Jeyaraj D. Pandian

Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study

Background: Global stroke epidemiology is changing rapidly. Although age-standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. Objectives: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. Methodology: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age-standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). Results: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. Conclusion: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority.

Prevalence, knowledge, attitude, and practice of epilepsy in Kerala, South India

Summary: Purpose: To ascertain the prevalence and pattern of epilepsy and to characterize and quantify knowledge, attitude, and practice (KAP) toward epilepsy among the people of the state of Kerala, which is distinguished from the rest of India by a high level of literacy and health awareness of its population.

Public Awareness of Warning Symptoms, Risk Factors, and Treatment of Stroke in Northwest India

Background and Purpose— This study assessed public awareness of warning symptoms, risk factors, and treatment of stroke in Ludhiana, Punjab, North West India. Methods— A hospital-based survey was conducted between February 2002 and September 2002 by the Stroke section of Christian Medical College. The study subjects were relatives of patients without history of stroke, attending the outpatient department of the hospital. Trained medical students, interns, and a nurse interviewed subjects using a structured, pretested, open-ended questionnaire. Results— Nine hundred forty-two individuals were interviewed during the study period (56.4% men, mean age 40.1 years, age range 15 to 80 years). Forty-five percent of the subjects did not recognize the brain as the affected organ in stroke. In the multivariate analysis, higher education (P<0.001; odds ratio 2.6; 95%, CI 1.8 to 3.8) and upper socioeconomic status (P<0.005; odds ratio 1.6; CI, 1.1 to 2.2) correlated with a better knowledge of which organ was affected in stroke. Twenty-three percent of the participants did not know a single warning symptom of stroke. Twenty-one percent of the subjects could not identify even a single risk factor for stroke. Seven percent of the study population believed that oil massage would improve stroke victims. A small proportion of subjects believed in witchcraft, faith healing, homeopathic, and ayurvedic treatment (3%). Conclusions— This hospital-based survey reveals a better awareness of stroke warning signs and risk factors. However, knowledge regarding the organ involved, etiology, and treatment of stroke is lacking. Considerable education is needed to increase public awareness in modern concepts of stroke treatment.

Stroke and Thrombolysis in Developing Countries

Abstract Background Over the past few decades, the burden of stroke in developing countries has grown to epidemic proportions. Two-thirds of global stroke occurs in low- and middle-income countries. We have found that little information is obtainable concerning the availability of thrombolysis therapy in developing countries. Summary of review The epidemiology of stroke is well investigated in the developed world; however, in the developing world stroke is less well documented. Most of the available stroke data from these countries are hospital-based. Stroke thrombolysis is currently used in few developing countries like Brazil, Argentina, Senegal, Iran, Pakistan, China, Thailand, and India. The two main barriers for implementation of thrombolysis therapy in developing countries are the high cost of tissue plasminogen activator and lack of proper infrastructure. Most of the centers with the infrastructure to deliver thrombolysis for stroke are predominantly private sector, and only available in urban areas. Conclusion Until a more cost-effective thrombolytic agent and the proper infrastructure for widespread use of thrombolysis therapy are available, developing nations should focus on primary and secondary stroke prevention strategies and the establishment of stroke units wherever possible. Such multi-faceted approaches will be more cost-effective for developing countries than the use of thrombolysis.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

BACKGROUND Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

Immune activation in the peripheral blood of patients with acute ischemic stroke.

Lymphocytes, neutrophils and macrophages are found in the brain in areas of acute ischaemic stroke. There is also evidence of modulation of systemic immune function after stroke, with post-stroke immunosuppression being observed. Because lymphocytes are activated in the peripheral immune compartment, before entry to the target organ, we reasoned that activated lymphocytes would be present in the circulation, prior to entering the brain, in patients after stroke. Because immune responses are controlled by regulatory mechanisms, we also reasoned that the post-stroke immunosuppression would involve T regulatory cells. The aim of the study was to look for evidence of immune activation and alterations in regulatory T cells in the peripheral blood of patients after acute ischaemic stroke, in comparison to age-matched healthy controls and patients with other neurological diseases (OND), and to determine the phenotype of the activated cells. The percentages of total and activated T cells, B cells, monocyte/ macrophages, and NK/NK-T cells were determined by labelling peripheral blood leukocytes with specific cell surface markers and analysis with 4-colour flow cytometry. The percentages of activated T cells and regulatory T cells were significantly increased in patients with ischemic stroke compared to healthy subjects and patients with OND. There was also an increase in the percentage of CCR7+ T cells. There were no significant differences in the activation of other cell types. In conclusion, there is evidence of immune activation and Treg cells in acute ischaemic stroke.

Poverty and Stroke in India A Time to Act

In developed countries, the predominant health problems are those lifestyle-related illnesses associated with increased wealth. In contrast, diseases occurring in developing countries can largely be attributed to poverty, poor healthcare infrastructure, and limited access to care. However, many developing countries such as India have undergone economic and demographic growth in recent years resulting in a transition from diseases caused by poverty toward chronic, noncommunicable, lifestyle-related diseases. Despite this recent rapid economic growth, a large proportion of the Indian population lives in poverty. Although risk factors for stroke in urban Indian populations are similar to developed nations, it is likely that they may be quite different among those afflicted by poverty. Furthermore, treatment options for stroke are fewer in developing countries like India. Well-organized stroke services and emergency transport services are lacking, many treatments are unaffordable, and sociocultural factors may influence access to medical care for many stroke victims. Most stroke centers are currently in the private sector and establishing such centers in the public sector will require enormous capital investment. Given the limited resources available for hospital treatments, it would be logical to place a greater emphasis on effective populationwide interventions to control or reduce exposure to leading stroke risk factors. There also needs to be a concerted effort to ensure access to stroke care programs that are tailored to suit Indian communities and are accessible to the large majority of the population, namely the poor.

Applicability of stroke-unit care to low-income and middle-income countries

Stroke units have become established as the central component of modern stroke services. However, most stroke-unit trials and service developments have been done in high-income countries, which raises the question of whether such care is relevant and applicable to low-income and middle-income settings. To address this question, we first need to show that stroke units are likely to provide important health gains to populations. Second, we need to identify those components of stroke units that could be important for a low-technology unit, and to learn from examples of stroke units in low-income and middle-income countries. Finally, we need to understand how barriers to the establishment of stroke units could be overcome. Although substantial challenges are present to the development of stroke units more widely across the world, the potential gains from such developments are substantial.

Psychosocial Problems, Quality of Life, and Functional Independence Among Indian Stroke Survivors

Background and Purpose— Data regarding psychosocial problems and quality of life (QoL) among stroke survivors from developing countries are scarce. The purpose of this study is to examine QoL, anxiety, depression, and functional independence of stroke survivors and the relationship of these variables with stroke characteristics. Methods— This was a prospective hospital-based study. Patients were interviewed after ≥1 month post stroke. World Health Organization QoL-BREF was used to assess QoL. Anxiety and depression measures were recorded using the Hospital Anxiety Depression Scale, and functional independence was evaluated using the Functional Independence Measure. Demography, stroke severity (measured by the National Institute of Health Stroke Scale), and stroke outcome (measured by the modified Rankin scale) were also documented. Univariate and multivariate analysis were completed using SPSS Statistics version 17.0 (SPSS, Inc, Chicago, Ill). Results— One hundred sixty-two patients participated (men=113, 69.8%); mean age was 54.3±12.9 years (range, 21–88 years). The mean duration of follow-up was 18.3 ±24.9 months (range, 1–180 months), and the mean National Institute of Health Stroke Scale score was 2.1±2.1 (range, 0–10). Presence of anxiety (odds ratio [OR] 0.20, CI 0.80–0.51, P=0.001), depression (OR 0.22, CI 0.10 to 0.47, P<0.0001), and functional dependence in Functional Independence Measure (OR 3.56, CI 1.70 to 7.42, P=0.001) were predictors of impaired QoL in the multivariate logistic regression analysis. Anxiety was seen in 39 patients (24%), and 60 patients (37%) had depression. Poor outcome predicted depression in logistic regression model (OR 4.40, CI 1.80 to 10.76, P=0.001). Functionally dependent patients were more likely to be older (OR 0.94, CI 0.92 to 0.97, P=0.001) and had severe stroke (OR 0.69, CI 0.53 to 0.88, P=0.004). Conclusion— Presence of anxiety, depression, and functional dependence were associated with impaired QoL. There was low prevalence of anxiety and depression. Older age and stroke severity resulted in increased functional dependence.

Rationale, Design, and Progress of the ENhanced Control of Hypertension ANd Thrombolysis Stroke Study (ENCHANTED) Trial: An International Multicenter 2 × 2 Quasi-Factorial Randomized Controlled Trial of Low- vs. Standard-Dose rt-PA and Early Intensive vs. Guideline-Recommended Blood Pressure Lowering in Patients with Acute Ischaemic Stroke Eligible for Thrombolysis Treatment

Rationale Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of iv rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. Aims The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) iv rt-PA; and (ii) early intensive BP lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). Design The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent, 2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] ‘rt-PA dose’ and/or Arm [B] ‘BP control’, using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. Study outcomes The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2–6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Results Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Conclusions Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.