Brain Pathology Case of the Month - August 2000



The clinical neurologic and neuropathologic manifestations of methanol poisoning have been the subject of several review articles over the past forty years(2, 12, 15) though original case studies with detailed post-mortem pathologic studies are relatively few. The earliest autopsy studies on methanol poisoning have emphasized the acute changes secondary to hypoxic/ischemic injury to the gray matter, namely, cerebral edema and acute neuronal injury(10, 14) (see also review(12)). Post-mortem studies of affected individuals who survive intoxication a period of several days or weeks have shown a distinctive pattern of brain injury characterized by bilateral putamen necrosis, particularly affecting the lateral portions of the nuclei(1, 4, 5, 7, 9, 11, 12, 17). In some of these cases there has also been a dramatic pattern of white matter hemorrhagic necrosis involving the centrum semiovale, especially affecting subcortical regions(11, 17). Two of the cases reported by Burger and Vogel have comparable findings (cases 1 and 2)(3). The lesions of the white matter and of the putamen may also be contiguous(5, 7, 13). The well documented toxic effect of methanol on the visual system has been noted in the absence of neurologic manifestations; however, there have also been reports of concomitant brain and ocular lesions(14, 16).

Case 1 shows the classic appearance of acute putamen necrosis and hemorrhage seen in methanol intoxication; the character and distribution of the lesion appears to be unique to methanol intoxication. The amount of hemorrhage may be variable, as has been documented in radiologic studies(6). Large hemorrhages with extension into the ventricular system have been noted (5, 13). The presence of large hemorrhages may correlate with systemic heparinization during dialysis(13) or may be seen without a recognized antecedent(6). If the patient survives the acute phase of the illness, resorption of the infarcted hemorrhagic putamen tissue occurs with the formation of cystic cavities within the nucleus(9, 11); some of these patients exhibit a Parkinsonian syndrome(8, 9, 13).

Case 2 exemplifies the second major type of pathology associated with methanol toxicity: white matter necrosis and hemorrhage. White matter lesions have been considered less specific of methanol poisoning, although it is difficult to find well-documented reports of their occurrence in other settings (the cases reported by Burger and Vogel may be an exception(3)); the coincident putamen hemorrhagic necrosis and large, hemorrhagic white matter lesions was first well described by Orthner(11); the phenomena at various stages of evolution are also well documented in the reports by McLean and collaborators(9) and by Suit and Estes(17).

The precise mechanism of methanol toxicity remains a matter of debate(2, 17). The observed lesions likely represent direct toxic effects of methanol and its metabolites, as well as injury secondary to anoxia and acidosis. Methanol is metabolized to formaldehyde and formic acid by hepatic alcohol dehydrogenase. High levels of formaldehyde do not appear in the blood, and toxic effects appear to be related to high levels of formic acid. In experimental animals, formic acid toxicity ensues despite correction of metabolic acidosis. The basis for the anatomic specificity of methanol poisoning is unknown. Injury to the putamen likely represents a selective toxic effect, possibly potentiated by poor venous drainage. The pathogenesis of the white matter hemorrhagic necrosis remains unexplained.

A number of commercial products including windshield wiper fluid, gasoline antifreeze, paint remover, and photocopying fluid, contain methanol, and may be ingested accidentally or during a suicide attempt. Contamination of recreational vehicle water stores by windshield wiper fluid, as occurred in Case 1, is a recognized cause of methanol poisoning.


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Contributed by Mel B. Feany, MD, PhD, Douglas C Anthony, MD, PhD, Matthew P Frosch, MD, PhD, William Zane, MD, and Umberto De Girolami, MD

International Society of Neuropathology