Gross Examination

Cerebral atrophy of variable degrees Ventricular enlargement Widening of sulci

Attenuation of deep cerebral white matter MICROSCOPIC EXAMINATION

HIV-1 encephalitis

Perivascular foci of inflammatory cells, microglia, macrophages, MGC involving the basal ganglia and subcortical white matter predominantly HIV-1 leukoencephalopathy

Diffuse myelin pallor and white matter damage, reactive astrogliosis, macrophages Calcific vasculopathy

Small vessel mineralization of basal ganglia, frontal white matter (children > adults) Leukoencephalopathy and gliosis

Basal ganglia calcific vasculopathy (infants and children) Diffuse poliodystrophy

Modified from Budka H, Wiley CA, Kleihues P, et al HIV-1 associated disease of the nervous system review of nomenclature and proposal for neuropathology-based terminology. Brain Pathol 1991;1:143-152.

MGC, Multinucleated giant cells.

seen in the hemispheres (. .. Fig 44-Z ) and less often in the cerebellum. Leukoencephalitis was reported in one third of patients clinically diagnosed with HIV

dementia'791 and in 38 percent of autopsy series cases. y A diffuse poliodystrophy has also been described in approximately 50 percent of cases. More recently, neuronal loss, dendritic changes, and reduced levels of synaptophysin have also been demonstrated by quantitative methods. A frontal and parieto- occipital predominance is noted.y , y

HIV-1 is most frequently localized in cells of bone marrow lineage (blood-derived macrophages), intrinsic microglia (the resident mononuclear phagocytic system of the brain), and multinucleated giant cells (formed by the fusion of these cell types). It is these cells that support productive infection. y , y , y By immunocytochemistry, HIV-1 antigen is localized most often in the basal ganglia, subthalamic nucleus, substantia nigra, dentate nucleus, and white matter. y PCR studies, though, show HIV to be more abundant in subcortical white matter than basal ganglia, deep white matter, or cortex. y With more sensitive and specific techniques of viral detection, both a greater number of infected cells and cell types infected have recently been demonstrated. These include endothelial cells, y astrocytes, y , y and neurons,y although this may be restricted infection.

The clinicopathological correlates of HIV-1-associated CNS disease are not clearly delineated, nor is the exact role of the virus defined. Although studies have confirmed direct HIV-1 CNS infection early in the disease, the development of clinical HIV-1-associated CNS disease does not occur until the late stage of HIV-1 infection when the patient is immunosuppressed. Moreover, the pathological changes seen at autopsy in some cases do not always correlate with the clinical course. Some patients with clinically severe neurological disease may have relatively mild neuropathological findings. Even in those cases with more marked pathological findings, there may be a relatively small proportion of infected cells and those actively replicating. Indeed, one recent prospective study found 50 percent of patients with clinically diagnosed dementia had neither the hallmark features of HIV encephalitis nor white matter pallor, and only 25 percent of dementia cases had multinucleated giant cells. y These discrepancies have suggested that other factors besides direct cellular damage by HIV-1 may be important in pathogenesis. '901 Both virological and neuroimmunological processes have been implicated (,Ia.b.!e.,4.4:9. ). Many questions remain unanswered concerning the role of the virus, CNS viral load, evolution of

Figure 44-6 (Figure Not Available) Multinucleated giant cellfarrows) obtained on biopsy from the brain of an AIDS patienReproduced with permission from Belman AL, Diamond G, Dickson D, et al: Am J Dis Child 1988:142:29-35.)

neurotropic strains, mechanisms underlying viral protein and cytokine-mediated effects and toxicities, yet undefined host factors, and viral-host interactions. Epidemiology and Risk Factors. Of the 1 to 1.5 million

Figure 44-7 A 30-year-old male with AIDS. This T2-weighted magnetic resonance image demonstrates atrophy and diffuse white matter hyperinteifCourfesy of Clemente Roque, M.D.)

HIV-1-infected persons in North America, y up to 30 percent will manifest some form of cognitive impairment during the course of their infection. However, estimates vary as to the frequency and degree of neurocognitive deficits. Two major factors account for the differences in

_TABLE 44-9 -- POSSIBLE FACTORS IN THE PATHOGENESIS OF HIV-ASSOCIATED CNS DISEASE_

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