Rabies is a fatal encephalitic infection transmitted to humans from rabid animals, usually by a bite. Various mammals are natural reservoirs. Exposure to some bat species, even without evidence of a bite, is also a risk factor. The virus enters the CNS by ascending along the peripheral nerves from the wound site, so the incubation period (usually a few months) depends on the distance between the wound and the brain. The disease manifests initially with nonspecific symptoms of malaise, headache, and fever. As the infection advances, the patient shows extraordinary CNS excitability; the slightest touch is painful, with violent motor responses progressing to convulsions. Contracture of the pharyngeal musculature may create an aversion to swallowing even water (hydrophobia). Periods of mania and stupor progress to coma and eventually death, typically from respiratory failure.
In the first 15 years or so after recognition of AIDS, neuropathologic changes were demonstrated at postmortem examination in as many as 80% to 90% of cases, owing to direct effects of the virus on the nervous system (HIV encephalitis), along with opportunistic infections and primary CNS lymphoma. Introduction of highly active antiretroviral therapy (HAART) has decreased the frequency of these secondary effects of HIV infection. However, cognitive dysfunction ranging from mild to full-blown dementia that is lumped under the umbrella term HIV-associated neurocognitive disorder (HAND) continues to be a source of morbidity. This syndrome is believed to stem from HIV infection of microglial cells in the brain and activation of innate immune responses. Neuronal injury likely stems from a combination of cytokine-induced inflammation and toxic effects of HIV-derived proteins.
Aseptic meningitis occurs within 1 to 2 weeks of onset of primary HIV infection in about 10% of patients; antibodies to HIV can be demonstrated, and the virus can be isolated from the CSF. The few neuropathologic studies of the early and acute phases of symptomatic or asymptomatic HIV invasion of the nervous system have shown mild lymphocytic meningitis, perivascular inflammation, and some myelin loss in the hemispheres.
When effective anti-HIV therapy is begun in the setting of established infection, there is a risk for neurologic involvement associated with the immune reconstitution inflammatory syndrome (IRIS). Neurologic manifestations include rapidly developing cognitive impairment and cerebral edema. The pathogenesis of IRIS is unclear but it is thought to be due to the activation of a previously suppressed inflammatory response brought about by effective treatment of HIV infection. IRIS is often associated with the presence of a mycobacterial, fungal or viral opportunistic CNS infection, although it can also occur in the absence of any other inciting disease.
MORPHOLOGYHIVencephalitisisachronicinflammatoryprocesswithwidelydistributedmicroglial nodules, sometimeswithassociatedfocioftissuenecrosisandreactivegliosis(see
Fig.23.18D ).Themicroglialnodulesalsoarefoundinthevicinityofsmallbloodvessels,whichshowabnormallyprominentendothelialcellsandperivascularfoamyorpigment-ladenmacrophages.Thesechangesareespeciallyprominentinthesubcorticalwhitematter,diencephalon,andbrainstem.Animportantcomponentofthemicroglialnodulearemacrophage-derivedmultinucleate cells. Insomecases,therealsoisadisorderofwhitemattercharacterizedbymultifocalordiffuseareasofmyelinpallor,axonalswellings,andgliosis.HIVispresentinCD4+ mononuclearandmultinucleatemacrophagesandmicroglia.