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Hemorrhagic Stroke in the Tropics

Michael J. Schneck, M.D.; José Biller, M.D.

November 15, 2005

Abstract and Introduction

Abstract

With the increasing industrialization of countries in the tropical and subtropical regions, cerebrovascular disease is becoming an increasingly recognized cause of morbidity and mortality. The incidence of hemorrhagic stroke versus ischemic stroke is unclear as data regarding hemorrhagic stroke in developing countries of the tropical and subtropical regions, especially in the English literature, continues to be sparse. As in the developed world, however, the major etiologies for hemorrhagic stroke in developing countries relate to typical vascular risk factors and, to a lesser extent, central nervous system vascular malformations, medications, and infectious etiologies.

Introduction

Cerebrovascular disease is probably the second most common cause of death on our planet.[1] Although cardiovascular disease is often described as a disease of industrialized countries, stroke is also rampant in the developing world. Countries in the developing world, predominantly centered on the equator, have a large burden of cerebrovascular disease for which the diagnosis and treatment is particularly challenged by the overall lack of economic resources in their health care systems.

Stroke is epidemic in the tropics with the frequency of disease estimated between 0.35 and 1.83 per 1000 in South America.[2] Although in developed countries, hemorrhagic stroke is responsible for ~15 to 20% of all stroke, the percentile of cerebrovascular disease represented by hemorrhagic stroke in the tropics is less clear.[3,4] The incidence of hemorrhagic stroke may be higher in the equatorial regions, but this may reflect ascertainment bias as most of the stroke subtype data are hospital-based and ischemic stroke may be less likely to have neuroimaging in developing countries.

Nevertheless, there may be some validity to the observation of an increased rate of intracranial hemorrhage in the tropics compared with ischemic stroke on the basis of various ethnicity and stroke studies in Western countries. Several studies in the United States, for example, suggest that African-Americans, Asian-Americans, and Hispanic-Americans have an increased frequency of hemorrhagic stroke compared with Caucasians. In the United States, the Northern Manhattan Stroke Study of Hispanics, Caucasians and Blacks and the Greater Cincinnati/Northern Kentucky Stroke Study both reported that the nonwhite populations had a greater incidence for all stroke subtypes including hemorrhagic stroke.[4,5] Similarly, in studies of migrants from South Asia to the United Kingdom, the risk of stroke was described as 1.5 times greater compared with Europeans, and African-Caribbean persons have stroke rates that are 1.5 to 2.5 times greater.

Reports from South America, Africa, and parts of Asia suggest that there are increased numbers of hemorrhagic strokes as a percent of all stroke admissions to the hospital compared with the industrialized countries. The community prevalence of stroke in South America ranges from 1.74 to 6.51 per 1000, with annual incidence rates from 0.35 to 1.83 per 1000. Hospital-based registries in South America suggest a hemorrhage rate of ~26 to 46%. In Joinville (Brazil), of 429 cases, 25.9% had an intracranial hemorrhage. In Guayaquil (Ecuador), 37.4% of 500 cerebrovascular cases were hemorrhagic strokes. In nonequatorial South America, 34% of 450 cases from Santiago (Chile) were cerebral hemorrhages and 12% were subarachnoid hemorrhages. Finally, in Buenos Aires (Argentina) the frequency of hemorrhages were higher among Argentinean natives versus white immigrants (34% versus 27%).[2]

Del Brutto reported that in Ecuador, 37.1% of patients admitted to a university hospital had intracranial hemorrhages exclusive of subarachnoid hemorrhage; 151 patients were described, aged 15 to 40 years, with nontraumatic intracerebral hemorrhage. Lobar hemorrhages were found in 41.7% of cases, putaminal hemorrhages in 25.8% of cases, posterior fossa hemorrhages in 24% of cases, and other central nervous system (CNS) locations comprised 16.6% of cases. A possible cause was determined in 72.2% of cases, with hypertensive disease (39.7%) and saccular aneurysms or other CNS vascular malformations comprising 21.9% of the cases.[6]

In the Caribbean, however, the frequency of ischemic versus hemorrhagic stroke appears to parallel to a greater extent the incidence rates described in the United States and Europe. As an example, stroke is a major cause of death in Jamaica. In the French West Indies, stroke is the single leading cause of death in adults.[7] In Martinique, which is one of the most developed islands in the Caribbean, a prospective community-based study of hospitalized and nonhospitalized patients with first-ever stroke in 1998 to 1999 showed a crude annual incidence of 164/100,000 per year.[7] Of these strokes, infarction comprised 79.8% of cases, intracerebral hemorrhage 14.3%, and subarachnoid hemorrhage 3.4%. Major risk factors for stroke were arterial hypertension (69.1%) and diabetes (29.5%). The 30-day case fatality rate was 19.3% (15.8% for ischemic stroke and 37.3% for hemorrhagic stroke). The authors concluded that epidemiological data on stroke among African-Caribbean persons from Martinique seemed comparable to those observed in the United States and the United Kingdom.

By contrast to Latin America, much less data are available on stroke subtypes in sub-Saharan Africa. It has been suggested, however, that hemorrhagic stroke is more common in sub-Saharan Africa. In a report from one hospital in Tanzania of patients who had a computed tomography (CT) scan in the period from April 2001 to May 2002, intracranial hemorrhages occurred in 89/148 cases (60.1%) and cerebral infarction in 59/148 case (39.9%).[8] In a study of adult persons in Tanzania, in urban, prosperous rural, and poor rural areas, 5.5% of deaths were attributable to stroke, with a yearly adjusted death rate for persons aged 15 to 64 years of 35 to 65 per 100,000 for men and 27 to 88 per 100,00 for women. The rates were highest in the urban area and lower in the poor rural area. The authors concluded that in Tanzania, there was an excess of hemorrhagic stroke compared with brain infarction. However, the difference in rates between rural and urban regions was not readily apparent. One can speculate that it may simply be related to ascertainment bias. However, the urban population may also have had greater exposure to Western cardiovascular risk factors including diet and cigarette use.

As to subarachnoid hemorrhage, previous observations claiming a low incidence of cerebral aneurysms in Africa, the Middle East, and Asia also appear to be unsupported based on an autopsy series from Morocco suggesting a similar incidence of aneurysms in the population compared with Western countries. Over time, an increasing number of subarachnoid hemorrhages related to aneurysmal rupture were described in that country. The authors hypothesized that previously reported differences between their series and other series describing both a male predominance and a younger age of subarachnoid hemorrhage reflect the following: a failure to diagnose, the younger overall age of the population in the developing world, and a gender bias against physician consultation in the developing world. In Morocco, the incidence of aneurysmal subarachnoid hemorrhage appeared to double every 5 years as better access to health care and advanced medical technologies improved evaluation and management of subarachnoid hemorrhage in that country. Similar findings may be likely in other parts of the developing world as well.[9]

In Asia, the rapid industrialization of China has thrust this country into the ranks of the developed world. With increased availability of CT scanning in China, a better estimate of the incidence of intracranial hemorrhage has become available. In the period from 1996 to 2000, 1.8% of patients had subarachnoid hemorrhage and 27.5% intracerebral hemorrhage in a series of 8268 first-ever stroke patients (with CT scan rate >75% in the study population). Mortality was similar to that reported in Western countries. There was a 33.3% 28-day case fatality rate for subarachnoid hemorrhage, and a 49.4% 28-day case fatality rate for intracerebral hemorrhage.[10]

However, the frequency of hemorrhagic stroke may be lower in South Asia compared with China and Japan. One report from India, in particular, suggested a low incidence of aneurysms clinically and by autopsy studies. The reported incidence of intracranial aneurysm was <1%.[11] Again, however, ascertainment bias may be a significant problem for these types of studies.

The problem of ascertainment bias is quite significant. Sudlow and Warlow, in a review of various international studies, noted that most of the Far Eastern studies showed an increased rate (35% higher) in intracerebral hemorrhage in Asians compared with Caucasians. Methodological issues, however, limit whether this observed higher incidence of hemorrhages is real, and the authors note that there was insufficient good clinical data from the Middle East, South America, Africa, and Asia.[12]

In a World Health Organization case control study of the risk of hemorrhagic stroke and use of oral contraceptives in Africa, Asia, Europe, and Latin America, only 23.6% of strokes in Africa were confirmed by magnetic resonance imaging (MRI) or CT. By contrast, in Europe only 0.8% of cases were diagnosed by "clinical criteria" of clinical history and spinal fluid analysis alone. In Africa, these clinical criteria were used in 70.6% of cases, in Asia in 9.9% of cases, and in Latin America in 4.6% of cases. The use of oral contraceptives was associated with an increased risk in developing countries but mainly among "older" women. Of note, oral contraceptive use risk was not higher among women from developing countries versus European women for younger patients, but more of the European women using oral contraceptives were younger when they started therapy.[13]

Causes of Hemorrhagic Stroke

The most common causes of intracranial hemorrhage in Western countries and the tropics are related to microvascular rupture, ruptured intracranial aneurysms, and other CNS vascular malformations, bleeding diatheses, cerebral amyloid angiopathy, neoplasm (primary or metastatic), vasculitis, and recent drug abuse, although there may be a greater frequency of infectious etiologies in the tropical world. Overall, however, the etiologies and comorbid risk factors are probably similar in the industrialized world and in the tropics. In developed countries, the major comorbidities for hemorrhage include hypertension, male gender and age, and ethnicity. In the United States, African-Americans and Hispanics have a greater frequency of intracerebral hemorrhage compared with Caucasians.[4] Brott and colleagues reported that the associated relative risk of arterial hypertension for hemorrhage in African-Americans compared with Caucasians was 3.9, which was twice as high as the risk for ischemic stroke.[14] Other contributory risk factors include alcoholism and anticoagulant use.[14-18] From clinical trial data there is a suggestion that low serum cholesterol may also be a risk factor for intracerebral hemorrhage in Western countries.[19] It is interesting to speculate that previous reports of a greater frequency of hemorrhagic stroke in the developing world could reflect a diet less rich in animal proteins. As the developing world diet becomes more similar to that of Western countries, one unintended side effect could be an increase in the rate of ischemic stroke as opposed to hemorrhagic stroke (balanced out, of course, by the increase in hypertensive disease within the developing world).

Arterial hypertension and atherosclerotic cardiovascular disease are usually considered to be diseases of the industrialized countries. However, these problems are also common in the developing world. In particular, developing countries may actually be at greater risk as growth in industrialization rises without concomitant growth in available medical treatments for these disabilities. Although there has been a decline in cardiovascular mortality in developed countries, cardiovascular mortality has rapidly been increasing in developing countries.[20] It has been projected that cardiovascular mortality rates worldwide from 1990 to 2020 would double with 82% of that increase attributable to the developing world. Most of that increase has been attributed to classic risk factors such as arterial hypertension, diabetes, cigarette use, and hyperlipidemia.[21] In Africa, arterial hypertension is rampant, and only 5 to 10% of hypertensive persons have any blood pressure control.[22,23] In Asia, the prevalence is estimated at 15 to 35% in the urban adult populations; the prevalence is two to three times lower in the rural populations.[22,24] In the rapidly industrializing countries of South and Southeast Asia (including China and India), there has been a rapid increase in both arterial hypertension prevalence and stroke mortality.[24-26] In South America and the Caribbean, the rate of death from cardiovascular disease related to arterial hypertension and other common risk factors has increased to the extent that the ratio of deaths from cardiovascular disease versus infectious disease is expected to triple by 2020 in that region.[2,27,28] Hemorrhagic stroke may affect a younger population compared with ischemic stroke. In the tropics, both hemorrhagic and ischemic stroke often occur at a younger age compared with Western countries. This too may be partly related to ethnicity. In the United States, African-American children are at higher risk for ischemic stroke (RR 2.59), subarachnoid hemorrhagic (RR 1.59), and intracerebral hemorrhage (RR 1.66), compared with Caucasians. Hispanic children, however, had a lower risk, and Asian children seem to have a risk of stroke equal to that of Caucasians. This excess risk of stroke for African-Americans persisted even when eliminating cases with coexisting sickle cell disease.[29]

Overall, in the developing world, stroke appears to occur at a younger age. However, some of that may also reflect referral biases. In Brazil, 10.6% of all stroke admissions in one prospective university hospital study were among patients aged 15 to 40 years, but this could reflect a common bias seen in academic medical centers in the United States as well. Similar reports from university hospitals in Africa describe stroke onset at median ages younger than in Western countries.[30,31]

Although in general risk factors for hemorrhagic stroke are similar in the developing and developed world, certain diseases that have an infectious component or association are of particular relevance in the tropics. Compared with industrialized countries, infectious etiologies are more likely in the developing world to contribute to stroke risk.

In Africa, sickle cell disease and human immunodeficiency virus (HIV) are of particular relevance as stroke etiologies.[32] The impact of sickle cell disease on stroke in Africa is significant. In Cameroon, for example, 31% of pediatric stroke has been attributed to sickle cell disease.[33] This frequency is similar to the previously noted case series of pediatric stroke in the United States, where sickle cell disease was a coexisting diagnosis in 38.4% of ischemic stroke cases among African-Americans.[29] In the United States, sickle cell disease as a comorbidity was much less common for African-American children with hemorrhagic strokes (4/81 cases of intracranial hemorrhage and 3/35 cases of subarachnoid hemorrhage). Furthermore, of 325 cases of sickle cell disease seen at the University of Illinois from 1975 to 1989, there were 11 cases of subarachnoid hemorrhage of which 10 had intracranial saccular aneurysms.[34] In the United States, the overall age-specific incidence for ischemic stroke in patients with sickle cell disease is low and peaks at 1% between ages 2 and 5 years.[35] However, the prevalence of "subclinical" ischemic stroke may be present in as many as 22% of patients with sickle cell disease. The risk of hemorrhage is higher in older children and adults and is associated with risk factors of low steady-state hemoglobin values and higher leukocyte counts.[35] Patients with sickle cell disease are also more prone to Moyamoya syndrome, with a similar risk of intracerebral hemorrhage as seen in Moyamoya disease.[36]

The relative resistance to malaria conveyed to individuals heterozygous for the sickle cell gene is well recognized.[37] Cerebral malaria occurs in 2% of individuals infected with Plasmodium falciparum with associated intravascular thrombosis of subcortical white matter and focal cortical hemorrhages. Regardless of therapy, the mortality in these patients is high.[38,39]

Indeed, infectious diseases are endemic in equatorial regions of the world and contribute to a small but real risk of intracranial bleeding and infarction. In particular, HIV has become rampant in sub-Saharan African nations. However, there are only a few reports of neurological complications of the disease in this region. In an autopsy series from Tanzania, in addition to opportunistic infections including brain abscess and meningitis, unsuspected intracerebral hemorrhage was discovered in those patients with otherwise undetected neurological disease and HIV infection.[40]

Other viral, bacterial, fungal, and parasitic diseases of the tropics that may be associated with ischemia and/or hemorrhagic stroke include viral hemorrhagic fevers, parasites (such as schistosomiasis and cysticercosis), infective endocarditis, leptospirosis, syphilis, and tuberculosis. Tuberculosis and syphilis, because of their spread along the basal meninges, may involve the intracranial arteries and thereby lead to ischemic thrombosis or rupture with resultant intracerebral hemorrhage or subarachnoid hemorrhage. Although now uncommon in the Western world, these infectious disorders remain endemic in the tropics and must be considered in all cases of unexplained intracerebral hemorrhages or nonaneurysmal subarachnoid hemorrhage.[41,42] Leptospirosis, another spirochetal disease, must also be considered as a cause of stroke in the tropics. Infection from this organism, via animal vectors, often presents with flulike symptoms, but in severe cases multisystem failure associated with Weil's Syndrome (jaundice, renal insufficiency, and bleeding diatheses) may result in intracranial hemorrhage.[43] Intracerebral hemorrhage has only rarely been described as a result of this organism.[44] In one study of 100 hospitalized patients in the Philippines, however, 5% of aseptic meningoencephalitis cases were due to leptospirosis.[45]

There has been great concern about the risk of viral hemorrhagic fever agents in bioterrorism. There are several of these viral hemorrhagic fever agents including the Filoviridae (ebola and Marbug), Arena viruses (Lassa fever, Junin virus, and other South-American hemorrhagic fever viruses), Bunya virus (Rift Valley fever), and Flaviviruses (including yellow fever and dengue).[46,47] Typically, patients present with fever, hypotension, bradycardia, tachypnea, conjunctivitis, and pharyngitis with variable types of skin rash depending on the agent. As the disease progresses, a hemorrhagic diathesis develops and patients may progress to disseminated intravascular coagulation (DIC) and shock (Fig. 1). Central nervous manifestations are associated with a poor prognosis and are usually secondary to the DIC and shock but intracranial hemorrhages may be present independent of DIC.

 

Figure 1. Noncontrast CT of the brain of a 20-year-old woman who visited Haiti and contracted hemorrhagic dengue with septic shock. The image shows cerebral edema and bilateral frontal hemorrhage and right parietal hemorrhages.

 

Parasitic infections that are common in the tropics rarely present with intracranial hemorrhages, but small case series have been reported for various organisms. For example, schistosomiasis is one parasite that is endemic in Africa, the Near East, South America, and eastern Caribbean. This disease results from a trematode blood fluke that causes chronic inflammation of the intestines and bladder. Cerebral involvement as a manifestation is apparently rare although ova of the parasite can be found intracranially in a majority of affected cases on autopsy. CNS complications of this parasite are uncommon; however, case reports of cystic lesions with secondary brain hemorrhages have been described.[48]

Cysticercosis has also been described with both intracerebral hemorrhages and subarachnoid hemorrhages.[49,50] In the case report on subarachnoid hemorrhage, the presumed etiology was an inflammatory distal cerebral aneurysm. Neurocysticercosis, however, presents more commonly with seizures as a result of brain infestation from the parasite Taenia solium, which is thought to be one of the main causes of epilepsy in the developing world.

In general, ruptured arteriovenous malformations and saccular aneurysm are not uncommon underlying causes of intracerebral hemorrhages and subarachnoid hemorrhages in the tropics and Western countries. However, not all aneurysmal bleeds are due to saccular lesions. Mycotic (infectious) aneurysms may also be associated with intracerebral hemorrhages and occur in distal branches of the intracranial arteries. As a result of various infectious agents, mycotic aneurysms may contribute to an undefined number of hemorrhagic strokes in the tropics. In the developed world, the underlying etiology is often infective endocarditis with embolization of vegetations.[51,52] Infectious intracerebral aneurysms may occur in 3 to 15% of patients with infective endocarditis; although hemorrhage is uncommon, it is associated with a very poor neurological outcome. In a small surgical series at the Mayo Clinic, streptococcal organisms were the most common cause of these infectious aneurysms and most of the aneurysms involved the anterior circulation. All patients with multiple aneurysms presented with intracerebral hemorrhage.[52]

Of the atypical, noninfectious arteriopathies and vascular malformations that could lead to hemorrhagic stroke, Moyamoya disease and Takayasu's arteritis are possibly more prevalent in tropical regions. Moyamoya disease is a nonatherosclerotic, noninflammatory vasculopathy characterized by stenosis or occlusion of the basal arterial branches of the circle of Willis with resulting small vessel collaterals at the basal pial interfaces. Originally described among Japanese patients, the disease occurs in all races but appears to be more common in patients with Asian (Japanese, Chinese, Southeast Asian) ancestry. In the United States, ischemic stroke appears more common than hemorrhagic stroke in patients with Moyamoya disease, but in Asian countries, hemorrhagic stroke associated with Moyamoya disease predominates.[53,54]

In contrast, Takayasu's arteritis is an autoimmune inflammatory arteritis of the aorta and/or cervicocerebral arteries.[55,56] The resulting fibrosis of the arterial wall may lead to weakening of the vessel with dissection of the artery, thrombotic occlusion, and hemorrhagic complications. Originally described in women from East Asia, the disease is now recognized worldwide. Most commonly, however, it has been described in Japan, South East Asia, India, and Mexico. Of note, Japanese patients are overwhelmingly female; in India, 37% in a reported series were male.

Finally, it is worth noting that cerebral venous thrombosis may have an increased frequency in developing countries. It has been hypothesized that there is an increased frequency and worse outcome for venous thrombosis in Africa or Asia related to infection, anemia, and pregnancy-related complications, although as with most of the epidemiological data about hemorrhagic stroke in the tropics, ascertainment bias complicates the analysis.[57]

Management

Management of intracerebral hemorrhage and subarachnoid hemorrhage is primarily focused on prevention of complications and supportive therapy with maintenance of adequate cerebral perfusion pressure by controlling blood pressure and intracranial pressure through medications and ventriculostomy. For aneurysmal subarachnoid hemorrhage, vascular control of the ruptured aneurysm by either surgical clipping/trapping or, increasingly in the industrialized world, by endovascular procedures is essential. In selected cases, such as lobar hemorrhage or cerebellar hemorrhage, surgical evacuation may be indicated. Otherwise, supportive care is the mainstay for intracerebral hemorrhage with recent suggestions of the potential value of recombinant factor VIIa.[58] Identification of underlying causes of intracerebral hemorrhage including aneurysms and other vascular malformations, reversal of coagulopathies, and treatment of other comorbidities that relate to the intracranial hemorrhage or contribute to worsening (including infectious etiologies) are critical. These diagnostic and management principles apply in both the industrialized world and in the tropical and developing countries. The main barrier to diagnosis and treatment in the tropics is not inherently related to technical skills of the medical personnel. Rather, there is often a scarcity of available technologies for diagnosis and limited economic resources for treatment of the population, particularly in rural areas, in sophisticated intensive care settings. In the Chicago metropolitan area, for example, there may be more MRI machines than in all of sub-Saharan Africa. Therefore, treating the risk factors for intracranial hemorrhage is probably of greater overall utility in developing countries.

Conclusion

Hemorrhagic stroke remains a devastating disease worldwide. The problems of developing countries of the tropics related to limited access to health care and limited economic resources also impact our understanding of the epidemiology of the disease. The challenge for future studies will be to better understand the prevalence of hemorrhagic stroke in these regions and determine the utility of various predictive models for diagnosing intracranial hemorrhage where neuroimaging is lacking.[12,59]

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Semin Neurol. 2005;25(3):300-306. 

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