The Role of Human Immunodeficiency Virus-Associated Vasculopathy in the Etiology of Stroke.

Background: Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms. Methods: We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011. Results: We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 [38%]), followed by opportunistic infections (16 [25%]). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution-like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001). Conclusions: HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. METHODS: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. FINDINGS: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. INTERPRETATION: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. FUNDING: Bill & Melinda Gates Foundation.

Differences in the nature of stroke in a multiethnic urban South African population: the Johannesburg hospital stroke register.

BACKGROUND AND PURPOSE: The burden of stroke is increasing in Sub-Saharan Africa (SSA) as the population undergoes epidemiological and demographic transition. Little is known about the nature (risk factors, stroke type and subtype, and causes) of stroke in SSA and whether it differs from stroke in high-income populations. We aimed to compare the nature of stroke between black and white populations in South Africa. METHODS: We used overlapping sources to ascertain consecutive first-ever-in-a-lifetime stroke patients admitted to Johannesburg Hospital over 23 months. We assessed each patient's demographic details, risk factors, CT confirmed pathological stroke type, ischemic stroke subtype and stroke severity, and compared the nature of stroke between black and white stroke patients. RESULTS: 524 patients with presumed stroke were referred. Of these, 432 were first-ever strokes; 308 patients were black and 76 white. Black patients were significantly younger (mean age 51) than white patients (61). Stroke severity was similar (median NIH stroke score 10; 95% CI 8 to 11). More black than white patients had cerebral hemorrhage (27% versus 15%), lacunar stroke (28% versus 22%) and total anterior circulation infarcts (28% versus 22%). Large vessel atherosclerosis (none detected) and ischemic heart disease were very uncommon (1%) as a cause of stroke in black patients. Hypertension (70% versus 68%) and diabetes (14 versus 15%) were as common in black and white stroke patients, but mean cholesterol levels were lower (4.6 mmol/L; 95% CI 4.3 to 4.9 versus 5.3 mmol/L; 4.8 to 5.7) and cigarette smoking less frequent in black patients (23 versus 54%). CONCLUSIONS: Although this was a hospital-based study, the difference in the nature of stroke between black and white stroke patients likely reflects the profile of stroke risk factors. There is an opportunity to prevent an otherwise inevitable increase in atherosclerotic stroke (and IHD) by targeting dietary and smoking habits in the black South African population.

Accuracy of the Siriraj and Guy's Hospital Stroke Scores in urban South Africans.

BACKGROUND AND PURPOSE: The burden of stroke in sub-Saharan Africa is already high and likely to increase, but few patients with stroke have access to brain imaging. Distinguishing pathologic stroke types is relevant both for clinical management and epidemiologic studies. We assessed the accuracy of two stroke scores in distinguishing stroke types in a population known to have a high prevalence of intracranial hemorrhage but low prevalence of atherosclerosis and compared them with the clinicians' assessment of stroke type with computed tomography brain scanning as the "gold standard." METHODS: We assessed the stroke scores and the clinicians' blind assessment of pathologic stroke type in consecutive black patients with stroke included in the Johannesburg Hospital Stroke Register over 23 months. We calculated the accuracy of the scores and clinicians compared with computed tomography brain scan (sensitivity, specificity, positive predictive value, likelihood ratio, kappa statistic). RESULTS: Two hundred twenty-two patients were scanned and assessed within 15 days. Sixty-two (28%) had cerebral hemorrhage and nine (4%) subarachnoid hemorrhage. Neither the Siriraj (sub-Saharan Africa) nor Guy's Hospital score was accurate or offered much advantage over clinician assessment (sensitivity 0.60 and 0.34, specificity 0.88 and 0.95 for intracranial hemorrhage in the Siriraj Stroke Score and Guy's Hospital Stroke Score, respectively; sensitivity 0.70 and 0.71, specificity 0.84 and 0.74, respectively, for ischemic stroke). Although the scores were more accurate when we used new cutoff points, they then failed to diagnose over 80% of stroke types. CONCLUSIONS: The Siriraj Stroke Score and Guy's Hospital Stroke Score are not sufficiently accurate for use in either epidemiologic studies or to guide clinical management in sub-Saharan Africa at present.

Burden of stroke in black populations in sub-Saharan Africa.

Sub-Saharan Africa is undergoing epidemiological transition. Stroke and other vascular diseases increasingly contribute to the burden of disease. There are no systematic reviews of stroke mortality, prevalence, incidence, and case fatality. We combined a thorough search and critical assessment of the published research. Stroke mortality is as high, perhaps higher, than in high-income regions and increases with age in sub-Saharan Africa as in high-income countries, but the absolute number of stroke deaths remains low. There are no adequate community-based stroke incidence studies. Hospital-based incidence is lower than in high-income regions, but higher in young people, possibly due to hospital admission bias. There are no community-based data on case fatality, but hospital-based case fatality is higher than elsewhere. The prevalence of stroke is lower than in high-income regions, but disabling stroke is as prevalent. As the region develops economically, the incidence of stroke and other vascular diseases will increase unless interventions are implemented. Only community-based incidence studies will accurately reveal the burden of stroke.

Understanding and managing hypertension in an African sub-district: a multidisciplinary approach.

AIMS: To use a multidisciplinary approach to describe the prevalence, lay beliefs, health impact, and treatment of hypertension in the Agincourt sub-district. METHODS: A multidisciplinary team used a range of methods including a cross-sectional random sample survey of vascular risk factors in adults aged 35 years and older, and rapid ethnographic assessment. People who had suffered a stroke were identified by a screening questionnaire followed by a detailed history and examination by a clinician to confirm the likely diagnosis of stroke. Workshops were held for nurses working in the local clinics and an audit of blood pressure measuring devices was carried out. RESULTS: Some 43% of the population 35 and over had hypertension. There was no relationship with gender but a strong positive relationship with age. Illnesses were classified by the population as being either African, with personal or social causes, or White/Western, with physical causes. The causes of hypertension were stated to be both physical and social. Main sources of treatment were the clinics and hospitals but people also sought help from churches and traditional healers. Some 84% of stroke survivors had evidence of hypertension. Few people received treatment for hypertension, although good levels of control were achieved in some. Barriers to providing effective treatment included unreliable drug supply and unreliable equipment to measure blood pressure. CONCLUSIONS: Hypertension is a major problem among older people in Agincourt. There is potential for effective secondary prevention. The potential for primary prevention is less clear. Further information on diet is required.

HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: A case-control study.

OBJECTIVE: To investigate HIV, its treatment, and hypertension as stroke risk factors in Malawian adults. METHODS: We performed a case-control study of 222 adults with acute stroke, confirmed by MRI in 86%, and 503 population controls, frequency-matched for age, sex, and place of residence, using Global Positioning System for random selection. Multivariate logistic regression models were used for case-control comparisons. RESULTS: HIV infection (population attributable fraction [PAF] 15%) and hypertension (PAF 46%) were strongly linked to stroke. HIV was the predominant risk factor for young stroke (≤45 years), with a prevalence of 67% and an adjusted odds ratio (aOR) (95% confidence interval) of 5.57 (2.43-12.8) (PAF 42%). There was an increased risk of a stroke in patients with untreated HIV infection (aOR 4.48 [2.44-8.24], p < 0.001), but the highest risk was in the first 6 months after starting antiretroviral therapy (ART) (aOR 15.6 [4.21-46.6], p < 0.001); this group had a lower median CD4(+) T-lymphocyte count (92 vs 375 cells/mm(3), p = 0.004). In older participants (HIV prevalence 17%), HIV was associated with stroke, but with a lower PAF than hypertension (5% vs 68%). There was no interaction between HIV and hypertension on stroke risk. CONCLUSIONS: In a population with high HIV prevalence, where stroke incidence is increasing, we have shown that HIV is an important risk factor. Early ART use in immunosuppressed patients poses an additional and potentially treatable stroke risk. Immune reconstitution inflammatory syndrome may be contributing to the disease mechanisms.

Arterial ischemic stroke in HIV: Defining and classifying etiology for research studies.

HIV infection, and potentially its treatment, increases the risk of an arterial ischemic stroke. Multiple etiologies and lack of clear case definitions inhibit progress in this field. Several etiologies, many treatable, are relevant to HIV-related stroke. To fully understand the mechanisms and the terminology used, a robust classification algorithm to help ascribe the various etiologies is needed. This consensus paper considers the strengths and limitations of current case definitions in the context of HIV infection. The case definitions for the major etiologies in HIV-related strokes were refined (e.g., varicella zoster vasculopathy and antiphospholipid syndrome) and in some instances new case definitions were described (e.g., HIV-associated vasculopathy). These case definitions provided a framework for an algorithm to help assign a final diagnosis, and help classify the subtypes of HIV etiology in ischemic stroke.

Prevalence and risk factors for active convulsive epilepsy in rural northeast South Africa.

RATIONALE: Epilepsy is among the most common neurological disorders worldwide. However, there are few large, population-based studies of the prevalence and risk factors for epilepsy in southern Africa. METHODS: From August 2008 to February 2009, as part of a multi-site study, we undertook a three-stage, population-based study, embedded within the Agincourt health and socio-demographic surveillance system, to estimate the prevalence and identify risk factors of active convulsive epilepsy (ACE) in a rural South African population. RESULTS: The crude prevalence of ACE, after adjusting for non-response and the sensitivity of the screening method, was 7.0/1,000 individuals (95% CI 6.4-7.6) with significant geographic heterogeneity across the study area. Being male (OR=2.3; 95% CI 1.6-3.2), family history of seizures (OR=4.0; 95% CI 2.0-8.1), a sibling with seizures (OR=7.0; 95% CI 1.6-31.7), problems after delivery (OR=5.9; 95% CI 1.2-24.6), and history of snoring (OR=6.5; 95% CI 4.5-9.5) were significantly associated with ACE. For children, their mother's exposure to some formal schooling was protective (OR=0.30; 95% CI 0.11-0.84) after controlling for age and sex. Human immunodeficiency virus was not found to be associated with ACE. CONCLUSIONS: ACE is less frequent in this part of rural South Africa than other parts of sub-Saharan Africa. Improving obstetric services could prevent epilepsy. The relationship between snoring and ACE requires further investigation, as does the relative contribution of genetic and environmental factors to examine the increased risk in those with a family history of epilepsy.

HIV infection and stroke: current perspectives and future directions.

HIV infection can result in stroke via several mechanisms, including opportunistic infection, vasculopathy, cardioembolism, and coagulopathy. However, the occurrence of stroke and HIV infection might often be coincidental. HIV-associated vasculopathy describes various cerebrovascular changes, including stenosis and aneurysm formation, vasculitis, and accelerated atherosclerosis, and might be caused directly or indirectly by HIV infection, although the mechanisms are controversial. HIV and associated infections contribute to chronic inflammation. Combination antiretroviral therapies (cART) are clearly beneficial, but can be atherogenic and could increase stroke risk. cART can prolong life, increasing the size of the ageing population at risk of stroke. Stroke management and prevention should include identification and treatment of the specific cause of stroke and stroke risk factors, and judicious adjustment of the cART regimen. Epidemiological, clinical, biological, and autopsy studies of risk, the pathogenesis of HIV-associated vasculopathy (particularly of arterial endothelial damage), the long-term effects of cART, and ideal stroke treatment in patients with HIV are needed, as are antiretrovirals that are without vascular risk.

Body size and blood pressure: an analysis of Africans and the African diaspora.

BACKGROUND: Blood pressure is directly and causally associated with body mass index (BMI) in populations worldwide. However, the relationship may vary across BMI in populations of African origin. METHODS: We compared the relationship between blood pressure and BMI in populations of African origin, using 13 samples from Africa, the Caribbean, the United Kingdom and the United States. We had access to data from individual participants for age, height, weight, blood pressure, and treatment of hypertension. Analysis was restricted to 18,072 participants (age 35-64 years; 44% men). We carried out multivariate regression analysis to estimate the relationship between blood pressure and BMI by country and by sex. The use of antihypertensive treatment was taken into account by exclusion and by sensitivity analysis. RESULTS: There was a positive relationship between both systolic and diastolic blood pressure and BMI. In men the slopes for systolic blood pressure varied from 0.27 mm Hg per kg/m (95% confidence interval = -0.01 to 0.56) in the United States to 1.72 mm Hg per kg/m (95% confidence interval = 0.92 to 2.53) in Ghana (Kumasi). In women, the slopes varied from 0.08 (-0.54 to 0.72) in South Africa to 1.32 (0.98 to 1.66) in the Republic of Congo. Similar variation in trends was seen for diastolic blood pressure. The higher the BMI, the shallower the slopes [-0.10 (-0.15 to -0.06) for systolic, -0.09 (-0.12 to -0.06) for diastolic]. No differences were seen after excluding persons who were being treated for hypertension. CONCLUSIONS: Blood pressure and BMI levels vary among populations of the African diaspora. The effect of BMI on blood pressure levels diminishes as BMI increases. These results suggest a complex relationship among excess body weight, adiposity, and energy expenditure.

Distribution of a subclinical marker of cardiovascular risk, the ankle brachial index, in a rural African population: SASPI study.

BACKGROUND: In sub-Saharan Africa, hypertension and stroke are emerging as an important cause of death and disability, whereas coronary heart disease appears still to be uncommon. The aim of our study was to measure for the first time in an African population the ankle brachial index (ABI), which is known to be a good marker of subclinical atheroma and of the risk of future cardiovascular events. METHODS: The study was part of the Southern African Stroke Prevention Initiative (SASPI). It comprised a cross-sectional survey conducted in rural north-east South Africa in the sub-district of Agincourt, in which the demography of the population has been closely monitored. A stratified sample of 10 villages were selected and within these a random sample was chosen of 526 men and women aged 35 years and older. Subjects were visited on up to three occasions to be interviewed and have a clinical examination by specially trained nurses. This included an assessment of cardiovascular risk factors and measurement of the ABI (ratio of ankle : brachial systolic pressure) using a Doppler ultrasound machine. RESULTS: The sample comprised 322 subjects in whom the mean ABI (lower of either leg) was 1.05 in both men and women. The distribution of ABI was negatively skewed and a low ABI of 0.9 or less, indicative of significant atheroma and higher cardiovascular risk, increased with age from 3.9% in 40-49 year olds to 39.7% in those aged 70 years and older. Lower ABI was related to current cigarette smoking (P=0.02) and higher systolic and diastolic blood pressure (P<0.01, P=0.02, respectively) but not total cholesterol levels, which were relatively low in this population (mean 4.47 mmol/l). CONCLUSION: The distribution of the ABI in this rural African population was very similar to that reported in western populations, and suggests that this population has subclinical peripheral atheroma and is at an increased risk of future cardiovascular events, thus providing further evidence of an epidemiological transition towards cardiovascular disease.