Internal Medicine

Introduction:

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

Case:

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

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

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

Figure 1: Mild hepatitis with portal tract lymphocytic infiltration.

Figure 2: Cholestasis.

Figure 3: Trichrome stain showing portal tract fibrosis.

Figure 4: Normal bile ducts in portal tract.

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

Discussion:

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

Literature review shows multiple reports of DILI with captopril^{2, 3}, ramipril⁴, fosinopril^{5, 6} and enalapril.^2,7 Most commonly implicated ACE-I are enalapril and captopril. The usual presentation for ACE-I induced hepatotoxicity is cholestasis mediated hepatitis. Till date there have been four case reports published reporting lisinopril as cause of hepatitis ^{1, 8, 9} All 4 cases of lisinopril induced hepatotoxicity have shown a hepatocellular pattern of liver injury and did not show any cholestatic features. We report the first case of lisinopril induced cholestasis mediated hepatotoxicity.

In our case, patient had received enalapril for 5 months before initiation of lisinopril; however patient developed symptoms 2 years after initiation of lisinopril. The patient had no past medical history of liver or biliary tract disease. A thorough investigative workup was negative for autoimmune and other viral causes of hepatitis. Older case reports of lisinopril induced toxicity have shown similar histopathological findings of portal inflammation by lymphocytes without centrilobular zonal necrosis.⁹ There are various theories regarding possible mechanisms for DILI with lisinopril, namely terminal proline ring mediated bile stasis^{8, 10} and hypersensitivity to the sulfhydryl group.² Discontinuation of metformin, pioglitazone, furosemide, atenolol and detemir did not result in clinical or biochemical improvement. Patient was initially continued on lisinopril since suspicion was low and then later discontinued. Similarity in histopathological findings along with a strong temporal relationship between lisinopril withdrawal and improved biochemical and clinical scenario, with absence of other constitutional symptoms and eosinophilia strongly point toward lisinopril-induced hepatotoxicity.

Our case had a long period of latency between drug intake and onset of hepatic injury which is consistent with other published reports of lisinopril induced hepatocellular injury^{9, 10, 11}; however the mechanism responsible for latency or hepatotoxicity remains unclear. Earlier report postulate metabolic idiosyncratic reaction as a possible molecular mechanism for hepatocellular injury⁹. However our case is unique as the primary mode of injury appears to be cholestatic. Since our patient received enalapril before initiation of lisinopril without any adverse events, this case adds further controversy as to whether this patient could have been safely continued on other ACE-I except lisinopril or whether she would have developed hepatotoxicity if enalapril was continued. This case highlights further need for research to evaluate ACE-I induced hepatotoxicity. Currently the awareness for ACE-I induced liver injury is low and there are no guidelines guiding physician to monitor for possible hepatic adverse events. Further research is needed to delineate the mechanism by which ACE-I cause hepatotoxicity and to define possible risk factors.

Conclusion:

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

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

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

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

Fig 2: Oesophagoscopy showing TOF

Correct answer:

2. Tracheo-oesophageal fistula

Discussion:

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

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

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

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

Central Line Associated Blood Stream Infection (CLABSI)

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

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

Ventilator Associated Pneumonia

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

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

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

Catheter Associated Urinary Tract Infection (CAUTI)

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

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

Final word

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

Introduction

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

Case report

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

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

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

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

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

Discussion

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

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

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

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

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

Introduction

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

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

Physical activity improves well-being after cancer

Dozens of interventional studies have tested the feasibility and potential benefits of exercise in cancer survivors^2,3,4. Recent meta-analyses of randomised trials involving exercise interventions after cancer, encouragingly demonstrate that the benefits of exercise spanned across several common cancer types and following a range of treatments including surgery, radiotherapy, chemotherapy, hormones and even the newer biological therapies. The most recent meta-analysis of 34 randomised trials published in the BMJ in 2012 involving patients exercising after cancer, demonstrated a benefit for a number of troublesome symptoms particularly fatigue, mood, anxiety and depression; muscle power, hand grip, exercise capacity and quality of life⁵.

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

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

Cancer related fatigue (CRF) is one of the most distressing symptoms experienced by patients during and after their anti-cancer therapies. It is reported by 60-96% of patients during chemotherapy, radiotherapy or after surgery, and by up to 40% of patients taking long-term therapies such as hormonal or biological therapies⁶. The first step to treating CRF is to correct, if possible, any medical conditions that may aggravate it, such as anaemia, electrolyte imbalance, liver failure and nocturia; or to eliminate drugs such as opiates, anti-histamines and anti-sickness medication⁷. The role of exercise was reviewed in 28 randomised, controlled trials (RCTs) involving 2083 participants in a variety of exercise programmes and showed that exercise improved CRF, although the benefit overall was small⁸. A second review of 18 RCTs involving 1,109 participants, sub-divided the data into types of exercise and demonstrated that supervised exercise programmes had the most impact on CRF⁹. Further meta-analyses and reviews have also showed that supervised exercise programmes had better results, with a greater reduction in CRF amongst breast cancer survivors assigned to exercise programmes compared to home-based programmes^4,5,8,10.

Psychological distress, including anxiety and depression, is common after cancer with reported prevalence rates of 25-30%¹¹. Patients with psychological distress have also been shown to have reduced survival compared to those who are psychologically healthy¹². Exercise may help alleviate this symptom and improve mood, as a number of observational studies have shown that cancer patients who exercise have reduced levels of depression and anxiety, better self-esteem and are happier, especially if they involve group activities¹³. The recent meta-analyses of RCTs also demonstrated a reduction in anxiety and depression among individuals assigned to exercise programmes^4,5.

Quality of life (QOL) is lower in many cancer sufferers and survivors, linked to other physical and psychological symptoms of cancer and its’ treatment. Meta-analyses of studies of exercise intervention programmes have demonstrated an improvement of QOL at all stages of the illness for the common cancer types and following several types of treatment^4,5. For example, in a study involving 1,966 patients with colorectal cancer, patients achieving at least 150 minutes of physical activity per week had an 18% higher QOL score than those who reported no physical activity, as measured by the QOL FACT-C¹⁴. Another study showed similar benefits for breast cancer survivors who had completed surgery, radiotherapy or chemotherapy, and also demonstrated that change in peak oxygen consumption correlated with change in overall QOL¹⁵.

Weight gain:45% of women with breast cancer report significant weight gain¹⁶, and in a study of 440 prostate cancer survivors, 53% were overweight or obese¹⁷. For patients with bowel cancer, the CALBG 8980 trial showed that 35% of patients post-chemotherapy were overweight (BMI 25.0–29.9), and 34% were obese (BMI 30.0–34.9) or very obese (BMI >35)¹⁶. The reasons for this are multifactorial, but may include other symptoms of cancer treatment such as fatigue and nausea, causing patients to stop exercising. Regardless of the reasons for weight gain, numerous reviews and a comprehensive meta-analysis of the published literature have demonstrated that individuals who gain weight after cancer treatments have worse survival and more complications¹⁸. Fortunately, supervised exercise programmes have been shown to reduce weight and have significant other benefits on body constitution and fitness, such as improved lean mass indices, bone mineral density, cardiopulmonary function, muscle strength and walking distance^18,19.

Bone mineral density (BMD): Pre-menopausal women who have had breast cancer treatment are at increased risk of osteoporosis, caused by reduced levels of oestrogen brought on by a premature menopause due to chemotherapy, surgery or hormones. Men who receive hormone deprivation therapy for prostate cancer are also at an increased risk of developing osteoporosis. Accelerated bone loss has also been reported for many other cancers, including testicular, thyroid, gastric and CNS cancers, as well as non-Hodgkin’s lymphoma and various haematological malignant diseases^20,21. Lifestyle factors linked to an increase in the risk for developing osteoporosis include a low calcium and vitamin D intake, a diet low in plant-based protein, lack of physical activity, smoking and excessive alcohol intake²². A number of studies have linked regular physical activity with a reduction in the risk of bone mineral loss. Sixty six women with breast cancer were randomized to a control group or an exercise programme. The rate of decline of BMD was -6.23% in the control group, -4.92% in the resistance exercise group, and -0.76% in the aerobic exercise group. The statistically significant benefit was even greater in pre-menopausal women²³. In another RCT of 223 women with breast cancer, it was found that exercise, over 30 minutes 4-7 times a week, helped preserve bone mineral density even when bisphosphonates (risedronate), calcium and vitamin D had already been prescribed²⁴.

Thromboembolism: Those with pelvic involvement, recent surgery and immobility, previous history of varicose veins or thrombosis or receiving chemotherapy, are at higher risk²⁵. Although strategies such as compression stockings, warfarin and low molecular weight heparin are essential, early mobilisation and exercise remains a practical additional aid in reducing this life-threatening complication^18,26.

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

Physical activity improves survival and reduces relapse

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

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

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

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

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

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

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

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

Quantity and type of exercise recommended for cancer patients

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

Table 1: Summary of exercise guidelines for cancer survivors

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

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

The body’s chemical environment significantly changes after exercise, best demonstrated in the Ornish study, which found that serum from prostate cancer patients who exercised, had an almost eight times greater inhibitory effect on the growth of cultured androgen dependent prostate cancer cells compared to serum from patients in the control group²⁷. The precise chemical mechanism, which the anti-cancer effect remains incompletely understood, but one of the most likely mechanisms involving growth factors such as insulin-like growth factor (IGF-1) and its’ binding proteins insulin-like growth factor binding proteins (IGFBPs), due to the central role of these proteins in the regulation of cell growth (see Table 2). After binding to its receptor tyrosine kinase, IGF-1 activates several signalling pathways including the AKT pathway, leading to the inhibition of apoptosis and the promotion of cell growth and angiogenesis^34,40,41. An inverse relationship of cancer risk with IGFBP3 levels has also been shown, although this effect has not been confirmed in all studies⁴². Exercise has been shown to increase the levels of IGFBP3, and this was associated with a 48% reduction of cancer-specific deaths in a large prospective cohort study of 41,528 participants⁴³. Decreased levels for IGF-1 in physically active patients have been reported with an associated survival benefit⁴⁴.

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

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

Another neuropeptide which changes after exercise is Vasoactive Intestinal Protein (VIP). Breast and prostate cancer patients have been found to have higher VIP titres compared to individuals who regularly exercise, and who have increased production of natural anti-VIP antibodies⁴⁵. In hormone-related cancers such as cancers of the breast, ovaries, prostate and testes, the association between high levels of circulating sex hormones and cancer risk is well established⁴⁶. Another mechanism through which exercise may affect cancer, is through decreasing the serum levels of these hormones. For breast cancer survivors, the link between exercise and lower levels of oestrogen has been shown^13,34,47. An indirect, related mechanism is that exercise helps reduce adiposity, and adiposity in turn influences the production and availability of sex hormones⁴⁸. In addition, greater adiposity leads to higher levels of Leptin, a neuropeptide cytokine with has cancer promoting properties^49,50.

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

Incorporating exercise into mainstream cancer management

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

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

Conclusion

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

Introduction

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

Case report

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

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

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

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

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

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

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

Discussion

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

Renal cell carcinoma is the most common tumour of paranasal sinus metastasis, 41.8%. The average age is 58 years, with slight predominance of males. The most common presentation was epistaxis, 31%. The most common causes of sphenoid metastasis are gastrointestinal and renal tumours⁵_.

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

Table 1: Cases of thyroid metastases to the sphenoid sinus

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

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

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

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

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

Acknowledgement

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

Introduction

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

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

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

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

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

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

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

Methods

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

Results

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

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

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

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

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

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

Discussion

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

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

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

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

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

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

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

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

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

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

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

What is the Fundus finding?

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

Discussion:

Correct answer: 3) Choroidal Tubercle.

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

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

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

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

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

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

Introduction:

Candida species is a leading cause of nosocomial infections and the most common fungal infection in intensive care units.  Candida infection ranges from invasive candidal disease to blood stream infections (candidaemia).  The incidence of Candida infection has been rising over the past two decades, particularly with the use of immunosuppressive drugs for cancer and HIV^1,2,3 , and most of these infections occur in ICU settings.⁴  Candida infection is associated with high mortality and morbidity. Studies have shown that mortality attributable to candidaemia ranges from 5 to 71% depending on the study. ^5.6.7Candidaemia is also associated with longer length of hospital stay and higher cost of care.

Early recognition of Candida BSI has been associated with improved outcome. Candida sepsis should be suspected in a patient who fails to improve and has multiple risk factors for invasive and bloodstream Candida infection. A variety of risk factors identified for candidaemia include previous use of antibiotics, sepsis, immunosupression, total parenteral nutrition, central venous line, surgery, malignancy and neutropaenia. Patients admitted to ICU are frequently colonised with Candida species. The role of colonisation in Candida blood stream infection and invasive candidal disease has always been debated. Few studies support the use of presumptive antifungal treatment in ICU based on colonisation and number of sites colonised by Candida. The NEMIS study has raised doubt about this approach of presumptive treatment.  The Infectious Disease Society of America (IDSA) 2009 guidelines identify Candida colonisation as one of the risk factors for invasive candidiasis, but warn about the low positive predictive value of the level of Candida colonisation. ⁸ We conducted a retrospective cohort study in our medical ICU to identify risk factors for Candida blood stream infections including the role of Candida colonisation.

Hospital and Definitions:

This study was conducted at Interfaith Medical Center, Brooklyn, New York.  It is a 280 bed community hospital with 13 medical ICU beds. A case of nosocomial Candida blood stream infection was defined as a growth of Candida Species in a blood culture drawn after 48 hours of admission. Cultures in our hospital are routinely done by the Bactec Method – aerobic and anaerobic cultures. Cultures are usually kept for 5 days at our facility and if yeast growth is identified, then species identification is done. In our ICU it is routine practice to do endotracheal culture and urine culture for all patients who are on mechanical ventilator supports and failing to improve. In patients who are not mechanically ventilated, it is routine practice to send sputum culture and nasal swabs to identify MRSA colonisation.

Study Design:

This study was a retrospective cohort study. We retrospectively reviewed all patients’ charts admitted to our medical ICU from 2000 to 2010 which stayed in the ICU for more than 7 days, irrespective of their diagnosis. Data were collected for demographics – age and sex. Data were also collected for risk factors for candidaemia – co-morbidities (HIV, cancer, COPD, diabetes mellitus, end-stage renal failure (ESRF)), presence or absence of sepsis, current or previous use of antibiotics, presence of central venous lines, steroid use during ICU stay, requirement of vasopressor support and use of total parenteral nutrition (TPN). Culture results for Candida including species identification were obtained for blood, urine and endotracheal aspirates.

Statistical Methods:

Patients were divided in two groups based on presence or absence of Candida BSI. Demographic data and risk factors were analysed using the chi square test to look at the difference between the two groups. Endotracheal aspirates and sputum cultures were combined to create a group with Candida respiratory tract colonisation. Binary logistic regression with forward likelihood ratio method was used to create models. Different models were generated for risk factors. Interactions between antibiotic use, steroid use, vasopressor support and sepsis were analysed in different models. Interactions between urine cultures and endotracheal aspirates/sputum cultures were also analysed by a different model. The model with the lowest Akaike information criterion (AIC) was chosen as the final model. The candidaemia risk score was calculated based on this final model to predict the risk of Candida BSI. Receiver operating curve (ROC) analysis was used to select the best cut-off value for the candidaemia risk score. Candida species in urine and endotracheal aspirates were compared with Candida species in blood culture using the kappa test. Data were analysed using SPSS statistical analysis software version 18.

Study Results:

A total of 1483 patients were included in the study.  56 patients (3.77%) had a blood culture positive for Candida species. Table 1 demonstrates demographic characteristics of the study population.  There were no significant differences in the both groups for age, sex, diabetes mellitus, COPD, HIV, cancer and ESRF. As demonstrated in the table, 82.1% of patients in candidaemia groups recently used or were taking antibiotics as compared to 39.6% of patients in groups with no candidaemia. The P value was significant for this difference.  Similarly, 71.4% of patients in the group with candidaemia had sepsis as compared to 30.6% in the other group with a P value of 0.000. Use of vasopressor (severe septic shock) was different between two groups – 23.2%  and 10.1%, P value of 0.004. Steroid use, central lines and total parenteral nutrition use was higher in the candidaemia group as compared to the group without candidaemia. Similarly the rate of positive Candida cultures in urine and endotracheal aspirates was higher in the candidaemia group as compared to the group without.

Table 2 shows that 57.1% of Candida BSI were caused by C. Albicans, 30.4% by C. Glabrata and 12.5% by C. Parapsilosis. This incidence rate of species is similar to that found in other studies. Table 3 shows the two models with the lowest AIC value. The only difference between these two models was antibiotic use- previous or current use of antibiotics compared to current use of antibiotic in sepsis. Table 4 shows that when multifocal site positivity (urine and endotracheal culture) were used in the model, the AIC value increased significantly. This means that when multifocal sites were used in place of individual sites for the model, good amounts of information were lost and this model did not have good predictive value as compared to the model where individual sites are used for prediction of candidaemia. The model with lowest AIC was chosen as the final model. Binary logistic regression analysis with forward conditional analysis showed that only TPN, central venous line, previous or current antibiotic use, endotracheal aspirate culture positivity for Candida species and urine culture positive for Candida species were included in a statistical significant model. The final model had a P value of 0.000.  Odds ratio with 95% confidence intervals and respective P values for all these risk factors are shown in Table 5.  Age greater than 65 years, sex, sepsis or septic shock, co-morbidities and steroid use were not significant risk factors for candidaemia.

From this model, the candidaemia risk score calculated would be: Candidaemia risk score = 1.184 for previous or current antibiotic use + 0.639 for presence of central venous line + 1.186 for total parenteral nutrition + 0.760 for positive endotracheal culture for Candida + 1.255 for positive urine  culture for Candida.

Table 6 shows the relationship between the Candida strain identified in endotracheal/sputum culture to that in blood culture. Similarly, Table 7 shows the relationship between the Candida strain identified in urine culture and that in blood culture. Strains identified in endotracheal aspirate culture had a very high value for the Kappa test and urine culture had a moderate value for agreement by the Kappa test. Thus, it can be inferred that Candida strain identified in blood culture was very similar to that identified in urine or endotracheal culture.

Table 1: Demographic characteristic of study population

Table 2: Candida strains responsible for Candida blood stream infection

Table 3: Models with lowest two AIC

Table 4: Model with 2 sites positive for Candida

Table 5: Odds ratio with 95% confidence interval for risk factors for candidaemia

Table 6: Endotracheal aspirate culture in candidaemic patients

Table 7: Urine cultures in candidaemic patients

Discussion

Candida is the most common nosocomial fungal infection in the ICU. Candidaemia accounts for approximately 5-8% of nosocomial BSI in the hospitals in the US.^9,10,11 It accounts for approximately 50-75% of the cases of invasive fungal infection in the ICU^12,13 and its rate varies from 0.2-1.73 per 1000 patient days.^9,14,15 In a study done by Theoklis et al., candidaemia was associated with a mean 10.1 day increase in length of stay and a mean $39,331 increase in hospital charges.¹⁶ A study of 1,765 patients in Europe found that Candida colonisation was associated with increased hospital length of stay and increase in cost of care by 8000 EUR.¹⁷ ICU patients are at increased risk of infection because of their underlying illness requiring ICU care, immunosuppressant use, invasive or surgical procedures and nosocomial transfer of infections. A number of risk factors have been identified in different studies. In a matched case-control trial, previous use of antibiotic therapy, Candida isolated at other sites, haemodialysis and presence of a Hickman catheter were associated with increased risk of candidaemia.¹³ Similarly age of more than 65 years, steroid use, leucocytosis and prolonged ICU stays were risk factors for Candida BSI in 130 cases.¹⁸ Surgery, steroids, chemotherapy and neutropaenia with malignancy are the other identified risk factors.¹⁹

Candida BSI has a very high mortality rate. The attributable mortality varies from 5-71% in different studies.^5,12,16,20 Even with treatment, there is high mortality as demonstrated in a study by Oude Lashof et al where out of 180 patients treated for candidaemia, 33% died during treatment and 55% completed treatment without complications.²¹ Risk factors for increased mortality in patients receiving antifungal treatment are delayed Candida antifungal treatment or inadequate dosing.²² Multivariate analysis of 157 patients with Candida BSI, APACHE II score, prior antibiotic treatment and delay in antifungal treatment were independent risk factors for mortality with odds ratio of 1.24, 4.05 and 2.09, respectively.²³ Delayed treatment is also associated with increased fluconazole resistance as compared to early treatment and preventive treatment.²⁴ Inadequate antifungal medication dose and retention of central venous catheters were also associated with increased mortality in a study of 245 Candida BSI, with adjusted odds ratios of 9.22 and 6.21, respectively.^25,26

Candida albicans accounts for 38.8-79.4 % of the cases of Candida BSI. C. Glabrata is responsible for 20-25% of cases of candidaemia and C. tropicalis is responsible for less than 10% of cases of candidaemia in the US.^9,20  ICU patients are frequently colonised with different Candida species. Candida colonisation can be from either endogenous or exogenous sources. Candida colonisation rates vary with the site- tracheal secretion (36%), throat swabs (27%), urine (25%) and stool (11%).²⁷ Candida colonisation increases with the duration of the stay, use of urinary catheters and use of antibiotics. ^28,29,30

The role of Candida colonisation in Candida BSI is frequently debated.  Some studies have suggested that Candida colonisation of one or more anatomical sites are associated with increased risk of candidaemia.^31,32,33,34 Typically, 84-94% of the patients developed candidaemia within a mean time of 5- 8 days after colonisation according to two studies.^35,36  In another study, only 25.5% of colonised patients developed candidaemia.³⁷ Similarity between strain identified in blood culture and that identified at various colonising sites was observed in one study.³⁸  Candida colonisation by exogenously acquired species has also been implicated as a cause of candidaemia.³⁹ In one study, 18-40% of cases of candidaemia were associated with clustering defined as “isolation of 2 or more strain with genotype that had more than 90% genetic relatedness in the same hospital within 90 days.” ⁴⁰ Similar correlations for clusters are also noted for C. tropicalis candiduria⁴¹ and for C. Parapsilopsis.⁴² In a prospective study of 29 surgical ICU patients colonised with Candida, the APACHE II score, length of previous antibiotic therapy and intensity of Candida colonisation was associated with a significant risk of candidaemia.  The Candida colonisation index calculated by non-blood body sites colonised by Candida over the total number of distinct sites tested for patients, was associated with a 100% positive and negative predictive value of candidaemia.²⁹ Other studies do not support Candida colonisation as a risk factor for candidaemia. In a case-control study of trauma patients, only total parenteral nutrition was associated with an increased risk of candidaemia. Candida colonisation, steroid use, use of central venous catheters, APACHE II score, mechanical ventilation for more than 3 days, number and duration of antibiotics, haemodialysis, gastrointestinal perforation and number of units of blood transfused in first 24 hours of surgery. were not significant risk factors for candidaemia.⁴³ NEMIS study found that in a surgical ICU, prior surgery, acute renal failure, total parenteral nutrition and triple lumen catheters were associated with increased risk of candidaemia; the relative risk for each risk factor being 7.3, 4.2, 3.6 and 5.4, respectively. Candida colonisation in urine, stool or both were not associated with increased risk of candidaemia.¹⁵

The effect of Candida colonisation of the respiratory tract on candidaemia and on mortality and morbidity is unclear. In a retrospective study of 639 patients, Candida respiratory tract colonisation was associated with increased hospital mortality (relative risk of 1.63) and increased length of stay (median increase of 21 days).³⁰ In a study of 803 patients by Azoulay et al., respiratory tract colonisation was associated with prolonged ICU and hospital stays. These colonised patients were at increased risk of ventilator-associated Pseudomonas pneumonia, with an odds ratio of 2.22.⁴⁴ However, in a postmortem study of 25 non-neutropaenic mechanically ventilated patients, 40% of the patients were colonised with Candida, but only 8% had Candida pneumonia.^45,46  Jordi et al. found that out of 37 patients, definite or possible colonisation was found in 89% of patients and only 5% of cases were defined as Candida BSI.⁴⁷.The effect of candiduria is also ill defined. Candida colonisation in urine has been implicated as a risk factor in certain studies. In a study done by Bross J et al., central lines, bladder catheters, 2 or more antibiotics, azotaemia, transfer from another hospital, diarrhoea and candiduria were significant risk factors for candidaemia. Candiduria had an odds ratio of 27 for development of candidaemia.⁴⁸ Similar findings about candiduria were noted by Alvarez-Lerma et al.⁴⁹

IDSA recommends starting empirical antifungal treatment for high risk neutropaenic patients who fail to improve on antibiotics after 4 days. Recommendation to start empirical antifungal therapy in low-risk neutropaenic patients and non-neutropaenic patients are not made by IDSA because of low risk of candidaemia.⁸ However, early detection of Candida BSI is vital because of increased mortality associated with delayed antifungal treatment and failure to remove central venous lines. Early detection of Candida BSI in a colonised patient can be facilitated by using a score based on the risk factors.^50,51Similarly, b-D glucan assays can be used in patient colonised with Candida, to determine Candida BSI and need for antifungal treatment.⁵² Combined used of such risk factor identification systems and b-D glucan assays will help to detect candidaemia in earlier stages and will decrease mortality. Our study suggests that total parenteral nutrition, previous or current antibiotic use, central lines, candiduria and respiratory tract colonisation are risk factors for Candida BSI. With the help of our candidaemia risk score system, a score of more than 2 is associated with a higher risk of Candida BSI. This risk factor scoring system along with b-D glucan assays can be used to detect Candida BSI in earlier stages.

Conclusion:

Our study suggests that urine or respiratory tract colonisation is associated with an increased risk of Candida BSI, along with total parenteral nutrition, central venous lines and previous or current antibiotic use. We identified a scoring system which can be used along with a b-D glucan assay to detect candidaemia earlier.

Case Presentation

A 29 year-old woman had been well until 7 months previously when, after a viral syndrome, she developed palpitations, fatigue, and frequent episodes of light headedness and near syncope. On further questioning she notes exercise intolerance and dyspnea on exertion. She has stopped working as cashier. Her mother thinks she is having panic attacks and needs “something to calm her nerves.” ECG, echocardiogram, and endocrine evaluation are all normal. On physical examination, she displayed a postural heart rate increase of 35 beats per minute on standing, along with a 15mmHg fall in diastolic blood pressure.

Introduction

Disorders of the autonomic nervous system present unique challenges to the practicing clinician. These syndromes have a significant impact on quality of life, offer subtle diagnostic clues, and have a propensity to mimic other disease processes. For these reasons clinicians should have basic familiarity with the differentiating features of autonomic disorders. While much investigation has focused on Neurocardiogenic syncope, a distinct subgroup has emerged characterized by postural tachycardia and exercise intolerance. Postural orthostatic tachycardia syndrome (POTS) is the final common pathway of a heterogeneous group of underlying disorders that display similar clinical characteristics .¹

The constellation of symptoms associated with POTS reflects underlying dysautonomia including palpitations, exercise intolerance, fatigue, lightheadedness, tremor, headache, nausea, near syncope, and syncope. Foremost amongst these is orthostatic intolerance. Besides being limited in the functional activities of daily living, increased sleep disturbances including excess daytime sleepiness, fatigue are also common and have been associated poor health-related quality of life. 2 We aim to discuss the clinical presentation, classification, evaluation and management of POTS.

Diagnosis

The current diagnostic criteria for POTS is the presence of orthostatic intolerance symptoms associated with a sustained heart rate increase of 30 beat per minute (bpm) or absolute rate exceeding 120 bpm within the first 10 minutes of standing or upright tilt in the absence of other chronic debilitating disorders, prolonged bed rest, or medications that impair vascular or autonomic tone. 3 Most patients will have orthostatic symptoms in the absence of orthostatic hypotension (a fall in BP >20/10 mmHg). A grading system for POTS has been developed (Table 1). This system focuses on the functional severity of orthostatic intolerance in a way similar to the NYHA heart classification.

The physical exam should be methodical and directed. Supine, sitting, and immediate standing heart rate and blood pressure should be recorded. Orthostatic tachycardia and acrocyanosis of the lower extremities may be the only physical signs in these patients. Standing and supine blood pressure measurements and baseline electrocardiogram are generally recommended. In patients with physical examination or clinical history suggestive of cardiovascular abnormalities, other diagnostic test including echocardiogram , stress test or coronary angiography may be indicated before a tilt test. In addition, other possible clinical disorders with similar clinical manifestations must be kept in mind and ruled out. Upright tilt test remains the diagnostic test of choice for POTS and other autonomic disorders. Implantable loop recorders, electrophysiological tests and Holter monitoring are not helpful in the evaluation of these disorders. Supine and upright serum catecholamine levels should be obtained if hyperadrenergic type is suspected. In the presence of gastrointestinal symptoms bowel motility studies may reflect the degree of involvement and help to tailor therapy. ⁴

Classification and Clinical Features

POTS is a heterogeneous group of disorders resulting in a common clinical scenario. This syndrome is classified as being either primary or secondary. Primary POTS is idiopathic and not associated with other disease processes. Secondary POTS occurs in association with a known disease or disorder. Subtype classification affects management and is therefore essential.^1,4 (Figure 1)

Partial dysautonomic (PD) POTS (also referred to as Neuropathic POTS) is the predominant form.1, 2 This is a mild peripheral autonomic neuropathy, characterized by inadequate peripheral vasculature constriction in the face of orthostatic challenge. Female predominance is seen with 5:1 female to male ratio. Presentation is commonly abrupt onset of symptoms after a febrile viral illness, pregnancy, immunization, sepsis, surgery, or trauma. The etiology of PD type POTS is postulated to be an autoimmune molecular antigen mimicry type pathogenesis. Serum autoantibodies to peripheral autonomic ganglion alpha-3 acetylcholine receptors may be positive in 10-15% of the cases. Anhidrosis of lower extremities is seen in more than 50% of these patients at quantitative sudomotor axon reflex testingDependent blood pooling when upright is greater than normal and heart rate and contractility increase as normal compensatory physiologic mechanisms to maintain cerebral perfusion. This autoregulatory response may initially be fully compensatory; however, peripheral venous pooling may increase with time and exceed this compensatory effect. Patients with PD type POTS become dependent on the skeletal muscle pump to augment their autoregulatory physiology. Ultimately, venous blood pooling increases beyond the body’s total ability to compensate and adequate blood pressure maintenance fails.

“Developmental” partial dysautonomic POTS is an adolescent subtype.6 The mean age of onset is 14 years. The clinical scenario is that of orthostatic intolerance following a period of very rapid growth. Symptoms are progressive and peak at a mean age of 16 years. Orthostatic intolerance may be severe, including severe headaches, and can be functionally disabling. Following their peak symptoms will slowly improve and resolve into young adulthood (19-24 years). Roughly 80% of patients with developmental PD POTS will experience complete resolution of symptoms. The etiology of this subtype is unclear and appears to be a transient period of autonomic imbalance occurring in rapidly growing adolescents.

Hyperadrenergic POTS is less common than the PD type ^,7This form is characterized by a gradual onset with slowly progressive symptoms. Patients report experiencing tremor, anxiety, and cold clammy extremities with upright posture. ⁷ Many patients note increased urine output when upright. True migraine headaches may be seen in over half of patients.⁷ Gastrointestinal symptoms in the form of recurrent diarrhea were seen in 30% of the patients. In contrast to PD type of POTS, the hyperadrenergic form demonstrates elevated serum catecholamine levels with serum norepinephrine levels >600ng/ml. This may be a familial syndrome in some instances determined by a careful history. The etiology of hyperadrenergic POTS is felt to be genetic with a single point mutation resulting in a dysfunctional norepinephrine reuptake transporter protein present in the intrasynaptic cleft. The result is excessive norepinephrine serum spillover with sympathetic stimulation resulting in a relative hyperadrenergic state appearing similar to pheochromocytoma. ⁸

A connective tissue disorder has been an increasingly recognized etiology of secondary POTS ⁹ . Joint hypermobility syndrome (JHS) is an inherited condition characterized by joint hypermobility, connective tissue fragility, and soft velvety skin with variable hyperextensibility. The condition is associated with ecchymotic predisposition, premature varicose veins, diffuse muscle and joint pain, and orthostatic acrocyanosis. The etiology of POTS in JHS patients is thought to be due to abnormal vascular (venous) elastic connective tissue. During orthostatic stress and increased hydrostatic pressure these patients exhibit increased vessel distensibility and orthostatic intolerance. Excessive peripheral venous pooling and compensatory tachycardia follows. Up to 70% of JHS patients suffer from some degree of orthostatic intolerance. It is observed that adolescent PD POTS patients have features similar to JHS patients and further studies may determine the significance of this potential relationship ^10.

Secondary POTS refers to a group of conditions which result in peripheral autonomic denervation with sparing of cardiac innervation. Most commonly, secondary POTS is associated with diabetes mellitus. Less commonly, this form may occur with heavy metal intoxication, multiple sclerosis, parkinsonism and chemotherapy, especially vinca alkaloids.^11,12

Severe autonomic nervous system disorders may present as POTS. These may include pure autonomic failure or multiple system atrophy. Paraneoplastic syndrome associated with adenocarcinoma of the lung, breast, ovary, or pancreas may also present as POTS. These tumors produce auto-antibodies targeting the acetylcholine receptors in the autonomic ganglia in a manner similar to post-viral syndromes.

Figure 1. Subtypes of postural orthostatic tachycardia syndrome

Evaluation and Management

Treatment is generally individualized to each patient. Confounding pharmacology should be identified and stopped if possible (Table 2). The presence of secondary POTS should be considered. Underlying diagnoses causing or augmenting POTS should be identified and treated appropriately. Deconditioning is frequent seen in POTS patient and a deliberate aerobic reconditioning program should be a component of the treatment plan. ¹³ This is encouraged to begin promptly working up to a goal of 20-30 minutes of activity at least 3 times a week. Resistance training of the lower extremities is helpful to increase the efficacy of the skeletal muscle pump. Salt and water ingestion are the most common employed non-pharmacolgical therapeutic intervention for POTS. Although, the intravenous saline infusion has been associated with reduction in standing tachycardia, the effect on this intervention on the symptom reduction remains unknown ¹⁴ . In general, since low blood volume may exacerbate symptoms patients are encouraged to have liberal salt and water intake. Excluding hyperadrenergic POTS, daily fluid and sodium intake should be greater than 2 liters and 3-5 grams.

The goal of pharmacotherapy in the treatment of POTS is to ameliorate the symptoms of POTS and thus maintain the functional capacity. Currently no drug is US FDA approved for the treatment of POTS. All pharmacology is inherently off-label. (Table 3).

Majority of the evidence for the use of different pharmacological agents in the management of POTS is based on some small randomised , observational and retrospective single center studies. In clinical practice most patients are treated with a single agent and second medication from different class with a different mechanism of action is added in case of treatment failure. Resistant cases are often treated with polypharmacy.

Fludrocortisone, a potent mineralocorticoid resulting in sodium retention, augmented fluid volume, and sensitized peripheral alpha adrenergic receptors. The effects are more pronounced in the younger population. Starting dose is 0.1-0.2 mg daily with a maximum dose of 0.4 mg. Common side effects include electrolyte imbalance and hypertension. In a study of 11 female POTS patients, fludricortisone alone or in combination with bisoprolol was associated with improvement in symptoms ¹⁵. Midodrine is an alpha -1 adrenoreceptor agonist and causes both arterial and venous vasoconstriction. It is commonly used as add on therapy and with starting dose at 5 mg orally three times a day. In our clinical experience we advise patients to take their first dose of midodrine 15 minutes prior to getting out of bed. An additional 5mg dose can be used for breakthrough symptoms. Midodrine is usually well tolerated with the most common complaints being nausea, “goose bumps,” and scalp pruritus. In a small study of 6 patients with POTS acute combination therapy of midodrine (10mg) with octreotide (0.9mcg/kg) was significantly associated with reduction in upright tachycardia and improved standing time.In another study of 53 children with POTS, midodrine was significantly associated with both higher clinical cure rate and reduced recurrence rate as compared to children treated with metoprolol or conventional therapy.

Patients may continue to be symptomatic despite dual-therapy as outlined above. In this population we add a serotonin reuptake inhibitor (SSRI) or norepinephrine reuptake inhibitor (SNRI). SSRI therapy has been found to be helpful in the prevention of neurocardiogenic syncope. However, SNRI therapy is more useful in the treatment of POTS. Usually, we use bupropion XL beginning with 150 mg orally daily titratable to 300 mg daily if necessary.

The most effective SSRI therapies combine serotonin and norepinephrine reuptake inhibition (venlafaxine and duloxetine). The agents are usually well tolerated with the most common side effects being gastrointestinal upset, tremor, sleep disturbance, and less commonly agitation and sexual dysfunction. Bupropion and SSRI therapy can be combined to achieve a similar effect.

Pyridostigmine is an acetylcholinesterase inhibitor that facilitates sympathetic and parasympathetic ganglionic neural transmission. In our single center experience of 203 patients of POTS treated with pyridostigmine; improved symptoms of orthostatic intolerance were seen in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to tolerate the drug. Fatigue (55%), palpitations (60%), presyncope (60%), and syncope (48%) were the most common symptoms that improved with pyridostigmine. Further, symptom reduction correlated with a statistically significant improvement in upright HR and diastolic blood pressure after treatment with pyridostigmine as compared to their baseline hemodynamic parameters (standing HR 94 ± 19 vs 82 ± 16, P < 0.003, standing diastolic blood pressure 71 ± 11 vs 74 ± 12, P < 0.02). Gastrointestinal problems were the most common adverse effects (n = 39, 19%) seen in our study. ¹⁸

Severely affected and refractory patients may benefit from erythropoietin (EPO) therapy. EPO increases red cell mass, central blood volume and augments response of blood vessels to the angiotensin-II and thus causes vasoconstriction. These effects are quite useful in the treatment of orthostatic disorders. Prior to initiation of EPO therapy obtain a complete blood count (CBC), total iron binding capacity, serum iron and ferritin levels. Hematocrit (HCT) levels must be monitored and should remain less than 50 on EPO. The starting dose is 10,000 units via subcutaneous injection once weekly. There is a 4-6 week delay between a given dose and the full clinical effect. The hematogenic and hemodynamic affects are independent but may occur simultaneously. A goal HCT of low to mid 40 will often result in optimum hemodynamic augmentation. Monitoring during EPO therapy should include monthly CBC to document HCT less than 50. EPO therapy may infrequently result in a “serum sickness” type reaction characterized by nausea, fever, chills, and general malaise. In another study of 39 patients (age 33 ± 12, 37 females) with resistant form of POTS, we reported sustained improvement in twenty-seven (71%) patients at mean follow-up of six month with EPO therapy. Eighty (21%) failed to respond to therapy while as 3 (8%) improved with therapy at 3months. Also, erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters.¹⁹ We reserve EPO therapy for patients that are refractory or intolerant of other forms of treatment because of its considerable expense and subcutaneous route of administration.

Beta blocker therapy such as metoprolol tartrate may be beneficial in adolescent type POTS patients. In a single center retrospective study of 121 patients with possible POTS, written survey at follow-up were used to evaluate response to therapy with beta-blockers and midodrine. 47 adolescents responded to survey (Walker Functional Disability Inventory Survey) and reported improvement with a β-blocker (100% vs 62%, P = 0.016) and more attributed their progress to medication (63.6% vs 36.4%, P = 0.011) than did those treated with midodrine ²⁰ .In addition, beta-blocker therapy was associated with improved quality of life. Great caution should be taken in using beta-blocker therapy in a rare form of hyperadrenergic POTS secondary to the mast cell activation disorders. Octreotide is a somatostatin analogue with potent vasoconstrictive effects and is useful in the treatment of orthostatic disorders. In patients with resistant POTS, octreotide may be a useful as add on therapy. It is administered by subcutaneous injection 2-3 times daily. The stating dose is 50 ug and may be titrated up to 100-200 ug three times daily.

Agents that block the release or effect of norepinephrine (noradrenaline) are very effective for hyperadrenergic type POTS patients. We use clonidine starting at 0.1 mg orally twice daily and titrating up as needed. The patch form may be preferable to some patients and has the added benefit of providing a steady state drug release for one week. Labetalol, an alpha and beta receptor blocker, is also useful in this group of patients. Dosages of 100-400 mg orally twice daily are used. Methyldopa may have a role in highly selected patients with POTS. Symptom control may be improved with both the SSRI and SNRI classes of medications.

Inappropriate sinus tachycardia (IST) is an important confounding finding in suspected POTS patients. This syndrome is similar to hyperadrenergic type POTS. The clinical presentation may be similar with IST being more common in females. These disease states display and exaggerated response to isoproterenol infusion. It has been postulated that they may represent different states of the same pathologic process. A greater degree of orthostatic change in heart rate is seen in POTS patients. The supine rate rarely exceeds 100 bmp (IST will often be >100). Postural changes in serum norepinephrine levels are much more pronounced in POTS patients. It is important to differentiate POTS and IST. Radiofrequency ablation of the sinus node will rarely benefit hyperadrenergic POTS patients and will make PD POTS patients markedly worse.

Treatment of secondary POTS should focus primarily on the underlying disorder to the greatest extent possible. Diabetes mellitus or JHS related POTS are treated as PD POTS. Secondary POTS due to sarcoidosis or amyloidosis may benefit from steroid therapy. Secondary POTS that is paraneoplastic may completely resolve with treatment of the underlying malignancy but may also respond to pyridostigmine.

Patients suffering from POTS have a disease that affects many aspects of their life. They are often unable to take advantage of meaningful employment or education opportunities. The pervasive life change experienced often results in significant psychosocial disruption as they may be excluded from social norms and certain environments. Frequently, patients require psychologists, social workers, and lawyers to address these aspects of living with POTS. The treating physician is a prominent and central figure who is a beacon of hope for this population. A positive, caring, and nurturing attitude may be the best medicine and lead to a rewarding rapport where an otherwise challenging disease exists.

Prognosis

There is limited data on the prognosis of POTS patients. Recent short term follow-up studies have shown better prognosis in patients with POTS. ²¹ Roughly 50% of post-viral POTS patients make a meaningful recovery over about 2-5 years. Meaningful recovery may be defined as the absence of orthostatic symptoms and the ability to perform the activities of daily living with little or no restriction. Some patients experience a partial recovery and still others may demonstrate a progressive functional decline with time. As a general principle, a younger age of onset portends a better prognosis. A majority of patients tend to adopt different lifestyle modifications including increased fluid and salt intake to improve and reduce exacerbation of the POTS symptoms. In secondary POTS syndromes have a prognosis consistent with the underlying causative disorder.

Conclusion

Disruption of normal autonomic function may manifest as one of a heterogeneous group of clinical disorders collectively referred to as postural orthostatic tachycardia syndrome. Treatment is most successful when diligence has been taken to investigate the underlying disorder or POTS subtype and a comprehensive targeted treatment program is instituted with frequent follow up. Goals of care should focus on functional milestones and maintenance of function.

Introduction:

In traumatic brain injury (TBI) the primary insult to the brain and the secondary insults as a result of systemic complications may result in a multitude of sequelae ranging from subtle neurological deficits to significant morbidity and mortality. As the brain recovers by repair and adaptation, changes become apparent and may result in physical, cognitive and psychosocial dysfunction. Rehabilitation is usually structured to recover physical ability, cognitive and social retraining with the aim of gaining independence in activities of daily living.

Case Report:

A 76 year old male patient was admitted to an intermediate neurorehabilitation unit following a traumatic brain injury(TBI) .He had fallen from a height of 11 feet resulting in intracerebral haemorrhage in the left parietal lobe and a left parietotemopral subarachnoid hemorrhage which was managed conservatively in the neurosurgical unit. He developed recurrent post traumatic seizures in the form of myoclonic jerks for which he was started on antiepileptic drugs (AEDs) sodium valproate ,clobazam and levetiracetam .During his stay in the acute neurorehabilitation unit, he was noted to be confused and wandering with a disrupted sleep wake cycle. Cognitive assessment showed global impairment across all cognitive domains suggesting that cognitive impairment was secondary to TBI with the chaotic sleeping pattern and fatigue having a significant effect on his cognition. He was then transferred to an intermediate neurorehabilitation unit four months post head injury for rehabilitation prior to discharge.

On admission he was confused, and disorientated. His neurological examination was normal except for mild expressive dysphasia. On the first night of his stay in the unit, he did not sleep at all, was restless, agitated and aggressive towards the staff. His initial agitation was attributed to the change of surroundings and general disorientation. However during his first week at the rehabilitation unit it was noted that his sleep wake cycle was completely disrupted .He would have short fragmented naps through the day and would regularly get agitated at night with threatening behaviour towards staff. On admission the Rancho Los Amigos scale^† was 4(confused-agitated) and he needed specialized supervision. Despite environmental modification and optimal pharmacotherapy to improve sleep and decrease agitation, the patient still continued to have aggressive outbursts and no identifiable sleep wake pattern. It was noted by the nursing staff that occasionally when very agitated, the patient refused to have his night time medications including all AEDs .On such occasions he was reported to have slept better at night and did not have any daytime naps. All blood investigations were within normal limits except for mild hyponatremia with a normal creatinine clearance and CT head showed changes consistent with previous TBI with no new pathology .A neurology opinion was sought and with a Naranjo adverse drug reaction probability score^†† of 7/10, a decision was taken to slowly decrease levetiracetam and wean it to stop, while continuing all other regular AEDs. The levetiracetam was reduced from an original dose of 750mg twice daily by 500mg every week with an aim to stop. This resulted in a considerable improvement in the patient’s agitation with a complete halt in the nighttime aggressiveness. His sleep wake cycle normalized and he started sleeping longer at night. His Ranchos Los Amigos scale improved from 4(confused-agitated) to 6(confused-appropriate). The patient could now participate more with the team of trained therapists in memory and attention exercises as well as regaining independence in activities of daily living.

Discussion:

TBI particularly in elderly aged over 64 years has a worse functional outcome as compared to non elderly.¹Closed head injury in older adults produces considerable cognitive deficits in the early stages of recovery² and there have been studies suggesting TBI to be a risk factor for developing Alzheimer’s disease.³Memory deficits, attention problems, loss of executive function and confusion are common after TBI.⁴This impaired cognitive function reduces the patient’s ability to recognize environmental stimuli often resulting in agitation and aggression towards perceived threats.TBI by itself may result in a variety of sleep disorders ranging from hypersomnia, narcolepsy, alteration of sleep wake cycle, insomnia to movement disorders^{. 5}Sleep wake schedule disorders following TBI are relatively rare and may clinically present as insomnia.⁶Often these sleep disorders result in additional neurocognitive deficits and functional impairment, which might often be attributed to the original brain injury itself and thus be left without specific treatment.

While dealing with disrupted sleep pattern and agitation in the elderly following TBI, treatable causes such as neurological, infectious, metabolic, and medications should be ruled out. This is imperative as they disrupt rehabilitation and achievement of functional goals. Long duration of agitation post TBI has been associated with longer duration of rehabilitation stay and persisting limitations in functional independence.⁷After ruling out all the treatable causes the first focus is on environmental management with provision of a safe, quiet, familiar, structured environment while reducing stimulation and providing emotional support. The next step is introduction of pharmacotherapy to reduce agitation. Though a variety of pharmacological agents are available, there is no firm evidence of efficacy of any one class and often the choice of drug is decided by monitoring its effectiveness in practice and watching for side-effects.⁸In pharmacotherapy, the general principle followed is start low and go slow while developing clear goals to help decide when to wean and stop medications. Atypical antipsychotics are often used for the agitation while benzodiazepines and non benzodiazepine hypnotics such as zopiclone are recommended for treatment of insomnia.⁹ However atypical antipsychotics carry a FDA black box warning being associated with increased risk of stroke and death among elderly.

But what does one do when all optimal non pharmacologic and pharmacologic measures fail? That brings us back to the drawing board which in this case led the team to rethink Levetiracetam, a novel new antiepileptic that has been used as monotherapy for partial seizures and adjunctive therapy for generalized tonic clonic and myoclonic seizures. Levetiracetam treated patients have been reported to have psychiatric adverse effects¹⁰ including agitation, hostility, anxiety, apathy, emotional lability, depersonalization, and depressionwith few case reports of frank psychosis ¹¹.While in healthy volunteers levetiracetam is noted to consolidate sleep¹²,in patients with complex partial seizures, levetiracetam has been noted to cause drowsiness decreasing day time motor activity and increasing naps without any major effects on total sleep time and sleep efficiency during night.¹³There has been an isolated report of psychic disturbances following administration of levetiracetam and valproate in a patient with epilepsy which resolved following withdrawal of valproate. ¹⁴However in practice it is used for recurrent post TBI seizures as it is a potent AED with a relatively mild adverse effect profile and no clinically significant interactions with commonly prescribed AEDs.¹⁵

Any adverse drug reaction (ADR) should be evaluated while keeping the patients clinical state in mind. This was, indeed, difficult in our case. With a history of TBI and cognitive decline, it became difficult to ascertain whether the neurocognitive issues were purely due to the nature of TBI or due to an ADR. Assigning causality to a single agent is difficult and fraught with errors. Using the Naranjo algorithm ¹⁶, with a score of 7/10(probable ADR) and a notable response on withdrawal of the offending drug as in this case helps establish possible causality.

This is a rare instance where sleep wake cycle disorder and agitation resolved following withdrawal of Levetiracetam in an elderly patient with TBI. This in turn led to the patient having a stable mood so that therapists could communicate and interact with him in order to improve basic cognitive functions such as attention, memory, thinking and executive control. This case illustrates the constant need to systematically and frequently reassess patients as they recover from TBI.

^†Appendix: Ranchos Los Amigos Levels of cognitive functioning.

^††Naranjo Adverse Drug Reaction Probability Score:

Score
<0 =Doubtful ADR
1-4=Possible ADR
5-8=Probable ADR
>9=Definite ADR

Introduction:

There are approximately over 1.6 billion overweight people with a body mass index (BMI) greater than 25 kg/mAnnually, around 2.8 million deaths are attributed to overweight and obesity worldwide⁽¹⁾. Many overweight individuals underestimate their weight and despite acknowledging their overweightness, many are not motivated to losing weight⁽²⁾.Accurate measurement is important as it identifies patients with diagnoses which subsequently impact on their management. Self-reported weight is often used as a means of surveillance but has been shown to bias towards under reporting of body weight and BMI as well as over reporting on height⁽³⁾. Several estimation techniques has been devised to quantify anthropomorphic measurements when actual measurement cannot take place^(4),(5),(6), however, these methods are associated with significant errors for hospitalised patients⁽⁷⁾. There is no published study that questions the validity of visual estimation of obesity in daily clinical setting despite its relevance to the daily practice. We aim to investigate the accuracy of visual estimation compared to actual clinical measurements in the diagnosis of overweight and obesity.

Methods:

This is a case control study. Patients for this study were attending the endocrinology, cardiology and chest pain out-patient clinic in Cork University Hospital, Cork, Ireland. The questionnaire session was carried out at every endocrinology, cardiology and chest pain clinic for 5 consecutive weeks. A total of 100 patients were recruited allowing for a 10% margin of error at 95% confidence level in a sample population of 150 000. Ten doctors of varying grades were chosen randomly to visually score the subjects. Exclusion criteria included patients who were pregnant and who are wheelchair bound. Consent was obtained from patients prior to filling questionnaires. Ethical approval was received from the Clinical Research Ethics Committee of the Cork Teaching Hospitals.

In the waiting room, patients were asked to self- report their weight, height and waist circumference to the best of their estimate. Demographics and cardiovascular risk were obtained from medical charts and presented in Table 1. The questionnaires have a section that specifically tests patients’ awareness of abdominal obesity and patients were asked to choose between obesity and abdominal obesity, relying on their own knowledge of markers of cardiovascular risks. Clinical measurements were taken in the nurses’ assessment room. Weight was measured by using portable SECA scales (Seca 755 Mechanical Column Scale) and was measured to the nearest 0.1kilogram. All patients were measured on the same weighing scale to minimize instrumental bias. Patients were asked to remove their heavy outer garments and shoes and empty their pockets and to stand in the centre of the platform, so that weight is distributed evenly to both feet.

Height was measured by using a height rule attached to a fixed measuring rod (Seca 220 Telescopic Measuring Rod). Patients were asked to remove their shoes and are asked to stand with their back to the height rule. It was ensured that the back of the head, back, buttocks, calves and heels are touching the wall. Patients were asked to remain upright with their feet together. The top of the external auditory meatus is leveled with the inferior margin of the bony orbit. The patients were asked to look straight. Height is recorded to the resolution of the height rule (i.e. nearest millimeter).

Waist circumferences were measured using a myotape. Patients were asked to remove their outer garments and stand with their feet close together. The tape is placed horizontally at a level midway between the lower rib margin and iliac crest around the body. They were then asked to breathe normally and the reading of the measurement was taken at the end of gentle exhaling. This prevents patients from holding their breath. The measuring tape is held firmly, ensuring its horizontal position and loose enough that it allows placement of one finger between the tape and the subject's body. A single operator who has been trained to measure waist circumference as per the WHO guidelines is used repeatedly in order to reduce measurement bias⁽⁸⁾.

The doctors were asked to visually estimate the patients' weight, height, waist circumference and BMI. The estimation is recorded on a separate sheet. All doctors were blinded to the actual clinical measurements. The questionnaires were then collected at the end of the clinic and matched to individual patients. Data entry was performed in Microsoft Excel and exported for statistical analysis on SPSS version 16.

Findings

The study enrolled 100 patients. Demographic and cardiovascular risk details are shown in Table 1. Among these, 42 were obese, 35 were overweight and 23 patients had a normal BMI. The sample has a mean BMI of 29.9kg/m² (95% CI 28.7-31.1) with a mean waist circumference (WC) of 103.2cm (95% CI 100.7-107.2). The average male waist circumference is 105.8 cm while the average female waist circumference is 101.6cm. The mean measured weight was 84.6kg (95% CI 81.0-88.2) and the mean height measurement was 1.68m (95% CI 1.66-1.70).

Table 1: Cardiovascular risk factors

Patient’s perception and doctor’s estimation of anthropomorphic measurements were compared to actual measurements and is displayed in Table 2.

Table 2. Deviation from actual measurement values in both groups

In terms of patients own estimation of height, weight and waist circumference, 49% of patients under estimated their weight by up to 1.5kg, 35% reported accurately to 1.5 kg and 16% over reported weight. 67% of patients estimated height accurately, 18% of patients under-estimated, and 15% over-estimated. When asked to estimate their waist circumference, 68% of patients under estimated by up to 5cm, 30% over estimated and 2 patients estimated accurately to 5cm (Figure 1). We found that 70% of patients regarded obesity as the higher threat to health compared to abdominal obesity. There were no differences in patient’s self reported weight and doctor’s weight estimation (p= 0.236).

Figure 1. Graphical representation of patients estimated weight, height and waist circumference

We then analysed the doctor’s estimation of height, weight, waist circumference and BMI. For the purpose of interpreting the data on BMI, the estimates that is recorded by doctors that matches the patient’s real BMI by clinical measurement is considered accurate. Therefore, for patients who have a normal BMI, 69.5% were correctly estimated as normal and the rest (30.5%) were estimated as overweight. For those patients who are obese, 81% were estimated as obese and by the doctors as a group and the rest (19%) is estimated to be overweight. In patients who are overweight, 63% were correctly estimated as being overweight by doctors, 9% were estimated as being obese and the rest (28%) were mistakenly estimated as having a normal BMI. Accurate BMI estimation by doctors was achieved in 72% patients (Figure 2).

Figure 2. Doctors estimation of BMI compared to actual clinical measurement

Doctors were noted to underestimate the patients’ weight in 53 patients, over estimated in 26, while being accurate in their estimation in 21 patients. Estimation of waist circumference to the nearest 5 cm shows marked under estimation of waist circumference in 71% of patients, over reporting in 3% of patients and 26% accurate estimation. The majority of underestimation of waist circumference happens in the region of 10 to 15cm. For patients who are obese, doctors were able to estimate waist circumference correctly in 58% of obese individuals.

Discussion:

This is the first study demonstrating the relationship of visual estimation of a cardiovascular risk factor and comparing to actual clinical measurements. As obesity and abdominal obesity becomes an increasingly common phenomenon, our perception of the 'normal' body habitus may be distorted⁽⁹⁾.

It is observed that in the bigger hospitals out-patient departments, physicians and nurses are commonly affected by clinical workload and tend to spend a limited amount of time with patients in order to achieve a quicker turnaround time. Cleator et al looked at whether clinically significant obesity is well detected in three different outpatient department and whether they are managed appropriately once diagnosed⁽¹⁰⁾. In all the outpatient departments involving the specialties of rheumatology, cardiology and orthopedics, the actual cases of clinical obesity is higher than what is being diagnosed and the management of obesity was heterogeneous and minimal in terms of intervention. With the ever increasing obese patients attending hospitals, it is understandable that healthcare providers such as physicians, nurses, dietician and physiotherapist resort to relying on visual estimation.

In terms of patient’s own estimation of height, weight and waist circumference, we gained that patients were reasonably good at estimating their own height but tend to under estimate weight. This is probably due to the fact that these patients have not had a recent measurement of weight and their weight estimation is based on previous historical measurement from months to years back, which in the majority of people, is less than their current weight. This also explains why their height estimation is more accurate, as adult heights do not undergo significant changes and are relatively constant.

When attempting to obtain patient’s own estimation of waist circumference, we found that most patients are not at all aware of the method used to measure waist circumference. Some patients even mistaken waist circumference as being their trousers’ waist size. In those who were able to give estimation, a large proportion would under estimate.

The majority of patients think that general obesity is more predictive of cardiovascular outcome compared to abdominal obesity. This lack of awareness is reflective on clinician’s effort in addressing abdominal obesity as an important cardiovascular risk factor to patients during consultations. The lack of proper awareness campaign by healthcare providers along with the evolving markers of cardiovascular risk may further confuse the general public.

Recently, waist circumference, waist to hip ratio along with many serum biomarkers have been noted to correlate to adverse outcomes in obese individuals, independent of BMI. Waist circumference measurement is a relatively new tool compared to the measurement of BMI. This would explain the discrepancy between doctors’ estimation of BMI and waist circumference. Visual estimation is further compromise as many patients would be covered in items of clothing during consultations. In order to obtain a better estimation of waist circumference, the individual have to be observed from many angles, a task that may be impossible in a busy clinic.

Although BMI is a convenient method to quantify obesity, recent studies have shown that waist circumference is a stronger predictor of cardiovascular outcomes^{(11),(12),(13),(14)}.The importance of waist circumference in predicting health risk is thought to be due to the relationship between waist circumference and intra-abdominal fat^{(15),(16),(17),(18),(19),(20)}.We now know that the presence of intra-abdominal visceral fat is associated with a poorer outcome in that patients are prone to develop metabolic syndrome and insulin resistance⁽²¹⁾.We have yet to devise a more accurate measurement on visceral fat and at present limited to using waist circumference measurements.

Although doctors are generally good at BMI estimation, we found that in estimating overweight patients’ BMI, close to 30% were wrongly estimated as having normal BMI. Next to the obese, these groups of patients are likely to have metabolic abnormalities and increased cardiovascular risk. If actual measurement of BMI is not routinely done, we may neglect patients who would benefit from intervention. A simple, short counseling during the outpatient visit with emphasis on weight loss, the need to increase their daily activity levels and the morbidity related to being overweight may be all that is needed to improve the population health in general. Further intervention may include referrals to hospital or community dieticians and prescribed exercise programmes. These intervention tools already exist in the healthcare system and could be accessed readily.

The nature of our study design exposes it to several potential selection and measurement biases. Future studies should include patients of differing ages and socioeconomic background. Additionally, clinicians of differing appointments from various different specialties should be included to obtain a more applicable result. A measure of diagnostic efficacy should also be employed to further assess the value of clinical measurement and therapeutic intervention.

Conclusion:

The appropriateness of visual scoring of markers of obesity by doctors is flawed and limited to the obese individuals. True anthropometric measurements would avoid misdiagnosing overweight individuals as normals. We can conclude that patients’ own estimation of weight is unreliable and that they are unaware of the impact of high abdominal fat deposition on cardiovascular outcome. The latter should be addressed in consultations by both hospital physicians and general practitioners. Further emphasis and education in schools and awareness campaigns should also advocate this emerging cardiovascular risk factor.

Malaria is caused by obligate intra-erythrocytic protozoa of the genus Plasmodium. Humans can be infected with one (or more) of the following five species: P. falciparum, P. vivax, P. ovale, and P. malariae and P. knowlesi. Plasmodia are transmitted by the bite of an infected female Anopheles mosquito and these patients commonly present with fever, headache, fatigue and musculoskeletal symptoms.

Diagnosis is made by demonstration of the parasite in peripheral blood smear. The thick and thin smears are prepared for identification of malarial parasite and genotype respectively. Rapid diagnosis of malaria can be done by fluorescence microscopy with light microscope and interference filter or by polymerase chain reaction.

We report a complicated case of P. ovale malaria without fever associated with Hepatitis B virus infection, pre-excitation (WPW pattern), and secondary adrenal insufficiency.

Case Report:

A 23 year old African American man presented to the emergency department with headache and dizziness for one week. He had 8/10 throbbing headaches associated with dizziness, nausea and ringing sensation in the ears and also complained of sweating but denied any fever. He had loose, watery bowel movements 3 times a day for a few days and had vomited once 5 days ago. He denied any past medical history or family history. He was a chronic smoker and smoked 1PPD for 8 years and denied alcohol or drug use. He had travelled to Africa 9 months before presentation and had stayed in Senegal for 1 month though he did not have any illnesses during or after returning from Africa.

On examination: T: 97.6, HR: 115/min, BP: 105/50, no orthostasis, SPO₂: 100% in room air and RR: 18/min. Head, neck and throat examinations were normal and respiratory and cardiovascular system examinations were unremarkable except for tachycardia. Abdominal examination revealed no organomegaly and his CNS examination was unremarkable.

Laboratory examination revealed: WBC: 6.4, Hb: 14.4 and Hct: 41.3, Platelets: 43, N: 83.2, L: 7.4, M: 9.3, B: 0.1. His serum chemistry was normal except for a creatinine of 1.3 (BUN 14) and albumin of 2.6 (total protein 5.7). A pre-excitation (WPW Pattern) was seen on ECG and head CT and Chest X-ray were normal.

He was admitted to the telemetry unit to monitor for arrhythmia. Peripheral blood smear (PBS) was sent because of thrombocytopenia and mild renal failure and revealed malarial parasites later identified as P. ovale (Pic. 1 and 2).

He was treated with Malarone; yet after 2 days of treatment, he was still complaining of headache, nausea and dizziness. There were no meningeal signs. His blood pressure readings were low (95/53) and he was orthostatic. His ECG showed sinus tachycardia and did not reveal any arrhythmias or QTc prolongation. His morning serum cortisol was 6.20 and subsequent cosyntropin stimulation test revealed a serum cortisol of 13.40 at one hour after injection. His Baseline ACTH was<1.1 suggesting a secondary adrenal insufficiency. His IGF-1, TSH, FT4, FSH, LH were all within normal limits. His bleeding and coagulation parameters were normal, CD4 was 634(CD4/CD8: 1.46) and rapid oral test for HIV was negative.  His Hepatitis B profile was as follows: HBsAg: positive, HBV Core IgM: negative, HBV core IgG: positive, HBeAg: negative, HBeAb: positive, HBV DNA: 1000 copies/ml, Log10 HBV DNA: 3000 copies/ml.

His Blood cultures were negative, his G6PD levels and hemoglobin electrophoresis were normal, haptoglobin was<15 and LDH was 326. MRI of the brain was unremarkable. The abdominal sonogram revealed a normal echo pattern of the liver and spleen and spleen size was 12 cm. The secondary adrenal insufficiency was treated with dexamethasone resulting in gradual improvement of his nausea, vomiting and headache. Furthermore the platelet count improved to 309. Primaquine was prescribed to complete the course of malaria treatment and he was discharged home following 8 days of hospitalization. Unfortunately he did not return for follow up.

Discussion:

Malaria continues to be a major health problem worldwide. In 2007 the CDC received reports of 1,505 cases of malaria among person in the United States. 326 cases were reported from New York with all but one of these cases being acquired outside of the United States¹.

While Plasmodia are primarily transmitted through the bite of an infected female Anopheles mosquito, infections can also occur through exposure to infected blood products (transfusion malaria) or by congenital transmission. In industrialized countries most cases of malaria occur among travellers, immigrants, or military personnel returning from areas endemic for malaria (imported malaria). Exceptionally, local transmission through mosquitoes occurs (indigenous malaria). For non-falciparum malaria the incubation period is usually longer (median 15–16 days) and both P. Vivax and P. Ovale malaria may relapse months or years after exposure due to the presence of hypnozoites in the liver of which the longest reported incubation period for P. vivax being 30 years².

Malaria without fever has been reported in cases of Plasmodium falciparum malaria in non- immune people³. Hepatitis B infection associated with asymptomatic malaria has been reported in the Brazilian Amazon⁴.  This study was done in P. falciparum and P. vivax infected person with HBV co-infection though not in the P. ovale group. HBV infection leads to increased IFN-gamma levels^5,6 which are important for plasmodium clearance in the liver⁷, in addition to its early importance for malarial clinical immunity⁸. High levels of IFN gamma, IL6 and TNF alpha are detectable in the blood of malaria patients and in the spleen and liver in the rodents’ model of malaria^9,10. These inflammatory cytokines are known to suppress HBV replication in HBV transgenic mice⁹. This might explain the low levels of HBV viremia in our patient although human studies are required to confirm this finding.

The hypothalamic-pituitary- adrenocortical axis suppression and primary and secondary adrenal insufficiency has been reported in severe falciparum malaria¹⁰. In our case, the patient did not have any features to characterize severe malaria, and parasitaemia was <5%. Further, the MRI did not reveal any secondary cause for adrenal insufficiency. This might indicate that patients with malaria are more prone for hypothalamo-pituitary adrenocortical axis dysregulation yet further studies are required to prove this phenomenon in patients without severe malaria.

Cardiac complications after malaria have rarely been reported. In our patient pre-excitation on ECG disappeared after starting antimalarial treatment. Whether WPW pattern and its subsequent disappearance was incidental or caused by malarial infection that improved with treatment could not be determined. Lengthening of the QTc and severe cardiac arrhythmia has been observed, particularly after treatment with halofantrine for chloroquine resistant Plasmodium falciparum malaria¹¹. Post-infectious myocarditis can be associated with cardiac events especially in combination with viral infections¹².  A case of likely acute coronary syndrome and possible myocarditis was reported after experimental human malaria infection¹³. To date, except for cardiac arrhythmias that developed after treatment with halofantrine and quinolines, no other arrhythmias has been reported in patients with malaria before treatment.

Transient thrombocytopenia is very common in uncomplicated malaria in semi -immune adults¹⁴. A person with a platelet count <150 × 10⁹/l is 4 times more likely to have asymptomatic malarial infection than one with a count ≥150 × 10⁹/l¹⁵. In an observational study among 131 patients, patients with involvement of more than one organ system was found to have a lower mean platelet count compared to those with single organ involvement¹⁶.

Conclusions:

Our case highlights the need for further studies to understand the multi-organ involvement in patients without severe malaria as well as early recognition of potential complications to prevent mortality and morbidity in this subgroup of patients.

Case Report

A 69 year old male with hypertension, body mass index 24 kg/m², neck circumference 16 inches, and moderate COPD, on home oxygen, presented to his pulmonary clinic appointment with worsening complaints of fatigue, leg cramps, and intermittent shortness of breath with chest discomfort.  A remote, questionable history of syncope five to ten years ago was elicited.  His vital signs were: temperature 98.8⁰F, blood pressure 119/76 mmHg, pulse 92/min and regular, and respirations 20/min.  Physical exam was significant for crowded oropharynx with a Mallampati score of four, distant breath sounds with a prolonged expiratory phase on lung exam with a normal cardiac exam.  Laboratory investigation showed normal complete blood counts, haemoglobin 15 g/dL, and normal chemistries.  Compared to his previous studies, a pulmonary function study showed stable parameters with a FEV1 1.47 L   (69%), FVC/FEV1 ratio 0.44 (62%), and a DLCO/alveolar volume ratio of 2.12 (49%).  A room air arterial blood gas revealed pH 7.41, PCO2 44 mmHg, and PO2 61 mmHg, with 92% oxygen saturation.  A six minute treadmill exercise test performed to assess the need for supplemental oxygen showed that he required supplemental oxygen at 1L/min via nasal cannula to eliminate hypoxemia during exercise.  His chest radiograph was significant for hyperinflation and prominence of interstitial markings.  A high resolution computed tomography of the chest demonstrated severe centrilobular and panacinar emphysema only.  A baseline electrocardiogram (EKG) showed normal sinus rhythm with an old anterior wall infarct (Figure 1).   Echocardiography of the heart revealed a normal left ventricle with an ejection fraction of 65%.  Right ventricular systolic function was normal although elevated mean pulmonary arterial pressure of 55 mmHg was noted.  A diagnostic polysomnogram performed for evaluation of daytime fatigue and snoring at night revealed mild OSA with an AHI of 6/hr. with sleep time spent with oxygen saturation below 90% (T-90%) of 19%.  The EKG showed normal sinus rhythm.  A full overnight polysomnogram for continuous positive airway pressure (CPAP) titration performed for treatment of sleep disordered breathing was sub-optimal,  however it demonstrated an apnoea–hypopnea index (AHI) of 28 during REM (rapid eye movement) sleep, and a T-90% of 93%.  The associated electrocardiogram showed Wenckebach second degree AV heart block during REM sleep usually near the nadir of oxygen desaturation.   On a repeat positive airway pressure titration study, therapy with Bilevel pressures (BPAP) of 18/14 cmH₂0 corrected the AHI and nocturnal hypoxemia to within normal limits during Non REM (NREM) and REM sleep.  His electrocardiogram remained in normal sinus rhythm .A twenty-four hour cardiac holter monitor revealed baseline sinus rhythm and confirmed the presence of second degree AV block of the Wenckebach type.  A one month cardiac event recording showed normal sinus rhythm with frequent episodes of second degree AV block.  These varied from Type I progressing to Type II with a 2:1 and 3:1 AV block, during sleep.  Progression to complete heart block was noted with the longest pause lasting 3.9 seconds during sleep.  The patient underwent an electrophysiology study with placement of a dual chamber pacemaker.  He was initiated on BIPAP therapy.  Subsequently, the patient was seen in clinic with improvements in his intermittent episodes of shortness of breath, fatigue, and daytime sleepiness.

Figure 1- Patient’s baseline EKG, normal sinus rhythm. Figure 2 -Progression to Mobitz Type II block 5:07 am. Figure 3 and 4- Sinus pauses, longest interval 11:07 pm 3.9 seconds (Figure 4).

Discussion

In healthy individuals, especially athletes, bradycardia, Mobitz I AV block, and sinus pauses up to 2 seconds are common during sleep and require no intervention⁵. Cardiac rhythm is controlled primarily by autonomic tone.  NREM sleep is accompanied by an increase in parasympathetic, and a decrease in sympathetic, tone. REM sleep is associated with decreased parasympathetic tone and variable sympathetic tone.  Bradyarrhythmias in patients with OSA are related to the apnoeic episodes and over 80% are found during REM sleep.   During these periods of low oxygen supply, increased vagal activity to the heart resulting in bradyarrhythmias may actually be cardioprotective by decreasing myocardial oxygen demand.  This may be important in patients with underlying coronary heart disease. 

Some studies have found that Mobitz I AV block may not be benign.  Shaw⁶ et al studied 147 patients with isolated chronic Mobitz I AV block.  They inserted pacemakers in 90 patients, 74 patients were symptomatic and 16 patients received a pacemaker for prophylaxis.  Outcome data included five-year survival, deterioration of conduction to higher degree AV block, and new onset of various forms of symptomatic bradycardia.  They concluded that survival was higher in the paced groups and that risk factors for poor outcomes in patients with Mobitz I included age greater than 45 years old, symptomatic bradycardia, organic heart disease, and the presence of a bundle branch block on EKG.

The Sleep Heart Health Study⁷ found a higher prevalence of first and second-degree heart block among subjects with sleep-disordered breathing (SDB) than in those without (1.8% vs. 0.3% and 2.2 vs. 0.9%, respectively). Gami et al⁸observed thatupon review of 112 Minnesota residents who hadundergone diagnostic polysomnography and subsequentlydied suddenly from a cardiac cause, sudden death occurred between the hours of  midnight and 6:00 AM in 46% of those with OSA, as compared with 21% of those without OSA.   In a study of twenty-three patients with moderate to severe OSA who were each implanted with an insertable loop recorder, about 50% were observed to have frequent episodes of bradycardia and long pauses (complete heart block or sinus arrest) during sleep⁹.  These events showed significant night-to-night intra individual variability and their incidence was under-estimated, only 13%, by conventional short-term EKG Holter recordings. 

Physiologic factors predisposing patients with OSA to arrhythmias include alterations in sympathetic and parasympathetic nervous system activity, acidosis, apnoea’s, and arousal^{2, 10, 11}.  Some patients with OSA may have an accentuation of the ‘Diving Reflex’.  This protective reflex consists of hypoxemia-induced sympathetic augmentation to muscles and vascular beds associated with increased cardiac vagal activity which results in increased brain perfusion, bradycardia and decreased cardiac oxygen demand.  In patients with cardiac ischemia, poor lung function (i.e. COPD), or both, it may be difficult to differentiate between these protective OSA-associated Bradyarrhythmias and those which may lead to sudden death.  It has been well established that patients with COPD are at higher risk for cardiovascular morbidity¹² and arrythmias¹³.  Fletcher¹⁴ and colleagues reported that the effects of oxygen supplementation on AHI, hypercapnea and supraventricular arrhythmias in patients with COPD and OSA were variable.  Out of twenty obese men with COPD studied, in most patients oxygen eliminated the bradycardia observed during obstructive apnoea’s and eliminated AV block in two patients.  In some patients supplemental oxygen worsened end-apnoea respiratory acidosis however this did not increase ventricular arrhythmias. 

CPAP therapy has been demonstrated to significantly reduce sleep–related Bradyarrhythmias, sinus pauses, and the increased risk for cardiac death ^{9, 15}.   Despite this, in certain situations placement of a pacemaker may be required.  These include persistent life-threatening arrhythmias present in patients with severe OSAS on CPAP, arrhythmias in patients who are non-compliant with CPAP, and in patients who may have persistent sympathovagal imbalance and hemodynamic fluctuations resulting in daytime bradyarrhythmias¹⁶.

Our case is interesting since it highlights the importance of recognizing the association between OSA, COPD, and life-threatening cardiac arrhythmias.  Primary care providers should note the possible association of OSA-associated bradyarrhythmias with life-threatening Type II bradyarrhythmias and pauses.  Since bradyarrhythmias related to OSA are relieved by CPAP, one option would be to treat with CPAP and observe for the elimination of these arrhythmias using a 24hour holter or event recorder¹⁷.  Compliance with CPAP is variable and if life-threatening bradycardia is present, placement of a permanent pacemaker may be preferred¹⁸. 

Our patient is unusual because most studies showing a correlation with the severity of OSA and magnitude of bradycardia have included overweight patients without COPD¹⁹. This patient’s electrocardiogram revealed a Type II AV block at 5am (Figure 2).  This is within the overnight time frame where patients with OSA have been observed to have an increased incidence of sudden death. Figures 3 and 4 show significant sinus pauses.   In selected cases where patients have significant co-morbidities (i.e. severe COPD with OSA), in addition to treatment with positive airway pressure, electrophysiological investigation with placement of a permanent pacemaker may be warranted.

Introduction

Normal sleep is divided into Non-REM and REM. REM occurs every 90-120 minutes during adult sleep throughout the night with each period of REM progressing in length such that the REM periods in the early morning hours are the longest and may last from 30-60 minutes. Overall, REM accounts for 20-25% of the sleep time but is weighted toward the second half of the night. During REM sleep with polysomnography monitoring one observes a low voltage mixed frequency amplitude EEG and low voltage EMG in the chin associated with intermittent bursts of rapid eye movements. During the periods of REM breathing becomes irregular, blood pressure rises and the heart rate also increases due to excess adrenergic activity. The brain is highly active during REM and the electrical activity recorded in the brain by EEG during REM sleep is similar to that of wakefulness.

Parasomnias are undesirable, unexpected, abnormal behavioral phenomena that occur during sleep. There are three broad categories in parasomnias. They are 

1. Disorders of Arousal (from Non-REM sleep)
2. Parasomnias usually associated with REM sleep, and
3. Other parasomnias which also includes secondary type of parasomnias.

RBD is the only parasomnia which requires polysomnographic testing as part of the essential diagnostic criteria.

Definition of RBD

“RBD is characterized by the intermittent loss of REM sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation” (ICSD-2).¹ These motor phenomena may be complex and highly integrated and often are associated with emotionally charged utterances and physically violent or vigorous activities. RBD was first recognized and described by Schenck CH et al. in 1986.² This diagnosis was first incorporated in the International Classification of Sleep Disorders (ICSD) in 1990. (American Academy of Sleep Medicine)

A defining feature of normal REM sleep is active paralysis of all somatic musculature (sparing the diaphragm to permit ventilation). This result in diffuse hypotonia of the skeletal muscles inhibiting the enactment of dreams associated with REM sleep. In RBD there is an intermittent loss of muscle atonia during REM sleep that can be objectively measured with EMG as intense phasic motor activity (figure 1 and 2).

Figure 1

Figure 2

This loss of inhibition often precedes the complex motor behaviors during REM sleep. Additionally, RBD patients will report that their dream content is often very violent or vigorous dream enacting behaviors include talking, yelling, punching, kicking, sitting, jumping from bed, arm flailing and grabbing etc. and most often the sufferer will upon waking from the dream immediately report a clear memory of the dream which coincides very well with the high amplitude violent defensive activity witnessed. This complex motor activity may result in a serious injury to the dreamer or bed partner that then prompts the evaluation.

Prevalence

The Prevalence of RBD is about 0.5% in general population.^{1, 3} RBD preferentially affect elderly men (in 6^th and 7^th decade) with ratio of women to men being 1 to 9.⁴ The mean age of disease onset is 60.9 years and at diagnosis is 64.4 years.⁵ RBD was reported in an 18 year old female with Juvenile Parkinson disease,⁶ so age and gender are not absolute criteria.

In Parkinson disease (PD) the reported prevalence ranges from 13-50%,^{7, 14-19} LewyBody Dementia (DLB) 95%,⁸ and Multiple System Atrophy (MSA) 90 %.⁹ The presence of RBD is a major diagnostic criterion for MSA. RBD has been reported in Juvenile Parkinson disease, and pure autonomic failure^10-12 all neurodegenerative disorders are synucleinopathies.¹³

Physiology

The neurons of locus coeruleus, raphe nuclei, tuberomammillary nucleus, pedunculopontine nucleus, laterodorsal tegmental area and the perifornical area are firing at a high rate, and cause arousal by activating the cerebral cortex. During REM sleep, the aforementioned excitatory areas fall silent with the exception of the pedunculopontine nucleus and laterodorsal tegmental areas. These regions project to the thalamus and activate the cortex during REM sleep. This cortical activation is associated with dreaming in REM. Descending excitatory fibers from the pedunculopontine nucleus and laterodorsal tegmental area innervate the medial medulla, which then sends inhibitory projections to motor neurons producing the skeletal muscle atonia of REM sleep.^20-21

There are two distinct neural systems which collaborate in the “paralysis” of normal REM sleep, one is mediated through the active inhibition by neurons in the nucleus reticularis magnocellularis in the medulla via the ventrolateral reticulospinal tract synapsing on the spinal motor neurons and the other system suppresses locomotor activity and is located in pontine region.²²

Pathophysiology

REM sleep contains two types of variables, tonic (occurring throughout the REM period), and phasic (occurring intermittently during a REM period). Tonic elements include desynchronized EEG and somatic muscle atonia (sparing the diaphragm). Phasic elements include rapid eye movements, middle ear muscle activity and extremity twitches. The tonic electromyogram suppression of REM sleep is the result of active inhibition of motor activity originating in the perilocus coeruleus region and terminating in the anterior horn cells via the medullary reticularis magnocellularis nucleus.

In RBD, the observed motor activity may result from either impairment of tonic REM muscle atonia or from increase phasic locomotor drive during REM sleep. One mechanism by which RBD results is the disruption in neurotransmission in the brainstem, particularly at the level of the pedunculopontine nucleus.²³Pathogenetically, reduced striatal dopaminergic mediation has been found^24-25 in those with RBD. Neuroimaging studies support dopaminergic abnormalities.

Types of RBD

RBD can be categorized based on severity:

1. Mild RBD occurring less than once per month,
2. Moderate RBD occurring more than once per month but less than once per week, associated with physical discomfort to the patient or bed partner, and
3. Severe RBD occurring more than once per week, associated with physical injury to patient or bed partner.

RBD can be categorized based on duration:

1. Acute presenting with one month or less,
2. Subacute with more than one month but less than 6 months,
3. Chronic with 6 months or more of symptoms prior to presentation.

Acute RBD: In 55 - 60% of patients with RBD the cause is unknown, but in 40 - 45% the RBD is secondary to another condition. Acute onset RBD is almost always induced or exacerbated by medications (especially Tri-Cyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, Mono-Amine Oxidase Inhibitors, Serotonin Norepinephrine Reuptake Inhibitors,²⁶ Mirtazapine, Selegiline, and Biperiden) or during withdrawal of alcohol, barbiturates, benzodiazepine or meprobamate. Selegiline may trigger RBD in patients with Parkinson disease. Cholinergic treatment of Alzheimer’s disease may trigger RBD.

Chronic RBD: The chronic form of RBD was initially thought to be idiopathic; however long term follow up has shown that many eventually exhibit signs and symptoms of a degenerative neurologic disorder. One recent retrospective study of 44 consecutive patients diagnosed with idiopathic RBD demonstrated that 45% (20 patients) subsequently developed a neurodegenerative disorder, most commonly Parkinson disease (PD) or Lewy body dementia, after a mean of 11.5 years from reported symptoms onset and 5.1 years after RBD diagnosis.²⁷

The relationship between RBD and PD is complex and not all persons with RBD develop PD. In one study of 29 men presenting with RBD followed prospectively, the incidence of PD was 38% at 5 years and 65% after 12 years.^{7, 28, 29} Contrast this with the prevalence of the condition in multiple system atrophy, where RBD is one of the primary symptoms occurring in 90% of cases.⁹ In cases of RBD, it is absolutely necessary not only to exclude any underlying neurodegenerative disease process but also to monitor for the development of one over time in follow up visits.

Clinical manifestations

Sufferers of RBD usually present to the doctor with complaints of sleep related injury or fear of injury as a result of dramatic violent, potentially dangerous motor activity during sleep. 96% of patients reporting harm to themselves or their bed partner. Behaviors during dreaming described include talking, yelling, swearing, grabbing, punching, kicking, jumping or running out of the bed. One clinical clue of the source of the sleep related injury is the timing of the behaviors. Because RBD occurs during REM sleep, it typically appears at least 90 minutes after falling asleep and is most often noted during the second half of the night when REM sleep is more abundant.

One fourth of subjects who develop RBD have prodromal symptoms several years prior to the diagnosis. These symptoms may consist of twitching during REM sleep but may also include other types of simple motor movements and sleep talking or yelling.^30-31 Day time somnolence and fatigue are rare because gross sleep architecture and the sleep-wake cycle remain largely normal.

RBD in other neurological disorders and Narcolepsy:

RBD has also been reported in other neurologic diseases such as Multiple Sclerosis, vascular encephalopathies, ischemic brain stem lesions, brain stem tumors, Guillain-Barre syndrome, mitochondrial encephalopathy, normal pressure hydrocephalus, subdural hemorrhage, and Tourette’s syndrome. In most of these there is likely a lesion affecting the primary regulatory centers for REM atonia.

RBD is particularly frequent in Narcolepsy. One study found 36% pts with Narcolepsy had symptoms suggestive of RBD. Unlike idiopathic RBD, women with narcolepsy are as likely to have RBD as men, and the mean age was found to be 41 years.³² While the mechanism allowing for RBD is not understood in this population, narcolepsy is considered a disorder of REM state disassociation. Cataplexy is paralysis of skeletal muscles in the setting of wakefulness and often is triggered by strong emotions such as humor. In narcoleptics who regularly experienced cataplexy, 68% reported RBD symptoms, compared to 14% of those who never or rarely experienced cataplexy.^32-33 There is evidence of a profound loss of hypocretin in the hypothalamus of the narcoleptics with cataplexy and this may be a link that needs further investigation in the understanding of the mechanism of RBD in Narcolepsy with cataplexy. It is prudent to follow Narcoleptics and questioned about symptoms of RBD and treated accordingly, especially those with cataplexy and other associated symptoms.

Diagnostic criteria for REM Behavior Disorder(ICSD-2: ICD-9 code: 327.42)¹

A. Presence of REM sleep without Atonia: the EMG finding of excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental or (upper or lower) limb EMG twitching (figure 1 and 2).

B. At least one of the following is present:

i. Sleep related injurious, potentially injurious, or disruptive behaviors by history

ii. Abnormal REM sleep behaviors documented during polysomnographic monitoring

C. Absence of EEG epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder.

D. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder.

Differential diagnosis

Several sleep disorders causing behaviors in sleep can be considered in the differential diagnosis, such as sleep walking (somnambulism), sleep terrors, nocturnal seizures, nightmares, psychogenic dissociative states, post-traumatic stress disorder, nocturnal panic disorder, delirium and malingering. RBD may be triggered by sleep apnea and has been described as triggered by nocturnal gastroesophageal reflux disease.

Evaluation and Diagnosis

• Detailed history of the sleep wake complaints
• Information from a bed partner is most valuable
• Thorough medical, neurological, and psychiatric history and examination
• Screening for alcohol and substance use
• Review of all medications
• PSG (mandatory): The polysomnographic study should be more extensive, with an expanded EEG montage, monitors for movements of all four extremities, continuous technologist observation and continuous video recording with good sound and visual quality to allow capture of any sleep related behaviors
• Multiple Sleep Latency Test (MSLT): Only recommended in the setting of suspected coexisting Narcolepsy
• Brain imaging (CT or MRI) is mandatory if there is suspicion of underlying neurodegenerative disease.

Management

RBD may have legal consequences or can be associated with substantial relationship strain; therefore accurate diagnosis and adequate treatment is important, which includes non-pharmacological and pharmacological management.

Non-pharmacological management: Acute form appears to be self-limited following discontinuation of the offending medication or completion of withdrawal treatment. For chronic forms, protective measures during sleep are warranted to minimize the risks for injury to patient and bed partner. These patients are at fall risk due to physical limitations and use of medications. Protective measure such as removing bed stands, bedposts, low dressers and applying heavy curtains to windows. In extreme cases, placing the mattress on the floor to prevent falls from the bed has been successful.

Pharmacological management: Clonazepam is highly effective in treatment and it is the drug of choice. A very low dose will resolve symptoms in 87 to 90% of patients.^{4, 5, 7-34} Recommended treatment is 0.5 mg Clonazepam 30 minutes prior to bed time and for more than 90% of patients this dose remains effective without tachyphylaxis. In the setting of breakthrough symptoms the dose can be slowly titrated up to 2.0 mg. The mechanism of action is not well understood but clonazepam appears to decrease REM sleep phasic activity but has no effect on REM sleep atonia.³⁵

Melatonin is also effective and can be used as monotherapy or in conjunction with clonazepam. The suggested dose is 3 to 12 mg at bed time. Pramipexole may also be effective^36-38 and suggested for use when clonazepam is contraindicated or ineffective. It is interesting to note that during holidays from the drug, the RBD can take several weeks to recur. Management of patients with concomitant disorder like narcolepsy, depression, dementia, Parkinson disease and Parkinsonism can be very challenging, because medications such as SSRIs, selegiline and cholinergic medications used to treat these disorders, can cause or exacerbate RBD. RBD associated with Narcolepsy, clonazepam is usually added in management and it is fairly effective.

Follow-up

Because RBD may occur in association with neurodegenerative disorder, it is important to consult a neurologist for every patient with RBD as early as possible, especially to diagnose and provide care plan for neurodegenerative disorder, which includes but not limited to early diagnosis and management, regular follow up, optimization of management to provide better quality of life and address medico-legal issues.

Prognosis

In acute and idiopathic chronic RBD, the prognosis with treatment is excellent. In the secondary chronic form, prognosis parallels that of the underlying neurologic disorder. Treatment of RBD should be continued indefinitely, as violent behaviors and nightmares promptly reoccur with discontinuation of medication in almost all patients.

Conclusions

RBD and neurodegenerative diseases are closely interconnected. RBD often antedates the development of a neurodegenerative disorder; diagnosis of idiopathic RBD portends a risk of greater than 45% for future development of a clinically defined neurodegenerative disease. Once identified, close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative diseases. Treatment for RBD is available and effective for the vast majority of cases.

Key Points

• Early diagnosis of RBD is of paramount importance
• Polysomnogram is an essential diagnostic element
• Effective treatment is available
• Early treatment is essential in preventing injuries to patient and bed partner
• Apparent idiopathic form may precede development of Neurodegenerative disorder by decades

Introduction

Lumbar punctures are commonly performed by both medical and anaesthetic trainees but in different contexts. Medically performed lumbar punctures are often used to confirm a diagnosis (meningitis, subarachnoid haemorrhage) whilst lumbar puncture performed by anaesthetists are usually a precedent to the injection of local anaesthetics into cerebrospinal fluid for spinal anaesthesia. The similarity relies on the fact that both involve the potential for iatrogenic infection into the subarachnoid space. The incidence of iatrogenic infection is very low in both fields; a recent survey by the Royal College of Anaesthetists¹ reported an incidence of 8/707 000 whilst there were only approximately 75 cases in the literature after ‘medical’ lumbar puncture.² However, the consequences of iatrogenic infection can be devastating. It is likely that appropriate infection control measures taken during lumbar puncture would reduce the risk of bacterial contamination. The purpose of the present study is to compare infection control measures taken by anaesthetic and medical staff when performing lumbar puncture.

Method

A survey was constructed online (www.surveymonkey.com) and sent by email to 50 anaesthetic and 50 acute medical trainees in January 2011. All participants were on an anaesthetic or medical training programme and all responses were anonymous. The survey asked whether trainees routinely used the following components of an aseptic technique³ when performing lumbar puncture:

• Sterile trolley
• Decontaminate hands
• Clean patient skin
• Apron/gown
• Dressing pack
• Non-touch technique
• Sterile gloves

No ethical approval was sought as the study was voluntary and anonymous.

Results

The overall response rate was 71% (40/50 anaesthetic trainees and 31/50 medical). All anaesthetic trainees routinely used the components of an aseptic technique when performing lumbar puncture. All medical trainees routinely cleaned the skin, decontaminated their hands and used a non-touch technique but only 80.6% used sterile gloves. 61.3% of medical trainees used a sterile trolley, 38.7% used an apron/gown and 77.4% used a dressing pack.

Discussion

This survey shows that adherence to infection control measures differ between anaesthetic and medical trainees when performing lumbar puncture. The anaesthetic trainees have a 100% compliance rate compared to 80% for the medical trainees for all components of the aseptic technique. Both groups routinely cleaned the patient’s skin, decontaminated their hands and used a non-touch technique. However, there were significant differences in the use of other equipment, with fewer medical trainees using sterile gloves, trolleys, aprons and dressing packs.

Although the incidence of iatrogenic infection after lumbar puncture is low, it is important to contribute to this low incidence by adopting an aseptic technique. There may be differences with regards to the risks of iatrogenic infection between anaesthetic and medical trainees. Anaesthetic lumbar punctures involve the injection of a foreign substance (local anaesthesia) into the cerebrospinal fluid and may therefore carry a higher risk. Crucially however, both anaesthetic and medical lumbar punctures involve accessing the subarachnoid space with medical equipment and so the risk is present.

There are many reasons for the differing compliance rates between the two specialties. Firstly, anaesthetic trainees perform lumbar punctures in a dedicated anaesthetic room whilst the presence of ‘procedure/treatment rooms’ is not universal on medical wards. Secondly, anaesthetic trainees will always have a trained assistant present (usually an operating department practitioner, ODP) who can assist with preparing equipment such as dressing trolleys.

The mechanism of iatrogenic infection during lumbar puncture is not completely clear.⁴ The source of microbial contamination could be external (incomplete aseptic technique, infected equipment) or internal (bacteraemia in the patient); the fact that a common cause of iatrogenic meningitis are viridans streptococcus strains⁵ (mouth commensals) supports the notion that external factors are relevant and an aseptic technique is important.

It is very likely that improved compliance amongst acute medical trainees would result from a dedicated treatment room on medical wards, but this is likely to involve financial and logistical barriers. The introduction of specific ‘lumbar puncture packs’, which include all necessary equipment (e.g. cleaning solution, aprons, sterile gloves) may reduce the risk of infection; the introduction of a specific pack containing equipment for central venous line insertion reduced colonisation rates from 31 to 12%.⁶ The presence of trained staff members to assist medical trainees when performing lumbar puncture may assist in improved compliance, similar to the role of an ODP for anaesthetic trainees.

The main limitation of this study is that the sample size is small. However, we feel that this study raises important questions as to why there is a difference in infection control measures taken by anaesthetic and medical trainees; it may be that the environment in which the procedure takes place is crucial and further work on the impact of ‘procedure rooms’ on medical wards is warranted.

Introduction:

The clinical features of early HAT are well defined, yet the features of delayed HAT are less clear. Delayed HAT is a rare complication of OLT that may present with biliary sepsis or remain asymptomatic. Sonography is extremely sensitive for the detection of HAT in symptomatic patients during the immediate postoperative period. However, the sensitivity of ultrasonography diminishes as the interval between transplantation and diagnosis of HAT increases due to collateral arterial flow. MRA is a useful adjunct in patients with indeterminate ultrasound exams and in those who have renal insufficiency or an allergy to iodinated contrast.

In the absence of hepatic failure, conservative treatment appears to be effective for patients with HAT but retransplantation may be necessary as a definitive treatment.

Case Presentation:

A 52 year old male with a history of whole graft OLT for primary sclerosing cholangitis presented with two days of fever, nausea, and mild abdominal discomfort.

One week prior to presentation, he was seen in the liver clinic for regular follow-up. At that time, he was totally asymptomatic and his laboratory workup including liver function tests were within normal range.

He has undergone OLT three years prior. At the time of transplant he required transfusion of 120 units of packed red blood cells, 60 units of fresh frozen plasma and 100 units of platelets due to extensive intraoperative bleeding secondary to chronic changes of pancreatitis and severe portal hypertension, but had an otherwise uneventful postoperative recovery.

On physical examination the temperature was 39C, heart rate was 125 beats per minute, respiratory rate was 22 bpm. Initial laboratory workup revealed a white blood cell count of 25,000/mm³, AST of 6230 U/L, ALT of 2450 U/L, total bilirubin of 11 mg/dL , BUN 55 mg/dL and Creatinine of 4.5 mg/dL. Lactate level was 5 mmol/L. Doppler ultrasonography revealed an extensive intrahepatic gas (Image 1A). Computed tomography of the abdomen and pelvis revealed extensive area of hepatic necrosis with abscess formation measuring 19x14 cm with extension of gas into the peripheral portal vein branches (Image 1B,C). Upon admission to the hospital, the patient required endotracheal intubation, mechanical ventilator support and aggressively fluid resuscitation. He was started on broad-spectrum antibiotics and a percutaneous drain was placed that drained dark, foul smelling fluid.  Cultures from the blood and the drain grew Clostridium perfringens.

Magnetic resonance imaging (MRI), MRA revealed occlusion of the hepatic artery 2 cm from its origin and also evidence of collaterals (Image 2A,B).

Image 1: (Pannel A) Doppler ultrasonography reveal extensive intrahepatic gas. (Pannel B&C) Computed tomography of the abdomen and pelvis reveal an extensive area of hepatic necrosis with abscess formation measuring 19x14 cm with extension of gas into the peripheral portal vein branches.

Image 2: MRI & MRA reveal occlusion of the hepatic artery 2 cm from its origin and also evidence of collaterals.

Following drain placement, the patient’s clinical condition markedly improved with significant reduction of liver function test values. Retransplantation was considered but delayed in the setting of infection and significant clinical and laboratory testing improvement.

The patient was transferred to the medical floor in stable condition, and the drain was then removed.

A week later the patient developed low grade fevers and tachycardia. One day later he began to experience mild abdominal discomfort and high grade fevers. Repeat CT of the abdomen revealed worsening hepatic necrosis and formation of new abscesses. His clinical condition decompensated quickly thereafter requiring endotracheal intubation, mechanical ventilation and aggressive resuscitation. Percutaneous drain was placed and again, drained pus-like, foul-smelling material. His overall condition deteriorated, and he eventually expired a few days later.

Discussion:

Delayed (more than 4 weeks after transplantation) HAT is a rare complication of OLT with an estimated incidence of at around 2.8%¹.

Risk factors associated with development of HAT include Roux-en-Y biliary reconstruction, cold ischaemia and operative time, the use of greater than 6 units of blood, the use of greater than 15 units of plasma, and the use of aortic conduits on arterial reconstruction during transplant surgery².

Collateralization is more likely to develop after Live Donor Liver Transplantation (LDLT) than after whole-graft cadaveric OLT³. Therefore, the latter is also associated with increased risk of late HAT.

Although the clinical features of early HAT are well described, the features of delayed HAT are less clearly defined¹: the patient may present with manifestations of biliary sepsis or may remain asymptomatic for years. Right upper quadrant pain has been reported to occur in both immediate and delayed HAT. The clinical presentations may include recurrent episodes of cholangitis, cholangitis with a stricture, cholangitis and intrahepatic abscesses, and bile leaks¹. Doppler ultrasonography has been extremely sensitive for the detection of HAT in symptomatic patients during the immediate postoperative period but becomes less sensitive as the interval between transplantation and diagnosis of HAT increases because of collateral arterial flow⁴.

3D gadolinium-enhanced MRA provides excellent visualization of arterial and venous anatomy with a fairly high technical success rate. MRA is a useful adjunct in patients with indeterminate ultrasonography examination in patients who have renal insufficiency or who have allergy to iodinated contrast ⁵.

Antiplatelet prophylaxis can effectively reduce the incidence of late HAT after liver transplantation, particularly in those patients at risk for this complication⁶. Vivarelli et al reported an overall incidence of late HAT of 1.67%, with a median time of presentation of 500 days; late HAT was reported in 0.4% of patients who were maintained on antiplatelet  prophylaxis compared to 2.2% in those who did not receive prophylaxis⁶. The option of performing thrombolysis remains controversial. Whether thrombolysis is a definitive therapy or mainly a necessary step in the proper diagnosis of the exact etiology of HAT depends mostly on the particular liver center and needs further analysis⁷. Definitive endoluminal success cannot be achieved without resolving associated and possible instigating underlying arterial anatomical defects. Reestablishing flow to the graft can unmask underlying lesions as well as assess surrounding vasculature thus providing anatomical information for a more elective, better plan and definitive surgical revision⁷. Whether surgical revascularization compared to retransplantation is a viable option or only a bridging measure to delay the second transplantation has been a longstanding controversy in the treatment of HAT.

Biliary or vascular reconstruction do not increase graft survival and ongoing severe sepsis at the time of re-graft results in poor survival⁷. However, although uncommon, delayed HAT is a major indication for re-transplantation⁷. In the absence of hepatic failure, conservative treatment appears to be effective for patients with hepatic artery thrombosis.

C. perfringensis an anaerobic, gram-positive rod frequently isolated from the biliary tree and gastrointestinal tract. Inoculation of Clostridium spores into necrotic tissue is associated with formation of hepatic abscess⁸.

Necrotizing infections of the transplanted liver are rare. There have been around 20 cases of gas gangrene or necrotizing infections of the liver reported in the literature. Around 60% of these  infections were caused by clostridial species with C. perfringens accounting for most of them. Around 80% of patients infected with Clostridium died, frequently within hours of becoming ill^9,10. Those who survived underwent prompt retransplantation and the infection had not resulted in shock or other systemic changes that significantly decreased the likelihood of successful retransplantation⁸.

Because the liver has contact with the gastrointestinal tract via the portal venous system, intestinal tract bacteria may enter the liver via translocation across the intestinal mucosa into the portal venous system. Clostridial species can also be found in the bile of healthy individuals undergoing cholecystectomy^9,10.

The donor liver can also be the source of bacteria. Donors may have conditions that favor the growth of bacteria in bile or the translocation of bacteria into the portal venous blood. These conditions include trauma to the gastrointestinal tract, prolonged intensive care unit admissions, periods of hypotension, use of inotropic agents, and other conditions that increase the risk of potential infection ^8,9,10. C. perfringens sepsis in OLT recipients has been uniformly fatal without emergent retransplantation. Survival from C. perfringens sepsis managed without exploratory laparotomy or emergency treatment has been extremely rarely reported⁸. In those patients who survived, and in whom the infection has not resulted in shock or multiple organ failure, retransplantation may be successful⁸.

Although our patient survived his intensive care course, his recovery was tenuous as he quickly developed additional hepatic abscesses that led to his eventual demise. Post-mortem examination in our patient revealed intra-hepatic presence of Clostridium perfringens.

He was managed conservatively since he markedly improved both clinically and by liver function tests. Because of this, retransplantation was delayed. He was also already on antiplatelet prophylaxis.

Conclusion:

We report an interesting case of Clostridium perfringens hepatic abscess due to late HAT following OLT. Although the patient initially improved with non-surgical treatment, he eventually died. In similar cases, besides aggressive work-up and medical management retransplantation may be necessary for a better long term outcome.

Introduction

Hyperthyroidism is one of the most frequently encountered conditions in clinical endocrinology.¹ The modes of treatment available are antithyroid drugs, surgery and radioiodine (RAI) and although each of these is highly successful in controlling or curing hyperthyroidism none leads to permanent euthyroidism on a consistent basis. ² Although over the last three decades RAI therapy has replaced surgery as the leading form of definitive treatment ^{3, 4, 5} there is no universally accepted dose or regime for its use. Previous attempts to individualise the dose of RAI to reduce the rate of post-RAI hyper- or hypothyroidism have been unsuccessful ^{6, 7}. Fixed dose RAI administration has therefore become the most commonly used regime although the actual dose of RAI used varies considerably and ranges between 185MBq to 600MBq ^{8, 9}. For the last two decades we have used a fixed RAI dose of 550MBq for all patients. Others have used this regime with a high success rate ¹⁰ and a prospective head to head comparison with the calculated dose method found the fixed dose regimen to be superior for curing Graves’ hyperthyroidism ¹¹.

Conflicting results have been produced in several studies that have attempted to predict outcome following RAI therapy by correlating cure rate with various pre-treatment factors including age, gender, aetiology of hyperthyroidism, goitre size, use of antithyroid drugs, free thyroxine levels at diagnosis and thyroid antibody status. Various forms of calculated or low fixed dose RAI therapy have been used in these studies but no study used a high fixed dose of 550MBq. In this study we have evaluated the overall success rate of high fixed dose RAI therapy and attempted to identify simple clinical predictors of failure to respond the initial RAI dose. 

Patients and Methods

The study is a retrospective analysis of 584 consecutive patients referred to the Shropshire endocrinology service (Princess Royal Hospital and Royal Shrewsbury Hospital) over a 14 year period for the treatment of hyperthyroidism. These patients received RAI therapy at Royal Shrewsbury Hospital, which is the only centre providing facilities for RAI administration in the county of Shropshire and also draws referral from adjoining trusts in Powys, North Wales. Information for this study was obtained from the thyroid database which is maintained on all patients who have received RAI since 1985 at the above hospitals.

RAI was administered both as a primary (53%) and as secondary (47%) treatment. A majority of patients with moderate to severe hyperthyroidism were rendered euthyroid by antithyroid drugs (ATD). Ninety percent (518/584) patients were pre-treated to euthyroidism by antithyroid drugs (carbimazole in 95% and propylthiouracil in 5%) before RAI therapy. Carbimazole was withdrawn one week and propylthiouracil 4 weeks prior to RAI therapy. A standard RAI dose of 550MBq was administered to all patients without a prior uptake study. Thyroid function was measured at 6 weeks and at 3, 6 and 12 months following RAI therapy. ATD drugs were not recommenced routinely following RAI therapy and were reserved for patients who were persistently and significantly hyperthyroid following RAI administration. Patients who developed clinical and biochemical hypothyroidism after the initial 6-8 weeks were commenced on thyroxine. Patients with high free thyroxine level (FT4) and a suppressed thyroid stimulating hormone (TSH) level and those on antithyroid medication were defined as being hyperthyroid, those with low FT4 or on thyroxine as hypothyroid and those with normal FT4 and a normal or low TSH as euthyroid. At the end of one year if a patient remained hyperthyroid, another RAI dose of 550MBq was administered. The patient was considered to have been “cured” if euthyroidism or hypothyroidism was achieved during the first year following RAI therapy and “not cured” if patient remained persistent hyperthyroidism at the end of this period.

 Information recorded on the database included age, gender, aetiology, indication (primary or secondary), dose of RAI, number of RAI doses, name and duration of antithyroid drugs used, if any, and FT4 and TSH levels at diagnosis, at the time of RAI therapy and at 6 weeks, 3, 6 and 12 months after RAI therapy. Diagnosis of Graves’ disease was based on the presence of Graves’ ophthalmopathy or a combination of a diffuse goitre and a significant titre of thyroid peroxidase antibodies or if radionuclide scan showed diffuse uptake. Toxic nodular disease was diagnosed on the grounds of a nodular goitre and a focal increase in radionuclide uptake. Patients who could not be classified to either of the groups on clinical grounds and where a radionuclide scan could not be performed for a variety of reasons, were categorised as “unclassified” on aetiological grounds.

Statistical analysis

Continuous random variables were compared using t-tests and association of categorical variables by using chi-squared tests. The effect on outcome (cure of hyperthyroidism) of all variables was assessed by using logistic regression analysis and a step-wise routine was applied to choose the best set of predictors. All analyses were carried out by using NCSS2000.

Results

Data on 584 patients was included with a mean age of 56 years (range 20-90) and a female preponderance (82%). Assessment of the aetiology of hyperthyroidism was made by the above-mentioned criteria. In 110(15%) patients precise aetiological diagnosis could not be made. 344/474 (72%) patients had hyperthyroidism secondary to Graves’ disease and 134/474(28%) had toxic nodular disease. 518 patients received pre-RAI antithyroid medications. Mean free thyroxine level at time of diagnosis was 45.4pmol/L in 259 patients in whom this information was available.  Data for thyroid status at 3, 6, and 12 months post-radioiodine were available in 97, 94 and 100% patients respectively (see Table 1).

Table 1: Thyroid status at 3, 6 and 12 months

FT4 values were entered onto the database more recently and this result was available in 259 patients. The group of patients where FT4 data was available was comparable to the group where this information was not available in all respects apart from age (mean age (SD) 54 (±15) vs 58 (±14) years respectively, p<0.02). Similarly, the group of patients in whom the aetiology could not be ascertained was not different from the group where the aetiology could be identified in any respect apart from the age (mean age (SD) 60 (±13) vs 55 (±15) respectively).

Table 2 – Forward Stepwise (Wald) logistic regression analysis to identify factors independently associated with failure to respond to first dose of RAI

* Regression analysis carried out with free T4 as a continuous variable and separately as a categorical variable at a cut off of 45pmol/l

One year following RAI treatment, 543(93%) patients were either euthyroid (162;28%) or hypothyroid (383;65%) and considered “cured”; 39(7%) patients remained hyperthyroid and required further doses of RAI, with 34(6%) patients requiring two doses and 5(1%)  patients three doses. At 3 months, 484 out of 571 (85%) patients, and at 6 months, 490 out of 549 (89%) patients were “cured” (table 2). On univariate analysis no correlation could be established between the failure to respond to the first dose RAI and age, gender, aetiology or use of antithyroid medication (p = ns for all) although the rate of hypothyroidism was significantly higher at the end of one year in patients with Graves’ disease as compared to those with toxic nodular disease (77.1% vs. 50.3%, p<0.01). These results were not affected by limiting the analyses to any of the following groups: only those patients in whom the aetiological diagnosis could be made (n=478), only those patients in whom FT4 value was available (n=259) or only those patients where both FT4 was available and aetiology could be ascertained (n=209). On univariate analysis FT4 at diagnosis was associated with the outcome when it was used as a continuous variable (p<0.05) or as a categorical variable with the cut off set at mean FT4 value of 45pmol/L (p=0.01) and high values were associated with failure to respond to the first dose of RAI (mean ± SD, 57.28±20.1 v 44.58±16.1 pmol/L, p<0.05). On multivariate analysis with all variables, FT4 was found to be independently associated with outcome and again this association was seen when FT4 was used as a continuous variable (p=0.01) as well as a categorical variable (p=0.02). On using step-wise selection routine only FT4 could be chosen as a predictor when criterion for selection was set at p=0.05 and a value of over 45pmol/L predicted failure to respond to the first dose of RAI.

Discussion

The use of a standard fixed-dose RAI therapy is gaining increasing popularity and several studies have now shown that formal estimation of the required dose based on the thyroid size and iodine kinetics does not lead to a higher cure rate ^6,7,10,11 or a lowerhypothyroidism rate ⁷. For several years we have used 550MBq dose for all patients of hyperthyroidism. The overall success rate with this regime was 93% and only 7% of patients required a repeat RAI dose. These figures are comparable to those from most other centres, which have used a similar dose of RAI ¹⁰. In addition to achieving a high cure rate, hyperthyroidism was controlled rapidly with 85% of the patients becoming either euthyroid or hypothyroid within 3 months of treatment. Early onset of hypothyroidism (>70% at 12 months) facilitated institution of thyroxine replacement therapy during the first year during which the patients were being closely followed.

The use of a relatively higher dose of RAI leads to more stringent restrictions to the normal life of patients and these have to be followed for a longer period of time than is the case with the use of a lower dose. Majority of patients accept these restrictions at the prospect of a cure of hyperthyroidism. However, even at this dose, 7% of patients required repeat dosing which in turn led to another restrictive period for these patients. In view of this it is useful to be able to predict failure of the first dose in an individual patient. This would enable us to warn these patients about the higher possibility of requiring repeat dosing, further period of post-RAI restrictions and target them for a closer follow up. To allow us to make this prediction we correlated simple clinical pre-treatment variables to the need for repeat dosing. We found that there was no statistically significant correlation between age, gender, aetiology and the use of anti-thyroid medication prior to RAI and the outcome following RAI therapy although a high free thyroxine level at diagnosis predicted a failure of the first dose to achieve a cure of hyperthyroidism. There are several conflicting reports in the literature on the correlation between these factors and the response to RAI therapy. Most of the studies have failed to show a significant association between the age of the patient and the outcome irrespective of whether the age was used as a continuous or a categorised variable ^12-15 although in a study where a standard 150 gray RAI was used age >50 was found to be associated with a higher failure rate ¹⁶. In one study, male gender was associated with a lower cure rate following a single dose of RAI in patients with Graves’ disease ¹² although others have failed to confirm this association ^13,14. Use of antithyroid drugs prior to RAI has been shown to independently reduce the success rate of RAI ^{17, 18} while other studies have shown such an association with the use of propylthiouracil but not with carbimazole ^{19, 20}. Literature on the association between the aetiology of hyperthyroidism and the outcome is even more confusing. Patients with toxic nodular disease have been considered to be more radio-resistant as compared to patients with Graves’ disease ²¹ although opposite results have also been noted ²². In other studies no correlation could be established on multivariate analysis between the aetiology and outcome following RAI ^{14, 18}. Our study is the only one which analyses the influence of these factors on the outcome following the use of a standard 550MBq RAI dose and the above studies which have attempted to identify clinical predictors of outcome have either used various forms of the calculated dose regime or a lower fixed-dose RAI regime. We feel that this is the reason for the inconsistencies in the results and when a 550MBq dose RAI is used only FT4 value at diagnosis could predict the failure of RAI therapy to achieve cure. This dose of RAI appears to override the variations in the response induced by the remaining pre-treatment variables studied.

Studies using smaller doses or calculated doses of RAI have shown the outcome to be inversely associated with the thyroid size ^{14, 16} although this could not be ascertained in our study due to the lack of consistent documentation of the size ofgoitre in the clinical notes. In addition there are several possible confounding factors. Firstly the overall cure rate could have been influenced by the long period of time over which patients have been included (15 years) and the resulting changes in the criteria and threshold for the use of RAI. However if we divide the figures into 3 time periods of 5 years each, the findings remain consistent during each of these periods. Secondly, in over 50% of our patients, RAI was administered as a primary measure and it could be argued that a larger number of patients with milder hyperthyroidism may have been included in our cohort as compared to the patients at other centres where RAI is mainly reserved for patients who fail to respond to ATD. However there was no significant difference in the cure rate between those patients who received RAI as a primary measure and those in whom RAI was administered as a secondary treatment (94% v 93%). Thirdly in 15% of patients the aetiology could not be ascertained by using our well-defined criteria, mainly because of the practical difficulty of performing radionuclide scans in some of the patients where the diagnosis could not be made clinically. We do not feel that our results on the association between the aetiology and the cure rate were affected, as the patients with undefined aetiology were comparable to the remaining patients in all respects apart from age and had similar outcomes. Lastly the information on the FT4 value at diagnosis was available in only 259 patients. To exclude a selection bias this group was compared to the group of patients where this information was not available. Again the only difference between the two groups was the age distribution. In both instances this difference was not large (though statistically significant) and we do not feel it affected the outcome, especially as age does not appear to influence the outcome following RAI therapy. We could not assess the impact of post-RAI use of antithyroid drugs as these were not routinely restarted following RAI therapy at our centre.

In conclusion, high fixed dose RAI therapy is a very effective treatment for patients with hyperthyroidism and has a high success rate. Failure to respond to this dose cannot be predicted by most of the pre-treatment variables apart from the severity of the hyperthyroidism as judged by the FT4 value at diagnosis. Patients who present with severe hyperthyroidism should be warned regarding the higher possibility of requiring further doses of radioiodine even when treated with a dose of 550MBq.

Introduction

Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterised by simultaneous thyrotoxicosis, hypokalaemia, and paralysis that occurs primarily in males of South Asian descent.¹ Many affected patients do not have obvious symptoms and signs of hyperthyroidism and hence may be misdiagnosed or overlooked on presentation.² We hereby report a male patient who presented to us with weakness of all four limbs. The patient was evaluated and diagnosed to be having TPP.

Case History

A 30-year-old male patient, who was an agriculturist by profession, presented with weakness of all four limbs of one-day duration. The weakness first appeared in his lower limbs and then in the upper limbs. There were no sensory symptoms or bladder involvement. He was not a known hypertensive, diabetic or thyrotoxic patient. He was not on any medication for any significant illness.

On general physical examination, there was no pallor, icterus, cyanosis, clubbing, lymphadenopathy or pedal oedema. Multinodular goitre was noted on thyroid examination. There was no exopthalmos, lid lag, pretibial myxoedema or other signs of thyrotoxicosis.  Thyroid bruit was absent.  Pulse rate was 96/minute, blood pressure of 140/80mmHg, and respiratory rate 18/minute. On central nervous system examination, the higher mental functions and cranial nerve examination were within normal limits. Motor system examination showed the presence of flaccid quadriparesis with areflexia. Sensory system examination was within normal limits. Cardiovascular and respiratory system examination were normal.

Investigations revealed: haemoglobin (Hb) -13.1 gm%, total count (TC) - 11,400/cmm, platelet count - 49,000/cmm, random blood sugar (RBS) - 110mg/dl, blood urea - 29 mg/dl, serum creatinine - 0.8 mg/dl. Serum electrolyte profile showed sodium - 143 mEq/L, potassium - 2.2mEq/L, chloride - 112mEq/L. Serum calcium and magnesium levels were within normal limits. Electrocardiogram (ECG) was normal. Human Immunodeficiency Virus (HIV) ELISA was non reactive. Bone marrow biopsy and ultrasonography of abdomen were normal. Fine Needle Aspiration Cytology (FNAC) of thyroid showed features of hyperplastic colloid goitre. Ultrasonography of thyroid showed hyperechoic small nodules in both lobes as well as isthmus suggestive of multinodular goitre. Thyroid profile was: total T3 - 2.34 (normal: 0.60 - 1.81ng/ml), total T4 - 13.9 (normal: 4.5 - 10.9 mcg/dl), thyroid-stimulating hormone (TSH) - 0.01 (normal: 0.35 - 5.5IU/ml). Antithyroid antibodies and antiplatelet antibodies were negative. Nerve conduction study was normal. A final diagnosis of TPP with idiopathic thrombocytopenia was made.

The patient was administered 40mmol potassium chloride intravenously.  He was treated with tablet carbimazole 10mg three times a day and tablet propanolol 10mg twice a day. The patient’s weakness in all four limbs improved dramatically within an hour after potassium chloride administration. As he had persistent thrombocytopenia during his stay in hospital, he was commenced on tablet prednisolone (1mg/kg body weight). His platelet count normalized in one month after which the steroid dose was tapered and stopped.

Discussion

TPP is an uncommon disorder characterised by simultaneous thyrotoxicosis, hypokalaemia and paralysis that occurs primarily in males of South Asian descent. The overall incidence of TPP in Chinese and Japanese thyrotoxic patients is 1.8% and 1.9% respectively.^{3, 4} Sporadic cases have been reported in non-Asian populations such as Caucasians, Afro-Americans, American Indians and Hispanics. With population mobility and admixture, TPP is becoming more common in Western countries. Many affected patients are in the age group of 20 - 40 years and do not have obvious symptoms and signs of hyperthyroidism.⁵ The attack is characterised by recurrent, transient episodes of muscle weakness that range from mild weakness to complete flaccid paralysis. The proximal muscles are affected more severely than distal muscles.  Attacks usually first involve the lower limbs, and progress to the girdle muscles and subsequently the upper limbs. Sensory function is not affected. Although patients can present with quadriparesis that resembles Guillain-Barre Syndrome or transverse myelitis, the bladder and bowel functions are never affected. Patient may experience recurrent episodes of weakness that last from a few hours up to 72 hours with complete recovery between the attacks. In the majority of patients, deep tendon jerks are markedly diminished or absent although some patients may have normal jerks.

Patients with TPP usually experience the attacks a few hours after a heavy meal or in the early morning hours upon waking. More than two-thirds present to the emergency department between 2100 and 0900 hours; hence it was initially described as nocturnal palsy or night palsy.⁶ It has been shown that plasma glucose and insulin responses to meals are markedly higher in the evening than in the morning in control subjects. Such a phenomenon suggests a possible mechanism for the nocturnal preponderance of TPP. Another explanation could be the circadian rhythmicity of many hormones reaching their peak levels during sleep. Hypokalaemia is considered to be the most consistent electrolyte abnormality in TPP and a hallmark of the syndrome along with hyperthyroidism. It has been demonstrated that hypokalaemia is a result of potassium shift into cells and that it is not caused by total body potassium depletion.⁷ Patients with thyrotoxic periodic paralysis have an underlying predisposition for activation of Na+/K+-ATPase activity either directly by thyroid hormones or indirectly via adrenergic stimulation, insulin or exercise. Increased Na+-K+ ATPase activity is postulated to contribute to hypokalaemia.⁸

The majority of cases of hyperthyroidism associated with thyrotoxic periodic paralysis are due to Graves disease although other conditions including thyroiditis, toxic multinodular goitre, toxic adenoma, TSH secreting pituitary tumour, ingestion of T4 and inadvertent iodine excess have also been implicated.⁹ Assaying of thyroid function in patients with hypokalaemic paralysis distinguishes thyrotoxic periodic paralysis from other forms of hypokalaemic periodic paralysis. Thyrotoxic periodic paralysis occurs only in the presence of hyperthyroidism and is abolished when thyroid hormones are normalised.

Immediate therapy with potassium supplementation and beta-adrenergic blockers can prevent serious cardiopulmonary complications and may hasten recovery of periodic paralysis.¹⁰ Potassium chloride is given intravenously and/or orally. Regular potassium supplementation as prophylaxis against further paralysis when the patient has normal serum potassium level is ineffective. Effective control of hyperthyroidism is indicated to prevent recurrence of paralysis.

Conclusion

To conclude, although the association of thyrotoxicosis and periodic paralysis has been well known, TPP is often not recognised when first seen because of lack of familiarity with the disorder and partly because of the subtleness of thyrotoxicosis. When a young male of South Asian descent is initially seen with severe lower limb weakness or paralysis, TPP should be considered in the differential diagnosis and investigated for its presence since it is a curable disorder that resolves when euthyroid state is achieved.

An 80-year old lady was referred to a gastroenterology clinic in August 2009 with deranged liver function tests; alkaline phosphatase 180 IU/L (35-120), alanine transferase 147 IU/L (<40), gamma glutamyl transferase 384 IU/L (<45) and globulins 45 g/L (20-35).  She had initially presented to her general practitioner with symptoms of lethargy and malaise four months previously. She denied any symptoms of obstructive jaundice and there were no risk factors for hepatitis; she seldom consumed alcohol. 

Past medical history included osteoarthritis, migraines and recurrent urinary tract infections; these had been investigated by urology and the patient had undergone cystoscopy and urethral dilatation in September 2003; despite this she continued to experience urinary tract infections and was therefore commenced on prophylactic nitrofurantion by her General Practitioner with approval by the Urologist.  This was initially commenced at 50mg at night.  This regime was continued for approximately three years however during this time she had a further three treatment courses of nitrofurantoin.  In October 2005 her prophylactic dose was therefore increased to 100mg at night. Other medication included lansoprazole 30mg daily, pizotifen 500 micrograms at night, metoprolol 100mg twice daily, simvastatin 10mg at night, senna 15mg at night and furosemide 40mg daily.

On examination there was evidence of palmar erythema and Dupuytren’s contractures but no other stigmata of chronic liver disease.  The liver was tender and palpable 4 cm below the costal margin. A liver ultrasound was performed which was normal.  Liver screen and autoimmune profile are shown in table 1; notably a positive nuclear antibody was found (1 in 1280 IgG) with Hep 2 cell staining showing a homogenous (ANA) pattern at 1:320 IgG, and a nuclear lamin pattern at 1:1280 IgG;.  Due to the positive ANA and raised globulins a suspected diagnosis of nitrofurantoin-induced autoimmune hepatitis was made and a liver biopsy performed.