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(Stroke. 1996;27:538-543.)
© 1996 American Heart Association, Inc.

Articles

AIDS and Cerebrovascular Disease

Amélia Nogueira Pinto, MD

From the Department of Epidemiology and Preventive Medicine, University of Maryland at Baltimore. Amélia N. Pinto is a visiting research fellow of the Department of Epidemiology and Preventive Medicine from the Department of Neurology, Santa Maria Hospital, Lisbon, Portugal.

Correspondence to Amélia Nogueira Pinto, MD, Centro de Estudos Egas Moniz, Hospital de Santa Maria, 1600 Lisboa, Portugal.

	Abstract

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Background Although neurological complications of human immunodeficiency virus (HIV) infection are common, the presence of cerebrovascular disease (CVD) has been seldom reported. The purpose of this report is to review available data on the association between stroke and acquired immunodeficiency syndrome (AIDS).

Summary of Review A review of all literature published between mid-1976 and December 1994 was performed through a MEDLINE search with the following key words: AIDS, CVD, human T-cell lymphotropic virus type III, and HIV-1. Only reports of clinical stroke in patients with AIDS or HIV infection and autopsy series with stroke findings were selected. The type of study, population, number of stroke patients, subtype and etiology of stroke, and associated AIDS conditions were described. Six clinical series and 11 autopsy series were found, with a total of 1885 cases with AIDS, AIDS-related complex, and HIV carriers. Forty percent had a neurological complication, but only 1.3% had a stroke syndrome. Ischemic infarcts were more common than intracerebral hemorrhages. Cerebral infarcts were generally due to nonbacterial thrombotic endocarditis or concomitant opportunistic central nervous system infection, and intracerebral hemorrhages were usually associated with thrombocytopenia, primary central nervous system lymphoma, and metastatic Kaposi's sarcoma. Autopsy findings of CVD were generally not related with clinical stroke before death. Data are not available to determine the role of risk factors for AIDS in CVD.

Conclusions Because of limitations of the available data, it is still not clear whether there is an association between AIDS and stroke. Further studies are needed to better define the epidemiology of CVD in association with AIDS.

Key Words: acquired immunodeficiency syndrome • cerebrovascular disorders • epidemiology

	Introduction

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Neurological complications of HIV infection are common since HIV can cross the blood-brain barrier early,¹ thus entering the nervous system at all levels of the neuraxis (brain, meninges, spinal cord, nerve, and muscle). However, subsequent neurological syndromes and their frequency, timing, and pathobiology are still not clear. The frequency of neurological complications varies according to the stage of the disease,² and it has been reported that neurological disease is the first manifestation of AIDS in 10% to 20% of symptomatic HIV infection.² Thirty percent to 40% of patients with AIDS will have clinical neurological dysfunction.² Based on pathological findings of patients with advanced-stage AIDS, neurological disease may be present in 75% to 90% of cases.² The most frequent neurological syndromes in AIDS, apart from AIDS dementia complex and peripheral neuropathy, are global cerebral dysfunction due to fungal, viral, or mycobacterial meningoencephalitis and focal dysfunction due to toxoplasmosis, primary CNS lymphoma, or progressive multifocal leukoencephalopathy.² The presence of CVD has been seldom reported, and ischemic infarcts are more common than ICH.^{3 4} However, most AIDS patients with strokelike syndromes had concomitant CNS infection or CNS tumor.^{3 4} The purpose of this report is to review available data on the association between stroke and AIDS.

	Methods

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A review of all literature published between mid-1976 and December 1994 was performed through a MEDLINE search. The key words used were "acquired immunodeficiency syndrome," with 38 292 citations, and "cerebrovascular disease," with 17 572 citations in titles and abstracts. As the result of joining these two key words with an "and" statement, 39 potentially relevant references were found. The "explode" option was used to search for even peripherally related articles to both topics. The key words "human T-cell lymphotropic virus type III" and "HIV-1" were also used without further yield.

From the 39 references, we excluded literature reviews on neurological complications of AIDS in which stroke was not mentioned^{5 6 7} or in which there were no primary data on stroke.^{8 9} News releases^{10 11 12} and reports of conferences^{13 14} were also excluded. Clinical or autopsy series of AIDS patients in which CVD was not described were excluded.^{15 16 17 18} Stroke in the pediatric AIDS population was not included because underlying mechanisms and associated findings appear to differ from those in the adult population.^{19 20 21}

For analysis, we selected all reports of clinical stroke in patients with AIDS or infected with HIV for whom denominator information was available and all autopsy series with stroke findings. The type of study, population, number of stroke patients, subtype and etiology of stroke, and associated AIDS conditions were described for each report. Subarachnoid hemorrhage was the only stroke subtype not included. Among common risk factors for HIV infection, intravenous illicit drug use may be associated with increased risk of ischemic infarct and ICH^{22 23} and is considered an independent risk factor for stroke.^{22 23} Thus, illicit drug use may be considered a "confounder."²⁴ All risk factors for HIV infection are therefore described. To facilitate comparison, clinical and autopsy series are considered separately.

	Results

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Clinical Series
Table 1 describes the characteristics of stroke patients reported in clinical series.^{25 26 27 28 29 30 31} AIDS diagnosis was made according to the CDC criteria from 1982³² or 1987.³³ Table 2 shows risk factors for HIV infection. In the series of Snider et al,²⁵ all patients had associated conditions that could explain the stroke. In the report of Berger et al,²⁷ stroke was related to a condition associated with AIDS in at least two of the four patients. According to Levy and Bredesen,²⁹ a neurological syndrome was the initial manifestation of AIDS in 10% of their cases, and 13.5% of the patients presented multiple neurological manifestations, although the number of stroke patients was not mentioned. Among 20 cases with multiple intracranial pathology, in whom autopsy or biopsy was performed, stroke was confirmed in six. The risk factors for HIV infection were not mentioned. However, in a previous report³⁰ of this same population, the authors stated that all patients were homosexual men. Engstrom et al³¹ included in their study some of the population examined by Levy et al^{29 30} and also cases detected by review of neurology inpatient/outpatient service records and neuropathological reports. Almost all cases were white homosexual men. Three of the stroke patients had history of IVDA. This series was the only one to estimate the frequency of CVD in AIDS patients. Over a 5-year period, there were 12 strokes recorded among the 1600 persons with AIDS (0.75%). Comparing this figure with the annual incidence of stroke among young adults (aged 35 to 45 years) in the general population (0.025%), the authors concluded that AIDS patients appear to be at a substantially higher risk for stroke. Follow-up was available in two thirds of the patients, with a mean survival time of 4 months (range, 1 day to 24 months). A poststroke neurological event, generally a CNS infection, was reported in one fourth of the patients. In the series of Koppel et al²⁶ and McArthur,²⁸ only one stroke patient was described. However, in McArthur's report only 56% of patients had AIDS, and the remaining 44% had either AIDS-related complex or HIV infection alone. In the report of Koppel et al, all cases fit the criteria for AIDS.

View this table: [in this window] [in a new window]   Table 1. Review of Literature: Clinical Series With AIDS and Stroke

View this table: [in this window] [in a new window]   Table 2. Risk Factors for HIV Infection

Autopsy Series
Risk factors for HIV infection are summarized in Table 2. The main findings related to stroke in the autopsy series of AIDS patients are shown in Table 3.^{34 35 36 37 38 39 40 41 42 43 44} In most cases, the pathological findings of CVD were not correlated with clinical stroke before death. Anders et al³⁸ reported CVD in 26 autopsies (29%). However, of these, 30% had subarachnoid hemorrhage or subdural hematoma. Mizusawa et al⁴¹ compared clinical and neuropathological findings among those with and those without CI in the postmortem examination. No differences were found concerning age, sex, and risk factors for AIDS. Subacute encephalitis and opportunistic CNS infections were more frequently observed in the CI group (50% and 37.5%, respectively) than in the non-CI group (37.3% and 30%, respectively). The great majority of CIs were microinfarcts, although size was not defined. Calcification (17/24) or mural thickening (12/24) of the small cerebral vessels was found in the CI group. Berger et al⁴³ reported a study in which the frequency of autopsy findings of CVD was higher (P<.04) among young adults without AIDS (23%) than in AIDS cases (8%). The risk factors for AIDS were only described in deceased AIDS cases with CI. In the series of Kieburtz et al,⁴⁴ three CI cases (15%) were clinically symptomatic and had confirmatory CT or MRI scans. In each of these three cases the postmortem examination identified vasculopathy related to an AIDS-associated condition. Risk factors for AIDS were not mentioned. Few stroke patients were described in the remaining series.^{34 35 36 37 39 40 42}

View this table: [in this window] [in a new window]   Table 3. Review of Literature: Autopsy Series With AIDS and Stroke

	Discussion

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In reports by Bredesen and Messing,¹⁵ Holtzman et al,¹⁶ Bursztyn et al,¹⁷ and Petito et al,¹⁸ no stroke patients were found with clinical,^{15 16 17} imaging,^{15 16 17} or pathological¹⁸ findings of stroke, respectively. Since we cannot be absolutely certain that stroke was not ignored in all these series^{15 16 17 18} instead of not being reported because it was not seen, bias probably was a factor. Also, in all of these reports^{15 16 17 18} a good description of patients' clinical stages was not provided, and the exact number of AIDS patients is not possible to obtain. Furthermore, in the series of Holtzman et al,¹⁶ the authors were only discussing patients with new-onset seizures, and a selection bias had probably occurred. Given these findings, the omission of CVD among the data stated in these reports^{15 16 17 18} is not absolutely reliable, and it is appropriate to exclude them from further analysis.

Most clinical series of HIV-infected patients included predominantly cases in "advanced stage of disease,"^{25 26 27 28 29 30 31} although staging was not defined. As a result of overlapping cases in some reported clinical series^{29 30 31} and ambiguity in reporting of stroke subtypes,²⁷ the exact number of AIDS patients, neurological complications, stroke syndrome, and the proportion of ischemic versus hemorrhagic strokes cannot be determined. In an attempt to obtain figures, and with the exclusion of the report of Engstrom et al,³¹ a total of 1885 cases with AIDS, AIDS-related complex, and persons infected with HIV were identified from this review. Of these cases, 763 (40%) had a neurological complication, and 25 (1.3%) had a stroke syndrome.^{25 26 27 28 29} Ischemic infarcts were more common than ICHs. CI appeared to constitute 19 of 28 cases (68%) and ICH 9 of 28 cases (32%).^{25 26 28 29} Although the proportion of AIDS cases with findings of CVD on neuropathological examinations was much higher than in clinical series, a similar ratio of ischemic to hemorrhagic cases (98 of 251 [39%]) was also observed.^{35 36 37 38 39 40 41 42 43 44} It is important to consider that these autopsy findings were not related to a recognized stroke before death; thus, the clinical significance of these neuropathological findings is uncertain. ICHs were usually associated with thrombocytopenia, primary CNS lymphoma, and metastatic Kaposi's sarcoma. CIs were generally due to nonbacterial thrombotic endocarditis or concomitant opportunistic CNS infection. In nearly all reports reviewed, underlying causes of acute neurological deficits in the patients, ie, opportunistic CNS infections or CNS tumors, were present and related to stroke. Since these conditions can have a strokelike presentation, misclassification⁴⁵ in identifying stroke cases may have occurred.

Hematologic conditions and cerebral vasculitis, particularly associated with herpes zoster or syphilitic infection, were related to thrombotic stroke in only a few reported cases.^{29 31 46 47 48} However, neuro-ophthalmological observations of AIDS patients often revealed cotton-wool spots, similar to those classically observed in systemic lupus erythematosus.^{49 50} Cotton-wool spots are believed to be related to a vasculitic process.^{49 50} Cho et al⁴⁰ and Kieburtz et al⁴⁴ also reported postmortem lesions suggestive of vasculitis in all cases and in 6 of 14 cases, respectively. Recent clinical series^{29 31} attributed unknown etiology to a high proportion of patients with CI. In the absence of an opportunistic CNS infection, these reports suggest that vasculitis may be an important etiology. There are several possible mechanisms that may explain the association between AIDS and vasculitis. One possibility is that vasculitis may be related to increased deposition of circulating immune complex, which is known to occur frequently in AIDS.^{31 49 51} Another explanation is that the virus may have a direct toxic effect on the vascular endothelium,^{31 50} possibly immune-mediated. There are reports in the literature^{46 47} of vasculitis cases in which HIV infection was the only risk factor detected.

Antiphospholipid antibodies, including anticardiolipin antibodies, are known to occur with a high frequency in patients with HIV infection and AIDS.⁵² However, there is no consensus on the significance of these autoantibodies in the setting of HIV infection. Maclean et al⁵² suggested that anticardiolipin antibodies are a nonspecific marker of HIV infection since no association was found between anticardiolipins and lupus anticoagulant antibody level and history of thromboembolic disease or thrombocytopenia.^{52 53 54 55} However, some authors reported an association with opportunistic infection, particularly Pneumocystis carinii.^{53 54} Others were not able to confirm this association.^{52 55} Levy and Bredesen²⁹ suggested that the presence of lupus anticoagulant antibodies in patients with AIDS may contribute to the high frequency of multifocal ischemic infarcts, although no data supporting these statements were provided. The role of antiphospholipid antibodies, including anticardiolipin antibodies, as a pathogenic mechanism of stroke in AIDS patients remains uncertain.

Data are not available to determine whether risk factors for AIDS influence the etiology and frequency of CVD. Drug use has been related to CI and ICH in young adults.^{22 23 56} CI associated with IVDA may be due to bacterial endocarditis, vasculitis, vasospasm, and foreign body embolism.²² ICH associated with IVDA may be related to aneurysms or arteriovenous malformation rupture, segmental brain vessel constriction, and cardiovascular changes.²³ Given these findings, a higher rate of stroke is to be expected in AIDS patients with an actual history of IVDA compared with an age-matched sample from the general population.

Based in part on the studies by Engstrom et al³¹ and Berger et al,⁴³ recent clinical textbooks on AIDS^{3 4} describe CVD as a rare complication. Although this may be true, the studies of Engstrom et al and Berger et al had major methodological problems, and the interpretation of these two studies does not fully justify this conclusion. In the series of Engstrom et al,³¹ a reported incidence of 0.5% to 8% was based on a review of their own data and data from previous series.^{25 27} Incidence can be defined as the number of new cases of a disease in a defined population, within a specified period of time, taking into account the period at risk for each person in the population.⁵⁷ However, the proportion of AIDS cases with stroke as reported by Engstrom et al should be considered a period prevalence rate⁵⁸ of CVD in the UCSF AIDS population. Also, the appropriate comparison for the study of Engstrom et al should be the age-matched period prevalence for stroke among persons without AIDS. However, a crude comparison of prevalence rates could lead to a biased estimate of the relative risk for stroke associated with AIDS. Prevalence is the product of incidence by average duration of the studied disease.⁵⁹ Since AIDS cases with stroke have a short survival period compared with non-AIDS stroke patients,^{31 60} using prevalence rates (prevalence rate of stroke in UCSF AIDS population divided by the prevalence rate of stroke in comparable population) to estimate relative risk instead of incidence rates (incidence rate of stroke in UCSF AIDS population divided by the incidence rate of stroke in comparable population) will yield an underestimate of the true relative risk of stroke in AIDS. Berger et al⁴³ proposed comparing the incidence of stroke in patients dying with AIDS to the incidence of stroke in young adults dying of other conditions. The diagnosis of stroke was based solely on neuropathology. By excluding AIDS cases with opportunistic CNS infections and CNS tumors, the authors reduced misclassification⁴⁵ in the diagnosis of stroke. However, no information was provided on the cause of death for the control patients. Furthermore, the reasons for autopsy in both case and control subjects were not described. Because of the strong possibility of selection bias (Berkson's bias⁶¹ ), the validity of the relative risk estimate in this report is uncertain.

In summary, as a result of the limitations of the available data it is still not clear whether there is an association between AIDS and stroke. Further studies with consideration of methodological issues are needed to better define the epidemiology of CVD in association with AIDS. Specifically, we recommend (1) a stringent case definition of both AIDS and stroke, (2) consideration of the denominator for both populations, (3) the time at risk for determining incidence, and (4) attention to potential confounder factors such as IVDA.

	Selected Abbreviations and Acronyms

 

AIDS = acquired immunodeficiency syndrome CDC = Centers for Disease Control and Prevention CI = cerebral infarct CNS = central nervous system CVD = cerebrovascular disease HIV = human immunodeficiency virus ICH = intracerebral hemorrhage IVDA = intravenous drug abuse UCSF = University of California at San Francisco

	Acknowledgments

 
The fellowship of Amélia N. Pinto was partially supported by funds from the Luso-American Foundation and the Calouste Gulbenkian Foundation. The author wishes to thank Drs Steven Kittner, Joana Rosário, and Richard Macko for their suggestions and help in reviewing this report.

Received November 14, 1995; revision received December 18, 1995; accepted December 18, 1995.

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