The burden, risk factors and unique etiologies of stroke in South-East Asia Region (SEAR).

The World Health Organization (WHO) South East Asia Region (SEAR) comprises 11 countries, which are one of the most culturally, topographically, and socially diverse areas worldwide, undergoing an epidemiological transition towards non-communicable diseases, including stroke and other cardiovascular diseases (CVDs). This region accounts for over 40% of the global stroke mortality. Few well-designed population-based epidemiological studies on stroke are available from SEAR countries, with considerable variations among them. Ischemic stroke, a common stroke subtype, has higher frequencies of intracerebral hemorrhage in many countries. Along with an aging population, the increased prevalence of risk factors such as hypertension, diabetes mellitus, tobacco and alcohol consumption, lack of physical activity, high ambient pollution, heat, and humidity contribute to the high burden of stroke in this region. SEAR's many unique and uncommon stroke etiologies include cerebral venous thrombosis, tuberculosis, dengue, scrub typhus, falciparum malaria, snake bite, scorpion sting, etc. Current data on stroke burden and risk factors is lacking, compelling an urgent need for high-quality hospital-level and population-level data in all SEAR countries. Strategies towards a consolidated approach for implementing improved stroke prevention measures, stroke surveillance, and established stroke systems of care are the path to bridging the gaps in stroke care.

Emerging tropical neurological infections.

A large majority of neurological infections remain undiagnosed worldwide. Emerging and re-emerging infections are likely to be responsible for a significant proportion of these. Over the last two decades, several new organisms producing neurological infection and the neurotropic potential of many other known pathogens have been identified. Large outbreaks caused by re-emerging pathogens such as Chikungunya virus, Zika virus and Ebola virus have led to better delineation of their neurological manifestations. Recognition of the pandemic potential of emerging pathogens and an improved understanding of their host-vector-environment interactions would help us be better prepared to meet these emerging threats.

Stroke in Sri Lanka: How Can We Minimise the Burden?

The burden of stroke in Sri Lanka is high and steadily increasing. Accurate estimation of the burden is hampered by a paucity of epidemiological data. More neurologists, stroke units, facilities for modern treatments and multi-disciplinary rehabilitation services are urgently needed. Essential drugs for risk factor control and secondary prevention are available in many hospitals. Aggressive preventive strategies and promoting stroke awareness are the best ways to minimise the stroke burden in Sri Lanka.

Awareness of clinical trial registration among healthcare professionals: An observational study.

AIM: Prospective registration in a freely accessible public platform is a key step in the ethical conduct of clinical trials. Little is known of the awareness of clinical trial registration among the scientific community. This study aimed to assess awareness of clinical trial registration among participants attending a medical congress in Sri Lanka. METHODS: Knowledge of trial registration was assessed using a self-administered questionnaire, which spanned domains such as involvement in research, and knowledge and perceptions regarding trial registration. A knowledge score was calculated and correlated with demographic variables. RESULTS: Of 251 survey respondents, 53.4% were male, 74.9% were below the age of 40 years, and 56.6% were currently engaged in research. Registration was considered necessary for trial publication by 73.3%, and 70.5% agreed that trials should be registered prospectively. Most achieved a knowledge score of 'Acceptable' (41%) or 'Good' (19.9%). Mid- or advanced career stages, postgraduate training, current involvement in research, and recent research publications/presentations were correlated with higher knowledge scores (P < 0.05). Beneficial effects considered to be associated with trial registration were access to findings of all trials (61.4%), access to negative results (47.8%), preventing trial duplication (69.3%), and preventing multiple publications (70.1%). Increasing research workload (49.8%), additional restrictions on research conduct (52.2%), and the possibility of 'intellectual theft' (56.2%) were seen as potential negative effects. CONCLUSIONS: Most participants were aware of the need for prospective registration as a requirement for publication of clinical trials. Concerns were expressed regarding several perceived negative effects of trial registration.

Ten years of clinical trial registration in a resource-limited setting: Experience of the Sri Lanka clinical trials registry.

AIM: We describe our experience of the first 10 years at the Sri Lanka Clinical Trials Registry (SLCTR). METHODS: We analyzed all trial records of the SLCTR over the study period. We collected information regarding trial characteristics and completeness of data entry in the SLCTR data set. RESULTS: During the study period, 210 trials (63% of all applications) were registered with the SLCTR. The number of registered trials showed an increasing trend over the years. All trial registrations had complete entries for all the data fields studied. Only 17.6% of the trials were registered retrospectively. All the registered trials were interventional studies, and the majority (87.6%) were randomized controlled trials. A significant proportion of trials (28.6%) were on noncommunicable diseases, and 12.4% were on pregnancy and its outcomes. Several trials (9.5%) were international collaborative studies. A majority of the Principal Investigators (70.9%) were affiliated to a university. Most of the studies (41.9%) were self-funded by the investigators. Details of ethics review committee approval were available for 96.7% of registered trials. Over a third of the registered trials (37.1%) had completed recruitment at the time of analysis. A majority of the trials (72.8%) had updated trial data since registration. CONCLUSIONS: There is a steady increase in the number of trials registered at the SLCTR. Complete entries for all the data fields were seen in all trial registrations. The SLCTR has made a positive contribution to the emergence of a healthy clinical research environment in Sri Lanka.

Case report of hypnic headache: a rare headache disorder with nocturnal symptoms.

BACKGROUND: Headache is one of the commonest complaints reported to physicians worldwide. Yet, arriving at the proper diagnosis can be a challenge in many patients. Although most headaches belong to common categories of migraine and tension-type headache, which are diagnosed and managed relatively easily, several uncommon headache disorders can lead to delays in diagnosis. Certain medications are more efficacious than others in managing these headache disorders, hence establishing the correct diagnosis is of paramount importance. CASE PRESENTATION: An 86-year-old female presented with chronic daily headache of 1 year duration. Her headaches were exclusively nocturnal and woke her up daily around midnight. Clinical examination was unremarkable. All basic investigations were normal. Subsequent gadolinium enhanced Magnetic Resonance Imaging (MRI) brain did not show any significant pathology. There was no satisfactory response to paracetamol, diclofenac sodium, mefenamic acid, tramadol, flunarizine and sodium valproate. Indomethacin was started with the provisional diagnosis of hypnic headache. There was absolute response by day 3 of indomethacin. She remains headache free on low dose indomethacin maintenance at 1 year after the diagnosis. CONCLUSION: Better understanding of uncommon headache syndromes can help in early diagnosis and appropriate treatment. Hypnic headache should be considered in the differential diagnosis of chronic daily headaches, especially when nocturnal and occurs during sleep.

Neurotoxicity in snakebite--the limits of our knowledge.

Snakebite is classified by the WHO as a neglected tropical disease. Envenoming is a significant public health problem in tropical and subtropical regions. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. Acute neuromuscular weakness with respiratory involvement is the most clinically important neurotoxic effect. Data is limited on the many other acute neurotoxic manifestations, and especially delayed neurotoxicity. Symptom evolution and recovery, patterns of weakness, respiratory involvement, and response to antivenom and acetyl cholinesterase inhibitors are variable, and seem to depend on the snake species, type of neurotoxicity, and geographical variations. Recent data have challenged the traditional concepts of neurotoxicity in snake envenoming, and highlight the rich diversity of snake neurotoxins. A uniform system of classification of the pattern of neuromuscular weakness and models for predicting type of toxicity and development of respiratory weakness are still lacking, and would greatly aid clinical decision making and future research. This review attempts to update the reader on the current state of knowledge regarding this important issue.

Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis.

BACKGROUND AND PURPOSE: High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack≥6 months previously. METHODS: A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 µg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score<24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. RESULTS: A total of 3089 participants (38%) voluntarily undertook the MMSE>6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 µmol/L versus 14.2 µmol/L; P<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855). CONCLUSIONS: Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.

Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial.

BACKGROUND: Previous studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transient ischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial. METHODS: In the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), and 500 µg vitamin B(12)) and followed up for a median 3·4 years (IQR 2·0-5·5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. FINDINGS: At baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of the participants taking antiplatelet drugs at baseline, B vitamins had no significant effect on the primary outcome (488 patients in the B-vitamins group [15%] vs 519 in the placebo group [16%]; hazard ratio [HR] 0·94, 95% CI 0·83-1·07). By contrast, of the participants not taking antiplatelet drugs at baseline, B vitamins had a significant effect on the primary outcome (123 in the B-vitamins group [17%] vs 153 in the placebo group [21%]; HR 0·76, 0·60-0·96). The interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome was significant after adjusting for imbalance in the baseline variables (adjusted p for interaction=0·0204). INTERPRETATION: Our findings support the hypothesis that antiplatelet therapy modifies the potential benefits of lowering homocysteine with B-vitamin supplementation in the secondary prevention of major vascular events. If validated, B vitamins might have a role in the prevention of ischaemic events in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy. FUNDING: Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, and Singapore National Medical Research Council.

Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial.

BACKGROUND AND PURPOSE: To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack. METHODS: A total of 8164 patients with recent stroke or transient ischemic attack were randomly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), 500 µg vitamin B(12)) and followed for a median of 3.4 years for any cancer as an adverse event. RESULTS: There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo (4.04% versus 4.59%; risk ratio, 0.86; 95% CI, 0.70-1.07) and no difference in cancer mortality (2.35% versus 2.09%; risk ratio, 1.09; 0.81-1.46). Among 1899 patients with diabetes, the incidence of cancer was higher among participants assigned B vitamins compared with placebo (5.35% versus 3.28%; adjusted risk ratio, 2.21; 1.31-3.73), whereas among 6168 patients without diabetes, the incidence of cancer was lower among participants assigned B vitamins compared with placebo (3.66% versus 5.03%; adjusted risk ratio, 0.67; 0.51-0.87; P for interaction=0.0001). CONCLUSIONS: Daily administration of folic acid, vitamin B(6), and vitamin B(12) to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack.

The Sri Lanka Clinical Trials Registry--moving forward.

The Sri Lanka Clinical Trials Registry (SLCTR) is a Primary Registry in the Registry Network of the World Health Organization's International Clinical Trials Registry Platform (WHO-ICTRP), and regularly feeds data to its Clinical Trials Search Portal. Over the last few years, the SLCTR has been able to achieve its original objective of providing a national trial register for Sri Lankan researchers, but its role has always been more than that of a mere storehouse of trial data. The research landscape is rapidly changing in Sri Lanka, and the SLCTR has been a key stimulus to a resurgent interest in clinical research among the Sri Lankan research community. The SLCTR is working together with its partner stakeholders to facilitate research in the country, and to ensure that clinical trials conducted in Sri Lanka meet the highest ethical and scientific standards.

Establishing the Sri Lanka clinical trials registry.

Recognizing the need for a national body for trial registration, the Sri Lanka Medical Association took up the challenge of setting up the Sri Lanka Clinical Trials Registry. The registry was established in November 2006, the first functioning trial registry in South Asia. The Sri Lanka Clinical Trials Registry is now a primary registry affiliated to the Registry Network of the International Clinical Trials Registry Platform of the World Health Organization. The Sri Lanka Clinical Trials Registry has not been a mere repository for trial data but has also had a positive influence on the research community in Sri Lanka.