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Download (739Kb) VIEWS & REVIEWS Arterial ischemic stroke in HIV Defining and classifying etiology for research studies Laura A. Benjamin, ABSTRACT MRCP, PhD HIV infection, and potentially its treatment, increases the risk of an arterial ischemic stroke. Mul- Alan Bryer, FCN (SA), tiple etiologies and lack of clear case definitions inhibit progress in this field. Several etiologies, PhD many treatable, are relevant to HIV-related stroke. To fully understand the mechanisms and the Sebastian Lucas, FRCP, terminology used, a robust classification algorithm to help ascribe the various etiologies is FRCPath needed. This consensus paper considers the strengths and limitations of current case definitions Alan Stanley, FCN (SA) in the context of HIV infection. The case definitions for the major etiologies in HIV-related strokes Theresa J. Allain, FRCP, were refined (e.g., varicella zoster vasculopathy and antiphospholipid syndrome) and in some in- PhD stances new case definitions were described (e.g., HIV-associated vasculopathy). These case def- Elizabeth Joekes, FRCR initions provided a framework for an algorithm to help assign a final diagnosis, and help classify Hedley Emsley, FRCP, the subtypes of HIV etiology in ischemic stroke. Neurol Neuroimmunol Neuroinflamm 2016;3:e254; PhD doi: 10.1212/NXI.0000000000000254 Ian Turnbull, FRCR Colin Downey, MIBMS GLOSSARY Cheng-Hock Toh, FRCP, ACL 5 anticardiolipin antibodies; anti-b2GP1 5 anti–b2-glycoprotein I; APS 5 antiphospholipid syndrome; HSV 5 herpes PhD simplex virus; IgG 5 immunoglobulin G; LA 5 lupus anticoagulant; RPR 5 rapid plasma reagin; SVD 5 small vessel disease; 5 5 5 Kevin Brown, FRCPath, TB tuberculosis; TOAST Trial of Org 10172 in Acute Stroke Treatment; TTP thrombotic thrombocytopenic purpura; VDRL 5 Venereal Disease Research Laboratory; VZV 5 varicella zoster virus. MD David Brown, FRCPath Stroke has become a prominent complication of HIV infection.1,2 Recent work suggests that the Catherine Ison, PhD outcome of HIV-related stroke is also poor.3 A variety of mechanisms has been postulated, Colin Smith, FRCPath, including opportunistic infections, cardio-thromboembolism, coagulopathy, and the incom- MD 4 Elizabeth L. Corbett, pletely understood HIV-associated vasculopathy. In addition, antiretroviral therapy may itself 2,4 FRCP, PhD exacerbate ischemic stroke risk through several mechanisms. In some patients, multiple path- Avindra Nath, MD ogenic processes may combine. Of the various types of stroke in people with HIV, arterial Robert S. Heyderman, ischemic stroke affecting the brain is most frequently described, and so is the focus of this FRCP, PhD review.4 Myles D. Connor, FRCP, In the 1990s, approaches to studying the etiology of ischemic stroke advanced considerably PhD with the development of the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classi- Tom Solomon, FRCP, fication.5 However, the TOAST classification was derived in a setting where HIV infection PhD was less prevalent; in these populations, approximately 75% of ischemic stroke patients are classified into 1 of 3 main categories (i.e., large artery atherosclerosis, small vessel disease [SVD], 6 Correspondence to and cardio-thromboembolism). In contrast, in HIV-infected stroke populations, less than 50% Dr. Benjamin: fall into the 3 main categories.7 The higher proportion in the generic categories (i.e., “other [email protected] determined,” and “undetermined”) is largely attributable to alternative causes and the Supplemental data From the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (L.A.B., E.L.C., R.S.H.) and Department of Medicine (L.A.B., T.J.A.), at Neurology.org/nn University of Malawi College of Medicine, Blantyre; Institute of Infection and Global Health (L.A.B., H.E., T.S.), University of Liverpool; Walton Centre NHS Foundation Trust (L.A.B., T.S.), Liverpool, UK; Department of Medicine (A.B., A.S.), Division of Neurology, Groote Schuur Hospital, University of Cape Town, South Africa; Department of Histopathology (S.L.), St. Thomas Hospital, London; Radiology Department (E.J.) and Haematology Department (C.D., C.-H.T.), Royal Liverpool Hospital; Preston Hospital (H.E.); North Manchester General Hospital (I.T.); Virus Reference Department (K.B., D.B.) and Syphilis Reference Department (C.I.), Public Health England, London; Centre for Clinical Brain Sciences (C.S.) and Division of Clinical Neurosciences (M.D.C.), University of Edinburgh; Department of Clinical Research (E.L.C.), London School of Hygiene and Tropical Medicine, UK; National Institutes of Health (A.N.), Bethesda, MD; Division of Infection and Immunity (R.S.H.), University College London; NHS Borders (M.D.C.), Melrose, UK; School of Public Health (M.D.C.), University of the Witwatersrand, South Africa; and National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections (T.S.), Liverpool, UK. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by University of Liverpool. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neurology.org/nn © 2016 American Academy of Neurology 1 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. occurrence of multiple etiologies in one indi- contraindications, the consensus was that a lumbar puncture was vidual. Without a reliable classification sys- justified to exclude infectious etiologies, irrespective of HIV stage and age of the individual. tem, the study of HIV stroke, particularly its We also defined a minimum investigation workup to help epidemiology and pathogenesis, will be classify the different etiologies (table 2). The use of optimal inhibited. tests further improved the level of evidence for causation. We Several types of vasculopathy have been then rationalized the ranking of the different etiologies to form an algorithm. The emerging roles of potential bio- described in individuals with HIV infection, markers were also considered. Our discussions formed the including accelerated atherosclerosis, HIV- basis of this document. associated vasculitis, a nonatherosclerotic group with intimal hyperplasia but without HANDLING MULTIPLE ETIOLOGIES IN HIV-RELATED STROKE: DEVELOPING THE ALGORITHM The entry atherosclerosis or vasculitis, and a group with point of this algorithm. Arterial ischemic stroke. This is 4 radiologically and clinically defined SVD. based on the definition of the Stroke Council of the While the larger vessel vasculopathies (e.g., American Heart Association/American Stroke the nonatherosclerotic group) may manifest Association.14 Despite recent revisions to this case as large artery stroke, SVD may be more definition, those presenting with an insidious onset important in HIV-associated neurocognitive of cognitive deterioration associated with multifo- disorders8; the pathogenesis of both is cal SVD on brain imaging, may still be overlooked. unclear. Greater consistency and accuracy HIV infection. This is based on a positive antibody across studies will be achieved by a standard- test (HIV enzyme immunoassay or rapid HIV anti- ized algorithm. body test) and confirmed with Western blot, antigen test, or PCR. In resource-poor settings, confirmation Recently, a ranked approach of applying is usually with a second antibody test using a different diagnostic test results, which allows for dif- manufacturer system. ferent levels of evidence, was developed for A complete “minimum” assessment. All patients should defining the range of etiologies of encephali- have at least the minimum set of investigations, as per tis, which also facilitated new large prospec- our proposed algorithm (table 2). In better resourced tive cohort studies.9,10 We therefore decided settings, further investigations comprising the “opti- to adopt a similar approach to help classify mum” set will improve the level of evidence to con- the subtypes of HIV etiology in ischemic firm a stroke etiology. stroke. Our proposed algorithm is presented The algorithm. Having defined the criteria for the dif- in figure 1. ferent etiologies of stroke in HIV, we developed an algorithm by which these etiologies would be consid- METHODS During the preparation of a recent review of HIV ered (figure 1). For some, the causal role is clear, the and stroke written by some of the present authors,4 it was clear disease mechanism relatively well described, and there that some case definitions needed refining, and more detailed are important treatment implications of making the consideration was needed in handling patients with multiple eti- diagnosis. For other putative causes, the evidence ologies. We therefore identified experts in the fields of HIV implicating them is less clear, and there are no direct infection and stroke and established a working group that treatment implications. For example, if a patient had included a broad range of relevant specialists. The first step was to determine the main etiologies of interest evidence of both confirmed cardio-thromboembolic for HIV-related arterial ischemic stroke; this was largely based on and atherosclerotic stroke, because the cardio- the classification described previously (table 1).4 Collectively, thromboembolic stroke has a high risk of recurrence these etiologies should account for
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