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Clioquinol

Source. Clioquinol is used to treat diarrhea caused by amoebae, lambliae, and shigellosae. In Japan, chronic use in the treatment of diarrhea induced signs of a subacute myelo-optic neuropathy syndrome (SMON) (Mamoli et al. 1975; Shigematsu and Yanagawa 1978). This disease occurred in epidemic proportions.

Clinical Features. The most salient symptoms are reduced vision, spinal ataxia, signs of a pyramidal tract lesion and sensorimotor deficits, together with bladder insufficiency.

Pathogenesis. There is a distal axonopathy confined to the CNS (Schaumburg and Spencer 1980) thought to be caused by impaired axonal transport (Thomas et al. 1984).

Morphology. The morphological picture is dominated by edematous alterations in the cerebrum and cerebellum with gliosis. Foci of demyelination are evident in the optic nerve, the posterior white columns as well as in the anterior and lateral funiculi of the spinal cord (Fig. 17.7).

Fig. 17.8a, b. Necrotizing leukoencephalopathy, as a morphologic marker of an intrathecal methotrexate application

17.6.3 Cytostatics and Antituberculous Agents

Many cytostatic agents, such as cyclohexyl-1-ni-trosourea (CCNU) or bischloroethyl nitrosourea (BCNU) as well as selected antituberculous agents, for example isoniazid, can cause CNS injury by a vascular mechanism (Omojola et al. 1982) but we concentrate here on agents damaging the brain by a mechanism directly acting on the nervous parenchyma.

17.6.3.1 Methotrexate

Source. Methotrexate is a folic acid antagonist used as a cytostatic, especially in the treatment of leukemias. For this purpose, methotrexate is applied intrathe-cally in combination with cranial and craniospinal radiotherapy. This combined treatment can cause neuronal injury. Intravenous application of metho-trexate alone has a neurotoxic effect in sufficiently high doses.

Clinical Features. The following clinical features have been described: acute myelopathy, subacute myelop-athy and chronic leukoencephalopathy. Acute signs of transient confusion, lethargy, and headache have also been reported. Chronic administration may induce fatigue, irritability, ataxia, and confusion. Spasticity has also been occasionally observed.

Morphology. Intrathecal or intraventricular metho-trexate treatment is known to cause a necrotizing leukoencephalopathy located mainly periventricu-larly, but which also occurs multifocally with coagulation necrosis (Shapiro et al. 1973) and axon swelling (Fig. 17.8). Intrathecal application combined with radiotherapy is associated with demyelination alone or in combination with disseminated necrosis, especially in the centrum semiovale (Rubinstein et al. 1975; Robain et al. 1984). It is striking that there is no significant cellular reaction.

The neurotoxic effect is especially conspicuous under the conditions of pregnancy which may cause a cytostatic embryopathy. The characteristic morphologic feature is systemic hypoxia-like damage of the entire brain (microcephaly, hydrocephalus, hy-poxic changes of the cortex) associated with malformation of the skull (Fig. 17.9).

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