Internal Medicine

Are mRNA Covid 19 vaccines safe in Long Covid patients? A Health Care Workers perspective

Authors
Tarek A-Z K Gaber, Abdul Ashish, Alison Unsworth & Jane Martindale
Article Citation and PDF Link
BJMP 2021;14(1):a008
Abstract / Summary
Abstract: 

Introduction: Long Covid patients may have concerns about the impact of mRNA vaccines on their symptoms.
Method: A short questionnaire was sent to users of a long covid service supporting an NHS Trust staff in Wigan 2 weeks following the conclusion of a mRNA vaccine first dose roll out. The questionnaire explored acceptance and compliance with the vaccine and any change in the symptoms at least 2 weeks following the vaccination.
Results: 77 HCW were offered the vaccine. 10 respondents declined mainly because of concerns regarding worsening long covid symptoms. 67% of respondents did not experience any change in symptoms whilst 21% experienced improvement of symptoms. 12% experienced worsening of symptoms.
Conclusion: mRNA vaccines can influence long covid symptoms. However, patients seemed to be twice as likely to experience improvement than worsening of symptoms.

Keywords: 
long covid / mRNA vaccine

Sceptical attitudes towards Covid 19 vaccines effectiveness and/ or safety are currently a major risk to global health. However, not every person declining Covid 19 vaccination is an irrational conspiracy theorist (1). Patients suffering from specific conditions may have justified concerns that in the absence of safety data for their specific health problems, they may find it difficult to appraise the risks associated with the vaccination in their condition.

Patients suffering from long term complications of Covid 19 have coined the term long covid to describe their debilitating illness (2). Many clinicians feel that long covid complexity may reflect different pathological processes (3) with respiratory symptoms being primarily secondary to tissue damage whilst fatigue and its associated post exertional symptoms such as physical pain or brain fog resulting from a dysregulated immune response (4).

Two mRNA vaccines developed by Pfizer Biontech and Moderna have demonstrated impressive levels of immunity against SARS CoV-2 virus in randomised controlled trials (5,6). This relatively new technology had several advantages that made it one of the earliest vaccines to be developed, tested, scaled up and subsequently approved for use all over the world. The potency of the immune response is another significant advantage of mRNA vaccine as suggested by previous in vitro and animal experiments (7).

This potency is naturally a positive characteristic especially when mRNA vaccine technology is used against an easily transmissible and potentially lethal disease. However, for patients suffering from long covid, such a strong immune response could be a cause for concern.

As vaccination programmes against SARS CoV. 2 Virus are rolled out around the world, long covid patients face a difficult decision as no data is available about the impact of the mRNA vaccines on their condition. In the UK, long covid is not considered to be a contraindication for vaccination (8); however, in the absence of any safety data for this group of patients, it is very difficult to provide an informed opinion about the risk.

Methods

In the summer of 2020, Wrightington, Wigan and Leigh NHS Trust Hospitals established a dedicated service for staff suffering from long covid. As Health Care Workers (HCW) in the UK were prioritised for vaccination, Pfizer Biontech Vaccine was offered to all Hospital employees with the first dose provided between end of December 2020 and end of January 2021.

A survey questionnaire was sent to all long covid staff members 2 weeks following the conclusion of the first dose roll out. The e-mail addresses were obtained from the long covid clinic data base.  This short questionnaire evaluated the rate of acceptance of the vaccine, reasons for declining, immediate side effects and any persistent change of the long covidsymptoms following the vaccination. The survey was approved by the information governance department.

Results

The questionnaire was sent to 117 HCW. Out of 83 responses, 77 subjects were offered the vaccine (age range:18 - 65 with only 7 male respondents).

10 HCW declined having the vaccine (13 %) with 5 of them citing concerns about worsening symptoms as the main reason. Out of 67 HCW receiving the vaccine 48 (72%) had immediate but self-limiting side effects.

Fatigue, shortness of breath and anxiety were the most common symptoms of long covid our cohort originally had (75%, 53% and 18% respectively). Several weeks following vaccination, 45 subjects reported no change (67%) in symptoms. Fourteen (21%) subjects reported improvement of one or more of their symptoms (8 of them experienced improving respiratory symptoms, 4 improving fatigue, 5 improving anxiety and 2 mentioned improving other symptoms).  Eight subjects (12%) reported worsening symptoms including fatigue (3 subjects), respiratory (1 subject), anxiety (2 subjects). Two subjects experienced worsening of other symptoms.

Discussion

When offered vaccination, our long covidpatients showed higher rates of compliance (86%) compared to the general population (9). However, five patients declined the vaccine because of their concerns about worsening symptoms.

Despite having a small number of subjects, limitations to the survey methodology and the relatively short period following vaccination, our report is the first to comment on the response of a cohort of long covid patients to mRNA vaccination. Most of our HCWs didn’t report any change in their symptoms with encouragingly 21% experiencing subjective improvement of symptoms with 10% of all participants reporting respiratory symptoms improvement. The 8 subjects reporting worsening of symptoms experienced more diverse problems with worsening fatigue the most common.

Our results were consisted with unpublished data reporting the feedback of 473 long covid social media users (10). 32% of this self-selecting population reported improvement of symptoms whilst 17% reported worsening of symptoms.

We would like to suggest two potential explanations for our findings. Comprehensive investigations for the respiratory system could be normal in some long covid patients complaining of shortness of breath (11). Dysfunctional breathing might contribute to the severity of shortness of breath (12). The confidence given to the patients from taking the vaccine may act in a positive way to reduce their anxiety and subsequently such perception of the respiratory effort.

Another potential explanation is the complex way mRNA vaccines manipulate the immune system potentially improving or worsening the already dysregulated immunity in long covid patients (4). It is encouraging to see that long covid patients are about twice as likely to experience improvement of symptoms compared to patients experiencing worsening of symptoms. We hope that our findings may be an early source of reassurance that mRNA Covid 19 vaccines are not commonly associated with adverse effects in long covid patients.

We feel that longitudinal studies appraising long covid symptoms and immunological markers  correlating the pre and post mRNA vaccines may have the potential not only to improve understanding of the main long covid pathologies but may also unlock the secrets of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (ME/CFS) as a common condition possibly sharing many of long covid characteristics.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
TAREK A-Z K GABER; FRCP; Consultant in Rehabilitation Medicine, Wrightington, Wigan and Leigh NHS Trust, UK. ABDUL ASHISH; MD FRCP; Consultant Respiratory Physician, Wrightngton, Wigan and Leigh NHS Trust, UK. ALISON UNSWORTH; Head of the audit department, Wrightngton, Wigan and Leigh NHS Trust, UK. JANE MARTINDALE; PHD; Research and Development department, Wrightngton, Wigan and Leigh NHS Trust, UK.
Corresponding Author Details: 
TAREK A-Z K GABER; FRCP; Consultant in Rehabilitation Medicine, Wrightington, Wigan and Leigh NHS Trust, UK.
Corresponding Author Email: 
t.gaber@nhs.net
References
References: 
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  4. Gaber T. Assessment and management of post covid fatigue. Progress in Neurology and Psychiatry 2021; 25(1): 36-39. https://doi.org/10.1002/pnp.698
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  6. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O'Dell S, Schmidt SD, Corbett KS, Swanson PA 2nd, Padilla M, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Martinez DR, Baric R, Buchanan W, Luke CJ, Phadke VK, Rostad CA, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med. 2020 Dec 17;383(25):2427-2438. doi: 10.1056/NEJMoa2028436. Epub 2020 Sep 29. PMID: 32991794; PMCID: PMC7556339. 
  7. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018 Apr;17(4):261-279. doi: 10.1038/nrd.2017.243. Epub 2018 Jan 12. PMID: 29326426; PMCID: PMC5906799. 
  8. Public Health England. Covid 19 Vaccination programme. Information for health care practitioners.  https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/965177/COVID-19_vaccination_programme_guidance_for_healthcare_workers_26_February_2021_v3.4.pdf(Accessed on line 2 March 2021)
  9. Lazarus, J.V., Ratzan, S.C., Palayew, A. et al. A global survey of potential acceptance of a COVID-19 vaccine. Nat Med 27, 225–228 (2021). https://doi.org/10.1038/s41591-020-1124-9 
  10. https://www.youtube.com/watch?v=Lio2ByLW4WE&t=518s (accessed on line 1 March 2021)
  11. Torres-Castro R, Vasconcello-Castillo L, Alsina-Restoy X, Solis-Navarro L, Burgos F, Puppo H, Vilaró J. Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis. Pulmonology. 2020 Nov 25:S2531-0437(20)30245-2. doi: 10.1016/j.pulmoe.2020.10.013. Epub ahead of print. PMID: 33262076; PMCID: PMC7687368. 
  12. Courtney R, van Dixhoorn J, Greenwood KM, Anthonissen EL. Medically unexplained dyspnea: partly moderated by dysfunctional (thoracic dominant) breathing pattern. J Asthma. 2011 Apr;48(3):259-65. doi: 10.3109/02770903.2011.554942. Epub 2011 Feb 22. PMID: 21341969. 

Predictors of in-hospital mortality in Covid-19: a study across two peripheral District General Hospitals in UK

Authors
Nil Kamal Samanta, Samik Kumar Bandyopadhyay, Dodiy Herman, Biman Chakraborty, Adrian Marsh, Subramanian Kumaran, Lauren Burnard, Gunalan Gnanaseelan , Saoirse Gibson, Benita Florence & Saibal Ganguly
Article Citation and PDF Link
BJMP 2021;14(1):a003
Abstract / Summary
Abstract: 

Aim - The mortality from Coronavirus Disease 2019 (COVID-19) has remained a significant medical challenge. Internationally, patient demographics and pre-existing co-morbidities are significant determinants of mortality from COVID-19. The mortality-risk in a local population is difficult to determine. The objective of our study is to examine the risk posed by epidemiological and demographic variables, and co-morbidities in our local population.

Method - A retrospective, observational study was conducted on confirmed COVID-19 patients, identified from the local microbiology database. A search of the electronic patient records was performed to collect demographic details and co-morbidities. Chi-square test and logistic regression analysis of the demographic variables and co-morbidities were utilised to calculate the predictive-risk for in-hospital mortality of adult COVID-19 patients.

Results - Final analysis included 263 samples. Univariate logistic regression analysis was performed using age as an independent categorical predictor with two cohorts – those <60 and those ≥60 years old. Age (χ2 =17.12, p<0.001) was found to be an independent predictor of mortality – this was independent of sex (χ2 =1.784, p<0.182).

Charlson Comorbidity Index (CCI) score was found to be a significant predictor of adverse outcome. The odds of death for patients with CCI scores 0-4 was less than half (44.8%) of those with CCI scores ≥5 (p=0.005).  Patients with no pre-existing medical conditions had a lower mortality-risk (OR=0.181, p=0.022) than those with known medical conditions. Pre-existing renal disease predicted a poor outcome (OR=1.996, p=0.027). The odds of death for the patients coming from their own-home was only 26% of the odds for those from a long-term care-home. Long-term care facility, advanced age (OR=1.058, p <0.001), and long-term oral steroid (OR=3.412, p=0.016) use were all associated with a poor prognosis.

Conclusion - People aged ≥60 years, residence in a long-term care-home, pre-existing renal diseases, a high CCI score and long-term oral steroids use were associated with an increased mortality-risk.

Abbreviations: 
CCI: Charlson Comorbidity Index; CI: Confidence Interval; CKD: Chronic Kidney Disease; CPR: Cardio-pulmonary resuscitation; OR: Odds Ratio; PRH: Princes Royal Hospital; RAAS: Renin angiotensin aldosterone system; RSH: Royal Shrewsbury Hospital; SaTH: Shrewsbury and Telford Hospitals NHS Trust.
Keywords: 
Co-morbidities, Covid-19, Immunomodulator, Mortality.

INTRODUCTION

The most recent outbreak of severe acute respiratory syndrome (SARS) has been caused by coronavirus-2 (SARS-CoV-2) – a new single-strand, positive-sense-RNA beta-coronavirus first reported in 2019 in Wuhan, China. The virus has spread to nearly all countries across the world.1-4

SARS-CoV-2 infection, also known as Coronavirus Disease 2019 (COVID-19), replicates mainly in the upper and lower respiratory tract. The transmission of COVID-19 from symptomatic and asymptomatic patients is usually through respiratory droplets, generated by coughing and sneezing or through contact with contaminated surfaces.4,5 The disease has an incubation period of approximately 5.2 days.6

Most infections are mild and uncomplicated.4 After one week of the onset of disease, 5-10% of patients tend to develop pneumonia, needing hospitalisation.4,6 Some of these patients develop further complications, often leading to death.4,6 The overall case fatality rate is 1.4%, with a noticeably higher rate after the sixth decade of life.4

People aged ≥ 60 years, especially with underlying medical conditions – such as cardiovascular disease, hypertension, diabetes mellitus (DM), chronic respiratory disease, cancer, immunodeficiency, obesity – and those of male-sex, have an increased risk of dying.4,7-12 Risk of severe adverse outcome is also associated with an increased number of associated co-morbidities.10

The impact of active cancer, endocrine disorders, autoimmune inflammatory rheumatic diseases etc. on COVID-19 outcomes has been investigated widely.13-18 Divergent views have emerged regarding the role of renin angiotensin aldosterone system (RAAS) inhibitors, steroids, and immunomodulators in COVID-19 mortality.

 

The objective of our study was to evaluate the risk posed by epidemiological and demographic variables in our local population. We also sought to analyse the impact of co-morbidities on in-hospital mortality in confirmed COVID-19 patients.

METHODS

Study design:

We conducted a retrospective analysis of demographics characteristics (age and sex) and medical co-morbidities – hypertension, chronic heart failure, ischaemic heart disease, DM, thyroid disorders, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2), chronic liver disease, active malignancy, immunosuppression, post-transplant status, chronic inflammatory arthritis and other rheumatic disorders – in all patients with confirmed COVID-19, who were admitted in two peripheral district general hospitals under a single National Health Service (NHS) trust serving primarily the rural population of western England.

Inclusion and Exclusion Criteria:

To determine COVID-19 status, nose and throat-swab specimens were obtained for real-time reverse transcription polymerase chain reactions (rt-PCR) in all adult (≥18 years) patients, attending one of the two district general hospitals (Royal Shrewsbury Hospital, Shrewsbury; and Princess Royal Hospital, Telford) under Shrewsbury & Telford Hospitals NHS Trust (SaTH) in the period from 1st March to 15th May 2020.

Patients who tested positive (either by N gene and ORF1ab gene positive / ORF1ab gene positive or N gene positive) and required subsequent in-hospital management were included in the study. Patients who were discharged after initial senior review (usually by a consultant physician), or brought in as a cardiac-respiratory arrest, were excluded. Re-admissions to the hospital beyond 48 hours following hospital discharge due to COVID-19 were excluded from the study. Patients diagnosed solely on radiological or clinical findings without a positive rt-PCR test were not included in our study.

We analysed the data based on the index-admission (including failed-discharge: re-admission within 48 hours following hospital discharge). No follow-up data was collected post-hospital discharge of these patients.

Data collection & analysis:

A list of all confirmed COVID-19 patients over a 76-day period was identified from the trust microbiology database. A search of the electronic patient records was completed by four members of our team. Supplementary data was gleaned from existing hospital paper records. Patient demographics, presenting symptoms, associated co-morbidities, medications, admission and discharge dates, intensive therapy unit (ITU) admissions, renal profile, referral source and outcomes were recorded in the specifically designed electronic datasheet.

Study Outcome:

The impact of epidemiological and demographic characteristics, and pre-existing medical conditions on the mortality of confirmed COVID-19 patients requiring in-hospital treatment was analysed.

RESULTS

A total of 303 confirmed COVID-19 (rt-PCR positive) samples were collected over a 76-day period. Five patients had been tested twice, and this was accounted for. Thirty-five patients were excluded from the study: twenty-four of them discharged after initial senior review without requiring in-hospital treatment, seven brought in with cardio-pulmonary resuscitation (CPR) in progress, three had inadequate data, and one was <18 years old. Of the 263 patients admitted, 70 (26.6%) died in hospital (Figure-1).

Figure-1: Flowchart of sampling and analysis

We stratified the mortality rates among the admitted patients by age (Table-1). A chi-square test of independence revealed that the mortality rate was significantly related to an advanced age (χ2 =27.078, p<0.001). The age and sex distributions of admissions and mortality are shown in Figure-2 (a, b, c).

Table-1: Medical admissions and mortality stratified by age

Age Admission N(m/f) Admission

(%)

Death

N(m/f)

Mortality

(%)

Chi-square

2)

P-value
18 – 20 Years 0 0% 0 0% 27.078 <0.001
21 – 30 Years 9(2/7) 3.4% 0 0%    
31 – 40 Years 9(6/3) 3.4% 0 0%    
41 – 50 Years 26(17/9) 9.9% 3(2/1) 11.5%    
51 – 60 Years 36(21/15) 13.7% 4(3/1) 11.1%    
61 – 70 Years 43(26/17) 16.3% 11(7/4) 25.6%    
71 – 80 Years 56(35/21) 21.3% 15(11/4) 26.8%    
81 and Above 84(52/32) 31.9% 37(24/13) 44.0%    
Total 263(159/104) 100.0% 70(47/23) 26.6%    

N: number of patients, m: male, f: female.

Figure-2 (a,b,c): Age, Sex, Admission and Mortality pyramids


We considered two age cohorts - below 60 and ≥60 years of age and other relevant demographic parameters (sex and residence in own-home/care-home) to analyse the impact on mortality rates (Table-2). Of the admitted patients, 159 (60.5%) were male, and 104 (39.5%) were female. The mortality rate was strongly associated with advanced age ≥60 years (χ2 =17.120, p<0.001) but independent of sex distribution (χ2 =1.784, p=0.182). However, it was also affected by the care facility (χ2 =18.146, p<0.001) with a higher mortality rate among the group of patients with residence in a long-term care-home.

Table-2: Admission and Mortality stratified by demographic variables

Variables Admission (N) Admission (%) Death (N) Mortality (%) Chi-square

2)

P-value
Age         17.120 <0.001
<60 years 77 29.3% 7 9.1%    
≥60 years 186 70.7% 63 33.9%    
Sex         1.784 0.182
Female 104 39.5% 23 22.1%    
Male 159 60.5% 47 29.6%    
Care facility         18.146 <0.001
Own-home 211 80.2% 44 20.9%    
Care-home 52 19.8% 26 50.0%    

N: Number of patients; Care-home: Long-term care in residential or nursing home.

To identify the strength of the associations, we conducted a univariate logistic regression analysis with mortality as the dependent variable and the demography and presence/absence of the co-morbidities as the independent variable (Table-3). We found that age as a continuous predictor had an odds ratio of 1.058 (p<0.001), which translated to increased odds of dying by 5.8% for every year of advanced age. Using age as a categorical predictor with the other two categories, the odds of death for patients aged below 60 years was found to be 0.195 times the odds of death for the patients aged 60 years or above.

Table-3: Univariate logistic regression analysis of the demographic variables and co-morbidities

   

Admission (N)

Admission (%)

Died (N)

Mortality (%)

Odds Ratio

95% C.I

 

Variables

Categories

Lower

Upper

P-value

Overall   263 100% 70 26.6%        
Age           1.058 1.035 1.082 <0.001
Age (Cat) <60 years 77 29.3% 7 9.1% 0.195 0.085 0.450 <0.001
  ≥60 Years 186 70.7% 63 33.9%        
CCI           1.255 1.114 1.414 <0.001
CCI (Cat) 0 – 4 158 60.1% 32 20.3% 0.448 0.257 0.781 0.005
  ≥5 105 39.9% 38 36.2%        
Sex Female 104 39.5% 23 22.1% 0.677 0.381 1.202 0.183
  Male 159 60.5% 47 29.6%        
Care Facility Own-Home 211 80.2% 44 20.9% 0.263 0.139 0.498 <0.001
  Care-Home 52 19.8% 26 50.0%        
eGFR           0.961 0.950 0.973 <0.001
Active malignancy Known 17 6.5% 1 5.9% 0.160 0.021 1.232 0.079
Cardiovascular* disease Known 125 47.5% 39 31.2% 1.565 0.903 2.714 0.111
Respiratory§ disease Known 55 20.9% 16 29.1% 1.170 0.605 2.262 0.641
DM & endocrine disorders$ Known 67 25.5% 21 31.3% 1.370 0.745 2.518 0.312
Renal disease£ Known 61 23.2% 23 37.7% 1.996 1.082 3.681 0.027
Rheumatic disorders§§ Known 10 3.8% 4 40.0% 1.889 0.517 6.903 0.336
Liver & hepato-biliary diseases± Known 8 3.0% 1 12.5% 0.385 0.047 3.187 0.376
Thyroid disorders Known 16 6.1% 4 25.0% 0.914 0.285 2.934 0.880
Long-term oral Steroids€€ Known 17 6.5% 9 52.9% 3.412 1.261 9.232 0.016
Immunomodulators$$ Known 9 3.4% 4 44.4% 2.279 0.594 8.741 0.230
No medical condition Known 29 11.0% 2 6.9% 0.181 0.042 0.782 0.022

*Cardiovascular: Hypertension, chronic heart failure, ischaemic heart disease, chronic arrhythmias; §Respiratory: Asthma, chronic obstructive pulmonary disease, interstitial lung disease, asbestosis; $DM & Endocrine: Diabetes Mellitus (DM), thyroid disorders, Addison's; £Renal: Chronic Kidney Disease (eGFR < 60 mL/min/1.73 m2), on dialysis, chronic nephritis, renal transplant; §§Rheumatic: Rheumatoid arthritis, inflammatory Polyarthritis, chronic vasculitis Syndrome, connective tissue disorders; ±Liver & hepato-biliary: Fatty liver, non-alcoholic steatohepatitis, liver transplant; Thyroid: Hypothyroidism, hyperthyroidism, post-thyroidectomy; €€Long-term oral steroids: Prednisolone, hydrocortisone, dexamethasone; $$Immunomodulators: Methotrexate, tacrolimus, sirolimus, mycophenolate, dapsone, sulfasalazine and azathioprine.

Based on the Charlson Comorbidity Index (CCI) score, the severity of co-morbidities was categorised into four cohorts: mild/no co-morbidity (CCI:0), moderate (CCI:1-2), severe (CCI:3-4), and very severe (CCI≥5) [Table-4(4a)].

Table-4: Impact of CCI score and specific medical-conditions on admission and mortality
4a) Admission and mortality stratified by CCI score based cohorts

CCI score Admission

(N)

Mortality

(N)

Mortality

(%)

OR (95% C.I) p-value
Overall 263 70 26.6    
0 31 1 3.2 - -
1-2 59 8 13.8 4.706 (0.56 – 39.49) 0.154
3-4 68 23 33.8 15.33 (1.97 – 119.67) 0.009
≥5 105 38 36.2 17.015 (2.23 – 129.78) 0.006

4b) Admission and mortality stratified by specific medical-conditions

Medical-conditions Admissions

(N)

Mortality

(N)

Mortality

(%)

OR (95% C.I.) p-value
DM 54 18 33.3 1.510 (0.791 – 2.883) 0.212
Thyroid Disorders 16 4 25.0% 0.914 (0.285 – 2.934) 0.880

Overall Hypertensives

75

16

21.3

0.707 (0.374 – 1.338) 0.287

ACEi/ARB* antihypertensives

51

11

21.6

0.760 (0.365 – 1.586) 0.465

Non ACEi/ARB§ antihypertensives

24

5

20.8

0.704 (0.253 – 1.964) 0.503

Long-term oral steroids

17

9

52.9

4.053 (1.091 – 15.063) 0.037

Immunomodulators

9

3

33.3

5.101 (0.659 – 39.460) 0.119

N: Number of patients; DM: Diabetes Mellitus; *RAAS-inhibitors; §Non RAAS-inhibitors.

The impact of CCI score-based cohorts on mortality are shown in Figure-3 (a-f). CCI value also predicted significant association with odds ratio 1.255 (p<0.001). If the CCI score was utilised as a categorical predictor with the other two parameters (age and place of primary care), it remained a significant predictor with the odds of death for the patients with CCI-scores between 0-4 turning out to be 44.8% (p=0.005) of the odds of death for the patients with CCI scores ≥5 (Table-3).

Figure-3(a - f): Pie-chart representing impact of CCI score-based cohorts on mortality


a) Overall admitted patients: discharge and mortality; b) CCI score 0: discharge and mortality; c) CCI score 1-2: discharge and mortality; d) CCI score 3-4: discharge and mortality; e) CCI score ≤4: discharge and mortality; f) CCI score ≥5: discharge and mortality.

Interestingly, the eGFR at presentation turned out to be a significant predictor of mortality (OR=0.961, p<0.001). Of the co-morbidities, pre-existing renal disease was found to be an important predictor of mortality with OR=1.996 (p=0.027). Long-term oral steroids were another significant predictor of mortality, with the odds of death for the patients with long-term oral steroids use being 341.2% (p=0.016) of the odds of death for the patients without such medication. Patients with no background medical conditions (OR=0.181, p=0.022) fared better, with significantly lower odds of death compared to patients with at least one known medical condition (Table-3).

We also analysed the mortality of our patients with specific medical condition-based cohorts [Table-4(4b)]. A high mortality of 52.9% [OR (95%CI): 4.053(1.091–15.063), p=0.037] was observed in patients who were on long-term oral steroids. A 33.3% [OR (95%CI):1.510(0.791–2.883), p=0.212] mortality rate was observed among in-patients with known diabetes on pharmacotherapy.

Many of the demographic variables and the co-morbidities were inter-related – the odds of death for a patient coming from their own-home was only 26% (OR=0.263, p<0.001) of the odds for those residing in a long-term care-home (Table-3). To offset the possibility of any confounding effect, we utilised multiple logistic regression analysis with all the important variables taken together (Table-5). Taking consideration of confounding effects, only age, care facility, presence of active malignancy and long-term oral steroids were found to be significant predictors of mortality. Interestingly, the presence of active malignancy was found to have a lower risk of death – this is possibly due to a bias on account of a relatively small number of patients in that subset of our study. Age was the most significant predictor of mortality, followed by a primary area of the care facility and the presence of active malignancy.

Table-5: Multiple logistic regression analysis of the demographic variables and co-morbidities

 

Odds Ratio

95% Confidence Interval

 

Variables

Lower

Upper

P-value

Age 1.049 1.013 1.086 .007
Sex (Female) .588 .296 1.165 .128
Care facility (own-home) .411 .195 .866 .019
CCI score 1.051 .826 1.337 .685
Active malignancy .078 .008 .725 .025
Cardiovascular disease .987 .491 1.984 .971
Respiratory disease 1.162 .517 2.612 .716
DM & endocrine disorders 1.370 .608 3.085 .448
Renal disease .901 .419 1.937 .789
Rheumatic disorders .927 .128 6.719 .941
Liver & hepato-biliary diseases .364 .030 4.357 .425
Thyroid disorders .827 .186 3.676 .803
Long-term oral steroids 4.053 1.091 15.063 .037
Immunomodulators 5.101 .659 39.460 .119
No medical condition .685 .128 3.670 .658

DM: Diabetes Mellitus

DISCUSSION

COVID-19 has taken 800,000 lives world-wide as reported by the World Health Organisation (WHO) on August 30, 2020. A recent systematic review and meta-analysis have reported the association of COVID-19 with a severe disease course in about 23% of infected patients and has a mortality of about 6%.19 The mortality rate varies in different geographical areas. In-hospital mortality was significantly higher in the United States of America (USA) (22.23%) and Europe (22.9%) compared to Asia (12.65%) – (p<0.0001).20 However, there was no significant difference when compared to each other (p=0.49).20 Our study showed a 26.6% in-hospital mortality.

The mean age of the patients in our study was 68.74 years (SD:16.89) – 60.5% of them were male and 39.5% female. 70.7% of these patients were aged ≥60 years. Univariate analysis showed that the mortality rate was significantly age-dependent (OR=1.058, p<0.001) – mortality (33.9%) was higher in patients aged ≥60 years, rising sharply ≥80 years to 44.0% (χ2 =27.078, p<0.001). Our results were consistent with other studies.21

Among the demographic characteristics, mortality-risk was independent of sex distribution (χ2 =1.784, p=0.182) in our study. This is in contrast to a meta-analysis, which reported the association between male-sex and COVID-19 mortality (OR =1.81; 95%CI:1.25–2.62).22 Multicentric studies in the United Kingdom (UK) would be warranted to see the trend in the local population.

Long-term care-home residents suffered 50.0% mortality (χ2 =18.146, p<0.001). The London School of Economics report on May 14, 2020, estimated that the COVID-19 related deaths of care-home residents contributed to 54% of all excess deaths in England and Wales. Our study findings indicate long-term care-homes as hot-spots requiring shielding and protective measures against COVID-19 – a conclusion corroborating other studies.23

We aimed to define the predictive-role of co-morbidities on COVID-19 mortality, an aspect that has been probed earlier as well.7-12 The CCI score remains a reliable method to measure co-morbidity.24 For admission to intensive care, NICE recommended CCI-score ≥ 5 requires critical care advice to help in treatment decision regarding the essential benefit of organ support for seriously unwell COVID-19 patients. We examined the predictive mortality-risk of CCI scores among the admitted patients.

The mortality rate in cohorts with CCI ≤4 and CCI scores ≥5 were 20.3% and 36.2% respectively. The odds of death for CCI ≤4 cohort was less than half (44.8%) compared with CCI scores ≥5 cohort. Based on this finding, we strongly recommend CCI scoring as a clinical risk-stratification tool in COVID-19.

We examined the impact of organ specific co-morbidities on in-hospital mortality in our study as well. Patients with no background medical conditions showed a low mortality rate 6.9% [OR (95%CI): 0.181(0.042–0.782), p=0.022] and had better outcomes with significantly lower odds of death, compared to patients with at least one medical condition on univariate logistic regression analysis (Table-3). The mortality rate was 3.2% in CCI-0 cohort [Table 4(4a)].

The impact of COVID-19 on patients with CKD, glomerulo-nephropathies, on dialysis dependent patients and post renal transplant patients remains unclear. Patients with SARS-CoV-2 infection were frequently found to have renal dysfunction – the latter was associated with greater complications and in-hospital mortality.25 A mortality rate of 3.6%, was reported in patients attending an outpatient haemodialysis centre.26 Another study has concluded 3.07-fold (95%CI:1.43–6.61)mortality among renal failure patients.27 We found, the pre-existing renal disease to be a cause of significant concern with 37.7% mortality [OR(95%CI): 1.996(1.082 – 3.681), p=0.027] with the eGFR at presentation being a significant predictor (OR=0.961, p <0.001) (Table-3).

The use of steroids in COVID-19 continues to be explored.The RECOVERY trial in UK, after evaluation at 28 days, concluded that dexamethasone reduced deaths by one-third in ventilated patients [age-adjusted rate ratio (RR) 0.65; 95% CI: 0.48–0.88; p=0.0003], and by one-fifth in other patients receiving supplemental oxygen with or without non-invasive ventilation (RR 0.80; 95%CI: 0.67 to 0.96; p=0.0021), although no benefit was observed in mild or moderate cases not requiring oxygen support (17.0% vs.13.2%; RR 1.22; 95% CI, 0.93e1.61; p¼0.14). In contrast, a systematic review concluded that the results from retrospective studies are heterogeneous, and it was difficult to assign a definite protective role of corticosteroids in this setting.28 We found long-term oral steroids use to be a significant predictor of mortality – 52.9% [OR(95%CI): 3.412(1.261–9.23), p=0.016] – this was 341.2% of the odds of death for the patients without any long-term oral steroids use (Table-3). The sample size of this cohort was relatively small with 9 deaths out of 17 patients. However, based on our results, it may be safe to suggest that further population-based studies would be required to determine the impact of long-term oral corticosteroid use in COVID-19.

A major proportion of endocrine disorders are of autoimmune aetiology. The impact of thyroid disorders on COVID-19 is yet to be studied widely.15,16 We found no increased risk of mortality [OR (95%CI): 0.914 (0.285–2.934), p=0.880] in patients with thyroid disorders. However, 33.33% [OR(95%CI): 1.510(0.791–2.883), p=0.212] mortality was seen among the diabetic patients on pharmacotherapy in our study [Table-4(4b)].

Pre-existing hypertension is an accepted risk factor for COVID-19 mortality.26,27 However, the role RAAS-inhibitors and upregulation of ACE-2 receptors in COVID-19 mortality call for targeted clinical research for further clarification.29 A meta-analysis of four studies showed that patients treated with RAAS-inhibitors had a lower risk of mortality [RR: 0.65(95%CI:0.45–0.94), P=0.20].30 We did not observe any significant mortality-risk difference between RAAS-inhibitors treatment group [OR(95%CI): 0.760(0.365–1.586), p=0.465] and non RAAS-inhibitor treatment groups [OR(95%CI): 0.704(0.253–1.964), p=0.503] [Table-4(4b)]. We recommend the continuation of RAAS-inhibitors during COVID-19 unless there exist other compelling medical reasons for their discontinuation.

A prospective study in the UK concluded that the mortality from COVID-19 in cancer patients appeared to be driven principally by age, gender, and co-morbidities.13 The study could not identify evidence suggesting cancer patients on cytotoxic chemotherapy, or other anticancer treatment, were at an increased risk of mortality from COVID-19 compared to the general population.13 We also did not detect any increased risk of mortality in patients with active malignancy [OR(95%CI): 0.078(0.008–0.725), p=0.025)] (Table-5).

The impact of various non-specific immunomodulators in COVID-19 outcome remains inconclusive.14 Our study did not reveal any significant predictive mortality-risk with the use of long-term immunomodulators (methotrexate, tacrolimus, sirolimus, mycophenolate, dapsone, sulfasalazine and azathioprine) on multiple logistic regression analysis. We reached the same conclusion with patients suffering from chronic rheumatic disorders on similar analysis (Table-5).

Our study had some unique characteristics. We analysed all the eligible samples over a consecutive 76-day period at the initial peak of the pandemic. The study was conducted across two district general hospitals, allowing an insight into two differently located rural populations. We conducted univariate and multiple logistic regression analysis of the demographic variables and co-morbidities to examine the predictive-risk of contributing factors in COVID-19 mortality. The association between CCI scores and in-hospital mortality was also analysed in detail. We included demographic characteristics such as age, sex and residence in a long-term care-home while factoring in the associations.

Our study was not without limitations, though. We were unable to study the predictive-risk of obesity, socioeconomic status and ethnicity due to inadequate data. The “White British” group consisted of 80.61% of admitted patients, and no ethnicity was documented in 17.11% of our patients (Table-6, Figure-4).

Table-6: Medical admissions and mortality stratified by ethnicity

Ethnicity Admission

(N)

Admission

(%)

Died

(N)

Mortality

(%)

White British 212 80.61 63 29.71
Asian 4 1.52 1 25.0
African 2 0.76 0 0.00
Not documented 45 17.11 6 13.33

N: Number of patients

Figure-4: Bar charts showing Admission and Mortality stratified by Ethnicity

We relied solely on electronic database and hospital records to conduct the study retrospectively. The few subsets of patients such as those on prescribed long-term oral steroids, immunomodulators, thyroid disorders, chronic liver disease, and active malignancy had relatively small sample sizes with possible introduction of bias. We did not categorise diabetic patients into insulin dependent/non-insulin dependent or well/poorly glycaemic control cohorts. We did not aim to split the respiratory group into well or poorly controlled asthma or COPD subsets. Patients on a long-term steroid inhalation treatment were not included in the steroid cohort – a more extensive population-based study may be better suited for such an analysis.

CONCLUSIONS

Patients aged ≥ 60 years, residence in a long-term care-home, pre-existing renal disease, multiple co-morbidities (especially those with CCI ≥ 5), and patients on long-term oral steroids need to be considered as having a high risk of dying from COVID-19, along with other established risk factors such as hypertension, diabetes and chronic respiratory disease. RAAS-inhibitors need not be discontinued due to COVID-19. Further studies are necessary to establish links between long-term oral steroids use, chronic rheumatic disease, non-specific immunomodulators and COVID-19 mortality.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Miss Lyndsey Green: Senior BMS, Microbiology, SaTH. Mrs Annette Meredith: ED/AMU Medical Secretary, SaTH. Dr N Zia: Consultant, Emergency medicine, Dudley Group of Hospitals NHS Foundation Trust, Dudley, UK. Dr I Thund: Consultant, Emergency medicine, Dudley Group of Hospitals NHS Foundation Trust, Dudley, UK. Dr S Das: Consultant, Emergency medicine, Stockport NHS Foundation Trust, Stockport, UK. Special thanks to Dr Mohyman El Habishi, Trainee, Anaesthetics, Dudley Group of Hospitals NHS Foundation Trust, Dudley, UK for his contribution of proof-reading, graphics and tables.
Competing Interests: 
The authors declare that they have no conflict of interest
Details of Authors: 
NIL KAMAL SAMANTA, MBBS, MRCP, MRCEM, FRCEM, Consultant, Emergency Medicine, Dudley Group of Hospitals NHS Foundation Trust, Dudley, DY1 2HQ, UK. SAMIK KUMAR BANDYOPADHYAY, MBBS, MS, MRCS, FNB(MAS), Speciality Trainee 5, General Surgery, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK. DODIY HERMAN, MBChB, FRCEM, Consultant, Emergency Medicine, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. BIMAN CHAKRABORTY, PhD (statistics), School of Mathematics, University of Birmingham, Birmingham B15 2TT, UK. ADRIAN MARSH, MBChB, BSc Med Sci (Hons), FRCEM, Consultant, Emergency Medicine, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. SUBRAMANIAN KUMARAN, MBBS, D Ortho, FECS, FRCEM, Consultant, Emergency Medicine, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. LAUREN BURNARD, MBBS, Speciality Trainee, Acute Common Care Stem, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. GUNALAN GNANASEELAN, MBBS, Foundation Year 2,Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. SAOIRSE GIBSON, MBBS, Foundation Year 1, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. BENITA FLORENCE, MBBS, MRCEM, Specialty Doctors and Associate Specialists, Shrewsbury and Telford Hospitals NHS Trust, Mytton Oak Road, Shrewsbury, SY3 8XQ. SAIBAL GANGULY, MBBS, FRCA, FFICM, EDIC, Consultant Anaesthetics and Intensivist, The Royal Wolverhampton NHS Trust, Wolverhampton Road, WV10 0QP, UK.
Corresponding Author Details: 
Dr Nil Kamal Samanta, Consultant, Emergency Medicine, Dudley Group of Hospitals NHS Foundation Trust, Dudley, DY1 2HQ, UK.
Corresponding Author Email: 
Nilkamal.samanta@nhs.net
References
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  2. Wu, C., X. Chen, Y. Cai, et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, JAMA Intern Med. 2020;180(7):934-943. 
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  7. Srivastava K. Association between COVID-19 and cardiovascular disease. IJC Heart and Vasculature. 2020;29:100583. DOI 10.1016/j.ijcha.2020.100583
  8. Hafiane A. SARS-CoV-2 and the cardiovascular system. Clinica Chimica Acta. 2020;510:311-316. 
  9. Escalera-Antezana JP, Lizon-Ferrufino NF, Maldonado-Alanoca A, et al. Risk factors for mortality in patients with Coronavirus Disease 2019 (COVID-19) in Bolivia: An analysis of the first 107 confirmed cases. Le infezioni in medicina. 2020;28 (2):238-242.
  10. Chanyuan Ye, Shanyan Zhang, Xiaoli Zhang , et al. Impact of co-morbidities on patients with COVID‐19: A large retrospective study in Zhejiang, China. J Med Virol. 2020;1-9. https://doi.org/10.1002/jmv.26183
  11. Li, Xintao, Guan, Bo, Su, Tong, et al. Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis. Heart 2020;0:1-6. 
  12. Pranata R; Huang I; Lim MA, et al.  Impact of Cerebrovascular and Cardiovascular Diseases on Mortality and Severity of COVID-19 - Systematic Review, Meta-analysis, and Meta-regression. J. Stroke Cerebrovasc. Dis. 2020;29(8):104949 DOI 10.1016/j.jstrokecerebrovasdis.2020.104949 
  13. Lee LYW, Cazier JB, Starkey T, Turnbull CD, et al. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. Lancet. 2020;395(10241):1919-1926.
  14. Rizk JG, Kalantar-Zadeh K, Mehra MR, et al.  Pharmaco-Immunomodulatory Therapy in COVID-19. Drugs. 2020; DOI 10.1007/s40265-020-01367-z
  15. Boelaert K, Visser WE, Taylor PN, et al.  ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of hyperthyroidism and hypothyroidism. Eur. J. Endocrinol 2020;183 (1):G33-G39. 
  16. Dworakowska D, Grossman AB.  Thyroid disease in the time of COVID-19. Endocrine. 2020;68 (3):471-474.
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Upgrading of Hospital Discharge Summary Software to Optimise COVID-19 Documentation and Safeguard Infection Prevention in the Community

Authors
Jack Donati-Bourne, Ning Lo, Wail Mohamed, Zain Kasmani, Masilamani Selvan & Jonathan O'Dair
Article Citation and PDF Link
BJMP 2021;14(1):a002
Abstract / Summary
Abstract: 

Aims: Early review of 50 discharge summaries at Royal Shrewsbury Hospital (SATH) in April 2020 revealed only 27% documented the patient’s in-hospital COVID-19 test result and 2% outlined any recommended self-isolation advice following hospital discharge.

This had potential adverse implications for community infection control as well as medico-legal sequalae for the Trust were the discharged patient to spread COVID-19 to other cohabitants.

The urology team worked with SATH IT to amend the existing discharge summary software, to add two tabs to make COVID-19 test result and self-isolation documentation mandatory for successful sign-off.

The aim of this quality improvement project was to evaluate the impact of updating the discharge summary software on documentation accuracy related to COVID-19 on discharge paperwork. 

Method: Following the implementation of the modified software, 50 consecutive discharge summaries for patients admitted under the urology team starting 1st October 2020 were retrospectively reviewed for documentation of COVID-19 result and self-isolation advice.

Results: 90% of discharge summaries included COVID-19 test result and 100% included self-isolation advice for the patient, or alternatively confirmed that no self-isolation was required.

Conclusions: This simple modification of an existing IT system greatly improved compliance with COVID-19 discharge summary documentation.

We propose all hospitals consider adopting similar measures in the interest of infection prevention, public safety and potential medico-legal sequalae.

Abbreviations: 
COVID-19 - Coronavirus disease 19; IT - Information technology; GMC - General Medical Council.
Keywords: 
discharge summary, COVID-19, IT

Introduction

The first documented case of COVID-19 in the UK was reported on 29 January 2020 followed by a rapid surge of infections leading to a UK national lockdown announced on 23 March 20201.

The COVID-19 pandemic has since required NHS hospitals to constantly adapt their protocols, workforce and logistics to keep pace with the evolving spread of the virus.

The variable clinical presentation of COVID-19 may result in those requiring admission being redirected under the care of different specialties within the hospital2. Furthermore the presence of asymptomatic carriers admitted with unrelated pathologies or cases of nosocomial cross-infections implies that COVID-19 related clinical noting and discharge summary documentation is likely to affect doctors across all hospital departments.

An initial review of 50 consecutive urology discharge summaries in Royal Shrewsbury Hospital in April 2020, revealed that only 27% included the patient’s in-hospital COVID-19 swab result (positive or negative) and only 2% documented any recommended patient self-isolation advice to be adhered to after discharge into the community.

Accurate COVID-19 related documentation is paramount to ensure the patient, their family and their GP / care setting where applicable are all aware of their COVID-19 status and any recommended self-isolation, to safeguard infection prevention in the community. Furthermore, there could be potential medicolegal sequalae for the Trust were a patient recently discharged from hospital to spread COVID-19 to their family and / or vulnerable adult cohabitants due to lack of clear self-isolation guidance.

An urgent collaboration between the urology team and the Trust IT department was undertaken to upgrade the Trust’s existing eScript discharge summary software.

Two new tabs were integrated:

1. COVID-19 test result [Figure 1] and date [Figure 2]: Positive / Negative / Not tested

2. Self-isolation advice [Figure 3]: No / Yes (please specify as free text)

Completion was made mandatory prior to being able to sign-off the document for printing and successful upload on the electronic records.

Figure 1

Figure 2

Collaboration with the infection prevention team (IPT) was undertaken to create a flow-chart style document accessible by hyperlink [Figure 3] to help discharging clinicians correctly determine and document patient self-isolation instructions following discharge from hospital, depending on individual circumstances. [Appendix 1]

Figure 3

The aim of this quality improvement project was to evaluate the impact of the dynamic upgrade made to the eScript discharge summary software in clinician compliance with COVID-19 related documentation.

Materials and Methods

The upgraded eScript discharge summary software was rolled out across the Shrewsbury and Telford NHS Trust (SATH) in the week beginning 28th September 2020.

All clinicians were informed regarding the upcoming software change by means of a Trust-wide email from the SATH Medical Director, with instructions provided on how to complete the new tabs.

The first 50 consecutive completed discharge summaries of patients admitted electively or as emergency under the urology team starting from 1st October 2020 were retrospectively reviewed by NL, EF, ZK by means of electronic records.

Note was taken of correct documentation of:

· any COVID-19 test outcome (positive or negative result)

· any recommended patient self-isolation advice after discharge from hospital

The findings were compared and contrasted with the results of the initial study in April 2020.

Results

49 / 50 (98%) patients had a COVID-19 test at any time during their admission – 1 patient did not have a COVID-19 test at any time in their admission.

3 patients were discharged prior to their COVID-19 result becoming available, 1 patient was discharged without a written discharge summary and 1 patient was incorrectly labelled as having been “not tested.”

46 patients’ results therefore became available in time before discharge and 44 (90% of all those tested) were documented on their discharge summary. All COVID-19 tests were negative. [Table 1]

All patients had either documented self-isolation advice or “none required” specified on their discharge summary following discharge from hospital. [Table 1]

The most common primary reasons for admission were urinary tract infection / sepsis (18%), catheter-related complications (14%) and urinary retention (12%).

Incidental note was made of two patient deaths within 28 days of admission.

Table 1

  Initial Review Review after software update
Number of patients 50 50
Patients tested for COVID-19 33 (66%) 49 (98%)
Patients testing positive 1 (3.3%) 0 (0%)
COVID-19 result on discharge summary 9 (27%) 44 (90%)
Self-isolation advice on discharge summary 1 (2.0%) 50 (100%)

Discussion

The results revealed that the upgraded eScript software resulted in a notable improvement in COVID-19 related documentation on discharge summaries.

In the initial study 33 / 50 (66%) had a COVID-19 test at any time during their admission – only 27% of these however had the result included on their discharge summary, compared to 90% compliance following the eScript software upgrade.

Following the finding of 3 patients’ (6%) COVID-19 result not becoming available prior to discharge, SATH IT was consulted and an extra option on the eScript COVID-19 result dropdown menu was added to include “awaiting result” to mitigate for this particular circumstance. [Figure 1]

Only 1 patient (2%) in the initial study had any self-isolation advice documented on their discharge summary – this figure soared to 100% following the eScript software upgrade. [Table 2]

The figures have to be interpreted in light of the change in COVID-19 testing availability, which only became widespread in mid-May 2020 and thus after the completion of the initial study3. This is likely to account for the lower proportion of in-patient COVID-19 tests being performed in the initial study (66%) vs. second study (98%).

Arguably a negative COVID-19 result such as those commonly encountered on the urology ward are less likely to be documented on a discharge summary compared to a positive test, particularly if admitted with unrelated pathologies (e.g. urinary retention) or asymptomatic carriers. By nonetheless documenting this pertinent negative, one ensures the patient is aware of their reassuring result and any community-based clinician such as district nurse or GP can be cognisant of this information if called to assess the patient soon after hospital discharge.

The findings of the study are directly relevant to all doctors working in acute NHS Trusts, as clear and accurate documentation is a key principle in the GMC’s “Good Medical Practice” document to which all registered practising doctors must abide to4. A discharge letter is a key component of the documentation of a patient’s journey and therefore must be completed accurately in line with GMC guidance. The updated software system safeguards the accuracy and clarity of the Trust’s discharge summaries in relation to COVID-19 results and self-isolation advice.

Self-isolation is a key principle of outbreak control for any infectious disease, and is a particularly important strategy in managing widespread vast numbers of cases such as in the COVID-19 pandemic in a libertarian society where strict quarantine is not routinely enforced5. The adherence with self-isolation has been notoriously poor in the UK – it is estimated that only 25% of symptomatic patients with proven COVID-19 complied fully with the government advice of not leaving the home during their isolation period6. It is therefore of paramount importance that patients being discharged from hospital in the COVID-19 pandemic era are given clear instructions on how to self-isolate and the recommended duration of this is documented.

Doctors preparing discharge summaries and their patients must be aware that COVID-19 may still be relevant to them even if the primary reason for admission was unrelated and their test on admission was negative – for example they may have been exposed to another in-patient or staff member later found to be positive for the virus. The discharging clinician should check for any such event and disclose this on the discharge summary where applicable.

From a medicolegal perspective, hospitals trusts may find themselves in a vulnerable position if COVID-19 positive or potentially exposed patients are discharged without any documented self-isolation advice. This in particular follows the controversy highlighted in the earlier months of the pandemic of thousands of elderly patients being discharged from hospital to care homes in the UK without a COVID-19 test7. Indeed, since then a judge has allowed legal action from a bereaved daughter to be brought against the Department for Health and Social Care, NHS England and Public Health England for failure to adequately protect vulnerable residents in an Oxfordshire care home8. Safeguarding the clear documentation of recommended patient self-isolation instructions on discharge summaries is likely to confer additional protection to a Trust facing any such legal challenge.

Writing a high-quality discharge summary is a difficult skill to teach and indeed they are often completed by the most junior members of the medical team9. The Trust’s IT software can therefore play a vital role in helping doctors ensure that COVID-19 result and self-isolation instructions are documented for all hospital discharges, by means of mandatory tabs for completion prior to sign off.

To our knowledge, although other Trusts have since similarly amended their discharge summary software in light of the COVID-19 pandemic, this is the only study in the literature which directly attests the degree of improvement in documentation as a result of such a software change. We urge that all Trusts in the UK consider amending their discharge summary software in line with the changes characterised in this study.

Conclusions

The updated eScript discharge summary software has greatly improved compliance within the Trust with COVID-19 test result and self-isolation advice documentation on discharge summaries.

This is a simple and highly effective modification whose benefits can have ramifications across the healthcare system.

By accurately documenting COVID-19 test results and any advised self-isolation for the patient after hospital discharge, one safeguards IPC in the community and protects the Trust from potential relevant medico-legal sequalae.

Appendix 1

Scenario 1: COVID-19 positive patient

Scenario 2: COVID-19 negative patient

Scenario 3: No COVID-19 test performed as rubbish and make someone else

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors wish to thank Dr Arne Rose, Mr Mark Cheetham, Pete McGinness, Ashley May, Joe Thelwell, Angela Lewis and Kelly Pardy for the completion of this project.
Competing Interests: 
None declared
Details of Authors: 
JACK DONATI-BOURNE, FRCS(Urol), Royal Shrewsbury Hospital, Mytton Oak Rd, Shrewsbury SY3 8XQ, UK. NING LO, MBChB, Royal Shrewsbury Hospital, Mytton Oak Rd, Shrewsbury SY3 8XQ, UK EAMONN FOLEY, MBChB, Royal Wolverhampton Hospital, Wolverhampton Road, Wolverhampton, WV10 0QP, UK. ZAIN KASMANI, MBChB, Worcestershire Acute Hospitals NHS Trust, Woodrow Drive, B98 7UB, Redditch, UK. MASILAMANI SELVAN, FRCS(Urol), Royal Shrewsbury Hospital, Mytton Oak Rd, Shrewsbury SY3 8XQ, UK. JONATHAN O'DAIR, FRCS(Urol), Royal Shrewsbury Hospital, Mytton Oak Rd, Shrewsbury SY3 8XQ, UK.
Corresponding Author Details: 
JACK DONATI-BOURNE, Urology Department, Royal Shrewsbury Hospital, Mytton Oak Rd, Shrewsbury SY3 8XQ, UK.
Corresponding Author Email: 
jack.donati-bourne@nhs.net
References
References: 
  1. Lillie PJ, Samson A, Li A, et al. Novel coronavirus disease (Covid-19): the first two patients in the UK with person to person transmission. J Infection 2020, 80(5), 578-606.
  2. Martín-Sánchez FJ, Del Toro E, Cardassay E, et al. (2020) Clinical presentation and outcome across age categories among patients with COVID-19 admitted to a Spanish Emergency Department. Eur geriatr med 2020, 11(5), pp.829-841.
  3. Surkova E, Nikolayevskyy V, Drobniewski F. False-positive COVID-19 results: hidden problems and costs.  Lancet Resp Med 2020, 8(12), pp.1167-1168.
  4. General Medical Council, “Good Medical Practice” [2013]. Available at: https://www.gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/good-medical-practice
  5. Salathé M, Althaus CL, Neher R, et al. COVID-19 epidemic in Switzerland: on the importance of testing, contact tracing and isolation. Swiss med weekly 2020, 150(11-12), 1-3
  6. Rubin GJ, Smith LE, Melendez-Torres GJ, et al. Improving adherence to ‘test, trace and isolate’. J Royal Soc Med 2020, 113(9), pp.335-338.
  7. BBC (British Broadcasting Corporation) (2020) Coronavirus: sending untested patients to care homes “reckless” – MPs. [Cited 30 December 2020] Available at: https://www.bbc.co.uk/news/uk-politics-53574265
  8. BBC (British Broadcasting Corporation) (2020) Covid: Judge allows legal challenge into care home deaths. [Cited 30 December 2020] Available at: https://www.bbc.co.uk/news/uk-england-devon-55007355
  9. Myers JS, Jaipaul CK, Kogan JR, et al. Are discharge summaries teachable? The effects of a discharge summary curriculum on the quality of discharge summaries in an internal medicine residency program. Acad Med 2006, 81(10), pp.S5-S8

An Unusual Manifestation of Adenocarcinoma of Lung - Skeletal Muscle Metastasis

Authors
Sharan Badiger & Siddarthkumar Chawath
Article Citation and PDF Link
BJMP 2020;13(2):a016
Abstract / Summary
Abstract: 

Introduction: Lung carcinoma is the most common malignancy in adults and the leading cause of death globally. It is responsible for 25% of all malignancy-related death worldwide. Among various types of lung carcinoma, adenocarcinoma is the most common (50%) of all the variants. Lung adenocarcinoma metastasising to skeletal muscle is rare in clinical practice. Case report: A fifty three year-old male patient presented with complaints of swelling over left arm of size 5x4 centimetres which was irregular in shape, soft to hard in consistency and gradually increasing in size. He was symptomatically treated but there was no improvement in clinical condition. In due course of time, patient presented with cough with expectoration. On general physical examination, pulse rate was eighty beats per minute, blood pressure 120/80 mmHg, respiratory rate eighteen cycles per minute. On systemic examination, respiratory system revealed bilateral normal vesicular breath sounds, cardiovascular, abdominal and neurological systems were clinically within normal limits. Panel of investigations were done as a part of work up, inclusive of ultrasonography (USG) and magnetic resonance imaging (MRI) of left arm, computerized tomography (CT) of chest, fine needle aspiration cytology and positron emission tomography (PET) scan which concluded adenocarcinoma of right lung with left triceps muscle metastasis. Conclusion: Though the metastasis of adenocarcinoma lung is common, metastasis to the skeletal muscle is not so well-known. A clinical suspicion about such pathology can help a clinician to arrive at right diagnosis on time. This case report emphasizes that even a trivial swelling in triceps muscle could be hiding the grave adenocarcinoma in the lung.

Abbreviations: 
Computerized Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Ultrasonography (USG).
Keywords: 
Adenocarcinoma, Metastasis, Skeletal Muscle.

Introduction

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

Case report

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


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

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


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

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

Discussion

Lung carcinoma is a leading cause of cancer-related mortality. The most common sites of distant metastasis in lung carcinoma are brain, bones, the liver, and the adrenal gland1. The most common tumours that cause skeletal muscle metastasis are tumours originating from thyroid, oesophagus, stomach, pancreas, colon, rectum, bladder, breast, ovary, and prostateand skeletal muscle metastasis of lung carcinoma was first reported by Fisher ER2. Willis RA reported four skeletal muscle metastases in their autopsy series composed of 500 lung carcinoma patients3. Skeletal muscle metastasis is a rare occurrence for any tumour with a reported incidence lees than one percent4-5. The most common sites of muscle metastasis are thigh muscles, iliopsoas, and paraspinous muscles6.

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

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

Conclusion

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

Acknowledgements

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

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SHARAN BADIGER, MD, Professor and Head, Department of Medicine, Sri B M Patil Medical College, (Deemed to be University), Vijayapur, Karnataka, India. SIDDARTHKUMAR CHAWATH, Junior Resident, Department of Medicine, Sri B M Patil Medical College, (Deemed to be University), Vijayapur, Karnataka, India.
Corresponding Author Details: 
SHARAN BADIGER, Professor and Head, Department of Medicine, Sri B M Patil Medical College, (Deemed to be University), Vijayapur, Karnataka, India
Corresponding Author Email: 
sharanrb@rediffmail.com
References
References: 
  1. Quraishi MA, Costanzi JJ and Hokanson J. The natural history of lung cancer with pericardial metastases. Cancer 1983; 51: 740-742.
  2. Fısher ER, Gıngrıch RM, Gruhn J, Laıng P. Ossifying metastatic carcinoma; report of a case with comments relative to histogenesis of ectopic ossification. Cancer 1959; 12:257-262.
  3. Wİllis RA. The Spread of Tumors in the Human Body. London: Butterworth; 1973. p. 282.
  4. Di Giorgio A, Sammartino P, Cardini CL, Al Mansour M, Accarpio F, Sibio S, et al. Lung cancer and skeletal muscle metastases. Ann Thorac Surg 2004; 78:709-711.
  5. Heyer CM, Rduch GJ, Zgoura P, Stachetzki U, Voigt E, Nicolas V. Metastasis to skeletal muscle from esophageal adenocarcinoma. Scand J Gastroenterol 2005; 40:1000-1004.
  6. Marioni G, Blandamura S, Calgaro N, Ferraro SM, Stramare R, Staffieri A, et al. Distant muscular (gluteus maximus muscle) metastasis from laryngeal squamous cell carcinoma. Acta Otolaryngol 2005; 125:678-682.
  7. Perisano C, Spinelli MS, Graci C, Scaramuzzo L, Marzetti E, Barone C, et al. Soft tissue metastases in lung cancer: A review of the literature. Eur Rev Med Pharmacol Sci 2012; 16:1908-1914.
  8. Bocchino M, Valente T, Somma F, de Rosa I, Bifulco M, Rea G. Detection of skeletal muscle metastases on initial staging of lung cancer: A retrospective case series. Jpn J Radiol 2014; 32:164-171.
  9. Schmidt GP, Reiser MF, Baur-Melnyk A. Whole-body imaging of the musculoskeletal system: The value of MR imaging. Skeletal Radiol 2007; 36:1109–1119.

Balancing Immune System

Authors
James Paul Pandarakalam
Article Citation and PDF Link
BJMP 2020;13(2):a014
Abstract / Summary
Abstract: 

The immigrant community in temperate climate zones from tropical or subtropical countries is observed to have a higher infection rate of COVID-19. This finding has posed many questions about the vulnerability factors of ethnic minority members to COVID-19 and many unconfirmed views are in circulation. Environmental factors appear to be the chief orchestrator of this anomaly. The recent findings about the durability of COVID-19 antibodies in the infected people has put some concerns about the prospects of long-term immunisation methods. Safe immunisation, effective medications to block the cytokine storm responsible for the complications of COVID-19 are sure ways of combatting the current pandemic, but these might take some time to come into realty. So, another option to deal with the toxic pathogen is optimising our immunity which in itself is another dimension of surviving the pandemic. It seems to be a neglected or forgotten aspect of combatting the pandemic. There ought to be more public and political awareness of harmonizing immunity. Adherents of integrated medicine seem to have more awareness of different facets of immunity and they go beyond the conventional methods. According to the principles of integrated medicine, there may also be an extra-physiological immunity that can be brought into action in times of physiological crisis.

Keywords: 
immunity, diet, sleep, exercise, destressing, abstinence,homeostasis

Introduction

World COVID-19 cases exceed 20 million as of today and the number of deaths surpass 733103. Behind these statistics is a great deal of pain and suffering. It is now increasingly getting recognized that COVID-19 is not just a respiratory disease at all. The face of COVID-19 is changing from a pulmonary disease to an inflammatory disease which particularly affects the blood vessels, the coronary vessels, the kidneys, the liver, brain and elsewhere. Its duration is also much longer with long term impact than initially speculated. Sufferers report a huge spectrum of problems beyond the three NHS-approved symptoms (persistent cough, fever and loss of taste or smell). These include fatigue, breathlessness, muscle aches, joint pain, 'brain fog,' memory loss, lack of concentration, and depression.

More morbidity is recognised in cases of infections among the aged populations and patients with suppressed immunity. The high incidence of complications among ethnic minority apparently points toward environmental factors of immunity rather than genetic factors. Underactive immune responses in cooler temperature and diminished synthesis of vit D and the genetic factors linked with these anomalies might explain only part of the higher incidence of COVID-19 among Black, Asian, and Minority Ethnic (BAME) communities.

Research on the first British patients to contract COVID-19 has shown that BAME people are more prone to critical impacts and care compared to white people. This research, conducted by the Intensive Care National Audit and Research Centre, observed that of nearly 2,000 COVID-19 patients, 35% were non-white, though people of BAME heritage only comprise 13% of the UK’s population.1 The study included data drawn from 286 critical care units across the UK and collected until 3 April 2020. According to another study from the UCL Institute for Global Health, Bangladeshi, Pakistani, Indian, Black African and Black Caribbean ethnic groups all had a substantially increased risk of death in comparison to white British and white Irish groups. Cook et al. pinpointed that of 119 NHS staff who died from COVID-19, 64 were from ethnic minority backgrounds.2 They also noted fewer deaths among critical care staff, highlighting PPE’s usefulness.

The UK BAME population’s mortality rate for the 2009 influenza A (H1N1) epidemic was nearly twice that of the white population.3 The Pakistani and Bangladeshi ethnic groups are now 1.8 times more likely to have a COVID-19-related morbidity than white males of a similar age, when other sociodemographic and health characteristics were compared.4Studies have also specified that Black men are 4.2 and Black women 4.3 times more likely to die from a COVID-19-related death than white people.5 Doherty et al. suggested that socioeconomic disadvantages and other circumstances only partially explicate this discrepancy, and that there are missing gaps that have not yet been expounded.6

There is some confusion regarding the cause of this higher incidence of morbidity and mortality among the BAME community, due to media propaganda failing to assess this relation’s intricacies. Higher morbidity and mortality have been observed among first-generation migrants to the UK, but not necessarily among the second generation, who were born and raised in the UK. Five months is a short period to develop any form of genetic immunity or susceptibility to a new viral infection. Each person’s genetic code differs only by 1% of 25,000 genes. The gene cluster largely responsible for our health is called the human leukocyte antigen (HLA), also known as the major histocompatibility complex (MHC). It also takes much longer for any sort of adaptation or mutation to occur. Suppressed general immunity due to various factors appears to be the main reason for the higher COVID-19 incidence among the BAME population. The following discussion examines the possible factors responsible for this anomaly.

a. Immunity and Temperature

Some data has suggested that immune cells are more active in higher temperatures, as supported by the fact that fevers are a bodily mechanism activated by the immune system to defend against pathogens. It has been established that if the body temperature is increased by 1°C, immunity instantly increases 5–6 times. Likewise, if the body temperature is reduced by 1°C, immunity decreases 5–6 times. This observation has some value in explaining the higher incidence of COVID-19 infection and mortality among BAME groups who were born and raised in warmer areas, then migrated to colder regions.

Temperature-dependent immune responses are linked to genetics. One probable explanation is that BAME individuals’ immune cells are genetically wired to function better in hot weather and are unable to optimally function in cold weather. Such a genetically determined immunological build-up means that their immune cells are slow to react to viral invaders. BAME individuals’ immune cells are well-adapted to warm weather but not so to cold weather, in comparison to white individuals who were born and raised in colder climates and adapted to lower temperatures. BAME individuals’ immune cells may even become underactive in cold weather. Though COVID-19 thrives equally well in hot and cold weather, the BAME population has immunity shortcomings in surviving colder months; this insight might prompt them to take special precautions in future cold seasons.

Low temperatures have been recognized as immunosuppressive. It has been observed that even coldblooded animals migrate to warmer places when they become ill. An increase in body temperature has long been a defence mechanism against infection and inflammation. The generation and differentiation of the lymphocytes CD8+ cytotoxic T-cells are enhanced by hyperthermia. Elevated body temperature changes T-cells’ membranes, which may help mediate micro-environmental temperature’s effects on cell function. Sub-thermoneutral laboratory housing temperature was shown to induce immunosuppression in mice experiments: when the mice were housed at a thermoneutral ambient temperature, striking reductions in tumour formation, growth rate and metastasis were observed.7

Mice experiments with antigens demonstrated that mice with antigen-induced raised temperatures showed a greater number of the CD8 T-cells capable of destroying infected cells.8,9 Parallels were observed in teleost fish.10 Higher temperatures also seem to interfere with microbe replication. This is particularly noticeable when a host has a high fever and their immune system temporarily enhances as their temperature rises. Hong Kong’s persistent cold weather was attributed to the rapid spread of SARS in 2003. BAME communities whose immune mechanisms are genetically evolved for survival in higher temperatures are compromised in Western countries’ lower temperatures. The cold weather puts additional stress on their immune cells, which give in to viral invaders.

This argument is further supported by the spread of the flu. During flu season, immune cells become less efficient and flu viruses, unaffected by low temperatures, are in an advantageous position to defeat these cells. Such a hypothesis explains the higher incidence of flu in the winter and challenges the misconception that the flu virus is killed by hot weather and thrives in cold weather. The 1918 Spanish flu that broke out in the United States in the winter seemed to ease off during the summer, but returned with a deadlier strain in the autumn, and a third wave followed the next year. The problem then seems to be in humans, as viruses are unaffected by seasonal temperature variations.

b. Diminished Vitamin D Synthesis

Other mitigating factors can explain the higher COVID-19 incidence among BAME people. Nearly all immune cells have vitamin D receptors that connect to vitamin D networks in the immune system. Vitamin D helps regulate both the innate and adaptive immune systems, and is critical for balancing immune function. Vitamin D has been demonstrated to reduce the production of pro-inflammatory cytokines associated with lung damage caused by acute viral respiratory infections, such as influenza and COVID-19.11 BAME communities are prone to vitamin D deficiency because higher melanin levels in their skin cause lower vitamin D absorption. Consequently, prolonged exposure to sunlight is required to accrue the equivalent vitamin D quantity produced in the white population. This is further exacerbated in colder countries like the UK, which see less sunlight, meaning BAME individuals spend more time indoors without much opportunity to absorb vitamin D. So, there may be a connection between lower vitamin D levels and more frequent COVID-19 cases in BAME communities, though there is no firm data defending this link.

Virtually all immune cells have vitamin D receptors, indicating vitamin D interacts with the immune system. Vitamin D is required to regulate both the innate and adaptive immune systems and its deficiency is associated with immune dysregulation. Many of the ways this vitamin affects the immune system are directly relevant to the body’s ability to defend against viruses. For example, vitamin D triggers the production of cathelicidin and other defensins, which are natural antivirals capable of preventing viruses from replicating and entering cells. Vitamin D also increases the number of CD8+ T-cells, which play a critical role in clearing acute viral infections in the lungs. Further, vitamin D suppresses pro-inflammatory cytokines and may also alleviate the cytokine storms occurring in the most severe COVID-19 cases. This vitamin plays an essential role as well in glucose homeostasis, insulin sensitivity and the regulation of adipokines, such as leptin and inflammatory cytokines.12

Evidence from randomized controlled trials suggested that regular vitamin D supplements may help protect against acute respiratory infections. Admittedly, the direct evidence of vitamin D’s role against COVID-19 is still scant. One study from the United States and another from Asia found a strong correlation between low vitamin D and severe COVID-19 infection. It is well-recognized that the elderly and people with pre-existing conditionsare more vulnerable to COVID-19. Notably, people with existing medical conditions are also often vitamin D–deficient. Studies assessing ICU patientshave reported these patients’ low vitamin D levels even before COVID-19. It appears logical to hypothesize a link between the high COVID-19 infection rates in UK and US BAME groups and their observed lower vitamin D levels. Moreover, it is not possible to gain a sufficient vitamin D supply through food alone, making exposure to sunlight indispensable.

c. Weakened Immunity

COVID-19’s spread in the UK is disproportionately high compared to its spread in the countries of origin of many BAME communities. BAME people should be mindful of their genetics in a new environment. These demographics also have higher rates of cardiovascular disease, type-2 diabetes and hypertension, conditions that have been linked to severe COVID-19 symptoms and complications. There may also be other genetic links that warrant further exploration.

Current evidence has illustrated that chronic stress can increase infection susceptibility by suppressing the T-helper 1 immune response in favour of the T-helper 2 immune response.40 Stress management, lifestyle changes and career management may reduce infection susceptibility in turn. When people are less mobile, food becomes a distraction and they can overindulge. Obesity is also an adaptation to cold weather, as fat protects against low temperatures. Black and South Asian populations in the UK have 3–5 times the prevalence of type-2 diabetes compared to the white population and are diagnosed 10–12 years sooner on average.13

Human immunity is generally fixed by age 5, as contributed to by bacterial flora, among other factors. Several trillion bacteria exist within our body, with the gut considered this bacterial colony’s front yard. We have 25,000 genes, but up to 3 million bacterial flora genes are the real immune cell trainers.14Bacterial worlds came into existence well before humans evolved. When people migrated to Western countries from tropical regions, their bacteria had to adjust to their host’s new lifestyle, with some even replaced. Others may not have survived at all; consequently, these individuals’ immunity may have weakened.

The high incidence of diabetes and coronary heart disease in the British Asian population has been well-recognized, along with many other risk factors and comorbidities, including obesity, chronic obstructive pulmonary disease, chronic kidney disease, hypertension, and age. These may partly account for this population’s increased COVID-19 mortality15,16, but warrant further exploration. Vitamin D level is also likely to drop with rising BMI and age.17Obesity is strongly associated with vitamin 19-22D deficiency.18 Admittedly, there are weaknesses in these data collections and interpretations, which are theoretical speculations yet to be confirmed, modified or falsified. 

There are diverse genetically linked immune responses in a given population, and the spread and survival of complications in a pandemic like this are not well-defined. Research has suggested that people living in close communities, like certain regions of Lombardy, Italy, have a poor genetically linked immune response to COVID-19. Like our fingerprints, immunity genetics contribute to our physical identity, but our immunity is not permanently fixed by genetics. There thus remain many unknowns in immunity research.

It is now increasingly recognized that immune ageing and organismal ageing are intimately inter-related. Aging weakens the immune system and immunity decline further accelerates the aging process. Immune system protects the individuals against viruses and bacteria and it also helps identify and remove cancer cells and toxins. The potential for these elements to cause damage in the body increases as age advances. Critical cells in the immune system decrease in number and become less functional as people get older. COVID-19 affects seriously the aging people of the BAME community as in the case of general population, but they are more disadvantaged in terms of health care access.

d. Social Factors

Alongside these factors, many BAME individuals work in fields that carry a high risk of infection, such as healthcare, transport services and retail. In the UK, 40% of doctors, 20% of nurses and a large number of social care and unskilled migrant workers belong to BAME backgrounds. Another reason why these infections may become more prevalent among ethnic minorities is that BAME community members tend to spend more time indoors clustered together, often in cramped accommodations, which increases the likelihood of person-to-person transmission. A multigenerational family set-up is not helpful either to social distancing in a pandemic, so this lifestyle could contribute to higher infection rates. Some people living in this arrangement may also become stressed and obese due to unhealthy nourishment.

Migrant communities tend to visit and keep in contact with their country of origin, which involve international air travel and thus increased infection risk. Family studies demonstrate that BAME people living in the colder countries develop COVID-19 at a faster rate, but most of their family members living in the tropical climate in the countries of birth are spared from the infection. Such an observation point towards extrinsic factors like lifestyle and weather conditions rather than intrinsic genetic links-nurture than genetics. The second-generation immigrant population are less affected and the mixed-race individuals because of diversity of immune cells appear more resilient to the viral pandemic. There appears to exist an epidemiological trend of transmission concentrations within BAME communities living in colder countries, such a situation runs the risk of racial stigmatisation and discrimination and also risks to social cohesion.

BAME individuals should be cognizant of the additional risks and take preventive and precautionary measures. They should also adapt to balance their immunity. Enough sleep, healthy diet, moderate exercise, abstaining from excess alcohol and smoking and de-stressing are the cornerstones of enhancing immunity. Immunity is not absence of a specific disease or illness; rather, it is a balanced physiological and psychological state, the most sophisticated and elegant system of human physiology. Vaccines are pathogen-specific, and they do not bestow an overall balanced immunity.

Supporting Immunity

To defeat the tiger, one may need to become stronger than the tiger. To do this with COVID-19, we may need to foster our existing immune system, which can be done in many subtle ways. We all must grapple with the unprecedented threat posed by COVID-19, and frontline health workers must be mindful of their own immune systems when advising their patients to do the same. Unreasonable fear of COVID-19 only weakens the immune system, and fear attracts that which is feared. According to many COVID-19 survivors, remaining positive is a crucial factor in combatting this illness. Knowledge about the enemy and our potential resources lessens fears and helps us to plan strategies to defeat the adversary. With a quarter of the world’s population in the grip of COVID-19, it is a highly challenging period to learn to survive and strengthen our body and mind and enhance our immune system, even using the wisdom of unconventional medicines and faith traditions. We will have to battle with this invisible enemy until an effective vaccine is identified. Anything that fosters self-immunity should be encouraged in this time of a global medical emergency.

The two functions of immune system are defending the body’s health and maintaining health.The immune system is depicted as having two components: the innate and adaptive immune responses. The innate system is the more primitive and less specific. It is the body’s first line of defence against foreign substances that may lead to disease. The adaptive system, found only in vertebrates, is a much more specific, delayed response and requires sanction from the innate system to be instigated. Though considered separate, each interacts with the other in critical and complex manner. A basic understanding of both responses facilitates to clarify and further substantiate the significance of immune balance.

There are many myths surrounding immunity enhancement. Enrichment of the immune system is possible so that it becomes vigilant and active in the event of an invasion by pathogens and it may possibly prevent immunity anomalies. It is defending the defenders of the body. Immune system is our protective shield. Metaphorically, immune cells are the guardian angels of the body. Balancing of immunity can be achieved by focussing on ample sleep, healthy diet, moderate exercise, weight monitoring, restricting alcohol, free of smoking and destressing.In the nutshell, it warrants lifestyle changes- one size may not fit all and immune balancing has to be adjusted on an individual basis.

a. Restful Sleep

One healthy habit vital to preventing sickness is getting a full eight hours of sleep each night, which may help regulate immune function.19 Studies reveal that people who are deprived of quality sleep are more likely to get sick after being exposed to a virus. Respiratory infection has been linked to poor sleep.20 One study of over 22,000 people, for example, found that those who slept less than six hours per night or had a sleep disorder were more likely to suffer colds and other respiratory infections.21 Lack of sleep can affect immune system adversely.

During sleep, immune system releases cytokines, some of which even help promote sleep. Certain cytokines need to increase during an infection, or under stress. Sleep deprivation may decrease production of these protective cytokines. In addition, infection-fighting antibodies and cells are reduced during periods when person is deprived of ample sleep. Sleep and the circadian system are strong regulators of immunological processes.22 There is a bidirectional communication between CNS and immune system. This is mediated by shared signals though neurotransmitters, hormones and cytokines and direct innervations of the immune system by the autonomic nervous system. Differentiated immune cells with immediate effect or functions, like cytotoxic NK cells and terminally differentiated CTL, peak during the wake period. 23 These chemicals permit an efficient and fast combat of obtrusive antigens and reparation of tissue damage. The more slowly evolving adaptive immune response is initiated during nocturnal sleep and undifferentiated or less differentiated cells like naïve and central memory T cells peak during the night.

It is during sleep, the immune system heals, repairs, and prepares for the challenges of wakeful periods. During the deep stages of NREM sleep, the body repairs and recuperates, and this deep sleep also reinforces immunological memories of previous pathogens.23 The endocrine milieu during early sleep critically supports (a) the interaction between APC and T cells, as evidenced by an enhanced production of IL-12, (b) a shift of the Th1/Th2 cytokine balance towards Th1 cytokines and (c) an increase in Th cell proliferation and (d) probably also facilitates the migration of naïve T cells to lymph nodes.22 A feeling of lethargy when fighting an infection may be a signal from the body—which produces chemicals that act on the brain—to sleep, so that the body can recover. A single night of poor sleep can lead to a dramatic reduction in NK cells, the first line of defence against viruses and cancer cells, which negatively impacts other immune cells.

b. Nutrition

The size of the inoculum, the virulence of the exposure, the immune response of the host, and the health of the host are the four vulnerability factors of an infection. The former three ingredients are beyond the control of the host and the fourth one is within the control of the host and is very much based on the nutritional status. Food is generally viewed in terms of calories, but nutritionists have started appreciating the noncaloric micronutrients in the food, including those that are neither vitamins nor minerals, but phytochemicals (plant-chemicals) that strengthen and support normal immune function. The recent research discovery that food is not only a calorie supplier, but also adds to disease resistance and longevity benefits, has rekindled an interest in phytochemicals that support defensive and self-reparative functions. Modern diet consists of processed food mixed with additives, colouring agents, and preservatives; there is no room for unrefined vegetables in the dietary pie. Nutritional excellence can be achieved through green vegetations and friuts.

Antioxidants are vitamins, minerals and phytochemicals that support the clearance of free radicals and controlling its production in the body. Free radicals are molecules that contain an unpaired electron which causes them to be highly chemically reactive and these unstable molecules are destructive as they come in contact with structures and other molecules within the cells.24 Antioxidants are the natural enemy of free radicals which creates inflammation leading to dysfunctional immune system and to premature aging. Vitamin C, E, folate, selenium, and alpha and beta-carotene, as well as various other phytochemicals have antioxidant properties. They are available in plentiful amounts in vegetables and fruits and consumption of them enhances the immune functions. The Namboothiri caste of Kerala are famous for their strict vegetarian dietary habits and disease-free life, and longevity. The nutritional status of the host is critical in permitting or prophylaxis against viral and bacterial infections as well as the nutritional deficiencies in the host allow mutation of viruses into more lethal forms. 24 This is evident in the meat-eating food markets where the SARS-Cov-2 initially began to breed and mutate.

Pro-inflammatory foods can sabotage the immune system and should thus be checked in its quantity of consumption. Thirty minutes after they are consumed, carbohydrates may begin suppressing the immune system, and this effect may last for up to five hours. Foods with extreme diuretic properties also have detrimental effects on the immune system, which functions better when well hydrated. Drinking plenty of water facilitates efficient cell operation and allows the body to process food and eliminate waste. Following a diet rich in antioxidants is also essential to supporting the immune system, so eating fruits and vegetables is recommended. Fruits and vegetables are rich in antioxidants that combat free radicals—chemical by-products known to damage DNA and suppress the immune system.25 Choosing healthy fats—such as the omega-3 fatty acids found in oily fish, flaxseed and krill oil—over the saturated fats found in meat and dairy products is generally recommended by health authorities. These oils may help increase the body’s production of compounds involved in regulating immunity.26

Dietary supplements and medicines may be required for people who suffer from micronutrient deficiencies. Vitamin D is linked with a healthy immune system, and a large body of well-established data highlights its antiviral effects; it not only directly interferes with viral replication but also has immunomodulatory and anti-inflammatory effects.27-29 A research study in the U.S. suggests that having low levels of vitamin D doubles the risk of death due to heart attack compared to having higher levels.30 It is therefore recommended that all UK citizens take a vitamin D supplement between October and March to help maintain healthy levels during less sunny months. Such supplements are available in several forms, including capsules, sublingual sprays, and liquid drops, that are usually oil-based, as the vitamin is fat-soluble.

Nutritional excellence is in one’s own individual control. An over-boosted immune system, however, can lead to autoimmune reactions, so it is important to balance supplements and not over-boost. Moreover, vitamin D toxicity can cause hypercalcemia, which may lead to excess calcium deposits in the kidneys, lungs, or heart. A well-balanced diet is crucial in balancing immunity. An ideal immunity diet maintains caloric balance and consists of healthy fats, phytonutrients, fibre, quality carbs and diverse protein sources. Multiple micronutrients, including lutein, lycopene, folate, bioflavonoids, riboflavin, zinc, selenium, and many others have immune modulating functions.31 In general, the Mediterranean diet pattern has been praised as anti-inflammatory and good for fortifying immunity.32 The Mediterranean diet is associated with older age, as well as increased activity and reduced stress

c. Hygiene

Simply keeping the hands clean is one of the best ways to ward off illness, according to the Centres for Disease Control and Prevention (CDC). By washing the hands for 20 seconds using warm water and soap before preparing food or eating, as well as after coughing, sneezing, using the bathroom, or touching public surfaces can prevent the invasion of several pathogens. Hygiene hypothesis in medicine is quite often misinterpreted and misunderstood. It does not suggest that having more infections during childhood would be an overall benefit.

The hygiene hypothesis promulgates the view that early childhood exposure to particular microorganisms such as the gut flora and helminth parasites shields against allergic diseases by contributing to the maturation of the immune system. Lack of exposure is thought to lead to defects in the establishment of immune tolerance. The time period for exposure to microbes commences in utero and probably terminates at school age.

d. In Praise of Microbes and Nature

The preindustrial lifestyle that made available for the daily intake of trillions of friendly microbes is now replaced by a world of sanitisers and wet wipes. Alternative medicine takes into account the friendly bacterial flora inhabiting human body and we ought to be mindful of their role in balancing immunity. Even though humans are controlled by 25000 genes, the genes of the microbes cohabiting with ours are taken into account, it would be more than 3 million. In fact, these genes of the microbes are the immunity trainers and coaches of human immunological genes. Conventional medicine also takes into account the existence of intestinal microbes and their role in health and illness. Approximately, 95 percent of the total number of cells in the human body are constituted by these GI tract microflorae and play a prominent role in the health of our immune system. In fact, these guts bacterial flora is the meeting point of alternative medicine and modern medicine.33

The intestinal microflora serve several useful functions that may include the supplementation of the digestive process, produce vitamins, short-chain fatty acids, protect against the overgrowth of pathogenic bacteria and yeasts, strengthen immune abilities and generate beneficial nutrients that stop weight gain. 24 Pathogenic bacteria, on the other hand, produce toxic substances, become bacterial invaders, cause digestive disturbances, trigger immune system dysfunctions, and even stimulate weight gain.

Modern urban life is at a low level on microbial variety and has poor contact with helpful environmental microbes.34 Asthma and allergies are found to be much less among children brought up in farm and drunk farm milk.35 People living in urban areas are more susceptible to allergies and inflammatory diseases. Children exposed to outdoor microbes have more robust immunity. Obese people with 30% fewer intestinal microbes tend to gain more weight. 36

People should enjoy the smell of green grasses and appreciate the healing powers of mother nature. Ecopsychology, which is the study that explores the connection between the world of nature and the world of humans, is a new branch of psychology. Studies have revealed that spending some time outdoors, in the nature, can actually reduce stress, as well as improve our overall emotions and feelings of happiness and wellbeing, raise the levels of energy, and enhance immunity. It is healthier to do exercises outdoors than indoors. A lifestyle admirably adapted to mother nature alone can guarantee robust mental and physical health.

e. Antibiotic Overuse

Research findings suggest that antibiotic abuse can result in damage to the immune system, and memory problems caused by a lack of growth in new brain cells. Overusing antibiotics, which happens when antibiotics are overprescribed or prescribed inappropriately, has many negative outcomes. In the first place there is no relief of symptoms or rationale in prescribing antibiotics for a viral rather than bacterial infection. It results in disruption of the normal, healthy flora in the digestive system, which can take nearly two years to correct and lead to other infections. Antimicrobial resistance is another established complication of overprescribing antibiotics. Antibacterial adverse effects are attributed to 25% of all drug reactions in hospital patients.37

Even a single course of antibiotics has a detrimental effect on the gut flora and can result in harmful alterations in the composition and diversity of gut flora disrupting ecosystem. 38 Antibiotic exposure in children have long standing impact on the health and is linked with increased risk of immune system disorders. Antibiotic induced autoimmunity has been reported. Low levels of antibiotic administration lead to fatter mice by up to 40%.39

f. Physical Activity

To enjoy a good night sleep, one has to be pleasantly tired. Being active reduces stress and causes individuals to feel more energetic and alert, thereby helping the body prepare for better sleep. The main principle underlying exercise is keeping the body moving. Stress hormones are slowly released during exercise, which has a favourable effect on the immune system.40 Physical activity can also facilitate clearing of bacteria from the pulmonary system and can alter levels of white blood cells and antibodies. It is believed that during exercise, leucocytes and antibodies move faster in the circulatory system, allowing them to detect internal threats and diseases sooner; however, there is not yet proof that infections are prevented by these changes. Bacterial growth may also be blocked by the increased body temperature during and after exercise, which may help the body fight infection in a way similar to a fever.

Keeping muscles active releases high levels of interleukin 7 into the blood, which helps to stop the thymus from shrinking. This would help production of new T cells and balance our immunity. Maintaining a healthy basal metabolic rate is crucial. Walking is the simplest but highly effective exercise. Regular walks strengthen our immune system. It improves the mood and energizes the body. Walking in green spaces could give a big mood boost Walking has no set rules and can be carried out in the busiest cities and in the sprawling countryside. Too much of exercise can become a stressor for the body and turn out to be counterproductive.

g. Immunity and Obesity

Obesity is the result of a disruption of energy balance that leads to weight gain and metabolic disturbances that cause tissue stress and dysfunction. 41Metabolic syndrome is a cluster of metabolic disorders and is rampant in the 21st century. It results in conditions combining diabetes, hypertension, and obesity. Metabolic syndrome is also linked to several types of cancers and it has strong inflammatory underpinnings linked to dysregulated immunity.

Obesity and immunity are inversely related. It has been observed, for example, that the same amount of vaccine generates different immune responses from obese and lean people. Obesity has been identified as a modifiable risk factor of severe COVID-19, but weight loss also brings other health benefits. Having a healthy body weight is important in maintaining strong immunity because the presence of too many fat cells suppresses immunity. Obesity can depress the immune system by reducing the body’s ability to produce leucocytes, generate antibodies and locate infection sites. Persistently enlarged fat cells place a body in a constant state of inflammation, keeping the immune system permanently on the go. Maintaining the right amount of body fat is crucial to immunity and health.

h. Alcohol Impairs Immune Cells

Much remains unclear about the impact of alcohol consumption to immune system. Alcohol abuse result in diminished liver and pancreas functioning which can lead to immune system problems. Chronic alcohol abuse and pneumonia are linked. Alcohol has an immunosuppressant effect, and binge drinking is particularly detrimental. One study reports that after four shots of vodka within a 20-minute period, blood samples reveal initial ramping of the immune system followed by sluggish immune responses a few hours later. Acute and chronic alcohol use impedes cellular immune function, placing binge drinkers at greater risk for bacterial and viral infections. A multi-layered interaction between alcohol and immunity exists, and alcohol abuse has negative effects on both innate and adaptive immunity.42

Drinking alcohol immoderately can cause damage to the immune system in two ways. First, it reduces the availability of nutrients, thus depriving the body of resources that strengthen immunity. Second, it can hinder the ability of white blood cells to destroy microbes. It is well recognised that excessive alcohol consumption suppresses white blood cell replication, inhibits the action of killer white cells on cancer cells and hampers macrophages’ production of tumour necrosis factors. Immune system damage increases in proportion to the quantity of alcohol consumed. While wine promoters assert that one daily glass of red wine may be helpful to maintaining health, any amount of alcohol large enough to cause intoxication is also large enough to suppress immunity.

There is a perilous myth circulating among the inner quarters of the public that consuming high-strength alcohol can kill the COVID-19 virus and it has stemmed from fear and helplessness and is totally unfounded. Consuming any alcohol poses health risks, but consuming high-strength ethyl alcohol (ethanol), particularly if it has been adulterated with methanol, can result in severe health consequences, including death. Alcohol consumption is associated with a range of communicable and noncommunicable diseases and mental health disorders, which can make a person more vulnerable to COVID-19. In particular, alcohol compromises the body’s immune system as described above and increases the risk of harmful health effects. Though there is still limited data on the link between alcohol and COVID-19, past evidence shows alcohol consumption can worsen the outcomes from other respiratory illnesses by damaging the lungs and gut and impairing the cells responsible for immune function.

i. Avoiding Substance Use

Marijuana, cocaine, heroin, and other opiates are widely used illegal drugs. Drug abuse compromises immunity, so it is imperative to stay clear of illicit drugs during a pandemic. Numerous clinical reports indicate the association between infectious diseases and the use of illegal drugs. These drugs alter not only neurophysiological and pathophysiological responses but also immunity responses. Thus, it is vital to determine the mechanisms through which drugs compromise immune responses both independently and in concert with immunosuppressive viruses.43

Snorting cocaine harms mucous membranes in the nasopharynx and pulmonary areas. This increases the chance of upper respiratory infections.44Marijuana affects several kinds of cells in the body, which can ultimately harm the immune system. Smoking marijuana reduces the body’s ability to resist infections from viruses, bacteria, fungi, and protozoa. Because of the suppressed ability of the immune system, it may also reduce the ability of an immune system to be able to destroy cancer cells. Drugs of abuse include heroin, morphine, fentanyl, opium, and prescription painkillers. While all narcotics have some effect on the immune system, injecting drugs into the veins increases the risk of viral infections like HIV and hepatitis B or C (due to sharing needles) and bacterial or fungal infections. This is especially dangerous in people whose immune systems are already compromised. Crushing and snorting narcotic drugs can also increase the risk of upper respiratory infections due to damage to the mucous membranes in the nasopharyngeal regions. Morphine and related opioids have been found to directly impact white blood cells, which can reduce the ability of the immune system to react to diseases.45

j. Pulmonary Health

As with marijuana and crack cocaine, smoking cigarettes can lead to upper respiratory problems and a lowered immune system response to infections in the pulmonary system.46 Studies indicate that smoking increases the risk of more severe lung disease in cases of SARS-CoV-2 infection. It has been argued that exposure to cigarette smoke increased the number of infected and apoptotic cells in the airway and that SARS-CoV-2 prevented the usual repair response to airway injury.47 SARS-CoV-2, the causative agent of the COVID-19, infects cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor present on host cells. ACE2 is highly expressed in ciliated cells of the upper airways. Smoking is linked with both a negative progression and adverse outcomes of COVID-19.48

Smokers touch their lips frequently, which may accidentally pass the virus to their mouths, and they tend to have existing respiratory conditions consequent to their smoking habit. These factors make them more vulnerable to viral respiratory infections and more prone to COVID-19-related complications. Indeed, smoking has been linked to a plethora of respiratory diseases and poor disease prognosis.49 Smokers are more vulnerable to infectious diseases because smoking harms the immune system, adversely affecting how it responds to infections.50 During the previous MERS-CoV epidemic, for example, smokers were found to have high mortality rates.51 One retrospective analysis of 78 patients in China found that smoking was correlated with greater COVID-19 severity and poorer prognosis. Though analytical studies conflict,52 smoking continues to be linked with higher risk.53

k. Balancing Bodily Temperature

It has been recognised that an increase in body temperature by 1°C than normal would result in an instantaneous increase of immunity by 5 to 6 times. On the contrary, as soon as the body temperature drops, the activity of white blood cells will be retarded, resulting in a decrease in immunity. Low temperature is well recognised as immunosuppressive. It is an accepted fact that fever is the body’s defence mechanism that activates the immune system in response to inflammation. The immune system functions optimally at higher comfortable temperatures and becomes underactive in cold environments. This is why seasonal infectious diseases like influenza are more prevalent during lower temperatures. Warm temperature restricts viral replication through type I IFN-dependent and -independent mechanisms in vitro.54 In addition, both humidity and temperature affect the frequency of influenza virus transmission among guinea pigs.55 One way to warm the body is to be metabolically active while keeping a relatively high room temperature and/or wearing warm clothes. The significance of thermal balancing to maintain healthy immunity has been discussed in preceding paragraphs.

l. Destressing

Good relationships protect mental health and wellbeing. People who are more socially connected are happier, physically healthier and have longevity. One should put more time aside to connect with friends and family, learn to live in the present and switch out of work mode whenever possible. It is important to invest time on and value relationships and make them a priority, listen to others, and speak openly about feelings. People should be good listeners and concentrate on the needs of other people. Happiness is the reflection of what one does for others. People should make an effort to be surrounded by positive individuals and allow themselves to be listened and supported. The key to destressing and happiness is being honest and respecting others.

Severe anxiety suppresses the immune system and the coronavirus may thus literally feed on fear. Relaxing and focussing on the present, however, can improve mental health and counteract negative feelings. Various forms of meditation and progressive muscle relaxation techniques, for example, can help one unwind from the assault of daily stressors, and such post-work relaxation may enhance the immune system. Incorporating relaxing practices like meditation, yoga or deep breathing into a daily routine has been found to be helpful. Psychological health and immunity are causally related. The current pandemic is forcing us all to adjust to new and strange ways of life, which can adversely affect mental wellbeing.

While short-term exposure to stressors can accelerate immune defence, prolonged stress may wear down the immune system, increasing vulnerability to illness. 56 In this way, chronic stress can be a killer. Immuno-psychiatry is a fledgling sub-speciality which deals with the immunological components of psychosis and depression.57 The autoimmune aetiology of schizophrenia is gaining ground 58-60 and the neurotoxic effects of cytokine storm due to COVID-19 have recently caught high attention.

Extra-physiological Immunity?

The chemical effects of allopathic medicines are a scientific reality, but their therapeutic effects are also partially due to placebo effect. Placebos are aimed at the symptomatic relief of illnesses. Disease and illness have different connotations; disease is understood scientifically in terms of pathophysiology and illness is understood phenomenologically, as a lived experience. 61 It is increasingly being recognized that what we call the ‘placebo effect’ may involve changes in brain chemistry induced by quantum bioenergy fields. That implies the placebo effect may be a quantum reality that is created by the mobilisation of quantum bioenergy fields.62 The placebo effect is believed to be brought about when the subjective mind produces medicinal agents and accelerates the healing process. It is estimated that up to 40 per cent of the effects of medicinal drugs may be a placebo effect. The placebo effect often seems to be associated with measurable changes in brain chemistry and there have been observed quantifiable changes in neurotransmitters, hormones, and immune regulators. 63 Placebos also relate to the disposition to heal, no matter what treatment is offered, if those being treated believe the treatment is helpful. 64 Regarding the effects of drugs, expectations appear to have a significant influence. The very existence of placebos offers an indirect proof for the existence of extrasomatic energy system and we need to incorporate their effect in the immune balancing. A quantum conceptual model of placebo is essential to understand certain hidden channels of medical sciences. The placebo component of immunity is highly significant and needs further evaluation.

Immunity is not a single entity; it is a system, and for a system to function well, it requires balance and harmony. Not everything about the immune system is known to science, and according to integrated medicine, immunity may not be confined to physiology alone, but may have non-physiological aspects as well. Numerical age and physiological age are two different things. This is particularly so if extra-physiological energy system is brought into the equation of immunity. It is true that the existence of extra-physiological systems is not scientifically well established, but they are strong hypothetical possibilities.

Studies of quantum bioenergy fields should be an integral part of the science of human physiology and homeostasis should be redefined as the state of steady internal physical and chemical conditions maintained by different regulators, including extrasomatic energy fields.65 Humans are multidimensional or psycho-spiritual entities with several layers of energy bodies with increasing subtilty.66 Complementary medicines work on the assumption that humans are associated with a subtle energy system, in addition to their material body. Even though such extrasomatic energy systems are not recognised in the modern medical sciences, there are energy fields that cannot be explained by the classic Maxwell–Schrodinger equation.

The material body and energy bodies are in a complementary relationship: if the material body is the container, vital energy is the content.67 Beverly Rubik postulated that biological systems may be regarded as complex, non-linear, dynamic, self-organising systems of energy and field phenomena68,69 Many researchers have attempted to bring the existence of extrasomatic energy fields into the arena of mainstream sciences.70--73 If such quantum bioenergy fields really exist, they may play a major role in maintaining homeostasis in the human physiology, and it would be of great clinical interest to evaluate their role in immune system functionality, as long as they do not overrun the scientifically accepted views. To bring the concept of extra-physiological immunity into immunology, we may also have to accept the possibility of ‘nano immune cells’ and a ‘nano-level immune mechanism’.

Conclusion

The high incidence of complications among ethnic minority points toward the thermal conditioning and the role of immunogeneticsgenetics. Underactive immune responses in cooler temperature and diminished synthesis of vit D and the genetic factors linked with these anomalies might explain part of the higher incidence of COVID-19 among BAME. It is the physically and psychologically resilient people of a community who normally migrate to overseas countries. If migrants are to develop mental health problems, it would manifest within 6 months of migration, but physical health problems come about any time of their stay abroad as the weakening of immunity is a slow process. COVID-19 has a direct impact on co-existing disease processes worsening them because of the added immunity impairment. There are still missing gaps in the pervasive occurrence of this viral affliction among the BAME people. They should be mindful of the vulnerability factors and special precautionary measures should be adapted to prevent the infection.

COVID-19 appears to be a test of self-immunity. To combat COVID-19, efficient tests, novel treatments, and vaccines are the three means. An effective and safe vaccine would drastically change the pandemic situation for good. Vaccination and developing novel form of medication would take some time to become available. In such circumstances, one way of protecting from COVID-19 is by balancing one’s own immune mechanisms. It is a good thing that there is ample promotion of preventive measures of the contagion, there should be more awareness of improving personal immunity. More research works are warranted in immunology including extra-physiological immunity. Strengthening immunity is achievable for everybody if sufficient attention is paid. A safe and effective vaccine with long term immunological properties would drastically change the pandemic situation for good. Thus far, the research findings of the pandemic are inconsistent, and many dimensions of this pandemic warrant further clarification. COVID-19 will have a serious impact on virology and the neurotoxic effects of cytokine storm may be a stimulus for the growth of immuno-psychiatry.

Science is good enough to study the physical and visible, but it has obvious limitations when it comes to the unphysical and non-physical. Unphysical is undetectable only because they cannot be identified with the present-day instrumentation but can become detectable when our technology advances and their presence should not be stubbornly denied. The well-established placebo effects may point towards the existence of quantum bioenergy fields. Existence of extrasomatic energy system indirectly support the concept of extra-physiological immunity. Placebo effects are not psychological artefacts, but quantum manifestations. If extra-physiological immunity exists, it may be guarding and supervising the physiological immune system.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAMES PAUL PANDARAKALAM, Consultant psychiatrist, Northwest Boroughs Healthcare NHS Foundation Trust, Hollins Park Hospital & AFG Rehab Hospitals, Warrington WA2 8WN, UK.
Corresponding Author Details: 
DR JAMES PAUL PANDARAKALAM, Consultant psychiatrist, Northwest Boroughs Healthcare NHS Foundation Trust, Hollins Park Hospital & AFG Rehab Hospitals, Warrington WA2 8WN, UK.
Corresponding Author Email: 
James.pandarakalam@nwbh.nhs.uk
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An overview of prolonged disorders of consciousness for the General Practitioner

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

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

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

Introduction

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

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

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

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

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

Identifying Patients

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

Table 1: Aetiology of acquired brain injury.5

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

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

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

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

Diagnosis

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

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

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

1. Establishing a cause

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

2. Reversible causes should be excluded

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

3. Structured assessment

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

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

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

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

Vegetative State & Minimally Conscious State

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

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

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

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

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

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

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

Emergence

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

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

Specialist Involvement

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

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

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

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

Medicolegal & Ethical Issues

Capacity Assessments

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

Identifying Advance Decisions

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

Best Interests Meetings

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

Ceiling of Care Discussions:

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

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

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

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

Conclusion

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

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

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

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

The less common presentation of pituitary apoplexy and its management: A case report

Authors
Huzairi Sani & Nada Syazana Zulkufli
Article Citation and PDF Link
BJMP 2020;13(1):a006
Abstract / Summary
Abstract: 

Pituitary apoplexy is the event of haemorrhage, infarction or both affecting the pituitary gland. It commonly occurs in non-functioning pituitary adenoma. This case study reports an uncommon presentation of pituitary apoplexy where the patient only presented with a 2-week history of visual symptoms and was otherwise clinically stable, causing the disastrous pituitary event to be unsuspected on initial presentation.

Keywords: 
pituitary disease, pituitary apoplexy, pituitary haemorrhage, pituitary infarction

INTRODUCTION

The pituitary gland is a tiny gland located at the base of the brain and is connected to the hypothalamus. Dubbed as the body’s “master gland”, it produces important hormones that control many bodily functions such as those involved in the control of haemodynamics, glucose, fight or flight response, body growth and many more. Any of the pituitary hormones may be affected in pituitary disease, with acute adrenocorticotropic hormone (ACTH) deficiency being the most catastrophic and life-threatening.

Pituitary apoplexy occurs following acute haemorrhage or infarction of the pituitary gland, causing patients to be acutely unwell due to hormonal as well as local compressive effects. These effects cause the usual presentation of pituitary apoplexy such as severe headache, diplopia, visual loss and hypopituitarism.

We report a case of pituitary apoplexy that presented with a 2-week history of loss of peripheral vision and lethargy with stable vital signs.

CASE PRESENTATION

A 49 years of age gentleman complained of loss of peripheral vision in the left eye and lethargy for 2 weeks. The loss of vision was sudden, painless and non-progressive and had caused him considerable difficulties with driving where he would shift into the wrong lane and was honked at. He had no known medical or surgical history of note. Prior to presentation, he had no history of eye pain, eye redness or a history of trauma to the left eye. There were no headaches, neurological deficits or constitutional symptoms.

Clinically, he had bitemporal hemianopia with no other cranial nerve deficits. His Glasgow Coma Scale was 15/15, vital signs were stable and there was no postural change in blood pressure. Examination of other systems was unremarkable. Blood investigations revealed a decreased morning cortisol of 46 nmol/L and a normal thyroid stimulating hormone (TSH) with borderline low free thyroxine. Serum electrolytes, plasma glucose and all other anterior pituitary hormones were within reference range.

A computed tomography (CT) of the brain showed an enlarged pituitary sella with a large well-circumscribed and heterogeneously enhancing mass within. This mass measured 3.5cm x2.7cm x3.5cm (AP xW xCC) and had no calcifications within. It was also compressing onto the optic chiasm.

Two days later, a brain pituitary Magnetic Resonance Imaging (MRI) was done which reported a heterogeneous mass occupying the sella with suprasellar extension measuring 2.7 x2.8 x2.9cm (AP xW xCC) (Figures 1.1 & 1.2). This mass returned mixed solid-cystic intensity with significant enhancement post-contrast administration. There was evidence of layering within the cystic component of this mass. Inferiorly, the right border ended lower than the left (Figures 2.1 & 2.2).

Following consultations with endocrinologists, neurosurgeons and radiologists, a clinical diagnosis of pituitary apoplexy with hypocortisolism and central hypothyroidism was reached. The patient was started on oral hydrocortisone 20mg in the morning and 10mg in the evening; and oral L-thyroxine 100mcg in the morning before he was referred to the neurosurgeon for trans-sphenoidal surgery. While awaiting surgery, no clinical deterioration was reported. An endoscopic trans-sphenoidal surgery successfully took place a week later which revealed an enlarged haemorrhagic pituitary gland (Figure 3.0). The patient was discharged well a week post-surgery.

His histopathology report later confirmed pituitary adenoma where monomorphic tumour cells arranged in nests and trabeculae and some pseudorosettes were seen. The tumour cells exhibited mild pleomorphism with moderate amount of cytoplasm. The stroma was highly vascularised. No necrosis, calcification or mitosis was seen. Immunohistochemistry studies were positive for follicle-stimulating hormone (FSH) and luteinising hormone (LH) and negative for ACTH, growth hormone, prolactin and TSH.


Figure 1.1 and 1.2: MRI brain on coronal view illustrating well-defined and heterogenous suprasellar mass


Figure 2.1 and 2.2: MRI brain on sagittal view illustrating mixed solid-cystic intensity pituitary mass


Figure 3.0: Intraoperative finding showing haemorrhage of the pituitary gland

DISCUSSION

Pituitary apoplexy is a potentially fatal condition caused by haemorrhage or infarction or both. Most cases occur during the fifth decade of life, predominantly in males.1 In the majority of cases, it is associated with a pre-existing non-functioning macro-adenoma which accounts for 14-54% of pituitary adenomas and has a prevalence of 7-41.3/100,000 population. The standardised incidence rate is 0.65-2.34/100,00.2

The many clinical presentations of pituitary apoplexy result from local compression of adjacent structures or deficiency of pituitary hormones – the former being more common where affected individuals present with headaches, visual disturbances and other symptoms of raised intracranial pressure.3

Subclinical haemorrhages refer to asymptomatic individuals with evidence of pituitary haemorrhage on MRI. In a 2018 retrospective transversal analysis involving 64 patients, 34.38% had subclinical haemorrhage within a non-functional adenoma.4 In another retrospective overview by Turgut et al, 186 cases of apoplectic pituitary adenoma presenting with monocular or binocular blindness were published in the last century.5 In a case report by Sasaki et al, a 65-year-old gentleman was only diagnosed with pituitary apoplexy following weeks of blood investigations for hyponatraemia and repeat imaging. His only presenting complaints were anorexia, low energy and fever for two weeks.6 These studies show that while an early correct diagnosis of pituitary apoplexy is important, it is not necessarily urgent.

On the other end of the spectrum, pituitary apoplexy may also present as a life-threatening situation where patients are unconscious and hemodynamically unstable due to hypopituitarism. In its acutely deficient state, ACTH causes acute adrenal insufficiency hence resulting in hypotension, hypoglycaemia, hyponatraemia and hyperkalaemia. Sometimes, non-specific symptoms precede the symptoms of hypocortisolism. A drop in consciousness level may be due to the tumour’s mass effect transmitting pressure to the brainstem or causing hypothalamic compression.7 Espinosa et al reported a 48-year-old gentleman with pituitary apoplexy who presented with the worst headache of his life, requiring urgent neurosurgical intervention which proved to be life-saving.8

Complex as it already is, diagnosing pituitary apoplexy may be further complicated when non-specific symptoms can be explained by other causes such as post-general anaesthesia drowsiness, hyponatraemia in a patient on diuretics and headaches in post-partum women receiving spinal anaesthesia.9, 10

While most patients consequently suffer from pituitary insufficiency, the extent, type and duration of therapy differs between patients. Cases of spontaneous recoveries whether a surgical or conservative approach was adopted have also been reported.11, 12 However, robust control studies comparing the outcome of surgical with conservative management in patients with pituitary apoplexy have yet to emerge. Nonetheless, studies have proven that visual outcomes significantly improve with surgery.13, 14

Having discussed the varied presentations of pituitary apoplexy, it can be agreed upon that the life-threatening endocrinal condition should be considered in any patient with abrupt neuro-ophthalmic deficits despite the state of clinical stability. This is imperative as prompt medical and surgical management may not only be life-saving, but also significantly improve visual and cranial nerve outcomes.15

CONCLUSION

Pituitary apoplexy is an endocrinal emergency which requires immediate investigation and treatment. Despite its disastrous pathology, there have been cases where affected patients present with isolated visual disturbances or with no symptoms at all. It is therefore important to have early suspicion of pituitary apoplexy in stable patients with eye complaints as early detection and management are life-saving and significantly improve neuro-ophthalmic outcome.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We would like to thank all doctors from the Department of Endocrinology, Putrajaya Hospital, Malaysia for their expert opinion, effort and support.
Competing Interests: 
None declared
Details of Authors: 
HUZAIRI SANI, MBBS MRCPI MMED, Medical faculty, Universiti Teknologi MARA, Selangor, Malaysia. NADA SYAZANA ZULKUFLI, MBBS MRCPI MPATH, Department of Pathology, Penang General Hospital, Malaysia.
Corresponding Author Details: 
HUZAIRI SANI, Medical faculty, Universiti Teknologi MARA, Selangor, Malaysia.
Corresponding Author Email: 
huzairi_s@hotmail.com
References
References: 
  1. Glezer A, Bronstein MD. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch Endocrinol Metab. 2015;59(3):259-64.
  2. Ntali G, Wass JA. Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas. Pituitary. 2018;21(2):111-8.
  3. Wildemberg LE, Glezer A, Bronstein MD, Gadelha MR. Apoplexy in nonfunctioning pituitary adenomas. Pituitary. 2018;21(2):138-44.
  4. Cebula H, Fasciglione E, Santin MDN, Todeschi J, Severac F, Proust F, et al. Subclinical haemorrhage in non-functional adenomas. Neurochirurgie. 2018;64(1):44-8.
  5. Turgut M, Ozsunar Y, Basak S, Guney E, Kir E, Meteoglu I. Pituitary apoplexy: an overview of 186 cases published during the last century. Acta Neurochir (Wien). 2010;152(5):749-61.
  6. Sasaki Y, Nakata K, Suzuki K, Ando Y. Pituitary apoplexy presenting with anorexia and hyponatraemia. BMJ Case Rep. 2015;2015.
  7. Verrees M, Arafah BM, Selman WR. Pituitary tumor apoplexy: characteristics, treatment, and outcomes. Neurosurg Focus. 2004;16(4):E6.
  8. Espinosa PS, Choudry B, Wilbourn R, Espinosa PH, Vaishnav AG. Pituitary apoplexy: a neurological emergency case report. J Ky Med Assoc. 2007;105(11):538-40.
  9. Madhusudhan S, Madhusudhan TR, Haslett RS, Sinha A. Pituitary apoplexy following shoulder arthroplasty: a case report. J Med Case Rep. 2011;5:284.
  10. Mathur D, Lim LF, Mathur M, Sng BL. Pituitary apoplexy with reversible cerebral vasoconstrictive syndrome after spinal anaesthesia for emergency caesarean section: an uncommon cause for postpartum headache. Anaesth Intensive Care. 2014;42(1):99-105.
  11. Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P. Pituitary Apoplexy. Endocr Rev. 2015;36(6):622-45.
  12. Rajasekaran S, Vanderpump M, Baldeweg S, Drake W, Reddy N, Lanyon M, et al. UK guidelines for the management of pituitary apoplexy. Clin Endocrinol (Oxf). 2011;74(1):9-20.
  13. Agrawal D, Mahapatra AK. Visual outcome of blind eyes in pituitary apoplexy after transsphenoidal surgery: a series of 14 eyes. Surg Neurol. 2005;63(1):42-6; discussion 6.
  14. Muthukumar N, Rossette D, Soundaram M, Senthilbabu S, Badrinarayanan T. Blindness following pituitary apoplexy: timing of surgery and neuro-ophthalmic outcome. J Clin Neurosci. 2008;15(8):873-9.
  15. Simon S, Torpy D, Brophy B, Blumbergs P, Selva D, Crompton JL. Neuro-ophthalmic manifestations and outcomes of pituitary apoplexy--a life and sight-threatening emergency. N Z Med J. 2011;124(1335):52-9.

COVID-19, Diagnostic Difficulties and Acute Psychosis

Authors
Abhinav Vepa, Amer Saleem, Diana Dharmaraj & Qasim Afzaal
Article Citation and PDF Link
BJMP 2020;13(1):a002
Abstract / Summary
Abstract: 

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID-19, has emerged as an epidemic contributing to more than 247,000 deaths worldwide as of 4th May 2020. It commonly presents with respiratory and occasionally gastrointestinal symptoms. Here we describe a rare case of COVID-19 presenting with acute psychosis which was also complicated by a false negative RT-PCR nasopharyngeal swab upon hospital admission.

Case Report: A 40 year old, previously fit and healthy male, presented to accident and emergency with respiratory tract symptoms and fever during the COVID-19 outbreak. His first RT-PCR nasopharyngeal swab tested negative for COVID-19, but due to a strong clinical suspicion of COVID-19, CT imaging was conducted which justified the sending of a repeat swab. In the meantime, he started to exhibit symptoms of acute psychosis such as hallucinations, paranoid delusions, an attempted suicide, derealisation and depersonalization. Due to failed conservative measures and haloperidol in managing acute psychosis, the patient was intubated for 24 hours. After extubating the patient recovered to baseline within 2 days.

Discussion: There are two clinically relevant learning points to be noted from this case report. Firstly, RT-PCR nasopharyngeal COVID-19 swabs are estimated to be only 70-75% sensitive, whereas CT scan changes are estimated to be as high as 97%-98% sensitive. CT imaging can thus be useful when there is a strong suspicion of COVID-19 despite negative nasopharyngeal swabs. Secondly, in order to reduce the work of breathing secondary to agitation, the cross-infection risks to others, and the risk of repeated suicide attempts, this patient was successfully managed with intubation and ventilation, despite the absence of respiratory failure.

Conclusion: False negative rate with RT-PCR COVID-19 nasopharyngeal swabs is high and this identifies a crucial diagnostic role for CT Thorax in swab-negative, symptomatic patients with suspected COVID-19. Secondly, acute psychosis is an emerging indication for intubation to consider when managing patients with highly virulent respiratory infections, such as COVID -19.

Abbreviations: 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, or, COVID-19), World Health Organisation (WHO), Real Time-Polymerase Chain Reaction (RT-PCR), Respiratory Syncytial Virus (RSV), Antero-Posterior (AP), Computerized Tomography (CT), Ground-Glass Opacification (GGO)
Keywords: 
COVID-19; Case Report; nasopharyngeal swab; acute psychosis; intubation; diagnosis; cross-infection

Background:

In December 2019, the Wuhan province of China was struck by an outbreak of viral pneumonia due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID-19.1 On the 30th of January, WHO declared a state of global emergency due to the rapid spread of COVID 19 2 and since then it has developed into an epidemic, contributing to over 247,000 global deaths as of 4th May 2020. COVID-19 has commonly presented with respiratory symptoms, but some gastrointestinal symptoms have also been described.3, 4 Here we describe a rare case of COVID-19 presenting with acute psychosis with initially false negative RT-PCR nasopharyngeal swab upon hospital admission.

Case Review

A 40 year old, previously fit and healthy male, with a six day history of dry cough, breathlessness and nasal congestion, presented to accident and emergency via ambulance. Prior to the respiratory tract symptoms, he had a progressively worsening fever, anosmia and intermittent diarrhoea for four days. His observations included a temperature of 39⁰C, oxygen saturations of 95% on room air and a respiratory rate of 30. His initial laboratory tests are shown in Table 1 and imaging in Figure 1.

Table 1: Table showing the relevant laboratory results of the patient upon admission

Investigations Value Reference Range
White cell count (x109/L) 12.0 3.7 - 11.1
Neutrophil count (x109/L) 10.3 1.7 - 7.5
Lymphocyte count (x109/L) 1.1 0.9 - 3.2
C-reactive protein (mg/L) 190 0 - 6
Cerebrospinal Fluid Protein (g/L) 2.4 0.15 - 0.45
Cerebrospinal Fluid Glucose (mmol/L) 3.7 2.5 - 4.5
Cerebrospinal Fluid White Cells (/µL) 0 0 - 5
Influenza A, B and RSV nasopharyngeal swab Negative
COVID-19 nasopharyngeal swab Negative
Pneumococcal urine antigen Negative
Legionella urine antigen Negative


Figure 1
: (Left) An AP X-ray showing bilateral patchy consolidation. (Right) A cross-sectional CT thorax image showing multifocal, peripheral, bilateral, ground-glass opacities with bilateral consolidation.

Over the course of the next two days, he developed acute confusion. A CT scan of his head was done in the first instance to identify any intracranial cause of confusion, but the scan was unremarkable. His behaviour included severe anxiety, aggression, wandering and agitation. His wife confirmed that he had never behaved like this before and had no history of psychiatric illness. He felt as if he was living in a dream, exhibiting derealisation and depersonalization. Worryingly, he also experienced suicidal ideation which he hoped would bring him back to reality. One of the ways in which he tried to kill himself was by jumping out of the hospital window. Due to verbal and non-verbal de-escalations being ineffective, 5mg of Haloperidol was given, but failed to settle the patient. This was the maximum daily dose of haloperidol in accordance with the British Geriatric Society Guidelines for the management of COVID-19 related confusion5. Subsequently, the patient was successfully managed with intubation and ventilation for 24 hours, despite the absence of respiratory failure. After extubating, he recovered back to baseline over 2 days, during which a 2nd RT-PCR nasopharyngeal swab result returned positive for COVID-19. After recovery, he had insight into the events that took place prior to intubation. Retrospectively, he reported auditory hallucinations of hospital staff talking about him all day and night, and the delusions that the hospital staff were against him, and that he was in a dream which could only be escaped by committing suicide.

Discussion

There are two clinically relevant learning points to convey from this case relating to, firstly, the difficulties encountered in diagnosis and, secondly, the management of acute psychosis in COVID-19 with intubation. The diagnosis of COVID-19 was confounded by the first nasopharyngeal RT-PCR swab being negative. Since his symptoms were typical of COVID-19 and with strongly suggestive radiographic findings, it was deemed appropriate to send a repeat COVID-19 nasopharyngeal RT-PCR swab (which indeed came back positive). This patient thus had COVID-19 pneumonia and the official diagnosis was delayed due to a false negative nasopharyngeal RT-PCR swab upon hospital admission.

Various studies have identified a high false negative rate with the COVID-19 swab.6, 7 Ai et al., describes 287 patients (n=1014) who had radiographic findings suggestive of COVID-19 with negative nasopharyngeal swabs.8 It is important for clinicians to be aware of the poor sensitivity of the RT-PCR COVID-19 swab so that it can be interpreted appropriately when being used to make clinical decisions. Various studies have estimated the RT-PCR COVID-19 swab sensitivity to be approximately 70-75%.9 This is hypothesised to be even lower if clinical staff do not use the correct technique when taking the nasopharyngeal swab. Subsequently, there is a growing clinical need for more sensitive laboratory tests for COVID-19 such as antibody tests.10

Chest radiographs may be normal in early or mild disease, but can assist diagnosis. Of patients with COVID-19 requiring hospitalisation, only 69% had an abnormal chest radiograph at the initial time of admission. Findings are most extensive about 10-12 days after symptom onset. The most frequent findings are bi-basal, peripheral, consolidative and ground-glass airspace opacities. In contrast to parenchymal abnormalities, pleural effusion is rare.11, 12 Indeed, this patient’s chest radiograph shown in Figure 1 (left) was performed after 10 days of symptoms, showing features of COVID-19.

The primary findings on CT have been reported in multiple studies to include ground glass opacification, ‘crazy-paving’ texture, air space consolidation, broncho vascular thickening, adjacent pleural thickening and traction bronchiectasis. The ground glass, or consolidative, opacities are usually bi-basal, peripheral and ill-defined.13-18 Four stages on CT have been described, as shown in Table 2 below.19, 20 This patient’s CT Thorax shown above in Figure 1 (right), was performed after 12 days of symptoms and displays features in keeping with the ‘peak’ stage.

Table 2: Table showing the radiographic staging of COVID-19

Stage Timescale Radiographic Findings
Early/initial stage 0-4 days Normal CT or GGO only
Progressive stage 5-8 days Increased GGO and crazy paving appearance
Peak stage 9-13 days Consolidation
Absorption stage 14 days< With an improvement in the disease course, "fibrous stripes" appear and the abnormalities resolve at one month and beyond

It is important to mention that in a retrospective, COVID-19 case-controlled study of 104 patients, 54% of asymptomatic patients had CT radiographic features in keeping with COVID-19.21 CT scan changes are estimated to be as high as 97%-98% sensitive and can thus be useful when there is a strong suspicion of COVID-19 despite negative nasopharyngeal swabs.8, 9, 22 This can avoid clinicians having a false sense of security when managing potential COVID-19 patients who may otherwise be nursed in open bays, consequently exposing unprotected clinical staff and patients; a common problem that we unfortunately encounter in our clinical practise.

The second interesting learning point in this case is with regards to the clinical reasoning behind why this patient was intubated. Patients with severe COVID-19 symptoms such as hypoxaemia, respiratory distress, shock or an SpO2 of <90% are usually commenced on supplemental oxygen therapy of 5L/min, which should then be titrated to maintain an SpO2 of >94%. Continuous positive airway pressure or non-invasive ventilation can then be trialled, and if ineffective, the patient can be intubated for ventilation.23 This patient’s SpO2 prior to intubation was 94%. Interestingly in this case, the clinical reasoning behind intubation was not respiratory failure, but instead acute psychosis secondary to COVID-19 which had failed to respond to conservative de-escalation measures, as well as haloperidol.

The intubation of this patient aimed to reduce respiratory effort, cross-infection risk, as well as prevent further suicide attempts. As mentioned in the history above, this patient was non-compliant with isolation regulations as he was severely confused and wandering around clinical areas, thus posing a cross-infection risk to staff and other patients.24 Self-isolation precautions have been heavily implemented in the UK because COVID-19 is an extremely virulent infectious disease.25 The basic reproductive number of COVID-19 has been estimated to be 1.55-5.5,26,27 making it more infectious than the seasonal influenza, at 1.28.28 This highlights the importance of strictly following isolation protocols, and thus, the rationale behind intubation.

Conclusion

There are two primary learning points to be appreciated from this case report. Firstly, the false negative rate with RT-PCR COVID-19 nasopharyngeal swabs is high, and this identifies a crucial diagnostic role for CT Thorax in ‘swab-negative’, symptomatic patients with suspected COVID-19. Secondly, acute psychosis is an emerging indication for intubation to consider when managing patients with highly virulent respiratory infections, such as COVID -19. The mechanisms behind COVID-19 induced acute psychosis remained yet to be elucidated, but, in this case, COVID-19-induced encephalitis was amongst the differential diagnoses.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ABHINAV VEPA, BSC, MBBS, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK. AMER SALEEM; BSC, MBBS, MCPS MEDICINE (PAK), MRCP (UK), FCPS Pulmonology ((PAK), FRCP (Glasgow), FCCP (USA), european diploma in adult respiratory Medicine, Speciality Certificate In Respiratory Medicine (RCP UK); Consultant Chest Physician, Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK. DIANA DHARMARAJ, MUDR, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK. QASIM AFZAAL, BSC, MBBS, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Details: 
ABHINAV VEPA, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Email: 
Dr_a_vepa@hotmail.com
References
References: 
  1. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 March 28;395(10229):1054-1062.
  2. Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health. 2020 Mar;25(3):278-80.
  3. Lovato A, De Filippis C, Marioni G. Upper airway symptoms in coronavirus disease 2019 (COVID-19). Am J Otolaryngol. 2020 Apr;4:102474.
  4. D'Amico F, Baumgart DC, Danese S, et al. Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention and management. Clin Gastroenterol Hepatol. 2020 Apr;8:S1542-3565(20):30481-X.
  5. British Geriatric Society. Coronavirus: Managing delirium in confirmed and suspected cases [Internet]. Good Practise Guide 2020 [Updated 2020 25th March, Cited 2020 20th April]. Available from: https://www.bgs.org.uk/resources/coronavirus-managing-delirium-in-confirmed-and-suspected-cases
  6. Li D, Wang D, Dong J, et al. False-Negative Results of Real-Time Reverse-Transcriptase Polymerase Chain Reaction for Severe Acute Respiratory Syndrome Coronavirus 2: Role of Deep-Learning-Based CT Diagnosis and Insights from Two Cases. Korean J Radiol. 2020 Apr;21(4):505-508. 
  7. Winichakoon P, Chaiwarith R, Liwsrisakun C, et al. Negative Nasopharyngeal and Oropharyngeal Swab Does Not Rule Out COVID-19. J Clin Microbiol. 2020 Feb 26. doi: 10.1128/JCM.00297-20.
  8. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020 Feb;26:200642. 
  9. Fang Y, Zhang H, Xie J, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology. 2020;19:200432
  10. Petherick A. Developing antibody tests for SARS-CoV-2. Lancet. 2020 Apr;4:395(10230):1101-1102.
  11. Wong HYF, Lam HYS, Fong AH, et al. Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients. Radiology. 2019 March;27:201160.
  12. Rodrigues J.C.L., Hare S.S., Edey A. An update on COVID-19 for the radiologist: a British society of Thoracic Imaging statement. Clin Radiol. 2020 May;75(5):323–325
  13. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020 Apr;20(4):425-434.
  14. Xu X, Yu C, Qu J, et al. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging. 2020 May;47(5):1275-1280.
  15. Xu YH, Dong JH, An WM, et al. Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2. J Infect. 2020 Apr;80(4):394-400.
  16. Yang W, Cao Q, Qin L, et al. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China. J Infect. 2020 Apr;80(4):388-393.
  17. Wang K, Kang S, Tian R, et al. Imaging manifestations and diagnostic value of chest CT of coronavirus disease 2019 (COVID-19) in the Xiaogan area. Clin Radiol. 2020 May;75(5):341-347.
  18. Li X, Zeng W, Li X, et al. CT imaging changes of corona virus disease 2019(COVID-19): a multi-center study in Southwest China. J Transl Med. 2020 Apr 6;18(1):154.
  19. Pan F, Ye T, Sun P, et al. Time Course of Lung Changes on Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia. Radiology. Doi:10.1148/radiol.2020200370.
  20. Pan Y, Guan H, Zhou S, et al. Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): a study of 63 patients in Wuhan, China. Eur Radiol. Doi:10.1007/s00330-020-06731-x.
  21. Inui S, Fujikawa A, Jitsu M et al. Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19). Radiol Cardiothorac Imaging . 2020;2(2):e200110.
  22. Li Y, Xia L. Coronavirus Disease 2019 (COVID-19): Role of Chest CT in Diagnosis and Management. Am J Roentgenol. 2020 Mar 4:1-7.
  23. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020 Mar 28.doi:10.1007/s00134-020-06022-5.
  24. Ferioli M, Cisternino C, Leo V, et al. Protecting healthcare workers from SARS-CoV-2 infection: practical indications. Eur Respir Rev. 2020 Apr 3;29(155).
  25. Mahase E. Coronavirus covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ. 2020 Feb 18;368:m641.
  26. Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med. 2020 (1-5). doi: 10.1038/s41591-020-0822-7.
  27. Zhao S, Ran J, Musa SS, et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak. Int J Infect Dis. 2020;92:214-217.
  28. Biggerstaff, M., Cauchemez, S., Reed, C. et al. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. BMC Infect Dis 14, 480 (2014). https://doi.org/10.1186/1471-2334-14-480

Disseminated Nocardiosis (nocardia farcinica) in Myasthenia Gravis: An Antimicrobial Dilemma

Authors
Raja Shariff REF & Sapuan S
Article Citation and PDF Link
BJMP 2020;13(1):a001
Abstract / Summary
Abstract: 

Introduction: Nocardiosis commonly occurs in immunocompromised patients. We report a case of disseminated nocardiosis in a Myasthenia Gravis (MG) patient, and how antimicrobial selection was complex.

Case Report: A 68-year old woman, with myasthenia gravis, a pre-existing stable subdural haematoma and history of azathioprine-related myelosuppression, presented to us following a week of diarrhea and lethargy. Her inpatient stay was complicated by dyspnoea and bilateral consolidation on chest radiography. Blood cultures grew nocardia farcinica. Computed Tomography (CT) of her thorax, abdomen and pelvis revealed bilateral lung consolidation and a sigmoid colon collection. Unfortunately, initiation of first-line antimicrobials in this patient proved to be difficult as she suffered from trimethoprim/sulfamethoxazole related pancytopenia, and was limited to non-amakicin, non-fluoroquinolone therapy, to avoid MG exacerbation. She was eventually commenced on concurrent co-amoxiclav and meropenem, alongside having her sigmoid abscess drained.

Discussion: Although nocardiosis is treatable, pre-existing MG and myelosuppression led to complex decision making. Use of prolonged intravenous antibiotics alongside surgical drainage of collections can improve prognosis, although mortality rates in disseminated nocardiosis remain high.

Conclusion: Nocardiosis poses a unique challenge in the MG population due to limitations in suitable antibiotics, and decision making on management should ideally be multi-disciplinary as seen in our case.

Abbreviations: 
myasthenia gravis (MG), computed tomography (CT), central nervous system (CNS)
Keywords: 
myasthenia gravis, disseminated nocardiosis, nocardia farcinica, case report

Introduction

Nocardia sp. are aerobic, gram-positive microorganisms found mainly in soil and stagnant water. Nocardiosis commonly occur in immunocompromised patients, is often multi-systemic and easily mistaken for tuberculosis when involving the lungs 1 2. We report a complex case of disseminated nocardiosis in a patient already suffering from Myasthenia Gravis (MG) and azathioprine-induced myelosuppression, in which selection of antimicrobials and management planning became complex.

Case Report

A 68-year old lady, known to have generalized MG for 12 years, presented to our centre following a week history of diarrhea and lethargy. She describes having loose stools, up to 8 times per day, chills and rigors, but denied per rectal bleeding or melaena. The patient was, on regular oral prednisolone (50mg a day). She had recently ceased her azathioprine 4 months prior due to severe anaemia, linked to myelosuppression following a bone marrow aspiration test revealing markedly reduced erythropoiesis, normal oesophageo-gastro-dudodenoscopy and colonosocopy, and having normal thiopurine methyltransferase levels prior to azathioprine initiation. The patient had several admissions in that 4 months due to her anaemia, requiring packed cell transfusions, and had recently sustained an interhemispheric subdural bleed two weeks prior following a mechanical fall. At the time, hemoglobin and platelet levels had returned within normal range. Clinical examination was unremarkable and her vitals on arrival included an oxygen saturation of 98% on room air with a normal chest radiography on arrival (Figure 1a). The patient was subsequently treated for infective gastroenteritis, and was started on metronidazole.


Figure 1
: Chest radiography on (a) initial presentation and (b) 48-hours into admission, showing newly developed diffuse bilateral consolidation.

Unfortunately, 48 hours into her inpatient stay, the patient developed acute dyspnoea in which her oxygen saturation dropped to 77% under room air and examination revealed diffuse, coarse crepitations bilaterally. A repeat chest radiograph confirmed diffuse consolidation bilaterally (Figure 1b). She was subsequently treated for a hospital-acquired pneumonia, and had her antibiotics swapped to intravenous ceftriaxone. Unfortunately, the patient showed little improvement on the ward, which prompted further investigation. Her blood cultures revealed presence of nocardia farcinica which was resistant to ceftriaxone. In view of being immunosuppressed, a computed tomography (CT) imaging of the brain, thorax, abdomen and pelvis (Figure 2) was performed. Imaging showed extensive bilateral lung consolidation and reticulonodular opacities, predominantly in upper lobes. There was also evidence of sigmoid colon diverticulitis with a rim-enhancing collection adjacent to the posterior aspect of the proximal-to-mid sigmoid colon (2.9 x 2.6 x 2.6 cm).


Figure 2:
Computed tomography (CT) imaging of (a) the brain, revealing inter-hemispheric hyperdensity consistent with a subdural haematoma, (b) the thorax, revealing extensive bilateral lung consolidation and reticulonodular opacities, predominantly in upper lobes, and (c) abdomen, showing sigmoid colon diverticulitis with a rim-enhancing collection adjacent to the posterior aspect of the proximal-to-mid sigmoid colon (2.9 x 2.6 x 2.6 cm).

Following consultation with our Infectious Disease team, the patient was treated for likely disseminated nocardiosis using intravenous trimethoprim/sulfamethoxazole as a recommended first line therapy. Unfortunately, following 72 hours of trimethoprim/sulfamethoxazole administration, the patient developed severe pancytopenia (haemoglobin 63 g/L, white cell count 2.0 x 109/L and platelets 33 x 109/L) requiring packed red cell and platelet transfusions, as well as immediate cessation of trimethoprim/sulfamethoxazole. Further decisions on antimicrobial proved difficult as it was noted that other effective alternatives against nocardiosis, including amikacin and fluoroquinolones may potentially exacerbate MG symptoms. Furthermore linezolid, another possible alternative, could potentially exacerbate her thrombocytopenia and worsen the pre-existing subdural haematoma. Thus, a decision was made to commence co-amoxiclav and meropenem concurrently despite neither being first-line therapy. The patient subsequently had an uneventful CT-guided drainage of the sigmoid abscess, with the assistance of our General Surgical colleagues, and was kept on prolonged intravenous antibiotic therapy for 3 months. Following improvement in clinical state, she was allowed discharge from hospital with ongoing oral co-amoxiclav and linezolid with regular bloods tests to monitor for myelosuppression as an outpatient, which has not occurred till this date. With support from clinical and radiological improvement, we aim for 12 months of therapy.

Discussion

Various cases of nocardia sp bacteraemia have been reported, in which immune system dysfunction was primarily due to chronic glucocorticoid therapy 1 3 4. A retrospective review of 40 patients from a Chinese tertiary hospital revealed that half of patient with nocardiosis were on corticosteroids prior to infection onset 5. An even larger case series reported up to 94% of pulmonary nocardial infection being linked to use of immunosuppressants 6.

Management of nocardiosis can be challenging. Often, imipenem, trimethoprim/sulfamethoxazole, amikacin or a combination of these antibiotics are recommended, with treatment duration being guided by clinical and radiological improvement often extending up to a year 7. Bactericidal agents including carbapenems and amikacin are often recommended alongside trimethoprim/sulfamethoxazole in cases of disseminated nocardiosis to ensure greater success in treatment 7, 8. The use of amikacin however should be cautioned in cases of MG, and reports have described management using linezolid as an alternative 1, 9.

In our patient, the risk of worsening pancytopenia as illustrated following trimethoprim/sulfamethoxazole administration led to hesitance in using linezolid. Furthermore, the consequences of thrombocytopenia would have been devastating for the patient due to having residual subdural hematoma. Thus, the choice of antibiotics was limited to that of second-line agents including co-amoxiclav and meropenem on top of surgical drainage of existing abscesses, which has also been shown to be beneficial 1 5. However, it should be noted that the risk of pancytopenia remains to be multifactorial in our patient, ranging from pre-exisitng myelosuppression to ongoing sepsis and initiation of culprit medications

Mortality of nocardiosis infections ranges depending on organ involved, rates being under 40% in cases of pulmonary spread, and up to 100% when disseminated to the central nervous system (CNS) 6. Unfortunately, nocardia farcinica, the subtype reported in our case, has been shown to be more resistant to antimicrobials and carries a greater risk of dissemination to the CNS, a point being greatly considered as our centre continues to manage the patient 10.

Conclusion

Nocardiosis, although not uncommon in immunocompromised individuals, poses a unique challenge in the MG population due to limitations in suitable antibiotics. Our case highlights the importance of a multi-disciplinary approach, involving various specialties including the infectious disease, neurology, general surgical and microbiology to ensure successful management of such complex cases.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors would like to acknowledge Universiti Teknologi MARA (UiTM) for supporting the submission of the following article.
Competing Interests: 
None declared
Details of Authors: 
RAJA SHARIFF REF, MRCP, Universiti Teknologi Mara Sungai Buloh, Selangor, Malaysia. SAPUAN S, MMED, Hospital Sungai Buloh, Selangor, Malaysia.
Corresponding Author Details: 
RAJA SHARIFF REF, MRCP, Universiti Teknologi Mara Sungai Buloh, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia.
Corresponding Author Email: 
rajaezman@gmail.com
References
References: 
  1. El-Herte RI, Kan SS, Araj GF, Chami H & Gharzuddine W. First Report of Nocardia Asiatica Presenting as an Anterior Mediastinal Mass in a Patient with Myasthenia Gravis: A Case Report and Review of the Literature. Case Reports in Infectious Diseases 2012; 2012, Article ID 325767. 
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  10. Anagnostou T, Arvanitis M, Kourkoumpetis TK, Desalermos A, Carneiro HA, et al. Nocardiosis of the central nervous system: Experience from a general hospital and review of 84 cases from the literature. Medicine 2014; 93: 19 32.

Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA) in the Diagnosis of Lung Cancer & Mediastinal/ Hilar Lymphadenopathy

Authors
Amer Saleem, Neal Navani & Vivek Vohra
Article Citation and PDF Link
BJMP 2019;12(3):a025
Abstract / Summary
Abstract: 

Background: EBUS-TBNA is an out-patient minimally invasive procedure of choice to explore mediastinal/hilar lymph nodes & lesions close to the tracheobronchial tree. In the UK there has been a significant growth in this area over the last 10 years.
Aim: To study the performance of EBUS service started in 2018 at a local district general hospital.
Methods: This is a retrospective study of patients who underwent EBUS-TBNA from 26th July 2018 till 25th July 2019 during the first year of the service. CT, PET-CT, pathology reports, EBUS reports & clinic notes were reviewed for the purpose of this analysis. Cases, where EBUS-TBNA did not reveal any pathology, were followed up with surveillance scans for a minimum of 12 months.
Results: During the first year of the service 82 EBUS procedures were performed & 122 nodes were sampled. Most commonly location sampled was station 7 (53.3%). Patients underwent EBUS-TBNA for the following reasons:
1. 51% (42) procedures were carried out for cancer reasons (diagnosis & staging). For the diagnosis of suspected lung cancer 38 procedures were carried out. Final pathology results showed 12 squamous cell cancers, 7 adenocarcinomas, 4 small cell lung cancers, 1 neuroendocrine tumour, 1 undifferentiated carcinoma, 1 metastatic prostate cancer, 1 metastatic parotid tumour & 9 patients had reactive lymphadenopathy. We had 2 false negatives in this group, one required CT biopsy & second had ultrasound guided biopsy. Three procedures were done for the diagnosis of suspected extra-thoracic cancer (histology confirmed prostate, colon & ovarian cancers). One patient underwent staging EBUS & was diagnosed with early stage squamous cell cancer.
2. 49% (40) procedures were carried out in 39 patients for isolated mediastinal & hilar lymphadenopathy (IMHL). Histology showed normal lymphocytes/ reactive nodes in 18 cases, 16 patients’ samples were consistent with clinical picture of sarcoidosis, 3 were diagnosed with tuberculosis (culture positive), 1 had diagnosis of unexpected metastatic cancer of upper GI origin & 1 patient was diagnosed with bronchogenic cyst. In 1 case, the sample was inadequate, and underwent repeat EBUS which demonstrated sarcoidosis.
Two patients had metastatic prostate cancer. One had locally advanced cancer with pelvic lymphadenopathy & bone metastases while second patient had prostate confined disease on MRI (this was unusual to find distant metastatic disease in organ confined prostate cancer). As surgical patients were directly referred to tertiary care centres hence, we do not have enough data on staging EBUS during this first year of our service. When compared with PET-CT diagnostic sensitivity for “staging EBUS” was 100%. For “diagnostic EBUS” our sensitivity was 95% (2 false negative out of 41 diagnostic procedures). In IMHL our diagnostic sensitivity was 97.5%. “Over all diagnostic sensitivity was 96.3%” (inadequate sample in 3 out of 82 procedures). None of our patients had airway bleeding, airways lacerations, mediastinal infection, pneumothorax, pneumo-mediastinum or haemo-mediastinum.
Conclusion: Over the past few years EBUS-TBNA has reduced the need for mediastinoscopy & is available in many hospitals including district general hospitals (in UK). We have clearly seen that this is being used for non-cancer reasons as well, about 49% procedures were for benign reasons. We carried out our EBUS-TBNA procedures without ROSE technique & feel that this is not mandatory to run a successful service. Local EBUS service saved 82 patients’ trips to the tertiary care centres in this first year (reducing the carbon foot print) & also reduced waiting times for this procedure. Service seems clinically very helpful for the patients of our trust. It is minimally invasive procedure with complications rate <1%.

Abbreviations: 
EBUS - endobronchial ultrasound, TBNA - transbronchial needle aspiration, GI - gastrointestinal, IMHL - Isolated Mediastinal & Hilar Lymphadenopathy.
Keywords: 
Endobronchial ultrasound transbronchial needle aspiration, EBUS, EBUS-TBNA, mediastinoscopy, lung cancer, mediastinal lymphadenopathy, hilar lymphadenopathy, extra-thoracic malignancy.

Introduction

Convex probe EBUS-TBNA has been a major development in respiratory medicine. In the last decade we have seen numerous articles supporting the high diagnostic accuracy of EBUS-TBNA in the diagnosis of lung cancer, staging of lung cancer, diagnosis of extra-thoracic malignancies & benign conditions (e.g., TB & sarcoidosis)1. Patients included in this study reflect the real-life referrals that we see as respiratory physicians in our daily practice. This shows that the trend of doing EBUS-TBNAs for non-cancer patients is rising. Lung cancer is a common cause of cancer death worldwide2. Various guidelines (including NICE) have found this procedure safe & recommend it for the staging of lung cancer. In the last 10 years, lots of district general hospitals have started this service in UK & it is mainly delivered by respiratory physicians.

This has provided a specialist service for patients in their local area, which has reduced travelling and waiting times.

Setting & Methods

In this district general hospital under discussion, EBUS service was setup in 2018, under supervision of a tertiary care centre. We carried out 82 procedures during the first year of this service. All of these cases were reviewed for this article. Data was recorded on an excel spreadsheet (data included: number of cases, age, gender, lymph node stations sampled, complications, pathology & microbiology results of EBUS TBNA). Minimum of 4 passes were done at each lymph node station. Where EBUS was done for diagnostic purposes, stations to be sampled were at the discretion of the operator. Samples obtained via EBUS-TBNA were flushed into CytoLyt (methanol-water solution). EBUS-TBNAs were carried out in the absence of rapid on-site evaluation (ROSE). Where a cancer was suspected but EBUS-TBNA showed normal findings, samples were obtained via another modalities (e.g., CT biopsy) & FDG PET was carried out as well (if not done already). In cases of isolated mediastinal & hilar lymphadenopathy (IMHL), where EBUS-TBNA did not reveal any pathology, interval surveillance CTs were carried out for monitoring purposes. Where lymphadenopathy did not resolve, surveillance scans were carried out for a year. The outcomes of these surveillance CTs & PET CTs were also reviewed for this study. Diagnosis of reactive lymphadenopathy was made if EBUS-TBNA sample did not reveal any pathology, repeat CT did not show any change (or showed reduction/ resolution of lymphadenopathy) & the clinician did not consider the patient to have another diagnosis. EBUS-TBNA was labelled as false negative, if pathology result was negative, but node was positive on PET (in suspected cancer patients).

Results

Out of these 82 patients who underwent EBUS-TBNA, 55 (about 67%) were male & 27 were female (about 33%) (Figure 1).

The age range of patients at the time of procedure was 28 to 88 years. Majority of the patients were between the age of 52 – 88 years (80% of the cases) (Figure 2).

The 82 EBUS-TBNA procedures were carried out for the following main reasons (Figure 3):
A. 42 procedures for cancer reasons (i.e. 51% of the total procedures)
a. For diagnosis of lung cancer (38 procedures)
b. Diagnosis of suspected extra-thoracic cancer (3 cases)
c. Staging of lung cancer (1 case)
B. 40 procedures for IMHL (i.e. 49%)

The final diagnoses in 38 procedures carried out for “diagnosis of lung cancer” were as follows:
1. 25 patients were diagnosed with lung cancer (12 squamous cell cancers, 7 adenocarcinomas, 4 small cell cancers, 1 undifferentiated lung cancer & 1 neuroendocrine tumour)
2. Final diagnosis in 9 cases was reactive lymphadenopathy (repeat CT showed resolution of lymph nodes in 3 cases, reduction in the size in 1 case & stable nodes in 5 cases)
3. Extra-thoracic malignancies were diagnosed in 2 cases (1 metastatic prostate cancer & 2nd was metastatic disease from primary parotid gland tumour)
4. We had false negative results in 2 cases (1 patient was diagnosed with small cell lung cancer on CT biopsy & 2nd with adenocarcinoma on ultrasound biopsy)

It was found in 11 cases, where the clinicians initial suspicion was a possible lung cancer, that the final diagnoses were reactive lymphadenopathy and extra-thoracic malignancies.

Some of these patients had lung nodules as well (along with mediastinal & hilar lymphadenopathy). These nodules either resolved or remained stable. In the case of metastatic prostate cancer, prior MRI showed prostate confined disease & the clinician suspected this size significant lymphadenopathy to be due to a lung primary. In the case of metastatic parotid tumour, the initial diagnosis of parotid cancer was a very long time ago & metastatic disease was not expected.

Final diagnoses in 3 patients who had EBUS-TBNA for “extra-thoracic malignancies” were as follows:
1. Prostate cancer (here pelvic MRI showed locally advanced disease)
2. Colon cancer (known colon cancer)
3. Ovarian cancer (patient had ovarian mass & abdominal/pelvic lymphadenopathy)

As most of the surgical patients go directly to tertiary care centres (from this hospital), we therefore didn’t have many patients for staging purposes during the 1st year of the service. We only had 1 patient for “staging EBUS-TBNA” during this time. In this case stations 4L, 7 & 12L were sampled. Only station 12L was PET positive & also positive on EBUS-TBNA sample. Station 4L & 7 were PET and EBUS-TBNA negative. There was no size significant nodes seen on staging CT in any other area, only 12L node was PET avid & we were not able to identify any size significant lymphadenopathy at any other station via EBUS as well. Sensitivity in this staging EBUS was 100%.

In these 42 diagnostic & staging procedures (carried out for cancers or suspected cancers), summary of the pathological diagnoses from lymph nodes aspirates is as follows:
1. Squamous cell carcinoma of lung 13 approximately (31%)
2. Adenocarcinoma of lung origin 7 approximately (17%)
3. Small cell lung cancer 4 approximately (9.5%)
4. Neuroendocrine tumour of lung origin 1 approximately (2.3%)
5. Undifferentiated lung cancer 1 approximately (2.3%)
6. Metastatic prostate cancer 2 approximately (4.75%)
7. Metastatic parotid gland cancer 1 approximately (2.3%)
8. Metastatic ovarian cancer 1 approximately (2.3%)
9. Metastatic colon cancer 1 approximately (2.3%)
10. False negative 2 approximately (4.75%)
11. Reactive lymphadenopathy 9 approximately (21.5%)

Out of the 40 procedures for IMHL, we were not able to get an adequate sample in 1 case and this patient underwent repeat EBUS-TBNA. Repeat sample showed granulomas; findings were consistent with the clinical diagnosis of sarcoidosis. Final diagnoses in these 40 cases are as follows:
1. Metastatic adenocarcinoma from pancreaticobiliary origin = 1 (2.5%)
2. Bronchogenic cyst = 1 (2.5%)
3. Insufficient sample = 1 (2.5%)
4. Tuberculosis = 3 (7.5%)
5. Granulomas = 16 (40%)
6. Reactive lymphadenopathy = 18 (45%)

Serious diagnoses were made in 10% cases of IMHL (4 out of 40). One patient had metastatic adenocarcinoma from pancreaticobiliary origin & didn’t have any abdominal symptoms or any abnormalities on CTs in the abdomen. 3 patients were diagnosed & later treated for active tuberculosis. Out of these 3 patients only 1 had features of active disease, but sputum negative. The other 2 patients had only mediastinal lymphadenopathy, no lung infiltrates & no sputum production.

A total of 122 lymph nodes were sampled. Details are as follows (figure 4):

Lymph node station Times sampled %
Station 7 65 53.3
4R 18 14.8
11R 15 12.3
11L 11 9
10R 4 3.2
4L 3 2.5
2R 2 1.6
10L 2 1.6
12R 2 1.6
2L 0 0
12L 0 0

Commonly sampled nodes were station 7 nodes. This is consistent with international literature published on EBUS-TBNA.

There were no complications from the procedures performed. None of our patients experienced significant airway bleeding (requiring admission or blood transfusion), mediastinal infection, pneumothorax, pneumo-mediastinum, haemo-mediastinum or airway lacerations.

Discussion

EBUS TBNA is one of the methods to access the mediastinal & hilar lymph nodes. This is a minimally invasive way to get samples from these nodes. Several invasive, minimally-invasive & non-invasive techniques are available to diagnose & stage lung cancers. Choice depends upon the extent of the disease. About 50% of lung cancer patients have evidence of metastatic disease at the time of presentation 3. Patients with intrathoracic disease undergo several investigations. Now we know that EBUS-TBNA should be considered as the initial investigation for patients with early stage suspected lung cancer 4. Research carried out has shown that EBUS-TBNA had a sensitivity of 90% 5. A recent national BTS audit on bronchoscopy & EBUS showed national diagnostic sensitivity of 90% for staging EBUS-TBNA. BTS quality standards statement sets target of 88% sensitivity for staging EBUS-TBNA6. As far as diagnostic EBUS-TBNA is concerned, we had 2 false negative results out of 41 (4.8%), that gives the sensitivity for diagnostic procedures of 95.2%.

There is significant evidence available that ROSE does not increase the diagnostic yield of even conventional TBNA 7. Trisolini et al demonstrated in this randomised controlled trial that ROSE did not give any significant diagnostic advantage & did not affect the percentage of adequate specimens. Articles have also shown that ROSE does not reduce the EBUS-TBNA procedure time 8. The use of immunohistochemistry on EBUS-TBNA reduces the rate of unclassified non-small cell lung cancer when compared with cytological diagnosis alone 9. EBUS-TBNA samples are sufficient to allow immunohistochemical and molecular analysis. I am happy to say that we were able to get ALK, EGFR & PDL1 testing on the EBUS-TBNA samples (where indicated), at our centre. The presence of a cytopathologist or cytotechnologist during the procedure for ROSE purposes can increase the cost significantly. This increased cost can have a significant impact on starting the service at the level of a district general hospital. Another issue which needs clarification, is the number of passes required before declaring the material is inadequate while using ROSE technique. Studies have shown that significant number of samples inadequate on ROSE were still able to give a diagnosis with the help of immunohistochemical analysis.

Here we have seen that 40 EBUS-TBNA procedures were carried out for IMHL. Unfortunately, in this group, one patient was diagnosed with unexpected malignancy, i.e., metastatic adenocarcinoma of pancreaticobiliary origin. In the remaining cases we had benign diagnoses. In the IMHL group about 45% cases had the diagnosis of reactive lymphadenopathy. Out of the total number of 82, about 33% cases were diagnosed with reactive lymphadenopathy. We made the diagnosis of reactive lymphadenopathy in patients where EBUS samples showed normal lymphocytes; these patients had surveillance CTs & clinical follow up as well. Clinicians’ impression & surveillance scans were also reviewed for the purpose of this diagnosis. In this IMHL group, 40% cases were diagnosed with sarcoidosis. In these cases, in addition to clinicians’ impressions, we reviewed cytology, microbiology & surveillance CT reports. Processing method for specimens impacts on the yield for granulomas. Cell block preparation, as carried out in this hospital, showed higher yield for granulomas 10.

During the first year of the EBUS service at this centre, there was no suspected or diagnosed lymphoma patient who underwent this procedure. International data suggests, for the diagnosis of lymphoma, EBUS-TBNA aspirates should be sent for cytopathology, immunohistochemistry, flow cytometry, cytogenetics and molecular studies 11,12,13.

Conclusion

EBUS-TBNA is a safe & minimally invasive procedure. It is a first line investigation for lung cancer staging. EBUS-TBNA has been effective in diagnosing extra-pulmonary malignancies 14. In the last decade we have also seen that its utility has increased significantly in diagnosing benign conditions like sarcoidosis and TB.

We feel operators’ training is also very important in achieving excellent results. Mastering the complexity of this procedure is time consuming. Standardised training is mandatory to achieve high skill levels15 and we hope there will be a standardised approach to this in future.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
AMER SALEEM, BSc MBBS MCPS MRCP FCPS FRCP FCCP, Speciality Certificate in Respiratory Medicine (RCP UK) & European Diploma in Adult Respiratory Medicine, Department of Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes MK6 5LD, UK. NEAL NAVANI, MA MSc PhD FRCP, Department of Thoracic Medicine, UCLH, 250-Euston Road London NW1 2PG, UK. VIVEK VOHRA, MD DMRD FRCR FFRRCSI, Department of Radiology, Bedford Hospital NHS Trust (South Wing), Kempston Road, Bedford MK42 9DJ, UK.
Corresponding Author Details: 
AMER SALEEM, Department of Respiratory Medicine Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes MK6 5LD, UK.
Corresponding Author Email: 
amersaleemmalik@gmail.com
References
References: 
  1. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009; 361:32-39.
  2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61:69-90.
  3. National Lung Cancer Audit Report, 2013.
  4. Navani N, Nankivell M, Lawrence D, et al. Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. The Lancet. 2015;3(4):282-289.
  5. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systemic review and meta-analysis. Eur J Cancer. 2009; 45:1389-1396.
  6. British Thoracic Society. Quality Standards for Flexible Bronchoscopy in Adults. British Thoracic Society Reports 2014;6(5).
  7. Trisolini R, Cancellieri A, Tinelli C, Paioli D, Scudeller L, Casadei GP, Parri SF, Livi V, Bondi A, Boaron M, Patelli M. Rapid on-site evaluation of transbronchial aspirates in the diagnosis of hilar and mediastinal adenopathy: a randomized trial. Chest. 2011; 139:395-401.
  8. Sehgal IS, Dhooria S, Aggarwal AN, Agarwal R. Impact of Rapid On-Site Cytological Evaluation (ROSE) on the Diagnostic Yield of Transbronchial Needle Aspiration During Mediastinal Lymph Node Sampling: systemic review and meta-analysis. Chest. 2018; 153(4):929-938.
  9. Navani N, Brown JM, Nankivell M, Woolhouse I, Harrison RN, Jeebun V, Munavvar M, Ng BJ, Rassl DM, Falzon M, Kocjan G, Rintoul RC, Nicholson AG, Janes SM: Suitability of endobronchial ultrasound-guided transbronchial needle aspiration specimens for subtyping and genotyping of non-small cell lung cancer: a multicentre study of 774 patients. Am J Respir Crit Care Med. 2012; 185:1316-1322.
  10. Schwartz LE, Griffin AC, Baloch Z. Cell block interpretation is helpful in the diagnosis of granulomas on cytology. Diagn Cytopathol. 2012; 40(10):939-40.
  11. Grosu HB, Iliesiu M, Caraway NP, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis and subtyping of lymphoma. Ann Am Thorac Soc. 2015; 12:1336-1344.
  12. Soldini D, Campo E. New insights into the diagnosis of lymphomas. Ann Oncol. 2012; 23:83-88.
  13. Ko HM, daCunha Santos G, Darling G, et al. Diagnosis and subclassification of lymphomas and non-neoplastic lesions involving mediastinal lymph nodes using endobronchial ultrasound-guided transbronchial needle aspiration. Diagn Cytopathol. 2013; 41:1023-1030.
  14. Jain D. EBUS-TBNA for diagnosis of extrapulmonary lesions. J Cytol. 2019; 36(1):59-60.
  15. Zhang WC, Chen W, Zhou JP, et al. A comparison of different training methods in the successful learning of endobronchial ultrasound-guided transbronchial needle aspiration. Respiration. 2017; 93:319-326.

Solitary Basal Ganglia Tuberculous Abscess in an Immunocompetent Individual

Authors
Raja Shariff REF & Sapuan S
Article Citation and PDF Link
BJMP 2019;12(3):a021
Abstract / Summary
Abstract: 

Background: Tuberculosis (TB) involving the central nervous system (CNS) account for 2 to 5% of all TB cases. Treatment should be guided by histological evidence, which unfortunately can be difficult to obtain in those with CNS dissemination. We present a rare case of solitary basal ganglia tuberculous abscess, with no evidence of pulmonary TB.
Case report: An immunocompetent 53-year old man presented with a history of fever, vomiting and altered mental behaviour. Initial computed tomography (CT) of the brain revealed a rim-enhanced, hypodense lesion in the left basal ganglia region. Cerebrospinal fluid (CSF) analysis was initially suggestive of bacterial infection, but due to worsening symptoms and subsequent imaging showing a non-resolving mass with worsening perilesional oedema, hydrocephalus, acute ventriculitis and basal cisterns involvement, the possibility of a tuberculous abscess (TBA) was entertained. Unfortunately, a biopsy was deemed too risky. A decision was made to start anti-tuberculous therapy (ATT) with Dexamethasone empirically, alongside performing a ventriculo-peritoneal shunting in view of the hydrocephalus. Following that and ATT, the patient improved clinically.
Discussion: Solitary TBA in the basal ganglia are extremely uncommon, even in endemic countries. TBA has been seen in both the immunocompromised, or otherwise. As histological evidence is often difficult to obtain, there are evidence to support presumptive ATT for diagnostic and therapeutic purposes, which was adopted in our case.
Conclusion: This case highlights the complexity of the decision to initiate empirical treatment of tuberculous abscess; when a direct biopsy of the lesion to further aid diagnosis is not possible.

Abbreviations: 
Anti-Tuberculous Therapy (ATT), Cerebrospinal Fluid (CSF), Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Central Nervous System (CNS), Mycobacterium Tuberculosis (MTB), Tuberculous Abscess (TBA), Ziehl-Neelsen (ZN), Nucleic Acid Amplification Test (NAAT)
Keywords: 
Tuberculous Abscess, Exra-Pulmonary Tuberculosis, Brain Abscess, Case Report

Background

Tuberculosis (TB) involving the central nervous system (CNS) account for 2 to 5% of all TB cases1. Commonly it manifests in three ways – meningo-encephalitis, tuberculomas or abscesses2. Treatment should be guided by histological evidence, which unfortunately can be difficult to obtained in those with CNS dissemination. We present a rare case of solitary basal ganglia tuberculous abscess, which provided a diagnostic dilemma and led to complex management planning.

Case Report

A 53-year old man, with no known medical illness, presented with a 5-day history of fever, vomiting and altered mental behaviour. His vital signs were stable, on arrival aside from being pyrexial at 38°C. There was, however, neck stiffness noted on clinical examination as well as evidence of increased tone on the right upper and lower limbs, with an upgoing right-sided plantar response. Power was preserved in all limbs.

An initial contrast-enhanced computed tomography (CT) imaging of the brain revealed a hypodense lesion measuring 1.6 cm x 2.1 cm x 1.8 cm in the left basal ganglia region, with rim enhancement, complicated by cerebral oedema causing mass effect and mild hydrocephalus (Figure 1). A lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis suggested the possibility of bacterial infiltration (Table 1). Initial, Ziehl-Neelsen (ZN) staining, mycobacterium tuberculosis (MTB) cultures and Gene Xpert nucleic acid amplification test (NAAT) from CSF were negative and a HIV antibody serology was negative as well. A transthoracic echocardiogram and CT imaging of the thorax and neck were both performed, failing to identify a possible source of spread. Furthermore, there was no evidence of focal lung infection or collection, and no evidence of lymphadenopathy of note.

The patient was initially treated for 2 weeks with intravenous antibiotics, using intravenous Ceftriaxone 2g BD and Metronidazole 500mg TDS. Intravenous Dexamethasone was also commenced in view of the cerebral oedema. Unfortunately, the patient showed no clinical improvement, prompting repeat CT and Magnetic Resonance Imaging (MRI) which revealed an unchanged left basal ganglia enhancing lesion, with worsening obstructive hydrocephalus, perilesional oedema causing midline shift. The lesion was in contact with the lateral wall of the left lateral ventricle, with evidence of acute ventriculitis and involvement of the basal cisterns (Figure 2). A right-sided ventriculo-peritoneal shunt was inserted in view of the worsening hydrocephalus and persistent symptoms of headache and vomiting. Subsequently, stereotactic drainage and biopsy of the lesion was discussed but could not be performed in view of its deep location. A decision was thus made to initiate anti-tuberculosis therapy (ATT) empirically and to cease antibiotics. Subsequently, the patient’s clinical state improved with ongoing ATT and active inpatient rehabilitation, alongside improvement in the lesion, via radiological evidence (Figure 3).

Table 1: Cerebrospinal Fluid (CSF) test and other investigations performed during admission.

Test for Cerebrospinal Fluid (CSF) Results Other Test Results
Micro-Total Protein 3.8 g/dL Lumbar Puncture Opening Pressure 19 cm H20
Glucose 1.65 mmol/L Lumbar Puncture Closing Pressure 16 cm H20
Culture & Sensitivity Negative Random Capillary Glucose 7.3 mmol/l
India Ink Negative    
Ziehl-Neelsen Stain Negative HIV Antibody Negative
MTB Culture Negative Echocardiogram No vegetation or mass
MTB NAAT (GeneXpert) Negative    
Cell Count & Cytology No atypical cells. Mixed of pleomorphs and lymphocytes seen    

Figure 1: CT imaging of the brain on (a) axial and (b) saggital view, illustrating a well-circumscribed, rim-enhanced lesion in the left basal ganglia region, suspicious of an abscess

Figure 2: T2-sequence of MRI brain on axial view (a) pre- and (b) post-procedure involving ventriculo-peritoneal shunting, illustrating a well-circumscribed hyperdense basal ganglia lesion, with peri-lesional oedema, as well as evidence of hydrocephalus.

Figure 3: Non-contrasted CT brain on axial view, illustrating less apparent left basal ganglia lesion, with hypodensities in areas of previous oedema, as well as an in-situ ventriculo-peritoneal shunt.

Discussion

Basal ganglia abscesses are very rare, incidence varying between 0.9 to 4% of total brain abscesses3. These are often disseminated lesions from sources such as congenital heart disease infections, intrathoracic and abdominal sepsis, dental caries, otitis media or sinusitis3-4. Solitary tuberculosis lesions, which includes tuberculous abscesses (TBA), in the basal ganglia are additionally more uncommon, even in endemic countries, as they normally have a predilection for the cerebellum and brainstem5. TBA has been seen in both the immunocompromised, or otherwise, where clinical presentation differs only slightly6-9.

Similar to other brain abscesses, stereotactic aspiration remains the gold standard diagnostic tool but there is a risk of rupture into ventricles or the subarachnoid space (leading to ependymitis or meningitis), worsening neurological deficits and more importantly the possible need for repeated procedures in as many as 70% of patients9.

Although experts advocate the combination of both surgical and chemotherapeutic therapy in managing TBA, the former was limited by the location of the lesion, whereas the latter was due to lack of histological evidence. Furthermore, the lack of risk factors, negative yield from cultures, NAAT and ZN stain, and inability to biopsy made the decision-making complex in our patient. Fortunately, there are evidence to support presumptive ATT for diagnostic and therapeutic purposes, which was adopted in our case5. This, however, requires cerebrospinal fluid examination, lung CT imaging and brain MRI that can provide circumferential evidence for diagnosis and to monitor treatment progress, all of which were performed in our gentleman5. In fact, CT imaging of the thorax is considered mandatory in cases suspicious of asymptomatic and subclinical extra-neurological tuberculosis, although yield remains poor (detecting abnormalities in only 38 to 56%)10.

Conclusion

Although CNS involvement in extra-pulmonary tuberculosis is not uncommon, TBA in the basal ganglia region remains a unique entity which poses a challenge in terms of diagnosis, as histological evidence is often difficult to obtain. As adopted in the case highlight, empirical therapy using ATT remains a valid option, especially in areas limited by resources and appropriate skills to perform intracranial biopsies, which is a common occurrence in endemic areas globally.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors would like to acknowledge Universiti Teknologi MARA and the Clinical Research Centre (Hospital Sungai Buloh) for supporting the submission of the following case report.
Competing Interests: 
None declared
Details of Authors: 
RAJA SHARIFF REF (MRCP), Universiti Teknologi MARA (UITM) Sungai Buloh, Malaysia. SAPUAN S (MMED), Hospital Sungai Buloh, Malaysia.
Corresponding Author Details: 
RAJA SHARIFF REF, Universiti Teknologi Mara Sungai Buloh, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia.
Corresponding Author Email: 
rajaezman@gmail.com
References
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  8. Whiteman M, Espinoza L, Post MJ, Bell MD & Falcone S. Central nervous system tuberculosis in HIV-infected patients: clinical and radiographic findings. Am J Neuroradiol 1995; 16(4): 1319-1327.
  9. Cardenas G, Soto-Hernandez JL, Orozco RV, et al. Tuberculous Brain Abscesses in Immunocompetent Patients: Management and Outcome. Neurosurgery 2010; 67: 1081–1087
  10. Yaramis A, Bukte Y, Katar S & Ozbek MN. Chest computerized tomography scan findings in 74 children with tuberculous meningitis in southeastern Turkey. Turk J Pediatr 2007; 49(4): 365–9

Changing trends in acute upper GI bleeding a single-centre study in the western region of Saudi Arabia

Authors
Ibrahim Masoodi, Hesham AlQurashi & Mohammad Al Sofiyani
Article Citation and PDF Link
BJMP 2019;12(3):a019
Abstract / Summary
Abstract: 

Background: Despite advancements in pharmacological and endoscopic management, upper GI bleeding continues to be a major medical emergency. 

Objective: This study aimed at identifying the etiological profile of upper GI bleeding in the western region of Saudi Arabia .The results were compared with previous Saudi Arabian data on upper GI bleeding.

Methodology: In this retrospective study data on upper GI bleeding was analyzed at King Abdul Aziz specialist hospital Taif Saudi Arabia, a tertiary care centre in the western region of Saudi Arabia from January 2015 to December 2017. 

Results: A total of 120 (76 males) patients with acute upper GI bleeding were enrolled. The mean age of the study cohort was 58.4± 18.7. Hemetemesis was the most common presentation of upper GI bleeding. Variceal bleed (HCV Cirrhosis , Child-Turcotte-Pugh class A or B) was the most common aetiology (45.0%) of upper GI bleeding followed by duodenal ulcer (20.0%).Upper GI bleeding due to drug-induced and gastric ulcer were (5.0%) each. Endotherapy [EVL for portal hypertension bleeds, (gold probe endoscopic sclerotherapy ,heater probe for peptic ulcer bleeds)] was given to 72 (60%) patients. Bleeding recurrence of 1.2% was noted in this study. The mean hospital stay was 4.1±2 days and mean blood transfusion requirement was 2±1units.

Conclusion: There is a decline in the prevalence of UGI bleeding due to duodenal ulcers in Saudi Arabia. Portal hypertension due to HCV related CLD was the most frequent cause of UGI bleeding in this study.

Keywords: 
Gastrointestinal bleeding, chronic liver disease, peptic ulcer, duodenal ulcer, Rockall score.

Introduction

Acute upper gastrointestinal bleeding presenting as either hematemesis or melena or both is an important medical emergency. The etiological spectrum of upper gastrointestinal bleeding (UGIB) varies from region to region1. Various endoscopic therapy for patients with signs of recent haemorrhage in peptic ulcer have changed the outlook of UGIB management. An addition of proton pump therapy to non-variceal UGIB has further reduced hospital stay, recurrent bleeding and need for surgery2. Another milestone in the decline of UGIB has been eradication of H pylori. Globally, the prevalence of H. Pylori infection has decreased due to better hygiene, early diagnosis and eradication3. These factors have contributed to the changing trends in UGIB. The patients with UGIB have 50% incidence of H. pylori infection positivity and re-bleeding occurs in 7-16 % of the total cases1. Once frequent UGIB due to peptic ulcer have now declined all over the globe as demonstrated by various researchers 4,5,6. Unfortunately, despite advancement in endoscopic and pharmacological treatment, the mortality in UGI bleeding ranges between 3 and 14%7. Particularly, patients with UGI bleeding due to the duodenal ulcer are known to be more prone to death as demonstrated by Quan et al8. The advanced age and patients admitted in hospital with comorbidity are at an increased risk of re-bleeding and mortality. Re-bleeding and mortality rates are higher among patients with variceal bleeds and invariably 50-60% of patients with cirrhosis have variceal bleeding1. This warrants a careful approach in the management of UGI bleed. To predict the re-bleeding rates in a given case of UGI bleeding various clinical and endoscopic models have been developed from time to time. Of these – Rockall score, combining clinical (Age, shock, presence of co-morbid diseases) and endoscopic findings have proved quite valuable in the prediction of hospital admission duration and mortality rate9. The reason for the feasibility of Rockall score is that it depends mainly on simple clinical data and after an endoscopic procedure the score becomes more practical 9. The Rockall score divides patients into 4 subgroups according to their clinical data to estimate death and re-bleeding tendency. While comparing Rockall score, Blatchford scores at first assessment, and the Addenbrooke score it was concluded that Rockall score has an accuracy of 98% in predicting death, and was sensitive in 86.4% of cases in predicting re-bleeding10. Hence we calculated Rockall score in our study cohort and assessed various prognostic factors including changing trends over the past decades.

Methods

Study design

This retrospective study was conducted from January 2015 to December 2017 at King Abdul Aziz Specialist hospital Taif, a tertiary care centre in the western region of Saudi Arabia. The data was collected from case files and electronic medical records. The data about age, comorbid diseases, presence of shock, endoscopic intervention, hospital stay duration, the requirement for blood transfusion, surgery were collected to measure the outcome of UGI bleeding.

Depending upon hemodynamic status upper GI bleeding patients were managed either in the intensive care unit (ICU) or high dependency unit of the hospital. Blood transfusion had been given to maintain Hb levels above 8gm/dl. Platelets transfusions if the platelet counts were < 70,000 and fresh frozen plasma when INR was deranged in chronic liver disease patients.

The recurrent bleeding was defined by hematemesis, melena, or both, with either shock

(pulse rate>100 beats/min, systolic blood pressure< 100mmHg accompanied by cold sweats, pallor, oliguria) or a decrease in haemoglobin concentration of 2 g/dL over 24 hours.

Re-endoscopy, if needed, was used only to confirm recurrent bleeding.

The timing of UGI endoscopy after admission was recorded in each patient. The details of stigmata of recent haemorrhage (spurting vessels, active bleeding in an ulcer, a visible vessel, or a clot over the ulcer that could not be dislodged upon gentle washing with water delivered through the endoscope channel). Rockall score was calculated in all patients.

Patients with variceal bleeding were primarily managed with octreotide infusion ,antibiotics and endoscopic variceal ligation (EVL) or endoscopic sclerotherapy (EST) depending upon the situation. All patients were followed for rebleeding clinically and by haemoglobin levels during their hospital stay. Patients who remained hemodynamically stable for 72 hours were discharged.

After the fifth day, patients positive for H. pylori on CLO test during endoscopy received triple therapy (Capsule Amoxicillin 1gm twice daily and Tab. Clarithromycin 500 mg twice daily for 2 weeks. Tab. Es omeprazole 20mgdaily twice daily was continued for 4weeks. The patients who were H. pylori-negative received Tab. Esomeprazole 20 mg twice daily for 4 weeks.

Inclusion criteria:

  • Patients with confirmed upper GI bleeding (variceal and non-variceal) were enrolled in this study.
  • The variceal bleeding due to portal hypertension included both cirrhotic & non-cirrhotic patients.

Exclusion criteria:

  • Patients with terminal cancer.
  • Patients with upper GI bleeding where endoscopy had not been done due to any reason and Rockall score could not be calculated.
  • Patients with persistent shock necessitating emergency surgery, as a life-saving procedure.

Statistical methodology:

Data were statistically described in terms of frequencies (number of cases) and valid percentages for categorical variables. Mean and the standard deviation was used to describe parametric numerical variables while the median and inter-quartile range were used for non-parametric variables. Spearman's rho test was used for testing the correlation between the non-parametric numerical variable (Rockall score) and patients’ age. All statistical calculations were done using computer program IBM SPSS (Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) release 21 for Microsoft Windows.

Results

A total of 120 participants (76 males,63.3%) with a mean± SD age of 58. 4± 18. 7 years, were included in this study. The Rockall score showed a median (IQR) value of 3 which indicates a low to moderate risk of bleeding recurrence and death.

Majority of the study cohort [n=88(74%)] were Saudi nationals and [32(6.7%)] patients were from other nations. All patients had received an initial resuscitation as per the UGIB protocol of the hospital. Of 120 patients, 30 patients (25%) had undergone endoscopy immediately after admission in the intensive care of the hospital due to hemodynamic instability. Fourteen patients (11.7%) had undergone endoscopy within 6 hours of hospital admission and 63% patients had undergone endoscopy within 24 hours of hospital admission. The details are shown in figure 1.

The Rockall score was calculated for all patients based on their age, presence of shock, comorbidities, diagnosis and major stigmata of recent haemorrhage. The details are shown in table 1.

Table 1: Parameters of Rockall score in the non-variceal bleeds

Percentage Frequency Category Parameter
52 43.3 <60=0

Age

16 13.3 >80=2
52 43.3 60- 79= 1
120 100.0 Total
80 66.7 No shock=0

Shock

40 33.3 Tachycardia: Pulse ≥100, Systolic BP ≥100= 1
120 100.0 Total
70 58.3 Any co-morbidities except renal failure, liver failure, and/ or disseminated malignancy=2

Co-morbidities

50 41.7 No major comorbidity= 0
120 100.0 Total
116 96.7 All other diagnoses= 1

Diagnosis

4 3.3 upper GIT malignancy= 2
120 100.0 Total
26 21.7 Adherent clot=3 ,ooze=2 vessel=2 spurting vessel=0

Major stigmata of recent hemorrhage

  100.0 Total

It was observed that 46(38.3%) patients had undergone endoscopic variceal ligation (EVL) , and 20(16.7%) patients endoscopic sclerotherapy (EST) .

Heater probe had been used in 5.0% and Gold probe in 5.0% of patients with signs of recent haemorrhage (SRH) . Nevertheless, 48(40.0%) patients had no features of SRH therefore they had not received any endotherapy. Instead they had been managed with IV proton pump inhibitors as per the protocol and supportive treatment.

The data on final EGD diagnosis are shown in table 2.

Table 2: The Most Frequent EGD Diagnoses

Diagnosis Frequency Percent
CLD with PHT 54 45.0
Duodenal ulcer 24 20
Drug induced GI bleed 20 16.67
Gastric ulcer 10 8.3
Hemorrhagic gastritis 8 6.67
GI Malignancy 4 3.3
Total 120  

(CLD: Chronic liver diseases, GI: Gastro intestinal, EGD: oesophagogastroduodenoscopy, PHT: Portal hypertension)

None of the study cohort patients had undergone surgery to control his or her UGI bleeding and there was no mortality due to UGIB recorded during this period.

In order to test the correlation between Rockall score and age, spearman rho correlation test was carried out and data showed a significant (p<0. 001) moderate positive relationship (correlation coefficient=0. 553) between age and Rockall score of included patients. This means a lower tendency for recurrent bleeding and a lower mortality rate among younger patients.

Discussion

The results of our study showed that hematemesis was the most frequent presenting symptom of UGI bleeding. These results are similar to the study by Minakari et al 11, however, majority of the patients in the above-mentioned study had a peptic ulcer as the commonest aetiology. Contrary to their results portal hypertension outnumbered the peptic ulcer disease as shown in Table 2 in this study. UGI endoscopy had been carried out immediately after admission in 25% of the patients due to ongoing bleeding and the majority of patients had UGI endoscopic examination within 24hrs as shown in Fig1.

Figure 1: Timing of Esophagogastroduodenoscopy (EGD) after hospital admission

While assessing the endoscopy timing especially among variceal bleeding Hsu YC et al 12 concluded that the delayed endoscopy for more than 15 hours , high MELD score, failure of the first endoscopy and hematemesis were independent risk factors for in-hospital mortality in cirrhotic patients with acute variceal haemorrhage. The cirrhotic patients in our study cohort were either Child-Turcotte-Pugh class A or B and none of the patients had hepatic encephalopathy on presentation. After endoscopic therapy, they were managed with standard treatment for variceal bleeding.

The prevalence of H. pylori positivity among UGI bleeding in this study was 60% and all positive patients had been given standard eradication therapy. Data from a different Saudi Arabian centre revealed H. pylori prevalence to the tune of 70% affecting predominantly females in patients with peptic ulcer disease13 but authors had not studied it’s prevalence in UGI bleeding.

This study demonstrated rebleeding in 16 (13. 33%) patients who were re-endoscoped and bleeding was controlled by various endotherapies. In this study re-bleeding was found to be more frequent among older patients with comorbidities. Rebleeding was also common among patients with history of NSAID intake and presence of oesophagal varices which is following literature14. While comparing present results with previous data we observed that previously the commonest cause of UGI bleeding was a duodenal ulcer it is the variceal bleeding due to cirrhosis (HCV) now. We also compared the results of the current study with previous studies across different parts of the globe14,15,16. Duodenal ulcer previously used to be the most frequent cause and invariably various surgical methods like vagotomy etc were used to control bleeding prior to PPI era. However, with the advent of PPI and H pylori eradication the frequency of UGI bleeding due to peptic ulcer have declined.

We recorded only 120 patients with UGI bleeding over three years at our centre nevertheless, this may not reflect the true incidence in the region as it was the data from a single centre only. But the overall incidence of UGI bleeding has decreased over the past decades all over the globe. The study by Loperfido et al17 compared the incidence of 587 patients with UGIB between 1983-1985 and 2002-2004 period. The authors observed that UGI bleeding decreased from 112.5 to 89.8 per 100,000/y. The peptic ulcer incidence also decreased to the half between the two studied periods. In the above-mentioned study it was also revealed that frequency of ulcer bleeding decreased by 41.6% in people younger than 70 years. There has been an obvious change in the trend of UGI bleeding in Saudi Arabia over the past 23 years like other regions of the globe. The number of patients with UGI bleeding has decreased and aetiology of UGI bleeding has also shifted from an ulcer to variceal one.

In a large study, published in 1995 ,the data on 1246 patients over 14 years Al Karawi et al18 observed that duodenal ulcer was the most common cause of UGI bleeding followed by varices. The bleeding rates per annum in their study was 89 cases per annum while this study recorded only 40 admissions of active UGI bleeding per annum. Further, the variceal bleeding outnumbered the duodenal ulcer bleeding contrary to their results connoting a changing trend in Saudi Arabia. The data from southern region of Saudi Arabia also showed variceal bleeding to be the commonest cause of UGI bleeding 19.

In yet another study from Riyadh central hospital, it was revealed that most of the patients with UGI bleeding were having oesophagal varices20. Non cirrhotic portal hypertension (NCPH) was documented in 8 patients in the current study and all were hailing from Egypt which is an endemic region for schistosomiasis and NCPH. The predominant cause of portal hypertension was Chronic liver disease due to chronic HCV in this study. While studying the pattern of liver disease in Saudi Arabia Fashir B et al20 have demonstrated HCV to be the commonest cause of CLD in this part of the globe. This reflects that meticulous screening and treatment of chronic HCV can go a long way in the reduction of UGIB in the region. Having said this it may not be out of place to mention that keeping in view the global epidemic of obesity variceal bleeding due to CLD following NASH may steep up in coming years and become the important cause of UGIB. This highlights a red alert to curb the menace of obesity all over the globe and halt the increasing trend of variceal bleeding in future.

Regarding the trend of gastric ulceration, UGI bleeding has now shifted from H. Pylori infection to the massive use of medications such as NSAIDs or steroids, all over the world16 especially among older people. We demonstrated drug-induced UGI bleeding in 20(16%) patients in this study as shown in table 2. Further the use of warfarin is estimated to increase as the population ages and atrial fibrillation , other cardiovascular ailments are increasing steadily. In a study by McGowan et al22 Tablet Warfarin was an independent predictor of major bleeding after the percutaneous coronary intervention (PCI) in patients receiving dual antiplatelet therapy.

Another most common diseases in the elderly population is Rheumatoid arthritis (RA) . Rheumatoid arthritis is considered as a comorbid disease in the Rockall score and increases the scale for mortality and hemorrhagic shock. The wide use of NSAIDs in RA patients steeps the incidence of peptic ulcers and its complications including UGIB23. This risk is significantly elevated when SSRI medications in combination with NSAIDs are prescribed to allay anxiety and depression in these chronic disorders. The physicians prescribing these medications together should exercise caution and discuss this risk of UGIB with patients24.

UGI bleeding due to malignancies were noted in 4 patients in our study cohort which is similar to the data shown in the southern region of Saudi Arabia19.

In this study, about 12-16% of the patients were diagnosed with either gastric ulcer or hemorrhagic gastritis. The data from Arar, the northern Saudi Arabian city , revealed prevalence of gastric ulcer to be twice as common as duodenal ulcer. The authors of this study observed that the use of NSAIDs, H. Pylori infection and stress were among the most relevant reasons for developing peptic ulcer disease , however authors in their study didn’t study bleeding complications of peptic ulcer disease25.

Conclusion

Based on discussed results, it can be concluded that the frequency of UGI bleeding has declined and peptic ulcer is no longer the most predominant cause of UGI bleeding in Saudi Arabia. Instead, variceal bleeding outnumbers other causes of UGIB. This changing trend now demands that to prevent variceal bleeding we need to focus on the management of chronic HBV, HCV and NASH. Further all medications especially NSAIDs must be cautiously used particularly in elderly people. A step further would be to control hypertension and subsequent atrial fibrillation so that drug-induced UGI bleeding are reduced in future.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
IBRAHIM MASOODI, College of Medicine, Taif University, KSA. HESHAM ALQURASHI, King Abdul Aziz specialist Hospital, Taif, KSA. MOHAMMAD AL SOFIYANI, King Abdul Aziz specialist Hospital, Taif, KSA.
Corresponding Author Details: 
Ibrahim Masoodi, Associate Professor, College of Medicine, Taif University, KSA.
Corresponding Author Email: 
ibrahimmasoodi@yahoo.co.in
References
References: 
  1. Leerdam V. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. 2008;22(2) :209-24
  2. Javid G, Masoodi I, Zargar SA, Khan BA, et alOmeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am J Med. 2001 Sep;111(4) :280-4.
  3. Frugis S, Czeczko NG, Malafaia O, Parada et al Prevalence of Helicobacter pylori ten years ago compared to the current prevalence in patients undergoing upper endoscopy Arq Bras Cir Dig. 2016 Jul-Sep;29(3) :151-154.
  4. Jiang M, Chen P, Gao Q: Systematic Review and Net-Work Meta-Analysis of Upper Gastrointestinal Hemorrhage Interventions. Cell Physiol Biochem 2016;39:2477-2491.
  5. Roberts-Thomson IC. Rise and fall of peptic ulceration: a disease of civilization?. JGH. 2018;33(7) : 1321-1326
  6. Malmi H. Peptic ulcer disease incidence, associated morbidity and mortality. Helsinki university hospital. 2018
  7. Van Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. 2008;22(2) :209-24.
  8. Quan, S. , Frolkis, A. , Milne, K, et al. Upper-gastrointestinal bleeding secondary to peptic ulcer disease: Incidence and outcomes. WJG, 2014; 20(46) , 17568–17577.
  9. Wang CY, Qin jJ, Wang J, Sun CY, Cao T, Zhu DD. Rockall score in predicting outcomes of elderly patients with acute upper gastrointestinal bleeding. world journal gastroenterol. 2013; 19(22) : 3466–3472.
  10. Dworzynski K, Pollit V, Kelsey A, Higgins B, Palmer K; Guideline Development Group. Management of acute upper gastrointestinal bleeding: summary of NICE guidance. BMJ. 2012 Jun 13;344:e3412.
  11. Minakari M, Badihian S, Jalalpour P, Sebghatollahi V. Etiology and outcome in patients with upper gastrointestinal bleeding: Study on 4747 patients in the central region of Iran. J Gastroenterol Hepatol. 2017 Apr;32(4) :789-796
  12. Hsu YC, Chung CS, Tseng CH, Lin TL, Liou JM, Wu MS, Hu FC, Wang HP. Delayed endoscopy as a risk factor for in-hospital mortality in cirrhotic patients withacute variceal hemorrhage. J Gastroenterol Hepatol. 2009 Jul;24(7) :1294-9.
  13. Karima TM, Bukhari SZ, Ghais MA, Fatani MI, Hussain WM. Prevalence of helicobacter pylori infection in patients with peptic ulcer diseases. Saudi med j. 2006; 27(5) :621-6.
  14. Gutermann IK, Niggemeier V, Zimmerli LU, Holzer BM, Battegay E, Scharl M. Gastrointestinal bleeding and anticoagulant or antiplatelet drugs: systematic search for clinical practice guidelines. Wang. H HWA, ed. Medicine. 2015;94(1)
  15. Tielleman T, Bujanda D, Cryer B. . Epidemiology and risk factors for upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am 2015; 25:415–28.
  16. Kuipers EJ. PPI for prevention and treatment of peptic ulcer. The lancet. Feb. 2018; 3(4) :214-215.
  17. Loperfido S1, Baldo V, Piovesana E, Bellina L, Rossi K, Groppo M,et al. Changing trends in acute upper-GI bleeding: a population-based study. Gastrointest Endosc. 2009 Aug;70(2) :212-24.
  18. Al Karawi MA, Ghandour Z, Mohamed Ael S. Causes of upper gastrointestinal bleeding: Experience at a major hospital in Riyadh. Ann Saudi Med. 1995 Nov;15(6) :606-8.
  19. Ahmed ME, al-Knaway B, al-Wabel AH, Malik GM, Foli AK. Acute upper gastrointestinal bleeding in southern Saudi Arabia. J R Coll Physicians Lond. 1997 Jan-Feb;31(1) :62-4.
  20. Al-mofarreh M, Facharzt Y, Fakunle M,Al-moagel A, Facharzt. Upper gastrointestinal bleeding among Saudis: etiology and prevalence the Riyadh central hospital experience. ASM. 1991;11(5) .
  21. Fashir B, Sivasubramaniam V, Al Momen S, Assaf H. Pattern of liver disease in a Saudi patient population: A decade of experience at security forces hospital, Riyadh, KSA. SJG. 1996;2(1) :50-52.
  22. McGowan C, Lee G, DeCaro M, Ruggiero N,et al. Risk of majorbleeding with concomitant dual antiplatelet therapy after percutaneous coronaryintervention in patients receiving long-term warfarin therapy. Pharmacotherapy. 2007 May;27(5) :691-6.
  23. Koff RS. Prevention on NSAIDS induced gastric ulcer. Gastroenterology. 1989; 97(4) :1054
  24. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of uppergastrointestinal bleeding with selective serotonin reuptake inhibitors with orwithout concurrent nonsteroidal anti-inflammatory use: a systematic review andmeta-analysis. Am J Gastroenterol. 2014 Jun;109(6) :811-9.
  25. Albaqawi A, Abo El-Fetoh N, Alanazi R, Alanazi N, Alrayya S, Alanazi A, et al. Profile of peptic ulcer disease and its risk factors in Arar, northern Saudi Arabia. Electron physician. 2017.

Serum Procalcitonin in Lower Respiratory Tract Infections in Adult Patients

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

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

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

Background

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

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

Community Acquired Pneumonia (CAP) and Procalcitonin

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

Ventilator Associated Pneumonia (VAP) and Procalcitonin

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

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

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

Acute Bronchitis and Procalcitonin

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

Summary

Table 2: Procalcitonin levels in lower respiratory tract infections:

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

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

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

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DR AMER SALEEM; BSC, MBBS, MCPS MEDICINE (PAK), MRCP (UK), FCPS PULMONOLOGY (PAK), FRCP (GLASGOW), FCCP (USA), EUROPEAN DIPLOMA IN ADULT RESPIRATORY MEDICINE, SPECIALITY CERTIFICATE IN RESPIRATORY MEDICINE (RCP UK); Consultant Chest Physician, Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Details: 
DR AMER SALEEM, Consultant Chest Physician, Respiratory Medicine, Milton Keynes University Hospital, Standing Way, Eaglestone, Milton Keynes, MK6 5LD, UK.
Corresponding Author Email: 
amersaleemmalik@gmail.com
References
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  2. Maruna P, NedelníkováK, Gürlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000; 49 Suppl 1:S57.
  3. Christ-Crain M, Müller B. Procalcitonin in bacterial infections - hype, hope, more or less? Swiss Med Wkly. 2005; 135(31-32):451.
  4. Meisner M. Update on procalcitonin measurements. Ann Lab Med. 2014;34(4):263. Epub 2014 Jun 19.
  5. Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis 2011; 52 Suppl 4: S346.
  6. Scheinpflug K, Schalk E, Grabert E, Achenbach HJ. Procalcitonin is not useful to discriminate between infectious and noninfectious CRP elevation in patients with non-small cell lung cancer. Infect Control Hosp Epidemiol 2015; 36:1117.
  7. Rao K, Walk ST, Micic D, et al. Procalcitonin levels associate with severity of Clostridium difficile infection. PLoS One 2013; 8: e58265.
  8. Li G, Zhu C, Li J, et al. Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke. Neurosci Lett 2018; 662:242.
  9. He D, Zhang Y, Zhang B, et al. Serum procalcitonin levels are associated with clinical outcome in intracerebral hemorrhage. Cell Mol Neurobiol 2017.
  10. Reinink AR, Limsrivilai J, Reutemann BA, et al. Differentiating Clostridium difficile colitis from Clostridium difficile colonization in ulcerative colitis: A role for procalcitonin. Digestion 2017; 96:207.
  11. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis 2014; 59:1761.
  12. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009; 302(10):1059.
  13. Wang JX, Zhang SM, Li XH, Zhang Y, Xu ZY, Cao B. Acute exacerbations of chronic obstructive pulmonary disease with low serum procalcitonin values do not benefit from antibiotic treatment: a prospective randomized controlled trial. Int J Infect Dis. 2016; 48:40. Epub 2016 May 4.

Assessment of risk factors and precipitating factors of delirium in patients admitted to intensive care unit of a tertiary care hospital

Authors
Nikita Nagari & M Suresh Babu
Article Citation and PDF Link
BJMP 2019;12(2):a011
Abstract / Summary
Abstract: 

Background and Aim: Delirium is defined as disturbance in attention and awareness. Delirium is a common complication in patients  admiited to intensive care unit. The focus of the researchers has shifted from treatment to prevention of the syndrome.  There is a need to study risk factors for prevention of delirium. Data on delirium in intensive care unit is scarce in the Indian subcontinent. Hence, the present study was done to assess risk factors and precipitating factors of delirium in patients admitted to medical intensive care unit of a tertiary care hospital.
Materials and Methods: This is an observational study done over a period of 1 year. Patients admitted to medical ICU were screened for presence of delirium within first 72 hours of admission using RASS and CAM-ICU. Comatose patients, with RASS score of -4 or -5, were excluded from the study. Risk Factors and precipitating factors associated with delirium were assessed. Independent t-sample test or the Pearson Chi-square test were used to calculate differences between delirious and non-delirious subjects. Odds ratios (OR) was calculated for all factors using univariate binary logistic regression.
Results: Percentage of patients developing delirium within the first 72 hours of admission was 25.7% (406/1582). 52% of patients had hypoactive delirium, 48% of them had hyperactive delirium. Alcohol (OR 6.54), sedatives usage at the time of admission (OR 2.48), visual disturbances (OR 2.22), bowel and bladder disturbances (OR 1.67) were significant modifiable risk factors contributing to delirium. Previous psychiatric illness (OR 3.73), previous cognition impairment (OR 2.73) were significant non-modifiable risk factors contributing to delirium.  Predominant precipitating factors among delirious subjects were uremia (25.1%), hepatic encephalopathy (22.7%), hyponatremia (19.5%).
Conclusion: Delirium is common in intensive care unit patients. Major risk factor contributing to delirium was alcohol consumption. Most common precipitating factors resulting in delirium were deranged metabolic parameters.  All ICUs should implement both RASS and CAM-ICU for early detection of delirium.

Abbreviations: 
CAM-ICU= Confusion Assessment Method for ICU, ICU = Intensive Care Unit, RASS= Richmond Agitation-Sedation Scale, OR = Odds ratio
Keywords: 
CAM-ICU, hypoactive and hyperactive delirium, RASS

Introduction:

According to DSM V, delirium is defined as disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). This disturbance develops over a short period of time and it represents an acute change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

The focus of the researchers has shifted from treatment to prevention of the syndrome. There is a need to study risk factors for prevention of delirium1. Data on delirium in the intensive care unit is scarce in the Indian subcontinent2.

A multicenter study indicated risk factors significantly contributing to delirium were related to patient characteristics (smoking, daily use of more than 3 units of alcohol, living alone at home), chronic pathology (pre-existing cognitive impairment), acute illness (use of drains, tubes, catheters, use of psychoactive medication, a preceding period of sedation, coma, mechanical ventilation) and the environment (isolation, absence of visit, absence of visible daylight, transfer from another ward, use of physical restraints)1. Psychoactive medications can provoke a delirious state. Lorazepam has an independent and dose related temporal association with delirium3.

Each additional day spent in delirium is associated with 20% increased risk of prolonged hospitalisation and 10% increased risk of death4.

Hence, the present study was done to assess risk factors and precipitating factors of delirium in a medical intensive care unit of a tertiary care hospital.

Materials and methods:

This is an observational study done over a period of 1 year in a tertiary care medical college hospital located in southern part of India. Ethical committee approval for the study was obtained from the institutional ethical committee.

All patients admitted to medical intensive care unit in our tertiary care hospital, were screened for presence of delirium during the first 72 hours of admission using Richmond Agitation Sedation Scale (RASS) and Confusion Assessment Method for ICU (CAM-ICU). Patients with delirium were classified as delirious and the remaining as non-delirious patients. Comatose patients (RASS score -4 or -5) were excluded from the study.

Patients were initially screened with Richmond Agitation Sedation Scale (RASS). It is a 10-point scale, with 4 levels of agitation (+1 to +4) and 5 levels of sedation (-1 to -5). Level zero indicates calm and alert patient. Patients with RASS score of -4 or -5 (deep sedation and unarousable patients) were excluded from the study. Patients with RASS score of +4 to -3 were then screened for presence of delirium using Confusion Assessment Method for ICU (CAM-ICU). CAM–ICU has 4 criteria:

1) Acute onset and fluctuating course of delirium

2) Inattention

3) Disorganized thinking

4) Altered level of consciousness

The diagnosis of delirium requires the presence of criteria 1 and 2 and of either criterion 3 or 4.

Risk factors for developing delirium were assessed in the study population. Risk factors are those proven factors which may also be present before patient’s admission to intensive care unit, and which predispose the patient to develop delirium. Risk factors were compared between delirious and non-delirious patients. Risk factors which were assessed were history of diabetes and hypertension, history of previous stroke, history of previous cognition impairment, history of previous psychiatric illness, history of previous trauma, history of previous episodes of delirium, history of bowel and bladder disturbances prior to admission (such as constipation and urinary retention respectively), history of alcohol abuse (consumption of more than 2 units of alcohol), history of smoking (more than 10 cigarettes per day), history of consumption of substances other than cigarettes and alcohol (such as cannabis, cocaine etc.), history of uncorrected visual or hearing disturbances before admission, history of usage of barbiturates (such as phenobarbital), benzodiazepines (such as alprazolam, chlordiazepoxide, clobazam, clonazepam) & opioids (such as morphine) before admission, history of usage of sedatives (such as haloperidol, midazolam, fentanyl) and pain killers (such as morphine, tramadol) at the time of admission. Metabolic risk factors which were compared between delirious and non-delirious subjects were uraemia, hyponatremia, hyperbilirubinemia, metabolic and respiratory acidosis.

Precipitating factors weredefined as factors that were the likely causes of delirium in delirious patients. Precipitating factors for delirium which were looked into were exposure to toxins (alcohol/drugs), deranged metabolic parameters, infections and central nervous system causes.

SPSS21 software was used to calculate statistics. Independent t-sample test and the Pearson Chi-square test were used to calculate differences between delirious and non-delirious subjects. Odds ratios (OR) was calculated for all factors using univariate binary logistic regression.

Results:

Total number of patients enrolled in the study was 1582, of which 406 were diagnosed with delirium. Percentage of patients developing delirium within first 72 hours of admission was 25.7%. Hypoactive delirium was present in 52% and hyperactive delirium in 48% of patients. Patients who experienced delirium (57.5 + 17 years) were older compared to their non-delirious (53.3 + 18.1 years) counterparts (p value <0.0001). Among delirious subjects, majority were in the age group of 61-70 years (Figure 1).

Figure 1- Age distribution among delirious patients

38.2% of delirious patients and 39.3% of non-delirious patients were females. 61.8% of delirious patients and 60.7% of non-delirious patients were males.

Alcohol consumption [OR = 6.54 (95% CI 3.76-11.4, p = 0.0001)], previous psychiatric illness [OR = 3.73 (95% CI 1.712-8.159, p = 0.033)], previous cognition impairment [OR = 2.739 (95% CI 1.509-4.972, p = 0.001)], sedatives usage at the time of admission [OR = 2.488 (95% CI; 1.452-4.264), p = 0.001)], visual disturbances [OR = 2.227 (95% CI; 1.328-3.733, p = 0.002)], bowel and bladder disturbances [OR = 1.677 (95% CI 1.044-2.693, p = 0.032)] were significant risk factors contributing to delirium after univariate analysis (Table 1). Metabolic acidosis [OR = 1.996 (95% CI 1.469-2.711, p = 0.0001)] and hyperbilirubinemia [OR = 1.448 (95% CI 1.111-1.886, p = 0.006)] were significant metabolic parameters contributing to delirium after univariate analysis (Table 2).

Precipitating factors (Table 3) for delirium are those factors that were considered the most likely causes of delirium among the delirious patients. Precipitating factors for delirium were classified into toxins, deranged metabolic parameters, infections and central nervous system causes, of which metabolic parameters were most common. Among metabolic parameters, uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%) contributed to the majority of cases with delirium.

Table 1 – Univariate analysis of risk factors of delirium

   

NO DELIRIUM

DELIRIUM

   
    COUNT % COUNT % P UNIVARIATE

Diabetes

No 729 62 226 55.7 .025 1.3(1.1-1.6)
Yes 447 38 180 44.3    

Hypertension

No 684 58.2 239 58.9 .8 .97(0.8-1.2)
Yes 492 41.8 167 41.1    

History of Stroke

No 1107 94.1 379 93.3 .6 1.14(0.7-1.8)
Yes 69 5.9 27 6.7    

Previous memory disturbances

No 1149 97.7 264 89.7 <.0001 4.9(2.9-8)
Yes 27 2.3 42 10.3    

Previous psychiatric illness

No 1161 98.7 386 95.1 <.0001 4(2-7.9)
Yes 15 1.3 20 4.9    

Trauma

No 1137 96.7 396 97.8 .3 0.6(0.3-1.3)
Yes 39 3.3 9 2.2    

Previous episodes of delirium

No 1155 98.2 402 99 .3 0.55(0.2-1.6)
Yes 21 1.8 4 1.0    

Bowel & bladder disturbances

No 1107 94.1 350 86.2 <.0001 2.6(1.8-3.7)
Yes 69 5.9 56 13.8    

Alcohol

No 1089 92.6 336 82.8 <.0001 2.6(1.8-3.7)
Yes 87 7.4 70 17.2    

Smoking

No 981 83.4 354 87.2 .07 0.7(0.5-1.03)
Yes 195 16.6 52 12.8    

Other substance abuse (apart from cigarettes and alcohol)

No 1071 91.1 391 96.3 .001 0.4(0.22-0.6)
Yes 105 8.9 15 3.7    

Visual disturbances

No 1062 90.3 298 73.4 <.0001 3.4(2.5-4.5)
Yes 114 9.7 108 26.6    

Hearing disturbances

No 1104 93.9 338 83.3 <.0001 3.1(2.2-4.4)
Yes 72 6.1 68 16.7    

Barbiturates

No 1155 98.2 401 98.8 .5 0.7(0.3-1.8)
Yes 21 1.8 5 1.2    

Benzodiazepines

No 1155 98.2 400 98.5 .7 0.8(0.3-2.1)
Yes 21 1.8 6 1.5    

Opioids

No 1176 100 405 99.8 .9 4.7(0-IN)
Yes 0 .0 1 .2    

Sedatives usage in present admission

No 1143 97.2 369 90.9 <.0001 3.5(2.1-5.6)
Yes 33 2.8 37 9.1    

Pain killers usage in present admission

No 1080 91.8 400 98.5 <.0001 0.17(0.07-0.39)
Yes 96 8.2 6 1.5    

Table 2- Univariate analysis of metabolic parameters

   

NO DELIRIUM

DELIRIUM

   
    COUNT % COUNT % P UNIVARIATE

Uraemia

NO 648 55.1 186 45.8 0.001 1.45(1.2-1.8)
YES 528 44.9 220 54.2    

Hyponatremia

NO 645 54.8 202 49.8 0.08 1.2(0.98-1.5)
YES 531 45.2 204 50.2    

Hyperbilirubinemia

NO 837 71.2 246 60.7 <0.0001 1.6(1.3-2)
YES 339 28.8 159 39.3    

Metabolic acidosis

NO 990 84.2 286 70.4 <0.0001 2.2(1.7-2.9)
YES 186 15.8 120 29.6    

Respiratory acidosis

NO 1092 92.9 377 92.9 1 1(0.6-1.5)
YES 84 7.1 29 7.1    

Table 3- Precipitating factors of delirium in the present study

PRECIPITATING FACTORS

%

Toxins

Drug or Alcohol overdosage 1.5
Alcohol withdrawal 2.7

Metabolic conditions

Hyponatremia 19.5
Hyperglycaemia 6.2
Hypoglycaemia 2.5
Hypercarbia 5.7
Uraemia 25.1
Hepatic encephalopathy (hyperammonemia) 22.7

Infections

Systemic infective causes 16.5
Meningitis/ Encephalitis 8.9

Central Nervous System causes

Hypoperfusion states 14.5
Hypertensive encephalopathy 5.9
Cerebrovascular accident (CVA) 7.6
Intracranial space occupying lesion (ICSOL) 5.4
Seizures 10.3
Psychiatric illness 4.9

Discussion:

Delirium is classified into hyperactive, hypoactive and mixed type. Hyperactive subtype is present if there is definite evidence in the previous 24 hours of at least two out of the following factors - increased quantity of motor activity, loss of control activity, restlessness, wandering. Hypoactive subtype is present if there is definite evidence in the previous 24 hours of at least two of the following factors - decreased amount of activity, decreased speed of actions, reduced awareness of surroundings, decreased amount of speech, decreased speed of speech, listlessness, reduced alertness, withdrawal. Mixed subtype is present if there is evidence of both hyperactive and hypoactive subtypes in the previous 24 hours5. Percentage of patients with hypoactive delirium was high in this study (52%). Hypoactive delirium often carries relatively poor prognosis, occurs more commonly in elderly patients and is frequently overlooked or misdiagnosed as having depression or a form of dementia.

In the present study, delirium was more prevalent in the elderly population. Most of the elderly patients will have multiple risk factors making them more vulnerable to delirium. Delirium is often the only sign of an underlying serious medical illness in an elderly patient and particular attention should be given to identify and correct the underlying illness.

History of alcohol consumption of more than 2 units per day, prior to admission of the patient, was the major risk factor contributing to delirium in this study (OR = 6.54). This was similar to other studies done by Bart1 et al & Ouimet6 et al where consumption of more than 3 units of alcohol (OR 3.23) & 2 units of alcohol (OR 2.03) respectively, was a significant risk factor for delirium. Patients with a previous psychiatric illness were at increased risk for delirium in this study (OR – 3.73). However, other studies explaining its importance in contributing to delirium were not available. Previous cognition impairment was a significant risk factor contributing to delirium (OR = 2.73). The study by Bart1 et al found that previously diagnosed dementia was an important risk factor (OR = 2.41). Positive correlation with dementia was reported by McNicoll et al7 (RR 1.4) and Pisani et al8 (OR 6.3). Usage of sedatives (OR = 2.48) at the time of admission was a significant risk factor for developing delirium. Bart1 et al found that use of psychoactive medication may disturb the neurotransmission in the brain provoking a delirious state and use of benzodiazepines is a risk factor for delirium (OR – 3.34). Pandharipande3 et al found that Lorazepam was an independent risk factor for daily transition to delirium (OR – 1.2). Pisani8 et al found that use of benzodiazepines was a significant risk factor for developing delirium with odds ratio of 3.4. Uncorrected visual disturbances were a significant risk factor for developing delirium in this study (OR-2.22). Inouye9 et al found that vision impairment (adjusted relative risk – 3.5) was an independent baseline risk factor for delirium. Bowel and bladder disturbances were a significant risk factor contributing to delirium in this study (OR – 1.67). Morley10 opined that constipation is a frequent, often overlooked precipitating factor for delirium. Tony11 et al was of the opinion that a careful history and physical, including a rectal examination with consideration of disimpaction, may be helpful in assessing and managing delirious patients. Waardenburg12 concluded that significant urinary retention can precipitate or exacerbate delirium, a disorder referred to as cystocerebral syndrome. Liem and Carter13 suggested that increased sympathetic tone and catecholamine surge triggered by the tension on the bladder wall may contribute to delirium. Metabolic acidosis and hyperbilirubinemia were significant metabolic parameters contributing to delirium in this study.Similar findings were reported by Aldemir14 et al.

Among delirious patients, most common precipitating factors for delirium in this study were uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%). Alterations of serum electrolytes, renal function predispose to delirium15. Hyponatremia causes delirium and the mechanism is not well understood16, 17. Blood urea nitrogen/creatinine ratio greater than 18 is an independent risk factor for delirium in general medical patients9.Hepatic failure leads to hyperammonemia, which leads to excessive NMDA (N-methyl-D-aspartate) receptor activation, resulting in dysfunction of glutamate-nitric oxide-cGMP pathway and causing impaired cognitive function in hepatic encephalopathy18.Excess activation of NMDA receptors results in neuronal degeneration and death19. In hepatic failure, there may be a shift in regional cerebral blood flow and cerebral metabolic rates from cortex to subcortex resulting in delirium20.

Patients who develop delirium during their stay in hospital have higher 6-month mortality rates, longer hospital stay, increased economic burden and a higher incidence of cognitive impairment at hospital discharge21. Limitation of this study was long term follow up of patients who developed delirium was not done.

Conclusion:

Delirium is common in intensive care unit patients and hypoactive delirium is more common. Major risk factor contributing to delirium was alcohol consumption before admission. Most common precipitating factors contributing to delirium were deranged metabolic parameters.

Delirium in ICU patients especially hypoactive delirium is easily missed. Hence, all ICUs should implement both RASS and CAM-ICU for early detection of delirium. Future research needs to be directed at development of scoring systems for detection of delirium, which are easy to use and are accurate.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Dr M Kishor, Associate Prof of Psychiatry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
Competing Interests: 
None declared
Details of Authors: 
NIKITA NAGARI, MD (Int Medicine), JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India. M SURESH BABU, MD (Internal Medicine), FRCP Edin, FACP, Professor of Medicine, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
Corresponding Author Details: 
Dr M SURESH BABU, MD (Internal Medicine), FRCP Edin,FACP, Professor of Medicine, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
Corresponding Author Email: 
drmsureshbabu@yahoo.co.in
References
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  2.  Grover S, Subodh BN, Avasthi A, Chakrabarti S, Kumar S, Sharan P et al. Prevalence and clinical profile of delirium: a study from a tertiary care hospital in north India. Gen Hosp Psychiatry. 2009;31(1):25-9.
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  4.  Pun BT, Ely EW. The importance of diagnosing and managing ICU delirium. Chest 2007 Aug;132(2):624-36.
  5. Meagher D. Motor subtypes of delirium: past, present and future. Int Rev Psychiatry. 2009 Feb;21(1):59-73.
  6. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007;33(1):66-73.
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  8. Pisani MA, Murphy TE, Van Ness PH, Araujo KL, Inouye SK. Characteristics associated with delirium in older patients in a medical intensive care unit. Arch Intern Med. 2007 Aug;167(15):1629-34.
  9. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med. 1993 Sep;119(6):474-81.
  10. Morley JE. Constipation and irritable bowel syndrome in the elderly. Clin Geriatr Med. 2007 Nov;23(4):823-32.
  11. Rosen T, Connors S, Clark S, Halpern A, Stern ME, DeWald J et al. Assessment and management of delirium in older adults in the emergency department: Literature review to inform development of a novel clinical protocol. Adv Emerg Nurs J. 2015 Jul-Sep;37(3):183-96.
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  14. Aldemir M, Ozen S, Kara IH, Sir A, Bac B. Predisposing factors for delirium in the surgical intensive care unit. Crit Care. 2001 Oct;5(5):265-70.
  15. Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Intern Med. 1998 Mar;13(3):204-12.
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Hyperglycaemia and Myocardial Infarction

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

Introduction

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

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

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

Table 1: Aetiology of Hyperglycaemia

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

 

Prevalence and risk of hyperglycemia

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

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

Pathogenesis of hyperglycaemia

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

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

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


Figure 1

Cardiovascular effects of hyperglycaemia

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

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

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

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

Table 2: Acute Cardiovascular Effects of Hyperglycaemia

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



Conclusion

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

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

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

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

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

Pericardial effusion unmasked SLE in a young schizophrenic male : A case report

Authors
Ibrahim Masoodi & Irshad Sirwal
Article Citation and PDF Link
BJMP 2019;12(1):a004
Abstract / Summary
Abstract: 

Systemic Lupus Erythematosus (SLE) is characterised by its multi-systemic involvement and has a chronic remitting and relapsing course. It can involve the nervous system on its central or peripheral components. While the prevalence of SLE is highest among females  aged 14 to 64 years, males are not immune.  The risk of SLE development in men is similar to that in the pre-pubertal or postmenopausal women. The median duration of clinical presentation to diagnosis ranges from  6 months to 12years. Keeping in view its female preponderance there is invariably a   low clinical suspicion of SLE among males.

The clinical scenario of a young man is presented in this report who presented with acute mania and remained  on psychiatric follow up for schizophrenia for one year after an initial electro convulsive therapy. The patient presented with fever and shortness of  breath to King Abdul Aziz specialist hospital Taif  ,Saudi Arabia .The index case was found to have pericardial effusion and on further evaluation proved to have SLE.Following treatment with steroids patient improved clinically, resumed his job and he is off all his anti-psychiatric medications now.

Keywords: 
SLE, Schizophrenia, Pericardial effusion, Electroconvulsive therapy

Introduction:

The spectrum of psychiatric illness in Systemic lupus erthyromatosus (SLE) include psychotic, depressive, subtle cognitive and personality disorders of histrionic type. The occurrence of psychiatric manifestations in SLE varies widely from 5 to 83%. It is postulated that there is a direct action of the disease on the central nervous system by autoantibodies namely anti phospholipid and anti-ribosome P auto antibodies or cytokines like interleukin 2, interleukin 6, alpha interferon 1. During the course of the disease side-effects of glucocorticosteroids and hydroxychloroquine or anxious reaction to chronic and potentially lethal illness is postulated to be another mechanism of psychiatric manifestation of SLE . SLE patients are prone to develop myriad of psychological distress in addition to neuropsychitric manifestations which require a social and psychological support. While some of these manifestations are treated by corticosteroids and psychotropic drugs1 medications with anticholinergic side-effects, like phenothiazines, tricyclic antidepressants and hydroxyzine which enhance the oral dryness should be avoided in SLE.

Clinical scenario:

A 27-year-old male suddenly developed aggressive behaviour for the first time in his life ,while on his work place. The patient had no insight into his illness and was brought to the local psychiatric hospital by his colleagues where he was admitted as a case of acute mania. He was managed with electroconvulsive therapy (EST) in addition to antipsychotic medication as neuro imaging including CT scan and MRI brain were normal. A few days later , the patient was discharged on anti-psychiatric medicines. However, after six months while on antipsychotic medication, he developed a low grade fever .He was admitted to a local hospital where in addition to base line investigations a lymph node biopsy was done which revealed follicular hyperplasia, without any abnormal cell. Patient’s HBV, HCV, HIV were negative. The patient developed anorexia , significant weight loss and progressive difficulty in getting up from a sitting position .He also developed shortness of breath and presented to King Abdul Aziz specialist hospital in Taif, Saudi Arabia virtually in a bed bound state . He was admitted in the intensive care unit of the hospital .The examination revealed pallor, generalised lymph-adenopathy, palmer rash, alopecia and mouth ulcers. The patient had mild pericardial effusion and Mitral regurgitation (MR)++ on echocardiography. Further evaluation showed significant proteinuria. Serum ANA, dsDNA were positive .Lupus anticoagulant was negative. Keeping in view above symptoms and signs the patient was diagnosed as a case of SLE2 (Mouth ulcers, Pericardial effusion ,ANA positive , dsDNA positive ) The patient was managed with pulse dose of methylprednisolone 1g intravenously (IV) daily for 5days, followed by oral prednisone 60 mg once daily, which was tapered on follow up . Patient tolerated the treatment well and improved progressively . He became ambulatory and rejoined his job. The psychiatric medications were stopped.

However, on follow up the patient continued to have proteinuria 1.8 gm/24 hr. He was readmitted and the kidney biopsy revealed class IV lupus nephritis. He was given pulse cyclophosphamide 1gm/m2 intravenously and later started on tablet Mycophenolate 1.5gm once daily. The proteinuria improved and he is following our clinic for the last two years now .Patient’s follow up investigations are shown in table 1.

Table: 1 Patients’ hospital investigations and results

Test Result
Pre-treatment
(On presentation )
Result
Post-treatment
(After 6 weeks )
Normal range
Haemoglobin 6.2 12.3 12. 2-15.3 gm/dl
White blood cell 3.2 6.7 6-16 × 109/l
Platelet 41,000 197 150-450 × 109/l
ESR 82mm first hour 56mm  
Total bilirubin 1.2 1.0 .0.8 to 1mg/dl
Direct bilirubin 1.0 0.8 0.-0.6µmol/L
AST 335 30 5-30U/L
ALT 257 29 5-30U/L
ALP 182 100 50-100U/L
GTT 497 65 7-30 IU/l
Albumin 39 39 38-54 g/l
Total protein 5.2 4.5  
INR 1.1 1.1 0.8-1.2
Urea 62 40  
Creatinine 1.2 1.0  
Na/K 131/3.8 142/3.6  
Serum glucose 100 102 65-110mg/dl
ANA Positive    
Anti DsDNA Positive    
Lupus anticoagulant Negative    
24 hr urinary protein 2.3gm/L 500mg/L <150mg/L

Discussion:

The correct diagnosis of central or even peripheral nervous system manifestations in patients with SLE can be challenging because of many SLE-related and non-SLE-related processes present in a patient. The index case proved to have acute mania as the first manifestation of SLE which remained under oblivion till he developed serositis another complication of SLE. While this patient came to clinical attention after one year a case of SLE masquerading schizophrenia for 14 years was reported by Funaunchi et al3. In another report, a 14-year-old boy with a two-year history of cognitive dysfunction and behavioural problems SLE was diagnosed after two years4 . It appears that the psychiatric symptoms may occur as the first manifestation of juvenile SLE. It will not be out of place to mention that the psychiatric manifestation can be at times dire which could even result in harm to others in a given society. The case of Folie a trios syndrome, characterized by the transfer of delusional ideas from one person to two other persons culminating in murder has been reported in a patient with SLE5 . In a significant retrospective data from China (a cohort of 518) neuropsychiatric manifestations in SLE were observed in 96(19%) of the above study cohort . The seizure disorder accounted for the most prevalent disorder of neuropsychiatric manifestations (NP) of SLE followed by cerebrovascular disease and acute confusional states. In the above study, 96 patients with psychiatric symptoms, acute psychosis was observed in 10(11%)patients. Authors in this study were of the opinion that this percentage could have been higher if subtle cognitive dysfunction were included as well. Authors of the same study further concluded that the antiphospholipid antibodies were significantly associated with NP manifestations, especially cerebrovascular disorders6.

The autoantibodies have been found to be biomarkers for future neuropsychiatric events in SLE. A prospective study throughout ten years conducted among 1047 SLE patients demonstrated that individuals who had evidence of lupus anticoagulant (LA) were at an increased future risk of intracranial thrombosis. Further, those with anti-ribosomal P antibodies were at an increased future risk of lupus psychosis7. The Lupus anticoagulant in the index case was negative, and anti-ribosomal P antibodies were not available . A study by Sanna et al8 have shown that an association exists between anti-NR2 antibodies and depressed mood in addition to decreased short-time memory and learning. Authors in this study concluded that antibodies to NMDA receptors thus might represent as one of the several mechanisms for cerebral dysfunction in patients with SLE.

The CT scan brain of the index case was normal. However, massive bilateral calcification of sub-cortical structures in a patient with SLE with the psychotic disorder has been reported9. The psychiatric diseases are related to vasculitis and non-inflammatory vasculopathy of the small cerebral blood vessels. Further, a study has shown that ninety per cent of the patients with psychosis, organic brain syndrome or generalised seizures had increased IgG antineuronal activity as compared with only 25 per cent of the patients who presented with hemiparesis or with chorea/hemiballismus. The authors in the above study concluded that the diffuse central nervous system manifestations of SLE are a direct result of the interaction of the antibody with neuronal cell membranes10.

The management neuropsychiatric manifestation in SLE should include treatment of the disease itself and specific psychotropic treatment. The index case had rapid improvement following Glucocorticosteroid therapy. Intravenous infusions of immunosuppressive agents, such as cyclophosphamide, have been found to be effective in such conditions 1 . Psychotropic drugs may be used, but it is prudent to mention that SLE-inducing drugs, like chlorpromazine, carbamazepine and lithium carbonate must be avoided. Following treatment with steroids, the index case improved and all his antipsychiatric medications were finally stopped and he resumed his job.

To conclude the index case highlights that even though SLE is more frequent among females of childbearing age but males are no way immune to SLE . While evaluating patients with multiple unexplained somatic complaints and psychiatric symptoms SLE ought to be ruled out. The existence of neuropsychiatric manifestations in SLE constitutes an indisputable clinical reality that every practitioner must be able to recognise and treat.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
IBRAHIM MASOODI, Department of Internal Medicine, College of Medicine, Taif University, KSA. IRSHAD SIRWAL, King Abdul Aziz Specialist Hospital, Taif, KSA.
Corresponding Author Details: 
Dr Ibrahim Masoodi, Associate Professor, College of Medicine, Taif University, KSA.
Corresponding Author Email: 
ibrahimmasoodi@yahoo.co.in
References
References: 
  1. Ampélas JF, Wattiaux MJ, Van Amerongen AP. [Psychiatric manifestations of lupus erythematosus systemic and Sjogren's syndrome]. Encephale. 2001;27(6):588-99.
  2. Petri M, Orbai AM, Alarcón GS, Gordon C, et al Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677-86
  3. Funauchi M, Yamagata T, Nozaki Y, Sugiyama M, Ikoma SY, Kinoshita K, Kanamaru A. A case of systemic lupus erythematosus that manifested in the course of schizophrenia.Scand J Rheumatol. 2002;31(6):374-6.
  4. Shiari R, Hassase Yegane M, Farivar S, Javadi Parvaneh V, Mirjavadi SA.Neuropsychiatric Symptoms as The First Manifestation of Juvenile Systemic Lupus Erythematosus: A Complicated Case with Klinefelter's Syndrome. Iran J Child Neurol. 2014 Winter;8(1):62-5
  5. Caribé AC, Daltro-Oliveira R, Araújo RH, Cardoso AP, Guimarães PB, Miranda-Scippa A, Quarantini LC. Systemic lupus, folie a trois and homicide. Compr Psychiatry. 2013 ,54(7):1032-3
  6. Mok CC, Lau CS, Wong RW. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol. 2001 ,28(4):766-71.
  7. Hanly JG, Urowitz MB, Su L, et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis. 2011, 70(10):1726-32
  8. Sanna G, Bertolaccini ML, Khamashta MA. Neuropsychiatric involvement in systemic lupus erythematosus: a current therapeutic approach. Curr Pharm Des. 2008;14(13):1261-9. Review
  9. Malec M, Malec M, Rudzińska M, Dudek D, Siwek M, Wnuk M, Szczudlik A. [Psychotic disorder in the course of Systemic Lupus Erythematosus with subcortical calcifications--case report]. Psychiatr Pol. 2014,48(2):299-306.
  10. Bluestein HG, Williams GW, Steinberg AD. Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med. 1981, 70(2):240-6.

Case Report: Co-Existing Sinus and Atrio-Ventricular Node Dysfunction Following Stress-Induced Cardiomyopathy

Authors
Raja Ezman Faridz Raja Shariff, Lim Chiao Wen, Rizmy Najme Khir, Khairul Shafiq Ibrahim, Ahmad Bakthiar Ahmad Radzi & Sazzli Kasim
Article Citation and PDF Link
BJMP 2019;12(1):a002
Abstract / Summary
Abbreviations: 
SCM: Stress-Induced Cardiomyopathy; ECG: electrocardiogram; SND: Sinus Node Dysfunction; AVN: Atrioventricular Node
Keywords: 
Takotsubo Cardiomyopathy, Stress-Induced Cardiomyopathy

Background

Stress-Induced Cardiomyopathy (SCM), also known as Takotsubo Cardiomyopathy or Apical Balooning Syndrome, is an acute, transient and non-ischaemic cause of left ventricular dysfunction often precipitated by periods of stress1. Diagnosis often follows evidence of left ventricular hypokinesia despite a normal coronary angiography. Prevalence is often underestimated, with an estimated 7% of suspected myocardial infarctions being in fact SCM2. We report a unique case of multi-nodal dysfunction following SCM.

Case Report

A 73-year old lady presented to our emergency department following a sudden onset of central, non-radiating chest heaviness 8 hours prior. She was a known chronic smoker of 20 pack years, and hypertension which had been left untreated for over 10 years. An initial electrocardiogram (ECG) revealed sinus bradycardia and T-wave inversions in the inferior, septal and lateral leads (Figure 1). Her Troponin-I levels was raised at 6532 pg/ml. She was treated as a Non-ST elevation myocardial infarction and was admitted to the coronary care unit for closer monitoring. She was kept on telemetry overnight, which disclosed several episodes of bradycardia. Rhythm strip revealed various transient conduction defects, including that of sinus node dysfunction (SND) and atrioventricular node (AVN) dissociation, although she remained asymptomatic throughout (Figure 2).


Figure 1: Electrocardiogram revealing sinus bradycardia, with T-wave inversion in the inferior, septal and lateral leads.


Figure 2: Telemetry rhythm strip revealing transient episodes of (a) sinus node dysfunction (SND) and (b) atrioventricular node (AVN) dissociation.


Figure 3: Electrocardiogram revealed ST-segment elevation with associated T-wave inversions in the inferior, septal and lateral leads.


Figure 4: An ‘Apical 4-Chamber’ view on echocardiography, revealing an akinetic apex on (a) diastole and (b) systole.

Unfortunately, following an episode of chest pain the following morning, her troponin levels and an electrocardiogram were repeated, showing a rise of the former to 12 996 pg/ml. A repeat ECG revealed evidence of ST-segment elevation in previously affected leads (Figure 3). She was brought into the catheterization laboratory within 1 hour. Her coronary angiogram showed no evidence of coronary obstruction. An echocardiogram was performed, which revealed an akinetic apex (Figure 4).

Upon further history taking, it was revealed that she was recently made redundant from her job as a cleaner, several hours prior to her presentation to the emergency department. Prior to that, she denied any other emotional or physical stressors. She was diagnosed as having Stress-Induced Cardiomyopathy (SCM). Following an observational period of close to 48 hours, she was allowed home. A 48-hour Holter monitoring was performed approximately 3 weeks from her initial admission, which returned unremarkable. A repeat echocardiography was also performed, revealing normal wall motion abnormality which further support a transient SCM.

Discussion

Despite being transient, multiple complications can arise from the condition, including arrhythmias. Prevalence of arrhythmias varies greatly, depending on population and types of defect (15% suffering atrial fibrillation, 2-5% of tachyarrhythmias, 2-5% of bradyarrhythmias and 5% of AVN dissociation amongst others)3,4. This is largely due to evidence being based on retrospective case report and series, leading to severe underestimation of their true prevalence. We suspect cases of sinus node dysfunction are far more uncommon, with only a handful of case report of note, and one retrospective review of 816 patients quoting a rate of 1.3%5. There are no reports of concomitant sinus node and atrio-ventricular node dysfunction, to our knowledge.

Proposed mechanisms for SCM-induced nodal dysfunction include reduced coronary flow to conduction tissues due to left ventricular dyskinesia, cathecolamine-driven coronary and microvascular vasospasm leading to both reduced blood supply and direct cardio-toxicity effects, and continual ischaemia-driven fibrosis of nodal tissue6. However, there have been reports of SND-triggered SCM, likely secondary to adrenergic compensative activation following bradycardia events. In both scenarios, pre-existing, subclinical SND may lower the threshold of developing significant, symptomatic bradycardia7-10. This is important to note, as majority of patients affected by SCM are post-menopausal women whom are already at risk of age-related SND.

In our patient, the SCM may have likely induced both SND and AVN dissociation, as subsequent 48 hours Holter monitoring, 3 weeks from presentation, was unremarkable. Furthermore, the patient denies any previous syncopal or pre-syncopal symptoms. However, the possibility of subclinical SND could still have existed, as we had earlier discussed, and ideally an internal loop recorder for prolonged monitoring, catheter-based electrophysiology studies and a Cardiac Magnetic Resonance Imaging to detect nodal and conduction tissue fibrosis would assist in ruling out pre-existing nodal dysfunction. However, due to financial and pragmatic reasons (as patient was asymptomatic), the patient declined further investigations, opting for periodic clinic reviews instead.

Conclusion

Both nodal and conduction tissue blocks are a rare but significant complications that can occur following SCM. The occurrence of SND following SCM should lead clinicians to routinely investigate for pre-existing conduction tissue diseases, if not already performed and allows for earlier device implantation if deemed indicated.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RAJA EZMAN FARIDZ RAJA SHARIFF (MBHCHB, MRCP) - CORRESPONDING AUTHOR 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia. LIM CHIAO WEN (MBBCH, MRCP) 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia. RIZMY NAJME KHIR (MBBCH, MRCP) 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia. KHAIRUL SHAFIQ IBRAHIM (MBCHB, MRCP) 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia. AHMAD BAKTHIAR AHMAD RADZI (MBBS, MMED) 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia. SAZZLI KASIM (MBBCh, BAO, BMedSc (NUI, Cork), MRCPI, CSCST (Ire), FNHAM) 1 Universiti Teknologi Mara, Sungai Buloh, Malaysia.
Corresponding Author Details: 
RAJA EZMAN FARIDZ RAJA SHARIFF, Universiti Teknologi Mara Sungai Buloh, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia.
Corresponding Author Email: 
rajaezman@gmail.com
References
References: 
  1. Kasim S, Moran D, O'Donnabhain R, et al. Takotsubo Cardiomyopathy – A Large Cohort, Multi-Centre Follow Up. Irish Jounral of Medical Science 2010; 179:S409.
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  3. Gamble DT, Shuttleworth KJ, Scally C, et al. Takotsubo cardiomyopathy with severe bradyarrhythmia following epidural insertion. BMJ Case Rep 2016; 0:1-3.
  4. Templin C, Ghadri JR, Diekmann J, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015; 373:929–938.
  5. Yassin AS, Subahi A, Abubakar H, et al. Sick Sinus Syndrome and Takotsubo Cardiomyopathy. Case Reports in Cardiology 2018; 0:1-5.
  6. Limm BN, Hoo AC & Azuma SS. Variable Conduction System Disorders in Takotsubo Cardiomyopathy: A Case Series. Hawaii Journal of Medicine & Public Health 2014; 73(5):148-151.
  7. Brunetti ND, Ieva R, Correale M, et al. Combined exogenous and endogenous catecholamine release associated with Tako-Tsubo like syndrome in a patient with atrio-ventricular block undergoing pace-maker implantation. Acute Cardiac Care 2011; 13(2):112-114.
  8. Ueyama T, Kasamatsu K, Hano T, et al. Emotional stress induces transient left ventricular hypocontraction in the rat via activation of cardiac adrenoceptors: a possible animal model of ‘tako-tsubo’ cardiomyopathy. Circulation Journal 2002; 66(7):712-713.
  9. Ueyama T, Senba E, Kasamatsu K, et al. Molecular mechanism of emotional stressinduced and catecholamine-induced heart attack. Journal of Cardiovascular Pharmacology 2003; 41:S115-S118.
  10. Syed FF, Asirvatham SJ, & Francis J. Arrhythmia occurrence with takotsubo cardiomyopathy: a literature review. Europace 2011; 13(6):780-788

Case Report: Group B Streptoccocus Related Lower Limb Necrotizing Fasciitis, Complicated by Purulent Pericarditis and Cardiac Tamponade

Authors
Raja Ezman Faridz Raja Shariff, Rizmy Najme Khir & Sazzli Kasim
Article Citation and PDF Link
BJMP 2019;12(1):a001
Abstract / Summary
Abstract: 

Background: Necrotizing soft tissue infections (NSTI) are severe and rapidly progressive. Rarely, Group B Streptococcus (GBS) can cause NSTI, majority due to an immunocompromised state. Even more uncommon is pericardial involvement following NSTI of a non-adjacent structure. 
Case Report: We report a challenging case of NSTI of the lower limbs due to GBS, with acute pericardial dissemination leading to cardiac tamponade. Bedside echocardiography revealed a massive pericardial effusion, measuring largest at 2 cm in depth, with evidence of both right atrial and ventricular collapse, leading to an urgent pericardiocentesis being performed which revealed turbid-looking aspirate. Urgent gram staining revealed moderate amounts of pus cells with occasional gram positive cocci. Wound debridement was performed on day 3 of admission, and tissue cultures were taken peri-operatively. Cultures from blood, pericardial aspirate and tissue aspirate were positive for Streptococcus Agalactiae. Unfortunately, the patient deteriorated post-operatively due to extensive blood loss and overwhelming septicaemia and succumbed to his illness 72 hours after. 
Conclusions: This case highlights the rare possibility of cardiac involvement in cases of NSTI, and the possibility of cardiac tamponade causing cardiogenic shock masquerading alongside septic shock, and reminds clinicians on the importance of combining clinical acumen and appropriate ancillary testing to facilitate early detection of a fatal condition.

Abbreviations: 
GBS: Group B Streptoccocus ECG: Electrocardiogram
Keywords: 
Case Report, Group B Streptoccocus, Streptococcus Agalactiae, Cardiac Tamponade, Purulent Pericarditis, Pericarditis

Background

Necrotising soft tissue infections (NSTI) are severe and rapidly progressive, requiring rapid recognitions and early, often surgically-based, management. Mono-microbial types of NSTI (i.e. Type 2 NSTI), which amounts for 20 to 30% of overall cases, are often linked to invasive Group A Streptococcus or Staphylococcus Aureus infections 1. Rarely, Group B Streptoccocus (GBS), also known as Streptococcus Agalactiae, are implicated 2. We report a unique case of NSTI of the lower limbs due to GBS, with acute pericardial dissemination leading to cardiac tamponade, leading to a diagnostic dilemma due to co-existing cardiogenic and septic shock.

Case Report

A 51-year old gentleman of Chinese ethnicity presented with right foot pain and swelling over 2 weeks, associated with chest pain and shortness of breath during that period. He had a 10-year history of poorly controlled diabetes mellitus with a Hba1c level of 8.8 %, hypertension and dyslipidaemia.

He was hypotensive on arrival, with a blood pressure of 91/60 mmHg and hypoxic, requiring high flow oxygen of 15L/min to maintain saturations at 100%. Otherwise other vitals were stable, pulse rate being 72 beats per minutes, respiratory rate 24 breaths per minute and a temperature of 37.4 degrees Celsius.

Clinical examination revealed a gangrenous lateral two toes extending into the lateral malleolus on the right foot, with evidence of pus discharge and associated warmth and crepitus up to hindfoot level on palpation. There was also evidence of dry gangrene in the fourth toe of the left foot, with presence of a small puncture at dorsum of foot with pus discharge. Similarly, crepitus was felt up to midfoot level on palpation of the left side. Bilateral dorsalis pedis and posterior tibialis pulses were palpable but feeble.

Table 1: Blood Investigations on Admission

Blood Test Results Blood Test Results
White Cell Count 26.99 x109L Alkaline Phosphatase 168 U/L
Neutrophil 90.30% Alanine Aminotransferase 37 U/L
Lymphocyte 4.50% Aspartate Aminotransferase 40 U/L
Platelets 210 x109L Sodium 121 mmol/L
Hemoglobin 10.0 g/dL Pottasium 7.6 mmol/L
Lactate Dehydrogenase 441 U/L Urea 40.5 mmol/L
International Normalised Ratio 1.2 Creatinine 323 μmol/L
Activated Partial Thromboplastin Time 36.5 s Creatinine Kinase 43 U/L
Prothrombin Time 14.6 s Total Bilirubin 21 μmol/L

Figure 1a & 1b: Radiography of the (1a) left foot and (1b) right foot respectively, demonstrating gas within soft tissue bilaterally.

Figure 2: Chest radiography demonstrating cardiomegaly and globular-shaped heart, with loss of left-sided cardiophrenic and costophrenic angles.

Figure 3: Electrocardiogram demonstrating widespread saddle-shaped ST-elevation, consistent with pericarditis.

Figure 4: Parasternal Long Axis view of bedside echocardiography showing evidence of pericardial effusion and right atrial and ventricular collapse

Figure 5: Purulent pericardial aspirate via pericardiocentesis

Initial blood investigations are highlighted in Table 1. HIV Antibody, Hepatitis B Surface Antigen and Hepatitis C Antibody serology were all negative. Lower limb radiography revealed evidence of gaseous shadows bilaterally (Figure 1). The clinical and radiological findings were consistent with necrotising soft tissue infection of bilateral feet, and the patient was advised for extensive wound debridement and possible amputation of the affected sites during an orthopaedic consult.

However, on closer review of the chest radiography, there was evidence of cardiomegaly with a globular-shaped heart (Figure 2). His electrocardiogram on arrival, revealed diffuse ST-segment elevations on majority of leads, ST-segment depression on lead aVR consistent with pericarditis (Figure 3).

A bedside echocardiogram was performed, revealing a massive pericardial effusion, measuring largest at 2 cm in depth, with evidence of both right atrial and ventricular collapse (Figure 4).

An urgent pericardiocentesis was performed, under echocardiographic guidance, which revealed turbid-looking aspirate (Figure 5). Urgent microscopic analysis revealed 45 Cells per mm3, majority of which were lymphocytes, and gram stain showed moderate amounts of pus cells with occasional gram positive cocci. Pericardial fluid was negative for acid-fast bacilli.

A repeat transthoracic echocardiogram was performed post-pericardial drain insertion, revealing minimal remnant pericardial fluid, with the pericardial drain in-situ, and no evidence of any mass or vegetation. Unfortunately, a transoesophageal echocardiography and Computed Tomography (CT) imaging of the mediastinum (to rule out mediastinitis and pneumonitis) was not performed, as management of the NSTI took precedence.

The patient was started on intravenous antibiotics, both tazobactom-pipericillin and clindamycin. There was a delay in performing limb saving wound debridement as the patient was reluctant for invasive management, but had later consented to the procedure which was performed only on day 3 of admission. Tissue cultures were taken peri-operatively. Unfortunately, the patient deteriorated post-operatively due to extensive blood loss and overwhelming septicaemia and succumbed to his illness 72 hours after. Subsequently, it was revealed that cultures from blood, pericardial aspirate and tissue aspirate were positive for GBS infection.

Discussion

GBS is a common microorganism, often colonising the gastrointestinal and reproductive tract 3. Rarely, GBS colonises the skin and can cause necrotising fasciitis, i.e. necrotising soft tissue infection (NSTI), with only 22 cases having been reported in the past ii. Majority of these patients are either immunocompromised or have other predisposing factors including recent thoracic intervention or trauma 4, 5.

GBS-related infections of cardiac structures are rare, as a whole, with 2 to 3% of cases presenting as native valve endocarditis and far less as pericarditis, mycotic aneurysms and intraventricular abscesses 3. Parikh et al reviewed the types of microorganisms isolated from purulent pericarditis samples and revealed that only 5% were due to streptococcal organism, sans Streptococcus Pneumoniae, possibly less so due to GBS 6. Our literature search revealed only one case of GBS-related purulent pericarditis reported although the case was not linked in any way to a NSTI to our knowledge 7.

Our case was unique as, at the time of writing, there were no other reports of GBS-related lower limb NSTI in combination with mediastinal involvement. There have been only a handful of cases of necrotising fasciitis reported with mediastinal involvement, the majority of which were supra-diaphragmatic with only one reporting NSTI of the lower limb due to Aspergillus infection 8 9.

The similarity in culture results obtained from blood, tissue aspirate and the pericardial fluid in our patient suggest dissemination of GBS from the NSTI, possibly via a haematogenous route, although bacterial-related pericardial dissemination can also occur via direct spread from infected foci from neighbouring intra-thoracic structures or sub-diaphragmatic 4. The possibility of multi-routed spread should remind clinicians that, albeit rare, mediastinal involvement in NSTI is a possible complication of such disease.

Conclusion

This case highlights the rare possibility of cardiac involvement in cases of NSTI, and the possibility of cardiac tamponade causing cardiogenic shock masquerading alongside septic shock. It also highlights the importance of combining clinical findings with ancillary testing, including bedside echocardiography, when faced with challenging cases of sepsis to help look for possible foci of infection.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RAJA EZMAN FARIDZ RAJA SHARIFF (MBCHB, MRCP), Universiti Teknologi Mara, Sungai Buloh, Malaysia. RIZMY NAJME KHIR (MBBCH, MRCP), Universiti Teknologi Mara, Sungai Buloh, Malaysia. SAZZLI KASIM (MBBCh, BAO, BMedSc, MRCPI, CSCST, FNHAM), Universiti Teknologi Mara, Sungai Buloh, Malaysia.
Corresponding Author Details: 
RAJA EZMAN FARIDZ RAJA SHARIFF, Universiti Teknologi Mara Sungai Buloh Campus, Jalan Hospital, Sungai Buloh, 47000, Selangor, Malaysia.
Corresponding Author Email: 
rajaezman@gmail.com
References
References: 
  1. Bonne SL & Kadri SS. Evaluation and Management of Necrotizing Soft Tissue Infections. Infect Dis Clin N Am. 2017. 31: 497–511
  2. Fukuda K, Ryujina M, Sakiod R, Satoshi S, Takanori F, et al. Bilateral Necrotizing Fasciitis of the Foot Associated with Group B Streptococcus. Case Rep Dermatol. 2016. 8:243–249
  3. Hirai N, Kasahara K, Uno K, Ogawa Y & Ogawa T. Infective Endocarditis Complicated by Intraventricular Abscesses, Pericarditis, and Mycotic Aneurysm Due to an Emerging Strain of Serotype VI Streptococcus agalactiae. Jpn. J. Infect. Dis. 2017. 70: 685–686
  4. Imaziao M, Brcatob A, DeRosac FG, Lestuzzid C, Bombanab E, et al. Aetiological diagnosis in acute and recurrent pericarditis: when and how. J Cardiovasc Med. 2009. 10: 217–230
  5. Wong CH, Kurup A & Tan KC. Group B Streptococcus necrotizing fasciitis: an emerging disease? Eur J Clin Microbiol Infect Dis. 2004. 23 (7): 573-5
  6. Parikh SV, Memon N, Echols M, Shah J, McGuire DK & Keely EC. Purulent Pericarditis Report of 2 Cases and Review of the Literature. Medicine. 2009. 88: 52-65
  7. Karim MA, Bach RG, Dressler F, Caracciolo E, Donohue T & Kern MJ. Purulent pericarditis caused by group B streptococcus with pericardial tamponade. AMHEARTJ. 1993. 126: 727-730
  8. Sergi C, Weitz J, Hofmann WJ, Sinn P, Eckart A, et al. Aspergillus endocarditis, myocarditis and pericarditis complicating necrotizing fasciitis. Case report and subject review. Virchows Arch. 1996. 429: 177-180
  9. Lalwani AK & Kaplan MJ. Mediastinal and Thoracic Complications of Necrotzing Fasciitis of the Head and Neck. Head & Neck. 1991. 13: 531-539

Arrhythmogenic Right Ventricular Dysplasia Diagnosed Through Characterization of Cardiac Tissue in a Deceased Sibling: A Case Report

Authors
Raja Ezman Faridz Raja Shariff, Rizmy Najme Khir & Sazzli Kasim
Article Citation and PDF Link
BJMP 2018;11(2):a1117
Abstract / Summary
Abstract: 

Introduction: Arrhythmogenic Right Ventricular Dysplasia (ARVD) is a rare cause of cardiomyopathy and sudden cardiac death. Often times, diagnosis relies on electrocardiography findings and magnetic resonance imaging of cardiac tissue, when available. Rarely, diagnosis is confirmed via histological evidence from an affected sibling.

Case Report: We present a rare case of ARVD diagnosed via characterization of cardiac tissue of an affected, deceased sibling. A 21-year old gentleman presented to the emergency department following an episode of loss of consciousness. Chest radiography revealed cardiomegaly and electrocardiogram (ECG) revealed deep T-wave inversions in leads V2 to V4, with ventricular ectopic beats. Troponin-I levels were elevated at 480 pg/ml. It was revealed that the patient had a sibling who had died from an unknown cause, 5 years prior. His younger brother, 14 years of age at the time, had collapsed whilst playing basketball in a school compound. Unfortunately, he was pronounced dead on arrival to a medical facility. Autopsy findings revealed epicardial surfaces infiltrated with excessive fat tissue and with nodular fibrosis with cut sections showing diffuse transmural fibrofatty replacement of the right ventricular free wall extending to the endocardium involving right ventricular septum. This knowledge led to our patient having a cardiac MR performed, confirming a diagnosis of ARVD.

Conclusion: The case highlights how having knowledge and confirmation of the inherited condition led to a quicker and more confident decision in managing a patient at high risk of SCD, as our patient was able to obtain an implantable cardiac defibrillator without much hesitation.

Abbreviations: 
ARVD: Arrhythromogenic Right Ventricular Dysplasia ECG: Electrocardiogram MRI: Magnetic Resonance Imaging ICD: Implantable Cardiac Defibrillator
Keywords: 
Case Report, Arrhythmogenic Right Ventricular Dysplasia, Arrhythmogenic Right Ventricular Cardiomyopathy, Cardiomyopathy, Heart Failure

Background

Arrhythmogenic Right Ventricular Dysplasia (ARVD) was first described in a case series of 24 patients back in 1982 1, 2. Since then, our understanding of its pathophysiology has improved dramatically, with dedicated guidelines and literature being published to help with both diagnosis and management. Prompt diagnosis remains a struggle in majority of developing countries, including Malaysia, where resources and expertise are scarce, and obtaining both cardiac magnetic resonance imaging or endomyocardial biopsies remain a challenge. Furthermore, diagnosis is difficult in most cases as clinical presentation may vary and wide range of clinical mimics exist. We present a unique case of ARVD, diagnosed early through the knowledge of having a deceased sibling, whom had endomyocardial tissue characterization performed in the past confirming the presence of the disease in a first degree relative.

Case Report

A 21-year old gentleman presented to the emergency department following an episode of loss of consciousness, lasting approximately 30 minutes which recovered spontaneously. He denies having any similar episodes in the past. However, he had been suffering from reduced exercise tolerance, with a New York Heart Association (NYHA) Class II, over the past 1 year. He had no known medical illness at the time but smoked 6 cigarettes a day for the past 7 years.

His vital signs were stable on arrival, with a heart rate of 73 beats per minute, regular in rhythm, a blood pressure of 143/84 mmHg, respiratory rate of 19 breaths per minute, temperature of 37 degrees Celcius and oxygen saturation of 98% on room air. Cardio-respiratory examination revealed no murmurs, and normal heart and breath sounds. There were no carotid bruits audible. There was no evidence of any neurological deficits on neurological examination.


Figure 1 – Chest radiography demonstrative cardiomegaly


Figure 2 – Electrocardiogram revealing T-wave inversions in leads V2 to V4 with ventricular ectopic beats

Chest radiography revealed cardiomegaly (Figure 1). Electrocardiogram (ECG) revealed deep T-wave inversions in leads V2 to V4, with ventricular ectopic beats (Figure 2). Due to the suspicious-looking ECG, a serum Troponin-I test was performed, which was elevated at 480 pg/ml. The patient was treated for acute coronary syndrome complicated by cardiac syncope, and was later referred to the medical team for further inpatient management.

However, on further history, it was revealed that the patient had a sibling who had died from an unknown cause, 5 years prior. His younger brother, 14 years of age at the time, was brought in after collapsing whilst playing basketball in a school compound. Unfortunately, he was pronounced dead on arrival to the clinic. A post-mortem was performed due to the unexpected nature of the event. Fortunately, our patient was brought into the same hospital as his sibling, allowing us to trace previous autopsy reports and images, with consent.

Macroscopic examination of the right ventricular cavity revealed epicardial surfaces showing infiltration of excessive fat tissue with nodular fibrosis. The right ventricular cavity appeared dilated and cut sections showed diffuse transmural fibro-fatty replacement of the right ventricular free wall, extending into the endocardium and involving the right ventricular septum (Figure 3a).


Figure 3a – Macroscopic examination of right ventricular cavity, which was dilated and showing signs of transmural fibrofatty infiltration. Figure 3b – Histological evidence of focal lymphocytic infiltration, myocyte hypertrophy and degenerative cytoplasmic changes.

Histology revealed extensive fatty infiltration with interstitial fibrosis, primarily in the epicardium. There was associated myocyte loss with hypertrophy of cardiac muscle cells remaining (Figure 3b). Both macroscopic and microscopic findings were suggestive of ARVD.

After learning of the autopsy results, changes in clinical management took place, with priorities being shifted towards obtaining an echocardiogram, cardiac Magnetic Resonance Imaging (MRI) and Holter recording, as opposed to diagnostic angiography and coronary evaluation. Echocardiography revealed an ejection fraction of 25 to 30%, with evidence of left ventricular dyssynchrony, a tethered posterior mitral valve leaflet with mild eccentric regurgitation, consistent with dilated cardiomyopathy.

Cardiac MRI revealed both left and right ventricular dilatation, end diastolic dimensions being 5.8 cm and 4.4 cm and end-diastolic volume being 153 ml/m2 and 149 ml/m2 respectively, with evidence of bi-ventricular dyssynchrony. Left ventricular and right ventricular ejection fraction measured 31% and 8% respectively. There was also bilateral atrial dilatation. Gadolinium study revealed late enhancement in areas of the right ventricular wall (Figure 4).


Figure 4 – Four-chamber view of cardiac magnetic resonance imaging revealing evidence of right ventricular enhancement following gadolinium study.

A 24-hours Holter recording revealed up to significant ventricular ectopic burden, many of which were bigeminy and trigeminy in nature. In view of symptoms and the above investigative findings, the patient consented to insertion of an implantable cardiac defibrillator (ICD) 4 weeks later in our centre, and has since recovered well with regular monitoring.

Discussion

ARVD is rare, prevalence ranging between 1 in 2000 to 1 in 5000 (taking into consideration geographical variations) and accounts for 5% of deaths in young adults and 25% of deaths in athletes 3, 4. Typical histopathological feature of ARVD is the loss of right ventricular myocardium, replaced heavily by fibro-fatty tissue. Less commonly, left ventricle involvement have been reported 5, 6. Consequence from such pathological process leads to arrhythmias, heart failure and more importantly sudden cardiac death (SCD), with mortality rate ranging between 4 to 20% and peaking in the fourth decade, equally in both males and females 5.

Diagnosis is difficult in most cases as clinical presentation may vary and wide range of clinical mimic exist, including myocarditis, sarcoidosis, Brugada syndrome, idiopathic RV outflow tract VT and congenital heart diseases with right chambers overload amongst others 6. A Diagnostic Criteria was developed in 1994, with further modification in 2010 to assist in the diagnosis of ARVD and although the criterion has been shown to be specific, it lacks sensitivity 7. Nevertheless, it highlights several key areas, a mix of clinical, radiological, histological and electrophysiological features, that assist in diagnosis 4.

Despite not having any further evaluation or investigations performed at the time of presentation, in view of circumstances, our patient’s deceased sibling had supportive histological features. Therefore, our patient met the major criteria of having a first degree relative affected by the disease. More importantly, the suspicious family history had prompted further evaluation for the disease, allowing the medical team to prioritize investigations performed, specifically the Cardiac MRI and Holter evaluation. This led to early risk stratification and decision to implant an ICD for the patient, as he was deemed at high risk of SCD.

Conclusion

This case highlights the importance of good history taking, including a detailed family history of SCD or cardiac-related diseases, especially in young patients presenting with typical cardiac-related symptoms. Early identification and appreciation of risk will subsequently affect the outcomes of such patients affected by ARVD. Furthermore, important diagnosis like ARVD will have implications to relatives and future off-springs, further highlighting the need for detailed evaluation of patients similar to ours described in the above case report.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
RAJA EZMAN FARIDZ RAJA SHARIFF (MBCHB, MRCP), Universiti Teknologi Mara, Sungai Buloh, Malaysia. RIZMY NAJME KHIR (MBBCH, MRCP), Universiti Teknologi Mara, Sungai Buloh, Malaysia. SAZZLI KASIM (MBBCh, BAO, BMedSc, MRCPI, CSCST, FNHAM), Universiti Teknologi Mara, Sungai Buloh, Malaysia.
Corresponding Author Details: 
RAJA EZMAN FARIDZ RAJA SHARIFF, Universiti Teknologi Mara Sungai Buloh Campus, Jalan Hospital, Sungai Buloh, 47000, Selangor, Malaysia.
Corresponding Author Email: 
rajaezman@gmail.com
References
References: 
  1. Marcus FI, Fontaine GH, Guiraudon G, et al. Right Ventricular Dysplasia: A Report of 24 Adult Cases. Circulation. 1982; 65:384–98.
  2. Sosman MC. ‘Illustrative Echocardiographic Cases’ in The Disorders of Cardiac Rhythm. Ed: Schamroth L. Blackwell. Oxford and Edinburgh. 1971; 335.
  3. Basso C, Pilichou K, Bauce B, et al. Diagnostic Criteria, Genetics, and Molecular Basis of Arrhythmogenic Cardiomyopathy. Heart Failure Clin. 2018; 14:201–213.
  4. Rao U, Agarwal S & Gilbert TJ. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Case Report and Review of Literature. Heart Asia. 2014; 6:145–149.
  5. Hoorntje ET, Rijdt WP, James CA, et al. Arrhythmogenic Cardiomyopathy: Pathology, Genetics, and Concepts in Pathogenesis. Cardiovascular Research. 2017; 113:1521–1531.
  6. Corrado D, Link MS & Calkins H. Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med. 2017; 376:61-72.
  7. Wang W, James CA, & Calkins H. Diagnostic and Therapeutic Strategies for Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy Patient. Europace. 2018; 0:1–13.

Are The Risk Scales a Useful Tool In Hospital Services?

Authors
Harold Ibagon, Patrick Tarquino & Juan S. Barajas-Gamboa
Article Citation and PDF Link
BJMP 2018;11(2):a1111
Abstract / Summary
Abstract: 

In the last decade, clinicians and practitioners have developed risk scales to improve clinical outcomes in patients during the hospital stay. Reduction of complications and mortality rates are priorities in any healthcare institution. In this manuscript, we propose the use of risk scales and highlight the benefits to daily clinical practice.

Keywords: 
Clinical Care, risk scales, patient, healthcare, mortality and complications

Physicians pursue the interest that during the hospital stay the best patient care needs to be provided; and achieving that in a short time - as a result the patient is expected to recover from illness and return to normal life.

The ability to prevent possible complications that the patients are exposed to, has always generated ambiguity in the current medical practice, since it is assumed, that the relief of the patients once the treatment is established, should always be the same1. However, it is the awareness and proper care of comorbidities and the baseline condition of the patients that determine the success rate of the treatment, without requiring additional interventions beyond the ones proposed at the beginning of the treatment 2, 3.

This important factor has generated in practitioners the need to be able to monitor the clinical evolution of the patients. Laboratory tests are an important basis of medical diagnosis, and are frequently used to monitor the clinical progress of the hospitalised patient. The patient clinical state sometimes changes suddenly or continuously; requiring the surveillance of the basic variables such as vital signs. Vital signs monitoring activate a warning signal for the immediate reassessment of the patient and reorient the medical decisions at any moment during the hospitalisation, with the goal of avoiding further deterioration or adequately treating any new disease state that the patient may develop 3, 4.

From that point of view and long time ago the medical community has observed the need to generate a code that could be universal and that could be used as an early warning of the patient worsening. As a result of this situation, in different countries around the world, researchers and clinicians have developed scales, scores, algorithms and others tools to identify early patients in risks to be in critical conditions. Those tools are based on the ability of easy data collection and simple clinical interpretations allowing the clinical personnel to make objective and early assessment of the overall clinical state of the patients 4.

These scales or scores are not ideal, since there is no perfect scale, and all have statistical weaknesses either in their sensitivity or specificity. The clinical judgment and the physician experience, added to a score from any of these scales, may guide the path to follow according to the particular scenario to treat the patient illness 5.

Selecting the ideal scale to be adopted is one of the controversial topics in which a practitioners and institutions can be involved in. Occasionally other services in the hospital such as clinical laboratory and clinical imaging values play an important role in the process of diagnosis of the disease and are counted in the risk scales making easier to have good standard of care. Scientific studies assess the statistical performance of these scales yield controversial results that sometimes distort or endorse these results 5. This is why the decision of the ideal scale is based first on the target population that physicians in charge will care of and select the appropriate scale or score that will be applied, to know the implications of the most representative age group of patients that will be attended and to use scales which data acquisition be a simple and quick task to perform6.

Based on that, the Royal College of Physicians of the United Kingdom headed by Bryan Williams and collaborators, and many other researchers worldwide have analysed a significant number of scales on the basis that the scale should use systems (track and trigger warning systems protocol) divided into three types. Single parameter systems, multi-parameter systems, total weighted scoring systems and combined systems 6.

The researchers came to the conclusion that the performance of these scales was better than those that conserve the third type of system, since not only the parameters are categorized but also those who develop the scale proposed management to be carried out in an easy, orderly scheme and logical within a framework of independent work or in addition to more robust strategies that involve management schemes within a hospital institutions - the so-called (Rapid Response Systems RRS) 7.

For Williams et al, the MEWS changed its name after being accepted by the Royal College of Physicians of the United Kingdom as the NEWS scale with its variables defined as (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, consciousness or new confusion and temperature). This score has been recognized and quickly adopted worldwide. The NEWS has an immediate applicability as a parameter of high sensitivity in the detection of clinical deterioration, despite its known low specificity. Thus inviting the attending physician to approach and reassess the state of the patient. The score makes changes in medical decisions according to the new conditions found during the patient’s assessment7.

This kind of scales must be endorsed internationally and be easily replicable by all practitioners who wish to adopt them. This allows other physicians to obtain results when implementing actions, reaching better clinical outcomes similar to clinical studies previously published. In the daily practice and clinical application we find different scenarios to use the scales, where the main problem of its application represent extra costs in lab test or clinical images and the time invested by the practitioners and medical personnel 7.

For this reason, the scales for clinical assessment should be easy and flexible to be implemented by any person, ideally for any member of the healthcare team to avoid barriers during the process of data acquisition. From this perspective, the scales that are based on easily collected parameters are the most appropriate, but they are often the scales that suffer the rigors of the biases when they are undervalued or overvalued, just the operability can be affected by personnel knowledge and skill.

The interesting thing about this exercise is to see that the people who have the most continuous contact with the patient, such as the nursing staff, physicians with the practice have the ability to use them in their practice and this would make the scales a valuable resource to perform clinical assessments and achieve the goal proposed.

In this new era where the reincorporation of a patient into daily life in a short time is ideal scenario, the medical and nurse staffs and also service providers seek to alleviate the patient's health breakdown. It is here from the hospital point of view where the proper care not only in the quality of care but also in the prevention of complications plays an important role in the applicability of these early detection scales. This is an invitation to success from its inception and to tend to patients being hospitalized for the minimum time required.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
HAROLD IBAGON, Department of Medicine, Clinica Colsanitas SA, Fundacion Universitaria Sanitas, Bogotá DC, Colombia. PATRICK TARQUINO, Department of Medicine, Clinica Colsanitas SA, Fundacion Universitaria Sanitas, Bogotá DC, Colombia. JUAN S. BARAJAS-GAMBOA,, Department of Medicine, Clinica Colsanitas SA, Fundacion Universitaria Sanitas, Bogotá DC, Colombia.
Corresponding Author Details: 
Harold Ibagon MD, Department of Medicine, Clinica Colsanitas SA, Fundacion Universitaria Sanitas, Bogotá DC, Colombia.
Corresponding Author Email: 
haibagon@colsanitas.com
References
References: 
  1. Bartkowiak B, Snyder AM, Benjamin A,et al. Validating the Electronic Cardiac Arrest Risk Triage (eCART) Score for Risk Stratification of Surgical Inpatients in the Postoperative Setting: Retrospective Cohort Study. Ann Surg. 2018 Jan 12. doi: 10.1097/SLA.0000000000002665. [Epub ahead of print]
  2. Faisal M, Scally A, Elgaali MA, et al. The National Early Warning Score and its subcomponents recorded within ±24 h of emergency medical admission are poor predictors of hospital-acquired acute kidney injury. Clin Med (Lond). 2018 Feb; 18(1):47-53. doi: 10.7861/clinmedicine.18-1-47.
  3. Churpek MM, Yuen TC, Edelson DP. Risk stratification of hospitalized patients on the wards. Chest. 2013 Jun; 143(6): 1758-1765. doi: 10.1378/chest.12-1605.
  4. Goulden R, Hoyle MC, Monis J, Railton D, et al. qSOFA, SIRS and NEWS for predicting inhospital mortality and ICU admission in emergency admissions treated as sepsis. Emerg Med J. 2018 Feb 21. pii: emermed-2017-207120. doi: 10.1136/emermed-2017-207120. [Epub ahead of print]
  5. Green M, Lander H, Snyder A, et al Comparison of the Between the Flags calling criteria to the MEWS, NEWS and the electronic Cardiac Arrest Risk Triage (eCART) score for the identification of deteriorating ward patients. Resuscitation. 2018 Feb; 123:86-91. doi: 10.1016/j.resuscitation.2017.10.028. Epub 2017 Nov 21.
  6. National Clinical Efectiveness Committee, Department of Health “An Roinn Slainte”, Royal College of Physicians and the Royal College of Surgeons in Ireland. National Early Warning Score. February 2013.
  7. National Early Warnig Score (NEWS) 2. Standardising the Assessment of Acute-illness severity in the NHS. Royal College of Physicians. December 2017.

Adult Onset Still's Disease: A Case Report

Authors
Yasmeen Ajaz, Ravinder Bhatt, Rabah Elbahnasawy, Asif khan, Ali Ganai & Sameem Matto.
Article Citation and PDF Link
BJMP 2018;11(1):a1107
Abstract / Summary
Abstract: 

Adult Onset Still’s disease (AOSD) is an inflammatory disorder characterized by quotidian (daily) fevers, arthritis, and an evanescent rash. It is a rare inflammatory disorder of unknown etiology. Due to lack of definitive diagnostic test, the diagnosis of AOSD can only be made after exclusion of other causes. We report a 46 year old male Indian patient who was admitted in our hospital with intermittent high grade fever, rash and polyarthritis for one month. History, examination and laboratory investigations fulfilled the Yamaguchi criteria for AOSD. The patient was treated with steroids and nonsteriodal anti-inflammatory drugs to which he responded and is completely free of symptoms. The authors here present a case of adult onset Still’s disease, and highlights the utility of high serum ferritin in identifying this febrile exanthema.

Abbreviations: 
AOSD -Adult Onset Still’s disease; AFB -Acid fast bacilli; CMV - Cytomegalovirus; EBV- Epistein bar virus; HIV -Human immunodeficiency virus; LDH- lactate dehydrogenase; WBC: White blood cell; ANA: Antinuclear antibody; RF: Rheumatoid factor; PMN: Polymorphonuclea; TNF -Tumor necrosis factoralpha .
Keywords: 
Adult onset Stills disease, skin rash, fever, polyarthritis.

INTRODUCTION

Adult Still’s disease (AOSD) is an inflammatory disorder of unknown etiology characterized by quotidian (daily) fevers, arthritis, and an evanescent rash and multi-organ involvement [1].First described in children by George Still in 1896, subsequently in 1971 Bywaters described 14 patients with similar presentation [2]. The clinical course of adult Still’s disease (AOSD) can be divided into three main patterns: monophasic (or monocyclic), intermittent, and chronic. Patients with monophasic AOSD have a disease course that typically lasts only weeks to months, completely resolving within less than a year in most patients [3]. Systemic features, including fever, rash, serositis, and hepatosplenomegaly, predominate in this group. The patient we diagnosed as AOSD, with monophasic course, went into remission after proper treatment and is symptom free even after stopping the treatment.

CASE REPORT

46 year old Indian male, non-smoker, married, nondiabetic, normotensive admitted at department of internal medicine in our hospital with history of high grade fever, polyarthritis, and skin rash for the last 4 weeks. The fever was high grade, with maximum temperature reaching 39.2°C. The patient also complained of joint pains involving the knee, ankle, wrist and proximal interphalangeal joints. There was no history of oral ulcers, morning stiffness, ocular symptoms, or contact with infected persons. In the hospital, during the febrile period, he developed macular rash mainly on chest and back [Figure 1]. On examination, the patient was sick looking, febrile-39.2°C. Chest on auscultation was normal, cardiovascular examination was unremarkable. Examination of abdomen revealed mild spleenomegaly. Neurological examination was unremarkable. Investigations revealed hemoglobin 12.7g/dl, erythrocyte sedimentation rate (ESR) 120 mm in 1st hour. Total leukocyte count-12.7 x10 9/L. Liver function showed elevated liver enzymes with Aspartate transaminase-125U/L, Alaninie aminotransferase 60 U/L, low albumin 2.3gms/dl. He was worked on lines of pyrexia of unknown origin and his blood, urine and sputum culture showed no growth. Procalcitonin level was less than 0.5ng/ml. Sputum for AFB was negative for three samples; qunatiferon gold test for tuberculosis was negative. IgM CMV, EBV, HIV, hepatitis B and C were negative malarial parasite, Widal and Brucella serology was negative. CT-chest and abdomen were normal, except for mild spleenomegaly. Echocardiogram was normal. ANA, rheumatoid factor was negative. Lactate dehydrogenase (LDH) 978 U/L, His CRP showed a progressive increase from 82mg/L to 284 mg/L, which decreased after starting steroids. His ferritin levels were 40, 000 (normal range 21.8 -274.6 ng/ml), which were reconfirmed by second sample and he had normal transferrin saturation. On the basis of his history, clinical examination and review of his laboratory investigations, diagnosis of AOSD was made. We started him on prednisolone 60 mgs daily along with Diclofenac potassium 50 mg twice daily, to which he responded and become afebrile. He was discharged with a tapering dose of steroids 5mgs weekly. He is doing well and is completely symptom free.

Figure 1: Skin Rash on the back

DISCUSSION

First described in children by George Still in 1896, “Still’s disease” has become the eponymous term for systemic juvenile idiopathic arthritis [4]. In 1971, the term “adult Still’s disease” was used to describe a series of adult patients who had features similar to the children with systemic juvenile idiopathic arthritis and did not fulfill criteria for classic rheumatoid arthritis.

The etiology of adult Still’s disease (ASD) is unknown; both genetic factors and a variety of infectious triggers have been suggested as important, but there has been no proof of an infectious etiology, and the evidence supporting a role for genetic factors has been mixed. It is uncertain whether all patients with AOSD share the same etiopathogenic factors. Proposed pathogens have included numerous viruses; suspected bacterial pathogens include Yersinia enterocolitica and Mycoplasma pneumoniae [5]. As an example of studies of the immunogenetics of ASD, in a series of 62 French patients, human leukocyte antigen (HLA)-B17, -B18, -B35, and -DR2 were associated with AOSD. However, other studies have not confirmed these findings [6].

Adult Still’s disease is very uncommon. Prevalence of AOSD is estimated to be 1.5 cases per 100, 000-1, 000, 000 people, with an equal distribution between the sexes [6]. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second between the ages of 36 and 46. The diagnosis of AOSD is possible only by recognizing the striking constellations of clinical and laboratory abnormalities. It is also to be to remember that AOSD is a diagnosis of exclusion. AOSD has been associated with markedly elevated serum ferritin concentrations in as much as 70 percent of patients. Serum ferritin values above 3000 ng/mL in a patient with compatible symptoms should lead to suspicion of AOSD in the absence of a bacterial or viral infection. Abnormally high serum ferritin values were reported in some case reports and it was suggested that high ferritin levels may be a diagnostic marker of Still's disease [7]. Our patient showed almost all features as laid down in Yamaguchi criteria[Table 1] for the diagnosis of AOSD [8] along with a markedly high ferritin levels.

Table 1 : Diagnostic criteria for AOSD (Yamaguchi)8

Major criteria Minor criteria
Fever > 39ºC, > 1 week Sore throat
Arthralgia/ arthritis > 2 weeks or splenomegaly Lymphadenopathy
Typical rash Abnormal LFT
WBC > 10, 000 with > 80% PMNs and RF Negative ANA

Exclusions: Infections, malignancy, rheumatological diseases. Five criteria with at least two major criteria. ASOD: Adult onset still’s disease. WBC: White blood cell, ANA: Antinuclear antibody, RF: Rheumatoid factor, PMN: Polymorphonuclea

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen or naproxen, help to reduce inflammation [9]. Patients with high-fever spikes, severe joint glucocorticoids, such as prednisone (0.5- 1mg/kg/day)Methotrexate has been used successfully in a small series of people to treat adult Still's disease [10]. Some patients are refractory to these conventional therapies. Tumor necrosis factoralpha (TNF) blockers include infliximab, adalimumab, etanercept, anti-interleukin-1, antiinterleukin-6 agents, and most recently anti CD20-expressing B-cell antibodies are also effective in some cases. Other experimental drugs, including cyclosporine and anakinra, have also been successful in small groups of people [9]. Interleukin 6 inhibitors like tocilzumab showed a good result in patients with AOSD resistant to other immunosuppressive agents such as methotrexate, TNF inhibitors and anakinara [11]. Even with treatment, it's difficult to predict the course of adult Still's disease. Some people might only experience a single episode, while for others adult Still's disease may develop occasional flair up or a chronic condition. About one-third of people with the disorder may fall into each of the above groups.

CONCLUSION

A diagnosis of AOSD should be kept in mind in case of pyrexia of unknown origin particularly in a patient who presents with high-grade intermittent fever, polyarthritis and skin rash of more than two weeks duration. However, the patient should be extensively evaluated to rule out other differentials of AOSD like acute or chronic infections, autoimmune disorders, vasculitis and malignant disorders. Serum ferritin values can be powerful adjuncts in making the diagnosis of AOSD [12], where they are usually higher than other inflammatory diseases. Indeed, extreme elevation of serum ferritin up to 75, 500ng/ mL has been reported in AOSD[12]. Several investigators agree that ferritin levels above l, 000 ng/mL are suggestive of AOSD while levels greater than 4, 000ng/mL are very specific for this diagnosis when accompanied by a compatible clinical picture.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
YASMEEN AJAZ, MD, FACE, Belhoul Speciality Hospital, Internal Medicine , Dubai, United Arab Emirates. RAVINDER BHATT , MD, Belhoul Speciality Hospital, Internal Medicine , Dubai, United Arab Emirates. ASIF KHAN, MRCP, Aster Medical Center, Sharjah, United Arab Emirates. ALI GANAI, MD, Mediclinic Welcare Hospital, Dubai, United Arab Emirates RABAH ELBAHNASAWY, MD, Belhoul Speciality Hospital, Internal Medicine , Dubai, United Arab Emirates. SAMEEM MATTO, MD, FACE, Canadian Specialist Hospital, Dubai, United Arab Emirates.
Corresponding Author Details: 
YASMEEN AJAZ, MD, FACE, Head Dept Of Internal Medicine, Belhoul Speciality Hospital, Internal Medicine , Dubai, United Arab Emirates.
Corresponding Author Email: 
ajazyasmin@yahoo.co.in
References
References: 
  1. Efthimiou P, Paik PK, Bielory L, Diagnosis and management of adult onset still’s disease. Ann Rheum Dis 2006; 65:564- 2. 
  2. Owlia MB, Mehrpoor G. Adult-onset still’s disease: A review. Indian J Med Science 2009; 63:207-21.
  3. Pouchot, J, Sampalis, JS, Beaudet, F, et al. Adult onset Still's disease: Manifestations, disease course and outcome in 62 patients. Medicine (Baltimore) 1991; 70:118.
  4. On a Form of Chronic Joint Disease in Children. Still GF Med Chir Trans. 1897; 80:47-60.9. 
  5. Adult-onset Still's disease: an unusual presentation of rubella infection.Huang SH, DeCoteau WE Can Med Assoc J. 1980; 122(11):1275. 
  6. Adult onset Still's disease and viral infections.Wouters JM, van der Veen J, van de Putte LB, de Rooij DJ Ann Rheum Dis. 1988; 47(9):764
  7.  Pelkonen P, Swanliung K, Siimes M A. Ferritinemia as an indicator of systemic disease activity in children with systemic juvenile rheumatoid arthritis. Acta Paediatr Scand 1986; 75: 64-8). 
  8. Ebrahim RA, Oraibi AKA, Mahdi N, Zaber K, Fareed E: Adult Onset Still's Disease (AOSD) - A Case Report; Bahrain Medical Bulletin, September 2002; 24(3): 1-6. 6.
  9. Franchini S, Dagna L, Salvo F Aiello P, Baldissera E, Sabbadini Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset still’s disease MG Arthritis Rheum. 2010;62 (8):2530. 
  10. Nakahara H, Mima T, Hoshino NY, Matsushita M, Hashimoto J, Nishimoto N; A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years. Japan College of Rheumatology 2008.
  11. Ortiz-Sanjuán F, Blanco R, Calvo-Rio V, Narvaez J , Efficacy of tocilizumab in conventional treatment-refractory adult-onset Still's disease: multicenter retrospective open-label study of thirty-four patients. Arthritis Rheumatol. 2014;66 (6):1659. 
  12. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still's disease. Meijvis SC, Endeman H, Geers AB, ter Borg EJ, Neth J Med. 2007 Jun; 65(6):212-4.

Acanthosis Nigricans in Pre-diabetic states

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

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

 

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

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

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




Figures 1,2,3 - Acanthosis Nigrans

Pathogenesis

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

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

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

Autoimmunity?

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

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

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

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

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

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

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

International studies

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

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

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

Acanthosis nigricans in different conditions

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

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

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

Table 1. Different types of acanthosis nigricans

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

Genetic links

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

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

Type 2 diabetes mellitus and schizophrenia

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

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

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

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

Diagnosis and treatment

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

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

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

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

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

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

Discussion

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

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

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

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Dr James Paul Pandarakalam, Consultant Psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, Warrington WA2 8WN, UK
Corresponding Author Details: 
Dr James Paul Pandarakalam, Consultant Psychiatrist, Northwest Boroughs Health Care NHS Foundation Trust, Hollins Park Hospital & AFG Rehab Hospitals, Winnick Lane, Warrington WA2 8WN, UK
Corresponding Author Email: 
jpandarak@hotmail.co.uk
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It takes all sorts – a curious case of pseudohyperaldosteronism, hypertension and liquorice tea.

Authors
Peter Allan, Michael Newman & Tareq Husein
Article Citation and PDF Link
BJMP 2018;11(1):a1101
Abstract / Summary
Abstract: 

Patient X is usually fit and well, slim 49-year old woman was admitted with a collapse in association with a 3-week history of headache, nausea and paraesthesia of the hands. She was found to be hypertensive, and investigations demonstrated a hypokalaemia, hypophosphataemic metabolic alkalosis. Upon further questioning, she stated she usually consumes 6 liquorice tea infusions per day, and a diagnosis of pseudohyperaldosteronism was made. She underwent intravenous phosphate and potassium replacement as an inpatient, and was initiated on 5mg of Amlodipine with oral potassium supplementation on discharge with a 3-month follow up. She was advised to stop consuming liquorice products. Upon follow up, she was normotensive and normokalaemic, and her Amlodipine and potassium supplementation were subsequently ceased.

Abbreviations: 
Na-Sodium, K-Potassium.

Background

This case highlights a rare and interesting medical condition bought about by liquorice ingestion.  While there have been many previous reports of liquorice toxicity secondary to eating confectionary, I have only found one case report of liquorice toxicity secondary to liquorice tea ingestion and the patient there had only a mild case of hypokalaemia and did not require hospital admission unlike patient X.1

Case presentation

Patient X is a usually fit and well 49-year-old woman who was admitted following a collapse.  Prior to this collapse she had experienced a 3-week history of gradual onset, slowly worsening dull headache and a feeling of tingling in her hands which increased over this timeframe.  On the day of admission, she experienced nausea.  Her past medical history included migraines, for which she self-medicated with paracetamol, ibuprofen and codeine as necessary.  She was also using Cerazette.  She was in full time work, was a lifelong non-smoker and used alcohol very rarely.  She had no family history of note.

On examination, Patient X was a slim individual who was hypertensive with a blood pressure of 170/100 mmHg.  Her other observations were normal.  Her general and neurological examinations were unremarkable.

While initially the medical team felt that Conn’s syndrome was a likely cause of the abnormalities, this was reconsidered on a ward round where, following research on the internet into her abnormalities, patient X brought it to the attention of the team that she had been consuming between six and eight liquorice tea infusions per day for the past two months and had been consuming around three a day for a significant period time prior to this (roughly 18 months).  The diagnosis was made based on her history. 

Investigations

A venous gas demonstrated a metabolic alkalosis with a pH of 7.57.

Blood tests revealed hypokalaemia (K+ = 2.2 mmol/L) and hypophosphataemia (PO4 = 0.35mmol/L).  No other abnormalities were detected. 

More specialist assays were undertaken, and demonstrated that her plasma renin was 2.3 ng/mL/hour (normal range 0.2 – 3.3 ng/mL/hour).  Her morning supine plasma aldosterone level was 29 pg/mL (normal range 30 – 160 pg/mL).  Her morning plasma cortisol level was 612 nmol/L (normal range 138-635 nmol/L).

In addition, the patient also underwent a CT head and a CT renal angiogram, both of which were normal.

DIFFERENTIAL DIAGNOSIS

  • Apparent mineralocorticoid excess
  • Exogenous mineralocorticoid excess
  • Liddle’s syndrome
  • Congenital adrenal hyperplasia
  • Cushing syndrome
  • Liquorice

Treatment

Intravenous potassium and phosphate replacement, cessation of liquorice intake and amlodipine 5mg OD.

Outcome and follow-up 

The patient was discharged with a blood pressure of 132/66 mmHg on amlodipine, a potassium level of 2.9, and a phosphate level of 1.16.  She was given oral potassium supplementation to be taken 3 times per day.  After two weeks, the amlodipine was stopped as she became mildly hypotensive.  Her blood pressure was 120/60 following cessation of amlodipine.  Three months later her plasma potassium level was 4.6 without supplementation.  Mrs X required no follow up although she reports an ongoing feeling of tingling in her hands. 

Discussion

Liquorice is an extract of the roots of the Glycyrrhiza glabra plant and has been used as both a confectionary flavouring agent and a herbal remedy.  It is also commonly used as a laxative, and as a flavouring agent in chewing gums, sweets, and food products.

The active ingredient in liquorice is glycyrrhetinic acid which inhibits the enzyme 11-β-hydroxysteroid dehydrogenase.  This enzyme converts cortisol into inactive cortisone within the distal tubule of the kidney and so in liquorice toxicity there is a build-up of cortisol in distal tubular cells.2  This results in increased mineralocorticoid like activity as there are structural similarities between cortisol and aldosterone, with increased Na+ and water retention in conjunction with increased H+ and K+ excretion.3  Here hyperaldosteronism occurs, but with a low or low-normal plasma aldosterone and renin level.  Serum glycyrrhetinic acid levels can be measured with enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC).   Urinary glycrrhetinic acid levels can be measured with gas chromatography-mass spectrometry (GC-MS).4

Pseudoaldosteronism secondary to liquorice consumption is a relatively rare occurrence.  Case reports demonstrate a range of clinical manifestations from an asymptomatic patient fortuitously diagnosed to those with more severe presentations such as rhabdomyolysis, hypertensive encephalopathy, asthenia, paralysis, heart failure, and cardiac arrhythmias such as polymorphic ventricular tachycardia and ventricular fibrillation secondary to hypokalaemia.  For these reasons, it has been suggested that the public should be made aware of the potential dangers associated with liquorice consumption. 5-13

The combination of alkalosis hypokalaemia and hypertension suggests increased mineralocorticoid activity leading to increased renal tubular Na+ reabsorption along with increased k+ and H+ excretion.  Both primary and secondary hyperaldosteronism cause these abnormalities, the former via an appropriate response (renin release) to decreased renal perfusion pressure or decreased sodium concentration in the ultra filtrate, the latter an inappropriate release of aldosterone from the adrenal cortex, often a result of an adrenal adenoma.

Other genetic syndromes, such as Bartter’s or Gitelman’s, cause hypokalaemia with alkalosis but without hypertension.14

Features of low potassium include generalised weakness and lethargy, ascending paralysis, and rhabdomyolysis.15-17   Decreased intake is rarely a cause of low potassium as the western diet usually contains significantly more potassium than is needed and because the renal tubular reabsorption mechanism can be extremely effective in limiting potassium excretion.17

The maximum recommended dose of liquorice is 100mg/day although cases of liquorice toxicity have been reported in association with doses as low as 80mg/day.  Each liquorice tea bag contains approximately 500mg of glycyrrhetic acid, of which approximately 20mg is ingested per infusion.

This is a relatively rare occurrence and it has been suggested that certain groups are more susceptible to toxicity than others – for example those with 11-β-hydroxysteroid dehydrogenase deficiency.18  It is also thought that those with essential hypertension are also more at risk.19

LEARNING POINTS/TAKE HOME MESSAGES

  • Consumption of liquorice can cause pseudoaldosteronism.
  • The clinical picture is similar to that of primary aldosteronism, but is characterised by low levels of both aldosterone and renin.
  • While liquorice toxicity can be asymptomatic, clinical manifestations are wide ranging and include cardiac arrhythmias, rhabdomyolysis, weakness and paralysis.
  • Pseudohyperaldosteronism caused by liquorice consumption is reversible and generally resolves upon cessation of liquorice consumption.  Prior to resolution, potassium supplements are usually necessary.
Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Dr Paul Johnston, Consultant Nephrologist, Royal Cornwall Hospital.
Competing Interests: 
None declared
Details of Authors: 
PETER ALLAN, MBChB(hons) and M(Biol), Royal Perth Hospital, Australia. MICHAEL NEWMAN, MBChB and MSc AND BSc(Hons), Queen Alexandra Hospital, Portsmouth, Uk. TAREQ HUSEIN, MBBS, Morriston Hospital, Swansea, Uk.
Corresponding Author Details: 
TAREQ HUSEIN, 43 Glan Yr Afon Gardens, Swansea, SA2 9HX.
Corresponding Author Email: 
tareqhusein@yahoo.co.uk
References
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  12. Brusselaers N, Vogelaers D, Blot S.  The rising problem of antimicrobial resistance in the intensive care unit.  Annals of Intensive Care.  2011. p. 47.
  13. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, et al. Licorice abuse: time to send a warning message.  Therapeutic Advances in Endocrinology and Metabolism.  2012.  p. 125–38.
  14. Simon DB, Lifton RP.  The molecular basis of inherited hypokalemic alkalosis: Bartter’s and Gitelman's syndromes.  Am J Physiol.  1996;271:F961–F966.
  15. Cumming AM, Boddy K, Brown JJ, Fraser R, Lever AF, Padfield PL, et al.  Severe hypokalaemia with paralysis induced by small doses of liquorice.  Postgraduate medical journal.  1980.  p. 526–9.
  16. Kishore B, Thurlow V, Kessel B.  Hypokalaemic rhabdomyolysis.  Annals of clinical biochemistry.  2007.  p. 308–11.
  17. Rastegar A, Soleimani M.  Hypokalaemia and hyperkalaemia.  Postgrad Med J. 2001;77:759–64.
  18. Edwards C.  lessons from licorice.  N Engl J Med.  1991;325:1242–3.
  19. Sigurjonsdottir HA, Manhem K, Axelson M, Wallerstedt S.  Subjects with essential hypertension are more sensitive to the inhibition of 11 beta-HSD by liquorice. Journal of human hypertension.  2003 p. 125–31.

Skin and Seizures: Tuberous Sclerosis Complex, A Pictorial Essay.

Authors
Murtaza Rashid, Samir Altalafha & Mohammed Al Mogbil
Article Citation and PDF Link
BJMP 2017;10(1):a1003

A 23 y/o male was brought to our Emergency Department after having a seizure. He was alert and his vital signs were stable. He is known to have epilepsy and is on regular anti-epileptic medication for three years. He is being followed up at a neighborhood medical center at his native village . On physical examination numerous brown papules were seen over his nose and both cheeks in a butterfly pattern which correspond to facial angiofibromas (Figure 1). Ash Leaf Hypomelanotic macules were seen over his extremities (Figure 2). Few hyperpigmented café au lait macules were observed over his trunk (Figure 3). A big fibroma was also seen over his scalp (Figure 4). Areas of thick leathery texture of orange peel known as Shagreen patches were observed on back (Figure 5).

Figure 1: Facial angiofibromas

Figure 2: Ash Leaf spot

Figure 3: Cafe au lait macule

Figure 4: Scalp fibroma

Figure 5: Shagreen patch

A Brain CT scan revealed multiple subependymal giant cell astrocytomas. Laboratory investigations were normal.

This patient was clinically diagnosed as Tuberous Sclerosis Complex having a myriad of skin lesions.1

Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia.2 Seizures are commonly encountered in Emergency Room however, conspicuous lesions as described above must alert the physician to guide the patient for a multidisciplinary approach.3

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MURTAZA RASHID; M.D Medicine; Royal Commission Hospital, Jubail, Saudi Arabia. SAMIR ALTALAFHA; M.D Emergency Medicne, Fellowship Critical Care, Royal Commission Hospital, Jubail, Saudi Arabia. MOHAMMED ALMOGBIL; M.D, FRCPC, Pediatric Emergency Medicine, Royal Commission Hospital, Jubail, Saudi Arabia.
Corresponding Author Details: 
MURTAZA RASHID; M.D.; Department Of Emergency Medicine, Royal Commission Hospital, Jubail Industrial City, 31961, Saudi Arabia
Corresponding Author Email: 
dr.murtazarashid@gmail.com
References
References: 
  1. DiMario FJ Jr, Sahin M, Ebrahimi-Fakhari D. Tuberous   sclerosis complex. Pediatr Clin North Am. 2015  Jun;62(3):633-4.
  2. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015 Jul;14(7):733-45. 
  3. Saxena A, Sampson JR. Epilepsy in Tuberous Sclerosis: Phenotypes, Mechanisms, and Treatments. Semin Neurol. 2015 Jun;35(3):269-76 . 

Combined Botulinum Toxin Injections and Phenol Nerve / Motor Point Blocks to Manage Multifocal Spasticity in Adults

Authors
Fahim Anwar & Shruthikaa Ramanathan
Article Citation and PDF Link
BJMP 2017;10(1):a1002
Abstract / Summary
Abstract: 

Objectives: To highlight the importance of combining phenol and botulinum toxin in the treatment of spasticity in adult patients resulting from upper motor neuron lesion.
Design: A retrospective case series.
Setting: A tertiary care hospital.
Participants: Patients in spasticity clinic
Intervention: 29 patients with spasticity resulting from various neurological conditions underwent combined botulinum toxin and phenol nerve block to manage spasticity.
Results: The most frequently used combination was obturator nerve block with botulinum toxin to hamstring muscles (34.4%). The combination of a posterior tibial nerve block with hamstring botulinum toxins was used in 3 (10.3%) patients. There were no adverse events from both phenol and botulinum toxins.
Conclusions: The combination of botulinum toxin and phenol nerve/motor point blocks allowed many muscles to be injected, during one clinic attendance, to manage spasticity in adults with neurological conditions.

Abbreviations: 
INR - International Normalised Ratio
Keywords: 
Phenol, botulinum toxin, spasticity, nerve blocks, motor point blocks

Introduction

Spasticity was first described by Lance1 in 1980, and according to him it was described as; a motor disorder characterised by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome. Spasticity can be a consequence of many neurological conditions including traumatic brain injury, spinal cord injury, stroke and multiple sclerosis. The annual incidence of spasticity in the lower limb following a stroke, traumatic brain injury and spinal cord injury is estimated to be 30 to 485 per 100,000, 100-235 per 100,000 and 0.2 to 8 per 100,000 respectively2. Spasticity is characterised by muscle overactivity and can lead to permanent changes in the muscle fibres leading to muscle contractures. Contractures can be very painful and may interfere with seating, posture, mobility and activities of daily living, thus increasing the care cost significantly.

Phenol has been used peripherally and intrathecally for the treatment of spasticity for many years. The botulinum toxin became available in the last decade for treatment of spasticity. Its use has increased since then, and this has led to a decline in the use of phenol. It is still being used in patients who are sensitive to botulinum toxins or have developed antibodies to them. Phenol is both neurolytic and anaesthetic in nature3. The anaesthetic effect of phenol can be seen immediately after the injection where the patient reports an immediate effect. The neurolytic effect takes at least two weeks, and therefore patients should be educated not to expect any significant change in the spasticity before two to four weeks. Phenol can also be used in combination with botulinum toxin to treat multifocal spasticity where the maximum dose of botulinum exceeds the recommended safe dose. This allows several groups of muscles to be treated in a single setting3.

The lethal dosage of phenol has been reported to be greater than eight grams4. Phenol in aqueous solution is preferred for peripheral nerve and motor point blocks and is available in 5, 6 and 7% concentration. Injecting botulinum toxins is quite different from performing nerve and motor point blocks. Phenol nerve and motor point blocks take a longer duration of time to perform as compared to botulinum toxins. For motor point blocks, a nerve stimulator with a surface electrode is needed to localise the motor points on the muscles. In the present study, we highlight the importance of management of spasticity in adults with a combination of botulinum toxin and phenol nerve /motor point blocks. A case series of patients who underwent combined phenol and botulinum toxin is presented, describing the diagnosis, number and location of muscles injected, types of phenol nerve and motor point blocks and any complications encountered.

Methods

This is a retrospective study conducted at the Rehabilitation Medicine Department of the University Hospital in Cambridge UK. The study period included from December 2014 to January 2017. The patients were identified from the spasticity clinic database. All patients were assessed in the spasticity clinic, and a plan to inject the botulinum toxin along with phenol nerve block/motor point block agreed with the patient. The patients who decided to have the procedure were appointed to a clinic to perform the agreed injections and blocks. If the patients were on anticoagulants (warfarin, dalteparin or clopidogrel), they were advised to stop the anticoagulation 3 days before the procedure. International Normalised Ratio (INR) was checked before the procedure. The usual dose of anticoagulation was started after the procedure.

Patients were consented and placed on a plinth. Botulinum toxin type A only was used in our study. It was diluted with normal saline, and the muscles were injected either using the surface anatomy or electrical stimulation. Each muscle was either injected at one to two sites, depending on the size of the individual muscle.

Phenol nerve blocks and motor point blocks were performed according to the techniques described by Roy3 and Gaid5. Aqueous phenol 5% (phenol in water) was used for all the procedures. The nerves were identified using a nerve stimulator with a surface electrode using 2mA current (Figure 1). The skin was infiltrated with 1% lignocaine, and the nerve was approached with a stimulator needle. The nerve was then ablated with 5% phenol under stimulation guidance. The dose of the phenol was titrated while the nerve was being stimulated. The motor points were located similarly with the help of a surface electrode and marked before ablation with 1 to 2 ml of 5% phenol. The amount of botulinum toxin and phenol was recorded. All patients were reviewed in 6 weeks’ time for any complications.

Figure 1: Nerve Stimulator with surface electrode

Results

Between December 2014 to January 2017, we treated 29 patients with spasticity caused by different neurological conditions with a combination of aqueous phenol and botulinum toxin injections. There were 15 males and 14 females with an age range of 18 to 80 years and a mean age of 49.3 years. The most common diagnosis was multiple sclerosis followed by stroke (Figure 2). A total of 40 phenol nerve or motor point blocks were performed in 29 patients. Nineteen patients (65.5%) received phenol blocks once, 9 (31%) twice and only 1 patient (3.4%) had the phenol block done three times. Where the phenol blocks were repeated, the mean duration between the phenol injection was 14.1 months (range 6-23 months). The procedure was bilateral in 16 (55.2%) and unilateral in 13 (44.8%). The local anaesthetic (trial block) was performed in 6 (20.6%) patients who were ambulatory before the phenol block.

Figure 2: Frequency of Diagnosis

Obturator nerve block was the most common phenol procedure performed (44.8%), followed by posterior tibial nerve block (37.9%). Two (6.9%) patients had both obturator nerve blocks and posterior tibial nerve blocks, whereas 1(3.4%) patient had hamstring motor point blocks, 1(3.4%) patient had gastrocnemius motor point blocks. One patient (3.4%) had bilateral obturator nerve blocks, posterior tibial nerve blocks and rectus femoris motor point blocks (Figure 3).

Figure 3: Frequency of Phenol Nerve/Motor Point Blocks

Botulinum toxin was also injected into various muscles in all 29 patients. The botulinum was repeated every 4 to 6 months in the same muscles. Botulinum toxins were injected bilaterally in 12 (41.4%) and unilaterally in 17 (63.6%) patients. The most common muscles injected with botulinum toxin were hamstrings (44.8%) followed by finger flexors (13.8%). The frequency of botulinum toxins injections is shown in Figure 4.

Figure 4: Muscles Injected with Botulinum Toxins

The most common combination in our series was obturator nerve block and hamstring botulinum toxin injections (34.4%). The combination of posterior tibial nerve block with hamstring botulinum toxins was used in 3 (10.3%), and 2 (6.8%) patients received posterior tibial nerve block with finger flexor botulinum toxin injections. The combination of phenol and botulinum toxin injection is shown in Table 1. There were no complications noted following both phenol as well as botulinum toxin injections.

Table 1: Combination of Phenol and Botulinum Toxins used

Phenol Nerve/Motor Point Blocks

    Obturator Nerve Block Posterior Tibial Nerve Block Obturator and Posterior Tibial Nerve Block Hamstrings Motor Point Blocks Gastrocnemius Motor Point Blocks Obturator, Posterior Tibial Nerve Block and Rectus Femoris Motor Point Block

Muscles Injected with Botulinum

Hamstrings 10 3 0 0 0 0
Finger Flexors 0 2 1 0 0 0
Finger and Wrist Flexors 0 2 0 1 0 0
Wrist, Finger Flexors and Hamstrings 1 0 1 0 0 0
Elbow and Finger Flexors 0 1 0 0 1 0
Elbow, Wrist and Finger Flexors 0 1 0 0 0 0
Elbow and Wrist Flexors 0 1 0 0 0 0
Wrist Flexors and Knee Extensors 1 0 0 0 0 0
Ankle Planter Flexors 1 0 0 0 0 0
Flexor Digitorum 0 1 0 0 0 0

Discussion

Perineural injection of aqueous phenol (3 to 7%) can reduce spasticity by blocking the nerve signals to the group of muscles supplied by the nerve. Phenol produces an initial local anaesthetic effect which is followed by neurolysis caused by protein coagulation and inflammation6. The neurolysis leaves the nerve with about 25% less function than before but does not disadvantage people with little or no residual function, as a mild progressive denervation can be beneficial in reducing spasticity6. Khalili et al7first described the technique of phenol nerve blocks and also suggested that the re-growth of most axons is seen with preservation of gamma motor neurons. This means that phenol reduces spasticity without reducing the strength of the muscle significantly.

The use of combining phenol with botulinum toxins injections has been documented in children with cerebral palsy and central nervous degenerative diseases8. To date, there are no studies in the literature showing the use of combined phenol and botulinum toxins in the treatment of spasticity in adults. The combination of phenol with botulinum toxin helps to treat multifocal spasticity allowing more spastic areas to be treated. The most frequent pattern used in Gooch et al8 study was obturator nerve block and gastrocnemius botulinum toxin injections. In our study, the most common combination was obturator nerve block and hamstring botulinum toxin injections. The possible explanation for this variance is that the majority of our study population suffered from multiple sclerosis and hamstring with hip adductor spasticity is a very common pattern.

The mechanism of action of phenol is different from botulinum toxins. However, the reduction in spasticity with phenol and botulinum toxins is comparable. Manca et al9 compared botulinum toxins and phenol nerve blocks to reduce ankle clonus in spastic paresis and concluded that both patient groups showed significant clonus reduction over time with the phenol group effect greater than the botulinum toxins group. They also suggested that the two drugs have a different mechanism of action with phenol reducing the excitability of the alpha motor neuron. A randomised double-blind trial by Kirazli et10 al compared the effects of botulinum toxins Type A and phenol on post-stroke ankle plantar flexor and invertor spasticity. There was a significant change in Ashworth scores at week 2 and 4 in the group who received botulinum toxins but there was no significant difference between the two groups at week 8 and 1210. Similarly, the decrease in clonus duration (detected by electromyography) was significant in both groups. However, the group that received botulinum toxins showed significant change at week 2 and 4 compared to phenol group. The reason for this may be the delayed onset of action of phenol as compared to botulinum toxins. Burkel et al6 studied the effects of phenol into the peripheral nerves of rats and showed that Wallerian degeneration of the nerves occurs before healing by fibrosis that starts after about 4-6 months following phenol injections. Their study also concluded that following phenol the nerves are left with 25% less function than before and this does not disadvantage the people with little or no residual function6.

There is always a risk of deteriorating the mobility or function due to weakness caused by the phenol nerve block. It is our usual practice to perform a local anaesthetic block (trial block) before injecting the phenol in all ambulatory patients or patients who are using spasticity functionally to their advantage. In our series, 20.6% of patients underwent local anaesthetic block before proceeding to the phenol block. There were no adverse effects noted following the local anaesthetic block, and all six patients chose to have the phenol blocks. A recent study by McCrea et al11 looked at the effects of phenol on position and velocity components of spasticity in addition to strength in post-stroke elbow flexor spasticity. The study concluded that phenol paradoxically improved muscle strength in addition to reducing hypertonia11.

In our series, we used phenol mainly for lower limb muscles and botulinum toxins for both the lower and upper limb muscles. For smaller muscles of the upper limb, it is difficult, but not impossible, to find the motor points. The technique for upper limb phenol blocks has been well described in literature3. However, when combining the botulinum toxins with phenol, we find it useful to prefer the phenol block for the lower limb muscles. Gooch et al8 also injected larger proximal muscles with phenol, and smaller distal and deeper muscles with botulinum toxins. In our series, the maximum dose of botulinum toxins used was 1000 units of Dysport and the maximum dose of phenol used was 20 ml of 5% aqueous phenol.

Conclusion

The combination of botulinum toxin with phenol injections is effective in treating multi-focal spasticity in clinical settings. The advantage of using phenol in combination with botulinum toxins is cost-reduction and the flexibility of managing various muscle groups at the same time. Further studies are needed to evaluate the long-term cost-effectiveness and complications of combining phenol and botulinum toxins, especially after repeated injections.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NONE
Competing Interests: 
None declared
Details of Authors: 
FAHIM ANWAR, MBBS, MRCS, FRCP, FEBPRM, Cambridge University Hospital Nhs Foundation Trust SHRUTHIKAA RAMANATHAN, MBBS, MRCP, Cambridge University Hospital Nhs Foundation Trust
Corresponding Author Details: 
FAHIM ANWAR, Box 248, Addenbrooke's Hospital, Cambridge, United Kingdom
Corresponding Author Email: 
fanwar@nhs.net
References
References: 
  1. Feldman RG, Young RR, Koella WP, Spasticity, disordered motor control. Miani, FL: Symposia Specialist; Chicago; 1980. 485-494p. 
  2. Martin A, Abogunrin S, Kurth H. Epidemiological, humanistic, and economic burden of illness of lower limb spasticity in adults: a systematic review. Neuropsychiatric Disease and Treatment 2014; 23(10):111-22.
  3. Roy C. Phenol Block for Upper Limb Spasticity. ACNR 2012; 12(5): 34-36.
  4. Gracies JM, Elovic E, McGuire J, et al. Traditional pharmacological treatments for spasticity. Part I: Local treatments. Muscle Nerve Suppl. 1997;6:S61–91.
  5. Gaid M. Phenol Nerve Block for the Management of Lower Limb Spasticity. ACNR 2012;12(13):1–3.
  6. Burkel WE, McPhee M. Effect of phenol injection into peripheral nerve of rat: electron microscope studies. Archives of physical medicine and Rehabilitation 1970 ;51(7):391–7.
  7. Khalili AA, Harmel MH, Forster S, Benton JG. Management of Spasticity by Selective Peripheral Nerve Block with Dilute Phenol Solutions in Clinical Rehabilitation. YAPMR. W.B. Saunders Ltd; 1964; 45:513–9.
  8. Gooch JL, Patton CP. Combining botulinum toxin and phenol to manage spasticity in children. Archives of Physical Medicine and Rehabilitation 2004;85(7):1121–4. 
  9. Manca M, Merlo A, Ferraresi G, et al. Botulinum toxin type A versus phenol. A clinical and neurophysiological study in the treatment of ankle clonus. Eur J Phys Rehabil Med 2010;46(1):11–8.
  10. Kirazli Y, On AY, Kismali B, et al. Comparison of Phenol Block and Botulinus Toxin Type A in the Treatment of Spastic Foot after Stroke: A Randomized, Double-Blind Trial. American Journal of Physical Medicine & Rehabilitation 1998;77(6):510.
  11. McCrea PH, Eng JJ, Willms R. Phenol Reduces Hypertonia and Enhances Strength: A Longitudinal Case Study. Neurorehabilitation and Neural Repair 2004;18(2):112–6.

Splenic tuberculosis : Report of two cases and literature review

Authors
Ibrahim Masoodi
Article Citation and PDF Link
BJMP 2017;10(1):a1001
Abstract / Summary
Abstract: 

Tuberculosis is endemic in many developing nations of the world. However, with the epidemic of AIDS, the disease has re-emerged in advanced countries as well. Tuberculosis presenting as pyrexia of unknown origin is well known and can affect any organ in the body. Two patients presented with pyrexia of unknown origin and on evaluation splenic lesions were discovered which proved to be splenic tuberculosis after fine needle aspiration. Both patients were HIV negative. One patient had well controlled diabetes mellitus   while as another patient had no co morbidities at all. Splenic abscesses could be one of the complications of bacterial Endocarditis and in the past splenectomy used to be the treatment of choice. But now CT-guided aspirations and demonstration of AFB have eased out management in these cases. After the demonstration of acid-fast bacilli both patients improved after therapy with antitubercular treatment. Clinical description and literature review is described in this brief report.

Keywords: 
Tuberculosis , HIV , Diabetes mellitus , Fever of unknown origin

Introduction

Isolated splenic tuberculosis is extremely rare, particularly in the immunocompetent persons. Splenic tuberculosis, however, can be part of military tuberculosis in immunocompromised patients. Tuberculosis spleen invariably presents in the form of an abscess. The risk factors for splenic abscess described in the literature are sickle cell disease, hemoglobinopathies, splenic trauma endocarditis or tuberculosis elsewhere in an immunocompetent patient. Although rare cases of splenic tuberculosis in immunocompetent patients have been described in the past. With re-emergence of tuberculosis due to AIDS and use of immunosuppressive medications around the globe, it is very important to bear this rare clinical condition while evaluating pyrexia of unknown origin in a given case.

Case 1

A 54-year-old male vet nary doctor by profession presented with the history of off and on fever of 8 weeks duration. The fever was low grade, intermittent and was associated with weight loss of 4 kilograms. There was no evening rise of temp and no sweating. The patient denied any history of a cough, urinary symptoms or diarrhoea. There was no history of travel or contact with sick people. He had been type II diabetic for last 12 years controlled on oral hypoglycemic agents and had no history of acute or chronic complications. There was no history of tuberculosis in the past or in close contacts . He was non-alcoholic and denied any high-risk behaviour. The clinical examination revealed an average built person who was conscious oriented and had stable vitals. There was no jaundice or lymphadenopathy. Abdominal examination revealed moderate splenomegaly. The liver was not palpable and there was no ascites. Respiratory and cardiovascular systems were normal. During the hospitalisation temp. recorded ranged from 380 C to 390C with no night sweats during his hospital stay. Patient’s evaluation showed haemoglobin levels of 10.5g/dl Leukocyte and platelet counts were normal. ESR was 88mm for the first hour. The tests on kidney and liver functions were normal. An ultrasound abdomen showed the presence of two heterogenic space occupying lesions measuring 3×4cms suggestive of splenic abscesses. An echocardiogram was done to rule out any features of subacute bacterial endocarditis. All the valves of his heart were normal and no feature of endocarditis was noted. The patient had normal ejection fraction and the pericardial cavity was normal too. Blood cultures and urine cultures were found to be sterile. A 24-hour collection of urine showed no evidence of albuminuria and funduscopic examination ruled out retinopathy. Keeping in view splenic abscesses CT guided fine needle aspiration was done and acid-fast bacillus were demonstrated by Zeal-Neilson s stain and the patient was put on antitubercular treatment. The culture of the aspirate a few weeks later turned out to be positive for Mycobacterium tuberculosis. His HIV serology was negative .The patient continued standard four-drug regimen for two months followed by two drug regimen for another seven months. Patients fever settled after two weeks of treatment and followed our clinic till completion of his treatment.

CASE 2

A 24-year-old female student presented with the history of off and on fever of 5 weeks duration. The fever was low grade intermittent and not associated with sweating She also complained of loss of appetite and weight loss of 3 kilogrammes over a period of 2months She denied any history of a cough, urinary symptoms. The patient had no history of contact with sick persons or travel. She had no co morbid illness. On examination she was conscious oriented and had mild pallor, no lymphadenopathy or jaundice was noted. Her respiratory and cardiovascular system was normal. Abdominal examination showed splenomegaly 5cms below the costal margin. Her laboratory data showed haemoglobin levels of 9.8gm/dl WBC count of 4200 and platelets were 1.5×103. ESR was 90mm in the first hour. Blood culture, widal tests and Brucella serology were negative. Tests on liver and kidney functions were normal. An ultrasound abdomen showed the presence of three small space occupying lesions in the spleen.Each was measuring 2×2 cms. Portal vein diameter and spleno-portal axis were normal. CT scan abdomen confirmed splenic abscesses and no abdominal lymphadenopathy was noted. CT guided fine needle aspiration was done which turned out to be positive for AFB and cultures a few weeks later confirmed Mycobacterium tuberculosis. Her transthoracic echocardiography showed normal values and didn’t show any features of vegetations. Her HIV serology was negative. The patient was started on conventional four drugs antitubercular regimen for two months followed by two drug regimen for another seven months. Her fever settled and she had marked improvement in her appetite and her weight increased.

DISCUSSION:

Splenic abscesses presenting as fever of unknown origin is well known. Most of the cases of TB spleen present as fever, vague ache in left hypochondrium or weight loss. Although the frequency of splenic tuberculosis is more common in immunosuppressed patients but splenic abscess due to tuberculosis has been described in immune competent patients as well1. Due to the advent of AIDS epidemic prevalence of tuberculosis has increased globally and more cases are now getting reported. Another scenario leading to increased frequency of this previously rare entity is the widespread use of immunosuppressed therapies for chronic disorders like Rheumatoid arthritis, Crohn's disease Psoriasis etc. The index cases were neither HIV positive nor where on any immunosuppressant medication but developed splenic lesions, reflecting some other hitherto unknown predisposing factor for such lesions. The splenic abscess does occur in the setting of infective endocarditis as infective emboli get lodged in the spleen. Splenic abscess following endocarditis in an 80 year old male presenting with abdominal pain during the course of treatment was reported by Pereira et al2 and in another series3 of 3 patients with bacterial endocarditis, splenic abscess was diagnosed based on CT abdomen with evidence of endocarditis on Echocardiography. In the same series two of the patients underwent splenectomy before valve repair while as splenectomy was performed after the valve repair in the other patient .The echocardiogram in index cases, however, were normal without any evidence of endocarditis. After the diagnosis and initiation of ATT, the index cases became afebrile and splenectomy was thus averted . While one of the cases had well controlled diabetes mellitus but the other patient was euglycemic and had no other known risk factor for splenic tuberculosis as is described in the literature. What lead to splenic tuberculosis in the second case remained unidentified? .There is a well known linkage between diabetes mellitus and TB and as per WHO a bidirectional screening has been recommended. Sri Lankan data4 on 112 patients with TB found that 8 patients with TB already were already known cases of diabetes mellitus and in their study further screening unravelled TB in another 17 patients. It is thought that metabolic adaptation is critical during the pathogenesis of mycobacterium tuberculosis5,6..

In time management of tubercular abscess is very crucial as without treatment patients can have complicated clinical course.Splenic abscess can rarely rupture or lead to fistulous communication with adjacent organs. A gastrosplenic fistula has been reported by Lee et al7 in a 61-year-old male presenting with abdominal discomfort and cough. The authors demonstrated a fistulous tract between the spleen and the stomach on endoscopic examination. The fistulous track healed in their case after completion of anti-tubercular treatment. It is quite possible that delay in diagnosis may be a factor that leads to such complications. The index cases, however, had favourable outcome without any complications and successfully completed anti-tubercular treatment.

The other side of the coin is that complications are even known during the antitubercular treatment as a result of reaction to antitubercular treatment. Spontaneous rupture during treatment leading to splenectomy was reported by et Yea et al8 .Splenic tubercular abscess are known to be associated with miliary tuberculosis or with haematological diseases where leucopenia and thrombocytopenia are profound9.The index cases had normal platelet count and leucocytic count highlighting that there was neither bone marrow suppression nor hypersplenism. The patients with ITP on treatment are also prone to develop Tuberculosis of spleen and conversely, patients with TB spleen can per se develop thrombocytopenia.

The management of splenic abscess used to be splenectomy in the past but with the advent of FNAC splenectomy is avoided . Here a word of caution is that various other lesions in spleen can mimick splenic TB hence it is very important to confirm the disease especially in endemic areas where TB is prevalent. Kunnathuparambil et al10 described melioidosis in a 47 year old male who was treated as case of splenic tuberculosis based on splenic lesions on imaging and fever. The diagnosis of splenic tuberculosis in past was mainly reached after histological examination of surgical specimens but now fine needle aspiration has become the procedure of choice. Spleen being highly vascular organ bleeding is the most feared complication of any intervention but fine needle aspiration has been found to be technically safe and in a retrospective data no significant complication was observed11 .With the advent of non-invasive biomarkers diagnosis of tuberculosis has advanced further and a step further is Quantiferon Gold test which has come up another non-invasive modality in the diagnosis of TB. In various studies12, the sensitivity of this test to the tune of 75% has been demonstrated.

While treating an HIV patient the clinician requires high alert in patients presenting with pain abdomen as the splenic abscess is one of the differentials and it is recommended that initial ultrasound must be carried out to diagnose this condition13. In modern era ,Splenectomy may be offered only to resistant cases otherwise ATT is considered to be the therapy of choice.

To conclude tuberculosis of spleen must be kept in mind while evaluating fever of unknown origin in any patient on immunosuppressant treatment or having HIV and even in immunocompetent patients as well. The Fine needle aspiration is a safe diagnostic modality and treatment with antitubercular medication is rarely unsuccessful.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
IBRAHIM MASOODI; MD, DM(Gastroenterology), FACP; Associate Professor, Taif University, Saudi Arabia
Corresponding Author Details: 
IBRAHIM MASOODI; MD, DM(Gastroenterology), FACP; Associate Professor, College of Medicine, Post Box 888, Taif University, Taif, Saudi Arabia 21974
Corresponding Author Email: 
ibrahimmasoodi@yahoo.co.in
References
References: 
  1. Basa JV, Singh L, Jaoude WA, Sugiyama G. A case of isolated splenic tuberculosis. Int J Surg Case Rep. 2015;8C:117-9.
  2. Pereira L, Machado A, Oliveira J, et al  . Infective Endocarditis Presenting as Acute Renal Failure and Unusual Complications. Intern Med. 2015;54(10):1259-63.
  3. Elasfar A, AlBaradai A, AlHarfi Z, et al . Splenic abscess associated with infective endocarditis; Case series. J Saudi Heart Assoc. 2015 Jul;27(3):210-5.
  4. Rajapakshe W, Isaakidis P, Sagili KD et al . Screening patients with tuberculosis for diabetes mellitus in Ampara, Sri Lanka. Public Health Action. 2015 Jun 21;5(2):150-2.
  5. Garay CD, Dreyfuss JM, Galagan JE. Metabolic modeling predicts metabolite changes in Mycobacterium tuberculosis. BMC Syst Biol. 2015 Sep 16;9:57.
  6. Riccomi A, Palma C. B Cells and Programmed Death-Ligand 2 Signaling Are Required for Maximal Interferon-γ Recall Response by Splenic CD4⁺ Memory T Cells of Mice Vaccinated with Mycobacterium tuberculosis Ag85B. PLoS One. 2015 Sep.17;10(9)
  7. Lee KJ, Yoo JS, Jeon H, et al A Case of Splenic Tuberculosis Forming a Gastro-splenic Fistula. Korean J Gastroenterol.2015 Sep;66(3):168-71
  8. Yeo HJ, Lee SY, Ahn E, et al  Spontaneous Splenic Rupture as a Paradoxical Reaction during Treatment for Splenic Tuberculosis. Tuberc Respir Dis (Seoul). 2013 Nov;75(5):218-21
  9. Dal MS, Dal T, Tekin R Idiopathic thrombocytopenic purpura associated with splenic tuberculosis: case report. Infez Med. 2013 Mar ;21(1):50-5.
  10. Kunnathuparambil SG, Sathar SA, Tank DC Splenic abscess due to chronic melioidosis in a patient previously misdiagnosed as tuberculosis.Ann Gastroenterol. 2013;26(1):77-79.
  11. Gochhait D, Dey P, Rajwanshi A, Role of fine needle aspiration cytology of spleen. APMIS. 2015 Mar;123(3):190-3
  12. Kwon JC, Kim SH, Park SH et al, Clinical characteristics and the usefulness of the QuantiFERON-TB Gold In-Tube test in hematologic patients with hepatic or splenic lesions. Korean J Intern Med. 2013 Mar;28(2):187-96
  13. Tiri B, Saraca LM, Luciano E Splenic tuberculosis in a patient with newly diagnosed advanced HIV infection. IDCases. 2016 Sep 3;6:20-2

 

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
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  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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Multiple ring enhancing lesions in brain: Neurocysticercosis or Tuberculoma? An extremely unusual / uncommon radiological presentation of a common disease: central nervous system tuberculosis

Authors
Manjunath M N, Bhakyalakshmi, Lakshmi, Chaitanya and Sharanya
Article Citation and PDF Link
BJMP 2016;9(1):a907
Abstract / Summary
Abstract: 

Cerebral tuberculomas is a rare and serious form of tuberculosis (TB) due to the haematogenous spread of Mycobacterium Tuberculosis (MT). Symptoms and radiologic features are nonspecific, leading sometimes to misdiagnosis. Multiple ring-enhancing lesions in the brain often raise many questions about the true diagnosis. It can present as tuberculous meningitis with complications such as infractions of cerebral cortex, cranial nerve dysfunction, brain stem being the site of greatest involvement, hydrocephalus, cerebral edema and tuberculoma.  The clinical progression of tuberculous meningitis may be rapid or gradual. Rapid progression is more often seen in young children.  The diagnoses can be difficult early in its course and radiographic studies can aid in diagnosis. Tuberculoma may be confused with Neurocysticercosis radiologically, however various distinguishing features exist.

We present a case of CNS tuberculosis presenting as multiple tuberculomas causing great difficulty to distinguish with other similar radiological lesions.

Abbreviations: 
MT- Mycobacterium Tuberculosis, AFB- Acid fast bacilli, ATT- Anti tubercular therapy, EVD- External ventricular drain
Keywords: 
Tuberculoma, Neurocysticercosis, Gene-Xpert, Ring enhancing lesions

Case Summary

Three and half year old male child presented to PICU, Narayana health BANGALORE, with a short history of fever of 8 days with headache  and  cough for 2 days. At admission the child was febrile, dull looking, haemodynamically stable with no meningeal signs or focal neurological deficit. He was admitted and evaluated for the cause of fever. Same day child developed generalized seizures along with fever, hence a possibility of meningitis or electrolyte imbalance (hyponatremia) kept as child had initial serum sodium of 128meq/l. The cause of hyponatremia was looked into and child managed with antiepileptic drugs and 3% normal saline infusion. The initial sepsis screen was in-conclusive and CSF analysis showed 3 lymphocytes with low glucose and elevated protein levels, hence partially treated meningitis was considered (as h/o admission to a hospital for 3 days prior to admission in our hospital). The antimeningitic dose of IV antibiotics were given.  On day 3 of admission child developed meningeal signs with worsening sensorium, hence  neuro imaging was done (MRI brain) which showed multiple well defined ring enhancing lesion at bilateral central and cerebrallar hemisphere, thalamus, pons with mild perilesional edema. This radiological picture suggested a possibility of nerucysticercosis, however the clinical picture did not match with the same, hence pediatric neurology opinion was taken and simultaneous workup for tuberculosis were started. Child was also started on IV steroid. A strong possibility of CNS toxoplasmosis was kept by neurologist based on radiological picture. The workup for TB was inconclusive (negative mantoux, normal ESR, negative gastric aspirate for AFB) however child was empirically started on category II ATT in view of deteriorating clinical state. Repeat CSF evaluation showed increasing cell counts and similar biochemical picture as before, the sample was also send for Gene-Xpert (DNA amplification study). On day 6 of admission child developed lethargy and drowsiness hence antiedema measures were initiated. Same day he developed tonic posturing with unequal pupil, hypertension and bradycardia indicating raised Intracranial pressure (ICP), for which he was intubated and ventilated and urgent repeat CT head was done which showed increase in ventricular size and hydrocephalus. Immediately EVD was put by neurosurgeons after which there was gradual improvement in child’s condition and he was extubated within 48 hours. The reports showed negative HIV and toxoplasma serology and positive CSF gene study for AFB confirming the diagnosis of CNS tuberculosis, hence ATT and antiedema measures were continued and the EVD was later converted into VP shunt. Child by 2nd week of illness became afebrile with improved sensorium and function.

Fig 1 & 2: MRI showing multiple ring enhancing lesions

Discussion

Tuberculosis remains a leading cause of morbidity and mortality in the developing world. CNS involvement is thought to occur in 2-5% of patients with tuberculosis and up to 15% of those with AIDS related tuberculosis 1,2. Although CNS involvement by tuberculosis is seen in all age groups, there is a predilection for younger patients, with 60-70% of cases occurring in patients younger than 20 years of age 2. Haematogeneous spread from the lungs or gastrointestinal tract is most common, leading to small subpial or subependymal infective foci. These are termed Rich foci and form a reservoir from which intracranial manifestations may arise 3,4. Tuberculomas often present with symptoms and signs of focal neurological deficit without evidence of systemic disease. The radiologic features are also nonspecific and differential diagnosis includes malignant lesions, sarcoidosis, pyogenic abscess, toxoplasmosis and cysticercosis.5,6

Regarding treatment, the Center for Disease Control and Prevention recommends 12 months of treatment for CNS TB when the MT strain is sensitive to all drugs.7 However numerous variables can affect the response of the disease to therapy and it has been suggested that treatment duration should be tailored to the radiological response.8 After 12 months of treatment more than two-thirds of the patients still have contrast enhancing lesions. Although it is not clear if this represents an active lesion or just inflammation, continuing treatment is probably prudent. Total resolution of the tuberculoma is observed when scans demonstrate no enhancing lesions or only an area of calcification.8

In the case described above child had tubercular mengitis, multiple tuberculous, hydrocephalus and raised ICP. Although clinical presentations were suggestive of same, however the radiological picture and initial CSF finding raised suspicion is diagnosis. As tuberculoma and NCC shows many common clinical features, there are few distinguishing features such as the cysticercosis is smaller, less perilesional edema, multiple numbers and less of midline shift as compared to tuberculoma. However in our patient the multiple tuberculi gave a suspicion of NCC. It was only gene expert which confirmed our diagnosis.

Hence clinical cases like Tuberculoma, the radiological findings of which can usually be distinguished from other common illness like Neurocysticercosis or Toxoplasmosis, sometimes pose challenge in terms of radiological diagnosis suggesting the need for detailed evaluation to reach the diagnosis and guide treatment.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
MANJUNATH M N, Junior Consultant, Columbia Asia Hospitals, Bangalore. LAKSHMI.K.N, Registrar, Rainbow Hospital, Bangalore. BHAKYALAKSHMI, Junior Consultant, Columbia Asia Hospitals, Bangalore. CHAITANYA NAIR, Registrar, Narayana Health, Bangalore. SHARANYA R, Registrar.
Corresponding Author Details: 
DR MANJUNATH M N, Junior Consultant, Columbia Asia Hospitals, Bangalore.
Corresponding Author Email: 
drmanju.drmanju@gmail.com
References
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  2. Kornienko VN, Pronin IN. Diagnostic Neuroradiology. Springer Verlag. (2009)            ISBN:3540756523. Read it at Google Books - Find it at Amazon.
  3. Engin G, Acunaş B, Acunaş G et-al. Imaging of extrapulmonary tuberculosis. Radiographics. 20 (2): 471-88. Radiographics (full text) - Pubmed citation
  4. Gupta RK, Lufkin RB. MR imaging and spectroscopy of central nervous system infection. Springer Us. (2001) ISBN:0306465515. Read it at Google Books - Find it at Amazon
  5. S.Sahaiu-Srivastava, B. Jones Brainstem tuberculoma in the immunocompetent: case report and literature review Clinical Neurology and Neurosurgery, 110 (2008), pp. 302–304
  6. G.I. Ogbole, O.S. Bassey, C.A. Okolo, S.O. Ukperi, A.O. Ogunseyinde Testicular tuberculosis presenting with metastatic intracranial tuberculomas: a case report.
  7. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003; 52 .
  8. S.I. Poonnoose, V. Rajshekhar Rate of resolution of histologically verified intracranial tuberculomas Neurosurgery, 53 (2003), pp. 873–879

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

                            

Medical Pain - A Forgotten Cousin, or Lost Cause?

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

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

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

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

Introduction

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

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

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

Predictability & On-Call Skills

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

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

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

A Surgical Predilection?

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

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

Community Confounders

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

Chronicity

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

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

Fear of Pain

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

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

Conclusion

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

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ANDREW GRECH, M.D. (MELIT.), Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Details: 
ANDREW GRECH, Department of Ophthalmic Surgery, Mater Dei Hospital, Msida MSD 2090, Malta.
Corresponding Author Email: 
andrew-kristian.grech@gov.mt
References
References: 
  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
References
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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.
  3. Chen Y, Peng Y, Zhou B, Wang Y, Zhou C, Song Y, Li C, Zhang J, Rao L: Analysis of adiponectin gene polymorphisms in dilated cardiomyopathy in a Han Chinese population. DNA Cell Biol 2010;29:313-317.
  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
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  10. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clinica chimica acta. 2007;380:24-30.
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  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.
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  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.
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  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.

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