CNS demyelination from zinc toxicity?

A 45-year-old man presented with a 4-month history of progressive fatigue, lethargy, shortness of breath on exercise, and generalized numbness with paresthesias. Initial bloodwork showed severe pancytopenia, with a hemoglobin of 4.9 g/dL, a white blood cell count of 1,000 mm⁻³, and a platelet count of 121,000 mm⁻³. Bone marrow biopsy showed aplastic anemia with ringed sideroblasts. This was subsequently attributed to zinc toxicity with associated copper deficiency. His serum zinc level was 192 μg/dL (normal, 70 to 150 μg/dL), his serum copper level was 0 μg/dL (normal, 70 to 155 μg/dL), and his serum ceruloplasmin level was 6.8 mg/dL (normal, 16.2 to 35.6 mg/dL). Blood levels of other heavy metals, including lead, mercury, and arsenic, were normal. He was transfused with 4 U of packed red blood cells, and treated with IV copper infusions. By the time of discharge his hemoglobin was 9.4 mg/dL and his systemic symptoms had resolved. No specific source for zinc poisoning was identified, despite extensive testing.

He was evaluated in our neurology clinic 5 months later because his neurologic complaints had not improved despite continued oral copper supplementation. His hemoglobin had risen to 15.8 mg/dL and his serum copper was 76 μg/dL with a ceruloplasmin level of 17.5 mg/dL. He had not experienced any marked cognitive difficulties. His paresthesias were unchanged and he also had limb clumsiness. There was no family history of neurologic diseases. His examination showed saccadic dysmetria, slow and clumsy rapid toe tapping, decreased vibratory and joint position sensitivity in the feet, brisk reflexes, extensor plantar responses, and truncal ataxia with a positive Romberg’s sign. Serum vitamin B12, methylmalonic acid, and homocysteine levels were all within normal limits. Syphilis, human T-cell lymphotrophic virus I, and HIV serologies were all negative. Serum vitamin E level was normal. Results of nerve conduction studies and needle electromyography were also normal.

Brain MRI showed multiple bilateral periventricular white matter hyperintensities on T2-weighted images, almost confluent in some areas, with extensive involvement of the corpus callosum (figure). Lesions were also present in the cerebellar peduncles (not shown). CSF studies including cell count, protein level, oligoclonal bands, myelin basic protein, immunoglobulin G index, and Venereal Disease Research Laboratory were all normal or negative. Pattern-shift visual evoked response latencies were prolonged asymmetrically bilaterally. Auditory brainstem evoked responses were normal. Serum very long-chain fatty acids and arylsulphatase A levels were normal.

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Figure. Brain MRI. (A, B) T2-weighted axial sections show multiple periventricular areas of increased signal intensity. (C) Sagittal fluid-attenuated inversion recovery image shows involvement of the corpus callosum.

Copper and zinc are absorbed across the proximal small bowel enterocytes. A proportion remains sequestered within the enterocytes bound to the intracellular ligand metallothionein, and the remainder is released into the enterohepatic circulation. Excess zinc levels cause an upregulation of metallothionein production, which effectively decreases intestinal absorption of both copper and zinc, resulting in copper deficiency.1 Sideroblastic anemia is a rare but recognized manifestation of zinc toxicity and associated copper deficiency.1 Previous epidemiologic studies have also implicated zinc toxicity in the pathogenesis of demyelinating diseases. Schiffer and colleagues2,3 reported a cluster of cases of MS in factory workers from northern New York with abnormally high serum zinc levels. Other studies from Canada showed an increased incidence of MS in an area with an elevated concentration of various metals including zinc.4-6

Our patient developed extensive CNS demyelination in close temporal association with documented zinc toxicity with resultant copper deficiency and sideroblastic anemia. There was no clinical or laboratory evidence of an alternative inflammatory, metabolic, or infectious etiology for his neurologic syndrome. This case lends additional support to a possible role played by zinc in the pathogenesis of demyelination and the chain of events leading to MS.