Mptp Intoxication

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Some intravenous drug addicts who use a synthetic heroin-like drug (meperidine) develop chronic parkinsonism as a result of contamination by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (193). MPTP is metabolized in the brain to 1-methyl-4-phenylpyridinium (MPP+) (194) and is selectively transported into dopaminergic cells, which it kills by inhibiting mitochondrial function (195). Human postmortem studies reveal severe depletion of pigmented neurons in the substantia nigra without LBs (196). The presence of active gliosis and microglial activity has been interpreted as indicating ongoing neurodegeneration, years after the initial exposure. MPTP-induced parkinsonism in experimental nonhuman primates has become a valuable model for studying idiopathic PD (197). In addition to nerve cell degeneration in both the substantia nigra and the locus ceruleus, these animals develop eosinophilic neuronal inclusions that show both similarities and differences compared with LBs in human disease (198).

Fig. 10. Postencephalitic parkinsonism (PEP). (A) Gross photograph showing atrophy of the midbrain with degeneration of the substantia nigra in PEP compared with normal control (C). (B) Globose neurofibrillary tangle (H&E stain).

WILSON'S DISEASE

Wilson's disease is an autosomal recessively inherited disorder of copper metabolism in which the metal deposits in a number of organs including brain. Neurologic findings vary but often include extrapyramidal features. The neuropathology also varies depending on the rate of disease progression. There is degeneration of the basal ganglia, which may appear shrunken or even cavitated and often has a brown discoloration (Fig. 11A). The putamen tends to be more severely affected than the caudate, globus pallidus, and substantia nigra. Other areas that may be involved include the pons, thalamus, cerebellum, and subcortical white matter. There is neuronal loss, extensive fibrillary glio-sis, and macrophages containing lipid and hemosiderin pigment. There may be visible accumulation of copper around capillaries. A number of more disease-specific cellular changes may be present. Alzheimer type II astrocytes are commonly seen in cases of chronic hepatic failure with neurological dysfunction and are numerous in most cases of Wilson's disease. They have swollen pale nuclei with little chromatin, prominent nucleoli, and sometimes contain small dots of glycogen (Fig. 11B). Large multinucleate Alzheimer type I cells are rare and not seen in every case (199). Most disease specific is the presence of cells with small nuclei, abundant granular or foamy cytoplasm, and no obvious processes (200). These "Opalski" cells are of uncertain origin, possible derived from astrocytes, macrophages, or degenerating neurons (Fig. 11C). They are most numerous in the thalamus, globus pallidus, and substantia nigra and rare in the striatum.

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