Stroke In HIV Infection

Dr Prashant Makhija

HIV & AIDS

Family- Human retroviruses (Retroviridae) & subfamily-lentiviruses

Human immunodeficiency viruses- HIV-1 and HIV-2

HIV-1- most common cause of HIV disease throughout the world

HIV-2 - originally confined to West Africa, now identified throughout the world

HIV-1- subgroups M, N, O, P

HIV-2 - subgroups A through G

The AIDS pandemic is primarily caused by the HIV-1 M group virusesHarrison’ s Principles Of Internal Medicine. 18th edition. Ch.189

Problem Statement

Joint United Nations Programme on HIV/AIDS (UNAIDS) 2009

Worldwide estimated 33.3 million individuals were living with HIV infection

~ 50% are female, and 2.5 million (7.5%) are children <15 years

AIDS deaths- totaled 1.8 million (including 2.6 lakh children <15 years)

India estimated number of people living with HIV/AIDS 2.39 million

~ 39% are female and 3.5% are children

1.72 lakh people were reported to have died from AIDS-related causes`

CDC classification system for HIV-infection Categorizes persons on the basis of clinical conditions associated with HIV

infection and CD4+ T lymphocyte counts

Once individuals have had a clinical condition in category B, their disease classification cannot be reverted back to category A, even if the condition resolves; the same holds true for category C in relation to category B

Harrison’ s Principles Of Internal Medicine. 18th edition. Ch.189

CD4+ T Cell Categories

A Asymptomatic,

Acute (Primary) HIV

or PGL

B Symptomatic,

Not A or C Conditions

C AIDS-

Indicator Conditions

>500/µL A1 B1 C1

200–499/µL A2 B2 C2

<200/µL A3 B3 C3

Category B: Symptomatic conditions in an HIV-infected Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent,

frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month Hairy leukoplakia, Oral Herpes zoster (shingles), involving at least two distinct episodes or more

than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tuboovarian abscess Peripheral neuropathy

Category C: Conditions listed in the AIDS surveillance case definition

Candidiasis of bronchi, trachea, or lungs ,Candidiasis esophageal Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month's duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) HIV-related Encephalopathy Herpes simplex: chronic ulcer(s) (>1 month's duration); or bronchitis, pneumonia, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month's duration) Kaposi's sarcoma Lymphoma, Burkitt's (or equivalent term) Primary Brain Lymphoma Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentified

species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV

Neurologic Diseases in Patients with HIV Infection

Opportunistic infections Toxoplasmosis Cryptococcosis Progressive multifocal leukoencephalopathy Cytomegalovirus Syphilis Mycobacterium tuberculosis HTLV-I infection Amebiasis Neoplasms Primary CNS lymphoma Kaposi's sarcoma

Result of HIV-1 infection Aseptic meningitis HIV-associated neurocognitive disorders, including HIV

encephalopathy/AIDS dementia complex

Myelopathy Vacuolar myelopathy Pure sensory ataxia Paresthesia/dysesthesia

Peripheral neuropathy Acute inflammatory demyelinating polyneuropathy (Guillain-Barré

syndrome) Chronic inflammatory demyelinating polyneuropathy (CIDP) Mononeuritis multiplex Distal symmetric polyneuropathy

Myopathy

STROKE Epidemiology Epidemiological data differs depending on the population (i.e. industrialized

countries vs. Sub-Saharan Africa) and the date of the study period [i.e.before vs. after highly active antiretroviral therapy (HAART) implementation]

The reported rate of stroke occurrence varies between 0.5 and 5% in different clinical series

Necropsy studies of HIV-infected subjects have shown a higher prevalence Pathological findings- asymptomatic

Most clinical series consistently show that strokes continue to occur at young age (< 50 years) in HIV-infected patients

HIV infection and particularly AIDS appear to be associated with an increased risk of stroke

Souvik Sen et.al. Recent Developments regarding Human Immunodeficiency Virus Infection and Stroke Cerebrovasc Dis 2012;33:209–218

First Author Population Method/Study Period

Rate

Engstrom (1989) 1,600 patients with AIDS

case series 1982–1987

12 (0.75%)

Connor (2000) 183 necropsies of HIV cases

necropsyseries

10 (5.5%)

Evers (2003) 772 patients with HIV

cohort study 1993–2001

15 IS/TIA (1.9%)

Corral (2009) 2,012 patients with HIV

treated with HAART

case series 1996–2008

27 IS/TIA in 25 patients (1.2%)

ISCHEMIC STROKE Clinical, radiological, and pathological series, there is an increased risk of IS in

AIDS patients

South Africa (2000–2006) 67 HIV- infected with Stroke 96% pts. Ischemic strokes 91% were younger than 46 years opportunistic infections- 37%, most common infection was tuberculosis (15%) HIV-associated vasculopathy-20% Cardioembolism- (14%) patients At the time of their stroke, 46% of these patients had CD4 counts < 200 cells/mm3 Traditional vascular risk factors were uncommon in these HIV-infected patients

with stroke

Tipping B et.al. J Neurol Neurosurg Psychiatry 2007;78:1320–1324

United States (1996-2004) - 82 HIV-infected patients with stroke 94% had Ischemic Strokes Most patients severely immunosuppressed at the time of the stroke

(85% had counts < 200cells/mm3) Mechanism - large artery atherosclerosis in 12%, cardiac embolism

in 18%,small artery occlusion in 18%, other determined cause in 23% and cryptogenic in 29%

Ortiz G et. al. Mechanisms of ischemic stroke in HIV-infected patients. Neurology 2007; 68: 1257–1261

Potential Causes of Ischemic Stroke in AIDS/HIV-Infected Patients

Cardioembolic Nonbacterial thrombotic endocarditis Infective endocarditis HIV myocarditis Myxoid valvular degeneration Mural thrombus Dilated cardiomyopathy

Cerebral opportunistic vasculitis/vasculopathy Cytomegalovirus Mycobacterium tuberculosis Varicella-Zoster virus Syphilis Cryptococcosis Mucormycosis Aspergillosis Candida albicans Toxoplasmosis Coccidioidomycosis Trypanosomiasis

Prothrombotic states Protein S deficiency Antiphospholipid antibodies Disseminated intravascular coagulation HIV-related vasculitis/vasculopathy Impaired vasoreactivity Impaired vascular bed-specific homeostasis Accelerated atherosclerosis with protease inhibitors Dyslipidemia, insulin resistance Endothelial dysfunction Cryptogenic

HIV-related Vasculopathy

Suggested as the mechanism of stroke in HIV/AIDS patients who are free of other vascular risk factors

Direct infection of the vessel walls by HIV

Characterized by small-vessels wall thickening, pigment deposition with vessel wall mineralization, and occasional perivascular inflammatory cells infiltrates

Vascular changes are similar to those found in elderly patients with vascular risk factors and cerebral atherosclerosis

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

Abnormalities of cerebral perfusion have been documented in asymptomatic HIV patients using 113Xe single-photon emission computed tomography

Suggesting alterations of cerebral resistance at the arteriolar level

Clinical relevance of HIV-related vasculopathy is still debatable

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

HAART Regimen andHIV-Infected/AIDS Patients

Pre HAART era- incidence of atherosclerosis was low in HIV-infected pts

With the introduction of HAART regimen- ↑ incidence of atherosclerosis

Mechanisms ↑ life expectancy- age related atherosclerosis Proatherosclerotic effects of the HIV infection itself Metabolic changes resulting from HAART regimen

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

Treatment with PIs has been associated with severe premature atherosclerotic vascular disease

Metabolic changes—dyslipidemia, insulin resistance

Lipid abnormalities may be present in 24 to 64%of patients treated with PIs

Studies have preferentially implicated Ritonavir

Fibric acid derivatives and statins can lower HAART-associated increases in dyslipidemia- Pravastatin showing least interactions with PIs

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

HEMORRHAGIC STROKE

ICH is a later complication of HIV infection, generally with CD4 T-lymphocytes cells < 200 mm3

Studies report conflicting data regarding the incidence of ICH in HIV-infected pts.

Cole and coworkers in the first population case-based study found an incidence of 0.11% per year for ICH with an adjusted RR of 12.7% (95% CI, 4 to 40)

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

Potential Causes of Intracerebral Hemorrhage inAIDS/HIV-Infected Patients

Opportunistic infection Mycobacterium tuberculosis Toxoplasmosis

Opportunistic neoplasm Lymphoma Metastatic Kaposi sarcoma

Coagulation/Bleeding disorders Disseminated intravascular coagulation Thrombocytopenia

Vascular Mycotic aneurysm (IVDA)

Amélia Nogueira Pinto . Semin Cerebrovasc Dis Stroke 5:40-46

CVT In HIV Patients

HIV infected patients are predisposed to venous thrombosis (Central & Peripheral Vasculature)

CVT has been reported as presenting feature in HIV-infected patients

Clinical presentation and radiological features are similar to dural venous thrombosis of any cause

M Saravanan et al. Brain: non-infective and non-neoplastic manifestations of HIV. The British Journal of Radiology, 82 (2009), 956–965

Muhammad Wasif Saif et.al. HIV and Thrombosis: A Review. AIDS Patient Care and STDs. January 2001, 15(1): 15-24

Etiology Clotting factor abnormalities- deficiencies of protein C, protein S,

heparin cofactor II, and antithrombin Antibodies- presence of antiphospholipid antibodies and the lupus

anticoagulant Presence of concurrent infectious or neoplastic diseases

Treatment Includes anticoagulation and treatment of the underlying disorder

M Saravanan et al. Brain: non-infective and non-neoplastic manifestations of HIV. The British Journal of Radiology, 82 (2009), 956–965

Muhammad Wasif Saif et.al. HIV and Thrombosis: A Review. AIDS Patient Care and STDs. January 2001, 15(1): 15-24

CONCLUSIONS Infection with HIV may contribute to an increased risk of stroke

Strokes tend to occur in young patients with uncontrolled HIV infection and more severe immunosuppression(CD4 <200/ mm3)

The most common underlying causes of ischemic stroke- Cardioembolic , infectious vasculitis, hypercoaguability and HIV vasculopathy

Hemorrhagic stroke - coagulation disturbances, thrombocytopenia, intracerebral tumors or CNS infection

The widespread adoption of highly active antiretroviral regimens has resulted in a decrease in the frequency of many of the neurological complications of HIV

However its effect may be counterbalanced by the proatherosclerotic effects of Protease Inhibitors

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