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

Abstract

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.

Keywords: Africa; HIV; immune reconstitution syndrome; stroke; vasculopathy.

Figure 1.

Selection procedure and classification of cases. *Noninvasive or invasive angiography has not been done and therefore the subcategory of “cryptogenic embolism” and “other cryptogenic” cannot be determined. Abbreviations: HIV, human immunodeficiency virus; MRI, magnetic resonance imaging.

Figure 2.

Clinical, radiologic, and laboratory features among those starting antiretroviral therapy (ART). A, Etiology by ART status shows human immunodeficiency virus (HIV)–associated vasculopathy to be the most common etiology among those starting ART. B, Radiologic examples of HIV-associated vasculopathy found among those starting ART: ID 32—diffusion-weighted (left) and fluid attenuated inversion recovery (FLAIR) (middle) sequences show a left middle cerebral artery infarct, while Doppler of the left common carotid artery (right) illustrates underlying concentric stenosis (≥70%) extending into the bulb; ID 278—middle cerebral artery infarct on diffusion-weighted (left) and T2-weighted (right) sequences; ID 46 and 85—diffusion-weighted and FLAIR sequences show multifocal ischemic lesions in the basal ganglia and cortices. C, Risk factors of immune reconstitution inflammatory syndrome compared across the ART groups. Kruskal-Wallis nonparametric analysis of variance was used to compare continuous variables across the ART status groups. *Noninvasive or invasive angiography has not been done and therefore the subcategory of “cryptogenic embolism” and “other cryptogenic” cannot be determined. Abbreviations: APS, antiphospholipid syndrome; ART, antiretroviral therapy; CTE, cardiothromboembolism; HIV, human immunodeficiency virus; IRIS, immune reconstitution inflammatory syndrome; O.I., opportunistic infection.

Figure 3.

Radiohistologic characteristics in patients presenting with human immunodeficiency virus (HIV)–associated vasculitis vs vasculitis related to tuberculous meningitis after starting antiretroviral therapy (ART). A–E, A-32 year-old (5 months pregnant) woman on ART for <6 months with an acute right arm monoparesis, dysphasia, and headache. Her CD4⁺ count was 175 cells/μL and HIV blood and cerebrospinal fluid (CSF) viral load were undetected on admission. Mild pleocytosis (white cell count was 10 cells/μL), moderately elevated protein (1.6 mg/L), and a glucose ratio of 0.48 was found on CSF examination. A–C, Magnetic resonance imaging (MRI) confirmed an acute middle cerebral artery infarct. D and E, Histopathology showed multiple infarction of the cortical laminar type, marked periarteritis with foci of muscle necrosis, present in all sized arteries. There was lymphocytic meningitis but no granuloma or caseation or giant cells typical of tuberculous meningitis. There were no cytomegalovirus inclusion bodies, and varicella zoster intrathecal immunoglobulin G was negative. F–J, A 34-year-old woman on ART for <6 months with an acute right arm weakness, headache, neck ache, and fever. CD4⁺ count was 128 cells/μL and HIV blood and CSF viral load on admission were 1.48 and 3.22 log₁₀ copies/mL, respectively. There was no CSF pleocytosis but a markedly elevated protein of 16.6 mg/L and CSF-to-glucose ratio of 0.28. Brain MRI confirmed an acute infarct of the basal ganglia with mild hydrocephalus. I and J, Histopathology showed endarteritis obliterans of the small arteries with and a recent infarct of the basal ganglia. There was widespread meningeal inflammation with confluent and discrete tuberculoid granulomas, typical caseating necrosis, and Langhans giant cells. There were superficial Rich foci (ie tuberculous cerebritis adjacent to the meninges). Acid-fast bacilli stain was negative but histology was characteristic of tuberculous meningitis. Abbreviations: ART, antiretroviral therapy; DW, diffusion weighted; HIV, human immunodeficiency virus; TB, tuberculosis.