy in Brugada syndrome. J Cardiovasc Electrophysiol. Feb 2007;18(2):234-40
  10. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110(13):1731–7
  11. Probst V, Evain S, Gournay V et al. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3 year old child. J Cardiovasc Electrophyiol 2006;17:97-100
  12. Probst V, Denjoy I, Meregalli PG et al: Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115:2042-2048

Case report: DiGeorge syndrome presenting with hypoparathyrodism and Learning Difficulties in adulthood.

Authors
Nawras Al-taie ,Sandra Scheuter-Mlaker , Michael Schlesinger , Heidemarie Abrahamian
Article Citation and PDF Link
BJMP 2014;7(4):a730
Abstract / Summary
Abstract: 

We report a 40 year old female with mild dysmorphic facial features, learning difficulties, epilepsy and chronic dermatitis, presenting with symptomatic hypocalcaemia. The laboratory investigations confirmed the diagnosis of hypoparathyroidism. The hint to DiGeorge syndrome was the hypoparathyroidism in association with learning difficulties and dysmorphic features. Chromosomal analysis using fluorescence in situ hybridization (FISH) analysis showed a deletion of chromosome 22q11.2 and confirmed the diagnosis of DiGeorge syndrome. This case report demonstrates that DiGeorge syndrome should be considered while investigating hypocalcaemia and Hypoparathyroidism in adulthood as this syndrome has very important implications for health and future family planning for patients and their families.

Case Report

Our patient is a 40-year-old lady who presented to our department feeling unwell with fever and numbness in both hands. Past medical history showed recurrent urinary tract infections, rheumatoid arthritis, chronic eczema and epilepsy .She was taking Levetiracetam 500mg twice daily and Clobazam 5 mg twice daily for the epilepsy. She is also known to have learning difficulties. Mild hypocalcaemia was documented few years back in a previous admission in other hospitals, but the cause was unclear. On admission, she was hemodynamically stable with mild facial dysmorphism, and positive Trousseau's and Chvostek's signs.

Blood tests showed a low corrected calcium 1.5 mmol/L (NR 2.25-2.5 mmol/L), high C-reactive protein, Leukocytosis, and 3.0 mmol/L serum potassium level (NR 3.5-5.0 mmol/L). Other routine blood tests were normal. Further investigations showed low Serum parathyroid hormone levels, normal magnesium levels and normal TSH level. A CT scan of the brain was unremarkable. Electrocardiogram showed QT prolongation (with QTc of 520 ms). The diagnosis of hypoparathyroidism and urinary tract infection was established and the patient was treated with antibiotics to cover urinary tract infection and calcium supplements for hypocalcaemia. The patient symptoms improved significantly and was discharged on calcium supplements and Calcitriol (Rocaltrol 0.25 mcg) with a calcium level of 2.1 mmol/L. The presence of hypoparathyroidism in association with learning difficulties, eczema and epilepsy prompted chromosomal analysis for DiGeorge syndrome. The microdeletion of chromosome 22q11.2 was confirmed by FISH (fluorescent in situ hybridization) analysis. Cardiac echo examination demonstrated no abnormalities and abdominal ultrasound examination showed no renal abnormalities. The patient was offered Genetic counselling together with her family.

Discussion:

DiGeorge syndrome is a well-known genetic disorder with a prevalence of 1:4000 live births1.  It was initially described by Angelo DiGeorge a physician and paediatric endocrinologist in 1968 2. DiGeorge is a developmental defect caused by a microdeletion of chromosome 22q11.2; it is also known as velocardiofacial syndrome or CATCH 22 syndrome to describe the classical features of this syndrome (C-Congenital heart disease, A-Abnormal facies, T-Thymus hypoplasia, C-Cleft Palate and H- Hypocalcaemia due to Hypoparathyroidism. Autoimmune disorders, skeletal defects, renal abnormalities, psychiatric and behavioural disorders are also associated with this syndrome.

DiGeorge is an autosomal dominant syndrome but the majority of patients have de novo mutations caused mainly by the microdeletion of chromosome 22q11.2 which leads to developmental disorders such as the failure of development of pharyngeal pouch system 3, 4. These developmental disorders are the main cause of the classic features and presentation of DiGeorge syndrome such as congenital heart diseases, hypoplasia of the parathyroid glands and thymus, congenital immune deficiency and renal abnormalities5  .

Congenital Conotruncal cardiac defects that involve truncoaortic sac can present in 70% patients with DiGeorge Syndrome. The most common cardiac anomalies are interrupted aortic arch, Tetralogy of Fallot, Atrial septal defect and ventricular septal defects 4, 5, 6  .

Hypocalcaemia is due to hypoparathyroidism and is present in about 60 % of patients 5, 7  . Hypocalcaemia is a strong predictor of DiGeorge syndrome if it is associated with other clinical features such as cardiac defect and immunodeficiency. Hypocalcaemia commonly presents as muscle cramps, numbness, tetany, focal or generalized seizures, prolong QT and hypotension.

Immunodeficiency is rare in adults and but it may present in up to 70-80% of the children with DiGeorge syndrome.  Immunodeficiency occurs because of the low T cell count due to thymus hypoplasia. The function of T cells is however, usually preserved. Patients with immunodeficiency may have recurrent viral chest infection, systemic fungal infections frequent bacterial infections 8 .

The characteristic facies of DiGeorge include long face, narrow palpebral fissures, broad nasal bridge, micrognathia and asymmetrical crying face.

Psychiatric disorders have been reported with 22q11.2 deletion syndromes such as schizophrenia, bipolar disorder, anxiety and affective disorders.

Other conditions that may be associated with DiGeorge are atopic disorders (asthma and eczema) rheumatoid arthritis, autoimmune thyroiditis, renal abnormalities (such as multicystic kidneys andVesicoureteral reflux).

Conclusion:

Due to the variety of symptoms and the de novo mutations, DiGeorge Syndrome should be considered in adults presenting with hypocalcaemia due to hypoparathyroidism even in the absence of the classical features. The syndrome has significant health implications, and confirming the diagnosis is important for future family planning.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAWRAS ALTAIE, Department of Internal Medicine, Otto-agner Hospital, Baumgartner Höhe 1, Vienna, Austria.
Corresponding Author Details: 
DR NAWRAS ALTAIE, Department of Internal Medicine, Otto-agner Hospital, 1140 Wien, Baumgartner Höhe 1,Pav.13/2, Vienna, Austria.
Corresponding Author Email: 
nawrasih@yahoo.com
References
References: 
  1. K. Devriendt, J. P. Fryns, G. Mortier, M. N. Van Thienen, and K. Keymolen, “The annual incidence of DiGeorge/velocardiofacial syndrome,” Journal of Medical Genetics, vol. 35, no. 9, pp. 789–790, 1998.
  2. DiGeorge AM. Discussion of paper by Cooper MD, Peterson RDA and Good RA: a new concept of the cellular base of immunology. J Pediatr 1965;67:907.
  3. H. B. Robinson, “DiGeorge's or the III-IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis,” Perspectives in Pediatric Pathology, vol. 2, pp. 173–206, 1975
  4. Kirsten Mølsted, Maria Boers and Inger Kjær , “The morphology of the sella turcica in velocardiofacial syndrome suggests involvement of a neural crest developmental field,” American Journal of Medical Genetics A, vol. 152, no. 6, pp. 1450–1457, 2010.
  5. Ryan AK, Goodship JA, Wilson DI. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997;34:798–804.
  6. Marino B, Digilio MC, Toscano A, Anaclerio S, Giannotti A, Feltri C, de Ioris MA, Angioni A, Dallapiccola B. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med. 2001;3:45–48
  7. Choi JH, Shin YL, Kim GH, Seo EJ, Kim Y, Park IS, et al. Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome. Horm Res. 2005;63(6):294-9
  8. L. M. Piliero, A. N. Sanford, D. M. McDonald-McGinn, E. H. Zackai, and K. E. Sullivan, “T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome,” Blood, vol. 103, no. 3, pp. 1020–1025, 2004

Association between plasma adiponectin and risk of myocardial infarction in Asian Indian patient with diabetes

Authors
Arun Narayan, Sanjay Kulkarni, Rahul Kothari, Telugu Seetharam Deepak, Punith Kempegowda
Article Citation and PDF Link
BJMP 2014;7(4):a729
Abstract / Summary
Abstract: 

Context: Recent epidemiological studies have established association of adiponectin with insulin resistance and cardiovascular risk factors. However, newer reports state an ethnic difference in this association.

Objectives: The present study was done to assess the association between plasma adiponectin levels and coronary event in Asian Indian patients with diabetes. The relation between plasma adiponectin and various cardiovascular risk factors in an acute coronary event was also studied.

Methodology: The prospective study was conducted at a tertiary care center in Bangalore, India. Three groups of 30 patients-Patients with diabetes with Myocardial Infarction (MI), Patients with diabetes without MI and controls (age and sex matched non-patients with diabetes)- were included in the study. The association between plasma adiponectin level and MI in patients with diabetes was studied in comparison to patients with diabetes without MI.

Statistical analysis used: Analysis of Variance, Spearman Correlation

Results: 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 (P<.001). Plasma adiponectin was significantly correlated with abdominal obesity (r=-.31), fasting glucose level (r=-.61), glycated haemoglobin (r=-.63) and triglycerides (r=-.54) (all P <.001). There was no significant correlation between plasma adiponectin levels and High Density Lipoprotein-Cholesterol in the present study.

Conclusions: 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 synergize to predispose to cardiovascular disorders.

Key Messages: Adiponectin is a potential target in future research for reducing morbidity and mortality associated with atherosclerotic disease.

Keywords: 
Adiponectin, Diabetes, Myocardial infarction, HDL cholesterol.

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 (HbA1C), 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, HbA1C, 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), HbA1C (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

Variable Controls Mean (±Std. Dev) Patients with diabetes without MI Mean(±Std. Dev) Patients with diabetes with MI Mean(±Std. Dev)
Plasma Adiponectin 6.11(±1.82) 9.47(±1.55) 17.82(±1.30)
Fasting Blood Glucose 123.50(±17.85) 133.23(±16.14) 88.80(±6.27)
Post-Prandial Blood Glucose 190.53(±19.27) 209.33(±28.72) 125.30(±6.200
Glycated Haemoglobin 7.81(±0.92) 8.04(±1.24) 4.06(±0.62)
Total Cholesterol 205.77(±19.92) 214.43(±21.54) 138.07(±10.38)
Serum Triglycerides 148.80(±11.32) 160.53(±14.61) 127.23(±6.11)
Serum HDL 45.13(±8.57) 37.43(±9.73) 44.87(±7.78)
Serum LDL 129.30(±22.55) 137.27(±18.83) 120.03(±8.27)
Body Mass Index 27.82(±2.39) 27.08(±2.20) 25.40(±2.63)

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, HbA1C, fasting and post-prandial glucose levels

  Adiponectin BMI FBG HBA1C TG HDL LDL
Adiponectin 1.00 -0.31** -0.61** -0.63** -0.54** 0.02 -0.16
BMI   1.00 0.37** 0.29** 0.25* -0.14 0.10
FBG     1.00 0.62** 0.61** -0.17 0.21*
HBA1C       1.00 0.83** -0.45** 0.35**
TG         1.00 -0.53** 0.33**
HDL           1.00 -0.07
LDL             1.00

** 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, HbA1C 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.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ARUN NARAYAN, M.D, D.T.M & H(U.K), Senior Professor and Head, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India . SANJAY KULKARNI, MD, Professor, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India. RAHUL KOTHARI, MD, Post-graduate resident, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India. TELUGU SEETHARAM DEEPAK, M.D, Department of Critical Care, M S Ramaiah Medical College, Bangalore-560054, India. PUNITH KEMPEGOWDA, MBBS, MSc, Academic Clinical Fellow in Diabetes and Endocrinology, University Hospitals Birmingham NHS Trust, United Kingdom.
Corresponding Author Details: 
PUNITH KEMPEGOWDA, Academic Clinical Fellow, University Hospitals Birmingham NHS Trust, UK.
Corresponding Author Email: 
drpunith@gmail.com
References
References: 
  1. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological chemistry. 1995;270:26746-9.
  2. Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. The Lancet. 2002;360:57-8.
  3. Daimon M, Oizumi T, Saitoh T, et al. Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population The Funagata study. Diabetes care. 2003;26:2015-20.
  4. Spranger J, Kroke A, Möhlig M, et al. Adiponectin and protection against type 2 diabetes mellitus. The Lancet. 2003;361:226-8.
  5. Snehalatha C, Mukesh B, Simon M, et al. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian Indians. Diabetes care. 2003;26:3226-9.
  6. Duncan BB, Schmidt MI, Pankow JS, et al. Adiponectin and the development of type 2 diabetes the atherosclerosis risk in communities study. Diabetes. 2004;53:2473-8.
  7. Kazumi T, Kawaguchi A, Hirano T, et al. Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men. Metabolism. 2004;53:589-93.
  8. Kobayashi K, Inoguchi T. Molecular Mechanisms of the Antiatherogenic Action of Adiponectin. Vascular Disease Prevention. 2007;4:7-9.
  9. Folco EJ, Rocha VZ, López-Ilasaca M, et al. Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10. Journal of Biological chemistry. 2009;284:25569-75.
  10. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clinica chimica acta. 2007;380:24-30.
  11. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA: the journal of the American Medical Association. 2004;291:1730-7.
  12. Lim H, Tayebjee M, Tan K, et al. Serum adiponectin in coronary heart disease: ethnic differences and relation to coronary artery disease severity. Heart. 2005;91:1605-6.
  13. Shojaie M, Sotoodah A, Shafaie G. Is adiponectin associated with acute myocardial infarction in Iranian non obese patients. Lipids Health Dis. 2009;8:17.
  14. Zhang MH, Spies C, Ali S, et al. Adiponectin and inducible ischemia in patients with stable coronary heart disease: data from the Heart and Soul study. Atherosclerosis. 2009;205:233-8.
  15. Laughlin GA, Barrett-Connor E, May S, et al. Association of adiponectin with coronary heart disease and mortality the rancho bernardo study. American journal of epidemiology. 2007;165:164-74.
  16. Mente A, Razak F, Blankenberg S, et al. Ethnic variation in adiponectin and leptin levels and their association with adiposity and insulin resistance. Diabetes care. 2010;33:1629-34.
  17. Snehalatha C, Yamuna A, Ramachandran A. Plasma adiponectin does not correlate with insulin resistance and cardiometabolic variables in nondiabetic Asian Indian teenagers. Diabetes care. 2008;31:2374-9.
  18. Rose GA, Blackburn H. Cardiovascular survey methods. Cardiovascular survey methods. 1968.
  19. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, thrombosis, and vascular biology. 2000;20:1595-9.
  20. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473-6.
  21. Koenig W, Khuseyinova N, Baumert J, et al. Serum Concentrations of Adiponectin and Risk of Type 2 Diabetes Mellitus and Coronary Heart Disease in Apparently Healthy Middle-Aged MenResults From the 18-Year Follow-Up of a Large Cohort From Southern Germany. Journal of the American College of Cardiology. 2006;48:1369-77.

Stem Cell Therapy: Future of Pain Medicine, Editorial for BJMP

Authors
YiLi Zhou, Bohdan Warycha, and Hoang Vu
Article Citation and PDF Link
BJMP 2014;7(3):a728

Nearly 30% of seniors have chronic musculoskeletal pain. The most common cause of pain in seniors is related to the degenerative changes of the spine and joints9. Conventional treatments are often restricted to the management of symptoms. Use of chronic anti-inflammatory medications in seniors may bear serious risks in gastrointestinal and renal systems. Physical therapy has limited value. Epidural steroid injection(s) may provide up to three months of pain relief. However, there are some risks involved. Spine surgery for degenerative spine diseases has a limited success rate. Up to 30% or 40% of patients may continue to have pain after back surgery. Surgical repair of a knee injury and knee replacement surgeries are popular. However, the costs are relatively high. Many senior patients may not be ideal candidates for surgery due to cardiovascular conditions. Furthermore, all these treatments do not address the key cause of spine and joint pain due to degeneration of cells and subsequent tissue damage9. Recent development in stem cells therapy (SCT) has provided a new hope for seniors.

Back Pain

The major cause of back pain is the degeneration of the cells in the intervertebral discs. Over the last few years molecular, cell-based therapies and tissue-engineering strategies with SCT for disc regeneration have significantly increased. A recent report showed that injection of mesenchymal stem cells (MSC) into bovine intervertebral discs can increase the expression of extracellular type II collagen and maximize extracellular matrix production7. Chun et al 1injected human adipose-derived stem cells (ADSCs) into 20 mature male New Zealand white rabbits. The proliferation of ADSCs at the L4-5 disc was found at 10 weeks after cell injection. Histologically, the ADSC-injected discs exhibited elevated extracellular matrix secretion and little ossification of damaged cartilage in the nucleus pulposus compared with degenerative control discs.

In addition to the promising results from animal research, preliminary human studies showed mixed results. In 2006, Haufe et al3 reported 10 patients who underwent intradiscal injection of hematopoietic precursor stem cells (HSCs) obtained from their pelvic bone marrow. Of the 10 patients, none achieved any improvement of their discogenic low back pain after one year follow-up. More recently Orozco et al 8 reported a study of ten patients with chronic back pain treated with intradiscal injection of autologous expanded bone marrow MSC. Patients were followed for 1 year. Rapid improvements of pain and disability were reported (85% of maximum in 3 months). Although disc height was not recovered, water content was significantly elevated at 12 months. Advantages of intradiscal MSC therapy include simpler and preservation of normal biomechanics without surgery. However, long term survival of the transplanted MSCs in the harsh environment of the discs is still a major challenge. To the date, no double-blind, controlled studies have been published to confirm the clinical efficacy of SCT for the pain due to degenerative disc diseases.

Knee Pain

It is estimated there will be seven-fold increase in knee replacements in the United States between 2005 and 2030. However, SCT may reduce the future need for knee replacement5. Autologous MSC and ex vivo expanded skeletal SC all have shown promising results in the treatment of knee pain caused by osteoarthritis (OA).

In an experimental animal meniscus injury model, it has been reported 10 that transplantation of human meniscus stem/progenitor cells (hMeSPCs) effectively protected articular cartilage, promoted neo-tissue formation with better-defined shape and more matured extracellular matrix and smother surface cartilage, and maintained joint space at 12 weeks postsurgery11. MSC therapy may also reduce animal pain behavior14.

In human studies, Turajane et al13 conducted a case-series study with five patients that failed conservative treatment. It was reported that the combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation along with hyaluronic acid in conjunction with arthroscopic microdrilling MCS resulted in Quality of Life improvements and succeeded in regenerating articular cartilage in early osteoarthritic knee disease. Skowronski12 reported 52 patients treated with autologous blood MSC for knee pain due to cartilage lesions. Scores improved across all scales with an average improvement of 23 points in the Knee Injury and Osteoarthritis Outcome Score scale and 35 points in the Lysholm knee scale at one year.

Koh et al4 treated eighteen patients with injection of autologous fat pad-derived MSC for knee pain due to OA. Patients were followed for 24 to 26 months after therapy. Western Ontario and McMaster Universities Osteoarthritis Index, Lyholm scores as well as VAS scores all significantly improved. Radiographic study showed the whole-organ MRI score had significantly improved from 60.0 points to 48.3 points at the final follow-up point. Particularly notable was the change in cartilage whole-organ MRI score, which improved from 28.3 points to 21.7 points. More recently, Vangsness et al reported15a randomized, double-blind, controlled study on adult human MSC delivered via intra-articular injection to the knee following partial medial meniscectomy. A single superolateral knee injection was given to 55 patients within seven to ten days after the meniscectomy. It was found that there was significantly increased meniscal volume determined by quantitative MRI in groups that received SCT. No patients in the control group had significant increase in meniscal volume. Patients with osteoarthritic changes who received MSC experienced a significant reduction in pain compared with those who received the control. This randomized, double-blind, controlled study confirmed that MSC could be a promising treatment for knee pain due to osteoarthritis and meniscus tear.

Challenges for SCT

The advantage of SCT is that stem cells can regenerate healthy and functionally specialized cells and tissues to replace the destroyed or degenerative tissues. Though it is promising, it is still facing a variety of challenges. Firstly, there are many studies reporting the clinical efficacy, most studies are open label. Only few, if any, double-blind, controlled studies have supported the efficacy of SCT for knee pain due to osteoarthritis. To the date, there are no controlled studies confirming the clinical efficacy of SCT for degenerative spine diseases. Thus more clinical studies are needed. Secondly, biological techniques for stem cell transplantation are waiting to be enhanced. For example, the stem cells transplanted into degenerated intervertebral discs will face a harsh environment, which has very high pressure, low nutrition and low oxygen. To enhance the cell survival rate and ensure the transplanted cells differentiating toward chondrocyte-like cells, which can produce proteoglycans and type II collagen, more basic science studies are needed2. The third challenge for SCT is iatrogenic cancerogenesis. Embryonic stem cells, including totipotent stem cells (produced from fusion of egg and sperm), and pluripotent stem cells (5-14 day old blastocytes) have a strong potency of cell reproducing and potentially highly teratogenic. Novel strategies such as using transgenic expression of the genetically engineered human recombinant DNases in proliferating and directed differentiation resisting stem cells are being developed to inhibit or prevent the iatrogenic cancerogenesis6. Adult SCs (Adipose, peripheral and bone marrow derived SCs) have the ability to differentiate and form a variety of tissues. These adult SCs have been used in researches to treat variety of human diseases. So far no iatrogenic carcinomas have been reported as the results of the treatment. The fourth major issue related to SCT is the legal challenge. Worldwide, different countries have different laws on SC research and use. Even President Barack Obama signed an executive order on March 9, 2009 to lift the restrictions on federally funded human embryonic stem cells (hESC) research, currently only adult stem cells (adipose, peripheral and bone marrow derived stem cells) are allowed to be used in most clinical settings. These cells should be minimally manipulated. Use of hESC from fetus, umbilical cord and amniotic fluid are all limited for research purposes. Researchers and clinicians must be familiar with the laws of their respective countries and states before becoming involved in SC therapy or research.

Conclusion

The treatment of chronic pain conditions is constantly evolving. Recent advancements in SCT for pain due to degenerative diseases in the spine and joints are promising and indicative that SCT will undoubtedly play a major role in the future. However, more studies are needed to enhance the biological techniques, confirm the clinical efficacy, reduce the risk of iatrogenic carcinoma and address the legal issues related to this exciting treatment. It is likely that SCT will be utilized more extensively in the future for replacing diseased tissues as an alternative to open back surgery or joint replacement.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None
Details of Authors: 
YILI ZHOU, MD, PhD,Florida Pain and Rehabilitation Center, USA. BOHDAN WARYCHA, MD, Florida Pain and Rehabilitation Center, USA. HOANG VU, DO, Florida Pain and Rehabilitation Center, USA.
Corresponding Author Details: 
YiLi Zhou, MD, PhD. 1910 SW 18th Court, Ocala, FL 34471 USA
Corresponding Author Email: 
yilizhoumd@yahoo.com
References
References: 
  1. Chun HJ, Kim YS, Kim BK et al. Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs. World Neurosurg. 2012;78:364-71.
  2. Gou S, Oxentenko SC, Eldrige JS et al. Stem Cell Therapy for Intervertebral Disk Regeneration. Am.J.Phys.Med.Rehabil. 2014.
  3. Haufe SM, Mork AR. Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev. 2006;15:136-7.
  4. Koh YG, Jo SB, Kwon OR et al. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy 2013;29:748-55.
  5. Maclaine SE, McNamara LE, Bennett AJ et al. Developments in stem cells: implications for future joint replacements. Proc.Inst.Mech.Eng H. 2013;227:275-83.
  6. Malecki M, LaVanne C, Alhambra D et al. Safeguarding Stem Cell-Based Regenerative Therapy against Iatrogenic Cancerogenesis: Transgenic Expression Controlled By Promoter in Proliferating and Directed Differentiation Resisting Human Autologous Pluripotent Induced Stem Cells Leads to their Death. J.Stem Cell Res.Ther. 2013;Suppl 9.
  7. Mwale F, Wang HT, Roughly P et al. Link N and MSCs can induce regeneration of the early degenerate intervertebral disc. Tissue Eng Part A 2014.
  8. Orozco L, Soler R, Morera C et al. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 2011;92:822-8.
  9. Rodrigues-Pinto R, Richardson SM, Hoyland JA. An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration. Eur.Spine J. 2014.
  10. Shen W, Chen J, Zhu T et al. Intra-articular injection of human meniscus stem/progenitor cells promotes meniscus regeneration and ameliorates osteoarthritis through stromal cell-derived factor-1/CXCR4-mediated homing. Stem Cells Transl.Med. 2014;3:387-94.
  11. Shen W, Chen J, Zhu T et al. Osteoarthritis prevention through meniscal regeneration induced by intra-articular injection of meniscus stem cells. Stem Cells Dev. 2013;22:2071-82.
  12. Skowronski J, Skowronski R, Rutka M. Cartilage lesions of the knee treated with blood mesenchymal stem cells - results. Ortop.Traumatol.Rehabil. 2012;14:569-77.
  13. Turajane T, Chaweewannakorn U, Larbpaiboonpong V et al. Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/ preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation Improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J.Med.Assoc.Thai. 2013;96:580-8.
  14. van Buul GM, Siebelt M, Leijs MJ et al. Mesenchymal stem cells reduce pain but not degenerative changes in a mono-iodoacetate rat model of osteoarthritis. J.Orthop.Res. 2014.
  15. Vangsness CT, Jr., Farr J, Boyd J et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J.Bone Joint Surg.Am. 2014;96:90-8.

Cyclophosphamide and Doxorubicin-induced Acute Pancreatitis in a Patient with Breast Cancer

Authors
Vincent Bryan Salvador, Manpreet Singh, Philip Witek and Gay Peress
Article Citation and PDF Link
BJMP 2014;7(3):a727
Abstract / Summary
Abstract: 

Predominantly occurring as a consequence of alcohol use or biliary stones, acute pancreatitis is rarely caused by chemotherapy. Lately, there have been increasing published reports and reviews of drug-induced pancreatitis from a wide array of antineoplastic drugs. We present a case of a patient recently diagnosed with Stage 3 breast cancer who was initially treated with cyclophosphamide and doxorubicin and subsequently developed acute pancreatitis, which recurred twice after a re-challenge with cyclophosphamide and epirubicin, a derivative of doxorubicin, given individually on two separate occasions. Acute pancreatitis reported in this case is defined by its clinical manifestations, biochemical evidence and imaging studies. To our knowledge, this is the first case of acute pancreatitis occurring in a patient with breast cancer associated with these chemotherapeutic agents.

Abbreviations: 
CBC-complete blood count, FDA-Federal Drug Administration, NPO-nothing per os
Keywords: 
acute pancreatitis, chemotherapy, cyclophosphamide, doxorubicin, drug-induced pancreatitis

INTRODUCTION

Although it is well appreciated that pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, trauma and viral infections, or even be associated with metabolic and connective tissue disorders.1 Knowledge of the true incidence of drug-induced acute pancreatitis is dependent on the clinician’s ability to exclude other possible causes, and by promptly reporting the occurrence. Based on individual case reports and case control studies of drug-induced acute pancreatitis, the estimated overall incidence ranges from between 0.1 and 2% of pancreatitis cases.2,3 In particular, drug-induced acute pancreatitis is of mild severity and usually resolves without significant complications.4

Attempts have been made to categorize the risk of drugs causing acute pancreatitis. A previous classification system described by Mallory and Kern Jr. categorized drugs associated with acute pancreatitis as definite, probable, or possible.5 Trivedi et al. proposed a newer classification system for commonly used medications associated with drug-induced pancreatitis. Class I drugs are those medications with at least 20 reported cases of acute pancreatitis and at least one case with a positive rechallenge. Drugs with fewer than 20 but more than 10 reported cases of acute pancreatitis, with or without a positive rechallenge, are designated into Class II. While those medications with 10 or less reported cases, or unpublished reports in pharmaceutical or FDA files, are grouped into Class III.6

Acute pancreatitis as a result of either doxorubicin or cyclophosphamide, or a combination of both, or fluorouracil or epirubicin is a rare occurrence and has seldom been reported in the literature. Even the drug package labels registered with the FDA do not indicate the possible occurrence of pancreatitis. In this case report, we present a rare occurrence of drug-induced acute pancreatitis after the completion of the first cycle of the chemotherapy protocol involving cyclophosphamide and doxorubicin in a patient with stage 3 breast cancer, with recurrences of acute pancreatitis after re-challenging with cyclophosphamide and a derivative of doxorubicin, given individually on two separate occasions.

CASE PRESENTATION

A 58 year-old female presented to the emergency room with a one day history of severe, diffuse, deep-seated abdominal pain that radiated to her back, associated with nausea and vomiting, and was unrelieved despite the intake of NSAIDs. There was no reported fever, chills, diarrhea, dysuria, or antecedent trauma. Her medical history is notable for well-controlled hypertension, hyperlipidemia and hypothyroidism for which she takes amlodipine, atorvastatin and levothyroxine. She was recently diagnosed with left-sided breast cancer, Stage III, two months prior to admission and underwent a left modified radical mastectomy. Three days prior to the hospital visit, she was given her first cycle of chemotherapy with Doxorubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 along with Pegfilgrastim 6 mg and Fosaprepitant 150 mg. She is a former cigarette smoker, drinks alcohol infrequently, and denies illicit drug use. Her family history is unremarkable.

Physical examination revealed stable vital signs without a fever (36.6C). She had non-icteric sclerae and a dry oral mucosa. Chest exam revealed a well-healed left mastectomy scar and an infusaport located on the right anterior chest wall. Her breath sounds were clear bilaterally. Her heart sounds were normal. Her abdominal exam was significant for mild tenderness to palpation in the epigastric area without palpable masses, organomegaly or ascites. There was no evident ecchymosis observed. The extremities were warm to touch with intact and symmetrical pulses, and without bipedal edema.

Initial work-up revealed an elevated leukocyte count of 42,000 with 80% neutrophils and 17% band forms. Basic metabolic panel was normal except for mild hyponatremia of 129 mEq/L. Serum amylase and lipase were markedly elevated at 2802 units/L and >2000 units/L, respectively. Liver function panel was normal (Alk phos 63 U/L [ref range 30-115 U/L], GGT 21 U/L [ref range 3-40 U/L], total bilirubin 0.90 mg/dL [ref range 0-1.5 mg/dL]). The coagulation profile was within normal range. Imaging of the abdomen with a CAT scan with intravenous and oral contrast showed haziness in the pancreatic fat plane suggestive of pancreatic inflammation, with no gallstones, focal abscesses, hepatic masses, or biliary ductal dilatation (Figure 1). Right upper quadrant ultrasound was essentially normal (Figure 2).

Figure 1. Coronal view of CT scan of abdomen and pelvis with IV and oral contrast showing haziness in the peripancreatic fat plane.

Figure 2. Sonogram of the right upper quadrant of the abdomen showing gallbladder devoid of gallstones and non-dilated common bile duct.

She was admitted to the medicine unit with the assessment of acute pancreatitis likely secondary to doxorubicin and cyclophosphamide. Intravenous fluid hydration with normal saline was initiated. She was kept NPO (nothing per os) and was started on empiric Imipenem and IV Esomeprazole. Her abdominal pain was controlled with intravenous morphine and her nausea with Ondansetron as needed. The serial basic chemistry panel was monitored and electrolyte deficits were replaced accordingly. Further work-up was performed to identify other possible etiologies of pancreatitis. The lipid panel was within normal limits (cholesterol 169 mg/dL [0-200 mg/dL], HDL 74 mg/dL, LDL 71 mg/dL and triglycerides 54 mg/dL [0-150 mg/dL]). The serum calcium levels remained within the normal range throughout her hospital stay. An abdominal sonogram demonstrated absence of gallstones or dilatation of the common bile duct, with a normal appearing liver parenchyma and pancreas. During her stay in the medicine unit, the patient’s abdominal pain improved and she was gradually started on an oral diet, which she tolerated well. Her serum electrolytes remained stable, while her serial CBC revealed progressively decreasing trends in leukocytes, hemoglobin, hematocrit, and platelet count, findings which were attributed to her prior chemotherapy. Repeat serum amylase and lipase both trended downward. The patient was discharged with follow up in the Oncology clinic. A month later, she was started on another chemotherapy regimen that consisted of weekly administration of Paclitaxel 80 mg/m2 which, over the next two months, the patient completed without any complications. Then, after explaining the risks of recurrent pancreatitis, the patient consented to have a trial of cyclophosphamide 500 mg/m2 along with fluorouracil 500 mg/m2. Five days after receiving the chemotherapy, the patient developed acute pancreatitis which was attributed to cyclophosphamide. She again made a full recovery at that time. Three weeks later, her chemotherapy regimen was again changed, to epirubicin 90 mg/m2 and fluorouracil. Four days after receiving this regimen, she again, for the third time, had a recurrence of acute pancreatitis. At this time, a repeat abdominal sonogram revealed a 4mm echogenic focus adherent to the anterior gallbladder wall with a comet tail sign, suggestive of cholesterol crystals lodged within Rokitansky-Aschoff sinuses of the gallbladder wall. There were no visible gallstones. A subsequent MRI of the abdomen with contrast revealed a small rounded hypointensity in the dependent portion of the gallbladder wall that was suggestive of a gallstone, however, there was no biliary obstruction, choledocholithiasis or an obstructing pancreatic mass. At this point, chemotherapy was stopped and anastrozole along with radiation therapy was initiated. The patient continues to be followed regularly and has had no recurrence of pancreatitis since her last episode.

DISCUSSION

The case presented described the development of acute pancreatitis in a patient with breast cancer three days after receiving the chemotherapy regimen consisting of cyclophosphamide and doxorubicin. After re-challenging the patient with cyclophosphamide, and again a few weeks later with a derivative of doxorubicin, epirubicin, acute pancreatitis recurred on each occasion. Despite the presence of cholelithiasis detected on the abdominal MRI, the temporal presentation of acute pancreatitis after chemotherapy exposure is highly suggestive of the role these chemotherapeutic agents played in triggering these three acute attacks. Acute pancreatitis was diagnosed based on the clinical suspicion and symptoms suggestive of the acute pancreatitis and was supported by the marked elevation in serum amylase and lipase, as well as, the radiologic evidence of pancreatic inflammation, both of which are markers of acute pancreatitis.

Chemotherapy-induced acute pancreatitis involving cyclophosphamide and doxorubicin either alone or in combination, is quite rare that even the drug labels registered with the FDA do not indicate acute pancreatitis as one of the possible complications. This scenario highlights the importance of drug surveillance and prompt reporting in order to maintain a credible drug safety database.

Though the drug latency, which is the interval between the initial exposure to the drug and the development of acute pancreatitis, differs variably, the present case is considered to have an intermediate latency (1-30 days). Other drugs may have short (< 24 hours) or long (>30 days) latency periods. Examples of drugs with short latency are acetaminophen, codeine, erythromycin and propofol. Intermediate latency drugs include L-asparaginase, pentamidine and stibugluconate. Drugs with long latency are estrogen, tamoxifen, valproate and dideoxyinosine.7

Based on the revised classification of Badalov et al, the combination of cyclophosphamide and doxorubicin is classified as Class IV drugs, which have the weakest association with acute pancreatitis due to limited information and the lack of adequate detailed case reports. Fluorouracil, which has been known to cause a gastrointestinal ulcer, is also categorized as a Class IV drug, while epirubicin, which is derived from doxorubicin, has not been classified, as it has not been reported before to cause acute pancreatitis. In implicating drugs in the etiology of acute pancreatitis, two conditions must be considered to weigh the strength of the association between the causality and the disease process, namely: a positive rechallenge test resulting in the recurrence of pancreatitis and a similar latency period between the drug exposure and development of the disease.7

The combination of drugs rather than a single agent was implicated for drug-induced pancreatitis in a previous case report that described the development of acute pancreatitis shortly after the second cycle of the chemotherapy regimen composed of cyclophosphamide, doxorubicin, and vincristine in a patient with mediastinal immunoblastic lymphoma. The pancreatitis episode resolved over 48 hours without complications.8

Another case was described in a patient with breast cancer developing acute pancreatitis four days after the third cycle of chemotherapy, which involved docetaxel and carboplatin.9

Toprak et al. reported the occurrence of acute pancreatitis in a patient with multiple myeloma after the initial treatment with the triple regimen chemotherapy protocol consisting of vincristine, doxorubicin, and dexamethasone. In this case report, symptoms suggestive of acute pancreatitis started to manifest on the first day of the treatment, with resolution following discontinuation of the drugs.10

Other antineoplastic agents for breast cancer associated with drug-induced pancreatitis are alemtuzumab, trastuzumab and tamoxifen. Extended use of these medications may cause chronic pancreatitis as a result of their causing repeated clinical or subclinical episodes of acute pancreatitis.6 Most cases of drug-induced pancreatitis follow a mild clinical course.7

In a retrospective study involving 1613 patients diagnosed with acute pancreatitis in a gastroenterology center, the incidence of drug-induced pancreatitis had been reported in 1.4% of patients treated for acute pancreatitis. It has been observed that a higher incidence of drug-induced acute pancreatitis occurs in elderly or pediatric patients, and in those patients with inflammatory bowel disease or AIDS.11

The pathophysiology behind drug-induced pancreatic injury remains unclear. Potential mechanisms underlying such pancreatic injury might be related to drug hepatotoxicity which can be secondary to intrinsic toxicity of the drugs affecting the tissue, or due to an idiosyncratic reaction. In the vast majority of the cases, an idiosyncratic reaction could be the main pathway for tissue injury through a hypersensitivity reaction or production of toxic intermediate metabolites. Idiosyncratic reactions have a longer latency period of months to years before the onset of pancreatitis while the onset of hypersensitivity reactions is earlier (i.e. 1-6 weeks).7

CONCLUSION

Due to a variable latent period between the initial drug exposure and the onset of clinical symptoms, drug-induced pancreatitis must remain as a differential diagnosis in patients receiving chemotherapy regimens and presenting with the constellation of symptoms typical of acute pancreatitis. Due to the unclear pathogenesis of chemotherapy-induced pancreatitis, post-marketing surveillance and adverse drug reporting are paramount in elucidating the effect these drugs have on the pancreas.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
VINCENT BRYAN SALVADOR, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. MANPREET SINGH, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. PHILIP WITEK, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. GAY PERESS, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432.
Corresponding Author Details: 
VINCENT BRYAN SALVADOR, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center. 82-68 164th Street, Jamaica, New York, USA 11432.
Corresponding Author Email: 
docvincesalvador@aol.com
References
References: 
  1. Sakorafas GH & Tsiotou AG. Etiology and pathogenesis of acute pancreatitis: current concepts. J Clin Gastroenterol. 2000;30:343-356.
  2. Nitsche CJ, Jamieson N, Lerch MM et al. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol.2010;24(2):143-145.
  3. Wilmink T & Frick TW. Drug induced pancreatitis. Drug Safety. 1996;14:406-423.
  4. Tonsi AF, Bacchion M, Crippa S, Malleo G & Bassi C. Acute pancreatitis at the beginning of the 21st century: The state of the art. World J Gastroenterol 2009; 15(24):2945-2959.
  5. Mallory A & Kern F Jr. Drug-induced Pancreatitis: A Critical Review. Gastroenterol. 1980;78:813-820.
  6. Trivedi CD & Pitchumoni CS. Drug-Induced Pancreatitis: An Update. J Clin Gastroenterol. 2005;39:709-716.
  7. Badalov N, Baradarian R, Iswara K et al. Drug-Induced Acute Pancreatitis: An Evidence-Based Review. Clin Gastroenterol Hepatol. 2007;5:648-661.
  8. Puckett JB, William B & McFarland JA. Pancreatitis and Cancer Chemotherapy. Ann Intern Med. 1982;97(3):453.
  9. Singh V, Devata S & Cheng YC. Carboplatin and docetaxel-induced acute pancreatitis: brief report. Int J Clin Oncol. 2010;15:642-644.
  10. Toprak SK, Ocal S, Erismis B et al. Acute Pancreatitis Following VAD Chemotherapy Combination Consisting of Vincristine, Doxorubicin, and Dexamethasone in a Newly Diagnosed Multiple Myeloma Patient: A Case Report. The Internet Journal of Oncology. 2012; 8(2). Accessed at: http://archive.ispub.com/journal/the-internet-journal-of-oncology/volume-8-issue-2/acute-pancreatitis-following-vad-chemotherapy-combination-consisting-of-vincristine-doxorubicin-and-dexamethasone-in-a-newly-diagnosed-multiple-myeloma-patient-a-case-report.html#sthash.BFCHZGAr.mjxZj1fi.dpuf. Accessed on: 18 October 2013.
  11. Lankisch PG, Droge M & Gottesleben F. Drug induced Acute Pancreatitis: Incidence and Severity. Gut. 1995;37:565-567.

Cholestatic hepatitis: An unusual presentation of lisinopril induced hepatotoxicity

Authors
Gurpinder Singh, Amit Kachalia, Jaspreet Kaur, Kinjal Kachalia, Shaojun Liu and Vincent Rizzo
Article Citation and PDF Link
BJMP 2014;7(3):a721
Abstract / Summary
Abstract: 

Previously published case reports have shown direct hepatocellular injury as the mechanism for lisinopril induced hepatotoxicity. We report case of a 47 year old female who presented with jaundice, diagnosed as cholestatic hepatitis;two years after initiation of lisinopril. Extensive work up was negative for other causes of hepatitis. Liver biopsy showed portal inflammation by lymphocytes without centrilobular necrosis, which is similar to earlier case reports. Discontinuation of angiotensin converting enzyme inhibitors (ACE-I) usually leads to normalization of liver enzymes, however continuation or re-initiation can be potentially fatal.

This is the first reported case of lisinopril induced hepatotoxicity via cholestatic mechanism. Some reports hypothesize a metabolic idiosyncratic reaction as the molecular mechanism but currently there is no validated literature. This case highlights the need for further research to explore mechanisms for ACE-I mediated hepatotoxicity and to create awareness amongst physicians to consider ACE-I as an etiology for drug induced liver injury.

Abbreviations: 
ACE-I: Angiotensin converting enzyme inhibitors; DILI: Drug induced liver injury; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase; ANA: Anti nuclear antibody; AMA: Anti mitochondrial antibody; ANCA: Anti-neutrophil cytoplasmic antibody; CKD: Chronic kidney disease
Keywords: 
Angiotensin coverting enzyme inhibitor, Hepatotoxicity, Cholestatic hepatitis, Lisinopril

Introduction:

Various classes of medications have been known to cause drug induced liver injury (DILI), however not much literature has been published regarding angiotensin converting enzyme inhibitors (ACE-I) causing DILI. Recent years have seen tremendous increases in ACE-I prescriptions for coronary artery disease, diabetic nephropathy and hypertension. We report the first case of lisinopril induced hepatitis via a cholestatic mechanism.

Case:

A 47 year old female with history of diabetes mellitus type 2, hypertension, chronic kidney disease (CKD)stage III, non-obstructive coronary artery disease was admitted with complains of generalized weakness, lack of appetite, yellow discoloration of skin and eyes, dark urine and white stools for 1 week prior to admission. She denied history of alcohol abuse, past liver disease, illicit drug use, recent sick contacts, fever, chills, travel. Current patient medications included lisinopril, pioglitazone, furosemide, atenolol, metformin and detemir. Patient was started on these medications about 2 years prior to admission. Patient received enalapril for 5 months before switching to lisinopril about 2 years prior to presentation.

Physical examination was positive for icteric sclera, icteric skin; negative for spider nevi, palmar erythema and asterixis. Exam did not reveal hepatomegaly or splenomegaly. Labs showed hemoglobin 8.7 gm/dl, normal white count and platelet, normal C-reactive protein, alkaline phosphatase (ALP) 750 U/L, aspartate transaminase (AST) 169 U/L, alanine transaminase (ALT) 210 U/L, gamma-glutamyl transferase (GGT) 813 U/L, total bilirubin 13.4mg/dl with conjugated fraction 7.7mg/dl, ammonia level 64. Prior to initiation of lisinopril ALP was 87 U/L, GGT 53 U/L, with AST18 U/L, ALT 11 U/L and normal bilirubin fractions. Hepatitis A, B, C and D serologies were negative. Serum acetaminophen level was normal. Anti nuclear antibody (ANA), anti- mitochondrial antibody (AMA), anti-endomysial antibody, c-anti-neutrophil cytoplasmic antibody (ANCA), p-ANCA was negative. Anti smooth muscle antibody was weakly positive in titre of 1: 40. Creatine kinase, ceruloplasmin and alpha -1 antitrypsin level were normal. Quantiferon gold was negative. Lipid panel was deranged with cholesterol level 1017 and low density lipoprotein 1006, triglycerides 255.

Ultrasonography and magnetic resonance imaging abdomen showed hepatomegaly 17.5cms but was negative for fatty infiltration of liver, stones, cirrhotic features or dilation of biliary tree. Liver biopsy was done which showed mild portal chronic hepatitis with lymphocytic infiltration (Fig: 1), cholestasis (Fig: 2), mild portal fibrosis (Fig: 3), negative for bile duct damage (Fig: 4), negative for cytoplasmic inclusion. Congo red stain was negative for amyloid.


Figure 1: Mild hepatitis with portal tract lymphocytic infiltration.


Figure 2: Cholestasis.


Figure 3: Trichrome stain showing portal tract fibrosis.


Figure 4: Normal bile ducts in portal tract.

Patient was treated with fluids, anti-histaminic, ursodeoxycholic acid. Patient was unable to tolerate coleveselam. Impression was drug induced hepatitis, lisinopril was discontinued and patient improved clinically and biochemically. Discharge labs two weeks after discontinuation of lisinopril showed AST 80 U/L, ALT 70 U/L, ALP 1045 U/L and GGT 1212 U/L; total bilirubin of 3.93 mg/dl with conjugated fraction 2.43mg/dl. Patient was discharged uneventfully with follow up in Hepatology clinic. Six months after discontinuation of lisinopril ALP was 199 U/L, GGT 168 U/L with AST 19 U/L, ALT 17 U/L, total bilirubin 0.9mg/dl and conjugated bilirubin 0.21mg/dl. Patient is currently asymptomatic and icterus has resolved.

Discussion:

ACE-I has been used widely for coronary artery disease, hypertension and diabetic nephropathy and approximately 159 million prescriptions for ACE-I are written annually. Recent JNCC guidelines recommended ACE-I to be used as first line anti-hypertensives for patients with CKD and diabetes. The common side effects known about ACE-I use are cough and angioedema, hypersensitivity. However not much awareness exists regarding ACE-I induced hepatotoxicity. It is important to consider ACE-I as an etiology for drug-induced liver injury (DILI) since continuation of the ACE-I beyond onset of hepatitis is fatal1.

Literature review shows multiple reports of DILI with captopril2, 3, ramipril4, fosinopril5, 6 and enalapril.2,7 Most commonly implicated ACE-I are enalapril and captopril. The usual presentation for ACE-I induced hepatotoxicity is cholestasis mediated hepatitis. Till date there have been four case reports published reporting lisinopril as cause of hepatitis 1, 8, 9 All 4 cases of lisinopril induced hepatotoxicity have shown a hepatocellular pattern of liver injury and did not show any cholestatic features. We report the first case of lisinopril induced cholestasis mediated hepatotoxicity.

In our case, patient had received enalapril for 5 months before initiation of lisinopril; however patient developed symptoms 2 years after initiation of lisinopril. The patient had no past medical history of liver or biliary tract disease. A thorough investigative workup was negative for autoimmune and other viral causes of hepatitis. Older case reports of lisinopril induced toxicity have shown similar histopathological findings of portal inflammation by lymphocytes without centrilobular zonal necrosis.9 There are various theories regarding possible mechanisms for DILI with lisinopril, namely terminal proline ring mediated bile stasis8, 10 and hypersensitivity to the sulfhydryl group.2 Discontinuation of metformin, pioglitazone, furosemide, atenolol and detemir did not result in clinical or biochemical improvement. Patient was initially continued on lisinopril since suspicion was low and then later discontinued. Similarity in histopathological findings along with a strong temporal relationship between lisinopril withdrawal and improved biochemical and clinical scenario, with absence of other constitutional symptoms and eosinophilia strongly point toward lisinopril-induced hepatotoxicity.

Our case had a long period of latency between drug intake and onset of hepatic injury which is consistent with other published reports of lisinopril induced hepatocellular injury9, 10, 11; however the mechanism responsible for latency or hepatotoxicity remains unclear. Earlier report postulate metabolic idiosyncratic reaction as a possible molecular mechanism for hepatocellular injury9. However our case is unique as the primary mode of injury appears to be cholestatic. Since our patient received enalapril before initiation of lisinopril without any adverse events, this case adds further controversy as to whether this patient could have been safely continued on other ACE-I except lisinopril or whether she would have developed hepatotoxicity if enalapril was continued. This case highlights further need for research to evaluate ACE-I induced hepatotoxicity. Currently the awareness for ACE-I induced liver injury is low and there are no guidelines guiding physician to monitor for possible hepatic adverse events. Further research is needed to delineate the mechanism by which ACE-I cause hepatotoxicity and to define possible risk factors.

Conclusion:

Discontinuation of ACE-I beyond recognition of DILI hepatitis usually leads to normalization of liver enzymes, however continuing or reinitiating ACE-I can be severe and potentially fatal. Thus, it is important to be aware of ACE-I as a possible cause of DILI, which can present with either hepatocellular or cholestatic mechanism and to promptly discontinue ACE inhibitor use. Currently there are no guidelines in place for monitoring of liver enzymes following initiation of ACE-I and more research is required to delineate possible mechanisms and prevent further DILI in such patients.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None
Details of Authors: 
GURPINDER SINGH, MD MBBS PGDHHM. Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. AMIT KACHALIA, MD MBBS.Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. JASPREET KAUR, MBBS. Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. KINJAL KACHALIA, DNB MBBS.Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. SHAOJUN LIU, MD. Icahn School of Medicine at Mount Sinai Queens Hospital Center,82-68 164 street, Jamaica, NY-11432, USA. VINCENT RIZZO, MD MBA, FACP. Icahn School of Medicine at Mount Sinai Queens Hospital Center,82-68 164 street,Jamaica, NY-11432, USA.
Corresponding Author Details: 
GURPINDER SINGH, Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 Street, Jamaica, NY 11432, USA.
Corresponding Author Email: 
drgurpinder@yahoo.co.in
References
References: 
  1. Larrey D, Babany G, Bernuau J, et al. Fulminant hepatitis after lisinopril administration. Gastroenterology. 1990; 99:1832–3.
  2. Shionoiri H, Nomura S, Oda H, et al. Hepatitis associated with captopril and enalapril but not with delapril in a patient with congestive heart failure receiving chronic hemodialysis. CurrTher Res. 1987; 42:1171–6.
  3. Schattner A, Kozak N, Friedman J. Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature. Am J Med Sci 2001; 322:236–240.
  4. Douros A, Kauffmann W, Bronder E, et al. Ramipril-induced liver injury: case report and review of the literature. Am J Hypertens. 2013 Sep;26(9):1070-5.
  5. Nunes AC, Amaro P, Mac AF, et al.Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report. Eur J GastroenterolHepatol 2001; 13:279–282.
  6. Chou JW, Yu CJ, Chuang PH, et al.Successful treatment of fosinopril-induced severe cholestatic jaundice with plasma exchange. Ann Pharmacother. 2008 Dec;42(12):1887-92.
  7. Da Silva GH, Alves AV, Duques P, et al. Acute hepatotoxicity caused by enalapril: a case report. J Gastrointestin Liver Dis. 2010 Jun;19(2):187-90.
  8. Hillburn RB, Bookstaver D, Whitlock WL. Angiotensin-converting enzyme inhibitor hepatotoxicity: further insights. Ann Pharmacother. 1993; 27:1142–3. Letter.
  9. Zalawadiya SK, Sethi S, Loe S, et al. Unique case of presumed lisinopril-induced hepatotoxicity. American Journal of Health-System Pharmacy August 15, 2010 vol. 67 no. 16 1354-1356.
  10. Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated with ACE inhibitors. Ann Pharmacother. 1993; 27:228–31.
  11. Droste HT, de Vries RA. Chronic hepatitis caused by lisinopril. Neth J Med. 1995; 46:95–8.

Extended spectrum beta lactamase positive uropathogenic E. coli - Epidemiological Factors and Resistance

Authors
Priya Datta, Varsha Gupta and Shailpreet Sidhu
Article Citation and PDF Link
BJMP 2014;7(2):a718
Abstract / Summary
Abstract: 

Introduction: There is increasing incidence ofESBL producing E. coli causing community urinary tract infections.The primary objective of this study was to study the epidemiological factors associated with ESBL (Extended spectrum beta lactamases) positive community acquired uropathogenic E. coli isolates and to determine their susceptibility to newer oral drugs including mecillinam.
Materials & Method: In this prospective study, from total of 140 community isolates of E. coli causing UTI, ESBL was detected by CLSI criteria. Drug susceptibility was done by Kirby-Bauer method disc diffusion method for various oral antimicrobial agents. Various epidemiological factors associated with ESBL for each patient were recorded on individual forms. This included age, presence of diabetes mellitus, renal calculi, pregnancy, history of urinary instrumentation, recurrent UTI and antibiotics intake.
Results: Out of total of 140 strains of E. coli, which were screened for ESBL production, 30 (21.4%) isolates were positive. High-level resistance 94 (70%) was seen for many antimicrobial agents. Only 4.5% of uropathogenic E. coli were resistant to Mecillinam. Various epidemiological factors associated with ESBL causing infections were female patients, H/o antimicrobial intake, elderly age > 60 years, renal calculi and H/o recurrent UTI.
Conclusions: The epidemiology of ESBL positive uropathogenic E. coli is becoming more multifaceted.

Abbreviations: 
ESBL( Extended spectrum beta lactamases), UTI( Urinary tract infection)
Keywords: 
ESBL, Community UTI, E.coli, epidemiology

Introduction

Community acquired urinary tract infection (UTI) due to Escherichia coli is one of the most common form of bacterial infections, affecting people of all ages. Originally ESBL (extended spectrum β-lactamases) producing E. coli was isolated from hospital setting but lately this organism has begun to disseminate in the community.1

In India community presence of ESBL producing organisms has been well documented. However, various epidemiological factors associated with ESBL producing strains need to be documented. This will allow clinicians to separate patients with community UTI with these factors so that appropriate and timely treatment can be given.A community UTI when complicated may be a potentially life-threatening condition. In addition, for deciding the empirical treatment for patients with a UTI a thorough knowledge of local epidemiology is required. Therefore, the primary objective of this study was to determine the epidemiological factors associated with ESBL positive community acquired uropathogenic E. coli isolates and to determine their susceptibility to newer oral drugs. Mecillinam is a novel β-lactam antibiotic that is active against many members of family Enterobacteriaceae. It binds to penicillin binding protein (PBP 2), an enzyme critical for the establishment and maintenance of bacillary cell shape. It is given as a prodrug that is hydrolyzed into active agent. It is well tolerated orally in the treatment of acute cystitis.3

Material and Methods

This prospective study was conducted, from Jan 2012- July 2012, in our tertiary care hospital, which caters to medical needs of the community in North India.

Study Group:

The study group included patients diagnosed as having a UTI in outpatient clinic, or the emergency room or patients diagnosed within 48 hrs after of hospitalization. These patients and were labeled as patients having a community UTI. A diagnosis of symptomatic UTI was made when patient had at least one of the following signs or symptoms with no other recognized cause: fever ≥ 38.8˚C, urgency, frequency, dysuria or suprapubic tenderness and a positive urine culture (i.e. ≥10microorganisms/ml of urine).Various epidemiological factors for each patient were recorded on individual forms. This included age, presence of diabetes mellitus, renal calculi, pregnancy, history of urinary instrumentation, recurrent UTI (more than 3 UTI episodes in the preceding year) and antibiotics intake (use of β-lactam in the preceding 3 months).2

Patients with a history of previous or recent hospitalization were excluded from study.

Antibiotic susceptibility testing was carried out following Clinical Laboratory Standards Institute (CLSI) guidelines using the Kirby-Bauer disc diffusion method.The antibiotics, which were tested included Amoxyclav (30/10µg), Norfloxacin (10µg), Ciprofloxacin (5µg), Tetracycline (30µg), Nitrofurantoin (300µg), Trimethoprim-sulfamethoxazole (23.75/1.25µg), Cephalexin (30µg), Cefaclor (30µg), Cefuroxime (30µg), Mecillinam (10µg) (Hi-Media, Mumbai, India).

Detection of ESBL

ESBL detection was done for all isolates according to latest CLSI criteria.5

Screening test - According to latest CLSI guidelines, zone diameter of E. coli strain for Ceftazidime <22mm and for Cefotaxime < 21mm is presumptively taken to indicate ESBL production.

Confirmatory test - As per CLSI guidelines, ESBLs were confirmed by placing a disc of Cefotaxime and Ceftazidime at a distance of 20mm from a disc of Cefotaxime /Clavulanic acid (30/10µg) and Ceftazidime/Clavulanic acid (30/10µg) respectively on a lawn culture of test strain (0.5 McFarland inoculum size) on Mueller-Hinton agar. After overnight incubation at 37° C, ESBL production was confirmed if there was a ≥5mm increase in zone diameter for either antimicrobial agent tested in combination with Clavulanic acid versus its zone when tested alone

Control strain - Standard strain of Klebsiella pneumonia ATCC 700603 was used as ESBL positive controland Escherichia coli ATCC 25922 was used as ESBL negative control.

Results

Out of total of 140 strains of E. coli, which were screened for ESBL production, 30 (21.4 %) isolates were found to be positive. High-level resistance was seen for many antimicrobial agents like Cephalexin (92.8%), Cefaclor (90%), Amoxy-clavulanate (88.57%), Cefuroxime (75.7%), Sulfamethoxazole-trimethoprim (72.8%), Norfloxacin (75.71%) and Ciprofloxacin (70%). Sensitivity to Nitrofurantoin was found to be 90%. Only 4.5% of uropathogenic E. coli were resistant to Mecillinam.

Various epidemiological factors seen in ESBL producers include female patients (n =24, 80%), history of antimicrobial intake (n = 17,57 %), elderly age >60 years (n =16 53%), renal calculi (n =15, 50%), history of recurrent UTI (n =11, 37 %), pregnancy (n = 11,37%), diabetes mellitus (n = 7, 23%) and history of urogenital instrumentation (n = 7, 23%).

Discussion

The epidemiology of ESBL positive uropathogenic E. coli is becoming more multifaceted, with increasingly indistinct boundaries between the community and hospital.6 In addition, infection with an ESBL producing organisms causing community UTI is associated with treatment failure, delayed clinical response, higher morbidity and mortality. These organisms are multi-resistant to other antimicrobials like Aminoglycosides, Quinolones and Co-trimoxazole. Therefore, empirical therapy with Cephalosporins and Fluoroquinolones often fail in patients with community UTI.7

The rate of ESBL producers in our study is lower than that described by other authors. In a similar study Mahesh E et al. reported higher rate (56.2%) of ESBL positivity from E. coli, which were causing UTIs from a community setting.8 Additionally Taneja N et al. described a higher rate (36.5%) of ESBL positivity in uropathogens. 9,10

A high rate of resistance was seen to almost all antimicrobial agents. This is in agreement with other authors like Mahesh et al. and Mandal J et al.8,11 Mecillinam showed very good results with only 4.5% resistance. Wootton M et al. reported similar high activity of Mecillinam against E. coli(93.5%).3 Auer S et al. reported that Mecillinam can be a good oral treatment options in patients with infections due to ESBL organisms.7

A limitation of our study was that being a developing country with limited resources, molecular typing and determination of antimicrobial resistance profiles of the isolates was not done. In our study female patients, elderly, patients with a history of antimicrobial intake, renal calculi and history of recurrent UTI were important factors for infection due to ESBL producers. These findings are similar to risk factors studied by other authors.2 In conclusion; this study confirms that ESBL-producing E. coli strains are a notable cause of community onset infections especially in predisposed patients. The widespread and rapid dissemination of ESBL-producing E. coli seems to be an emerging issue worldwide. Further clinical studies are needed to guide clinicians in the management of community onset infections caused by E. coli.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
PRIYA DATTA, MD, Assistant Prof, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India. VARSHA GUPTA, MD DNB, Professor, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India. SHAILPREET SIDHU, MD, Senior Resident, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India.
Corresponding Author Details: 
DR SHAILPREET SIDHU, Senior Resident, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India.
Corresponding Author Email: 
shailpreet78@hotmail.com
References
References: 
  1. Rodríguez BJ,  Alcalá CJ, Cisneros MJ, Grill F, Oliver A, Juan P et al. Community Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli. Arch Intern Med. 2008; 168: 1897-1902.
  2. Azap OK,  Arslan H, Serefhanoglu K, Colakoglu S, Erdogan H, Timurkaynak F et al. Risk factors for extended-spectrum  β -lactamase positivity in uropathogenic Escherichia coli isolated from community-acquired urinary tract infections. Clin Microbiol Infect .2010;16: 147-51.
  3.  Wootton M, Walsh TM, Macfarlane L, Howe R. Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins. J Antimicrob Chemother. 2010; 65: 79-81.
  4. Dong SL, Chung BL, Seung-JL. Prevalence and Risk Factors for Extended Spectrum Beta-Lactamase-Producing Uropathogens in Patients with Urinary Tract Infection. Korean J Urology. 2010; 51:492-7.
  5. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty First Informational Supplement M100-S21. CLSI, Wayne, PA, USA, 2011.
  6. Nesher L, Novack V, Riesenberg F, Schlaeffer F. Regional community-acquired urinary tracts in Israel; diagnosis, pathogens, and antibiotics guidelines adherence: A prospective study. International J Infect Dis 2007; 11:245-50.
  7. Auer S, Wojna A, Hell M. Oral Treatment Options for Ambulatory Patients with Urinary Tract Infections Caused by Extended-Spectrum beta-Lactamase-Producing Escherichia coli. Antimicro Agents Chemo. 2010,54: 4006-8.
  8. Mahesh E, Ramesh D, Indumathi VA, Khan MW, Kumar PS, Punith K. Risk Factors for Community Acquired Urinary Tract Infection caused by ESBL-producing Bacteria. J Indian acad  clinl med.. 2010; 11:271-6.
  9. Taneja N, Rao P, Arora J, Dogra A. Occurrence of ESBL & Amp-C β-lactamases & susceptibility to newer antimicrobial agents in complicated UTI. Indian J Med Res 2008; 127: 85-8.
  10.  Taneja N, Singh G, Singh M, Madhup S, Pahil S, Sharma M .High occurrence of bla CMY-1 Amp C lactamase producing Escherichia coli in cases of complicated urinary tract infection (UTI) from a tertiary health care centre in north India. Indian J Med Res 2012; 136: 289-91.
  11.  Mandal J, Acharya NS, Buddapriya D, Parija SC.Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant Escherichia coli. Indian J Med Res 2012; 136: 842-9.

Tracheo esophageal fistula

Authors
M Suresh Babu, Deepak Suvarna, Chandrashekhar Shetty and Aditya Nadella
Article Citation and PDF Link
BJMP 2014;7(2):a717
Abstract / Summary
Abbreviations: 
TEF - Tracheoesophageal fistula
Keywords: 
TEF - Tracheoesophageal fistula

A 40 year old patient presented to the hospital outpatient department with one year history of cough, choking sensation following swallowing, hoarseness of voice and loss of weight. History revealed his previous hospital admission 1 year back for management of organophosphorus poisoning during which he was intubated and put on mechanical ventilator for 10 days. Patient developed the symptoms a month after his discharge from the hospital. Cranial nerve examination was within normal limits. What is the possible diagnosis?

  1. Gastro-oesophageal reflux disease
  2. Tracheo-oesophageal fistula
  3. Oesophageal diverticula
  4. Oesophageal rupture


Fig 1: Barium swallow illustrating a dilated oesophagus and the TOF with resultant contamination of the trachea and bronchial tree


Fig 2: Oesophagoscopy showing TOF

Correct answer:

2. Tracheo-oesophageal fistula

Discussion:

A tracheo-oesophageal fistula (TOF) is a communication between the trachea and oesophagus which can be congenital or acquired. Congenital and acquired TOFs are associated with multiple complications, including poor nutrition, recurrent pneumonia, acute lung injury, acute respiratory distress syndrome, lung abscess, bronchiectasis from recurrent aspiration, respiratory failure, and death. Acquired TOFs occur secondary to malignant disease, infection, ruptured diverticula, and trauma.1, 2 Acquired TOFs are quite rare, and incidence rates have not been well documented. Post intubation TOFs uncommonly occur following prolonged mechanical ventilation with an endotracheal or tracheostomy tube. TOFs caused by endotracheal tube intubation depend on several factors, including prolonged intubation, an irritating or abrasive tube, and pressure exerted by the cuff. Pressures exceeding 30 mm Hg can significantly reduce mucosal capillary circulation and result in tracheal necrosis. Cuff pressure is particularly risky when exerted posteriorly against a rigid nasogastric tube in the oesophagus. Poor nutrition, infection, and steroid use cause tissue alteration, which predisposes patients for the development of TOFs. As a result of laryngeal bypass, spillage of oesophageal contents occurs into the trachea. Saliva, food and gastric juice contaminate the airways. This leads to congestion, infection, pneumonia, bronchial obstruction, atelectasis and respiratory distress. The severity of contamination depends on the width and length of the fistula as well as the posture of the patient. Spontaneous closure of non-malignant TOFs is exceptional.

Patients with acquired TOFs have high mortality and morbidity rates because of critical illnesses and co-morbidities. Acquired TOFs may occur in individuals of any age, and elderly individuals are at increased risk if they become ventilator dependent because of respiratory failure. Acquired TOFs can be diagnosed by instillation of contrast media into the oesophagus (Fig.1) or during direct visualization by flexible oesophagoscopy (Fig.2) or bronchoscopy. A high index of suspicion is needed to diagnose tracheo-oesophageal fistula in a post intubated patient presenting with symptom of cough following deglutition. Since acquired TOFs do not close spontaneously, surgical repair is needed if the patient is stable enough.3, 4 Critically ill patients are managed conservatively until stable enough for a major surgical procedure.

Typical oesophageal symptoms of gastro-oesophageal reflux disease include heartburn, regurgitation and dysphagia. The classic presentation of spontaneous oesophageal rupture is chest pain and subcutaneous emphysema after recent vomiting or retching (Mackler’s triad) in a middle-aged man with a history of dietary over-indulgence and over consumption of alcohol. Oesophageal diverticula presents with oropharyngeal dysphagia, usually to both solids and liquids, which is the most common symptom. Retention of food material and secretions in the diverticulum, particularly when it is large, can result in regurgitation of undigested food, halitosis, cough, and even aspiration pneumonia. The patient may note food on the pillow upon waking up in the morning.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
M SURESH BABU, MBBS MD FCCP FICP FICS FIMSA FIACM FISE FACP(USA), Associate Professor, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. DEEPAK SUVARNA, MBBS MD DNB(Gastroenterology), Professor, Department of Gastroenterology, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. CHANDRASHEKHAR SHETTY, MBBS MD(Radiology), Professor and Head of Department, Department of Radiology, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. ADITYA NADELLA, MBBS, Junior Resident, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India.
Corresponding Author Details: 
Dr. M. Suresh Babu MBBS, MD, FCCP, FICP Associate Professor, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India-570004 PH: +91-9448052680 Email :drmsureshbabu@yahoo.co.in Postal Address: #739, E and F Block, Kuvempunagar, Mysore-570023, Karnataka, India
Corresponding Author Email: 
drmsureshbabu@yahoo.co.in
References
References: 
  1. Diddee R, IH Shaw IH Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 3 2006
  2. Sharma S  Tracheoesophageal fistula -  e medicine.medscape.com/article Medscape reference  2012
  3. Reed MF and Mathisen DJ “Tracheoesophageal fistula,” Chest Surgery Clinics of North America, vol. 13, no. 2, pp. 271–289, 2003.
  4. Chauhan SS, Long JD, “Management of tracheoesophageal fistulas in adults,” Current Treatment Options in Gastroenterology, vol. 7, no. 1, pp. 31–40, 2004

The twitching leg

Authors
Jose A Egido and Ana M Garcia
Article Citation and PDF Link
BJMP 2014;7(2):a716
Abstract / Summary
Abstract: 

A 87-year-old man was admitted to the Acute Stroke Unit and incidental spontaneous movements were seen at rest. Differential diagnosis and ancillary tests are discussed in this article.

Abbreviations: 
ALS: amyotrophic lateral sclerosis EMG: electromyography MRI: magnetic resonance imaging
Keywords: 
Fasciculation, neurological examination, radiculopathy

Clinical Scenario / Question

An 87-year-old gentleman was admitted after sudden dysarthria and left facial palsy due to a right internal carotid artery occlusion. On examination, incidental spontaneous movements were seen at rest in the left leg (video), with bilaterally diminished Achilles reflexes. Patient was unaware of this finding. Muscle atrophy and hypoesthesia were not present. When walking on heels, left foot dorsiflexion was impaired.

What kind of physical finding is shown in this video?

A. Myoclonus
B. Dystonia
C. Tremor
D. Chorea
E. Fasciculation
F. Myokymia

Answer / Discussion

Focal fasciculations in the tibialis anterior muscle are shown. When walking on heels, left foot dorsiflexion was slightly impaired.

Fasciculation is a brief, twitching, spontaneous involuntary contraction affecting muscle fibres served by one motor unit, which may be visible under skin. When present, they reflect denervation.

A complete history intake and neurological examination will lead to a sensible diagnostic work-up and to set a prognosis. Clinical differential diagnosis is presented in table 1.

Table 1: Key points for clinical diagnosis

Myoclonus Brief, shocklike involuntary contraction of a muscle or group of muscles
Dystonia Involuntary muscle contraction that can cause slow repetitive movements or abnormal postures
Tremor Involuntary rhytmic contraction of antagonistic muscles
Chorea Involuntary irregular movement that starts in one part of the body and moves unpredictably and continously to another part, like “dancing”
Myokymia Involuntary spontaneous quivering, writhing movements within a single muscle not extensive enough to cause a movement of a joint

Localization helps in diagnosis: fasciculations can be generalised, in metabolic-toxic conditions, the benign fasciculation syndrome and degenerative disorders of anterior horn of spinal cord, as amyotrophic lateral sclerosis; segmental, as in syringomyelia; or focal, affecting the muscles controlled by a nerve or spinal root. When fasciculations are in a distribution that cannot be explained by plexus, root or nerve lesion amyotrophic lateral sclerosis (ALS) must be ruled out as soon as possible.

Evolution findings are also pivotal. The absence of muscle atrophy suggests that an acute or subacute nerve lesion is present, although a limited chronic nerve lesion cannot be excluded based on that observation alone. A clinical examination should be repeated at least every six months to assess progression, muscle weakness, upper motor neuron signs and other findings, such as bilateral wasting of the tongue, the “split hand”, head drop, emotionality and cognitive or behavioral impairment1

It is also very important to rule out any possible metabolic disorder, as toxic conditions. Earl Grey tea intoxication has been reported as a cause of widespread fasciculations and cramps2

Electromyography (EMG) is the recording of the electrical activity of the muscles. It supports the clinical suspicion and helps in the topographic diagnosis. If ALS is suspected, a systematic examination of clinically uninvolved muscles has to be done for 2 minutes as fasciculations are the hallmark of this condition. As fasciculation potentials in ALS and benign fasciculation syndrome are indistinguishable on grounds of waveform parameters3 and there is not a reliable biological marker of the disease, a minimum follow-up of 6 months is required before setting a prognosis. When non-progressive isolated fasciculations of the tibialis anterior muscle, it has to been examined the 5th lumbar root and the deep peroneal nerve, as localizer sensory symptoms may be absent4, and to rule out any more diffuse neurogenic processes.

Magnetic resonance imaging (MRI) is supportive to EMG findings as it is very sensitive in detecting anatomic changes that could be responsible for the radiculopathy, but there are other causes of radiculopathy besides nerve root compression. Moreover, lumbar disk protrusions can be found in asymptomatic patients independent of age5. Therefore, MRI is not appropriate if pain or foot drop are not present.

Finally, an isolated chronic left L5 radiculopathy was diagnosed related to lumbar spondyloarthrosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JOSE A EGIDO, MD MPHIL FESO, Stroke Unit and Neurosonology Laboratory Clinical Lead, Hospital Clinico San Carlos, Madrid, Spain. ANA M GARCIA, MD MPHIL, Consultant Neurologist and Stroke Physician, Worcestershire Royal Hospital, Worcester, United Kingdom.
Corresponding Author Details: 
ANA M GARCIA, Consultant Neurologist and Stroke Physician, Worcestershire Royal Hospital, Worcester, United Kingdom.
Corresponding Author Email: 
amgarciagarcia@gmail.com
References
References: 
  1. Turner MR, Talbot K. Mimics and Chamaleons in Motor Neuron Disease. Practical Neurol 2013; 13 (3): 153 – 164, doi: 10.1136/practneurol-2013-000557
  2. Finsterer J. Earl Grey Tea Intoxication. Lancet 2002; 359 (9316): 1484, doi: 10.1016/S0140-6736(02)08436-2
  3. Mills KR. Characteristics of Fasciculations in Amyotrophic Lateral Sclerosis and the Benign Fasciculation Syndrome. Brain: a Journal of Neurology 2010; 133 (11): 3458–3469, doi:10.1093/brain/awq290.
  4. Garland H and Moorhouse D. Compressive Lesions of the External Popliteal (Common Peroneal) Nerve. British Medical Journal 1952; 2 (4799):1373–1378.
  5. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al. Magnetic Resonance Imaging of the Lumbar Spine in People Without Back Pain. New England Journal of Medicine 1994; 331 (2): 69–73, doi:10.1056/NEJM199407143310201.

Health care quality and hospital acquired infection in Intensive care: Bundles and checklists

Authors
Sandeep Tripathi
Article Citation and PDF Link
BJMP 2014;7(2):a715

Hospital acquired infections (HAI) are one of the most common complications involving hospital care and are the leading cause of death in U.S. Central line associated Blood stream Infection (CLABSI), Ventilator Associated Pneumonia (VAP), Surgical site infection (SSI) and Catheter associated urinary tract infection (CAUTI) represent 75% of all HAI1 . HAI prevention is one of the 20 ‘priority areas’ identified in the Institute of Medicine (IOM) 2003 report ‘transforming health care quality’2. Certain HAI are preventable, but as the prevention efforts become more defined, there remains a lack of evidence of a strong return of investment for hospitals and health care payers in preventing these infections. This lack of evidence presents potential obstacles in advancing efforts to prevent infections.

Central Line Associated Blood Stream Infection (CLABSI)

CLABSI is a primary blood stream infection that develops in a patient with a central line in place within the 48 hour period before the onset of blood stream infection, which is not related to infection at another site. Central line associated blood stream infection occurs up to 80,000 times per year resulting in 28,000 deaths among patients in the Intensive Care unit (ICU). Average cost of CLABSI is approximately $ 45,000 per incidence3. CLABSI reduction is also one of the success story of how inexpensive interventions, grouped as a checklist could reduce the rate of nosocomial infections to a median rate of zero. Although quality control interventions in many areas of ICU have been studied, the idea of integrating quality indicators with group of interventions known as bundles has been validated in the ICU most successfully in CLABSI. The landmark study on reduction of CLABSI was the ‘Keystone ICU’ project funded by the Agency for Health care Research and Quality (AHRQ) 4. One hundred and three ICUs in Michigan participated in this state wide safety initiative. The study intervention recommended five evidence based procedures that were identified as having the greatest effect on the rate of catheter related BSI and the lowest barriers to implementation. The interventions were remarkably successful, nearly eliminating CLABSI entirely in most ICUs over an 18 month follow up period.

Although in short term intensive training and monitoring can lead to improved outcomes, in long term the biggest impact on decreasing HAI, is of the safety climate of the unit. Studies have linked safety climate to clinical and patient outcomes in addition to showing that the safety climate is responsive to interventions. A large study targeting the culture of safety was a follow up of the Michigan Keystone study. The study was a prospective cohort study to improve quality of care and safety culture by implementing and evaluating patient safety interventions in participating ICUs and showed large scale improvements in safety climate among diverse organizations5. As part of the national effort to reduce the HAI, the Department of Health and Human Services (HHS) launched the HHS action plan to reduce the health care associated infections in 2009. The project was titled ‘On the cusp: Stop BSI’, designed to apply the principles of comprehensive unit based safety program (CUSP) to improve the culture of patient safety and implement evidence based best practices to reduce the risk of infection. The initiative ultimately reduced mean rates of CLABSI in participating units by an average of 40%, preventing more than 2000 CLABSI, saving more than 500 lives and avoiding more than $34 million in excess health care costs6.

Ventilator Associated Pneumonia

Optimizing the care of mechanically ventilated patients is an important goal of health care providers and hospital administrators. An easily acquired and reliable marker for medical quality has been elusive for this patient population. VAP has historically been used as a marker of the quality of care associated with mechanically ventilated patient and is associated with worse outcomes7. However the diagnosis of VAP is non-specific, the clinical diagnosis by the widely used American College of Chest Physicians (ACCP) criteria includes a new progressive consolidation on chest radiography plus at least two of the following clinical criteria: fever > 38, leucocytosis or leucopenia and purulent secretions. Unfortunately, all these findings alone or in combination can occur in other non-infectious conditions, making the diagnosis of VAP subjective and prone to bias. In fact, for the last many years, the surveillance rates of VAP are decreasing, whereas the clinical diagnosis of VAP and tracheobronchitis as well as antibiotic prescribing remains prevalent. External reporting pressures may be encouraging stricter interpretation of the subjective signs that can cause artifactual lowering of the VAP rates. The result is that, it is almost impossible to detangle the relative contribution of quality improvement efforts in the ICU versus surveillance efforts as explanation for the currently observed lower rates of VAP8.

To eliminate the subjectivity and inaccuracy and to create an objective , streamlined and potentially automatable criteria, Center of Disease Control (CDC) now recommends surveillance of ventilator associated events (VAE) as a more general marker and defines it as sustained increase in patient’s ventilator settings after a period of stable or decreasing support . There are three definition tiers within the VAE algorithm; 1) Ventilator Associated Condition (VAC); 2) Infection Related Ventilator Associated Complication (IVAC); and 3) Possible and probable VAP. The screening for VAC captures a similar set of complications to traditional VAP surveillance, but it is faster, more objective and potentially a superior predictor of clinical outcomes9. In a CDC funded study of 597 mechanically ventilated patients on use of VAC as an outcome predictor, it was noted that 9.3% of the study population had a VAP, whereas 23% had VAC. VAC was associated with increased mortality (odds ratio of 2.0) but VAP was not. VAC assessment was also faster (mean 1.8 minutes vs 3.9 minute per patient) 10.

Similar to the CLABSI bundles, prevention of VAP by utilization of evidence-based bundles of care has proved to be a very successful. Heimes and colleagues recently conducted a study examining 696 consecutive ventilated patients in a level 1 trauma center to evaluate a VAP prevention bundle with 7 elements. They found a VAP rate of 5.2/1000 days of ventilator support in the pre intervention phase, while a 2.4 /1000 and 1.2/1000 days (p= 0.085) in the implementation and enforcement periods respectively11.

Catheter Associated Urinary Tract Infection (CAUTI)

Health care associated UTI account for up to 40% of infections in hospitals and 23% of the infections in the ICU. The vast majority of UTIs are related to indwelling urinary catheters. CAUTI result in as much as $ 131million excess direct medical costs nationwide annually12. Since October 2008, Center of Medicare Services (CMS) no longer reimburses hospitals for the extra costs of managing a patient with hospital acquired CAUTI.

There are certain factors like Diabetes mellitus, old age or severe underlying illness that places patients at a greater risk of CAUTI, but there also are modifiable factors like non adherence to aseptic catheter care recommendations and duration of catheterization that can be targeted by quality improvement efforts, to decrease the risk13. The key strategies for prevention of CAUTI include avoiding insertion if possible, early removal by implementation of checklists, nurse based interventions or daily electronic reminders, utilization of proper techniques for insertion and maintenance and considering alternatives to indwelling catheters like intermittent catheterization, condom catheters and portable bladder ultrasound scanner. Most of these strategies have been utilized in quality improvement efforts to decrease CAUTI. Assessment of the need is essential as Munasinghe et al have found urinary catheter placed in 21 to 50% of patients for inappropriate reasons14. A nurse based reminder to physician to remove unnecessary urinary catheters in a Taiwanese hospital resulted in reduction of CAUTI from 11.5 to 8.3 /1000 catheter days15. Similarly utilization of electronic urinary catheter reminders system and stop orders have been shown to reduce the mean duration of catheters by 37% and CAUTI by 2%16. Utilization of condom catheter has also been shown to be effective in reducing bacteriuria, symptomatic UT and mortality as compared to indwelling catheter17.

Final word

Health care is often compared with airline industry with six sigma efficiency. This would translate to 0.002 defective parts or errors/million, obviously we are not close to that and may not be realistic. However this also cannot be an excuse to rationalize poor practice culture. As in any industry, in health care to establish change it is essential to regulate interpersonal interactions. With behaviors change leading to changes in processes of care, change is not only possible, it is sustainable.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SANDEEP TRIPATHI, MD, Consultant, Pediatric Intensive Care Unit, Assist Professor of Pediatrics, Mayo Clinic, Rochester, MN.
Corresponding Author Details: 
DR SANDEEP TRIPATHI, 3107 Avalon Cove Court NW, Rochester, MN 55901
Corresponding Author Email: 
sandeeptripathi2000@yahoo.com
References
References: 
  1. Klevens RM, Edwards JR, Richards CL Jr, et al. Estimating health care associated infections and deaths in U.S. hospitals, 2002. Public Health Rep 2007;122:160–166.
  2. National Research Council. Priority Areas for National Action: Transforming Health Care Quality. Washington, DC: The National Academies Press, 2003.
  3. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infections in critically ill patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598–601.
  4. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 2006;355(26): 2725–2732.
  5. Sexton JB, Berenholtz SM, Goeschel CA, et al. Assessing and improving safety climate in a large cohort on intensive care units. Crit Care Med 2011;39:934–9.
  6. AHRQ Patient Safety Project Reduces Bloodstream Infections by 40 Percent. September 2012. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/news/newsroom/press-releases/2012/20120910.html
  7. Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 2012;33: 250–6.
  8. Klompas M. Is a ventilator-associated pneumonia rate of zero really possible? Curr Opin Infect Dis 2012;25:176–82.
  9. Marin H. Kollef. Ventilator-associated Complications, Including Infection-related Complications:The Way Forward. Crit Care Clin 2013;29:33–50.
  10. Klompas M, Khan Y, Kleinman K, et al. Multicenter evaluation of a novel surveillance paradigm for complications of mechanical ventilation. PLoS One 2011;6: e18062.
  11. Heimes J, Braxton C, Nazir N, et al. Implementation and enforcement of ventilator-associated pneumonia prevention strategies in trauma patients. Surg Infect (Larchmt) 2011;12:99–103.
  12. Burton DC, Edwards JR, Srinivasan A, et al. Trends in catheter-associated urinary tract infections in adult intensive care units-United States, 1990-2007. Infect Control Hosp Epidemiol 2011;32:748–56.
  13. Umsheid CA, Mitchell MD, Doshi JA, et al. Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality costs. Infect Control Hosp Epidemiol 2011;32:101–14.
  14. Munasinghe RL, Yazdani H, Siddique M, et al. Appropriateness of use of indwelling urinary catheters in patients admitted to the medical service. Infect Control Hosp Epidemiol 2001;22(10):647–9.
  15. Huang WC, Wann SR, Lin SL, et al. Catheter-associated urinary tract infections in intensive care units can be reduced by prompting physicians to remove unnecessary catheters. Infect Control Hosp Epidemiol 2004;25:974–8.
  16. Meddings J, Rogers MAM, Macy M, et al. Systematic review and metaanalysis: reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients. Clin Infect Dis 2010; 51:550–60.
  17. Saint S, Kaufman SR, Rogers MA, et al. Condom versus indwelling urinary catheters: A randomized trial. J Am Geriatr Soc 2006;54:1055–61.

Spotted Bone - A Spot Diagnosis

Authors
Abdul Rehman Arshad, Asif Rahman, Shafqat Hussain
Article Citation and PDF Link
BJMP 2014;7(2):a713
Abstract / Summary
Abstract: 

A young male was incidentally diagnosed to have a rare disorder on X rays done to rule out a bony injury after trauma to his left wrist. The radiological findings and differential diagnosis are briefly discussed.

Keywords: 
bone dysplasia, osteosclerosis, osteopoikilosis

Clinical Scenario / Question

A 26-year-old previously healthy male presented with a two day history of pain in his left wrist following trauma inflicted while playing volleyball. It was aggravated by movements around the affected joint. Clinical examination revealed mild tenderness over the left wrist with full range of movements and absence of any swelling. Distal neurovascular status was intact. X-ray of the left hand and wrist was done to rule out an injury to the bones (Fig. 1).

Fig. 1: X-Rays of left hand and wrist

What diagnosis does the X-ray findings indicate?

  1. Fracture of left scaphoid bone
  2. Osteoblastic metastases
  3. Osteopathia striata
  4. Tuberous sclerosis
  5. Osteopoikilosis

Answer / Discussion

The X-ray in Fig. 1 shows multiple small hyperdense oval and circular lesions scattered in all small bones of the left hand, with preservation of cortical thickness. These findings are suggestive of osteopoikilosis. Similar lesions were also present in the contralateral hand and wrist, as well as the pelvis (Fig. 2), on X-rays done subsequently.


Fig. 2: X-Ray Pelvis showing bone islands

Patient was counselled and reassured about the radiological findings. He was prescribed oral Paracetamol and topical Piroxicam for three days and asked to rest the affected joint. Osteopoikilosis (also called spotted bone) is a benign, possibly autosomal dominant dysplasia of bones, occurring in 1 per 50,000 people.1 Small bones of hand and feet, long tubular bones and pelvis are most frequently affected. The condition is asymptomatic and is diagnosed incidentally on radiographs taken for other problems. The diagnosis is straightforward, based on the typical radiological appearances of small (up to 10mm) hyperdense opacities distributed symmetrically. No further investigations or any specific treatment are indicated. Patients need to be reassured about the benign nature of radiological findings.

Osteoblastic metastases occur in the older age group, are generally larger in size and do not have such a uniformly symmetric distribution. Osteopathia striata is another rare bone dysplasia, characterized by long hyperdense striations mainly in the metaphyses of long bones and pelvis.2 Sclerotic bone lesions in tuberous sclerosis are frequently seen in the axial skeleton especially calvarias and spine, are at times distributed focally and have irregular borders and variable size.3 Subperiosteal new bone formation may be present and other clinical features like epilepsy may also provide a clue. As seen in Fig. 1, there is no break in the continuity of scaphoid bone, thus ruling out a fracture.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ABDUL REHMAN ARSHAD, MCPS, FCPS(Pak). 1 Mountain Medical Battalion, Bagh, AJK Pakistan. ASIF RAHMAN, MCPS, FCPS(Pak). Combined Military Hospital Bannu, Pakistan. SHAFQAT HUSSAIN, MBBS. 1 Mountain Medical Battalion, Bagh, AJK Pakistan.
Corresponding Author Details: 
Dr ABDUL REHMAN ARSHAD, Classified Specialist in Medicine, 1 Mountain Medical Battalion (MDS), Bagh 12500, Azad Kashmir, Pakistan.
Corresponding Author Email: 
maj.abdulrehman@gmail.com
References
References: 
  1. Meena S, Saini P, Chowdhary B. Multiple spots on bone: diagnostic challenge or spot diagnosis? Osteopoikilosis. Neth J Med 2013; 71(7):372, 376.
  2. Perdu B, de Freitas F, Frints SG, et al. Osteopathia striata with cranial sclerosis owing to WTX gene defect. J Bone Miner Res 2010; 25(1):82-90. doi: 10.1359/jbmr.090707.
  3. Umeoka S, Koyama T, Miki Y, et al. Pictorial review of tuberous sclerosis in various organs. Radiographics 2008; 28(7):e32. doi: 10.1148/rg.e32. Epub 2008 Sep 4.

Carbimazole induced ANCA Positive Vasculitis

Authors
Yasmeen Ajaz and Sameem Matto
Article Citation and PDF Link
BJMP 2014;7(2):a712
Abstract / Summary
Abstract: 

Anti-throid drugs like propylthiouracil and carbimazole are the main drugs prescribed for hyperthyroidism worldwide. Vasculitis related to anti-thyroid medication is very rare and can be potentially life threatening, if not recognized early. We report a female patient with Graves’ Disease who developed ANCA positive vasculitis due to carbimazole. The episode was characterized by a Raynaud’s Phenomenon of hands and feet and small joint arthritis. To our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from United Arab Emirates.

Abbreviations: 
TSH-Thyroid stimulating hormone, FT3-Freetri-iodothyronine, FT4-Free thyroxine, ANCA-Antineutrophilic cytoplasmic antibodies, CRP-C reactive protien, ESR-Erythromicin sedimentation rate, ECG-electrocardiogram, ATD-Antithyroid drugs, PTU-Proplythiouracil, ANTI-TPO-thyroperoxidase, MPO-Myeloperoxidase
Keywords: 
Carbimazole, ANCA, Vasculitis, Hyperthyroidism, Raynauds Phenomenon, Graves Disease, Antithyroid Drugs.

Introduction

Hyperthyroidism is a common endocrine disorder and is mainly treated with anti-thyroid medications like propylthiouracil (PTU) and carbimazole. These medications have a large number of adverse effects, the commonest being skin rashes, and some are rare like agranulocytosis. Vasculitis is uncommon, but ANCA positivity is reported more in propylthiouracil and rarely with carbimazole or methimazole (1).We report a female patient with Graves’ disease who developed ANCA associated vasculitis while on carbimazole treatment.

Case report

A 29 year old female Filipino patient came to us with history of palpitations, tremors and weight loss for the last one month. Her thyroid profile showed severe hyperthyroidism (TSH <0.005, FT3-11.5, FT4-45.6) She was diagnosed with Graves’ disease as her anti-TSH receptor positive and was started on carbimazole 10mg tds. After three weeks of treatment, she developed macular rash over arms and legs and swelling of small joints of both hands. She noticed pain and colour change of both the hands and experienced typical Raynaud’s phenomenon. She had no renal or lung involvement.

On examination her blood pressure was 120/84mmHG, pulse 104 beats per min, temperature -37.1̊C. She had a mild diffuse goiter. Her X-ray chest, ECG and urine dipstick routine were all normal. Her CRP and ESR were raised. X-rays of the hands were normal. P-ANCA was positive. Antimyeloperoxidase antibody was positive. Anti-TPO and TSH receptor antibodies were positive.

Diagnosis of carbimazole induced vasculitis was made. The patient was treated with prednisolone 40mg daily once daily which was tapered over three weeks. She improved within 48hours and was asymptomatic after three weeks. She was treated successfully with radioiodine ablation. Her MPO-ANCA after 6 months was negative.


Figure 1. Pictures of the hands showing Raynaud’s phenomenon


Figure 2. Pictures of the hands showing Raynaud’s phenomenon

Discussion

ANCA positive vasculitis in association with antithyroid drugs was first reported in 1992 (2).There has been 32 cases of ANCA positive vasculitis associated with antithyroid medications reported up until now (3). The presenting symptoms are variable and may include renal involvement (67%), arthralgias (48%), fever (37%), skin involvement (30%), respiratory tract involvement (27%), myalgias (22%), scleritis (15%) and other manifestations (18%) (3).

In these patients the underlying thyroid disease is most commonly Graves’ disease but ANCA positive vasculitis has also been seen with association with toxic multinodular goitre (4). Recent studies have shown high frequency of ANCA positivity in patients with Graves’ disease treated with antithyroid medications, especially with PTU. Most cases of ANCA positivity are seen in patients on long term therapy (greater than 18 months) or in those with recent commencement of therapy as seen in our patient. However, a small percentage of these go on to develop features of vasculitis (3).

The majority of cases of vasculitis (88%) have been reported in association with PTU, vasculitis associated with carbimazole is very rare (5, 6, and 7). The pathogenesis of ATD associated vasculitis is not clearly understood. PTU has been shown to accumulate within neutrophils (8) and bind myeloperoxidase (9). The binding alters the configuration of myeloperoxidase (9) and may promote formation of autoantibodies in susceptible people. There has been no data with regards to whether carbimazole can alter the configuration of myeloperoxidase. ANCA positive vasculitis may be more common in patients of Asian ethnic origin, with half of cases reported from Japan (3). Our patient was from Philippines.

Wadw et al have reported 25% of patients were positive for MPO-ANCA in PTU group whereas in methimazole group 3.4% were positive (10).

This case highlights the awareness of this relatively rare adverse effect of a thyroid medication which may lead to fatal renal and pulmonary complications. Early diagnosis and withdrawal of the offending medication is important. In asymptomatic patients the significance of ANCA positivity is not clear but early definitive therapy in the form of radioiodine ablation or surgery should be considered.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NONE
Competing Interests: 
None declared
Details of Authors: 
YASMEEN AJAZ (M.D, F.A.C.E, PGDD, SCE) Specialist Internal Medicine And Endocrinology, Belhoul Speciality Hospital, Dubai, UAE. SAMEEM MATTO (M.D, PGDD, SCE) Specialist Internal Medicine And Endocrinology, Canadian Specialist Hospital, Dubai, UAE.
Corresponding Author Details: 
DR SAMEEM MATTO, Canadian Specialist Hospital, Abuhail Deira, PO BOX 15881, Dubai, UAE.
Corresponding Author Email: 
sameematto@hotmail.com
References
References: 
  1. Sera N, Ashizawa K, Ando T, et al. Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves’ disease. Thyroid 2000; 10:595-9.
  2. Stankus SJ & Johnson NT. Propylthiouracil-induced hypersensitivity vasculitis presenting as Respiratory failure. Chest 1992 102, 595–1596.
  3. Gunton JE, Stiel J, Clifton-Bligh P, et al. Prevalence of positive antineutrophil cytoplasmic  antibody   (ANCA) in patients receiving antithyroid medication. Eur J Endocrinol 2000; 142: 587-96.
  4. Gunton JE, Stiel J, Caterson RJ & McElduff A. Anti-thyroid drugs and antineutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature. Journal of Clinical Endocrinology and Metabolism1999 8413–16.
  5. Day C, Bridger J, Rylance P, et al. Leukocytoclastic vasculitis and interstitial nephritis with Carbimazole treatment. Nephrol Dial Transplant 2003; 18: 429-31.
  6. Sève P, Stankovic K, Michalet V, et al. Carbimazole induced eosinophilic granulomatous vasculitis localized to the stomach. J Intern Med 2005; 258: 191-5.
  7. Calañas-Continente A, Espinosa M, Manzano-García G, et al.Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy. Thyroid 2005; 15: 286-8.
  8. Lam DCC & Lindsay RH. Accumulation of 2-[14C]-propylthiouracil in human polymorphonuclear leukocytes. Biochemical Pharmacology 1979 282289–2296.
  9. Lee H, Hirouchi M, Hosokawa M, Sayo H, Kohno M & Kariya K.Inactivation of peroxidase of rate bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure. Biochemical Pharmacology 1988 372151–2153.
  10. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, et al. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA Vasculitides. Arthritis Res Ther 2005; 7:1072-81. 

Liver Veno-Occlusive Disease (VOD) in a patient given 6-Thioguanine for Crohn’s Disease

Authors
Agata Salerno, Marco Vacante, Donatella Pollina, Benedetta Stancanelli, Silvia Martini, Ezio David, Lorenzo Malatino
Article Citation and PDF Link
BJMP 2014;7(2):a711
Abstract / Summary
Abstract: 

6-Thioguanine (6-TG) is being given to patients with Crohn's disease failing conventional immunosuppression, but cases of hepatotoxicity have been reported. We report the case of a patient who developed acute sinusoidal obstruction syndrome after 3 months of successful 6-TG treatment. A complete regression of liver injury was observed after withdrawal of 6-TG. Our case-report underscores the risk of hepatic injury due to the administration of 6-TG for Crohn’s disease. We strongly recommend alternative therapeutic options in patients intolerant or resistant to conventional thiopurines.

Keywords: 
6-thioguanine, Crohn’s disease, hepatotoxicity, veno-occlusive disease.

A 44-yr-old patient with history of ileal Crohn’s disease was admitted to our Department because of asthenia, subclinical jaundice, painful hepatomegaly, fluid retention and ascites. In 2008 the patient was diagnosed with bladder cancer and was treated by surgical resection of the cancer and intravesical chemotherapy with mitomicyn C. In 2010 he was given azathioprine (AZA) at 2 mg/kg for Crohn’s disease and 3 months later he developed an increase in serum alkaline phosphatase, gamma-glutamyl transpeptidase and transaminases. He was then started on 1.5 mg/kg 6-mercaptopurine (6-MP) once daily. After 9 months he stopped 6-MP because of nausea, vomiting and abnormal liver function tests; 6-MP was therefore discontinued until the normalisation of markers of liver function. Two months later, when the transaminases were within the normal range, he received 6-thioguanine (6-TG) 25 mg a day, that was progressively increased to 80 mg a day. Three months later, the patient was referred to our Department with painful hepatomegaly, ascites and asthenia. Laboratory tests on admission revealed an elevation in AST 198 U/l and ALT 209 U/l. Total bilirubin was 3 mg/dl (direct bilirubin 1.5 mg/dl), LDH 784 U/l, alkaline phosphatase 191 U/l and ammonia 112 umol/l. Virological markers (HBsAg, HBcAb, anti HCV, HBV DNA) were negative. Patient was apyrexial, showed normal blood pressure (130/80 mmHg), tachycardia (110 bpm) and 97% SaO2 on room air. Physical examination revealed right hypochondrial tenderness, abdominal distension and shifting dullness, suggesting the presence of ascites. The rest of the physical examination was unremarkable. An echo-Doppler evaluation revealed thin linear suprahepatic veins and confirmed the presence of ascites. A CT scan of the abdomen showed hepatomegaly with dishomogeneous enhancement after dye injection (mosaic pattern). There was no evidence of any venous thrombosis or splenomegaly (Figure 1A); 6-TG was withdrawn empirically and the patient was started on therapy with albumin 25 g/day and spironolactone 200 mg/day. The average serum Na+ level during diuretic treatment was 134 mEq/l. An abdominal paracentesis of two litres was necessary, due to the progressive increase of ascites.


FIGURE 1A. CT scan of the abdomen on admission: Dishomogeneous enhancement of the liver after dye injection (mosaic pattern) (arrow). Suprahepatic veins are not detectable.


FIGURE 1B. Histological pattern of the liver biopsy specimen: marked centrilobular congestion (arrows) with hepatocyte dropout. There is no evidence of centrolobular veins thrombosis.

A routine laboratory investigation of ascitic fluid showed < 500 leukocytes/µL and < 250 polymorphonuclear leukocytes (PMNs)/µL. The ascitic fluid total protein level was 2.1 g/dl and serum-ascites albumin gradient (SAAG) was > 1.1 g/dL. No neoplastic cells were found. A transjugular liver biopsy was then performed, showing marked centrilobular hemorrhage with hepatocyte necrosis. There was mild ductular reaction, with no evidence of centrilobular vein thrombosis. The histologic diagnosis confirmed veno-occlusive disease (VOD) (Figure 1B). Screening for thrombophilia was also done, showing low levels of serum protein C and protein S. There was no mutation of JAK-2 V617F. The patient was then treated with a hyposodic diet, mild hydric restriction, enoxaparin,spironolactone, lactulose and omeprazole. He was discharged two weeks later, and after 3 months a complete regression of ascites and hepatomegaly occurred, and echography of the liver was unremarkable (Figure 2A and 2B).


FIGURE 2A. Echography of the liver at follow up. No evidence of ascites.


FIGURE 2B. Echography of the liver at follow up. No evidence of ascites. Suprahepatic veins are detectable (arrow)

Discussion

Although VOD was known among complications of 6-TG in childhood, this case-report emphasises the occurrence of VOD in adults with Crohn’s disease, as first described by Kane et al. in 20041. The thiopurine drugs were developed more than 50 years ago, and 6-MP was first used as a drug in 19522. Since then, 6-MP and 6-TG have been widely used to treat acute lymphoblastic leukemia in children. VOD mimicking Budd-Chiari like disease was then described as a frequent complication of 6-TG in pediatric patients given the drug for lymphoblastic leukaemia. Later on, in 1976, Griner et al. described the cases of two adult male patients with acute leukaemia developing a fatal Budd-Chiari-like disease while receiving 6-TG3. Since patients were given 6-TG plus cytosine arabinoside, authors were unable to ascribe this complication solely to 6-TG3. VOD exclusively related to 6-TG was first described by Gill et al., who observed a clinically reversible liver VOD developing in a young man with acute lymphocytic leukemia after 10 month administration of 6-TG4. Furthermore, sinusoidal obstruction was also reported in a patient with psoriasis treated with 6-TG and other cytotoxic therapy5. In 2006, a European 6-TG Working Party established that 6-TG should be considered a rescue drug in stringently defined indications in inflammatory bowel diseases (IBD). The indication for administration of 6-TG should only include its use for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Moreover, 6-TG must be withdrawn in case of overt or histologically proven hepatotoxicity6. Although Ansari et al 7 found no nodular regenerative hyperplasia (NRH) in the liver of patients given 6-TG, Dubinsky et al.8 described NHR as a common finding in 6-TG-treated patients with inflammatory bowel disease in the absence of VOD. By contrast, in our case report we showed histological pattern of VOD and, in accord with Gisbert et al.9, would suggest that 6-TG should not be administered out of a clinical trial setting. Given that the proportion of patients with Crohn’s disease achieving an improvement of symptoms during 6-TG treatment is similar to that after methotrexate10 or infliximab6, these drugs should therefore be considered as second line therapy in patients intolerant or resistant to azathioprine and 6-mercaptopurine.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
AGATA SALERNO MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. MARCO VACANTE, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. DONATELLA POLLINA, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. BENEDETTA STANCANELLI, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. SILVIA MARTINI, MD,SSCVD Insufficienza Epatica e Trapianto, Azienda Ospedaliera Città della Salute e della Scienza – Molinette, C.so Bramante 88, 10126 Turin, Italy. EZIO DAVID, MD,SCDU II Anatomia Patologica, Azienda Ospedaliera Città della Salute e della Scienza – Molinette, C.so Bramante 88, 10126 Turin, Italy. LORENZO MALATINO, MD, PROFESSOR OF MEDICINE Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
Corresponding Author Details: 
MARCO VACANTE, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
Corresponding Author Email: 
marcovacante@yahoo.it
References
References: 
  1. Kane S, Cohen SM, Hart J. Acute sinusoidal obstruction syndrome after 6-thioguanine therapy for Crohn's disease. Inflamm Bowel Dis. 2004;10:652-4.
  2. Elion G, Burgi E, Hitchings G. Studies on condensed pyrimidine systems, IX. The synthesis of some 6-substituted purines. J Am Chem Soc 1952;74:411-4.
  3. Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases.Ann Intern Med. 1976;85:578-82.
  4. Gill RA, Onstad GR, Cardamone JM, Maneval DC, Sumner HW. Hepatic veno-occlusive disease caused by 6-thioguanine.Ann Intern Med. 1982;96:58-60.
  5. Kao NL, Rosenblate HJ. 6-Thioguanine therapy for psoriasis causing toxic hepatic venoocclusive disease. J Am Acad Dermatol. 1993;28:1017-1018.
  6. de Boer NK, Reinisch W, Teml A, van Bodegraven AA, Schwab M, Lukas M, et al; Dutch 6-TG working group. 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party.Digestion. 2006;73:25-31.
  7. Ansari A, Elliott T, Fong F, Arenas-Hernandez M, Rottenberg G, Portmann B, et al. Further experience with the use of 6-thioguanine in patients with Crohn's disease.Inflamm Bowel Dis. 2008;14:1399-405.
  8. Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.Gastroenterology. 2003;125:298-303.
  9. Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518-27.
  10. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995;332:292-7.

Physical activity after cancer: An evidence review of the international literature

Authors
Robert James Thomas, Mea Holm and Ali Al-Adhami
Article Citation and PDF Link
BJMP 2014;7(1):a708
Abstract / Summary
Abstract: 

The importance of physical activity during and after cancer treatments is now being appreciated, as emerging evidence suggests that it improves several common side-effects of cancer treatments, as well as correlating with improving overall survival and reduced the probability of relapse. The biological mechanisms through which these benefits are achieved may include effects on cell growth regulatory pathways, levels of hormones, gene expression patterns and tumour immunity. Here we review the evidence for the benefits of exercise during and after cancer, discuss the possible underlying biological mechanisms, and suggest ways in which this knowledge may be used to improve mainstream care of cancer patients.

Keywords: 
Exercise, cancer, survival, side effects.

Introduction

The number of individuals surviving cancer is expected to rise by one-third according to estimates from the American Cancer Society and the National Cancer Institute1. This means that in the UK over 3 million individuals, and in the USA over 18 million individuals, will be living with the consequences of cancer by 2,022. The increase in the number of survivors is attributed to earlier diagnosis, an aging population, better cure rates and more effective systemic therapies to keep patients with metastatic disease alive for longer. To achieve these benefits, patients often have to endure more complex and arduous therapies, frequently leaving them beleaguered with acute and long-term adverse effects. In addition to being unpleasant, these adverse effects result in financial implications for patients and their families, as well as resulting in a greater usage of health resources.

Although the importance of exercise is beginning to be recognised by health professionals, advocacy groups and charities, it still remains an under-utilised resource. This article highlights the evidence that a physically active lifestyle and formal exercise programmes can help relieve many of the common concerns and adverse effects which plague individuals in the cancer survivorship period.

Physical activity improves well-being after cancer

Dozens of interventional studies have tested the feasibility and potential benefits of exercise in cancer survivors2,3,4. Recent meta-analyses of randomised trials involving exercise interventions after cancer, encouragingly demonstrate that the benefits of exercise spanned across several common cancer types and following a range of treatments including surgery, radiotherapy, chemotherapy, hormones and even the newer biological therapies. The most recent meta-analysis of 34 randomised trials published in the BMJ in 2012 involving patients exercising after cancer, demonstrated a benefit for a number of troublesome symptoms particularly fatigue, mood, anxiety and depression; muscle power, hand grip, exercise capacity and quality of life5.

The American College of Sports Medicine also published a comprehensive review of exercise intervention studies in cancer populations which included data from 85 RCT’s of exercise in cancer survivors. Evidence consistently demonstrated that exercise could be performed safely in adjuvant and post-treatment settings. Exercise led to significant improvements in aerobic fitness; increased flexibility and strength; quality of life; anxiety and depression; fatigue, body image, size and composition4.

The individual categories of symptoms which commonly afflict cancer survivors are now discussed in more detail:

Cancer related fatigue (CRF) is one of the most distressing symptoms experienced by patients during and after their anti-cancer therapies. It is reported by 60-96% of patients during chemotherapy, radiotherapy or after surgery, and by up to 40% of patients taking long-term therapies such as hormonal or biological therapies6. The first step to treating CRF is to correct, if possible, any medical conditions that may aggravate it, such as anaemia, electrolyte imbalance, liver failure and nocturia; or to eliminate drugs such as opiates, anti-histamines and anti-sickness medication7. The role of exercise was reviewed in 28 randomised, controlled trials (RCTs) involving 2083 participants in a variety of exercise programmes and showed that exercise improved CRF, although the benefit overall was small8. A second review of 18 RCTs involving 1,109 participants, sub-divided the data into types of exercise and demonstrated that supervised exercise programmes had the most impact on CRF9. Further meta-analyses and reviews have also showed that supervised exercise programmes had better results, with a greater reduction in CRF amongst breast cancer survivors assigned to exercise programmes compared to home-based programmes4,5,8,10.

Psychological distress, including anxiety and depression, is common after cancer with reported prevalence rates of 25-30%11. Patients with psychological distress have also been shown to have reduced survival compared to those who are psychologically healthy12. Exercise may help alleviate this symptom and improve mood, as a number of observational studies have shown that cancer patients who exercise have reduced levels of depression and anxiety, better self-esteem and are happier, especially if they involve group activities13. The recent meta-analyses of RCTs also demonstrated a reduction in anxiety and depression among individuals assigned to exercise programmes4,5.

Quality of life (QOL) is lower in many cancer sufferers and survivors, linked to other physical and psychological symptoms of cancer and its’ treatment. Meta-analyses of studies of exercise intervention programmes have demonstrated an improvement of QOL at all stages of the illness for the common cancer types and following several types of treatment4,5. For example, in a study involving 1,966 patients with colorectal cancer, patients achieving at least 150 minutes of physical activity per week had an 18% higher QOL score than those who reported no physical activity, as measured by the QOL FACT-C14. Another study showed similar benefits for breast cancer survivors who had completed surgery, radiotherapy or chemotherapy, and also demonstrated that change in peak oxygen consumption correlated with change in overall QOL15.

Weight gain:45% of women with breast cancer report significant weight gain16, and in a study of 440 prostate cancer survivors, 53% were overweight or obese17. For patients with bowel cancer, the CALBG 8980 trial showed that 35% of patients post-chemotherapy were overweight (BMI 25.0–29.9), and 34% were obese (BMI 30.0–34.9) or very obese (BMI >35)16. The reasons for this are multifactorial, but may include other symptoms of cancer treatment such as fatigue and nausea, causing patients to stop exercising. Regardless of the reasons for weight gain, numerous reviews and a comprehensive meta-analysis of the published literature have demonstrated that individuals who gain weight after cancer treatments have worse survival and more complications18. Fortunately, supervised exercise programmes have been shown to reduce weight and have significant other benefits on body constitution and fitness, such as improved lean mass indices, bone mineral density, cardiopulmonary function, muscle strength and walking distance18,19.

Bone mineral density (BMD): Pre-menopausal women who have had breast cancer treatment are at increased risk of osteoporosis, caused by reduced levels of oestrogen brought on by a premature menopause due to chemotherapy, surgery or hormones. Men who receive hormone deprivation therapy for prostate cancer are also at an increased risk of developing osteoporosis. Accelerated bone loss has also been reported for many other cancers, including testicular, thyroid, gastric and CNS cancers, as well as non-Hodgkin’s lymphoma and various haematological malignant diseases20,21. Lifestyle factors linked to an increase in the risk for developing osteoporosis include a low calcium and vitamin D intake, a diet low in plant-based protein, lack of physical activity, smoking and excessive alcohol intake22. A number of studies have linked regular physical activity with a reduction in the risk of bone mineral loss. Sixty six women with breast cancer were randomized to a control group or an exercise programme. The rate of decline of BMD was -6.23% in the control group, -4.92% in the resistance exercise group, and -0.76% in the aerobic exercise group. The statistically significant benefit was even greater in pre-menopausal women23. In another RCT of 223 women with breast cancer, it was found that exercise, over 30 minutes 4-7 times a week, helped preserve bone mineral density even when bisphosphonates (risedronate), calcium and vitamin D had already been prescribed24.

Thromboembolism: Those with pelvic involvement, recent surgery and immobility, previous history of varicose veins or thrombosis or receiving chemotherapy, are at higher risk25. Although strategies such as compression stockings, warfarin and low molecular weight heparin are essential, early mobilisation and exercise remains a practical additional aid in reducing this life-threatening complication18,26.

Constipation caused by immobility, opiate analgesics or anti-emetics during chemotherapy is a significant patient concern. Exercise reduces bowel transit time, and ameliorates constipation and its’ associated abdominal cramps26.

Physical activity improves survival and reduces relapse

In addition to improving the side effects of treatment for cancer, regular physical activity during and after cancer appears to improve overall survival and reduces the probability of relapse. One of the most convincing studies was an RCT in which 2,437 post-menopausal women with early breast cancer were randomised to nutritional and exercise counselling, or no counselling, as part of routine follow-ups19. In the group receiving counselling, fewer women relapsed and overall survival was greater in the oestrogen-negative subgroup. In another RCT, men with early prostate cancer were randomised to an exercise and lifestyle intervention or standard active surveillance. The average PSA in the intervention group went down, whilst in the control group it went up27. This supports a previous RCT of which the primary end point evaluated a salicylate-based food supplement, but it required men in both arms to receive exercise and lifestyle counselling. Although there was no difference in the primary end point, 34% of men, who’s prostate specific antigen (PSA) was climbing before trial entry, stabilized28.

The majority of the other published evidence for a reduced relapse rate and improved survival after cancer originates from retrospective analysis or prospective cohort studies. The National Cancer Institute, in a recent meta-analysis, reviewed 45 of these observational studies. The strongest evidence was demonstrated for breast cancer survivors; the next strongest evidence was for colorectal cancer survivors, followed by prostate cancer10. The most notable are summarised below:

Breast cancer: The five most prominent prospective cohort studies (in aggregate more than 15,000 women), have examined the relationship between physical activity cancer and prognosis:

  • Irwin et al. (2008)29 investigated a cohort of 933 breast cancer survivors and found that those who consistently exercised for >2.5 hours per week had a 67% lower risk of all deaths compared to sedentary women.
  • Holmes et al. (2005)30 performed a separate evaluation of 2,987 women in the Nurses’ Health Study and found that women walking >3 hours a week had lower recurrence rates, and better overall survival.
  • Holick et al. (2008)31 performed a prospective observational study of 4,482 breast cancer survivors, and found that women who were physically active for >2.8 hours per week had a 35-49% lower risk of dying from breast cancer.
  • Pierce et al. (2007)32 found that the benefits of 3 hours of exercise were even greater if combined with a healthy diet.
  • Sternfeld et al. (2009)33 in the LACE study, evaluated 1,870 women within 39 months of diagnosis. There was a significant difference in overall death rate between the highest and lowest quartile of exercise levels.

Colorectal cancer: The scientific community eagerly awaits the results of the CHALLENGE RCT mentioned above, but a number of retrospective analyses of randomised chemotherapy and cohort trials have been published:

  • Haydon et al. (2006)34retrospectively analysed a RCT involving patients with stage III bowel cancer and found a significant association between exercise and a 31% reduction in relapse rate.
  • Giles et al. (2002)35found that of 526 patients recruited into the Australian Cohort Study, those participating in recreational sport 1-2 days per week had a 5 year overall survival of 71%, as opposed to 57% in non exercisers.
  • Meyerhardt et al. (2006)16 found in an analysis of the Intergroup CALGB study, that physically active patients with bowel cancer had 35% reduction in relapse rate in after chemotherapy.
  • Meyerhardt et al. (2009)36 analysed 668 patients with colorectal cancer within the Health Professionals Study. Men who exercised >27 vs. < 3METS-hours / week had a lower cancer-specific mortality.

Prostate cancer: Three cohort studies have demonstrated a survival benefit for physically active men with prostate cancer:

  • Kenfield et al. (2011)37performed a subset analysis of 2,686 men with prostate cancer, within the Health Professional Study, who exercised >30minutes per week or >3 MET-hours of total activity, had a 35% lower risk of overall death, and men who walked at a brisk pace for >90 minutes had a 51% lower risk of overall death.
  • Richman et al. (2011)38 reported that 1,455 men with prostate cancer, walking more than 3 hours a week, correlated with an improved survival but only if >3miles/hour.
  • Giavannucci (2005)39, within a prospective analysis, reported that men who exercised vigorously had a lower risk for fatal prostate cancer, although this effect was only seen for men over the age of 65.

Quantity and type of exercise recommended for cancer patients

For reduced cancer relapse and improved well-being, most of the cohort studies summarized above suggest moderate exercise of around 2.5 to 3 hours a week for breast cancer survivors. However, for prostate cancer survivors, mortality continues to decrease if the patient walks 4 or more hours per week, and more vigorous activity is also associated with significant further reductions in risk for all-cause mortality37. When the mode of exercise is primarily walking, a pace of at least 3 miles/hour (for >3 hours/week) is recommended for a reduced risk of relapse 38. Therefore, both the pace and duration of exercise affect the survival benefit achievable from exercise, with more vigorous activity generally having a greater benefit (see Table 1). The best results appear to be with programmes including a combination of aerobic and resistance exercises, particularly within a social group.

Table 1: Summary of exercise guidelines for cancer survivors

· Exercising for >3 hours/week has proven benefits for cancer survival
· A pace of at least 3 miles/hour when walking provides greater benefit than a slower pace
· For optimal benefit, exercise should consist of a combination of resistance and aerobic exercises
· Supervised exercise programmes have shown greater benefits for cancer survivors than home-based programmes

The precise amount of exercise has to be determined on an individual basis and depends on pre-treatment ability, current disability caused by the cancer itself or the treatment, as well as time proximity to major treatments. An exercise programme supervised by a trained professional has major advantages, as they can design a regimen which starts slowly and gradually builds up to an acceptable and enjoyable pace. In addition, they can help motivate the individual to continue exercising for the short and the long-term, and they can judge the optimal exercise levels to improve fatigue, and not aggravate it.

The underlying mechanisms of the potential anti-cancer effects of exercise

The body’s chemical environment significantly changes after exercise, best demonstrated in the Ornish study, which found that serum from prostate cancer patients who exercised, had an almost eight times greater inhibitory effect on the growth of cultured androgen dependent prostate cancer cells compared to serum from patients in the control group27. The precise chemical mechanism, which the anti-cancer effect remains incompletely understood, but one of the most likely mechanisms involving growth factors such as insulin-like growth factor (IGF-1) and its’ binding proteins insulin-like growth factor binding proteins (IGFBPs), due to the central role of these proteins in the regulation of cell growth (see Table 2). After binding to its receptor tyrosine kinase, IGF-1 activates several signalling pathways including the AKT pathway, leading to the inhibition of apoptosis and the promotion of cell growth and angiogenesis34,40,41. An inverse relationship of cancer risk with IGFBP3 levels has also been shown, although this effect has not been confirmed in all studies42. Exercise has been shown to increase the levels of IGFBP3, and this was associated with a 48% reduction of cancer-specific deaths in a large prospective cohort study of 41,528 participants43. Decreased levels for IGF-1 in physically active patients have been reported with an associated survival benefit44.

Table 2: Summary of the potential biochemical pathways of the anticancer effects of exercise

Class of Effector Molecule Effector Molecule Effects of Exercise on Effector Molecule

Cell growth regulators

IGF1 Decreased levels
IGFBP3 Increased levels

Proteins involved in DNA damage repair

BRCA1 Increased expression
BRCA2 Increased expression
Regulator of apoptosis and cell cycle arrest p53 Enhanced activity

Hormones

Oestrogen Decreased levels
Vasoactive intestinal protein (VIP) Decreased levels
Leptin Decreased levels (indirect)

Immune system components

NK cells Enhanced activity
Monocyte function Enhanced activity
Circulating granulocytes Increased proportion

Exercise has also been shown to have a large impact on gene expression, although the mechanisms through which the patterns of gene expression are affected remain to be determined. In a recent study of the mechanisms through which exercise impacts prostate cancer survival, it was found that 184 genes are differentially expressed between prostate cancer patients who engage in vigorous activity, and those who do not 37. Amongst the genes that were more highly expressed in men who exercise were BRCA1 and BRCA2, both of which are involved in DNA repair processes.

Another neuropeptide which changes after exercise is Vasoactive Intestinal Protein (VIP). Breast and prostate cancer patients have been found to have higher VIP titres compared to individuals who regularly exercise, and who have increased production of natural anti-VIP antibodies45. In hormone-related cancers such as cancers of the breast, ovaries, prostate and testes, the association between high levels of circulating sex hormones and cancer risk is well established46. Another mechanism through which exercise may affect cancer, is through decreasing the serum levels of these hormones. For breast cancer survivors, the link between exercise and lower levels of oestrogen has been shown13,34,47. An indirect, related mechanism is that exercise helps reduce adiposity, and adiposity in turn influences the production and availability of sex hormones48. In addition, greater adiposity leads to higher levels of Leptin, a neuropeptide cytokine with has cancer promoting properties49,50.

Other pathways include the modulation of immunity, such as improvements in NK cell cytolytic activity 11; the modulation of apoptotic pathways through impacting on a key regulator, p5351, and an exciting recent discovery, the messenger protein irisin, which is produced in muscle cells in response to exercise and is found is to be an important molecule in linking exercise to the health benefits52 , However, we are only beginning to scratch the surface with these and the other mechanisms discussed here, and much more research needs to be done to in this area.

Incorporating exercise into mainstream cancer management

The challenge for health professionals is how to encourage and motivate individuals with cancer to increase their exercise levels. Some, of course, are motivated to increase physical activity or remain active after cancer. However, a recent survey of 440 men with prostate cancer found that only 4% of patients exercised for more than the 3 hours a week recommended by the WCRF17. Macmillan Cancer Relief has produced a series of helpful booklets and web-based patient information materials designed to inform and motivate individuals to exercise as part of its ‘Move More’programme. The Cancernet website has a facility to search for local exercise facilities by postcode, which can be an aid for health professionals when counselling patients. It highlights activities that men will hopefully find feasible and enjoyable such as golf, exercise groups and walking groups, and are encouraged to attend in addition to work place activity and gardening.

Several pilot schemes have been started throughout the UK with the aim to incorporate exercise programmes into standard oncology practice. The difficulty with small schemes is that they tend to be poorly funded, often poorly attended and are unlikely to be sustainable in the longer term. Many agree that the gold standard model would be similar to the cardiac rehabilitation programme53. This would involve a hospital scheme run by a physiotherapist or an occupational therapist, supervising patients immediately after surgery, radiotherapy and even during chemotherapy. This is followed by refering the patient to a community-based scheme for the longer term. Unfortunately, this type of scheme is expensive and unlikely to be funded at present, despite the obvious savings by preventing patient relapsing and ultilising health care facilities to help late effects of cancer treatment54. However, expanding existing services, such as the National Exercise Referral Scheme, is a practical solution. The National Exercise Referral Scheme exists for other chronic conditions such as cardiac rehabilitation, obesity and lower back pain. The national standards for the scheme to be expanded to include cancer rehabilitation were written and accepted in 2010. Training providers have now developed training courses for exercise professionals set against these standards. Trainers completing the course gain a Register of Exercise Professionals (REPs) Level Four qualification, allowing them to receive referrals from GPs and other health professionals.

Conclusion

There are a wealth of well-conducted studies which have demonstrated an association between regular exercise and lower risk of side effects after cancer, as well as reasonable prospective data for a lower relapse rates and better overall survival. However, as there are several overlapping lifestyle factors, which are difficult to investigate on their own, there remain some concerns that exercisers may do better in these studies because they are less likely to be over-weight, more likely to have better diets and to be non-smokers. Although the existing RCTs provide encouraging evidence that exercise intervention programmes are beneficial, further large RCTs are needed, particularly in terms of cost-effectiveness, before commissioner’s start investing more in this area.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ROBERT THOMAS, MRCP MD FRCR, CONSULTANT ONCOLOGIST, Bedford Hospital and Addenbrooke’s University Hospital, c/o The Primrose Research Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. United Kingdom. MEA HOLM, MSc, STUDENT c/o The Primrose Research Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. United Kingdom. ALI AL-ADHAMI, MBChB MACP, CLINICAL RESEARCH FELLOW, University of Buckingham and the Lister Hospital, Coreys Mill Lane, Stevenage, Hertfordshire. SG1 4AB. United Kingdom.
Corresponding Author Details: 
ROBERT THOMAS, The Primrose Oncology Unit, Bedford Hospital, Kempston Road, Bedford. MK42 9DJ. UK
Corresponding Author Email: 
robert.thomas@bedfordhospital.nhs.uk
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Anemia and Hemoglobin A1c level: Is there a case for redefining reference ranges and therapeutic goals?

Authors
Segun Adeoye, Sherly Abraham, Irina Erlikh, Sylvester Sarfraz, Tomas Borda and Lap Yeung.
Article Citation and PDF Link
BJMP 2014;7(1):a706
Abstract / Summary
Abstract: 

Background: Hemoglobin A1c (HbA1c) has been adopted by physicians as a surrogate for monitoring glycemic control. There exists concern that other factors beyond serum glucose concentration may affect glycation rates and by extrapolation HbA1c levels. 
Study Objectives: The study attempts to discern clinical differences in HbA1c levels in patients with anaemia compared to patients without anemia, quantifying and showing the direction of such differences.
Study Design: Using a convenient sampling method and a set of inclusion and exclusion criteria, it examined (retrospectively) patterns in [Hb] and HbA1c in non-diabetics with and without anemia. 
Results: The study observed a statistically significant 0.4units (8%) difference in the mean HbA1c in anaemia vs. non-anaemic populations. Reference ranges of HbA1c for non-anaemic population and anaemia subtypes was computed. Computed ranges for anaemia group and its subgroups were significantly wider compared to non-anaemia population. Modest but statistically significant correction of anaemia did not result in significant changes in HbA1c. 
Discussion: i. The linear relationship between [Hb] and HbA1c holds true for anaemic and non-anaemia populations. ii. Non-diabetic, anaemic have a significantly lower mean HbA1c (5.3% vs. 5.7%), but a similar upper limit of reference range due to a higher variance. iii. The variance and proposed reference ranges for anaemia group and its subtypes was greater than in non-anaemia group, perhaps due to homogenization of clinically heterogeneous entities. iv. Modest correction anaemia did not cause significant change in HbAIc, perhaps the increase in  [Hb] was too modest or persistence of correction was too short to be impactful. 
Conclusion: It makes the case for defining HbA1c reference ranges for each anaemia subtype, as well as utilizing other surrogates for monitoring glycemic control in populations with anaemia.

Abbreviations: 
Hb hemoglobin, HbA1c: glycosylated hemoglobin, delta sin change
Keywords: 
Anaemia, hemoglobin A1c, glycosylated hemoglobin, HbA1c reference range(s), HbA1c therapeutic goals,

Introduction

The American Diabetic Association (ADA) and the American College of Endocrinology (ACE) recommend HbA1c levels as diagnostic criteria for diabetes mellitus. Physicians have adopted HbA1c levels as a convenient way to screen for diabetes, as well as to monitor therapy. There exists concern that because HbA1c is formed from the glycation of the terminal Valine unit of the β-chain of haemoglobin, it may not be an accurate surrogate to ascertain glycemic control in certain conditions that affect the concentration, structure and function of haemoglobin. It makes logical sense to infer that HbA1c levels should at least in part reflect the average haemoglobin concentration ([Hb]). Kim et al (2010) stated that iron deficiency is associated with shifts in HbA1c distribution from <5.0 to ≥5.5% 1 and significant increases was observed in the patients' absolute HbA1c levels 2 months after treatment of anaemia.2 There is a dearth of literature on HbA1c levels in the anaemia population, and a reference range for this unique population does not currently exist. There are a few documented studies on this matter, the findings of which are at best, inconsistent.

It is thought that the various types of haemoglobin found in the myriad of haemoglobinopathies may affect haemoglobin-glucose bonding and/or the lifespan of haemoglobin, and by extrapolation, HbA1c level. Hence, extending target HbA1c values to certain haemoglobinopathaties may be erroneous due to potential differences in glycation rates, analytical methods (HbF interfers with the immunoassay method) and some physiological challenges (markedly decreased red cell survival).3

There is a significant positive correlation between haemoglobin concentration and HbA1c in the patients with haemolytic anaemia.4,5 Cohen et al (2008) reported that observed variation in red blood cell survival was large enough to cause clinically important differences in HbA1c for a given mean blood glucose,6 and haemolytic disorders may cause falsely reassuring HbA1c values.7 Jandric et al (2012) inferred that in diabetic population with haemolytic anaemia, HbA1c is a very poor marker of both overall glycemia and haemolysis.8 Mongia et al (2008) report that immunoassay methods for measuring HbA1c may exhibit clinically significant differences owing to the presence of HbC and HbS traits.9 However, Bleyer et al report that sickle cell trait does not affect the relationship between HbA1c and serum glucose concentration and it does not appear to account for ethnic difference in this relationship in African Americans and Caucasians.10

Koga & Kasayama (2010) advise that caution should be entertained when diagnosing pre-diabetes and diabetes in people with low or high haemoglobin concentration when the HbA1c level is near 5.7% or 6.5% respectively, citing the implication of changes in erythrocyte turnover. They further assert that the trend for HbA1c to increase with iron deficiency does not appear to necessitate screening for iron deficiency to ascertain the reliability of HbA1c in this population.11

In the light of the uncertainty in the influence of anaemia and haemoglobinopathies on HbA1c, it is imperative that clinicians are aware of the caveats with HbA1c values when they make management decisions in the anaemic population.12 There is currently a call for the use of other surrogates for ascertaining average glycemic control in pregnancy, elderly, non-Hispanic blacks, alcoholism, in diseases associated with postprandial hyperglycemia, genetic states associated with hyperglycation, iron deficiency anaemia, haemolytic anaemias, variant haemoglobin states, chronic liver disease, and end-stage renal disease (ESRD).13,14

Study objectives and hypothesis

The study attempts to discern clinical differences in HbA1c levels in patients with anaemia compared to non-anaemic population, as well as to quantify and show the direction of such difference if they indeed exist. We hypothesize that as glucose is covalently bound to haemoglobin in glycosylated haemoglobin, HbA1c levels in non-diabetic anaemic population is significantly lower than in non-diabetic, non-anaemic population.2 However, this relationship may not hold true for certain anaemias, haemoglobinopathies and hyperglycation states in some genetic syndromes.

Study design and method

The study is a retrospective chart review of patients with and without anaemia who underwent haemoglobin concentration and HbA1c level testing at The Brooklyn Hospital Center (TBHC) from July, 2009 to June, 2013. Using Cohen (1987) power table, assuming a power of 0.8, alpha level of 0.05, and a small effect size of 0.2 standard deviations (SD), sample size estimation of 461 was computed. A convenient sampling method was used to select patients who meet inclusion criteria, absent exclusionary conditions. In using this sampling method, we queried the electronic medical record at the TBHC using the below-listed inclusion and exclusion criteria. The query generated a list of “potential subjects”. We then reviewed the electronic chart of each patient on this list to confirm that they indeed meet all study criteria (excluding further if any exclusion criteria was identified on “second look”. We continued the selection until the computed minimum sample size of 461 was significantly exceeded. During this process, we had to examine every patient on the “potential subject” list generated by the initial query to achieve this goal. For the purpose of the study, anaemia is defined as haemoglobin concentration <11g/dl.

Inclusion criteria:

  • iStudy participant must be at least 21 years of age. We adopted this age criteria because at TBHC, electronic medical records was only available for the non-pediatric population over the study period. Patients below 21 years were managed at the pediatrics department using paper charts until the recent adoption of the EMR system. It would have been difficult conducting the study using paper charts.
  • iStudy participant must have at least one documented HbA1c level obtained within a month of a haemoglobin concentration assay. This criterion was adopted to allow for more inclusiveness in the study. It is our experience that haemoglobin assays may not be available on the same day as HbA1C assays considering the retrospective nature of the study.

Exclusion criteria:

  • Confirmed cases of diabetes mellitus (using two or more of the following: presence of symptoms related to diabetes, fasting blood glucose, 2 hours post-prandial glucose, and oral glucose tolerance test).
  • Documented history of gestational diabetes (GDM)
  • Documented history of endocrinopathy with affect for glycemic control
  • Current or prior use of medication with potential to increase or decrease HbA1c (includes, but not limited to antidiabetics, corticosteroids, statins, and antipsychotics)
  • Pregnancy or pregnancy-related condition within three months of HbA1c assay
  • Haemoglobin concentration <6 g/dl or >16g/dl.
  • Blood loss or blood transfusion within two months of HbA1c assay

The study assumed a consistent HbA1c assay method at the study center over the study period. 482 (229 anaemic and 253 non-anaemic) were selected. The study reviewed electronic medical records of selected patients, extracting data on HbA1c, fasting blood glucose (FBG), 2-hour post-prandial serum glucose (2HPPG), 2-hour oral glucose tolerance test (OGTT), haemoglobin concentration and electrophoresis, and anaemia work-up results when available. Subsequent measures of HbA1c two months after correction of anaemia was also documented and compared to pre-treatment levels.

Results and Analysis

The mean age of the anaemic and non-anaemic was 51.8 and 64.6 years respectively. Using the student’s t-test and x2 analysis respectively, the difference in mean age of both groups (anaemia and non-anaemic) was significant at p0.05 while gender distribution was similar (p>0.05), see table 1. The mean HbA1c for anaemic and non-anaemic groups was 5.35% and 5.74% respectively, amounting to a 0.4 unit difference in (8%) in mean HbA1c. This difference was statistically significant (p0.02). A significantly higher variance was observed in the anaemia group (0.79 vs. 0.64).

Table 1: Gender and age distribution and statistics

Age in years Anaemia #(%) Gender (M/F) Mean Age (in yrs)
21-44 20(8.7) 17/41  
45-64 76(33.2) 43/86  
≥65 133(58.1) 10/32  
Total 229(100.0) 70/159 64.6
Non-anaemic      
21-44 64(25.3) 23/42  
45-64 134(53.0) 58/81  
≥65 55(21.7) 18/31  
Total 253(100) 99//154 51.8

p-Values: Age=0.023, Gender=0.061

Assuming that 95% of the population is normal, computation of HA1c reference range (mean ±1.96SD) for the anaemia and non-anaemic group yielded 3.8-6.9 and 4.5-7.0 respectively. There was a significantly positive spearman correlation between [Hb] and HbA1C (r=0.28, p0.00). The mean HbA1c level and proposed reference ranges for the five anaemia subgroups (anaemia of chronic disease [ACD], iron deficiency anaemia [IDA], mixed anaemia, macrocytic anaemia and sickle-cell disease) are shown in table 2. Using one-way ANOVA analysis, the difference in the mean [Hb] and HbA1c across anaemia subtypes was not statistically significant (p0.08 and p0.36 respectively), see table 2.

Table 2: Anaemia subtypes with HbA1c statistics

Anaemia Type # Mean[Hb] MeanHbA1c 95% CI (HbA1c) Ref. range (HbA1c)
ACD 92 9.23 5.41 5.24-5.59 3.5-7.1
IDA 78 9.41 5.38 5.22-5.54 3.9-6.8
Mixed 11 9.11 5.21 4.82-5.59 3.9-6.5
Macrocytic 43 8.83 5.14 4.92-5.37 3.7-6.6
SCD 5 9.12 5.55 4.84-6.26 3.8-7.3
Anaemia (all types) 229 9.21 5.35 5.24-5.44 3.8-6.9
Non-anaemic 253 12.87 5.735 5.66-5.81 4.5-7.0

p-values: [Hb] for anaemia subtypes=0.08, HbA1C for anaemia subtypes=0.36, HbA1C anaemia vs. non-anaemia=0.02. ACD: anaemia of chronic disease, IDA: iron deficiency anaemia, SCD: sickle cell disease.

The study also examined the anaemia group to document the effect of anaemia correction on HbA1c levels. Only 62 of the 229 anaemic participants had documented [Hb] and HbA1c after interventions to correct anaemia, see table 3 and 4.

Table 3: Trend in [Hb] and HbA1c

  N Mean SD SEM Change p-Value
[Hb]1 62 9.2 1.07 0.14    
[Hb]2 62 10.1 1.98 0.25 [Hb]=0.9 0.00
HbA1c1 62 5.37 0.69 0.88    
HbA1c2 62 5.35 0.66 0.83 HbA1c=0.02 0.78

[Hb]1 and [Hb]2: haemoglobin concentration pre- and post- treatment for anaemia. HbA1c1 and HbA1c2: HbA1c pre- and post-treatment for anaemia

Table 4: Trend in [Hb] and HbA1c for anaemia subtypes

  N Mean [Hb]1 Mean [Hb]2 Δ Hb p Value MeanHbA1c1 MeanHbA1c2 Δ A1c p Val
ACD 33 9.1 9.7 0.6 0.0 5.44 5.35 0.09 0.3
IDA 21 9.4 10.7 1.3 0.0 5.30 5.33 0.03 0.8
Mixed 1                
Macrocytic 6                
SCD 1                
Total 62 9.2 10.1 0.9 0.0 5.37 5.35 0.02 0.8

ΔHb: change in haemoglobin concentration ([Hb]), ΔA1c: change in HbA1c

Using the student’s t-test, analysis, a 0.9g/dl mean improvement in [Hb] in the anaemia group (significant at p0.00) did not result in a statistically significant change in HbA1c (-0.02 units, p0.78). Similar results were obtained with anaemia of chronic disease and iron deficiency anaemia (ICD: change [Hb] =+0.6g/dl, change HbA1c=0.09, p0.31; IDA: change [Hb]=+1.3g/dl, change HbA1c=0.03, p0.79).

Discussion

There was an over-representation of the elderly in the anaemia group (58.1% vs. 21.7%). This is not unexpected as nutritional anaemia and anaemia of chronic disease increase in prevalence with the increasing co-morbidities associated with increasing age. The linear relationship between [Hb] and HbA1c holds true for anaemic and non-anaemia populations. There is a statistically significant difference of 0.4units (8%) in the mean HbA1c between the anaemic and the non-anaemic population. This difference is even more marked when the lower limit of the range is compared (3.8 vs. 4.5, difference of 0.7unit, 18%), the significance of which is not as clinically impacting as the upper limit of the range (diabetes mellitus diagnostic criteria). However, the relatively lower limit of normal for HbA1c in anaemic subgroups (especially of anaemia of chronic disease) may make low values of HbA1c in these patients less indicative of over-enthusiastic glycemic control, as well as less predictive of the increase in mortality associated with such tight control.

The upper range of normal for HbA1c for the anaemia and the non-anaemic groups and by extrapolation the proposed diagnostic criteria for diabetes, is however more similar (6.9 vs. 7.0%). This result appear consistent with Koga and Kasavama (2010) assertion that the trend in HbA1c does not appear to necessitate screening for iron deficiency to ascertain the reliability of HbA1c in this population.11 Our observation is explained by the greater variance associated within the anaemia group. The significantly higher variance observed in the anaemia may be explained by the convenient homogenization of clinically heterogeneous anaemia entities in the anaemia group. Perhaps a prospective study that avoids this may report differently.

The significantly higher variance (23%) in the anaemia is explained by the heterogeneity of the subtypes within the anaemia group. The myriad of pathophysiologies (from variant haemoglobin affecting structure and function, and perhaps glycation rates of haemoglobin, to shortened erythrocyte lifespan due to intravascular and extravascular haemolysis) accounts for a less precise HbA1c reference range for the anaemia group. Separating the anaemia group into unique anaemia subtypes created less heterogeneity, reduced some within group variance and yielded a more precise references range for some anaemia subtypes.

The widened 95% CI of mean and reference ranges observed with mixed and sickle cell anaemia (95% CI of mean =4.82-5.59 and 4.84-6.26 respectively) may be attributable in part to the small number of participants in these subgroups (11 and 5 respectively, the normal curve is less robust in these circumstances [when n<30])). Furthermore, the marked variability in the type, severity, and the number of chronic morbidities and deficiencies causing mixed anaemia may be contributing. The imprecision of HbA1c observed with the sickle cell may be compounded by the unstable clinical course of sickle disease, marked by periodic crises with fluctuating [Hb] associated with intermittent or chronic haemolysis. These observations make the case for defining HbA1c reference ranges for each anaemia type.

A modest correction of anaemia (Δ [Hb] of +0.9g/dl, i.e <1g/dl) did not appear to cause a significant change in HbA1c levels. It is possible that higher increments in [Hb] may produce significant change in HbA1c (we predict in the direction of increment). A similar pattern was observed with anaemia of chronic disease and iron deficiency anaemia subtypes, where improvements in [Hb] of 0.6 and 1.3g/dl respectively did not cause a significant change in HbA1c. We propose that with anaemia of chronic disease, the change in [Hb] concentration was too modest to cause a significant change in HbA1c. The relative small size of participants (33) examined also makes type II statistical errors highly likely. We further propose that with anaemia of chronic disease, the myriad of functional cellular and system abnormalities (many, potentially affecting cellular homeostasis, especially acid-base balance and haemoglobin molecule covalent binding) associated with the primary disorder may impact on the potential for increase in HbA1c with increasing [Hb]. In view of the retrospective nature of the study, we could not ascertain the timelines of certain interventions and hence accurately determine the persistence of anaemia correction. Theoretically, a recent correction in [Hb] is less likely to impact on HbA1c. As alluded to above Kim et al (2010) evaluated for changes in HbA1c two months after correction of anaemia. Similar explanations are offered for the observation with iron deficiency anaemia. There were only 21 participants in the iron anaemia subgroup (i.e. <30, probable violation of a rule for use of parametric tests), making the parametric statistical tests less robust for the analysis. We did not study patterns with mixed, macrocytic and SCD, as each subtype had <7 (1,6,1) participants.

The study examined a large volume of data, eliminating as much as possible, potential extraneous factors in the relationship between [Hb] and HbA1c levels. However, the retrospective nature of the study made the control of other extraneous variables and certain patient attributes infeasible. It was also difficult to discern critical timelines and hence eliminate the potential impact of certain therapeutic interventions. Also, our exclusion of the younger population of patients (i.e. 16-20 years) does not necessarily indicate the result of the study may not be extended to this population of anaemia patients. In fact the similar human haemoglobin physiology in this group advises that the results may be extended to this younger population without concern. Due to the retrospective nature of the study, and in our attempt to increase inclusiveness, we allowed haemoglobin concentration and HbA1c assays done within a month of each other. In reality though, the majority (57%) had same day assays and even a greater majority (79%) had within same week assays. We recommend a larger scale prospective study with participants representative of all anaemia subtypes and ages so that the results can be extrapolated to the general population of anaemia patients.

Conclusion

The study emphasizes the need to exercise caution when applying HbA1c reference ranges to anaemic populations. It makes the case for defining HbA1c reference ranges and thus, therapeutic goals for each anaemia subtype. Redefining such reference ranges may increase the sensitivity of HbA1c in diagnosing diabetes in anaemic population if indeed the lower mean HbA1c (observed in this study) translates into significantly lower upper limits of references ranges (not observed in this study). Also, the realized reduced lower limits of reference range in this population will lead to appropriate clinical tolerance for lower HbA1c levels, with avoidance of inappropriate intervention for erroneous perception of over-enthusiastic control of diabetic hyperglycemia. We recommend that, absent risks factors for and symptoms relatable to diabetes, marginal elevations in HbA1c levels (i.e. HbA1c >6%) in anaemic patients should warrant confirmation of diagnosis using fasting blood glucose and 2HPPG or OGTT. The use of other surrogates of glycemic control, immune to the blur associated with haemoglobin type and concentration, may circumvent the problem associated with use of HbA1c in this special population. To this end, fructosamine and glycated albumin assays are currently being examined. 1,15

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
SEGUN ADEOYE, MD, MS. Attending Physician, University of Pittsburgh Medical Center, Horizon, Greenville, Pennsylvania, USA. SHERLY ABRAHAM, MD, Attending Physician, The Department of Family Medicine, The Brooklyn Hospital Center, New York City, New York, USA. IRINA ERLIKH, MD, Attending Physicinan, Department of Family Medicine,The Brooklyn Hospital Center, New York City, New York, USA. SYLVESTER SARFRAZ, MD, Fellow, Geriatric Medicine, Brown University/Rhode Island University, Providence, Rhode Island. TOMAS BORDA, MD, Volunteer Researcher, Department of Family Medicine,The Brooklyn Hospital Center, New York City, New York, USA. LAP YEUNG, MD, Volunteer Researcher, Department of Family Medicine,The Brooklyn Hospital Center, New York, U City, New York, USA.
Corresponding Author Details: 
SEGUN ADEOYE, MD, MS. Attending Physician, University of Pittsburgh Medical Center, Horizon, Greenville, Pennsylvania, USA.
Corresponding Author Email: 
adeoye.segun@yahoo.com
References
References: 
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  2. Sinha, N.,  Mishra, T.,  Singh, T., Gupta, N. (2012). Effect of Iron Deficiency Anemia on Hemoglobin A1c Level. Ann Lab Med. 2012 January; 32(1): 17–22. Published online 2011 Dec 20. doi: 10.3343/alm.2012.32.1.17
  3. Higgins, T., Stewart D., Boehr E. (2008). Challenges in HbA1c analysis and reporting: an interesting case illustrating the many pitfalls. Clin Biochem. 2008 Sep;41(13):1104-6. Epub 2008 Jun 19.
  4. Koga, M., Hashimoto, K., Murai J, Saito, H., Mukai, M., Ikegame, K., Ogawa, H., Kasayama, S. (2011). Usefulness of glycated albumin as an indicator of glycemic control status in patients with hemolytic anemia. Clin Chim Acta. 2011 Jan 30;412(3-4):253-7. Epub 2010 Oct 18.
  5. Ford, E., Cowie C., Li C., Handelsman Y., Bloomgarden Z. (2011). Iron-deficiency anemia, non-iron-deficiency anemia and HbA1c among adults in the US. J Diabetes. 2011 Mar;3(1):67-73.
  6. Cohen, R., Franco, R., Khera, P., Lindsell, S., Ciraolo, P., Palascak, M., Joiner, C. (2008). Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. Nov 15; 112(10): 4284–4291.
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An aggressive follicular variant of papillary thyroid carcinoma with unusual metastases - A case report and review of literature

Authors
Isaac Sachmechi, Rachelle N Bitton, Susan Sanelli-Russo and Supat Thongpooswan
Article Citation and PDF Link
BJMP 2014;7(1):a705
Abstract / Summary
Abstract: 

Metastatic carcinoma to the sinonasal tract is rare, by papillary thyroid cancer even rarer. We describe a 44-year old Hispanic woman with follicular variant papillary thyroid carcinoma treated with total thyroidectomy and post-surgery I 131 ablation. Post therapy, two consecutive body scans were negative and thyroglobulin level was less than 5 ng/ml. A year later, she presented with history of urinary retention and lower extremity weakness. A myelogram revealed block at T1-T2. Patient underwent laminectomy followed by external radiation. Pathology revealed metastatic follicular variant of papillary thyroid carcinoma. Total body scan post surgery was negative, and the thyroglobulin level was 5 ng/ml. Patient was maintained on thyroxine suppression therapy.

Two years later, patient started complaining of headaches and double vision. Magnetic resonance imaging (MRI) was done and revealed a soft tissue mass in the sphenoid sinus, eroding the basi-sphenoid and extending into the nasopharynx. Biopsy was positive for metastatic papillary thyroid cancer, follicular variant. Pituitary function testing revealed TSH 0.1 mIU/ml, free T4 level 1.2 mIU/ml.  AM cortisol 5.3 mcg/dl, prolactin 182 ng/ml, ACTH 12 pg/ml, FSH 11.5 mIU/ml, LH 4.0 mIU/ml, and Estradiol 20 pg/ml.

Metastasis to the sphenoid sinus is rare from any tumour, and from papillary thyroid cancer is extremely rare. An extensive world literature review revealed only 4 cases of papillary thyroid carcinoma with spread to sphenoid sinus region. Of 12 case reports of thyroid carcinoma with spread to the sphenoid sinus, 6 were follicular thyroid carcinoma.  Generally, total body scan negative with low stimulated thyroglobulin is an excellent prognostic sign. Our patient demonstrates that we need to remain vigilant for the unusual tumour especially when the initial presentation showed a large lesion.

Abbreviations: 
MRI- Magnetic resonance imaging TSH- Thyroid stimulating hormone PET- positron emission tomography CT- computerized tomography
Keywords: 
papillary thyroid carcinoma, metastasis, sphenoid sinus

Introduction

Metastatic carcinoma to the sinonasal tract is rare. We describe a patient with an aggressive follicular variant of papillary thyroid carcinoma who presented with an unusual metastasis to sphenoid sinus.

Case report

A 44 year old Hispanic woman presented at Queens Hospital Center in June 1988 with airway obstruction and was found to have a 10x12 cm firm mass in the left thyroid lobe, and palpable left supraclavicular node. She had no prior history of radiation, and no family of thyroid cancer. She underwent a total thyroidectomy with a modified radical neck dissection. Pathology revealed a follicular variant of papillary thyroid carcinoma: non-tall cell variant. Six of fifty (6/50) lymph nodes were positive. Post-surgery, patient received Iodine-131 ablation therapy (93 mCi) and was placed on thyroid hormone suppressive therapy. Non-stimulated thyrogen total body scan a week after therapy was negative. Thyrogen was not available at that time.

The patient was non-compliant with thyroxine and thyroid stimulating hormone (TSH) was often elevated (13-80 mlU/ml). However, the serum thyroglobulin remained less than 5.0 ng/ml and antithyroglobulin antibody was negative. A repeat total body scan (with 5 mCi I131) 6 months later and 4 years later with thyroxin withdrawal (TSH 36 mIU/ml and 48 mIU/ml respectively) was negative, and patient was continued on thyroxine suppression therapy.

Five years after initial presentation, the patient developed urinary retention and lower extremity weakness. A myelogram revealed block at T1-T2. Patient underwent laminectomy. Pathology revealed metastatic follicular variant of papillary thyroid carcinoma. Since iodine containing contrast was used during the myelogram, I131 iodine therapy was not given. External radiation of 2000 CGY to C7-T5 was administered.

A total body scan 8 weeks post laminectomy (when 24 hour urine iodine < 100 microgram/litre, and TSH was 38 mIU/ml after thyroid hormone withdrawal) was negative, the thyroglobulin level was 5 ng/ml and negative antithyroglobulin antibody (at that period of time, positron emission tomography (PET) scan was not an available option). For the next 2 years of follow up, the patient was maintained on thyroxin suppression therapy, this time with good compliance (TSH 0.1 mIU/ml, thyroglobulin less than 5 ng/ml and negative antithyroglobulin antibody). She did not show up for follow up lumbar computerised tomography (CT).

Seven years after the initial presentation, she complained of headache and double vision, and a three month history of amenorrhea. The thyroglobulin at this time was elevated (20 ng/ml). Chest X-ray was positive for two nodules in the right lung. Magnetic resonance imaging (MRI) revealed a soft tissue mass in the sphenoid sinus, eroding the basi-sphenoid and extending into the nasopharynx (Fig. 1 ABCD). The mass also eroded the sella floor displacing the pituitary gland upwards (arrows). Bone scan revealed focal abnormalities in the upper thoracic spine, ethmoid bones and base of the skull. At that period of time, PET scan was not an available option. Pituitary function testing revealed TSH 0.1 mIU/ml, free T4 level 1.2 mIU/ml.  AM cortisol 5.3 mcg/dl, prolactin 182 ng/ml, ACTH 12 pg/ml, FSH 11.5 mIU/ml, LH 4.0 mIU/ml, and Estradiol 20 pg/ml.


Figure 1
: A-T1 weighted midline sagittal MRI scan without contrast. B-T1 weighted midline sagittal MRI scan with contrast. C-T2 weighted axial MRI scan through the lesion. D-Axial CT scans without (on the left) and with (on the right) contrast. Note: The large destructive and enhancing lesion (*) in the sphenoid sinus associated with destruction of the basisphenoid, clivus and sellar floor. Note the normal pituitary gland (arrow) is displaced upwards out the sellaturcica.

Biopsy of the sphenoid sinus mass confirmed that it was metastatic papillary thyroid cancer, follicular variant. The tumour cell nuclear DNA was diploid and P53 and K167 were negative (Impat, NY). The patient was placed on hydrocortisone replacement and continued on thyroxine suppression therapy. Three months later the patient suffered a cardiorespiratory arrest and expired.

Discussion

Metastasis to the sphenoid sinus is rare from any tumour, and from papillary thyroid cancer it is extremely rare. An extensive world literature review revealed only 4 cases of spread to sphenoid sinus region from papillary thyroid cancer.1-4

Renal cell carcinoma is the most common tumour of paranasal sinus metastasis, 41.8%. The average age is 58 years, with slight predominance of males. The most common presentation was epistaxis, 31%. The most common causes of sphenoid metastasis are gastrointestinal and renal tumours5.

Von Eiselsberg et  al. in 1893 described one case of metastasising thyroid carcinoma to sphenoid sinus.6 Harmer et al., 1899, reported a case of medullary thyroid carcinoma metastasis to sphenoid/ ethmoid sinus and nose. 7 Barrs et al. in 1979 reported a case of metastasis of follicular thyroid carcinoma to sphenoid sinus and sphenoid bone.8 Chang et al. in 1983 described a case of metastatic carcinoma of the thyroid to the sphenoid sinus.9 Renners et al. in 1992 reported one case of metastasis of follicular thyroid carcinoma to the paranasal sinuses, including the sphenoid sinus. 10Yamasoba et al. in 1994 reported a case with follicular thyroid carcinoma metastasising to sinonasal tract which also included sphenoid sinus.11 In the same year, Cumberworth et al. reported a case of metastasis of a thyroid follicular carcinoma to the sinonasal cavity which head CT showed sphenoid, ethmoid, frontal and maxillary sinuses. 12In 1997, Altman et al. described a case of follicular metastatic thyroid carcinoma to paranasal sinuses which included the sphenoid sinus. 13 The reported cases of thyroid cancer metastasis to sphenoid sinus are in table 1. Four cases were papillary thyroid carcinoma (included follicular variant of papillary thyroid carcinoma), six cases were follicular thyroid carcinoma, 1 case was medullary thyroid carcinoma and 1 case was unspecified thyroid carcinoma. 

Table 1: Cases of thyroid metastases to the sphenoid sinus

Author Age Sex Presenting symptoms Histologic type
Present case 44 F Headache, double vision and amenorrhea Follicular variant papillary thyroid carcinoma
Mandronio (2011) 53 F Blurring of vision of left eye Papillary metastatic thyroid carcinoma
Nishijima (2010) 81 F Epistaxis Differentiated papillary thyroid carcinoma
Argibay Vasquez (2005) 53 F Headache, paresthesia in the right eye region and left monocular diplopia Differentiated carcinoma of thyroid, follicular variant of papillary cell
Altman (1997) 81 F Progressive headache Follicular thyroid carcinoma
Freeman (1996) 50 M Facial pain, proptosis of the left globe and left horner’s syndrome Metastatic papillary thyroid carcinoma
Yamatosoba (1994) 34 F Hearing loss in right ear Follicular thyroid carcinoma
Cumberworth (1994) 62 F Right nasal blockage Follicular carcinoma of the thyroid
Renner (1984) 61 F Profuse right unilateral epistaxis Follicular thyroid adenocarcinoma
Chang (1983) 50 F Intermittent epistaxis, weight loss and pain in the right nasopharyngeal region Follicular carcinoma with papillary foci
Barrs (1979) 54 F Progressive loss of vision in the left eye Follicular thyroid carcinoma
Harmer (1899) 44 F Headache Medullary thyroid carcinoma
von Eiselsberg (1893) 38 M Chronic meningitis Thyroid carcinoma

Pathologic lesions involving the sphenoid sinus include inflammatory disease, mucocele, chordoma, nasopharyngeal carcinoma, plasmacytoma, primary sphenoid sinus carcinoma, adenocystic carcinoma, pituitary adenoma, and giant cell granuloma. Benign disease often presents with a more gradual obstruction and disturbance of vision. This contrasts with the acute and progressive disturbances of vision in all cases reported with malignant lesions of the sphenoid sinus.14

Our patient presented with complaints of double vision for 6 months and headache. After imaging with MRI and given her previous history of metastatic thyroid cancer, the most likely diagnosis was metastases to the sphenoid sinus from the thyroid cancer, which was confirmed by tissue biopsy. Since this patient had evidence of bone metastasis, it is likely that the tumour first metastasised to the bone and then ruptured into the sphenoid sinus. The tumour appears to have eroded the sellar floor, extending into and displacing the pituitary gland, causing secondary hypoadrenalism.

In our patient, low thyroglobulin proved to be an unreliable marker because it was low when the patient had metastasis of the tumour in the spine. These tumours are more aggressive and today, PET scanning has proved more reliable in following them, a modality that was not available at the time for our patient. The possible explanations for negative total body scans in patients with metastatic differentiated thyroid cancer are a) technical limitations of the scan in detecting the tumour cells, and b) failure of the tumour tissue to trap iodine.

There are several unusual aspects in this patient’s presentation. Firstly, the initial presentation was unusual, since this tumour was very aggressive with rare sites of distant metastases. Perhaps the long periods of hypothyroidism when patient was noncompliant promoted the aggressive nature of this tumour. Secondly, the failure of known tumour markers, i.e. serum thyroglobulin and total body scan to identify these metastases. Thirdly, our patient’s tumour cell nuclear DNA was diploid. Investigations have shown that the DNA ploidy pattern as determined by flow cytometry is an important and independent prognostic variable.15-17 Fortunately, aggressive follicular variant papillary cancer of thyroid (non-tall cell type) is very uncommon.

Generally, total body scan negative with low stimulated thyroglobulin is an excellent prognostic sign. Our patient demonstrates that we need to remain vigilant for the unusual tumour especially when the initial presentation showed so much bulky disease. The need for additional tumour markers will help to identify aggressive well differentiated thyroid carcinoma cases.

Acknowledgement

Appreciation is extended to Ms. Deborah Goss and Mr. Timothy O’Mara, librarians, in helping with literature search and preparing the manuscript. No other financial sources or funding involved in the formation of manuscript. No potential financial conflicts of interest. 

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Appreciation is extended to Ms. Deborah Goss and Mr. Timothy O’mara, Librarians, in helping with literature search. No other financial sources or funding involved in the formation of manuscript. No potential financial conflicts of interest.
Competing Interests: 
None declared
Details of Authors: 
ISAAC SACHMECHI, MD, FACE, FACP, Queens Hospital Center, Department of Medicine, 82-68 164th street, Jamaica, New York 11432, USA. RACHELLE N. BITTON, MD, FACE, Pro Health, New Hyde Park, New York 11040, USA SUSAN SANELLI-RUSSO, MD, Queens Hospital Center, Department of Medicine, 82-68 164th street, Jamaica, New York 11432, USA. SUPAT THONGPOOSWAN, MD, Queens Hospital Center, Department of Medicine, 82-68 164th street, Jamaica, New York 11432, USA.
Corresponding Author Details: 
SUPAT THONGPOOSWAN, MD, Queens Hospital Center, Department of Medicine, 82-68 164th street, Jamaica, New York 11432.
Corresponding Author Email: 
th.supat@gmail.com
References
References: 
  1. Mandronio EB, Lantion-Ang FL. The tale of two tumours: an undiagnosed case of papillary thyroid carcinoma. BMJ Case Reports. 20 Dec 2011.
  2. Nishijima H, Kitahara N, Murata M, Egami N. A case of papillary thyroid carcinoma metastatic to the sphenoid sinus presenting with epistaxis. Nihon Jibiinkoka Gakkai Kaiho. 2010; 113(2):62-66.
  3. Argibay Vázquez S, Lancha Hernández C, Martínez Muñiz A. Metastasis in the sphenoidal sinus in a patient with papillary thyroid cancer. Clin Transl Oncol. 2005; 7(7):324-327.
  4. Freeman JL, Gershon A, Liavaag PG, Walfish PG.  Papillary thyroid carcinoma metastasizing to the sphenoid-ethmoid sinuses and skull base. Thyroid. 1996; 6: 59-61.
  5. Bernstein JM, Montgomery WW, Baloh K Jr. Metastatic tumours to the maxilla, nose and paranasal sinuses. The Laryngoscope. 1966; 76:621-650.
  6. Von Eiselsberg, A. Uber Knochen-metastasen des schilddrusenkrebses.  Verhandlungen der Deutschen Gesellschaft für Chirurgie. 1893; 22:225-268.
  7. Harmer, L. Schilddrusenmetastase in der Nasenhohle. Weiner Klinische Wochenschrift. 1899; 23: 628-631.
  8. Barrs DM, McDonald TJ, Whisnant JP. Metastatic tumours to the sphenoid sinus. The Laryngoscope. 1979; 89:1239-1242.
  9. Chang G, Weber A, Pappanikov A. X-ray study of the month-Metastatic carcinoma of the thyroid to the sphenoid sinus. Ann Otol Rhinol Laryngol. 1983; 92:309-310.
  10. Renner GJ, Davis WE, Templer JW. Metastasis of thyroid carcinoma to the paranasal sinuses. Otolaryngology-Head and Neck Surgery. 1984; 92:233-237.
  11. Yamasoba T, Kikuchi S, Sugasawa M, Higo R, Sasaki T. Occult follicular carcinoma metastasizing to the sinonasal tract.ORL J Otorhinolaryngol Relat Spec. 1994 Jul-Aug; 56(4):239-43.
  12. Cumberworth VL, Ohri A, Morrissey G, Stirling R. Late sino-nasal metastasis from follicular thyroid carcinoma. J Laryngol Otol. 1994; 108:110-111.
  13. Altman KW, Mirza N, Philippe L. Metastatic follicular thyroid carcinoma to the paranasal sinuses: a case report and review. J Laryngol Otol 1997;111: 647-651.
  14. Wyllie JW III, Kern EB and Djalilian M. Isolated sphenoid sinus lesions. The Laryngoscope. 1973; 83:1252-1265.
  15. Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am. 1990; 19:545-576.  
  16. Backdahl M, Carstensen J, Auer G, Tallroth E. Statistical evaluation of the prognostic value of nuclear DNA content in papillary, follicular, and medullary thyroid tumours. World J Surg 1986; 10:974-980.
  17. Ozata M, Suzuki S, Miyamoto T, Liu RT, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the follow-up of patients with treated differentiated thyroid cancer. J Clin Endocrinol Metab. 1944; 79:98-105.

Self-induced burn injury from thermal footbath in patients with diabetes neuropathy—a common mishap in Asian culture

Authors
Huai Heng Loh and Florence Tan
Article Citation and PDF Link
BJMP 2014;7(1):a702
Abstract / Summary
Abstract: 

We report three cases of diabetic patients with peripheral neuropathy who sustained severe burn injuries to the foot due to use of thermal footbath with the intention to “improve circulation” and “relieve numbness”. Use of thermal footbath is common among Asian diabetic patients with peripheral neuropathy. This has resulted in accidental burn injuries. Due to high susceptibility to secondary infection, delayed presentation further complicates and prolongs hospital stay. There is a need for greater public awareness. Education regarding avoidance and consequences of this highly preventable injury should be incorporated into standard diabetic foot care education in clinical practice.

Keywords: 
Thermal footbath, severe burn injuries, diabetic neuropathy

Introduction

Diabetic patients with peripheral neuropathy are predisposed to foot injury. In Asian countries, a common culture among patients with peripheral neuropathy is to immerse their feet in hot water baths, with a belief that it will “improve circulation” and hence “cure the numbness”. We hereby report three cases of severe burn injuries of the feet presented to our hospital over a span of six months due to the above belief.

Case Report

The first patient was a 53-year old Malay gentleman with poorly controlled diabetes mellitus for six years, complicated with peripheral neuropathy, diabetic nephropathy and right eye cataract (latest HbA1C 8.1%), treated with oral anti-diabetic agents. He had a habit of using hot footbaths for numbness of both feet. Two weeks prior to presentation, due to increased feeling of numbness, he immersed his right foot into a self-prepared tub of hot water with added salt, followed by application of traditional sea cucumber gel. That evening, he noticed blistering of his right foot. Despite advice for admission, he chose to do the dressing as an outpatient in a local clinic. He presented two weeks later due to a worsening wound. At presentation, 4% full thickness burn of his right foot was noted, complicated by secondary infection (Figure 1). He underwent wound debridement, and subsequent split skin grafting. He had a prolonged hospitalization of five weeks due to secondary pseudomonas wound infection requiring parenteral antibiotics.

Figure 1. Right lower limb upon presentation to our hospital

The second patient was a 26-year old Indian gentleman with type I diabetes mellitus for nine years, complicated with diabetic nephropathy and peripheral neuropathy. His wife usually prepared hot water footbaths for him to improve his feet circulation. He developed 5% full thickness burn when he immersed his right foot into a pail of boiling water, not knowing that his wife had not added cold water into the footbath. He presented himself after two days and was hospitalized for two weeks. He recovered after wound debridement and split skin grafting.

The third patient was a 17-year old Chinese lady with poorly controlled type I diabetes mellitus for eight years, complicated with diabetic nephropathy (latest HbA1C 10.0%). She used hot water steam therapy with an aim to cure her recent onset of left foot drop, but was unaware of the temperature of the water. She developed blisters on her left foot, but only presented herself two weeks later when she developed left foot gas gangrene.  She had a prolonged hospital stay of eight weeks with recurrent hospital acquired infections, including Methicillin-resistant Staphylcoccus aureus (MRSA). Despite multiple wound debridement, she required amputation of her left fifth toe (Figure 2).

Figure 2. Left lower limb post Ray amputation

Discussion

Peripheral neuropathy is a known complication of diabetes mellitus. More than 50% of patients who are over 60 years old have this complication.1, 2 Thermal injury to the feet in patients with neuropathy has been reported after walking barefoot on hot surfaces3 and after application of hot water bottles or heating pads during winter months.4, 5 The use of thermal footbath as a cause of burn injury is mostly due to patient-misuse or ignorance of correct usage.6, 7 In contrast, in Asian countries, a common culture among patients with peripheral neuropathy is to immerse their feet in self-prepared hot water without checking the water temperature,8 with a belief that it will “improve circulation” and hence “cure the numbness”. This practice has led to accidental burn injuries as described in our case reports.

There are a few reasons why patients with diabetic peripheral neuropathy end up with such a severe complication after the use of thermal footbath. Firstly, the temperature of the thermal bath may be underestimated. The time to develop full thickness burn reduces exponentially with just minimal increments in water temperature.9 Secondly, lack of pain despite the burn can prolong exposure to the heat source. In addition, concomitant peripheral vascular disease and endothelial function can limit vasodilatation to conduct heat away hence further aggravate the thermal insult.

Another important contributing factor of complicated wounds are the delays in seeking treatment as the result of lack of pain despite the burn injury. In a study done by Memmel et al on 1794 patients (of which 130 were diabetics) who presented with burn injuries, the majority of non-diabetic burn patients (63%) presented within 48 hours of injury, but only 40% of diabetic patients sought treatment within that time frame. Significantly more patients with diabetes presented after two weeks compared to those without diabetes. As burn injuries are highly susceptible to secondary infection, any delay in presentation further complicates and prolongs hospital stay.10,11 Not surprisingly, our two patients who presented two weeks after their burn injury had a prolonged and complicated hospital course compared to our second patient who presented soon after the burn injury. Increased susceptibility to infection and delayed wound healing from poor circulation contribute to prolonged recovery and poorer clinical outcomes in patients with diabetes mellitus, with some needing amputation as noted in our third patient.

As a healthcare provider we play a role in preventing this misfortune. Routine screening for the presence of peripheral neuropathy and vascular disease should be done during clinic visits to identify high-risk patients. Specific education regarding avoidance of thermal footbath and consequences of this highly preventable injury should be incorporated into standard diabetic foot care education. If patients choose to immerse their feet in hot water, temperature of the water should always be measured with a thermometer and immersion time should be limited. If a wound develops, they should present early to hospital for immediate treatment.

Conclusion

Thermal footbath for therapeutic purposes is commonly practiced in Asian culture. Our case reports highlight the serious consequences of this practice in diabetic patients with peripheral neuropathy. More public awareness and patient education is needed to prevent these injuries and to avoid the high cost of prolonged hospital stay and losses to the patient.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
HUAI HENG LOH, MRCP (UK), University Malaysia Sarawak, Kuching, Malaysia. FLORENCE TAN, MRCP (UK), Sarawak General Hospital, Kuching, Malaysia.
Corresponding Author Details: 
HUAI HENG LOH, University Malaysia Sarawak, Faculty of Medicine and Health Sciences, Lot 77 Section 22, KTLD Jalan Tun Ahmad Zaidi Adruce, 93150 Kuching Sarawak, Malaysia.
Corresponding Author Email: 
luohuaixin@gmail.com
References
References: 

1. Young MJ, Boulton JM, Macleod AF, et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: 150-154

2. Mimi O, Teng CL, Chia YC. The prevalence of diabetic peripheral neuropathy in an outpatient setting. Med J Malaysia 2003; 58: 533-538

3. Gaztelu V, Gago Fornells M, Garcia Gonzales RF, et al. Hot sand burns on the sole of a patient with diabetes. J Wound Care 2002; 11: 170-171

4. Katcher ML, Shapiro MM. Lower extremity burns related to sensory loss in diabetes mellitus. J Fam Pract 1987; 24: 149-151

5. Jose RM, Vidyadharan R, Roy DK, et al. Hot water bottles and diabetic patients – a cautionary tale. Br J Gen Pract 2005; 55: 222-223

6. Dijkstra S, vd Bent MJ, vd Brand HJ, et al. Diabetic patients with foot burns. Diabetic Medicine 1997; 14: 1080-1083

7. Balakrishnan C, Rak TP, Meininger MS. Burns of the neuropathic foot following use of therapeutic footbaths. Burns 1995; 8: 622-623

8. Thng P, Lim RMC, Low BY. Thermal Burns in Diabetic Feet. Singapore Med J1999; 40(05): 362-364

9. Accurate Building Inspectors. New York: Ubell Enterprises, Inc; c2003-2013 [cited 2012 June 12] Hot Water Burn & Consumer Safety. Available from: www.accuratebuilding.com

10. Zachary LS, Heggers JP, Robson MC, et al. Burns of the feet. J Burn Care Rehabil1987; 8: 192-194

11. Memmel H, Kowal-Vern A, Latenser BA. Infection in Diabetic Burn Patients. Diabetes Care 2004; 27(1): 229-233

Impact of diabetes education and peer support group on the metabolic parameters of patients with Diabetes Mellitus (Type 1 and Type 2)

Authors
Issac Sachmechi, Aileen Wang, Paul Kim, David Reich, Hildegarde Payne and Vincent Bryan Salvador
Article Citation and PDF Link
BJMP 2013;6(4):a635
Abstract / Summary
Abstract: 

Aim This study was undertaken to investigate the effect of diabetes education (DE) alone versus diabetes education plus peer support group (DE+PS) in improving metabolic parameters in patients with diabetes mellitus (DM).
MethodsWe retrospectively included a total of 188 subjects with DM who were seen at the Diabetes Centre and Primary Care clinics at Queens Hospital Centre, Jamaica, New York. The patients were categorized into three main groups: (1) control group (n=62), who received primary care only, (2) DE group (n=63), who received primary care plus diabetes teaching from a certified diabetes nurse educator and (3) DE+PS group (n=63) who received education in diabetes and who joined a peer support group for at least two or more sessions.   The mean change from baseline in hemoglobin A1C (HbA1C), weight, body mass index (BMI), systolic blood pressure (SBP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG-C) was calculated after 3 follow up visits.
Results The patients in DE group were observed to have statistically significant decrease in mean HbA1C (mean change: -0.78%, p=0.013), TC (mean change: -16.89 mg/dL, p=0.01) and LDL-C (mean change: -11.75 mg/dL, p=0.04) from baseline to final follow. The same group also exhibited consistently significant reductions in HbA1C and LDL-C throughout from the third month to the thirteenth month of follow up. The patients in DE+PS group had a moderate decrease in HbA1C, SBP, TG-C and weight, and an increase in HDL-C, LDL-C and BMI in the final follow up, but all were not statistically significant.
ConclusionThe present study suggested that participation in DE may assist with optimizing metabolic parameters such as HbA1C, TC and LDL-C levels in patients with diabetes. This benefit may perpetuate through time. The addition of peer support group to DE may or may not confer additional benefit. 

Abbreviations: 
DM – diabetes mellitus, HB A1C - Hemoglobin A1C (HB A1C), BMI - body mass index (kg/m2), SBP - systolic blood pressure, TC - total cholesterol, HDL-C - HDL cholesterol, LDL-C - LDL cholesterol, TG - triglycerides, ADA - American Diabetes Association
Keywords: 
diabetes mellitus, metabolic parameters, diabetes education, diabetes peer support group

Introduction

Population-based studies indicated that diabetes remains as a nationwide epidemic that continues to grow tremendously affecting 25.8 million people or 8.3% of the US population.1 This number is expected to reach 68 million or 25% of the population by 20302 as incidence of obesity is rising.3

The American Diabetes Association (ADA) recognizes diabetes education (DE) as an essential part of comprehensive care for patients with diabetes mellitus and recommends assessing self-management skills and knowledge at least annually in addition to participation in DE.4 With the objective of improving the quality of life and reducing the disease burden, the ADA and the U.S. Department of Health and Human Services through its Healthy People 2020 program have emphasized three key components for effective disease management planning: regular medical care, self-management education and ongoing diabetes support.5,6

The hallmark of preventing the chronic complications of diabetes lies in optimizing metabolic parameters such as glycaemic control, blood pressure, weight and lipid profile. Pharmacologic intervention can only do so much in achieving treatment goals. It should be complemented with appropriate DE emphasizing dietary control, physical activity and strict medication adherence.7,8 Adequate glycaemic control is clinically important because a percentile reduction in mean HbA1C is associated with a 21% reduction in diabetes-related death risk, 14% reduction in heart attacks and 37% reduction in microvascular complications.9

Diabetes self-management (DSM) education programs are valuable strategy for improving health behaviours which have significant impact on metabolic parameters.10 This is supported by chronic care model that is based on the notion that improving the health of patients with chronic diseases depends on a number of factors that include patients’ knowledge about their disease, daily practice of self-management techniques and healthy behaviors.11,12,13

A systematic review by Norris et al. has shown that DSM training confers positive effect on patients’ knowledge about diabetes, blood glucose monitoring, and importance of dietary practices and glycaemic control.14 In another retrospective observational study, evidence has suggested that participation in a multifactorial diabetes health education significantly improved glycaemic and lipid levels in the short term.10

Diabetes education/support group provides a comprehensive patient education, fosters a sense of community, and engages the patients to become active part of a team managing their diabetes. The diabetes support group at Queens Hospital Centre provides services to a diverse population from different socioeconomic backgrounds and is offered to any patients with diabetes. It is facilitated by certified diabetes nurse educators in the hospital and in the clinic. Patients meet once a month per session and are provided education in self-management of diabetes, education in medication, diet, lifestyle modifications, regular exercise, weight management and translation in their respective languages, if needed.

Few researches have been conducted comparing the efficacy of DE and combination of diabetes education and peer support group (DE+PS) in improving the metabolic parameters of patients with DM. In patients with DM, the primary objective of this study was to assess the clinical impact of DE and combined DE+PS group on metabolic parameters such as lowering HbA1C, reducing weight or BMI, controlling blood pressure, and improving lipid profile.

Methods

The study subjects were identified through retrospective review of electronic medical records of adult patients aged more than 18 years old with diabetes and being treated at the Diabetes Centre and/or Primary Care Clinic of Queens Hospital Centre, Jamaica, New York from January 01, 2007 to June 01, 2011. A total of 188 study subjects were selected and assigned to three groups: (1) control group (n=62), who received primary care only, (2) DE group (n=63), who received diabetes teaching from DM nurse educator in addition to primary care, and (3) DE+PS group (n=63), who received both diabetes education and attended at least 2 or more sessions of peer support group in addition to primary care. The subjects in control group, education group, education plus peer support group were matched on age, sex, weight and BMI. Considering the data availability, the duration of follow up measured in each group varied; the control group was followed up for 8 months, the DE group for 13 months and the DE+PS group for 19 months. The changes from mean baseline to the third month, sixth month and final follow up period were calculated for the following metabolic parameters: HbA1C, weight, BMI, SBP, TC, HDL-C, LDL-C and TG-C. T sample T-test was used to compare statistical differences in the mean changes in the metabolic parameters in each group from baseline to follow up period. All data management and statistical analyses were conducted with MiniTab version 14. A p-value of less than 0.05 is considered statistically significant.

Results

Among the 188 study subjects included in our study between ages 20 to 88 years with mean age of 60, the predominant gender was female (n=132, 70%). African American makes up the majority (n=74, 39%), followed by Asian (n=40, 21%), Caucasian (n=34, 18%), Hispanic (n=22, 12%) and Indian (n=18, 10%). Majority of our patients with DM have concurrent hypertension (91%), hyperlipidemia (90%), and obesity (47%). See Table 1 for baseline demographics.

Table 1. Baseline demographic characteristics of the study population
  Control [C]
N=62
Diabetes Education [DE]
N=63
Diabetes Education +
Peer support [DE+PS]
N=63
Baseline Characteristics      
Age range (years) [median] 32-76 [61] 20-88 [58] 26-86 [62]
Sex-male [N (%)] 22 (35) 20 (32) 14 (22)
Race      
African American 31 (50) 26 (41) 17 (27)
White 11 (17) 23 (37) 0 (0)
Indian 18 (29) 0 (0) 0 (0)
Asian 1 (2) 10 (16) 29 (46)
Hispanic 1 (2) 4 (6) 17 (27)
Comorbidities [N (%)]      
Hypertension# 54 (87) 59 (94) 58 (92)
Hyperlipidemia¥ 56 (90) 61 (97) 53 (84)
Obesity* 29 (47) 29 (46) 31 (49)
Active cigarette smoker 6 (10) 5 (8) 1 (2)

# Hypertension is defined as mean systolic blood pressure > 140 mmHg and/or diastolic > 90 mmHg measured on two separate occasions. These patients have either hypertension diagnosed prior to or after diagnosis of DM.
¥ Hyperlipidemia is defined as LDL > 100 mg/dl in patients with diabetes and diagnosis hyperlipidemia could be before or after diagnosis of DM.
* Obesity is defined as body mass index (BMI) of at least 30 kg/m2 or greater.

The group analysis showed that the DE group had a statistically significant decrease in mean HbA1C (mean change: -0.78%, p=0.013), TC (mean change: -16.89 mg/dL, p=0.01) and LDL-C (mean change: -11.75 mg/dL, p=0.04) from baseline to final follow up (see Table 2). The DE group had non-significant mean weight gain of 2.17 pounds and BMI of 0.52 kg/m2.

* Final follow up varies for the three groups. 8 months for control (C), 13 months for education (DE) group and 19 months for education plus peer support (DE+PS) group

Although DE+PS group were observed to have decreased in mean HbA1C (-0.48%), weight (-0.38 pounds), SBP (-3.24 mmHg), TC (-4.43 mg/dL) and TG-C (-12.89 mg/dL) and increased in HDL-C (+095 mg/dL), they were not statistically significant from initial to final follow up period. There were greater improvements in HbA1C and SBP from baseline to final follow up in DE+PS group compared to the control group. Only the control and DE+PS groups showed a decrease in weight from initial to final follow up.

Between the two intervention arms, the DE group exhibited greater reduction compared to DE+PS group in mean HbA1C (-0.78 vs. -0.48%), SBP (-3.78 vs. -3.24 mmHg), TC (-16.89 vs. -4.43 mg/dL), LDL-C (-11.75 vs. +0.08 mg/dL) and TG-C (-14.75 vs. -12.89 mg/dL).

Discussion

Our results suggested that among patients with DM, the subjects who participated in DE exhibited significant reduction in baseline HbA1C, TC and LDL-C compared to control. Furthermore, the significant impact of DE alone on optimizing control of HbA1C and LDL-C appeared to persist through time. In addition patients who received DE+PS also demonstrated moderate improvement in HbA1C, SBP, TC and TG-C and HDL-C even though they were not statistically significant on final follow up. It must be noted that the baseline mean HbA1Cs were higher in both interventions DE and DE+PS groups compared to control group and this may be associated with greater reduction in HbA1C in the intervention groups and may skew the finding. Our study results showed that DE group had greater percentage reduction in HbA1C (9%) compared to DE+PS group (5%) from baseline to the first follow up. The average change in HbA1C and LDL-C levels recorded in our study is similar to what has been reported in a previous study which showed significantly greater improvement in mean glycaemic levels and LDL-C levels in patients who participated in DE.10

However our findings are in stark contrast to a previous study that showed that DE+PS intervention has led to substantially greater weight reduction and improvement in HbA1C at second month post-intervention compared to education and control group.15 This difference may be accounted for by the effect of sample size and the duration of follow up. The DE+PS group in our study included twice the number of patients being sampled compared to previous study (63 patients vs. 32 patients), and longer duration of follow up (19 months vs. 4 months)15. These differences are significant as they can influence the data trend.

In general, all groups had improvement in HbA1C, TC, TG-C levels, and SBP (though not significant). Only control and DE+PS groups had weight reduction and DE group had weight increase. Although the DE+PS group had improvement in most of the metabolic parameters they were not statistically significant throughout the entire follow up period compared to DE group. This scenario might be attributed to retrospective nature of the study, possible non-compliance of patients to medications, differences in duration of follow up between groups, and limited number of patients sampled thus hindering the appreciation of potential significant effect. The statistically significant differences in baseline HB A1C among the three groups could also explain the differing magnitude of change from baseline; DE group had higher baseline HbA1C compared to control group (9.3 vs. 7.5%; p=0.00) allowing for a greater change from baseline value. Similarly in DE+PS group, baseline HbA1C was considered statistically significant compared to control group (8.3 vs. 7.5%, p=0.018).

A previous randomized controlled trial assessing the effect of peer support on patients with type 2 diabetes with a 2-year follow up demonstrated no significant differences in HbA1C (-0.08%, 95% CI -0.35% to 0.18%), SBP (-3.9 mmHg, -8.9 to 1.1 mmHg) and TC (-0.03 mmol/l, -0.28 to 0.22 mmol/l).16 It was suggested that the effect of DSM education on glycaemic control is greatest in the short-term and progressively attenuated over time and this may suggest that learned behaviour changes with time.17,18 However, the result of the present study showed a persistently significant beneficial effect on HbA1C and LDL-C from the earliest follow up until the final month for patients receiving DE alone.

Previous meta-analysis of randomized trials of DSM education programs by Norris and colleagues (2002) demonstrated the beneficial effect of DE with estimated effect on glycaemic control (HbA1C) at -0.76% (95% CI: 0.34,1.18) compared to control immediately after the intervention.17 However, the findings of the present study on the effect of peer education are in direct contrast with the results of the randomized trial using the Project Dulce model of peer-led education showing significant improvement from baseline to the tenth month of follow-up in HB A1C (-1.5%, p=0.01), TC (-7.2 mg/dl, p=0.04), HDL-C (+1.6 mg/dl, p=0.01) and LDL-C (-8.1 mg/dl, p=0.02).19 This could be accounted for the different baseline values of the metabolic parameters in the present study, thus creating a bias in the magnitude of change.

It has been suggested that the most effective peer support model includes both peer support and a structured educational program. The emphasis on peer support is based on the recognition that people living with chronic illness can share their knowledge and experiences to one another.20 It has been observed that participants in peer support groups were not interested in the topic of diabetes itself but on the effect and meaning of the disease on the lives of the patients.21

There are a number of limitations to be taken into consideration when interpreting the results of our study. Since our study is a retrospective review of medical records, the data collection was limited to availability of the required clinical data. Some parameters were not possible to obtain on a consistently uniform time frame. This resulted in varying mean duration for the 3 study groups (8 months for control group, 13 months for DE and 19 months DE+PS group). Because of unavailability of some of the clinical parameters at a specific time frame, there were variables missing on the earlier follow-ups. Our study also examined the effect of the intervention over a relatively short time. A longer-term study is necessary to determine if the intervention has lasting impact on improving the metabolic parameters, uplifting the quality of life and preventing morbidity and mortality from diabetes. The limited sample size could also be important factor that may influence the generalizability of the data. The differing baseline values in the metabolic parameters could have blunted the appreciation of possible significant improvement in the metabolic parameters in the DE+PS group. Other confounding factors that were not analysed in the present study and could have affected the results include the use of insulin regimen among the different groups, initiation of additional oral hypoglycemic agents, medication adherence by the patients and adjustment by physicians, and whether the patients were seen by endocrinologists or not.

The present study suggested that participation in DE may assist with optimizing HbA1C, TC and LDL-C. The DE group had improvement in glycaemic control and other metabolic parameters. The significant metabolic improvement gained from DE appeared to be sustained over time. However, participation in both DE+PS showed relative improvement but not significant as it is likely due to confounding different baseline metabolic parameter and duration being compared. Our findings underscore the importance of DE as part of the treatment plan for patients with DM. The addition of peer support group may or may not contribute to significant improvement of metabolic parameters.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors would like to extend their gratitude to: Nayab Bakshi, Edan Elias and Dorota Pazdrowska for assistance on data recording.
Competing Interests: 
None declared
Details of Authors: 
ISSAC SACHMECHI, M.D., FACP, FACE, Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, Jamaica, NY, USA 11432. AILEEN WANG, M.D., Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, Jamaica, NY, USA 11432. PAUL KIM, M.D., FACE, Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, Jamaica, NY, USA 11432. DAVID REICH, M.D., FACE, Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, Jamaica, NY, USA 11432. HILDEGARDE PAYNE, R.N., CDE, Diabetes Clinic, Queens Hospital Center, Jamaica, NY, USA 11432. VINCENT BRYAN SALVADOR, M.D., Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, Jamaica, NY, USA 11432.
Corresponding Author Details: 
VINCENT BRYAN SALVADOR, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, NY, USA 11432.
Corresponding Author Email: 
docvincesalvador@aol.com
References
References: 
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  2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modelling of incidence, mortality and prediabetes prevalence. Popul Health Metr. 2010; 8:29.
  3. S. Wild, G Roglic, A. Green, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27 (5);2004; 1047-1053.
  4. American Diabetes Association. Standards of medical care for patients with diabetes mellitus (position statement). Diabetes Care 2001;24 (Suppl 1):S33-43.
  5. Healthy People.gov. Healthy People 2020:goals and objectives-diabetes [Internet]. Washington (DC):Department of Health and Human Services; 2011. Available from: http://healthypeople.gov/2020/topicsobjectives 2020/overview.aspx?topicid=8.
  6. American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care. 2011;34 (Suppl 1):S11-8
  7. Gaede P, Lund-Andersen H, PArving H-H, et al. Effect of multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-591.
  8. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death and microvascular events in type 2 diabetes: meta-analysis of randomized controlled trials. BMJ 2011;343:d4169.
  9. Stratton IM, Adler AI, Neil JA, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35):prospective observational study. BMJ 2000;321(7258):405-12.
  10. Roblin DW, Ntekop E, Becker ER. Improved intermediate clinical outcomes from participation in a diabetes health education program. J Ambulatory Care Manage 2007; 30(1);64-73.
  11. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness. JAMA 2002a. 288(14), 1775-1779.
  12. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness:the chronic care model, part 2. JAMA 2002b, 288(15),1909-1914.
  13. Wagner EH, Austin BT, Von Korff M. Organizing care for patients with chronic illness. Milbank Quarterly 1996, 74(4), 511-544.
  14. Norris SL, Engelgau MM, Narayan KM. Effectiveness of self-management training in type 2 diabetes. A systematic review of randomized controlled trials. Diabetes Care 2011, 24(3),561-587.
  15. Wilson W. Pratt C. The impact of diabetes education and peer support upon weight and glycaemic control of elderly persons with noninsulin dependent diabetes mellitus (NIDDM).Am J Public Health May 1987; 77(5),634-635.
  16. Smith SM, Paul G, Kelly A, Whitford DL, et al. Peer support for patients with type 2 diabetes: cluster randomized controlled trial. BMJ 2011;342:d715.
  17. Norris SL, Lau JS, Schmid CH, et al. Self-management education for adults with type 2 diabetes: A meta-analysis of the effect on glycaemic control. Diabetes Care 2002; 25(7),1159-1171.
  18. Brown S. Meta-analysis of diabetes patient education research: variation in intervention effects across studies. Res Nurs Health 1992;15:409-419. 
  19. Philis-Tsimikas A, Fortmann A, Lleva-Ocana L, et al. Peer-led diabetes education programs in high-risk Mexican Americans improve glycaemic control compared with standard approaches. Diabetes Care 2011;34:1926-1931.
  20. Heisler M. Overview of peer support models to improve diabetes self-management and clinical outcomes. Diabetes Spectrum 2007;20(4):214-221.
  21. Rugh D. Design of a rural diabetes self-directed care program. Soc Work Health Care 2011;50(10):775-786.

 

Bortezomib induced reversible left ventricular systolic dysfunction: A case report and review of literature.

Authors
Rajshekhar Chakraborty, Shiva Kumar R Mukkamalla, Natalia Calderon
Article Citation and PDF Link
BJMP 2013;6(4):a631
Abstract / Summary
Abstract: 

Bortezomib is a reversible proteasome inhibitor, currently approved by US FDA for use in multiple myeloma and mantle cell lymphoma. Bortezomib has been shown to cause new onset and exacerbation of underlying congestive cardiac failure (CHF) in some case reports. Studies on human tissue have shown dysregulation of ubiquitin proteasome system (UPS) in cardiac tissues in end stage heart failure. Recently, an animal study has shown reduced left ventricular contractility after bortezomib administration, which was attributed to reduced ATP synthesis in mitochondria of cardiac myocytes.

Our case demonstrates development of new onset severe reversible left ventricular systolic dysfunction after 4 cycles of bortezomib in a 58 year old female with multiple myeloma. Her only medical condition was well controlled hypertension and she did not have any other risk factor for coronary artery disease. We also present a review of all case reports of CHF associated with bortezomib administration published till date and occurrence of CHF with bortezomib administration in major clinical trials of multiple myeloma.

Our manuscript highlights the importance of maintaining a high level of suspicion for development of CHF after therapy with bortezomib. Currently, there is no guideline for routine evaluation and monitoring of cardiac function in all patients during the course of bortezomib therapy. Further studies are required in future to address this issue.

Keywords: 
Bortezomib, Congestive heart failure, Ubiquitin proteasome system.

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 failure1-3. 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 failure1-3. 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 levels7, 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.

Author Age/sex Prior cardiac history and risk factors Baseline cardiac function Number of Bortezomib containing cycles Exposure to other cardiotoxic medications Amount of Bortezomib received before onset of cardiac symptoms Lowest EF** after Bortezomib administration EF on follow up visits
Voortman et al7 53/M 36 pack years of smoking and COPD Echo not available; NT-Pro BNP 1389 ng/l 4 Gemcitabine 3 mg/m2 10-15% on Echo after 4 cycles 45% on MUGA scan at 6 months
Orciuolo et al9 73/M NK* NK 6 1 Anthracycline containing regimen 20.8 mg/m2 EF 25% NK
Orcioulo et al9 61/F NK NK 4 2 Anthracycline containing regimens 20.8 mg/m2 EF 20% NK
Orciuolo et al9 80/F NK NK 4 1 prior non anthracycline chemotherapy regimen received 20.8 mg/m2 EF 35% NK
Hasihanefioglu et al10 47/M None EF 70% and normal coronary angiogram 2 1 cycle of Vincristine, Doxorubicin and Dexamethasone 10.4 mg/m2 EF 10% EF 20% at 6 month follow up
Bockorny et al8 56/F Hypertension, well controlled NK 4 None 20.8 mg/m2 EF 20-25% EF 55-60%
INDEX CASE 58/F Hypertension, well controlled NK 4 None 20.8 mg/m2 EF 30-35% EF 55% at 4 month and 65% at 2 year follow up.

*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.
 

Authors (ref) Study Study population Significant Cardiac events (n)
Berenson, J.R. et al. 200513 Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma 63 patients with relapsed and/or refractory MM Cardiomegaly (1) MI, SVT, Pulmonary oedema (1) Complete AV block (1)
Chen, C.I. et al. 200714 Bortezomib in Waldenström’s Macroglobulinemia 27 patients with untreated or relapsed WM Congestive Heart Failure (1)
D’Arena, G. et al. 201215 Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukaemia 29 patients with untreated PPCL None reported
Hjorth, M. et al. 201212 Thal-Dex vs. Bort-Dex in refractory myeloma 131 patients with Melphalan refractory MM 2 cases of cardiac failure in Thal-Dex group and 3 in Bort-dex group
Jagannath, S. et al 200916 Bortezomib for Relapsed or Refractory Multiple Myeloma 54 patients with relapsed or refractory MM None reported
Jagannath, S. et al 201017 Extended follow-up of Frontline Bortezomib ± Dexamethasone for MM 49 patients with untreated MM None reported
Kobayashi, T. et al. 201018 Bortezomib plus dexamethasone for relapsed or treatment refractory multiple myeloma 88 patients with relapse/refractory MM None reported
Mikhael, J.R. et al. 200919 High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma 638 patients with refractory or relapsed MM None reported
Richardson, P.G. et al. 200320 A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma 202 patients with relapsed MM None reported
Richardson, P.G. et al. 200511 Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma(APEX trial) 669 patients with relapsed MM Congestive cardiac failure in 2% of each arm.
       
Rosino, L. et al. 200721 Phase II PETHEMA Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma 40 patients with newly diagnosed MM None reported
Sonneveld, P. et al. 201222 Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma 827 patients with newly diagnosed MM Cardiac Disorders in 5% of patient in VAD group vs. 8% of patients in PAD group.
Yuan, Z.G. et al. 201123 Different dose combinations of bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma 168 patients with relapsed MM None reported
Suvannasankha et al 200624 Weekly bortezomib/methylprednisolone in relapsed multiple myeloma 29 patients with relapsed multiple myeloma 1 case of congestive cardiac failure

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.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None.
Details of Authors: 
RAJSHEKHAR CHAKRABORTY, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA. SHIVA KUMAR R. MUKKAMALLA, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA. NATALIA CALDERON, MD, Queens Hospital Center(Affiliated to Icahn School of Medicine at Mount Sinai), New York, USA.
Corresponding Author Details: 
DR RAJSHEKHAR CHAKRABORTY, Queens Hospital Center, Dept. of Internal Medicine, 82-68, 164th street, Jamaica, NY 11432. USA.
Corresponding Author Email: 
rajshekhar.ucms@gmail.com
References
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  12. Hjorth M, Hjertner O, Knudsen LM, et al. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: A randomized study. Eur J Haematol. 2012;88(6):485-496. doi: 10.1111/j.1600-0609.2012.01775.x; 10.1111/j.1600-0609.2012.01775.x.
  13. Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer. 2005;104(10):2141-2148. doi: 10.1002/cncr.21427.
  14. Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed waldenstrom's macroglobulinemia: A phase II study of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007;25(12):1570-1575. doi: 10.1200/JCO.2006.07.8659.
  15. D'Arena G, Valentini CG, Pietrantuono G, et al. Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: A retrospective study from GIMEMA multiple myeloma working party. Ann Oncol. 2012;23(6):1499-1502. doi: 10.1093/annonc/mdr480; 10.1093/annonc/mdr480.
  16. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127(2):165-172. doi: 10.1111/j.1365-2141.2004.05188.x.
  17. Jagannath S, Durie BG, Wolf JL, et al. Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma. Br J Haematol. 2009;146(6):619-626. doi: 10.1111/j.1365-2141.2009.07803.x; 10.1111/j.1365-2141.2009.07803.x.
  18. Kobayashi T, Kuroda J, Shimura K, et al. Bortezomib plus dexamethasone for relapsed or treatment refractory multiple myeloma: The collaborative study at six institutes in kyoto and osaka. Int J Hematol. 2010;92(4):579-586. doi: 10.1007/s12185-010-0696-4; 10.1007/s12185-010-0696-4.
  19. Mikhael JR, Belch AR, Prince HM, et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: Results of a global phase 3b expanded access program. Br J Haematol. 2009;144(2):169-175. doi: 10.1111/j.1365-2141.2008.07409.x; 10.1111/j.1365-2141.2008.07409.x.
  20. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609-2617. doi: 10.1056/NEJMoa030288.
  21. Rosinol L, Oriol A, Mateos MV, et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: Efficacy and clinical implications of tumor response kinetics. J Clin Oncol. 2007;25(28):4452-4458. doi: 10.1200/JCO.2007.12.3323.
  22. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: Results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955. doi: 10.1200/JCO.2011.39.6820; 10.1200/JCO.2011.39.6820.
  23. Yuan ZG, Jin J, Huang XJ, et al. Different dose combinations of bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma: An open-label, observational, multi-center study in china. Chin Med J (Engl). 2011;124(19):2969-2974.
  24. Suvannasankha A, Smith GG, Juliar BE, Abonour R. Weekly bortezomib/methylprednisolone is effective and well tolerated in relapsed multiple myeloma. Clin Lymphoma Myeloma. 2006;7(2):131-134. doi: 10.3816/CLM.2006.n.050.

The hidden clinical sign on fundoscopy

Authors
M Suresh Babu and K.V.K.S.N.Murthy
Article Citation and PDF Link
BJMP 2013;6(3):a625

A 26 year old male was brought to Emergency department with history of altered sensorium of 1 day duration. He had a 2 week history of fever prior to admission. On examination, meningeal signs were present. Fundus examination showed evidence of papilloedema and a round pale yellow spot near the optic disc (Figure 1). CT scan of head did not reveal any abnormality.

Mantoux test and HIV ELISA were negative. CSF analysis showed:  

  • Glucose – 40mg/dl;  Protein: 2gm/l;   
  • Cell Count: 1200cells/µl;
  • Cell Type: 80% lymphocytes;
  • CSF VDRL- negative;
  • CSF Grams stain, India ink staining and Ziehl Neelsen staining were unremarkable.

What is the Fundus finding?

  1. Roth Spot
  2. Cotton Wool Spot
  3. Choroidal tubercle
  4. A-V malformation

Discussion:

Correct answer: 3) Choroidal Tubercle.

Intraocular tuberculosis is a rare event and occurs in 1% of all diagnosed cases of tuberculosis.1 It occurs by haematogenous spread of mycobacterial organism. Choroidal tuberculosis is the most common initial manifestation of intraocular tuberculosis. They may be seen in 1.4% to 60% of patients with different forms of tuberculosis and are highly specific for tuberculosis. 2, 3

Choroidal tubercles may be unilateral or bilateral and appear as polymorphic yellowish lesions with discrete borders. They are of 2 types, solitary tubercle or granuloma (seen in chronic tuberculosis) and choroidal miliary tubercles (seen in acute miliary tuberculosis). Their size varies from 0.4 to 5 mm and may be associated with retinal vasculitis, panuveitis, choroiditis and neuroretinitis.

When they involve macula they present with visual loss and any delay in appropriate treatment results in irreversible visual loss. Peripherally situated tubercles are asymptomatic.  Definitive diagnosis can be daunting due to difficulty in getting ocular samples for histological evaluation, however when available reveal features of granulomatous inflammation. Fundus angiography exhibits hypofluorescence in early stages and hyperfluorescence in later stages.

On treatment they heal by varying degrees of scar formation and marginal pigmentation.4 Untreated tubercles grow into large tumour like mass called tuberculoma.

Roth spots are retinal haemorrhages with a pale centre and are associated with bacterial endocarditis. Cotton wool spots appear as fluffy white patches on the retina and are associated with diabetes. A-V malformations are developmental vascular anomalies and appear as marked arterial and venous dilation associated with a tortuous pattern of vessels. They may have an associated bruit or chemosis of the eye.

The presence of ocular tuberculosis may be subtle. A high index of suspicion is required for its diagnosis. Delay in treatment or misdiagnosis may lead to irreversible visual loss. 

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors wish to thank Department of Ophthalmology, JSS Medical College, JSS University, Mysore for their contributions to the case.
Competing Interests: 
None declared
Details of Authors: 
M Suresh Babu, MBBS, MD, FCCP, FICP, Associate Professor of Internal Medicine, JSS Medical College, JSS University, Mysore, Karnataka, India. K.V.K.S.N.Murthy, MBBS, MD, JSS Medical College, JSS University, Mysore, Karnataka, India.
Corresponding Author Details: 
Dr. M SURESH BABU, Associate Professor of Internal Medicine, JSS Medical College, JSS University, Mysore, Karnataka, India.
Corresponding Author Email: 
drmsureshbabu@yahoo.co.in
References
References: 

  1. Ocular tuberculosis. A prospective study in a general hospital. Medicine (Baltimore) 1997, 76:53–61. Bouza E, Merino P, Munoz P, et al.
  2. Biswas J, Badrinath SS. Ocular morbidity in patients with active systemic tuberculosis. Int Ophthalmol 1995- 1996;19:293-8.
  3. Illingworth RS, Lorber J. Tubercles of the choroid. Arch Dis Child 1956;31:467-9.
  4. Mehta S. Healing patterns of choroidal tubercles after antitubercular therapy: a photographic and OCT study. J.Ophthalmic Inflamm. Infect. 2(2), 95–97(2012).

An atypical presentation of Neuroleptic Malignant Syndrome coexisting with Staphylococcus Pneumonia: a diagnostic challenge

Authors
Preaw Hanseree, Joanna M Tulczynska
Article Citation and PDF Link
BJMP 2013;6(3):a620
Abstract / Summary
Abstract: 

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic disorder associated with the use of neuroleptic agents. NMS typically characterized by a distinctive clinical syndrome of mental status change, muscle rigidity, fever, and autonomic instability. Atypical cases may present without muscle rigidity and/or hyperthermia. Association of infection in atypical case can make the diagnosis challenging. We describe a case of NMS in a patient who presented with acute onset of altered mental status complicated with aspiration pneumonia.

Keywords: 
neuroleptic malignant syndrome, atypical presentation, complication, pneumonia, infection

Introduction

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic disorder associated with the use of neuroleptic agents. NMS is typically characterized by a distinctive clinical syndrome of mental status change, muscle rigidity, fever, and autonomic instability. Atypical cases may present without muscle rigidity and/or hyperthermia. Association of infection in an atypical case can make the diagnosis challenging. We describe a case of NMS in a patient who presented with acute onset of altered mental status complicated with aspiration pneumonia.

Case Report

A 22-year-old female with a history of schizophrenia and seizure disorder presented with acute onset of altered mental status. Her home medications included haloperidol, clonazepam, olanzapine, trazodone, topiramate, benztropine, and trihexyphenadyl. The patient was found unarousable by her mother. She had multiple suicidal attempts in the past (overdosed on acetaminophen, drank cleaning detergent, and cut her wrist). She usually medicated herself without supervision. On examination, the patient was drowsy, afebrile (Temp 36.8oC/98.3oF), hypotensive (BP 85/64 mmHg), tachycardic (HR 105 bpm), and tachypnic (24/min). She was noted to be grunting with both inspiratory and expiratory stridor; therefore she was intubated for airway protection. Initial drug screen was negative for all substances of abuse. Acetaminophen and salicylate levels were undetectable. Head CT was unremarkable. Supportive care was provided as the patient was suspected to be overdosed with multiple medications. On the second day of admission the patient developed fever of 38.9oC/102oF. Chest xray and chest CT showed bilateral infiltrations (Fig.1), so empirical piperacillin/tazobactam and vancomycin were started for aspiration pneumonia. Sputum culture came back positive for Methicillin-resistant Staphylococcus aureus. However, the patient remained febrile with a temperature of 39.6 oC /103.2oF, despite appropriate antibiotic treatment. We suspected that there might be some other coexisting condition causing high fever. Serum creatine kinase (CK) was checked and found to be 8,105 U/L, up from 106 U/L on admission. We considered the diagnosis of NMS based on alteration of mental status, hyperthermia, autonomic instability, and elevated CK level, with the use of neuroleptic agents, although the patient did not have any muscle rigidity. The patient was started on dantrolene in addition to intravenous fluid and antibiotics. Shortly afterwards temperature and CK level started to trend down (Fig.2,3). Dantrolene was subsequently increased to maximum weight-based dose. Her mental status was gradually improved and returned to baseline. She became afebrile on day 10 of dantrolene treatment and serum CK went back to normal level after 2 weeks. Then bromocriptine was started orally and continued for 2 weeks.

Figure 1A: chest xray  on admission

Figure 1B: chest xray on second day of admission

Figure 1C: chest CT on second day of admission

Figure 2. Temperature trend after starting treatment for NMS

Figure 3. CK trend after starting treatment for NMS

Atypical presentations of NMS can sometimes be difficult to diagnose, as in our patient who presented with altered mental status, fever, and coexisting infection, in the absence of muscle rigidity. We emphasize the importance of a high index of suspicion of NMS in patients using neuroleptic agents.

Discussion

NMS is an idiosyncratic drug reaction to antipsychotic medications and a potentially life threatening condition that occurs in an estimated 0.07% to 2.2% of patients treated with antipsychotics.1 Patients typically present with fever, rigidity, changes in mental status, and autonomic instability, often attributed to first generation antipsychotics, in particular after the start of medication or an increase in dosage.2 Atypical cases of NMS without muscle rigidity and/or hyperthermia have been reported, usually associated with atypical antipsychotic treatment. It has been hypothesized that atypical cases represent early or impending NMS; however pathogenesis remains unclear.3 Risk factors that have been established in case series and case-control studies include agitation, dehydration, acute medical illness, concomitant use of other psychotropic drugs, intramuscular injections and high doses of antipsychotic medications.4-6

Complications of NMS are often consequences of its symptoms. Pneumonia is the most common complication found in 13% of patient with NMS, likely due to altered mental status combined with difficulty swallowing that lead to aspiration.7 Renal failure is the second most common complication (8%), as a result of rhabdomyolysis and myoglobinuria. Other complications have been reported including myocardial infarction, disseminated intravascular coagulation, deep venous thrombosis, pulmonary embolism, hepatic failure, sepsis, and seizure.8 Mortality rate of NMS was around 20-30%.9-10 With early identification and treatment, mortality has significantly reduced to averages 10%.6

Withdrawal of the causative agent is the first step in the management of NMS. Supportive therapy, in particular, hydration, fever reduction, and careful monitoring, is the mainstay of management of NMS. In mild cases, supportive treatment alone may be sufficient.4 Adding specific therapies, such as dantrolene, bromocriptine, and benzodiazepine to supportive measures has been shown to reduce time to complete recovery, from a mean of 15 days with supportive care alone, to 9 days with dantrolene, and 10 days with bromocriptine.1 In severe cases, empirical trial of specific pharmacological agents should be started promptly. Electroconvulsive therapy is found to be effective when pharmacotherapy has failed.11

Sometimes NMS is difficult to identify in the presence of critical illnesses which can obscure the manifestation of NMS. As in our case, the patient presented with altered mental status, fever, and autonomic instability which could be simply explained by the presence of pneumonia and sepsis. However, due to lack of clinical response after appropriate antibiotic treatment, other coexisting condition was suspected. It is important to have a high index of suspicion for NMS in the setting of antipsychotic therapy. An absence of muscle rigidity should not exclude a diagnosis of NMS when the rest of the clinical picture points to this diagnosis. Elevated CK level helps support the diagnosis of NMS in patients with atypical presentation. Discontinuation of offending agent and supportive care should initiate promptly, and specific pharmacotherapy should be considered in severe cases. An early diagnosis is the key to successful treatment and patient outcome.

Conclusion

NMS is a rare but potentially life-threatening condition. Atypical presentation makes it more difficult to identify in patients with critical illnesses. Aspirated pneumonia is one of the common complications of NMS and sometimes can obscure signs and symptoms of NMS and delay diagnosis. High index of suspicion for NMS in patients taking antipsychotics is crucial. If not recognized or left untreated, NMD may be fatal.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
PREAW HANSEREE, MD, Mount Sinai School of Medicine at Queens Hospital Center, New York, USA. JOANNA M TULCZYNSKA, MD, FCCP, Mount Sinai School of Medicine at Queens Hospital Center, New York, USA.
Corresponding Author Details: 
PREAW HANSEREE, Queens Hospital Center 82-68 164th Street, Jamaica, NY 11432, USA
Corresponding Author Email: 
phanseree@hotmail.com
References
References: 
  1. Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000;85(1):1290-1297
  2. Rosebush P, Stewart T. A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989;146:717-25.
  3. Picard LS, Lindsay S, Strawn JR, Kaneria RM, Patel NC, Keck PE,Jr. Atypical neuroleptic malignant syndrome: diagnosis controversies and considerations. Pharmacotherapy 2008;28(4):530-535.
  4. Strawn JR, Keck PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007;164:870-876
  5. Keck PE Jr, Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA: Risk factors for neuroleptic malignant syndrome. Arch Gen Psychiatry 1989;46:914-918
  6. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993;77:185-202
  7. Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: Review and analysis of 115 cases. Biol Psychiatry 1987;22:1004-1020
  8. Bilanakis N, Peritoqiannis V, Kalampokis G. Infections as complications of neuroleptic malignant syndrome. World J Biol Psychiatry 2009;10(4):973-976
  9. Robinson MB, Kennett RP, Harding AE, Legg NJ, Clarke B. Neuroleptic malignant syndrome associated with metoclopramide. J Neurol Neurosurg Psychiatry 1985;48:1304
  10. Saunders BP, Trewby PN. The neuroleptic malignant syndrome: a missed diagnosis? Br J Clin Pract 1993;47:170-171
  11. Trollor JN, Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases. Aust N Z J Psychiatry 1999;33(5):650-659

Risk factors for candida blood stream infection in medical ICU and role of colonization – A retrospective study.

Authors
Setu Patolia, Eneh Kennedy, Mehjabin Zahir, Swati Patolia, Neerja Gulati, Dharani Narendra, Rakesh Vadde, Saurav Pokharel, Frances M. Schmidt, Danilo Enriquez and Joseph Quist
Article Citation and PDF Link
BJMP 2013;6(2):a618
Abstract / Summary
Abstract: 

Candida blood stream infection (candidaemia) is one of the most serious hospital acquired infections with high morbidity and mortality rates in the Intensive Care Unit (ICU).  A number of risk factors have been identified in a variety of studies.  ICU patients are frequently colonised with Candida species. The role of Candida colonisation as a causal factor for candidaemia remains controversial. Our objective for the study was to evaluate the risk factors for candidaemia and to evaluate the role of colonisation to predict candidaemia. We evaluated a total of 1483 patients aged over 18 years who stayed in ICU for more than 7 days. We collected various data about risk factors for candidaemia. A total of 56 patients (3.77%) developed candidaemia. We collected demographic and risk factor data including Candida colonisation of the urinary and respiratory tract. Binary logistic regression with forward likelihood ratio method model was used to analyse these risk factors. In our study, total parenteral nutrition (odds ratio (OR)- 3.274, 95% confidence interval (CI) 1.263-8.486 ), presence of central venous line (OR- 1.895, CI 1.032-3.478), previous or current antibiotic use (OR 3.268, CI 1.532-6.972), respiratory tract colonisation (OR 2.150, CI 1.078-4.289) and urinary tract colonisation (OR 3.508, CI 1.926-6.388) were significant risk factors for Candida blood stream infection (BSI). Based on the model, we calculated the candidaemia risk score and based on the receiver operative curve analysis, a score more than 2 would be associated with a higher risk of candidaemia.  Candida species isolated in the respiratory tract or urine were similar to that found in Candida BSI (Kappa coefficient for agreement of 0.83 and 0.47 respectively). So, it can be concluded that Candida colonisation of the respiratory tract and/or urine is a significant risk factor for Candida BSI along with the other risk factors.

Abbreviations: 
ICU- intensive care unit,OR- odds ratio,CI- confidence interval,BSI- blood stream infection,HIV- Human immunodeficiency virus,IDSA- Infectious Disease Society of America,COPD- Chronic obstructive pulmonary disease,DM- Diabetes Mellitus,ESRD- End stage renal disease, TPN- Total parenteral nutrition.
Keywords: 
Candidemia, Risk factors, Central Venous line, Colonization.

Introduction:

Candida species is a leading cause of nosocomial infections and the most common fungal infection in intensive care units.  Candida infection ranges from invasive candidal disease to blood stream infections (candidaemia).  The incidence of Candida infection has been rising over the past two decades, particularly with the use of immunosuppressive drugs for cancer and HIV1,2,3 , and most of these infections occur in ICU settings.4  Candida infection is associated with high mortality and morbidity. Studies have shown that mortality attributable to candidaemia ranges from 5 to 71% depending on the study. 5.6.7Candidaemia is also associated with longer length of hospital stay and higher cost of care.

Early recognition of Candida BSI has been associated with improved outcome. Candida sepsis should be suspected in a patient who fails to improve and has multiple risk factors for invasive and bloodstream Candida infection. A variety of risk factors identified for candidaemia include previous use of antibiotics, sepsis, immunosupression, total parenteral nutrition, central venous line, surgery, malignancy and neutropaenia. Patients admitted to ICU are frequently colonised with Candida species. The role of colonisation in Candida blood stream infection and invasive candidal disease has always been debated. Few studies support the use of presumptive antifungal treatment in ICU based on colonisation and number of sites colonised by Candida. The NEMIS study has raised doubt about this approach of presumptive treatment.  The Infectious Disease Society of America (IDSA) 2009 guidelines identify Candida colonisation as one of the risk factors for invasive candidiasis, but warn about the low positive predictive value of the level of Candida colonisation. 8 We conducted a retrospective cohort study in our medical ICU to identify risk factors for Candida blood stream infections including the role of Candida colonisation.

Hospital and Definitions:

This study was conducted at Interfaith Medical Center, Brooklyn, New York.  It is a 280 bed community hospital with 13 medical ICU beds. A case of nosocomial Candida blood stream infection was defined as a growth of Candida Species in a blood culture drawn after 48 hours of admission. Cultures in our hospital are routinely done by the Bactec Method – aerobic and anaerobic cultures. Cultures are usually kept for 5 days at our facility and if yeast growth is identified, then species identification is done. In our ICU it is routine practice to do endotracheal culture and urine culture for all patients who are on mechanical ventilator supports and failing to improve. In patients who are not mechanically ventilated, it is routine practice to send sputum culture and nasal swabs to identify MRSA colonisation.

Study Design:

This study was a retrospective cohort study. We retrospectively reviewed all patients’ charts admitted to our medical ICU from 2000 to 2010 which stayed in the ICU for more than 7 days, irrespective of their diagnosis. Data were collected for demographics – age and sex. Data were also collected for risk factors for candidaemia – co-morbidities (HIV, cancer, COPD, diabetes mellitus, end-stage renal failure (ESRF)), presence or absence of sepsis, current or previous use of antibiotics, presence of central venous lines, steroid use during ICU stay, requirement of vasopressor support and use of total parenteral nutrition (TPN). Culture results for Candida including species identification were obtained for blood, urine and endotracheal aspirates.

Statistical Methods:

Patients were divided in two groups based on presence or absence of Candida BSI. Demographic data and risk factors were analysed using the chi square test to look at the difference between the two groups. Endotracheal aspirates and sputum cultures were combined to create a group with Candida respiratory tract colonisation. Binary logistic regression with forward likelihood ratio method was used to create models. Different models were generated for risk factors. Interactions between antibiotic use, steroid use, vasopressor support and sepsis were analysed in different models. Interactions between urine cultures and endotracheal aspirates/sputum cultures were also analysed by a different model. The model with the lowest Akaike information criterion (AIC) was chosen as the final model. The candidaemia risk score was calculated based on this final model to predict the risk of Candida BSI. Receiver operating curve (ROC) analysis was used to select the best cut-off value for the candidaemia risk score. Candida species in urine and endotracheal aspirates were compared with Candida species in blood culture using the kappa test. Data were analysed using SPSS statistical analysis software version 18.

Study Results:

A total of 1483 patients were included in the study.  56 patients (3.77%) had a blood culture positive for Candida species. Table 1 demonstrates demographic characteristics of the study population.  There were no significant differences in the both groups for age, sex, diabetes mellitus, COPD, HIV, cancer and ESRF. As demonstrated in the table, 82.1% of patients in candidaemia groups recently used or were taking antibiotics as compared to 39.6% of patients in groups with no candidaemia. The P value was significant for this difference.  Similarly, 71.4% of patients in the group with candidaemia had sepsis as compared to 30.6% in the other group with a P value of 0.000. Use of vasopressor (severe septic shock) was different between two groups – 23.2%  and 10.1%, P value of 0.004. Steroid use, central lines and total parenteral nutrition use was higher in the candidaemia group as compared to the group without candidaemia. Similarly the rate of positive Candida cultures in urine and endotracheal aspirates was higher in the candidaemia group as compared to the group without.

Table 2 shows that 57.1% of Candida BSI were caused by C. Albicans, 30.4% by C. Glabrata and 12.5% by C. Parapsilosis. This incidence rate of species is similar to that found in other studies. Table 3 shows the two models with the lowest AIC value. The only difference between these two models was antibiotic use- previous or current use of antibiotics compared to current use of antibiotic in sepsis. Table 4 shows that when multifocal site positivity (urine and endotracheal culture) were used in the model, the AIC value increased significantly. This means that when multifocal sites were used in place of individual sites for the model, good amounts of information were lost and this model did not have good predictive value as compared to the model where individual sites are used for prediction of candidaemia. The model with lowest AIC was chosen as the final model. Binary logistic regression analysis with forward conditional analysis showed that only TPN, central venous line, previous or current antibiotic use, endotracheal aspirate culture positivity for Candida species and urine culture positive for Candida species were included in a statistical significant model. The final model had a P value of 0.000.  Odds ratio with 95% confidence intervals and respective P values for all these risk factors are shown in Table 5.  Age greater than 65 years, sex, sepsis or septic shock, co-morbidities and steroid use were not significant risk factors for candidaemia.

From this model, the candidaemia risk score calculated would be: Candidaemia risk score = 1.184 for previous or current antibiotic use + 0.639 for presence of central venous line + 1.186 for total parenteral nutrition + 0.760 for positive endotracheal culture for Candida + 1.255 for positive urine  culture for Candida.

Table 6 shows the relationship between the Candida strain identified in endotracheal/sputum culture to that in blood culture. Similarly, Table 7 shows the relationship between the Candida strain identified in urine culture and that in blood culture. Strains identified in endotracheal aspirate culture had a very high value for the Kappa test and urine culture had a moderate value for agreement by the Kappa test. Thus, it can be inferred that Candida strain identified in blood culture was very similar to that identified in urine or endotracheal culture.

Table 1: Demographic characteristic of study population

Characteristic Candidaemia (total 56)
N (% of candidaemia)
No candidaemia (total 1427)
N (% of no candidaemia)
Chi Square
Age >65 years 34 (60.7%) 676(47.40%) 0.06
Male sex 27 (48.2%) 694(48.6%) 0.530
Diabetes mellitus 22 (39.3%) 506(35.5%) 0.325
COPD 1(1.8%) 75(5.3%) 0.206
HIV 9 (16.1%) 253(17.7%) 0.458
Cancer 4(7.1%) 99(6.9%)  
ESRF 11(19.6%) 251(17.6%) 0.401
Previous or current antibiotic use 46 (82.1%) 565(39.6%) 0.00
Sepsis 40(71.4%) 436(30.6%) 0.000
Vasopressor support (Septic shock) 13(23.2%) 144(10.1%) 0.004
Steroid use 27(48.2%) 431(30.2%) 0.004
Central line 30(53.6%) 267(18.7%) 0.000
Total parenteral nutrition 7(12.5%) 29(2.0%) 0.000
Candida in endotracheal aspirate/sputum culture 13(23.2%) 112(7.8%) 0.000
Candida in urine culture 34(60.7%) 262(18.4%) 0.000


Table 2: Candida strains responsible for Candida blood stream infection

Species in the blood culture Number (%)
Candida Albicans 32(57.1%)
Candida Glabrata 17 (30.4%)
Candida Parapsilosis 7 (12.5%)


Table 3: Models with lowest two AIC

Variables -2 log likelihood AIC
Previous or current antibiotic use CVP line Total parenteral nutrition Endotracheal culture Urine culture 394.822 406.822
CVP line Total parenteral nutrition Endotracheal culture Urine culture Current antibiotic use in sepsis 395.730 407.73


Table 4: Model with 2 sites positive for Candida

Variables -2 log likelihood AIC
Sepsis CVP line Total parenteral nutrition Endotracheal and urine culture 407.920 417.92


Table 5: Odds ratio with 95% confidence interval for risk factors for candidaemia

Effect Co efficient (β) Odds ratio 95 % Confidence limit P value
Lower Upper
TPN 1.186 3.274 1.263 8.486 0.015
CVP line 0.639 1.895 1.032 3.478 0.039
Antibiotic Use 1.184 3.268 1.532 6.972 0.002
Endotracheal/ sputum culture 0.760 2.150 1.078 4.289 0.030
Urine 1.255 3.508 1.926 6.388 0.000


Table 6: Endotracheal aspirate culture in candidaemic patients

Endotracheal/Sputum Culture Blood Culture Kappa Test For Agreement
C. Albicans C. Glabrata
C. Albicans 9 0 0.83
C.Glabrata 0 3
C. Tropicalis 0 1


Table 7: Urine cultures in candidaemic patients

Urine culture Blood culture Kappa Test for the agreement
C. Albicans C. Glabrata C. Tropicalis
C. Albicans 15 5 1 0.47
C. Glabrata 1 10 0
C. Krusei 1 1 0

Discussion

Candida is the most common nosocomial fungal infection in the ICU. Candidaemia accounts for approximately 5-8% of nosocomial BSI in the hospitals in the US.9,10,11 It accounts for approximately 50-75% of the cases of invasive fungal infection in the ICU12,13 and its rate varies from 0.2-1.73 per 1000 patient days.9,14,15 In a study done by Theoklis et al., candidaemia was associated with a mean 10.1 day increase in length of stay and a mean $39,331 increase in hospital charges.16 A study of 1,765 patients in Europe found that Candida colonisation was associated with increased hospital length of stay and increase in cost of care by 8000 EUR.17 ICU patients are at increased risk of infection because of their underlying illness requiring ICU care, immunosuppressant use, invasive or surgical procedures and nosocomial transfer of infections. A number of risk factors have been identified in different studies. In a matched case-control trial, previous use of antibiotic therapy, Candida isolated at other sites, haemodialysis and presence of a Hickman catheter were associated with increased risk of candidaemia.13 Similarly age of more than 65 years, steroid use, leucocytosis and prolonged ICU stays were risk factors for Candida BSI in 130 cases.18 Surgery, steroids, chemotherapy and neutropaenia with malignancy are the other identified risk factors.19

Candida BSI has a very high mortality rate. The attributable mortality varies from 5-71% in different studies.5,12,16,20 Even with treatment, there is high mortality as demonstrated in a study by Oude Lashof et al where out of 180 patients treated for candidaemia, 33% died during treatment and 55% completed treatment without complications.21 Risk factors for increased mortality in patients receiving antifungal treatment are delayed Candida antifungal treatment or inadequate dosing.22 Multivariate analysis of 157 patients with Candida BSI, APACHE II score, prior antibiotic treatment and delay in antifungal treatment were independent risk factors for mortality with odds ratio of 1.24, 4.05 and 2.09, respectively.23 Delayed treatment is also associated with increased fluconazole resistance as compared to early treatment and preventive treatment.24 Inadequate antifungal medication dose and retention of central venous catheters were also associated with increased mortality in a study of 245 Candida BSI, with adjusted odds ratios of 9.22 and 6.21, respectively.25,26

Candida albicans accounts for 38.8-79.4 % of the cases of Candida BSI. C. Glabrata is responsible for 20-25% of cases of candidaemia and C. tropicalis is responsible for less than 10% of cases of candidaemia in the US.9,20  ICU patients are frequently colonised with different Candida species. Candida colonisation can be from either endogenous or exogenous sources. Candida colonisation rates vary with the site- tracheal secretion (36%), throat swabs (27%), urine (25%) and stool (11%).27 Candida colonisation increases with the duration of the stay, use of urinary catheters and use of antibiotics. 28,29,30

The role of Candida colonisation in Candida BSI is frequently debated.  Some studies have suggested that Candida colonisation of one or more anatomical sites are associated with increased risk of candidaemia.31,32,33,34 Typically, 84-94% of the patients developed candidaemia within a mean time of 5- 8 days after colonisation according to two studies.35,36  In another study, only 25.5% of colonised patients developed candidaemia.37 Similarity between strain identified in blood culture and that identified at various colonising sites was observed in one study.38  Candida colonisation by exogenously acquired species has also been implicated as a cause of candidaemia.39 In one study, 18-40% of cases of candidaemia were associated with clustering defined as “isolation of 2 or more strain with genotype that had more than 90% genetic relatedness in the same hospital within 90 days.” 40 Similar correlations for clusters are also noted for C. tropicalis candiduria41 and for C. Parapsilopsis.42 In a prospective study of 29 surgical ICU patients colonised with Candida, the APACHE II score, length of previous antibiotic therapy and intensity of Candida colonisation was associated with a significant risk of candidaemia.  The Candida colonisation index calculated by non-blood body sites colonised by Candida over the total number of distinct sites tested for patients, was associated with a 100% positive and negative predictive value of candidaemia.29 Other studies do not support Candida colonisation as a risk factor for candidaemia. In a case-control study of trauma patients, only total parenteral nutrition was associated with an increased risk of candidaemia. Candida colonisation, steroid use, use of central venous catheters, APACHE II score, mechanical ventilation for more than 3 days, number and duration of antibiotics, haemodialysis, gastrointestinal perforation and number of units of blood transfused in first 24 hours of surgery. were not significant risk factors for candidaemia.43 NEMIS study found that in a surgical ICU, prior surgery, acute renal failure, total parenteral nutrition and triple lumen catheters were associated with increased risk of candidaemia; the relative risk for each risk factor being 7.3, 4.2, 3.6 and 5.4, respectively. Candida colonisation in urine, stool or both were not associated with increased risk of candidaemia.15

The effect of Candida colonisation of the respiratory tract on candidaemia and on mortality and morbidity is unclear. In a retrospective study of 639 patients, Candida respiratory tract colonisation was associated with increased hospital mortality (relative risk of 1.63) and increased length of stay (median increase of 21 days).30 In a study of 803 patients by Azoulay et al., respiratory tract colonisation was associated with prolonged ICU and hospital stays. These colonised patients were at increased risk of ventilator-associated Pseudomonas pneumonia, with an odds ratio of 2.22.44 However, in a postmortem study of 25 non-neutropaenic mechanically ventilated patients, 40% of the patients were colonised with Candida, but only 8% had Candida pneumonia.45,46  Jordi et al. found that out of 37 patients, definite or possible colonisation was found in 89% of patients and only 5% of cases were defined as Candida BSI.47.The effect of candiduria is also ill defined. Candida colonisation in urine has been implicated as a risk factor in certain studies. In a study done by Bross J et al., central lines, bladder catheters, 2 or more antibiotics, azotaemia, transfer from another hospital, diarrhoea and candiduria were significant risk factors for candidaemia. Candiduria had an odds ratio of 27 for development of candidaemia.48 Similar findings about candiduria were noted by Alvarez-Lerma et al.49

IDSA recommends starting empirical antifungal treatment for high risk neutropaenic patients who fail to improve on antibiotics after 4 days. Recommendation to start empirical antifungal therapy in low-risk neutropaenic patients and non-neutropaenic patients are not made by IDSA because of low risk of candidaemia.8 However, early detection of Candida BSI is vital because of increased mortality associated with delayed antifungal treatment and failure to remove central venous lines. Early detection of Candida BSI in a colonised patient can be facilitated by using a score based on the risk factors.50,51Similarly, b-D glucan assays can be used in patient colonised with Candida, to determine Candida BSI and need for antifungal treatment.52 Combined used of such risk factor identification systems and b-D glucan assays will help to detect candidaemia in earlier stages and will decrease mortality. Our study suggests that total parenteral nutrition, previous or current antibiotic use, central lines, candiduria and respiratory tract colonisation are risk factors for Candida BSI. With the help of our candidaemia risk score system, a score of more than 2 is associated with a higher risk of Candida BSI. This risk factor scoring system along with b-D glucan assays can be used to detect Candida BSI in earlier stages.

Conclusion:

Our study suggests that urine or respiratory tract colonisation is associated with an increased risk of Candida BSI, along with total parenteral nutrition, central venous lines and previous or current antibiotic use. We identified a scoring system which can be used along with a b-D glucan assay to detect candidaemia earlier.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None
Details of Authors: 
SETU K PATOLIA, MD, Interfaith Medical Center, Brooklyn, NY, USA. ENEH KENNEDY, MD, Interfaith Medical Center, Brooklyn, NY, USA. MEHJABIN ZAHIR, MD, Interfaith Medical Center, Brooklyn, NY, USA. SWATI S. PATOLIA, MD, Interfaith Medical Center, Brooklyn, NY, USA. NEERJA GULATI, MD, Interfaith Medical Center, Brooklyn, NY, USA. DHARANI K. NARENDRA, MD, Interfaith Medical Center, Brooklyn, NY, USA. RAKESH VADDE, MD, Interfaith Medical Center, Brooklyn, NY, USA. SAURAV POKHAREL, MD, Interfaith Medical Center, Brooklyn, NY, USA. FRANCES M. SCHMIDT, MD, FACP, Interfaith Medical Center, Brooklyn, NY, USA. DANILO ENRIQUEZ, MD, Interfaith Medical Center, Brooklyn, NY, USA. JOSEPH B QUIST, MD, Interfaith Medical Center, Brooklyn, NY, USA.
Corresponding Author Details: 
SETU K PATOLIA, MD, Interfaith Medical Center, Brooklyn, NY, USA.
Corresponding Author Email: 
patoliasetu@gmail.com
References
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HBsAg carriers with normal ALT levels: Healthy carriers or true patients?

Authors
Claudio Puoti
Article Citation and PDF Link
BJMP 2013;6(1):a609

It is well documented that many HBsAg-positive / HBeAg-negative patients show normal alanine aminotransferase (ALT) levels. However, two different scenarios have been proven to exist: inactive Hepatitis B Virus (HBV) carriers (previously defined as “healthy” HBV carriers) and patients with chronic hepatitis B (CHB) with transient virological and biochemical remission. These subsets of patients share HBsAg positivity and normal ALT levels; however, progression of disease, outcome, HBV DNA levels, severity of liver damage, requirement for liver biopsy and antiviral treatment significantly differ between the two patient populations.

Thus, among HBsAg-positive / HBeAg-negative subjects with normal liver biochemistry, it is important and sometimes difficult to distinguish the ‘true inactive HBV carriers’ from patients with ‘active CHB’ in whom phases of spontaneous remission have occurred. The former have a good prognosis with a low risk of complications, while the latter patient population have active liver disease with a high risk of progression to liver cirrhosis and/or hepatocellular carcinoma (HCC). Therefore, prolonged biochemical and virological follow-up are mandatory for diagnosis and decision to treat.

The term ‘chronic hepatitis B’ refers to a chronic necroinflammatory disease of the liver caused by persistent HBV infection 1. The term ‘necroinflammatory’ describes the presence of death of periportal hepatocytes (periportal necrosis) with or without disruption of the limiting plate by inflammatory cells, intralobular necrosis, portal or intralobular inflammation, and formation of bridges between vascular structures (the so-called bridging necrosis). Chronic hepatitis B can be subdivided into HbeAg positive and HBeAg-negative chronic hepatitis B 1,2. These two forms may have different natural histories and different response rates to antiviral treatment, although both may progress to more severe liver damage 3, such as, liver cirrhosis 4 or HCC 5.

The second subset is called the ‘inactive HBsAg carrier state’. It means a persistent HBV infection of the liver but without continual significant necroinflammatory disease. It is characterized by very low or undetectable serum HBV DNA levels and normal serum aminotransferases 1. It has been shown that histologically significant liver damage is rare in these patients, particularly when HBV DNA is lower than 2000 IU/ml, and thus a liver biopsy is not indicated in these subjects 4. Even among HBeAg-negative carriers with serum HBV DNA between 2000 and 20,000 IU/ml, histologically significant liver disease is also rare 6. Thus, these subjects should be followed up closely, but biopsy and treatment are not currently indicated.

As mentioned above, it is sometimes difficult to distinguish true inactive HBV carriers from patients with active HBeAg-negative CHB in whom phases of spontaneous remission may have occurred 1. The former patients have a good prognosis with a very low risk of complications, while the latter have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and subsequent complications such as decompensated cirrhosis and HCC 3-6. Thus, a minimum follow-up of 1 year with ALT levels every 3–4 months and periodical measurements of serum HBV DNA levels are required before classifying a patient as an inactive HBV carrier 1. ALT levels should remain consistently within the normal range, and HBV DNA should be below 2000 IU/ml 7. Thereafter, the inactive HBV carrier with undetectable or very low HBV DNA levels should be followed up with ALT determinations every 6 months after the first year and periodical measurement of HBV DNA levels 6 for the rest of their lifetime. This follow-up policy usually allows detection of fluctuations of activity in patients with true HBeAg-negative CHB 8.

It is important to underline that some inactive carriers may have HBV DNA levels greater than 2000 IU/ml (usually below 20,000 IU/ml), despite their persistently normal ALT levels 1,6,9. In these carriers the follow-up should be much more condensed, with ALT determinations every 3 months and HBV DNA measurements every 6–12 months for at least 3 years 1. After these 3 years, these patients should be followed up for life like all inactive chronic HBV carriers 6. After all, the inactive HBV carrier state confers a favourable long-term outcome with a very low risk of cirrhosis or HCC in the majority of patients 1,10,11. Patients with high baseline viremia levels have higher risk of subsequent reactivation. A liver biopsy should be recommended if ALT levels become abnormal and HBV DNA increases above 20,000 IU/ml. Non-invasive evaluation of liver fibrosis 12 may be useful, although these non-invasive tools, such as transient elastography, need further evaluation 6.

HBsAg clearance and seroconversion to anti-HBs antibody may occur spontaneously only in 1–3% of cases per year, usually after several years with persistently undetectable HBV DNA 7. On the other hand, progression to HBeAg-negative CHB may also occur 10.

Although the optimal definition of persistently normal ALT (PNALT) levels has not been established, the fluctuating nature of chronic HBV infection reasonably justifies serial ALT determinations. These should be done with a minimum of four to five tests 3–4 months apart within the first year of presentation, before determining whether an HBeAg-negative patient truly has PNALT. An initial follow-up of at least 1 year is supported by the finding of mild histological lesions in HBeAg-negative patients with true PNALT during the first year 6. The risk of developing abnormal ALT levels in HBeAg-negative patients with a normal baseline ALT have been reported to be higher during the first year (15–20%) and decline after 3 years of follow-up, therefore frequent monitoring during the first 1–3 years is critical 6,10.

Antiviral treatment of inactive HBsAg subjects is not indicated 1. Patients should be considered for treatment only when they have HBV DNA levels above 2000 IU/ml, serum ALT levels above the upper limit of normal and severity of liver damage assessed by liver biopsy showing moderate to severe active necroinflammation and/or at least moderate fibrosis 1,2.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
CLAUDIO PUOTI, MD, Chief, Dept. of Internal Medicine and Liver Unit, Marino General Hospital, Marino, Rome, Italy
Corresponding Author Details: 
CLAUDIO PUOTI, Chief, Dept. of Internal Medicine and Liver Unit, Marino General Hospital, Viale XXIV Maggio, 00047, Marino, Rome, Italy.
Corresponding Author Email: 
puoti@epatologia.org
References
References: 
  1. EASL Clinical Practice Guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.
  2. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50: 661-2.
  3. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47-58.
  4. McMahon BJ. The natural history of chronic hepatitis B virus infection. Semin Liver Dis 2004;24:17-21.
  5. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50.
  6. Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012;57:196-202.
  7. Martinot-Peignoux M, Boyer N, Colombat M, Akremi R, Pham B-N, Ollivier S, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol 2002;36:543-8.
  8. Feld JJ, Ayers M, El-Ashry D, Mazzulli T, Tellier RD, Heathcote EJ. Hepatitis B virus DNA prediction rules for hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2007;46:1057-70.
  9. Chen YC, Huang SF, Chu CM, Liang YF. Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion. J Viral Hepat 2012;19:138-46.
  10.  Papatheodoridis GV, Chrysanthos N, Hadziyannis E, Cholongitas E, Manesis EK. Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection. J Viral Hepat 2008;15:434-41.
  11.  Ikeda K, Arase Y, Saitoh S, Kobayashi M, Someya T, Hosaka T, et al. Long-term outcome of HBV carriers with negative HBe antigen and normal aminotransferase. Am J Med 2006;119:977-85.
  12.  Castera L, Bernard PH, Le BB, Foucher J, Trimoulet P, Merrouche W, et al. Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers. Aliment Pharmacol Ther 2011;33:455-65.

Management of Painful Peripheral Diabetic Neuropathy

Authors
Namita Arora and G Niraj
Article Citation and PDF Link
BJMP 2013;6(1):a606
Abstract / Summary
Abstract: 
Diabetes Mellitus is an endocrine disorder which causes metabolic disturbance producing a state of hyperglycaemia. Hyperglycaemia adversely affects cardiovascular, renal, nervous and visual systems. The importance of good glycaemic control in these patients has been emphasised in literature to reduce the end organ damage. Diabetes can cause autonomic and peripheral neuropathy. The autonomic neuropathy can affect the cardiovascular, genitourinary and gastrointestinal systems. Peripheral neuropathy can cause acute and chronic sensorimotor neuropathy, which can cause significant morbidity in these patients affecting their daily activities and quality of life. It can be challenging to treat them because the pain can be resistant to the medication and the effective medication can be associated with adverse effects which the patients may find difficult to tolerate. It is very important to increase the dose of the drugs to their highest effective dose (within the therapeutic range of that drug) for each patient with a balance of the side effects caused by that drug in that patient. These patients often need more than one drug to provide adequate pain relief. There are guidelines and recommendations available to help the clinicians to use appropriate combination of available treatment options.

Epidemiology:

The WHO estimated that 171 million people had diabetes in the year 2000 and predicted this number to increase to 366 million in the year 2030. Given the increasing prevalence of obesity it is likely that these figures provide an underestimate of future diabetes prevalence1. Peripheral diabetic neuropathy (PDN) may be present in 60 to 65% diabetic patients, with 11% patients of diabetic neuropathy complaining of pain. The management of this condition can be particularly challenging as these patients may not get good response to the medications used for the treatment and the medications used are associated with side effects which the patients may find difficult to tolerate.

Pathophysiology:

Pathophysiology of PDN is complex and incompletely understood. Both peripheral and central processes contribute to the chronic neuropathic pain in diabetes.  Peripherally at the molecular level due to hyperglycaemia, glycosylated end products are generated, which deposit around the nerve fibres causing demyelination, axonal degeneration and reduction in nerve conduction velocity. Deposition of glycosylated end products around the capillary basement membrane causes basement membrane thickening and capillary endothelial damage, which in association with a hypercoaguable state causes peripheral arterial disease. The peripheral arterial disease leads to neuronal ischemia which worsens nerve damage. There also occurs depletion of NADPH by activation of NADPH oxidase causing increased oxidative stress and generation of oxidative free radicals which aggravate the nerve damage. Calcium and sodium channel dysfunction, changes in receptor expression are the other peripheral processes which cause further neuronal tissue injury. The nerve damage can cause neuronal hyperexcitability. Neurotropic factors are required for nerve regeneration. In diabetes there occurs a low level of both nerve growth factors and insulin-like growth factors resulting in impaired neuronal regeneration. This can lead to peripheral hyperexcitability. Central sensitization is cause by increased excitability at the synapse, which recruits several sub-threshold inputs and amplifies noxious and non-noxious stimuli. Loss of inhibitory interneurons, growth of non-damaged touch fibres into the territory of damaged pain pathways, increased concentration of neurotransmitters and wind up caused by NMDA receptors are responsible for central sensitization at the level of dorsal horn in the spinal cord2.

Clinical Presentation:

Chronic sensorimotor distal polyneuropathy is the most common type of diabetic neuropathy. Acute sensorimotor neuropathy is rare and is usually associated with diabetic ketoacidosis and acute neuritis caused by hyperglycaemia. Autonomic neuropathy is common and often under reported. It can affect cardiovascular, gastrointestinal and genitourinary system. The other presentations can be cranial neuropathies, thoraco-abdominal neuropathies or peripheral mononeuropathies involving median, ulnar, radial, femoral, lateral cutaneous nerve of the thigh or common peritoneal nerve.

The patients usually complain of one or more of the following symptoms. They can have a chronic continuous or intermittent pain described as burning, aching, crushing, cramping or gnawing pain. The pain can be associated with numbness. They can have brief abnormal stimulus evoked pain like allodynia or hyperalgesia. Some patients also complain of brief lancinating pains described as electrical or lightening pains which can be spontaneous or evoked. The symptoms typically start in the toes and feet and ascend in the lower limb over years and are worse at night. Diabetic distal polyneuropathy is typically described in glove and stocking distribution but the upper limb involvement is rare. On examination there can be paradoxically reduced sensation to light touch and pin prick in the area of pain. Examination can also show features of allodynia (pain caused by a stimulus that does not normally cause pain), hyperalgesia (pain of abnormal severity in response to a stimulus that normally produces pain), hyperpathia (painful reaction to a repetitive stimulus associated with increased threshold to pain), dysaesthesia (unpleasant abnormal sensation as numbness, pins and needles or burning), paraesthesia (abnormal sensation which is not unpleasant) or evoke electric shock like pains. There can be features of peripheral autonomic neuropathy including vasomotor changes like colour changes of feet which can be red, pale or cyanotic and temperature changes like warm or cold feet. With autonomic neuropathy there can also occur trophic changes which includes dry skin, callouses in pressure areas and abnormal hair and nail growth and sudomotor changes involving swollen feet with increased or decreased sweating. Mechanical allodynia is the most common type of allodynia, but there can be thermal allodynia described as cold or warmth allodynia. Patient often describes cold allodynia as the pain getting worse in cold weather and warmth allodynia can make the patient keep the effected limb cool by using fan or ice bags. There can be reduced joint position sense, reduced vibration sense, reduced temperature sensation and reduced ankle jerks.

Diagnosis:

The diagnosis of PDN can be made by clinical tests using pinprick, temperature and vibration perception (using a 128-Hz tuning fork). The feet should be examined for ulcers, calluses and deformities. Combinations of more than one test have >87% sensitivity in detecting PDN. Other forms of neuropathy, including chronic inflammatory demyelinating polyneuropathy, B12 deficiency, hypothyroidism and uraemia, occur more frequently in diabetes and should be ruled out. If required these patients should be referred to a neurologist for specialized examination and testing3.

Treatment Options:

US Food and Drug Administration has approved duloxetine in 2004 and pregabalin in 2005 for the treatment of painful DPN. Amitriptyline, nortriptyline and imipramine are not licenced for the treatment of neuropathic pain.

NICE clinical guidance on pharmacological management of neuropathic pain in adults in non-specialist settings as shown in Figure 1, recommends duloxetine as the first line treatment, which if contraindicated amitriptyline is suggested to be the first line. Second line treatment is amitriptyline or pregabalin. Pregabalin can be used alone or in combination with either amitriptyline or duloxetine, which if ineffective the patient should be referred to specialist pain services. While awaiting the referral tramadol can be started as the third line treatment. NICE also recommends that these patients should be reviewed to titrate the doses of the medication started, to assess the tolerability, adverse effects, pain reduction, improvement in daily activities, mood, quality of sleep and the overall improvement caused by the medication as reported by the patient4.

The Mayo clinic recommends5 the first tier of drugs for peripheral diabetic neuropathy are duloxetine, oxycodone CR, pregabalin and tricyclic antidepressants. The second tier of drugs iscarbamazepine, gabapentin, lamotrigine, tramadol and venlafaxine extended release. The topical agents suggested are capsaicin and lidocaine.

“Evidence Based guideline on treatment of Painful Diabetic Neuropathy”, was formulated by American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. A  systematic review of the literature between time period 1960 to 2008 was carried out. The review included the articles which looked at the efficacy of a given treatment either pharmacological or non-pharmacological to reduce pain and improve physical function and quality of life (QOL) in patients with PDN. They subsequently recommended that Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and quality of life6.

Non-pharmacological techniques:

Letícia et al. following their literature review on therapies used for PDN concluded that for non-pharmacological techniques like acupuncture, reiki, photic stimulation, electromagnetic stimulation of neural electrical stimulation, laser therapy, there is a lack of consensus about their effectiveness and there is scarce knowledge about them. They suggested new researches, including treatments for a longer period of time, with dosimetry control, and representative samples are necessary to discover the actual importance of these therapies for pain relief7.Spinal Cord Stimulators have however been shown to be effective and safe in severe resistant cases8,9.

Pharmacological Therapies:

Pregabalin: Pregabalin is a gamma aminobutyric acid analogue which binds to α2δ subunit of calcium channels and modulates them. Its starting dose is 150 mg/day with a maximum dose of 600 mg/day. As 98% of the drug is excreted unchanged in the urine, its dose is reduced in patients with renal impairment (creatinine clearance below 60 ml/min)10. A Cochrane Database Systematic Review in 2009 showed that Pregabalin was effective at daily doses of 300 mg, 450 mg and 600 mg, but a daily dose of 150 mg was generally ineffective. The NNT for at least 50% pain relief for 600 mg daily pregabalin dose compared with placebo was 5.0 (4.0 to 6.6) for PDN11.

Duloxetine: Duloxetine reduces the reuptake of serotonin and noradrenaline at the level of spinal cord, thereby potentiating the descending inhibitory pain pathways to reduce pain. It is started at a dose of 30 mg/day and its dose can be increased to 120mg/day10. Sultan et al. in their systematic review found that pain relief achieved with daily dose of 60 mg Duloxetine was comparable with daily dose of 120 mg of Duloxetine. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo was 5.8 as compared to NNT of 5.7 for daily dose of 120 mg of duloxetine. The side effects reported with Duloxetine were reduction in appetite, nausea, constipation and somnolence12. Systematic Reviews and cohort studies have shown that duloxetine provides overall savings in terms of better health outcomes and reduction in opioid use, in comparison to gabapentin and pregabalin, tricyclic antidepressants and venlafaxine, in pain caused by PDN13, 14.

Gabapetin: Gabapentin is structurally related to gamma-aminobutyric acid (GABA) but acts by binding to the alpha2-delta subunit of voltage-gated calcium channels and thereby reducing the transmission of neuronal signals. Gabapentin bioavailability is non-linear and it tends to decrease with increasing dose. Gabapentin is not bound to plasma proteins and has a high volume of distribution. It is eliminated unchanged by the kidneys so in elderly patients and in patients with impaired renal function, its dose must be reduced. Gabapentin can be started froma daily dose of 300 to 900 mg and the dose can be increased to a maximum daily dose of 3600 mg over 3 weeks period10.  Gabapentin provides good pain relief in about one third of patients when taken for neuropathic pain. Adverse events are frequent, but most of them are tolerable15.

Tricyclic Antidepressants (TCA): Amitriptyline and nortriptyline are the commonly used TCA for PDN. They may be used if there is no benefit from pregabalin or gabapentin and duloxetine. They may be used alone or in combination with pregabalin or gabapentin. In small RCTs, amitriptyline has been found to relieve pain better than placebo in patients with diabetic neuropathy10. Amitriptyline is a tricyclic antidepressant with marked anticholinergic and sedative properties. It increases the synaptic concentration of noradrenaline and serotonin in the CNS by inhibiting their re-uptake by the pre-synaptic neuronal membrane. For neuropathic pain it is started at 10-25 mg orally once daily at bed time initially and increased according to response to a maximum of 150 mg/day.

 TCA should be used with caution in patients with a history of epilepsy, cardiovascular disorders, deranged liver function, prostatic hypertrophy, history of urinary retention, blood dyscrasias, narrow-angle glaucoma or increased intra-ocular pressure. It’s other side-effects are agitation, confusion and postural hypotension in elderly patients10. Amitriptyline is the most studied TCA for DPN and has been compared with placebo, imipramine, and desipramine. Amitriptyline, when compared with placebo, reduced pain to a significant degree. Pain relief was evident as early as the second week of therapy, with greater pain relief noted at higher doses (at a mean dose of 90 mg). A decrease in pain was not associated with improvement in mood. A systematic review of the TCAs, including fewer than 200 patients, found no difference in efficacy between the agents16. Nortriptyline is associated with fewer adverse events than amitriptyline and therefore it should be preferred in elderly patients.

Opioids: The use of opioids in chronic neuropathic pain has been a topic of debate because of uncertainty about their effectiveness, the concerns about addiction problems, the loss of efficacy with their long term use due to development of tolerance with their long term use and the development of hyperalgesia associated with their use. Cochrane review of twenty-three trials of opiates was carried out. The short-term studies showed equivocal evidence, while the intermediate-term studies showed significant efficacy of opioids over placebo, in reducing the intensity of neuropathic pain. Adverse events of opioids were reported to be common but were not life threatening. The authors recommended the need for further randomized controlled trials to establish long-term efficacy, safety (including addiction potential) and effects on quality of life17.  In RCT Tramadol/Acetaminophen combination was shown to be associated with significantly greater improvement than placebo (p < or = 0.05) in reducing pain intensity, sleep interference and several measures of quality of life and mood18.  In another RCT, controlled release (CR) oxycodone was compared with placebo, CR oxycodone resulted in significantly lower mean daily pain, steady pain, brief pain, skin pain, total pain and disability. In this study the number needed to treat to obtain one patient with at least 50% pain relief is 2.619. Gabapentin and morphine combination in randomised controlled trial showed that the combination of the two drugs provided better analgesia at lower doses of each drug than either of the drugs used as a single agent20.

Capsaicin: Capsaicin is the active component of chilli peppers. Capsaicin works by releasing the pro-inflammatory mediators like substance P from the peripheral sensory nerve endings and thereby causes its depletion from the peripheral nerve. Pharmacological preparations of Capsaicin are available as 0.025% cream, 0.075% cream and 8% capsaicin patches10.  Repeated application of a low dose (0.075%) cream, or a single application of a high dose (8%) patch has been shown to provide a degree of pain relief in some patients with painful neuropathy. Common side effect includes local skin irritation which causes burning and stinging. It is often mild and transient but sometimes severe and not tolerated by the patients leading to withdrawal from treatment. Capsaicin rarely causes systemic adverse effects. Capsaicin can be used either alone or in combination with other treatment to provide useful pain relief in individuals with neuropathic pain21.

5% Lidocaine medicated plasters: A recent systematic review showed that 5% Lidocaine medicated plaster causes pain relief comparable to pain relief caused by amitriptyline, capsaicin, gabapentin and pregabalin in treatment of painful diabetic peripheral neuropathy. Lidocaine plaster being a topical agent may be associated with lesser clinically significant adverse events than the side effects of systemic agents. The need for further studies has been recommended by the reviewer as limited number and size of studies were included in the systematic review 22.

Conclusion:

The American Academy of Neurology, Mayo Clinic and NICE have both developed guidelines for treatment of peripheral diabetic neuropathic pain. There are several peripheral and central pathological mechanisms leading to the development of this condition and no single drug is available to target all these pathological mechanisms. Therefore often a combination of drugs is required for their management. Despite using a combination of medicines, managing these cases can be challenging. At the same time there is limited evidence on combination therapy in diabetic neuropathy and much work is required in this area. While using opioids for this condition the controversies over the use of opioids in non-malignant pain should be kept in mind and the advantages and disadvantages of using them should be discussed with the patients. Opioids should only be started with patient’s consensus. The treatment should be modified from the guidelines on an individual basis to achieve the optimal pain relief.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAMITA ARORA, FFPMRCA, FRCA, MD Anaesthesiology, Specialist Trainee 7, Cambridge University Hospitals NHS Foundation Trust, UK. G NIRAJ, FFPMRCA, FRCA, MD, Consultant in Anaesthesia & Pain Medicine, University Hospitals of Leicester NHS Trust, Honorary Clinical Lecturer Department of Health Sciences, University of Leicester, UK.
Corresponding Author Details: 
NAMITA ARORA, Specialist Trainee 7, Cambridge University Hospitals NHS Foundation Trust, UK.
Corresponding Author Email: 
namitaarora@hotmail.co.uk
References
References: 
  1. Wild S, Roglic G, Green A et al. Global prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53.
  2. Tavakoli M, Mojaddidi M, Fadavi H et al. Pathophysiology and treatment of painful diabetic neuropathy. Curr Pain Headache Rep. 2008;12(3):192-7.
  3. Boulton A, Vinik A, Arezzo J et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28(4):956-62.
  4. Tan T, Barry P, Reken S et al. Pharmacological management of neuropathic pain in non-specialist settings: summary of NICE guidance. BMJ. 2010;24;340:c1079.doi: 10.1136/bmj.c1079
  5. Argoff C, Backonja M, Belgrade M et al. Consensus Guidelines: treatment and planning options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 Suppl):S12-25.
  6. Bril V, England J, Franklin G et al. Evidence-based guideline: Treatment of painful diabetic neuropathy:  report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PMR. 2011;3(4): 345-52,352.e1-21. doi: 10.1016/j.pmrj.2011.03.008.
  7. Franco L, Ferreira Souza L, Costa Pessoa A et al. Nonpharmacologic therapies in diabetic neuropathic pain: a review. Acta Paul Enferm 2011;24(2):284-8.
  8. Tesfaye S, Watt J, Benbow S et al. Electric spinal cord stimulation for painful diabetic peripheral neuropathy. Lancet. 1996;21-28;348(9043):1698-701.
  9. Daousi C, Benbow S, MacFarlane I et al. Electrical spinal cord stimulation in the long term treatment of chronic painful diabetic neuropathy. Diabet Med. 2005; 22(4):393-8.
  10. http://www.medicines.org.uk/emc/
  11. Moore R, Straube S, Wiffen P et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;8;(3):CD007076. doi: 10.1002/14651858. CD007076.pub2
  12. Sultan A, Gaskell H, Derry S et al. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol. 2008;1;8:29. doi: 10.1186/1471-2377-8-29.
  13. Carlos F, Ramírez-Gámez J, Dueñas H et al. Economic evaluation of duloxetine as a first-line treatment for painful diabetic peripheral neuropathy in Mexico. J Med Econ. 2012;15(2):233-44.
  14. Wu N, Chen S, Hallett L et al. Opioid utilization and health-care costs among patients with  diabetic peripheral  neuropathic pain treated with duloxetine vs. other therapies. Pain Pract. 2011;11(1):48-56.
  15. Moore R, Wiffen P,  Derry S et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;16;(3):CD007938. doi:10.1002/14651858.CD007938.pub2
  16. McQuay H, Tramèr M, Nye B et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-27.
  17. Eisenberg E, McNicol E, Carr D. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;19;(3):CD006146.
  18. Freeman R, Raskin P, Hewitt D et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic neuropathy. Curr Med Res Opin. 2007;23(1):147-61.
  19. Watson C, Moulin D, Watt-Watson J et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1-2):71-8.
  20. Gilron I, Bailey J, Tu D et al. Morphine, Gabapentin, or their Combination for Neuropathic Pain. N Engl J Med. 2005;31;352(13):1324-34.
  21. Derry S, Lloyd R, Moore R et al. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009;7;(4):CD007393. doi: 10.1002/14651858.CD007393.pub2.
  22. Wolff R, Bala M, Westwood M et al. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): a systematic review. Swiss Med Wkly. 2010;29;140(21-22):297-306. doi: smw-12995.

Eslicarbazepine use in Multiple Sclerosis with refractory Trigeminal Neuralgaia

Authors
Tarek A-Z K Gaber, Myint Myint Kyu and Wah Wah Oo
Article Citation and PDF Link
BJMP 2013;6(1):a602
Abstract / Summary
Abstract: 

When associated with Multiple Sclerosis (MS), Trigeminal Neuralgia (TN) is often bilateral and more refractory to treatment. Carbamazepine is the first line of treatment for TN, however, common side effects of carbamazepine such as hyponatremia occasionally limit its use.

We report the case of a 62 year old female patient with a well controlled MS associated TN using carbamazepine. This drug needed to be discontinued because of recurrent symptomatic hyponatremia. Several agents including topiramate, gabapentine and amitriptyline were tried but none had any beneficial effect on TN. A small dose of eslicarbazepine (400 mg daily) provided excellent control of the TN pain on one hand and did not affect the plasma sodium levels on the other hand.

Eslicarbazepine main advantage is providing the same effects of carbamazepine or oxcarbazepine but with an incidence of hyponatremia of less than 1%. It is much safer to use when the risk of hyponatremia is increased. To our knowledge, this is the first case that reports the use of eslicarbazepine in one of the several indications of carbamazepine such as pain and mental health problems. Eslicarbazepine use in epilepsy was reported extensively.

We feel that a therapeutic trial of eslicarbazepine is justified when either carbamazepine or oxcarbazepine have to be discontinued because of hyponatremia despite their efficacy. 

Keywords: 
Eslicarbazepine, Trigeminal Neuralgia, Multiple Sclerosis, hyponatremia

Trigeminal Neuralgia (TN) is relatively rare in Multiple Sclerosis (MS) affecting approximately 2% of patients1. The severity of the pain is indistinguishable whether TN is an isolated impairment or is associated with MS. However, when associated with MS, TN is often bilateral, affecting younger patients and is more refractory to medical treatment 2

Several pharmacological agents are reported to be effective in TN associated with MS. Topiramate3,4, gabapentin5 and lamotrigine6 were all reported to benefit patients with TN associated with MS in small uncontrolled trials. Several other drugs such as phenytoin, misoprostol and amitriptyline are routinely tried in patients with TN despite the lack of convincing evidence of their efficacy7.

In 2008, Both the American Academy of Neurology and the European Federation of Neurological Societies launched joint Task Force general guidelines for the management of TN. After systematic review of the literature the Task Force came to a series of evidence-based recommendations 8. Carbamazepine and oxcarbazepine had the strongest evidence of efficacy and were recommended as the first line treatment. An earlier Cochrane systematic review reached the same conclusion. 9.

Case report

A 62 year old female patient had been suffering from MS for about 20 years. The MS presented with trigeminal neuralgia from the outset and this was then followed by pyramidal lower limbs’ weakness and sphincteric dysfunction. The patient started to use a wheelchair 10 years ago but she became totally wheelchair dependent about 6 years later.

Trigeminal neuralgia remained active throughout the 20 years. Carbamazepine (300 mg daily) provided the patient with a satisfactory control of TN. Despite having occasional break through TN pain; the patient declined having higher doses of carbamazepine as excessive sedation was an unacceptable side effect.

Recently; the patient was admitted to hospital in two separate occasions complaining of increasing malaise and confusion. Plasma sodium levels were found to be low in both occasions (first presentation 118 mmol/l and second admission 114 mmol/l). Clinical evaluation confirmed Syndrome of Anti Diuretic Hormone Secretion (SIADH) as the cause of the hyponatremia and in the absence of any other explanation for the SIADH; carbamazepine was thought to be the main reason and was duly discontinued.

Unfortunately, TN attacks came back with vengeance. During the following 6 months, therapeutic trials using gabapentine, topiramate and amitriptyline failed to show any beneficial effect on either the severity or the frequency of the TN attacks. All three drugs were duly discontinued.

The patient was started on eslicrbazepine 400 mg on a single daily dose. This dose lead to almost complete eradication of the TN attacks. The control of TN and the plasma sodium levels remained stable a year following the initiation of the therapy.

Comments

Hyponatremia, defined as a sodium level < 135 mmol/l is a common side effect of carbamazepine and oxcarbazepine therapy. The incidence of hyponatremia secondary to carbamazepine therapy ranges between 4.8 and 40 % depending on the population studied10,11. In most cases, hyponatremia is asymptomatic and continuation of the carbamazepine use is possible whilst a close eye is kept on the plasma sodium level10. In rare occasions hyponatremia is symptomatic and discontinuation of carbamazepine is warranted. Administration of demeclocycline to normalise the sodium level was suggested by some authors12 However, the long term use of demeclocycline is associated with several complications and this approach is hardly a standard practice.

Clinicians often face a dilemma when carbamazepine is the only agent able to control a specific clinical problem. With many antiepileptics available, it is unusual to face such a problem in epileptic patients. Trigeminal neuralgia on the other hand can be extremely difficult to control and carbamazepine was found to have a unique ability to manage such unpleasant condition even before its antiepileptic effects were noticed on 196213.

Eslicarbazepine is promoted as an alternative to carbamazepine when side effects occurs on otherwise responsive patients to its favourable antiepileptic effects14. Hyponatremia is rare in eslacarbazepine users with only an incidence of less than 1% in the small populations studied15,16.  Frequency of hyponatraemia increased with increasing eslicarbazepine dose. In patients with pre-existing renal disease leading to hyponatraemia, or in patients concomitantly treated with medicinal products which may themselves lead to hyponatraemia17.

Our patient showed the same favourable response to eslicarbazepine as she experienced with carbamazepine. However, hyponatremia did not occur with eslicarbazepine therapy. This enabled our patient to continue with pharmacological management and avoid surgical interventions.

With the exception of epilepsy, no reports are available commenting on the use of eslicarbazepine on the wide range of conditions that carbamazepine is traditionally used for such as mental health problems and neuropathic pain. When patients are well controlled on carbamazepine whatever the indication is, the occurrence of side effects such as hyponatremia is often managed by an automatic replacement with another agent. We feel that in such patients a therapeutic trial of eslicarbazepine might be appropriate especially if the control on carbamazepine was robust or if the benefits of carbamazepine therapy were clearly superior to other pharmacological agents potentially useful for the targeted clinical condition.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
TAREK A-Z K GABER, FRCP (London), Consultant in Neurological Rehabilitation, Wrightington, Wigan and Leigh NHS Foundation Trust, UK. MYINT MYINT KYU, MRCP, Specialist Registrar in Rehabilitation Medicine, North West of England Deanery, UK. WAH WAH OO, MRCP, Specialist Registrar in Rehabilitation Medicine, North West of England Deanery, UK.
Corresponding Author Details: 
DR TAREK GABER, Consultant in Neurological Rehabilitation, Leigh Infirmary, Leigh, Lancs. WN7 3NF, UK.
Corresponding Author Email: 
tgaber@doctors.net.uk
References
References: 
  1. Hooge JP, Redekop WK. Trigeminal Neuralgia in Multiple Sclerosis. Neurology 1995; 45: 1294-6
  2. Brisman R. Trigeminal neuralgia and Multiple Sclerosis. Arch Neurol. 1987; 44(4):379-381.
  3. Zvartau-Hind M, Din MU, Gilani A, Lisak RP, Khan OA. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology 2000; 55(10):1587-8.
  4. Gilron I, Booker SL, Rowan JS, Max MB. Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study. Clin Neuropharmacol 2001; 24(2):109-12
  5. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology 1998; 51(2):611-4.
  6. Leandri M, Lundardi G, Inglese M, Messmer-Uccelli M, Mancardi GL, Gottlieb A, Solaro C. Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol 2000; 247(7):556-8.
  7. Cheng JS, Sanchez-Mejia RO, Limbo M, Ward MM, Barbaro NM. Management of medically refractory traigeminal neuralgia in patients with multiple sclerosis. Neurosurg Focus 2005; 18(5):e13
  8. Gronseth G, Cruccu G, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM; American Academy of Neurology Society; European Federation of Neurological Society. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neur. 2008 Oct;15(10):1013-28. 
  9. Wiffen P, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2000;(2):CD001133.
  10. Dong X, Leppik IE, White J, Rarick J. Hyponatremia from Oxcarbazepine and Carbamazepine. Neurology 2005; 65(12): 1976-1978
  11. Van Amelsvoort TH, Bakshi R, Devaux CB, Schwabe S. Hyponatremia Associated with Carbamazepine and Oxcarbazepine Therapy: A Review. Epilepsia 1994; 35(1): 181-188
  12. Brewerton TD, Jackson CW. Prophylaxis of carbamazepine-induced hyponatremia by demeclocycline in six patients. The Journal of Clinical Psychiatry 1994; 55(6): 249-251 
  13. Schindler W, Häfliger F. Über Derivate des Iminodibenzyl. Helvetica Chimica Acta 1954; 37 (2): 472–83.
  14. Elger C et al Efficacy & Safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomised, double-blind, placebo-controlled, parallel group, phase III study, Epilepsia, 2009; 50; (3): 453-63. 
  15. Versavel M et al, An investigation of the effects of eslicarbazepine acetate on hyponatraemia: A pooled analysis of three double-blind phase III clinical studies. Poster presented AES Annual Meeting Dec 2009, San Antonio
  16. Nunes T et al. Incidence of rash and hyponatraemia in adult patients with refractory partial seizures treated with adjunctive eslicarbazepine acetate: Results from three phase III studies and 1-year open-label extensions. Poster presented at ECE Annual Meeting June 2010, Rhodes.
  17. Gil-Nagel A et al, Efficacy and safety of 800 mg and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures, Acta Neurol Scand, 2009; 120: 281-287. 

Postural Orthostatic Tachycardia Syndrome (POTS): Evaluation and Management

Authors
Ronald Conner, Mujeeb Sheikh and Blair Grubb
Article Citation and PDF Link
BJMP 2012;5(4):a540
Abstract / Summary
Abbreviations: 
JHS - Joint hypermobility syndrome, POTS - Postural Orthostatic Tachycardia Syndrome, SSRI - serotonin reuptake inhibitor, SNRI - norepinephrine reuptake inhibitor, EPO - erythropoietin

Case Presentation

A 29 year-old woman had been well until 7 months previously when, after a viral syndrome, she developed palpitations, fatigue, and frequent episodes of light headedness and near syncope. On further questioning she notes exercise intolerance and dyspnea on exertion. She has stopped working as cashier. Her mother thinks she is having panic attacks and needs “something to calm her nerves.” ECG, echocardiogram, and endocrine evaluation are all normal. On physical examination, she displayed a postural heart rate increase of 35 beats per minute on standing, along with a 15mmHg fall in diastolic blood pressure.

Introduction

Disorders of the autonomic nervous system present unique challenges to the practicing clinician. These syndromes have a significant impact on quality of life, offer subtle diagnostic clues, and have a propensity to mimic other disease processes. For these reasons clinicians should have basic familiarity with the differentiating features of autonomic disorders. While much investigation has focused on Neurocardiogenic syncope, a distinct subgroup has emerged characterized by postural tachycardia and exercise intolerance. Postural orthostatic tachycardia syndrome (POTS) is the final common pathway of a heterogeneous group of underlying disorders that display similar clinical characteristics .1

The constellation of symptoms associated with POTS reflects underlying dysautonomia including palpitations, exercise intolerance, fatigue, lightheadedness, tremor, headache, nausea, near syncope, and syncope. Foremost amongst these is orthostatic intolerance. Besides being limited in the functional activities of daily living, increased sleep disturbances including excess daytime sleepiness, fatigue are also common and have been associated poor health-related quality of life. 2 We aim to discuss the clinical presentation, classification, evaluation and management of POTS.

Diagnosis

The current diagnostic criteria for POTS is the presence of orthostatic intolerance symptoms associated with a sustained heart rate increase of 30 beat per minute (bpm) or absolute rate exceeding 120 bpm within the first 10 minutes of standing or upright tilt in the absence of other chronic debilitating disorders, prolonged bed rest, or medications that impair vascular or autonomic tone. 3 Most patients will have orthostatic symptoms in the absence of orthostatic hypotension (a fall in BP >20/10 mmHg). A grading system for POTS has been developed (Table 1). This system focuses on the functional severity of orthostatic intolerance in a way similar to the NYHA heart classification.

The physical exam should be methodical and directed. Supine, sitting, and immediate standing heart rate and blood pressure should be recorded. Orthostatic tachycardia and acrocyanosis of the lower extremities may be the only physical signs in these patients. Standing and supine blood pressure measurements and baseline electrocardiogram are generally recommended. In patients with physical examination or clinical history suggestive of cardiovascular abnormalities, other diagnostic test including echocardiogram , stress test or coronary angiography may be indicated before a tilt test. In addition, other possible clinical disorders with similar clinical manifestations must be kept in mind and ruled out. Upright tilt test remains the diagnostic test of choice for POTS and other autonomic disorders. Implantable loop recorders, electrophysiological tests and Holter monitoring are not helpful in the evaluation of these disorders. Supine and upright serum catecholamine levels should be obtained if hyperadrenergic type is suspected. In the presence of gastrointestinal symptoms bowel motility studies may reflect the degree of involvement and help to tailor therapy. 4

Table 1 : The Grading of Orthostatic Intolerance*
Grade 0
Normal orthostatic tolerance
Grade 1
Orthostatic symptoms are infrequent or occur only under conditions of increased orthostatic stress
Subject is able to stand >15 minutes on most occasions
Subject typically has unrestricted activities of daily living
Grade II
Orthostatic symptoms are frequent, developing at least once a week
Orthostatic symptoms commonly develop with orthostatic stress
Subject is able to stand >5 minutes on most occasions
Some limitation in activities of daily living is typical
Grade III
Orthostatic symptoms develop on most occasions and are regularly unmasked by orthostatic stresses
Subject is able to stand for >1 minute on most occasions
Patient is seriously incapacitated, being bed or wheelchair bound because of orthostatic intolerance
Syncope / presyncope is common if patient attempts to stand
*Symptoms may vary with time and state of hydration and circumstances. Orthostatic stresses include prolonged standing, a meal, exertion, and head stress.

Classification and Clinical Features

POTS is a heterogeneous group of disorders resulting in a common clinical scenario. This syndrome is classified as being either primary or secondary. Primary POTS is idiopathic and not associated with other disease processes. Secondary POTS occurs in association with a known disease or disorder. Subtype classification affects management and is therefore essential.1,4 (Figure 1)

Partial dysautonomic (PD) POTS (also referred to as Neuropathic POTS) is the predominant form.1, 2 This is a mild peripheral autonomic neuropathy, characterized by inadequate peripheral vasculature constriction in the face of orthostatic challenge. Female predominance is seen with 5:1 female to male ratio. Presentation is commonly abrupt onset of symptoms after a febrile viral illness, pregnancy, immunization, sepsis, surgery, or trauma. The etiology of PD type POTS is postulated to be an autoimmune molecular antigen mimicry type pathogenesis. Serum autoantibodies to peripheral autonomic ganglion alpha-3 acetylcholine receptors may be positive in 10-15% of the cases. Anhidrosis of lower extremities is seen in more than 50% of these patients at quantitative sudomotor axon reflex testingDependent blood pooling when upright is greater than normal and heart rate and contractility increase as normal compensatory physiologic mechanisms to maintain cerebral perfusion. This autoregulatory response may initially be fully compensatory; however, peripheral venous pooling may increase with time and exceed this compensatory effect. Patients with PD type POTS become dependent on the skeletal muscle pump to augment their autoregulatory physiology. Ultimately, venous blood pooling increases beyond the body’s total ability to compensate and adequate blood pressure maintenance fails.

“Developmental” partial dysautonomic POTS is an adolescent subtype.6 The mean age of onset is 14 years. The clinical scenario is that of orthostatic intolerance following a period of very rapid growth. Symptoms are progressive and peak at a mean age of 16 years. Orthostatic intolerance may be severe, including severe headaches, and can be functionally disabling. Following their peak symptoms will slowly improve and resolve into young adulthood (19-24 years). Roughly 80% of patients with developmental PD POTS will experience complete resolution of symptoms. The etiology of this subtype is unclear and appears to be a transient period of autonomic imbalance occurring in rapidly growing adolescents.

Hyperadrenergic POTS is less common than the PD type ,7This form is characterized by a gradual onset with slowly progressive symptoms. Patients report experiencing tremor, anxiety, and cold clammy extremities with upright posture. 7 Many patients note increased urine output when upright. True migraine headaches may be seen in over half of patients.7 Gastrointestinal symptoms in the form of recurrent diarrhea were seen in 30% of the patients. In contrast to PD type of POTS, the hyperadrenergic form demonstrates elevated serum catecholamine levels with serum norepinephrine levels >600ng/ml. This may be a familial syndrome in some instances determined by a careful history. The etiology of hyperadrenergic POTS is felt to be genetic with a single point mutation resulting in a dysfunctional norepinephrine reuptake transporter protein present in the intrasynaptic cleft. The result is excessive norepinephrine serum spillover with sympathetic stimulation resulting in a relative hyperadrenergic state appearing similar to pheochromocytoma. 8

A connective tissue disorder has been an increasingly recognized etiology of secondary POTS 9 . Joint hypermobility syndrome (JHS) is an inherited condition characterized by joint hypermobility, connective tissue fragility, and soft velvety skin with variable hyperextensibility. The condition is associated with ecchymotic predisposition, premature varicose veins, diffuse muscle and joint pain, and orthostatic acrocyanosis. The etiology of POTS in JHS patients is thought to be due to abnormal vascular (venous) elastic connective tissue. During orthostatic stress and increased hydrostatic pressure these patients exhibit increased vessel distensibility and orthostatic intolerance. Excessive peripheral venous pooling and compensatory tachycardia follows. Up to 70% of JHS patients suffer from some degree of orthostatic intolerance. It is observed that adolescent PD POTS patients have features similar to JHS patients and further studies may determine the significance of this potential relationship 10.

Secondary POTS refers to a group of conditions which result in peripheral autonomic denervation with sparing of cardiac innervation. Most commonly, secondary POTS is associated with diabetes mellitus. Less commonly, this form may occur with heavy metal intoxication, multiple sclerosis, parkinsonism and chemotherapy, especially vinca alkaloids.11,12

Severe autonomic nervous system disorders may present as POTS. These may include pure autonomic failure or multiple system atrophy. Paraneoplastic syndrome associated with adenocarcinoma of the lung, breast, ovary, or pancreas may also present as POTS. These tumors produce auto-antibodies targeting the acetylcholine receptors in the autonomic ganglia in a manner similar to post-viral syndromes.

Figure 1. Subtypes of postural orthostatic tachycardia syndrome

Evaluation and Management

Treatment is generally individualized to each patient. Confounding pharmacology should be identified and stopped if possible (Table 2). The presence of secondary POTS should be considered. Underlying diagnoses causing or augmenting POTS should be identified and treated appropriately. Deconditioning is frequent seen in POTS patient and a deliberate aerobic reconditioning program should be a component of the treatment plan. 13 This is encouraged to begin promptly working up to a goal of 20-30 minutes of activity at least 3 times a week. Resistance training of the lower extremities is helpful to increase the efficacy of the skeletal muscle pump. Salt and water ingestion are the most common employed non-pharmacolgical therapeutic intervention for POTS. Although, the intravenous saline infusion has been associated with reduction in standing tachycardia, the effect on this intervention on the symptom reduction remains unknown 14 . In general, since low blood volume may exacerbate symptoms patients are encouraged to have liberal salt and water intake. Excluding hyperadrenergic POTS, daily fluid and sodium intake should be greater than 2 liters and 3-5 grams.

Table 2: Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance
Angiotensin-converting enzyme inhibitors
Alpha receptor blockers
Calcium channel blockers
Beta blockers
Phenothiazines
Tricyclic antidepressants
Bromocriptine
Ethanol
Opiates
Diuretics
Hydralazine
Ganglionic-blocking agents
Nitrates
Sildenafil citrate
Monoamine oxidase (MAO) inhibitors

The goal of pharmacotherapy in the treatment of POTS is to ameliorate the symptoms of POTS and thus maintain the functional capacity. Currently no drug is US FDA approved for the treatment of POTS. All pharmacology is inherently off-label. (Table 3).

Table 3: Therapeutic Options in POTS
Treatment Application Form Effective in Problems
Reconditioning Aerobic exercise 20 min 3 times / week PD, H If too vigorous may worsen symptoms
Hydration 2 liters PO/day PD Edema
Salt 2-4 grams/day PD Edema
Fludrocortisone 0.1-0.2 mg PO daily PD Hypokalemia, hypomagnesemia, edema
Midodrine 5-10 mg PO TID PD Nausea, scalp pruritus, supine hypertension
Methylphenidate 5-10 mg PO TID PD Anorexia, insomnia, dependency
Bupropion 150-300 mg XL daily PD, H Tremor, agitation, insomnia
SSRI-Escitalopram 10 mg PO Daily PD, H Tremor, agitation, sexual problems
Pyridostigmine 30-60 mg PO BID PD Nausea, diarrhea
Erythropoietin 10,000-20,000 IV SQ weekly PD Pain at injection site, expensive
Octreotide 50-200 ug SQ TID PD Nausea, diarrhea, gallstones
Clonidine 0.1-0.3 mg PO BID; 0.1-03 mg patch weekly H Dry mouth, blurred vision
Labetalol 100-200 mg PO BID H Fatigue
PD = partial dysautonomic; H = hyperadrenergic; POTS = postural tachycardia syndrome

Majority of the evidence for the use of different pharmacological agents in the management of POTS is based on some small randomised , observational and retrospective single center studies. In clinical practice most patients are treated with a single agent and second medication from different class with a different mechanism of action is added in case of treatment failure. Resistant cases are often treated with polypharmacy.

Fludrocortisone, a potent mineralocorticoid resulting in sodium retention, augmented fluid volume, and sensitized peripheral alpha adrenergic receptors. The effects are more pronounced in the younger population. Starting dose is 0.1-0.2 mg daily with a maximum dose of 0.4 mg. Common side effects include electrolyte imbalance and hypertension. In a study of 11 female POTS patients, fludricortisone alone or in combination with bisoprolol was associated with improvement in symptoms 15. Midodrine is an alpha -1 adrenoreceptor agonist and causes both arterial and venous vasoconstriction. It is commonly used as add on therapy and with starting dose at 5 mg orally three times a day. In our clinical experience we advise patients to take their first dose of midodrine 15 minutes prior to getting out of bed. An additional 5mg dose can be used for breakthrough symptoms. Midodrine is usually well tolerated with the most common complaints being nausea, “goose bumps,” and scalp pruritus. In a small study of 6 patients with POTS acute combination therapy of midodrine (10mg) with octreotide (0.9mcg/kg) was significantly associated with reduction in upright tachycardia and improved standing time.In another study of 53 children with POTS, midodrine was significantly associated with both higher clinical cure rate and reduced recurrence rate as compared to children treated with metoprolol or conventional therapy.

Patients may continue to be symptomatic despite dual-therapy as outlined above. In this population we add a serotonin reuptake inhibitor (SSRI) or norepinephrine reuptake inhibitor (SNRI). SSRI therapy has been found to be helpful in the prevention of neurocardiogenic syncope. However, SNRI therapy is more useful in the treatment of POTS. Usually, we use bupropion XL beginning with 150 mg orally daily titratable to 300 mg daily if necessary.

The most effective SSRI therapies combine serotonin and norepinephrine reuptake inhibition (venlafaxine and duloxetine). The agents are usually well tolerated with the most common side effects being gastrointestinal upset, tremor, sleep disturbance, and less commonly agitation and sexual dysfunction. Bupropion and SSRI therapy can be combined to achieve a similar effect.

Pyridostigmine is an acetylcholinesterase inhibitor that facilitates sympathetic and parasympathetic ganglionic neural transmission. In our single center experience of 203 patients of POTS treated with pyridostigmine; improved symptoms of orthostatic intolerance were seen in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to tolerate the drug. Fatigue (55%), palpitations (60%), presyncope (60%), and syncope (48%) were the most common symptoms that improved with pyridostigmine. Further, symptom reduction correlated with a statistically significant improvement in upright HR and diastolic blood pressure after treatment with pyridostigmine as compared to their baseline hemodynamic parameters (standing HR 94 ± 19 vs 82 ± 16, P < 0.003, standing diastolic blood pressure 71 ± 11 vs 74 ± 12, P < 0.02). Gastrointestinal problems were the most common adverse effects (n = 39, 19%) seen in our study. 18

Severely affected and refractory patients may benefit from erythropoietin (EPO) therapy. EPO increases red cell mass, central blood volume and augments response of blood vessels to the angiotensin-II and thus causes vasoconstriction. These effects are quite useful in the treatment of orthostatic disorders. Prior to initiation of EPO therapy obtain a complete blood count (CBC), total iron binding capacity, serum iron and ferritin levels. Hematocrit (HCT) levels must be monitored and should remain less than 50 on EPO. The starting dose is 10,000 units via subcutaneous injection once weekly. There is a 4-6 week delay between a given dose and the full clinical effect. The hematogenic and hemodynamic affects are independent but may occur simultaneously. A goal HCT of low to mid 40 will often result in optimum hemodynamic augmentation. Monitoring during EPO therapy should include monthly CBC to document HCT less than 50. EPO therapy may infrequently result in a “serum sickness” type reaction characterized by nausea, fever, chills, and general malaise. In another study of 39 patients (age 33 ± 12, 37 females) with resistant form of POTS, we reported sustained improvement in twenty-seven (71%) patients at mean follow-up of six month with EPO therapy. Eighty (21%) failed to respond to therapy while as 3 (8%) improved with therapy at 3months. Also, erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters.19 We reserve EPO therapy for patients that are refractory or intolerant of other forms of treatment because of its considerable expense and subcutaneous route of administration.

Beta blocker therapy such as metoprolol tartrate may be beneficial in adolescent type POTS patients. In a single center retrospective study of 121 patients with possible POTS, written survey at follow-up were used to evaluate response to therapy with beta-blockers and midodrine. 47 adolescents responded to survey (Walker Functional Disability Inventory Survey) and reported improvement with a β-blocker (100% vs 62%, P = 0.016) and more attributed their progress to medication (63.6% vs 36.4%, P = 0.011) than did those treated with midodrine 20 .In addition, beta-blocker therapy was associated with improved quality of life. Great caution should be taken in using beta-blocker therapy in a rare form of hyperadrenergic POTS secondary to the mast cell activation disorders. Octreotide is a somatostatin analogue with potent vasoconstrictive effects and is useful in the treatment of orthostatic disorders. In patients with resistant POTS, octreotide may be a useful as add on therapy. It is administered by subcutaneous injection 2-3 times daily. The stating dose is 50 ug and may be titrated up to 100-200 ug three times daily.

Agents that block the release or effect of norepinephrine (noradrenaline) are very effective for hyperadrenergic type POTS patients. We use clonidine starting at 0.1 mg orally twice daily and titrating up as needed. The patch form may be preferable to some patients and has the added benefit of providing a steady state drug release for one week. Labetalol, an alpha and beta receptor blocker, is also useful in this group of patients. Dosages of 100-400 mg orally twice daily are used. Methyldopa may have a role in highly selected patients with POTS. Symptom control may be improved with both the SSRI and SNRI classes of medications.

Inappropriate sinus tachycardia (IST) is an important confounding finding in suspected POTS patients. This syndrome is similar to hyperadrenergic type POTS. The clinical presentation may be similar with IST being more common in females. These disease states display and exaggerated response to isoproterenol infusion. It has been postulated that they may represent different states of the same pathologic process. A greater degree of orthostatic change in heart rate is seen in POTS patients. The supine rate rarely exceeds 100 bmp (IST will often be >100). Postural changes in serum norepinephrine levels are much more pronounced in POTS patients. It is important to differentiate POTS and IST. Radiofrequency ablation of the sinus node will rarely benefit hyperadrenergic POTS patients and will make PD POTS patients markedly worse.

Treatment of secondary POTS should focus primarily on the underlying disorder to the greatest extent possible. Diabetes mellitus or JHS related POTS are treated as PD POTS. Secondary POTS due to sarcoidosis or amyloidosis may benefit from steroid therapy. Secondary POTS that is paraneoplastic may completely resolve with treatment of the underlying malignancy but may also respond to pyridostigmine.

Patients suffering from POTS have a disease that affects many aspects of their life. They are often unable to take advantage of meaningful employment or education opportunities. The pervasive life change experienced often results in significant psychosocial disruption as they may be excluded from social norms and certain environments. Frequently, patients require psychologists, social workers, and lawyers to address these aspects of living with POTS. The treating physician is a prominent and central figure who is a beacon of hope for this population. A positive, caring, and nurturing attitude may be the best medicine and lead to a rewarding rapport where an otherwise challenging disease exists.

Prognosis

There is limited data on the prognosis of POTS patients. Recent short term follow-up studies have shown better prognosis in patients with POTS. 21 Roughly 50% of post-viral POTS patients make a meaningful recovery over about 2-5 years. Meaningful recovery may be defined as the absence of orthostatic symptoms and the ability to perform the activities of daily living with little or no restriction. Some patients experience a partial recovery and still others may demonstrate a progressive functional decline with time. As a general principle, a younger age of onset portends a better prognosis. A majority of patients tend to adopt different lifestyle modifications including increased fluid and salt intake to improve and reduce exacerbation of the POTS symptoms. In secondary POTS syndromes have a prognosis consistent with the underlying causative disorder.

Conclusion

Disruption of normal autonomic function may manifest as one of a heterogeneous group of clinical disorders collectively referred to as postural orthostatic tachycardia syndrome. Treatment is most successful when diligence has been taken to investigate the underlying disorder or POTS subtype and a comprehensive targeted treatment program is instituted with frequent follow up. Goals of care should focus on functional milestones and maintenance of function.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RONALD CONNER, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA. MUJEEB SHEIKH, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA. BLAIR GRUBB, MD, Professor of Medicine, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, USA.
Corresponding Author Details: 
Mujeeb Sheikh, MD, Cardiovascular fellow, Cardiovascular division, Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, Ohio, USA, 43614.
Corresponding Author Email: 
Mujeeb.sheikh@utoledo.edu
References
References: 
  1. Kanjwal Y, Kosinski D, Grubb BP: The postural tachycardia syndrome: Definition, diagnosis and management. Pacing Clin Electrophyiol 2003;26:1747-1757.
  2. Bagai K, Song Y, Ling JF et al.Sleep disturbances and diminished quality of life in postural tachycardia syndrome. J Clin Sleep Med. 2011 Apr 15; 7(2):204-10.
  3. Grubb BP, Kanjwal Y, Kosinski DJ: The Postural Tachycardia Syndrome: A Concise Guide to Diagnosis and Management. J Cardiovasc Electrophysiol 2006;17:108-112.
  4. Grubb BP: Postural Tachycardia Syndrome. Circulation 2008;117:2814-2817
  5. Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007 Mar; 82(3):308-13.
  6. Grubb BP: The Postural Tachycardia Syndrome: When to Consider it in Adolescents. Family Practice Recertification 2006;28:19-30
  7. Khalil K, Saeed B, Karabin B, et al. Clinical Presentation and Management of Patients with Hyperadrenergic Postural Orthostatic Tachycardia Syndrome. A Single Center Experience. Cardiol J 2011;18:1-5.
  8. Shannon JR, Flattem NL, Jordan J, Jacob G et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency N Engl J Med. 2000 Feb 24;342(8):541-9.
  9. Mathias CJ, Low DA, Iodice V et al. Postural tachycardia syndrome--current experience and concepts. Nat Rev Neurol. 2011 Dec 6;8(1):22-34. doi: 10.1038/nrneurol.2011.187.
  10. Kanjwal K, Saeed B, Karabin B et al. Comparative clinical profile of postural orthostatic tachycardia patients with and without joint hypermobility syndrome. Indian Pacing Electrophysiol J. 2010 Apr 1;10(4):173-8.
  11. Grubb BP: Postural Tachycardia Syndrome. Circulation 2008;117:2814-2817
  12. Kanjwal K, Karabin B, Kanjwal Y et al. Autonomic dysfunction presenting as postural orthostatic tachycardia syndrome in patients with multiple sclerosis.Int J Med Sci. 2010 Mar 11;7:62-7.
  13. Parsaik A, Allison TG, Singer W et al. Deconditioning in patients with orthostatic intolerance Neurology. 2012 Oct 2;79(14):1435-9.
  14. Raj SR, Robertson D. Blood volume perturbations in the postural tachycardia syndrome. Am J Med Sci 2007;334:57–60.
  15. Freitas J, Santos R, Azevedo E, et al.Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone. Clin Auton Res. 2000 Oct;10(5):293-9.
  16. Hoeldtke RD, Bryner KD, Hoeldtke ME, et al. Treatment of postural tachycardia syndrome: a comparison of octreotide and midodrine.Clin Auton Res. 2006 Dec;16(6):390-5. Epub 2006 Oct 11.
  17.  Chen L, Wang L, Sun J, et al.Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. Circ J. 2011;75(4):927-31. Epub 2011 Feb 2.
  18. Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience. Pacing Clin Electrophysiol. 2011 Jun;34(6):750-5
  19. Kanjwal K, Saeed B, Karabin B, et al.Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Am J Ther. 2012 Mar;19(2):92-5.
  20. Lai CC, Fischer PR, Brands CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers.Pacing Clin Electrophysiol. 2009 Feb;32(2):234-8.
  21. Alexandra Sousa, Ana Lebreiro, Joa˜o Freitas, et al. Long-term follow-up of patients with postural tachycardia syndrome. Clin Auton Res (2012) 22:151–153

Co-incidental finding of pancytopenia

Authors
W Thomas and M Beveridge
Article Citation and PDF Link
BJMP 2012;5(4):a533
Abstract / Summary
Abstract: 

A 73 year old man was found to be pancytopenic after visiting his General Practitioner for a routine health check.  He had a history of spinal bulbar atrophy and hypertension.  In this teaching case we discuss the investigation and immediate management of the patient, with the outcome of the case also being revealed.  The case is an educational piece intended to be at the level required of candidates preparing to sit the membership of the Royal College of Physicians of the United Kingdom.

Keywords: 
pancytopenia, differential diagnosis.

CASE REPORT

A 73 year old male retired civil servant with a background of spinal bulbar atrophy and hypertension presented to his General Practitioner (GP) for a routine health check.  He was taking bendroflumethiazide, propranolol, atorvastatin and aspirin.  His brother also has spinal bulbar atrophy.

The GP sent routine blood tests, which came back as follows: Haemoglobin 8.5 (13-17g/dL), Mean Cell Volume 84.9 (80-100fl), White Cell Count 3.4 (4-11 x10^9/L), Neutrophil Count 0.68 (2-8 x10^9/L), Platelets 19 (150-400 x10^9/L).  A random blood sugar reading was 18 (3.9-7.8mmol/L).  Renal function, bone profile and hepatic function tests were normal.  The General Practitioner referred the patient urgently to the local Haematology unit for further assessment. 

On further review the patient complained of tiredness but had had no infections or bleeding.  There were no night sweats or recent foreign travel.  Physical examination was unremarkable, with no lymphadenopathy or organomegaly.

A blood film showed marked anaemia with red cell anisopoikilocytosis, prominent tear drop cells and neutropenia with normal white cell morphology.  There were no platelet clumps.  A diagnostic investigation followed.

QUESTIONS

What are the differential diagnoses of pancytopenia and which causes are likely here given the findings on examination of the peripheral blood film?

  • Infections - Viral infections including cytomegalovirus, hepatitis A-E, Epstein-Barr virus, Parvovirus B19 and non A-E hepatitis viruses can cause aplastic anaemia1.  The classical picture would be pancytopenia in a young patient who has recently had ‘slapped cheek syndrome’ from parvovirus B19 who has transient bone marrow aplasia.  Tropical infections such as visceral leishmania may cause pancytopenia, splenomegaly and a polyclonal rise in immunoglobulins2.  Overwhelming sepsis may also cause pancytopenia with a leucoerythroblastic blood film (myeloid precursors, nucleated red blood cells and tear drop red cells).  HIV is also an important cause of cytopenias.
  • Medications - common medications may cause aplastic anaemia, such as chloramphenicol, azathioprine and sodium valproate.  The history in this case did not have any recent medications introduced.  The other very common cause of pancytopenia in modern practice would be in the context of chemotherapy.
  • Bone marrow disorders - tear drop cells are a key finding and clue in this case.  They suggest an underlying bone marrow disorder and stress.  In the context of a known active malignancy they are nearly indicative of bony metastases.  Our patient did not have a known malignancy and there was nothing to suggest this on the history or physical examination, although in a man of this age metastatic prostate cancer should be considered.  Other bone marrow disorders that would need to be considered are acute leukaemia (which was the diagnosis here), myelodysplasia and myelofibrosis.  Splenomegaly would be especially significant in this case as it would be highly suggestive of myelofibrosis in combination with tear drop cells wit pancytopenia in an elderly patient3. 
  • B12 and folate deficiency – this may cause pancytopenia, tear drop cells and leucoerythroblastic blood findings4&5.  The mean corpuscular volume in this case however is normal which would somewhat argue against B12 and folate deficiency, as well as the fact that there were no hypersegmented neutrophils seen on the blood film.  This cause is however very important given how it is easily reversible and treatable.
  • Haemophagocytosis – this is a bone marrow manifestation of severe inflammation and is a manifestation of systemic disease6.  It has various causes including viruses (e.g. Epstein Barr virus), malignancy and autoimmune disease.  It should be considered in patients with prolonged fever, splenomegaly and cytopenias.  It is diagnosed by characteristic findings on bone marrow biopsy.
  • Paroxysmal nocturnal haemoglobinuria – this is a triad of pancytopenia, thrombosis and haemolysis caused by a clonal stem cell disorder with loss of membrane proteins (e.g. CD55 and CD59) that prevent complement activation7. 
  • Genetic disease – Fanconi anaemia is a rare autosomal recessive disease with progressive pancytopenia, malignancy and developmental delay.  It is caused be defects in DNA repair genes.  

The key finding in this case was tear drop cells on the blood film.  These are part of a leucoerythroblastic blood picture seen in bone marrow disease, malignant marrow infiltration, systemic illness and occasionally haematinic deficiency.  See above for why this is unlikely to be haematinic deficiency.  Although tear drop cells can occur in systemic illness such as severe infection, the history here was not in keeping with this.  The diagnoses remaining therefore are malignant bone marrow infiltration or a primary bone marrow disorder (myelodysplasia, acute leukaemia or myelofibrosis).  There were no features in the history pointing towards a metastatic malignancy and therefore primary bone marrow disorder is the most likely diagnosis.  The diagnosis was later established as acute myeloid leukaemia on bone marrow examination. 

What investigations would help to confirm or eliminate the possible diagnoses?

  • Blood tests including a clotting screen, liver function tests, inflammatory markers and renal function shall help to exclude other systemic disease such as disseminated intravascular coagulation, sepsis, liver disease and thrombotic thrombocytopenic purpura which may all give rise to cytopenias.  Autoimmune screening may also suggest vasculitis which can cause cytopenias.
  • Microbiology studies including virology tests (e.g. human immunodeficiency virus, Epstein Barr virus and hepatitis viruses) may also be requested as appropriate given the clinical scenario and findings.  Visceral leishmania should be tested for according to travel history and clinical likelihood.  Leishmania may be identified through serology and light microscopy (for amastigotes) or polymerase chain reaction of the bone marrow aspirate.  Tuberculosis could be cultured from the bone marrow is suspected. 
  • Haematinics are a crucial test and the aim should be to try and withhold transfusion until these results are known in case they can easily be replaced thereby negating the need for blood products.  Remember that if haematinics are not tested before transfusion then the blood products will confound the tests results. 
  • Bone marrow biopsy, including aspirate and trephine are a crucial investigation for morphological examination and microbiological testing if indicated.  This will distinguish the bone marrow disorders including acute leukaemia, myelofibrosis, bone marrow metastatic infiltration and myelodysplasia.  Haemophagocytic syndrome may also be suggested by bone marrow examination findings.
  • Imaging if there is suspicion of an underlying malignancy (e.g. CT chest, abdomen and pelvis) and then further blood tests such as the prostate specific antigen.  Ultrasound could also be used to check for splenomegaly where clinical examination has not been conclusive.
  • Medication review is vital as this may reveal the diagnosis (e.g. use of chloramphenicol) 
  • Flow cytometry may be considered to investigate for an abnormal clone in the case of paroxysmal nocturnal haemoglobinuria and may be used on bone marrow samples to further evaluate the cells.

Unless a very clear cause for the pancytopenia is obvious (e.g. haematinic deficiency or malignant infiltration) then bone marrow examination is crucial for establishing a diagnosis.  This will also prevent inappropriate treatments being initiated.

What immediate management steps and advice would be given to this patient?

General measures for pancytopenia include blood product support.  Red cells and platelets can be given for symptomatic anaemia and bleeding.  There is no need to transfuse platelets in the patient if there are no signs of bleeding.  Alternatively he could also be treated with tranexamic acid as an alternative to avoiding risks associated with platelet transfusion.  Infection should be treated urgently.  Due to the neutropenia he should be advised to seek medical help if he develops a fever or sore throat.  He should urgently be followed up in clinic with the results and given the contact details for the haematology department in the interim period in case he develops any problems.

The specific treatments for pancytopenia rests on the exact cause found after investigation.  In this case the diagnosis was acute myeloid leukaemia arising from a background of myelodysplasia.  The treatment for acute myeloid leukaemia in general, with curative intent, would consist of induction chemotherapy with DA (daunorubicin and cytosine arabinoside) followed by consolidation with further chemotherapy, the type of which (e.g. high dose cytosine arabinoside or FLAG-Ida) would depend on the risk assessment of the disease and possible consideration of an allograft bone marrow transplant after consolidation.  Currently different approaches to consolidation chemotherapy, transplantation and small molecule inhibitors are being evaluated in clinical trial (e.g. AML 17 clinical trial).

The other options, in older more frail patients where high dose chemotherapy will be very toxic, are low dose palliative chemotherapy and support with transfusion.   

PATIENT OUTCOME

He has been supported with blood products (platelets and packed red cells for bleeding and anaemia respectively).  After discussion with him and his wife he has elected to have palliative chemotherapy with low dose cytosine arabinoside.  He will be seen regularly in the haematology clinic and day unit for review.  We do not suspect a link between the leukaemia and spinal bulbar atrophy.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
W THOMAS, MBBS MRCP, Core Medical Trainee Year 2, Department of Haematology, Addenbrookes Hospital, Cambridge. M BEVERIDGE, MBBS MRCP, Core Medical Trainee Year 2, Department of Haematology, Addenbrookes Hospital, Cambridge.
Corresponding Author Details: 
DR W THOMAS, Core Medical Trainee Year 2, Department of Haematology, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ.
Corresponding Author Email: 
whcthomas@gmail.com
References
References: 
  1. Rauff B, Idrees M, Shah SA, Butt S, Butt AM, Ali L et al.  Hepatitis associated aplastic anaemia: a review.  Virol J, 2011: 8: 87.
  2. Varma N & Naseem S.  Haematological changes in visceral leishmania/kala azar.  Indian J hematol Blood Transfus, 2010: 26(3): 78-82.
  3. Campbell PJ & Green AR.  Myeloproliferative neoplasms (Chapter 36).  In: Hoffbrand AV, Catovsky D, Tuddenham EGD & Green AR, editors.  Postgraduate haematology.  6th ed.  UK: Wiley-Blackwell; 2011. p. 686-709.
  4. Halfdanarson TR, Walker JA, Litzow MR & Hanson CA.  Severe vitamin B12 deficency resulting in pancytopenia, splenomegaly and leukoerythroblastosis.  Eur J Haematol, 2008: 80(5): 448-51.
  5. Hansen PB & Jorgensen LM.  Pancytopenia – a rare manifestation of folic acid deficiency.  J Intern Med, 1989: 225(2): 143-4. 
  6. Jordan MB, Allen CE, Weitzman S, Filipovich AH & McCain KL.  How I treat haemophagocytic lymphohistiocytosis.  Blood, 2011: 118(15): 4041-52.
  7. Brodsky RA.  How I treat paroxysmal nocturnal hemoglobinuria.   Blood, 2009: 113(26): 6522-6527.

Case Report: Sleep wake cycle disorder and agitation associated with Levetiracetam in an elderly patient with traumatic brain injury

Authors
Nair CV and Kadies MA
Article Citation and PDF Link
BJMP 2012;5(3):a527
Abstract / Summary
Abstract: 

Rehabilitation following traumatic brain injury (TBI) in the elderly is challenging. They tend to have poorer functional outcomes and often have associated cognitive decline. Rehabilitation interventions directed towards functional recovery are often hampered by agitation, confusion and fatigue. Identifying and correcting all possible causes is imperative in aiding rehabilitation. We present a 76 year old man who was admitted to an intermediate neurorehabilitation unit for cognitive rehabilitation following TBI. He was on multiple antiepileptic drugs(AED) for post TBI seizures. He was noted to have  persistent sleep wake cycle disorder and agitation which were attributed to his TBI and consequent cognitive decline .However following withdrawal of Levetiracetam from his AED drug regimen, there was a marked decrease in his agitation with gradual normalization of his sleep wake cycle. This in turn led to his better participation in the rehabilitation program.

Keywords: 
Traumatic brain injury, Levetiracetam, Sleep wake cycle disorder, Agitation

Introduction:

In traumatic brain injury (TBI) the primary insult to the brain and the secondary insults as a result of systemic complications may result in a multitude of sequelae ranging from subtle neurological deficits to significant morbidity and mortality. As the brain recovers by repair and adaptation, changes become apparent and may result in physical, cognitive and psychosocial dysfunction. Rehabilitation is usually structured to recover physical ability, cognitive and social retraining with the aim of gaining independence in activities of daily living.

Case Report:

A 76 year old male patient was admitted to an intermediate neurorehabilitation unit following a traumatic brain injury(TBI) .He had fallen from a height of 11 feet resulting in intracerebral haemorrhage in the left parietal lobe and a left parietotemopral subarachnoid hemorrhage which was managed conservatively in the neurosurgical unit. He developed recurrent post traumatic seizures in the form of myoclonic jerks for which he was started on antiepileptic drugs (AEDs) sodium valproate ,clobazam and levetiracetam .During his stay in the acute neurorehabilitation unit, he was noted to be confused and wandering with a disrupted sleep wake cycle. Cognitive assessment showed global impairment across all cognitive domains suggesting that cognitive impairment was secondary to TBI with the chaotic sleeping pattern and fatigue having a significant effect on his cognition. He was then transferred to an intermediate neurorehabilitation unit four months post head injury for rehabilitation prior to discharge.

On admission he was confused, and disorientated. His neurological examination was normal except for mild expressive dysphasia. On the first night of his stay in the unit, he did not sleep at all, was restless, agitated and aggressive towards the staff. His initial agitation was attributed to the change of surroundings and general disorientation. However during his first week at the rehabilitation unit it was noted that his sleep wake cycle was completely disrupted .He would have short fragmented naps through the day and would regularly get agitated at night with threatening behaviour towards staff. On admission the Rancho Los Amigos scale was 4(confused-agitated) and he needed specialized supervision. Despite environmental modification and optimal pharmacotherapy to improve sleep and decrease agitation, the patient still continued to have aggressive outbursts and no identifiable sleep wake pattern. It was noted by the nursing staff that occasionally when very agitated, the patient refused to have his night time medications including all AEDs .On such occasions he was reported to have slept better at night and did not have any daytime naps. All blood investigations were within normal limits except for mild hyponatremia with a normal creatinine clearance and CT head showed changes consistent with previous TBI with no new pathology .A neurology opinion was sought and with a Naranjo adverse drug reaction probability score†† of 7/10, a decision was taken to slowly decrease levetiracetam and wean it to stop, while continuing all other regular AEDs. The levetiracetam was reduced from an original dose of 750mg twice daily by 500mg every week with an aim to stop. This resulted in a considerable improvement in the patient’s agitation with a complete halt in the nighttime aggressiveness. His sleep wake cycle normalized and he started sleeping longer at night. His Ranchos Los Amigos scale improved from 4(confused-agitated) to 6(confused-appropriate). The patient could now participate more with the team of trained therapists in memory and attention exercises as well as regaining independence in activities of daily living.

Discussion:

TBI particularly in elderly aged over 64 years has a worse functional outcome as compared to non elderly.1Closed head injury in older adults produces considerable cognitive deficits in the early stages of recovery2 and there have been studies suggesting TBI to be a risk factor for developing Alzheimer’s disease.3Memory deficits, attention problems, loss of executive function and confusion are common after TBI.4This impaired cognitive function reduces the patient’s ability to recognize environmental stimuli often resulting in agitation and aggression towards perceived threats.TBI by itself may result in a variety of sleep disorders ranging from hypersomnia, narcolepsy, alteration of sleep wake cycle, insomnia to movement disorders. 5Sleep wake schedule disorders following TBI are relatively rare and may clinically present as insomnia.6Often these sleep disorders result in additional neurocognitive deficits and functional impairment, which might often be attributed to the original brain injury itself and thus be left without specific treatment.

While dealing with disrupted sleep pattern and agitation in the elderly following TBI, treatable causes such as neurological, infectious, metabolic, and medications should be ruled out. This is imperative as they disrupt rehabilitation and achievement of functional goals. Long duration of agitation post TBI has been associated with longer duration of rehabilitation stay and persisting limitations in functional independence.7After ruling out all the treatable causes the first focus is on environmental management with provision of a safe, quiet, familiar, structured environment while reducing stimulation and providing emotional support. The next step is introduction of pharmacotherapy to reduce agitation. Though a variety of pharmacological agents are available, there is no firm evidence of efficacy of any one class and often the choice of drug is decided by monitoring its effectiveness in practice and watching for side-effects.8In pharmacotherapy, the general principle followed is start low and go slow while developing clear goals to help decide when to wean and stop medications. Atypical antipsychotics are often used for the agitation while benzodiazepines and non benzodiazepine hypnotics such as zopiclone are recommended for treatment of insomnia.9 However atypical antipsychotics carry a FDA black box warning being associated with increased risk of stroke and death among elderly.

But what does one do when all optimal non pharmacologic and pharmacologic measures fail? That brings us back to the drawing board which in this case led the team to rethink Levetiracetam, a novel new antiepileptic that has been used as monotherapy for partial seizures and adjunctive therapy for generalized tonic clonic and myoclonic seizures. Levetiracetam treated patients have been reported to have psychiatric adverse effects10 including agitation, hostility, anxiety, apathy, emotional lability, depersonalization, and depressionwith few case reports of frank psychosis 11.While in healthy volunteers levetiracetam is noted to consolidate sleep12,in patients with complex partial seizures, levetiracetam has been noted to cause drowsiness decreasing day time motor activity and increasing naps without any major effects on total sleep time and sleep efficiency during night.13There has been an isolated report of psychic disturbances following administration of levetiracetam and valproate in a patient with epilepsy which resolved following withdrawal of valproate. 14However in practice it is used for recurrent post TBI seizures as it is a potent AED with a relatively mild adverse effect profile and no clinically significant interactions with commonly prescribed AEDs.15

Any adverse drug reaction (ADR) should be evaluated while keeping the patients clinical state in mind. This was, indeed, difficult in our case. With a history of TBI and cognitive decline, it became difficult to ascertain whether the neurocognitive issues were purely due to the nature of TBI or due to an ADR. Assigning causality to a single agent is difficult and fraught with errors. Using the Naranjo algorithm 16, with a score of 7/10(probable ADR) and a notable response on withdrawal of the offending drug as in this case helps establish possible causality.

This is a rare instance where sleep wake cycle disorder and agitation resolved following withdrawal of Levetiracetam in an elderly patient with TBI. This in turn led to the patient having a stable mood so that therapists could communicate and interact with him in order to improve basic cognitive functions such as attention, memory, thinking and executive control. This case illustrates the constant need to systematically and frequently reassess patients as they recover from TBI.

Appendix: Ranchos Los Amigos Levels of cognitive functioning.

I No response: Total assistance
II Generalized response: Total assistance
III Localized response: Total assistance
IV Confused-agitated: Maximal assistance
V Confused-inappropriate, non-agitated: Maximal assistance
VI Confused-appropriate: Moderate assistance
VII Automatic-appropriate: Minimal assistance for daily living skills
VIII Purposeful-appropriate: Stand-by assistance
IX

Purposeful-appropriate: Stand-by assistance on request

X

Purposeful-appropriate: Modified independent

††Naranjo Adverse Drug Reaction Probability Score:

  1. Question
Yes No Do Not Know Score
1. Are there previous conclusive reports on this reaction? +1 0 0  
2. Did the adverse event appear after the suspected drug was administered? +2 -1 0  
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0  
4. Did the adverse reaction reappear when the drug was readministered? +2 -1 0  
5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? -1 +2 0  
6. Did the reaction reappear when a placebo was given? -1 +1 0  
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0  
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0  
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0  
Was the adverse event confirmed by any objective evidence? +1 0 0  

Score
<0 =Doubtful ADR
1-4=Possible ADR
5-8=Probable ADR
>9=Definite ADR

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAIR CV, MBBS, Senior clinical fellow,Rehabilitation Medicine, Devonshire Centre for Neurorehabilitation,Stockport,United Kingdom. KADIES MA, FRCP, Consultant,Rehabilitation Medicine, Devonshire Centre for Neurorehabilitation,Stockport, United Kingdom.
Corresponding Author Details: 
Nair CV, Senior clinical fellow,Rehabilitation Medicine, Devonshire Centre for Neurorehabilitation,Stockport,United Kingdom.
Corresponding Author Email: 
drvchitra@yahoo.com
References
References: 

1. Susman M, DiRusso SM, Sullivan T. Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. J Trauma. 2002 Aug; 53(2):219-23.

2. Goldstein FC, Levin HS, Presley RM. Neurobehavioural consequences of closed head injury in older adults.J Neurol Neurosurg Psychiatry. 1994 Aug; 57(8):961-6.

3. Lye TC,  Shores EA.Traumatic brain injury as a risk factor for Alzheimer's disease: a review.   Neuropsychol Rev. 2000 Jun; 10(2):115-29.  

4. Verma A, Anand V, Verma NP .Sleep disorders in chronic traumatic brain injury. J Clin Sleep Med. 2007 Jun 15; 3(4):357-62.

5. Patten SB, Lauderdale WM. Delayed sleep phase disorder after traumatic brain injury.J Am Acad Child Adolesc Psychiatry. 1992 Jan; 31(1):100-2.

6. Nott MT, Chapparo C, Baguley I. Agitation following traumatic brain injury: an Australian sample .JBrain Inj. 2006 Oct;20(11):1175-82.

7. Fleminger S, GreenwoodRJ, Oliver DL. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003299.

8. Li Pi ,Shan RS, Ashworth NL. Comparison of lorazepam and zopiclone for insomnia in patients with stroke and brain injury: a randomized, crossover, double-blinded trial. Am J Phys Med Rehabil 2004;83:421-427.

9. Mula M, Trimble MR, Yuen A. Psychiatric adverse events during levetiracetam therapy. Neurology. 2003 Sep 9;61(5):704-6.

10.Aggarwal A,Dutt D,Sharma RC.Probable psychosis associated with Levetiracetam. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):274-5.

11. Cicolin A, Magliola U, Giordano A. Effects of levetiracetam on nocturnal sleep and daytime vigilance in healthy volunteers.Epilepsia. 2006 Jan;47(1):82-5.

12 Yilmaz H.Comparison of motor activity and sleep in patients with complex partial seizures on levetiracetam treatment and a group of healthy subjects. Behav Neurol. 2007;18(3):165-70.

13. Siniscalchi A, L Gallelli L, De Fazio S. Psychic Disturbances Associated with Sodium Valproate Plus Levetiracetam, Ann Pharmacother March 2007 vol. 41 no. 3 527-528.

14. Pinto A, Sander JW.Levetiracetam: a new therapeutic option for refractory epilepsy. Int J Clin Pract. 2003 Sep;57(7):616-21

15. Naranjo CA, Busto U, Sellers EM. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239–45.

Integrative model of chronically activated immune-hormonal pathways important in the generation of fibromyalgia

Authors
Paul C. Breeding, Nancy C. Russell and Garth L. Nicolson
Article Citation and PDF Link
BJMP 2012;5(3):a524
Abstract / Summary
Abstract: 

Clinicians are often challenged by patients presenting with a syndrome of chronic and diffuse full body pain with long standing fatigue and a cluster of related symptoms.    Fibromyalgia has become the commonly accepted term for this syndrome.  Diagnosis is established through recognized subjective symptoms, such as tender points and other indicators of chronic full body pain and fatigue. Suspected triggers have included bacterial and viral infections, toxins, allergens, and emotional and physical trauma. Unknown causes limit the prescription of effective treatments; however, neuropathic pain and fatigue have been identified as key components so dual reuptake inhibitors and anti-convulsants have shown some effectiveness for some patients.  Based upon laboratory and clinical studies of the last decade, this article proposes a model for a subset of fibromyalgia patients who have prolonged immune activation with related oxidative and nitrogenous stress leading to multiple hormonal repression, disrupted collagen physiology, neuropathic pain and fatigue. This integrative model of fibromyalgia is based on chronic up-regulation of the immune system with subsequent hormonal, connective tissue and nervous system implications.

Introduction

Fibromyalgia (FM) is a challenging set of chronic, overlapping and debilitating syndromes with widespread pain, abnormal pain processing, sleep disturbance, fatigue and psychological distress.1 The American College of Rheumatology (ACR) 1990 diagnostic guidelines were based primarily on tender point examination findings at 11 of 18 potential tender points;2 however, lack of consistent application of these guidelines in clinical settings led the ACR in 2010 to develop new diagnostic criteria based on a Widespread Pain Index (WPI) and symptom severity (SS) scale with no requirement of a tender point examination.  Symptoms must have been present for at least three months with the absence of any other disorder that would otherwise explain the pain and other signs and symptoms.3

Type of pain and other symptoms vary widely in FM, complicating diagnosis and treatment.  A cross-sectional survey of 3,035 patients in Germany utilized cluster analysis to evaluate daily records of symptoms noted by patients on handheld computers. Five subgroups were described: four with pain evoked by thermal stimuli, spontaneous burning pain, pressure pain, and pressure pain combined with spontaneous pain; the fifth subgroup had moderate sensory disturbances, but greater sleep disturbances and the highest depression scores.4

Estimates of the prevalence of FM have varied based on case definitions and survey methods.  Using 1990 ACR guidelines, it was estimated to affect between 0.1 to 3.3% of populations in western countries and 2.0% in the United States. Greater prevalence occurs among females, with estimates ranging from 1.0 to 4.9%.1, 5  Reasons for the gender difference have not been determined.6-9 

Fibromyalgia Risk Factors

Identification of risk factors for FM has been complicated by the array of seemingly unrelated signs and symptoms. The United States Centers for Disease Control (CDC) notes  loose association with genetic predisposition,10 bacterial and viral infections, toxins, allergies, autoimmunity, obesity and both physical and emotional trauma.1, 11  

Chronic fatigue syndrome and infection

Although chronic fatigue syndrome (CFS) has been defined as a separate syndrome, up to 70% of patients with FM are also diagnosed with CFS and 35-70% of patients with CFS have also been diagnosed with FM.12   Thus studies of patients with CFS may have clinical relevance to FM. Several case controlled studies of CFS and one of CFS/FM have been associated with chronic bacterial infections due to Chlamydia (Chlamydophila p.), Mycoplasma, Brucella, and Borrelia.12-18  The most prevalent chronic infection found has been that of the various Mycoplasmaspecies.15-23 

Mycoplasmas are commonly found in the mucosa of the oral cavity, intestinal and urogenital tracts, but risk of systemic illness occurs with invasion into the blood vascular system and subsequent colonization of organs and other tissues.15-23  Mycoplasmal infections have been identified in 52 – 70% of CFS patients compared with 5 to 10% of healthy subjects in North America15-17, 19-22 and Europe (Belgium)23.  For example, the odds ratio (OR) of finding Mycoplasma species in CFS was 13.8 (95% CL 5.8-32.9,  p< 0.001) in North America.17  A review by Endresen12 concluded that mycoplasmal blood infection could be detected in about 50% of patients with CFS and/or FM.  A CDC case-control study attempted to replicate these findings based on the hypothesis that intracellular bacteria would leave some evidence of cellular debris in cell-free plasma samples.  Results were that the healthy subjects actually had evidence of more bacteria although the difference was not significant. The authors noted the complexity and limitations of this type of analysis and also postulated that since the CFS patients were years past the onset of illness, they might have previously cleared the triggering agent.24  However, most studies found Mycoplasma DNA in intracellular but not extracellular compartments in CFS patients, and this could explain the discrepancy.15-23  Other studies have found that 10.8% of CFS patients were positive for Brucella species (OR=8.2, 95% CL 1-66, p<0.01)16 and 8% werepositive for  Chlamydia pn. (OR= 8.6; 95% CL 1-71.1,p< 0.01)17.

The presence of multiple co-infections may be an especially critical factor associated with either initiation or progression of CFS.  Multiple infections have been found in about one-half of Mycoplasma-positive CFS patients (OR = 18.0, 95% CL 8.5-37.9, p< 0.001), compared with single infections in the few control subjects with any evidence of infection.17 A  North American study identified chronic infections in 142 of  200 patients (71%) with 22% of all patients having multiple mycoplasmal infections while just 12 of the 100 control subjects (12%) had infections (p<0.01) and none had multiple infections.15 Similarly, a European study reported chronic mycoplasmal infections in 68.6% of CFS and 5.6% of controls.  Multiple infections were found in 17.2% of the CFS patients compared with none in the controls (p<0.001).23 Multiple co-infections were also associated with significantly increased severity of symptoms (p<0.01).15, 23 

Viral infections associated with CFS have included Epstein Barr virus, human herpes virus-6, cytomegalovirus, enteroviruses and several other viruses.15, 25, 26

Despite indications of single or multiple bacterial and/or viral infections in most patients with CFS, antibiotic or antiviral treatments have yielded inconsistent results.27  Slow growing intracellular bacteria are relatively insensitive to most antibiotics and have inactive phases when they would be completely insensitive to any antibiotics.28 23   Some treatments may actually have resolved the infections, but not the immune pathways that may remain in an activated state capable of producing symptoms. 

Fibromyalgia and infection

Bacterial infections associated with FM as a separate syndrome have included small intestinal bacterial overgrowth (SIBO)29, 30 and helicobacter pylori (HP)31.   Utilizing the lactulose hydrogen breath test (LHBT), investigators found SIBO in 100% of 42 patients with FM.   They noted that 30-75% of patients with FM have also been found to have irritable bowel syndrome (IBS).29, 30  A confounding factor is that medications prescribed for FM often have gastrointestinal side effects.29  HP diagnosed by positive immunoglobulin gamma (IgG) serum antibody was significantly higher in women with FM (44/65 or 67.7%) compared with controls (18/41 or 43.9%) (p=0.025) in Turkey31.

Viral infections associated with FM have included hepatitis C, in which two studies found an association,32-34 and two studies found no association.35, 36 Associations with FM have also been found with hepatitis B, 37 human immunodeficiency virus (HIV)38, 39 and human T cell lymphotropic virus type I (HTLV-1).40

Fibromyalgia and non-infectious associations

Non-infectious triggers associated with FM have included toxins, allergens, and physical or emotional trauma. These triggers may not have been strictly “non-infectious” as allergens and toxins may also be produced by infections, and physical or emotional trauma may lead to the reactivation of previously controlled infections. Respondents to an internet survey of people with FM (n=2,596) also identified triggers as chronic stress (41.9%), emotional trauma (31.3%), acute illness (26.7%) and accidents (motor vehicle 16.1%, non-motor vehicle 17.1%).41 Physical trauma associated with FM has included cervical spine injuries as well as motor vehicle and other accidents.42-44 

Fibromyalgia and autoimmunity

Three studies have found thyroid autoantibodies to be in greater percentages in subjects with FM compared with controls, in spite of normal thyroid hormone levels.  One study reported autoantibodies in 41% of FM patients versus 15% of controls.45  The second study reported 16% in FM versus 7.3% in controls, p<0.01.46 The third study reported 34.4% in FM versus 18.8% in controls (p=0.025)47 and OR =3.87, 95% CL  1.54-10.13.48  This could also have been the result of thyroiditis, because infections like Mycoplasma are often found in thyroiditis patients.15

Autoantibodies to serotonin were identified in 74% of 50 patients with FM compared with 6% of 32 healthy (blood donor) controls. Notably, serotonin levels were normal in 90% of the FM patients indicating serotonin receptor involvement.49

Fibromyalgia and Metabolic Syndrome

Metabolic Syndrome consisting of abdominal obesity, high triglycerides, high blood pressure, elevated fasting glucose and decreased high-density lipids, was associated with FM in a U.S. study in which  cases were 5.6 times as likely to have Metabolic Syndrome as controls (C2MH = 3.84, p = .047, 95% CL 1.25 – 24.74).50 

Fibromyalgia and emotional trauma

Although emotional trauma has been acknowledged as a contributing factor, most studies of CFS/FM have used recognized tests such as Beck’s Depression Index, Beck’s Anxiety Index and Minnesota Multi Personality Index (MMPI) to exclude potential subjects with actual psychiatric illnesses.51, 52

Psychological and physiological subsets of fibromyalgia 

A Wisconsin cross sectional survey of 107 women with confirmed diagnoses of FM used validated psychological and physiological measures followed by cluster analysis. Four distinct subsets were identified: (I) history of childhood maltreatment and hypocortisolism with the most pain and disability; (II) “physiological dysregulation” described as “distinctive on nearly every biological index measured” with high levels of pain, fatigue and disability; (III) normal biomarkers with intermediate pain severity and higher global functioning; and (IV) psychological well-being with less disability and pain.53

The “physiological dysregulation” of FM subset II  consisted of the highest antinuclear antibody (ANA) titers (t=4.06, p=0.001), highest total cholesterol levels (t=3.96, p<0.001), larger body mass index (BMI) values t=2.21, p<0.04), lowest Natural Killer (NK) cell numbers (t=3.95, p<0.001), lowest growth hormone (t=3.20, p<0.002), and lowest testosterone levels (t=3.80, p<0.001).  Trends were also indicated toward the highest erythrocyte sedimentation rate (ESR) (t=2.02, p=0.056), lowest creatinine clearance (t=1.85, p=0.067) and lowest cortisol (t=2.78, p<0.007).53

Proposed Model of Fibromyalgia

The authors’ proposed model of FM develops a rationale for the “physiological dysregulation” indicated in subset II of the Wisconsin study.  In this model, various triggers are followed by prolonged immune activation with subsequent multiple hormonal repression, disrupted collagen physiology and neuropathic pain.

 Activation of immune response pathways

Innate immune responses begin with anatomical barriers, such as the epithelium and mucosal layers of the gastrointestinal, urogenital and respiratory tracts, and physiological barriers, such as the low pH of stomach acid and hydrolytic enzymes in bodily secretions. 54 Breeching of these barriers activates cell-mediated immunity launched by leucocytes with pattern recognition receptors: neutrophils, macrophages and dendritic cells (DCs).54 Insufficient or damaged anatomical or physiological barriers would necessarily keep this cell mediated level of innate defense in a constant state of alert and activity.

In contrast to the innate immune response, adaptive immunity has highly specific recognition and response activities resulting in lasting changes produced by leukocytes known as lymphocytes.   B lymphocytes (B cells) secrete plasma cells producing antibodies to specific pathogens. T lymphocytes (T cells), the other major cells of adaptive immunity, can be either cytotoxic (Tc) or helper cells (Th).  Tc cells produce progeny that are toxic to non-self peptides and Th lymphocytes secrete small proteins (cytokines) that mediate signaling between leukocytes and other cell types.  All types of lymphocytes retain memory so that subsequent invasions provoke faster and more rapid differentiation into effector cells. 54, 55  Some Th cells respond to intracellular pathogens (Th1) and some to extracellular pathogens (Th2).  A third type (Th17) appears to respond to certain bacterial and fungal infections, tumor cells and are also involved in autoimmune diseases.56  

In the presence of environmental stressors, cells may release stress proteins to alert the organism to potentially damaging conditions. These proteins can bind to peptides and other proteins to facilitate surveillance of both the intracellular and extracellular protein environment.  One form of stress proteins, heat shock proteins (HSP), can mimic the effects of inflammation and can be microbicidal.52, 57

One of the earliest responses to intracellular viral or bacterial infections involves production of three types of interferon (IFNa, IFNb and IFNg).  Any of these can initiate a series of metabolic events in uninfected host cells that produce an antiviral or anti-bacterial state.58, 59 When IFN-γ targets genes in uninfected cells, the targeted genes become microbicidal by encoding enzymes generating oxygen (O2) and nitric oxide (NO) radicals.58  Activation of O2 or NO radicals triggers another cascade involving IL-6, IL-1b, the cytokine Tumor Necrosis Factor-a (TNF-a) and the transcription nuclear factor kB (IKKb-NF-kB).  NF-kB can be activated by a variety of inflammatory stimuli, such as cytokines, growth factors, hormones, oncogenes, viruses and their products, bacteria and fungi and their products, eukaryotic parasites, oxidative and chemical stresses, therapeutic and recreational drugs, additional chemical agents, natural products, and physical and psychological stresses.60 Activation of NF-kB releases its subunits; the p50 subunit has been associated with autoimmunity and the RelA/p65 unit with transcriptional activity involving cell adhesion molecules, cytokines, hematopoietic growth factors, acute phase proteins, transcription factors and viral genes.61  The authors propose that chronic infection or other stress would be a sustaining trigger of an immune cascade that includes NF-kB and resultant cell signaling processes that drive many of the symptoms of fibromyalgia.

The cytokine interleukin-6 (IL-6) can either activate or repress NF-kB through a switching mechanism involving IL-1ra and Interleukin 1b(IL-1b).   IL-6 first activates Interleukin 1b  (IL-1b), which then activates TNF-a, leading to the subsequent activation of NF-kB. 62, 63 Specifically, the release of the RelA/p65 subunit of activated  NF-kB switches on an inhibitory signaling protein gene (Smad 7) that blocks phosphorylation of Transforming Growth Factor Beta (TGF-b) resulting in the repression of multiple genes.  Alternatively, IL-6 activates IL-1ra, which allows TGF-b to phosphorylate and induce the expression of activating signaling protein genes Smad2 and Smad3, resulting in the full expression of multiple genes.61  

NF-kB plays a key role in the development and maintenance of intra- (Th1) and inter- (Th2) cellular immunity through the regulation of developing B and T lymphocytes. The p50 dimer of NF-kB has been shown to block B Cell Receptor (BCR) editing in macrophages, resulting in loss of recognition and tolerance of host cells (autoimmunity). T cells that are strongly auto-reactive are normally eliminated in the thymus, but weakly reactive ones are allowed to survive to be subsequently regulated by regulatory T-cells and macrophages.  Acquired defects in peripheral T-regulatory cells may mean failure to recognize and eliminate weakly reactive ones.54, 64  The IL-17 cytokine associated with autoimmunity can activate NF-kB through a pathway that does not require TNF-a.56 NF-kB activity can also be activated or repressed by the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (c AMP) in the early phases (3 days) of nerve injury through its main effector enzyme, protein kinase A (PKA).65, 66  PKA decreases during later stages as the enzyme protein kinase C (PKC) increases.  PKC then plays important roles in several cell type specific signal transduction cascades.67 An isoform of PKC within primary afferent nociceptive nerve fibers signals through IL-1b and prostaglandins E2 (PGE2) as demonstrated in animal studies.68  This process has been called “hyperalgesic priming,” and it has been described as responsible for the switch from acute to long-lasting hypersensitivity to inflammatory cytokines.69

Figure 1 depicts key immune pathways leading to expression or repression of multiple genes proposed to be important in FM and neuropathic pain.

Fibromyalgia and immune - hormonal interactions

Reciprocity exists between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis through its production of glucocorticoid signal transduction cascades. 63, 70, 71. Hormones such as cortisol (hydrocortisone) produced by the adrenal cortex, affect metabolism of glucose, fat and protein.72  The glucocorticoid receptor (GR), a member of the steroid/thyroid/retinoid super family of nuclear receptors is expressed in “virtually all cells”.  When the GR in the cytoplasm binds a glucocorticoid, it migrates to the nucleus where it modulates gene transcription resulting in either expression or repression of TNF-a, IL-1bβ and the NF-kB p65/Rel A subunit.  However, the RelA/p65 protein can also repress the Glucocorticoid Receptor. 63, 70, 71, 73

Growth hormone (GH), an activator of NF-kB,74  is usually secreted by the anterior pituitary, but changes found in FM may be hypothalamic in origin.  GH is needed for normal childhood growth and adult recovery from physical stresses.75  Although low levels of GH were found in subset II of the Wisconsin study, 53 functional deficiency may be expressed as low insulin-like growth factor 1 (IGF-1) combined with elevated GH, suggesting GH resistance.76, 77   Defective GH response to exercise has been associated with increased pain and elevated levels of IL-1b, IL-6, and IL-8.77, 78

The hormones serotonin and norepinephrine modulate the movement of pain signals within the brain.  Serotonin has been found to suppress inflammatory cytokine generation by human monocytes through inhibition of the NF-kB cytokine pathway in vitro;79 however, NF-kB promotion of antibodies can repress serotonin.49  Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), such as duloxetine and milnacipran, are key treatment options for fibromyalgia and have been approved of by the U.S. Food and Drug Administration (FDA).80, 81  Although serotonin has been best measured in cerebral spinal fluid (CSF), recently improved methods of collection were utilized  (using rats and in 18 women) that yielded a high degree of correlation (r=0.97) between CSF and plasma, platelet, and urine measurements.82

NF-kB activation has also been documented to interfere with thyroid hormone action through impairment of Triiodothyronine (T3) gene expression in hepatic cells. 83  However, T3 administration has induced oxidative stress and activated NF-kB in rats.84 

Metabolic Syndrome, a confounding factor in Fibromyalgia

Leptin and insulin hormones interact to regulate appetite and energy metabolism.  Leptin, produced by adipose cells, circulates in the blood eventually crossing the blood-brain barrier to bond with a network of receptors within the hypothalamus.   Insulin, produced by beta cells in the pancreas, similarly crosses the blood brain barrier to interact with its own network of hypothalamic receptors.  Leptin and its receptors share structural and functional similarities to long-chain helical cytokines, such as IL-6, and it has been suggested that leptin be classified as a cytokine.85-89

Metabolic syndrome can be a confounding factor in FM due to peripheral accumulation of fatty acids, acylglycerols and lipid intermediates in liver, bone, skeletal muscle and endothelial cells.  This promotes oxidative endoplasmic reticulum (ER) stress and the activation of inflammatory pathways involving PKC and hypothalamic NF-kB, leading to central insulin and leptin repression.85-87, 89-91   Hyperinsulinemia further stimulates adipose cells to secrete and attract cytokines such as TNFa and IL-6 that trigger NF-kB in a positive feedback loop, which can be complicated by chronic over nutrition that increases the generation of reactive oxygen intermediates and monocyte chemoattractant protein-1 (MCP-1).87, 89  When exposed to a chronic high fat diet, hypothalamic NF-kB was activated two fold in normal mice and six times in mice with the obese (OB) gene.89

Fibromyalgia and indicators of immune-hormonal activity

Although most components of either innate or adaptive cell mediated immune responses exist for only fractions of seconds, some of their effects and products can be detected long after in the skin, muscle, blood, saliva or sweat92, 93.  

One component,  nitric oxide (NO),  can suppress bacteria; however, endothelial damage causes dysfunction with impaired release of NO and loss of its protective properties.86 The enzyme transaldolase acts as a counterbalance by limiting NO damage to normal cells.  Thus, high levels of transaldolase indicate elevated reactive oxygen species, reactive nitrogen species (ROS/RNS) and cellular stress. The “exclusive and significant over-expression of transaldolase” in the saliva samples of 22 women with FM compared with 26 healthy controls (77.3% sensitivity and 84.6% specificity, p<0.0001; 3 times greater than