AIDS and stroke risk

Reflection & Reaction AIDS and stroke risk Although an increased risk of stroke in people with AIDS has been suggested by clinical,1,2 radiographic,3 and pathological series,4–10 none of these studies included a control population to assess this risk. A case-control study at a large, university-affiliated, county hospital in south Florida in the late 1980s compared the prevalence of cerebrovascular disease in autopsied patients between the ages of 20 years and 50 years old with and without AIDS.11 Cerebrovascular disease was present, as determined by neuropathological criteria, in 13 (8%) of 154 patients with AIDS—a large proportion for a young adult population. However, there was no statistically significant difference in the prevalence of stroke in dying patients with AIDS from dying patients matched for age and sex who did not have AIDS. Similarly, there has been only one clinical study of stroke in patients with HIV infection published before 2004 that included a control population for comparison.12 This South African study, which analysed the risk of stroke in people with HIV infection, used data accumulated from a stroke registry from the KwaZulu Natal province. The results showed a prevalence of HIV in a young (<50 years of age) stroke population of 16%.12 The prevalence of HIV in the young black population in general was identical, which suggests that there was no significant increase in the risk of stroke associated with HIV infection. However, large-vessel cryptogenic stroke was more common among the HIV-infected cohort. In a recent population-based study of AIDS-associated stroke by Cole and colleagues,1 the authors estimated that the incidence of both ischaemic stroke and intracerebral haemorrhage in individuals with AIDS was 0·2% per year. If identifiable causes for either disorder were excluded, the incidence of ischaemic stroke and intracerebral haemorrhage in individuals with AIDS was 0·14% and 0·11% per year, respectively. The relative risks for both ischaemic stroke and intracerebral haemorrhage were both significantly increased at 9·1 (95% CI, 3·4–24·6)

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for ischaemic stroke and 12·7 (95% CI, 4·0–40·0) for intracerebral haemorrhage, with a combined adjusted relative risk of 10·4.1 By contrast with the South African study,12 Cole and colleagues1 used the 1987 Centers for Disease Control (CDC) definition of AIDS,13 rather than HIV seropositivity, to define their study population. In fact, HIVseropositive patients who did not meet criteria for AIDS (ten with ischaemic stroke and five with intracerebral haemorrhage) were included in the non-AIDS stroke group. The authors speculate that had these patients been more comparable to patients with AIDS in terms of stroke risk, their inclusion would have decreased the observed association between stroke and AIDS. Therefore, for various reasons, these two clinical studies are not entirely comparable. As with many multi-institutional, population-based studies, certain shortcomings are unavoidable. The authors recognised that underreporting of AIDS in their study population is a potential confounding factor. Similarly, the authors expressed concern about the possible underreporting of stroke in the AIDS population as patients in this group may have had multiple diagnoses during hospitalisation that may have obscured the diagnosis of stroke or relegated it to a minor role. Additionally, assumptions were made regarding the thoroughness of AIDS diagnosis by public-health surveillance in the study region. It is unlikely, however, that these or other potential confounding factors would have significantly changed the authors’ conclusion with regard to the increased relative risk of ischaemic stroke and intracerebral haemorrhage in the AIDS population. The finding of an increased risk of stroke in this population compared with a nonimmunosuppressed cohort is not unexpected. Despite the absence of data for CD4 T-lymphocyte counts and other measures of immunological function, the use of the strict CDC criteria for the definition of AIDS in this study and the analysis of a

population before highly active retroviral therapy was available resulted in the inclusion of patients with profound immunosuppression. There are many potential causes of stroke in advanced HIV infection; opportunistic infections, intracranial malignancies, marantic endocarditis, cachexia and dehydration, and coagulation abnormalities are among those disorders that substantially contribute to the increased risk of stroke in AIDS.11 The fundamental question is whether HIV infection uniquely predisposes to cerebrovascular diseases in the absence of other disorders that increase stroke risk. Cole and colleagues attempt to address this point by excluding patients with other potential causes of stroke from their secondary analysis. However, possible contributing factors for stroke (cocaine abuse, neurosyphilis, thrombocytopenia, varicella-zoster infection, and Kaposi’s sarcoma) persist in their remaining study cohort and only pathological study would comfortably permit the exclusion of these factors. If HIV infection was convincingly shown to be associated with stroke in the absence of other causes, possible explanations might include unique HIV-related changes in the cerebral vasculature or HIV-associated coagulation disorders. Various cerebral vasculopathies14–18 have been reported in patients with HIV infection that could contribute to an increased risk of both ischaemic and haemorrhagic stroke. In addition, various disorders that predispose to a hypercoagulable state have been reported in HIV infection, including antiphospholipid antibodies and the lupus anticoagulant; deficiencies of protein C, protein S, heparin cofactor II, and antithrombin; and increased concentrations of von Willebrand factor, and d-dimers.19 Physicians also need to be aware of the potential risk of accelerated atherosclerosis that may accompany dyslipidaemia and insulin resistance associated with highly active another antiretroviral therapy,20 possible risk factor for stroke in the present AIDS population.

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Reflection & Reaction In summary, Cole and colleagues’ study1 confirms the association between ischaemic stroke, intracerebral haemorrhage, and AIDS. The treating physician should always consider cerebrovascular disease in the differential diagnosis of neurological disease that occurs in association with AIDS. An underlying, potentially treatable, cause of cerebrovascular disease should be sought. Future studies will need to address whether HIV in the absence of profound immunosuppression and other potential causes of cerebrovascular disease predisposes to ischaemic and haemorrhagic stroke.

References 1 2

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Joseph R Berger Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky, USA. Email [email protected]

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Cole JW, Pinto AN, Hebel JR, et al. Acquired immunodeficiency syndrome and the risk of stroke. Stroke 2004; 35: 51–56. Evers S, Nabavi D, Rahmann A, Heese C, Reichelt D, Husstedt IW. Ischaemic cerebrovascular events in HIV infection: a cohort study. Cerebrovasc Dis 2003; 15: 199–205. Gillams AR, Allen E, Hrieb K, Venna N, Craven D, Carter AP. Cerebral infarction in patients with AIDS. AJNR Am J Neuroradiol 1997; 18: 1581–85. Kure K, Llena JF, Lyman WD, et al. Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains. Hum Pathol 1991; 22: 700–10. Mizusawa H, Hirano A, Llena JF, Shintaku M. Cerebrovascular lesions in acquired immune deficiency syndrome (AIDS). Acta Neuropathol 1988; 76: 451–57. Lang W, Miklossy J, Deruaz JP, et al. Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathol (Berl) 1989; 77: 379–90. Anders KH, Guerra WF, Tomiyasu U, Verity MA, Vinters HV. The neuropathology of AIDS: UCLA experience and review. Am J Pathol 1986; 124: 537–58. Petito CK, Cho ES, Lemann W, Navia BA, Price RW. Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol 1986; 45: 635–46. Budka H, Costanzi G, Cristina S, et al. Brain pathology induced by infection with the human immunodeficiency virus (HIV): a histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropathol (Berl) 1987; 75: 185–98.

10 Rhodes RH. Histopathology of the central nervous system in the acquired immunodeficiency syndrome. Hum Pathol 1987; 18: 636–43. 11 Berger JR, Harris JO, Gregorios J, Norenberg M. Cerebrovascular disease in AIDS: a case-control study. Aids 1990; 4: 239–44. 12 Hoffmann M, Berger JR, Nath A, Rayens M. Cerebrovascular disease in young, HIV-infected, black Africans in the KwaZulu Natal province of South Africa. J Neurovirol 2000; 6: 229–36. 13 Human immunodeficiency virus (HIV) infection codes: official authorized addendum. ICD-9-CM (Revision No.1) effective January 1, 1988. MMWR Morb Mortal Wkly Rep, 1987; 36 (suppl 7): 1S–20S. 14 Nogueras C, Sala M, Sasal M, et al. Recurrent stroke as a manifestation of primary angiitis of the central nervous system in a patient infected with human immunodeficiency virus. Arch Neurol 2002; 59: 468–73. 15 Chetty R. Vasculitides associated with HIV infection. J Clin Pathol 2001; 54: 275–78. 16 Scaravilli F, Daniel SE, Harcourt-Webster N, Guiloff RJ. Chronic basal meningitis and vasculitis in acquired immunodeficiency syndrome: a possible role for human immunodeficiency virus. Arch Pathol Lab Med 1989; 113: 192–95. 17 Vinters HV, Guerra WF, Eppolito L, Keith PE 3rd. Necrotizing vasculitis of the nervous system in a patient with AIDS-related complex. Neuropathol Appl Neurobiol 1988; 14: 417–24. 18 Yankner BA, Skolnik PR, Shoukimas GM, Gabuzda DH, Sobel RA, Ho DD. Cerebral granulomatous angiitis associated with isolation of human Tlymphotropic virus type III from the central nervous system. Ann Neurol 1986; 20: 362–64. 19 Saif MW, Greenberg B. HIV and thrombosis: a review. AIDS Patient Care STDS 2001; 15: 15–24. 20 Mallon PW, Cooper DA, Carr A. HIV-associated lipodystrophy. HIV Med 2001; 2: 166–73.

Anticysticercal treatment and seizures in neurocysticercosis Neurocysticercosis, caused by infection with the larvae of Taenia solium, is a major public-health problem in many resource-poor countries and is becoming increasingly important in developed countries.1,2 An estimated 20 million people are affected worldwide.2 Seizures are the most common manifestation of neurocysticercosis. A recent, multi-centre survey in the USA showed that about 2% of patients who presented to casualty with seizures had radiological evidence of neurocysticercosis.3 Historically, although the clinical features of neurocysticercosis are well understood, treatment has been problematic, despite demonstrable cysticidal actions of praziquantel and albendazole. In 1934, Fairley4 remarked that cysticerci should be kept alive for as long as possible and that specific treatment seemed to be contraindicated. Much of the controversy over treatment arose from concerns about seizures and other neurological events triggered by the inflammatory reaction to treatmentinduced cysticercal degeneration and of potential epileptogenicity of the inflammatory scar after treatment. In addition, results of serial imaging THE LANCET Neurology Vol 3 April 2004

studies—showing that most parenchymal cysticerci resolve spontaneously—were used as justification to avoid anticysticercal treatment. The opposite hypothesis was that treatment would cause early degeneration of cysticerci and could therefore decrease the risk of seizures. The few studies that attempted to resolve this debate about treatment were insufficient because of small numbers of participants and lack of randomisation, control, and blinding. The role of anticysticercal treatment is also complicated by the range of cyst burden and of evolutionary stages of cysticerci. For example, treatment of people with heavy parasitic loads can lead to potentially life-threatening cerebral oedema, and treatment of inactive yet symptomatic neurocysticercosis is of no use. In the past decade, several prospective, controlled trials of anticysticercal treatment have been done.5–8 The primary outcome measure in most of these trials was complete or partial resolution of brain lesions. The results of these trials suggest that treatment increases radiological clearance in people with few active, non-inflamed cysts.7,8 With greater cyst

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load, radiological improvement can occur but may not be complete.7 Anticysticercal treatment is probably not beneficial in transitional or inflamed, degenerating cysts.5,6 Seizure outcome—a more meaningful clinical measure—has been assessed in only three randomised, placebo-controlled trials of anticysticercal treatment.7–9 One study of individuals with active, single, or multiple neurocysticercosis found no difference in the proportion of seizure-free individuals over a 2 year follow-up period in the treated group compared with the control group.7 However, a study of patients with solitary cysticercus granuloma found a trend towards favourable seizure outcomes with albendazole treatment, although differences in outcome in the treated and control groups were not significant.8 The discrepancy in these results may have been due to variations in study protocols. Recently, Garcia and colleagues9 reported a rigorous, randomised, double-blind, placebo-controlled trial of albendazole plus dexamethasone treatment for 10 days in patients with active parenchymal cysticercosis. They reported a significant reduction in the

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