Epidemiology
The occurrence of cerebrovascular events, either ischemic or hemorrhagic, was recognized as early as 1983 in HIV-1 infection, before any antiretroviral therapy was available [8].
Ischemic strokes are more frequent than intracerebral hemorrhages, roughly in a proportion of two thirds to one third in several former series [13]. In more recent series, cerebral infarction accounted for 90% of stroke [14, 15]. A 50% ratio has exceptionally been reported [16]. Both types of stroke are frequently asymptomatic[13].
Although studies have often reached conflicting conclusions, there is evidence for an increased general risk of cerebrovascular events during HIV-1 infection. As early as 1988, a large study of AIDS patients found that 1.6% of the subjects had cerebrovascular complications [17]. The prevalence of clinically diagnosed stroke syndrome has been reported to be between 0.5 and 3.75% in more than 2,000 patients with AIDS or AIDS-related complex from six clinical series [9]. A population-based study conducted in the USA before the HAART era showed that AIDS was strongly associated with both ischemic stroke and intracerebral hemorrhage, with a similar incidence rate of 0.2% per year [16]. After exclusion of cases with AIDS-related medical conditions or other concomitant etiologies for stroke, the adjusted relative risk was still high: 10.4 for both types of stroke (95% confidence interval, 4.9-22.0) and 9.1 for cerebral infarction (95% confidence interval, 3.4-24.6) [16]. A European study including patients treated with HAART found the same annual incidence rate for transient ischemic accident (TIA) or ischemic stroke (0.216%), five times higher than in the non- HIV-infected population of the same age and country [18]. By contrast, there was no significant overall increase in the stroke rate in HIV-1-infected patients as compared to noninfected subjects in an African-population-based case-control retrospective study performed in South Africa [19].
There was, however, a higher rate of large-vessel cryptogenic strokes in the HIV population (91%) than in age- and sex-matched HIV- seronegative control subjects (36%), suggesting a possible intrinsic predisposition to stroke among HIV-infected patients [16, 19]. Results from the DAD (Data collection on Adverse events of anti-HIV Drugs) study, involving over 36,145 person-years of followup, confirm that combination antiretroviral treatment increases the risk of cardio- and cerebrovascular disease [20]. The incidence of first cardio- and cerebrovascular events was 5.7 per 1,000 person-years and increased with longer exposure to antiretroviral treatment (relative risk per year of exposure=1.26) above that which can be explained by increasing age. This study, however, had insufficient statistical power to determine whether PIs and non-nucleo- side reverse transcriptase inhibitors were associated with the same vascular risk.The majority of available clinical and autopsy series were performed before the HAART era. Nonetheless, combined therapies with PIs do not seem to modify the incidence of stroke. No significant association was found between the use of any class of antiretroviral agent and the incidence of cerebrovascular events in a retrospective study [21]. The incidence of cerebrovascular accidents was not different between patients receiving PIs and those not receiving PIs [22]. No difference in the incidence rate of stroke before and after the introduction of HAART was observed in the series of Evers et al. [18], but the sample was too small to draw firm conclusions. The atherogenic metabolic side effects of HAART are discussed further.
Due to HIV epidemiology, most stroke patients are young, and in published series the mean age varies from 33.4 years [15] to 42 years [14] and more than 90% of patients are less than 46 years. The prevalence of cerebral infarction varies in clinical series from 0.3 to 6% [8, 23-27], and in autopsy series from 2 to 34% [13, 28-35]; in radiological series, it has been reported to be 18% [36].
Engstrom et al. [27] retrospectively identified 12 cases of ischemic stroke among 1,600 AIDS patients studied over a period of 5 years. The annual risk of ischemic stroke of these patients (0.75%) was higher than that expected (0.010-0.034%) in the general population younger than 45 years of age [37-39]. In a retrospective case-control study [40], HIV-1 infection was particularly associated with the occurrence of ischemic stroke (odds ratio, 3.4; 95% confidence interval, 1.1-8.9; p=0.03) after adjustment for several cerebrovascular risk factors; however, this association was no longer statistically significant if cases with meningitis and protein S deficiency were excluded, suggesting that the excess risk of stroke in HIV-1 patients could be mediated by these two mechanisms. In a cohort study performed over a 9year period (1993-2001), 15 patients were diagnosed with TIA (n=6) or ischemic stroke (n=9) out of 772 HIV-1-infected patients, representing a total prevalence rate of 1.9% (1.2% for ischemic stroke only) whatever the age [18]. The prevalence for juvenile ischemic strokes occurring under the age of 46 years was 1.6%, higher than in the HIVnegative population [18]. The stroke patients were older, had a lower CD4 cell count, and were in more advanced stages of the disease than infected patients without stroke. The prevalence of ischemic cerebrovascular events according to the CDC classification increased with the stage of the disease: 0.6% for stage A, 1.1% for stage B, and 3.2% for stage C [18]. However, Bajwa et al. [41] did not find differences between asymptomatic, AIDS-related-complex, or AIDS patients.The prevalence of TIA is about 0.8-0.9% [17, 27, 42], and the annual incidence in a prospective study reached 0.8% in HIV-1- infected patients versus 0.4% in noninfected individuals [43]. Whether these attacks are truly ischemic is unknown and transient neurological deficits (TNDs) is a better definition. A local vasospasm comparable to migrainous aura is also evoked [44].
The differential diagnosis of focal TND includes a variety of nonvascular causes such as toxoplasmic abscess, primary cerebral lymphoma, and cryptococcal and cytomegalovirus infection [43, 45]. Recurrent TNDs are usually described in late stages of HIV-1 infection and have been associated with AIDS dementia complex [43]. They can, however, occur in primary infection and can be associated with a high viral load [46]. Brain infarction rarely follows TND. Only 2 of 27 patients progressed to cerebral infraction in the series of Brew and Miller [43] and none in the series of Baily and Mandal [42].It is disputed whether hemorrhagic strokes are more frequent in the HIV-1- infected population [13, 40], but some authors have suggested that could be the case [16, 47]. A study [16] has indeed demonstrated an adjusted relative risk of 25.5 for intracerebral hemorrhage (95% confidence interval, 11.2-58.0). Moreover, the increased hepatic involvement and longer survival in HIV-1-infected patients could be responsible for prolonged hemostatic perturbations and consequently cerebral hemorrhages.