Steven L. Wesselingh

Clinical‐neuropathologic correlation in HIV‐associated dementia

The structural abnormalities that correlate with the clinical manifestations of HIV-associated dementia (HIVD) are unclear. In a prospectively categorized group of patients with and without HIVD who were followed to autopsy, we correlated HIV-related neuropathologic changes with the presence and severity of HIVD. We also assessed the effect of antiretroviral therapy on the neuropathologic changes. Finally, using reverse transcriptase-poly-merase chain reaction on homogenized brain tissue, we correlated the relative expression of mRNA for tumor necrosis factor-α (TNF-α) with cognitive impairment and with the patterns of neuropathologic changes. The presence of multinucleated giant cells and diffuse myelin pallor were specific for HIVD, but these pathologic changes occurred in only 50% of patients with dementia. Patients treated with antiretroviral agents for >12 months were less likely to show multinucleated giant cells or diffuse myelin pallor. Levels of mRNA for TNF-α from frontal subcortical white matter were significantly greater in patients with HIVD than in AIDS patients without dementia or in seronegative controls. We conclude that routine histopathologic examination of the brain fails to detect multinucleated giant cells and diffuse myelin pallor in 50% of patients dying with HIVD. This suggests that more subtle neuropathologic correlates for the clinical manifestations of HIVD exist. Our observations of elevated levels of TNF-α mRNA in HIVD indicate that indirect mechanisms of brain dysfunction, such as abnormal cytokine expression, may contribute to the pathogenesis of HIVD.

Brain Endothelial Cell Infection in Children with Acute Fatal Measles

Neurologic diseases are important complications of measles. The role of virus infection of the central nervous system as well as the route of virus entry has been unclear. Five autopsied cases of individuals who died with severe acute measles 3-10 d after the onset of the rash were studied for evidence of viral involvement of the central nervous system. In all cases, in situ hybridization and RT-PCR in situ hybridization techniques showed endothelial cell infection. Immunoperoxidase staining with an anti-ferritin antibody revealed a reactive microgliosis. These data suggest that endothelial cells in the brain are frequently infected during acute fatal measles. This site of infection may provide a portal of entry for virus in individuals who subsequently develop subacute sclerosing panencephalitis or measles inclusion body encephalitis and a target for immunologic reactions in post-measles encephalomyelitis.

Peripheral Neuropathy in AIDS: New Investigative Approaches

An extensive group of neurologic diseases affect the peripheral nervous system (PNS) of individuals infected with HIV (for reviews, see refs.1–3). As in the central nervous system (CNS), some of these disorders are due to opportunistic infections such as cytomegalovirus (CMV) infection of spinal roots and peripheral nerves.4,5 Others, including the inflammatory demyelinating neuropathies occasionally seen in early stages of HIV infection,6,7 are undoubtedly autoimmune in origin. Toxic neuropathies are of increasing importance because of the prominence of peripheral neurotoxicity resulting from the use of the antiretrovirals, dideoxycytidine (ddC) and dideoxyinosine (ddI).8–10 The major PNS complication of HIV infection is the predominantly sensory neuropathy (PSN) of AIDS.2,11–19 PSN is a disorder of unknown pathogenesis that is usually seen in advanced stages of AIDS. It has become one of the most frequent causes of new cases of symptomatic neuropathy in the U.S., with more than 30,000 cases annually. The incidence of neuropathy in individuals with HIV infection appears to be rising substantially, related both to the neurotoxic effects of antiretrovirals and to the HIV infection itself.20 While this may in part be due to increased attention to the disorder in prospective studies, it undoubtedly also reflects the increasing numbers of severely immunodeficient individuals surviving longer after AIDS (and reaching later stages of HIV infection) together with the increasing use of antiretroviral neurotoxins.