Young Ischemic Stroke in South Asia : A review

Stroke in young adults may have early impact on quality of life in survivors. Uncontrolled stroke risk factors, lack of treatment facilities and a dense population has made its special significance in South Asia. The main aim of this study is to evaluate incidence, risk factors, etiology and clinical characteristics of young ischemic stroke in South Asia. Incidence of young stroke is more common in South Asian countries than developed western countries and has higher prevalence in rural areas. Traditional risk factors, such as hypertension, smoking, hyperlipidemia and diabetes are associated with majority of cases. Cardioembolism and undetermined etiology contribute to a large proportion of stroke etiology. Appropriate stepwise investigations are suggested to diagnose stroke of other determined etiology. Regular intake of drugs to control risk factors, cessation of smoking, and promote physical activity is suggested to reduce the burden of young stroke. Accepted on December 15th, 2012


INTRODUCTION
Stroke is a leading cause of death and long-term disability among young adults. 1,2It comprises about 85% of global death in developing countries. 3ost studies on young ischemic stroke were found to be conducted in developed countries.Young ischemic stroke is not a rare event in South Asia.But only a few studies have been reported and stroke is regarded as an under recognized burden here. 4According to United Nations statistics division, nine countries are included in South Asia: Afghanistan, Bangladesh, Bhutan, India, Iran, Maldives, Nepal, Pakistan, and Sri Lanka. 5outh Asia comprises of more than one fifth of the world population and its people scattered all around the world. 4Due to dense population and being in one of the poorest regions, most people in these countries are still abandoned from proper education system, unaware of controllable risk factors like hypertension, diabetes, habit of smoking and alcohol abuse, and lack of healthcare centers and experts.Studies have reported the higher frequency of young stroke patients in these regions than in western countries. 6,7South Asian stroke patients were also comparatively found to be younger than the stroke patients in western countries. 8,9 this review, we will describe the incidence, risk factors, etiology and clinical characteristics of young ischemic stroke from various countries in South-Asia.We will further discuss the characteristics of stroke in South Asian countries and other Asian or Western countries.

METHODS
We used "Pubmed" and "Google Scholar" for selection of relevant articles published between 1988 and 2012.The keywords used were: "stroke", "Ischemic stroke", "cerebral infarction", "incidence", "young stroke", "young adults", "etiology", "epidemiology", "female stroke" and "risk factors".These keywords were combined with name of each country in South Asia or their capital or famous place or ethnic group: for example," Nepalese young stroke", "etiology of stroke in Dhaka", etc. References from these articles were further checked for any related articles.Those articles which were written in English, or at least had English abstract were included.Inclusion criteria for the study were: (a) study should be conducted in South Asia or in South Asian people living in countries Seventeen relevant articles were found to have major discussion topic on incidence, risk factors, etiology and clinical features of young stroke in South Asia.Some of other articles which didn't discuss about young stroke, but have included the stroke patients < 50 years in their studies were also reviewed.Some studies were difficult to analyze and interpret due to the reason that their subjects weren't categorized according to agegroup.Most of the studies commonly focused on risk factors and etiology.Clinical characteristics and outcome were found to be reported only in few studies.In most studies, no extensive work-up was found to perform on the stroke cases of undetermined etiology.Maximum number of research papers on young stroke were found to be published from Indian studies.No published journal articles were found from Afghanistan, Bhutan and Maldives.

INCIDENCE
Incidence of stroke increases with the advanced age and usually high in male.Few studies have shown the predominance of female in age group below 35, but no such study was reported in South Asian study. 10,11 ge limit of young stroke was found to vary with different studies, and usually below 45 or 50 years were specified in most literatures.Prevalence of stroke was found to be more in rural than urban area. 12,13 he incidence of young ischemic stroke patients was found to be 5% in Pakistan (age≤45) 14 , 6% in Bangladesh 15 , 9.2% in Nepal (age≤40) 16 and 3.8% in India(age≤40). 17lthough no recent data relating incidence rate is reported from Sri Lanka, previous studies showed the higher stroke rate of about 10-30%. 9Similarly, a community study in Pakistan has reported about 30% of stroke patients are ≤ 45 years suggesting a high burden of young strokes. 18In another large population based Iranian study, incidence of young stroke patients was 7.9 per 100000 per year. 19In contrast to South Asian countries, young stroke was comparatively less in frequency in most of the developed countries 9 : 4.9% in United States (age<45) 20 and 6% in Germany (age≤45). 21

RISK FACTORS
Traditional risk factors of stroke are hypertension, diabetes, atrial fibrillation, smoking and dyslipidemia.Smoking, trauma, oral contraceptives, migraine, drug abuse, obesity, sedentary lifestyle and pregnancy are modifiable risk factors more frequent in young. 22Race, ethnicity, family history of stroke or Transient ischemic attack, and low birth weight were identified as other important non-modifiable risk factors of young stroke which are more prevalent in South Asian people. 23Multiple risk factors carries the higher risk of stroke, but no risk factors can also be identified in many cases. 24

Hypertension
Hypertension was found to be the most common risk factor of young stroke in many South Asian studies (Table1). 9,14,15 Sme studies showed that hypertension was more associated with intracerebral hemorrhage than cerebral infarction. 25,26 igh blood pressure is also related with increased risk of stroke death. 27The prevalence of hypertension is higher in South Asia and is predominant in urban areas: 23% in Pakistan, 17% in Sri Lanka and 20-40% in India. 28In a hospital based prospective study in Nepal, hypertension was reported 78% in patients ≥60years and 74% in patients of age-group 40-59 years 29 which is higher than other previous studies. 16,26  study in Pakistan reported the increase in frequency of young stroke is due to higher prevalence of early onset of hypertension in their community. 18Similarly, higher prevalence of hypertension was found among ethnic South Asian young strokes in United Kingdom and Singapore. 30,31

Hyperlipidemia
High level of total cholesterol or low density lipoprotein and low level of high density lipoprotein are associated with ischemic stroke. 32,33Table 1 shows the higher prevalence (83%) of hyperlipidemia among young stroke patients of age-group 15-45 years in Bangladesh. 34Hossain et al and Lipska et al also reported significant number of hyperlipidemic young strokes, 38% and 29% respectively. 15,17Study in Iran, Pakistan and Srilanka showed a relative less prevalence of hyperlipidemia among young stroke. 9,14,35,36A comparative study of ethnic South Asians and Whites in United Kingdom reported that the percentage of hyperlipidemic people was significantly higher among young South Asians. 8Various studies in Nepal have reported less prevalence of dyslipidemia in their studies. 26,37 n Indian study reported 9 young stroke patients of Familial hyperlipidemia, a rarely diagnosed condition in other studies. 38

Diabetes Mellitus
Diabetes is a known risk factor of stroke and its prevalence in younger age has been increasing worldwide. 39,40Worse prognosis and severe disability was found in stroke patients with diabetes. 41,42Diabetic patients in India were reported to be high, already exceeded 32.7 million in 2000. 28Similar higher trend of diabetes was seen in young stroke patients in India. 17revalence of diabetes in urban areas was found to be higher in Nepal and Bangladesh, 15% and 8% respectively. 43,44Among ischemic young strokes in South Asia, prevalence of diabetes mellitus was found comparatively lesser than other traditional risk factors, as shown in Table 1.

Smoking and Tobacco chewing
Cigarette smoking is a major independent risk factor for ischemic stroke, particularly in young. 45Relative risk of ischemic stroke may increase with the rate of smoking per day and also with the total duration of smoking. 46n a Nepalese stroke study, 60% young subjects were found to have habit of smoking. 26Tobacco chewing was found to be more common than smoking in a stroke study in Eastern Nepal. 16Strong association of smoking and young ischemic stroke has also been reported from India, Iran and Pakistan. 14,17,36,47 A opulation based case study in Bangladesh also found betel consumption as an important risk factor for stroke death. 12

Obesity
Obesity and lack of physical activity in young population are the reasons for high prevalence of risk factors for cerebrovascular diseases. 48arious studies in India and Pakistan reported significant incidence of obesity among stroke patients. 35,49 nique anthropometry and Thinfat phenotype among South Asians, where there is low Basal metabolic index and higher amount of central obesity, are the cardiometabolic risk factors. 50Abdominal obesity in young, which is more associated with atherosclerosis, hypertension and diabetes, is found to be more common in South Asians than westerners. 48,51 besity was found to be neglected in most studies of South Asian young stroke.So, a further epidemiological study on obesity in young stroke is needed.

Large and small artery atherosclerosis
Doppler ultrasonogram and angiography are the important tools to diagnose the atherosclerosis of large cerebral arteries.Small arterial atherosclerosis is a common finding in young adults with history of hypertension and diabetes. 52,53 ut atherosclerosis was found to be less common in most of the studies.This may be due to lack of use of vascular imaging applications in hospitals of South Asia.In a previous angiographic study, atherosclerosis of large vessels, especially internal carotid artery, was the major findings in young stroke in India. 54

Cardioembolism
Cardioembolism is a common cause for about 20% of ischemic stroke in young adults. 45South Asian studies have shown that Transesophagial echocardiography (TEE) has an important role to diagnose varieties of causes of cardioembolism among young stroke. 19,45 n an Indian study, TEE was also found to be superior to Transthoracic echocardiography (TTE) in detecting mitral valve prolapsed and other cardiac abnormalities.55 Figure 1 shows higher frequency of cardioembolism was present among young ischemic stroke patients of Hossain and Ghandehari.15,19 Valvular heart diseases, including congenital and acquired, were the major findings in their studies.Other common sources of cardioembolism in young stroke were infective endocarditis, cardiomyopathy, myxoma, acute myocardial infarction, akinetic ventricular segment, etc (Table 2).

Other determined etiology
Stroke of other determined etiology is an important finding in young strokes.Since angiography is not a routine investigation technique in most South-Asian countries, 14 diagnosis of arterial dissection is not common.However, Lipska et al have reported about 7% of arterial dissection in their study.In an etiological study of young stroke in 1984, meningovascular neurosyphilis in men and puerperal cerebral venous thrombosis in women were the common findings among Indian patients. 57][60][61][62] South Asian people are at higher risk of deaths and disabilities due to infectious diseases. 63Infectious diseases like meningitis, syphilis, malaria, borreliosis, varicella-zoster vasculopathy and cerebral vasculopathy due to human immunodeficiency virus are the well-known causes of stroke worldwide, but are unusual findings in most studies. 11,64,65In a study of young Pakistani patients, infective meningitis was recognized as a major cause of stroke (34%) as shown in Table 3. 25 Tuberculous meningitis (TM) was diagnosed in 53% and bacterial meningitis in remaining patients which showed the higher prevalence of infectious diseases in Pakistan.Since prevalence of TM among Nepalese adult patients was found to be high, central nervous system infections are important findings to be sought for in young strokes. 66

CLINICAL CHARACTERISTICS AND LESION PATTERN
Advance neuroimaging techniques such as Diffusion weighted imaging (DWI) and magnetic resonance angiography (MRA) have high degree of reliability in diagnosis of acute ischemic infarction in young patients and are frequently used in the study of lesion pattern and vessels status of cerebral arteries. 67Intracranial large artery disease was found to be common among ethnic South Asians in Singapore. 31Among major intracranial vessels, middle cerebral artery is the commonest site of stenosis in young patients. 54Ethnic South Asians in England reported higher frequency of lacunar infarction in younger age-group. 8In a study in Sri Lanka, OCSP (Oxfordshire Community Stroke Project) classification was used to classify the young stroke. 9They also reported the majority of cases were lacunar infarcts and partial anterior circulation infarcts, followed by posterior circulation infarcts.Hemiplegia or hemiparesis and dysarthria were the most common clinical presentations. 14,26 azzaq et al reported the parietal lobe as the most common site of infarction. 14They further categorized the infarction into large size(>3cm), medium size(1.5-3.0cm) and small size(<1.5cm)which were found in 46%, 20% and 34% of their young patients respectively.

AFGHANISTAN:
No studies regarding incidence on stroke cases has been reported from Afghanistan. 68In account of stroke mortality, WHO estimated 118.6/100,000 deaths in 2002. 69In their study, young women (15-49 years) showed the BMI ≥25kg/m² in 11.5% of cases which may be a rising risk factor for young stroke. 48,69 nother study in Kabul showed the significant hypertensive cases (14.33%) among university students. 70Risk factors like hypertension, diabetes and coronary artery diseases were also found to be highly prevalent in Afghani population. 71According to WHO data 2011, age adjusted stroke death rate in Afghanistan was estimated to be 109.47per 100,000 of population. 72

BHUTAN:
No surveys on incidence or prevalence of stroke have been reported from Bhutan.According to STEP 2007, risk factors like hypertension, diabetes, alcohol, lack of exercises, low intake of fruits and vegetables and high intake of salty butter tea "suja" are common in Bhutanese community. 73very single person of Bhutan is associated with 1-2 risk factors of noncommunicable diseases.Smoking is not acceptable in Bhutanese culture, and banning of Tobacco has made this risk factor less common in Bhutan. 74ccording to WHO data 2011, age adjusted stroke death rate in Bhutan was estimated as 117.68 per 100,000 of population. 75

MALDIVES:
According to Steps survey, risk factors like hypertension, diabetes, tobacco use, less physical activity, low consumption of fruits and vegetables, and obesity are highly prevalent, and are the major risk factors of stroke in Maldives. 7610-year risk of stroke was also high in poor community with higher predominance in male. 76World Health Organization (WHO) data has shown that 6.5% of total deaths in Maldives are due to stroke. 77ccording to WHO data 2011, age adjusted stroke death rate in Maldives was 37.56 per 100,000 of population. 78

CONCLUSION
Ischemic stroke in young in this region can mainly be attributed to hypertension and smoking.Hyperlipidemias, diabetes mellitus, obesity, less physical activity, stress and drug abuse are the rising risk factors.So, healthy lifestyle changes and pharmacological interventions should be aggressively applied to modify these risk factors.Valvular heart diseases, arterial dissection, cardiomyopathy, infective meningitis, autoimmune and genetic disorders are common findings.The cause of young stroke remained undetermined in majority of studies.A further extensive diagnostic work up is thus recommended to determine the etiology in young ischemic stroke.FAST (Face, Arm, Speech, Time) test, which is a useful way to diagnose stroke by paramedics, needs to be popularized in South Asian countries. 79Use of emergency thrombolysis is needed to be promoted in clinical practice which may lead to early neurological improvement and decrease post-stroke economic burden.Further, the services of stroke rehabilitation center should be considered to improve the stroke care facility and to decrease the death rate of stroke patients.

outside
South Asia; (b) acute ischemic stroke; (c) age equal to 50 or below during onset; (d) the study should have data related to incidence, risk factors, etiology or clinical characteristics.Exclusion criteria were: (a) cerebral or subarachnoid hemorrhages; (b) Transient ischemic attack.SPSS 14.0 was used to design the clustered bar diagram to graphically display the stroke subtypes in various studies.

Figure 1 :
Figure 1: Stroke subtypes in different South Asian studies of young ischemic stroke

Table 3
56splays frequency and distribution of various causes of stroke of other determined etiology with preferred investigations.Arterial dissection is an important cause of stroke among young adults in western countries.56