Copper is an essential trace metal and plays key roles in the structure and function of the nervous system, vascular, and skeletal tissues and in hematopoiesis and catecholamine metabolism. Inherited copper deficiency (Menkes’ disease) results in intellectual deterioration, failure to thrive, seizures, abnormal hair, and connective tissue abnormalities. Due to the ubiquitous distribution of copper and the low daily requirement, acquired copper deficiency is extremely rare in humans. Ataxic myelopathy due to copper deficiency does occur in ruminants and is called swayback.1 The hematologic manifestations of acquired copper deficiency are well described,2 but the neurologic manifestations of acquired copper deficiency in humans are not widely appreciated. We describe a case of myelopathy that occurred in the setting of copper deficiency.
Case report.
A 65-year-old man was evaluated for a 5-year history of progressive gait difficulty. For 1 year prior to evaluation, he had been using a cane and had paresthesias involving the feet and hands. He had been taking 200 to 400 mg of zinc a day for cold prevention for 22 years (recommended daily allowance of zinc, 15 mg/day). Neurologic examination revealed increased lower limb tone with mild lower limb weakness in an upper motor neuron pattern. Rapid foot tapping was slow and clumsy. Vibration perception in the lower limbs was impaired in a graded manner up to the knees, and perception of position sense at the toes was decreased. The reflexes were brisk except the ankle jerks, which were depressed. The plantar response was extensor bilaterally. The patient had a spastic ataxic gait, and Romberg test was positive.
The hematology group, erythrocyte sedimentation rate, electrolytes, liver enzymes, glucose, antinuclear antibody, immunoelectrophoresis, thyroid-stimulating hormone, fatty acid profile, and vitamin E levels were all normal. The vitamin B12 level was normal at 565 ng/L (normal, 200 to 650 ng/L). Syphilis, Lyme, human T-lymphotrophic virus-I, and HIV serologies were negative. A spinal tap was unremarkable except for a slight elevation in the protein level to 61 mg/dL. Nerve conduction studies showed a moderately severe axonal sensorimotor peripheral neuropathy, as suggested by an absent right peroneal and sural response, a marked reduction in the right tibial amplitude, and a mild reduction in the right median and ulnar sensory amplitudes. The median somatosensory evoked potentials showed a slowing in the central sensory pathways between the cervical spine and the cortex, and the tibial response was absent. Brain MRI (figure) showed a right pontine lacune (see the figure, A) and changes attributed to small-vessel ischemic disease (see the figure, B). Spine MRI showed mild degenerative changes. The serum ceruloplasmin level was low at 7.3 mg/dL (normal 22.9 to 43.1 mg/dL), with a proportional reduction in the serum copper level to 0.45 μg/dL (normal, 0.75 to 1.45 μg/dL). The serum zinc level was elevated to 1.51 μg/mL (normal, 0.66 to 1.10 μg/mL). The urinary zinc excretion was markedly increased to 4,264 μg (normal, 300 to 600 μg); copper excretion was normal at 22 μg (normal, 15 to 60 μg).
Figure. Axial T2 brain MRI showing a right pontine lacune (A) and changes attributed to small-vessel ischemic disease (B).
The zinc was discontinued, and the patient was started on oral copper supplementation (copper gluconate 2 mg/day). He was seen 6 weeks later and reported a resolution of his paresthesias and improvement in gait. The serum ceruloplasmin (32.5 mg/dL), serum copper (1.08 μg/mL), and zinc (0.95 μg/mL) levels had all normalized. There was improvement in the median somatosensory evoked potentials, and the tibial evoked potentials were now obtainable, albeit abnormal. Symptomatic improvement was maintained 5 months later.
Discussion.
The literature concerning the neurologic manifestations of acquired copper deficiency in humans is limited. In one report, a 46-year-old woman developed spastic tetraparesis and painful paresthesias with a hyperintense T2 signal in the cervical cord.3 She had anemia and copper deficiency, which were attributed to malabsorption due to prior gastric resections. The other report describes two cases with spasticity, ataxia, paresthesias, and sensory deficits linked to copper deficiency.4,5⇓ These two patients had brain MRI changes consistent with demyelination. Both had mild hyperzincemia, which was felt to be secondary to the copper deficit. Elevated plasma zinc levels have been described as a heritable anomaly with no clinical manifestations.6 A cluster of patients with CNS demyelination (presumed multiple sclerosis) has been described in association with zinc exposure in the workplace.7
Our patient consumed 15 to 30 times the recommended daily allowance of zinc for over two decades. Zinc is well known to reduce body copper stores; in fact, zinc therapy is standard treatment for Wilson’s disease. Zinc and copper are absorbed in the proximal part of the small intestine. Increased intake of zinc induces high concentrations of metallothionein in enterocytes. Copper has a higher affinity for metallothionein than zinc, so it displaces zinc from metallothionein. Copper remains in the enterocytes, which are sloughed off into the intestinal tract. There is too little experience to decide how best to treat neurologic conditions due to acquired copper deficiency. The three previously described cases suggest that the hematologic and biochemical parameters show a quicker response than the neurologic manifestations. The sensory symptoms seem to respond better than the motor manifestations.
Potential causes of copper deficiency include malnutrition, prematurity, parenteral or enteral feeding without copper supplementation, gastrectomy, ingestion of copper-chelating agents, and zinc therapy. Neurologic syndromes due to acquired copper deficiency may include a myelopathy or MRI changes suggestive of demyelination. Early recognition and institution of therapy might prevent neurologic deterioration.
- Received February 3, 2003.
- Accepted March 2, 2003.
Letters: Rapid online correspondence
- Reply to Prodan et al
- Myelopathy due to copper deficiency
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