Abstract
Background: Copper deficiency in ruminants is known to cause an ataxic myelopathy. Copper deficiency as a cause of progressive myelopathy in adults is underrecognized.
Objective: To describe the clinical, biochemical, electrophysiologic, and imaging characteristics in 13 patients with myelopathy associated with copper deficiency.
Methods: The records of patients with a copper deficiency–associated myelopathy were reviewed. Clinical characteristics, laboratory investigations, and responses to therapeutic intervention were summarized.
Results: Thirteen such patients were found, 11 of them in a 15-month period. All patients presented with prominent gait difficulty, reflecting a sensory ataxia due to dorsal column dysfunction and lower limb spasticity. All patients had polyneuropathy. A high or high-normal serum zinc level was seen in 7 of the 11 patients for whom this information was available. Somatosensory evoked potential studies done in eight patients showed impaired conduction in central proprioceptive pathways. Dorsal column signal change on spine MRI was present in three patients. An initial clue to the diagnosis was a very low ceruloplasmin level; further tests of copper metabolism excluded Wilson disease. The cause remained unexplained in most patients. Oral copper supplementation restored normal or near-normal copper levels in 7 of the 12 patients in whom adequate follow-up data were available; parenteral supplementation restored normal level in 3 further patients. Copper supplementation prevented further neurologic deterioration, but the degree of actual improvement was variable.
Conclusions: Unrecognized copper deficiency appears to be a common cause of idiopathic myelopathy in adults. The clinical picture bears striking similarities to the syndrome of subacute combined degeneration associated with vitamin B12 deficiency. Early recognition and copper supplementation may prevent neurologic deterioration.
We recently reported a case of progressive myeloneuropathy caused by severe, isolated copper deficiency due to long-term, high-dose zinc ingestion.1 Four cases with neurologic manifestations in association with copper deficiency had previously been published.2–4⇓⇓ Shortly thereafter, we encountered two additional patients with progressive myeloneuropathy and copper deficiency in the setting of previous gastrointestinal surgery.5 Subsequently, we have encountered additional cases of myeloneuropathy due to isolated copper deficiency. We summarize our findings in 13 cases, 11 of which were prospectively identified over a 15-month period. Until recently, the cause would have gone unrecognized because serum copper and ceruloplasmin have not been part of the diagnostic workup of myeloneuropathy. The syndrome resembles subacute combined degeneration including a spastic ataxic gait with marked dorsal column deficits.
Methods.
All 13 patients were evaluated as part of our routine clinical practice within the Department of Neurology, Mayo Clinic, although 2 had previously been seen and were identified retrospectively (Cases 7 and 8). All patients had extensive investigations done to identify the etiology of the myeloneuropathy.
Results.
Clinical presentation.
The demographics are summarized in table 1 and the clinical characteristics in table 2. The presentation was in middle age or beyond, ranging from 45 to 78 years (mean 56.2 years, SD 11.2 years). The average duration of symptoms was 2.9 years with a wide range (0.17 to 10 years). Ten of the 13 patients were women (all except Cases 1, 5, and 6). The chief complaint was gait difficulty, and all reported lower limb paresthesias. Increased urinary frequency was reported by six patients (Cases 1, 2, 4, 6, 10, and 13). The neurologic examination revealed a fairly stereotyped clinical appearance. The abnormalities were primarily confined to gait and lower limbs. The gait was at least moderately ataxic, which was in proportion to the degree of proprioceptive loss. There was also a superimposed spastic appearance to the gait in most, with mild stiffness of lower extremity movement. The sensory examination revealed impaired perception of proprioception and vibration in the distal lower limbs, with the latter being more severely affected. Perceptions of pinprick and touch were variably reduced in a stocking distribution in nine cases (Cases 3, 4, 5, 6, 9, 10, 11, 12, and 13). No sensory levels were identified over the trunk. The knee jerks were increased in 11, normal in 1 (Case 12), and reduced in 1 other (Case 7). The ankle jerks were decreased in eight (Cases 1, 2, 3, 7, 8, 10, 11, and 12) and increased in the other five. Babinski or Chaddock signs were present in 10 (all except Cases 2, 8, and 12). When present, lower limb weakness was mild and of an upper motor neuron pattern. Lower limb rapid alternating movements were normal or slowed. Symptoms or signs were mild or absent in the upper limbs.
Table 1 Demographics
Table 2 Clinical characteristics
Laboratory studies.
The serum ceruloplasmin was very low in all 13 patients, ranging from 0.5 to 8.4 mg/dL (normal 22.9 to 43.1 mg/dL) with a mean of 3.37 mg/dL (table 3; figure 1). Serum copper levels were decreased in proportion to the low ceruloplasmin values, ranging from undetectable to 0.45 μg/mL (normal 0.75 to 1.45 μg/mL), with a mean of 0.16 μg/mL. Twenty-four-hour urinary copper excretion was measured in all except Case 11 and ranged from 5 to 24 μg/specimen (normal 15 to 60 μg/specimen). Serum zinc was measured in 11 patients, and 24-hour urinary zinc was measured in 10 patients (table 3). Serum zinc was elevated in five (Cases 1, 5, 8, 9, and 10), near the upper limit of the normal range in two (Cases 3 and 12), and reduced in two (Cases 2 and 4). Twenty-four-hour urinary zinc was elevated in 8 of the 10 patients (Cases 1, 3, 4, 7, 8, 9, 10, and 12). Nine patients underwent ophthalmologic evaluation (Cases 1, 3, 4, 6, 7, 9, 10, 12, and 13); none of them had slit-lamp evidence of Kayser–Fleischer rings. Two patients (Cases 12 and 13) had a liver biopsy showing no elevation in quantitative tissue copper.
Table 3 Serum copper, ceruloplasmin, zinc, and urine 24-hour copper and zinc levels
Figure 1. Copper and zinc levels in the patients.
Despite the clinical picture of subacute combined degeneration, the serum vitamin B12 level was normal in all patients (table 4⇓). Serum methylmalonic acid was measured in nine (Cases 2, 3, 4, 5, 6, 8, 9, 10, and 11) and was elevated in one (Case 4); her symptoms had progressed despite vitamin B12 injections and normal serum B12 levels. Homocysteine levels were checked in nine patients (Cases 3, 5, 6, 8, 9, 10, 11, 12, and 13) and were normal.
Table 4 Investigations
Table 4 (Continued)
Some or all the following determinations were done in each patient and were unremarkable: white cell count, sedimentation rate, serum glucose, liver enzymes, serum creatinine, vitamin B12 and E, homocysteine, folate, lipid profile, iron studies, thyroid-stimulating hormone, immunoelectrophoresis, antinuclear antibody, extractable nuclear antigen, paraneoplastic antibody profile, long chain fatty acids, serum lactate, serologies for Lyme, syphilis, HTLV-I, HIV, and urine heavy metal screen (arsenic, lead, mercury, cadmium). CSF analysis was done in all except Case 3, with no remarkable abnormalities except for a mild elevation in CSF protein in Cases 1, 6, 8, and 9.
Neuroimaging studies.
All patients underwent MRI scans of the spinal cord, and all except Case 5 had a brain MRI (see table 4⇑). Two patients (Cases 5 and 6) showed increased T2 signal in the paramedian dorsal cervical cord extending from the upper cervical to the lower thoracic levels. Figure 2 shows the MRI findings in Case 6. In another patient (Case 9), the increased signal extended from C2 to C7. Brain MRI findings were nonspecific and included lacunes (Cases 1, 3, and 11), mild atrophy (Case 8), and nonspecific foci of increased T2 signal (Cases 4, 6, and 10). The two patients with cirrhosis had more pronounced findings including increased signal in the basal ganglia, which is a recognized finding in liver failure (Case 12), and a confluent area of increased T2 signal in the periventricular white matter (Case 13).
Figure 2. Cervical (A, B) and thoracic (C) spine MRI from Case 6, showing a diffuse cord signal abnormality (arrows) involving the central posterior aspect extending from the cervicomedullary junction to the lower thoracic levels.
Electrodiagnostic testing.
Electromyography (EMG) and nerve conduction studies were obtained in all patients (see table 4⇑). All had a varying degree of axonal neuropathy. In eight (Cases 2, 3, 4, 5, 6, 10, 12, and 13), the findings were felt to be mild and in four predominantly motor (Cases 10 to 13). Two patients (Cases 12 and 13) showed myopathic potentials also. Somatosensory evoked potential studies were done on eight patients (Cases 1, 2, 5, 6, 9, 10, 12, and 13) and showed impairment of central conduction. In one patient (Case 8), the combination of clinical and electrodiagnostic findings suggested the presence of a neuronopathy.
Nerve and muscle biopsy.
A nerve biopsy was done in four patients (Cases 7, 8, 9, and 11) and showed evidence of an axonal degeneration (see table 4⇑). Muscle biopsy done on one patient (Case 7) showed vacuolar changes.
Cause of copper deficiency.
A definite cause of copper deficiency was evident in one patient (Case 1), and a possible cause was identified in seven other patients (Cases 2 to 8). No cause was found in the remaining five patients. One patient (Case 1) had been consuming 15 to 30 times the recommended daily allowance of zinc for cold prevention for many years1; zinc is known to reduce body copper stores and is used in the treatment of Wilson disease. Three patients had a history of gastrectomy for ulcer-related complications (Cases 3, 5, and 6); one of these patients (Case 3)5 also had a terminal small bowel resection done for Crohn disease. One patient (Case 4)5 had a history of gastric bypass for obesity. Two patients had biochemical evidence of malabsorption (Cases 7 and 8); one (Case 7) had a small bowel biopsy suggestive of celiac disease. Among the remaining five patients, two (Cases 12 and 13) had cirrhosis; both had liver biopsies showing normal tissue copper levels. Copper deficiency is not known to be associated with liver failure.
Associated abnormalities.
Anemia is known to be associated with copper deficiency and was found in seven patients (Cases 3, 4, 5, 7, 8, 10, 11), and eight (Cases 2, 3, 5, 7, 8, 9, 11, and 12) had a past history of anemia. Leukopenia at presentation was seen in four (Cases 3, 8, 11, and 12), and one other had a past history of leukopenia (Case 7). Six patients (Cases 2, 3, 4, 5, 6, and 8) had a past history of vitamin B12 deficiency; four of these (Cases 3 to 6) had a history of gastric surgery (gastrectomy in Cases 3, 5, and 6 and gastric bypass in Case 4). These patients had received periodic vitamin B12 injections despite normal serum B12 levels, and their condition had progressed.
Response to copper supplementation.
Oral copper treatment normalized the serum copper concentration in seven patients (Cases 1, 5, 7, 8, 10, 11, and 13) (table 5). With IV and oral supplementation, normal levels were achieved in an additional three patients (Cases 2, 4, and 12). In all 10 patients, the serum ceruloplasmin normalized in parallel with the serum copper, confirming that the low ceruloplasmin levels were secondary to copper deficiency.
Table 5 Response to copper supplementation
Residual neurologic deficits were present in all. Further deterioration was prevented in all cases, although two patients (Cases 10 and 13) were stable even prior to the institution of copper supplementation. The degree of improvement was variable. Of the five patients who had definite improvement (Cases 1, 2, 7, 8, and 11), three (Cases 1, 2, and 8) had improved position and vibration perception on follow-up examination; however, subjective improvement exceeded objective findings. The single patient undergoing follow-up somatosensory evoked potentials (Case 1) showed improved central conduction. Follow-up nerve conduction and EMG studies were performed after copper therapy in three patients, with one improved (Case 7) but two unchanged (Cases 8 and 9). Follow-up serum and urine zinc data were available in four patients (Cases 3, 8, 9, and 12) (table 6). With copper supplementation and improvement in serum copper, the serum zinc also increased and the urine zinc increased (Cases 9 and 12) or remained elevated (Cases 3 and 8).
Table 6 Initial and follow-up serum copper and zinc and 24-h urine zinc levels in Cases 3, 8, 9, and 12, along with initial and follow-up serum copper and zinc levels reported by Prodan et al.3
Discussion.
All of these patients had gait difficulty due primarily to severe sensory ataxia. The clinical presentation was suggestive of a myeloneuropathy in all except in one (Case 8) in whom the clinical and electrophysiologic presentation suggested an associated neuronopathy. Involvement of the peripheral nervous system was not the predominant reason for the sensory ataxia in any patient. The somatosensory evoked potentials in eight patients and the spine MRI changes in three patients provided additional evidence of posterior column dysfunction as being the primary reason for the sensory ataxia.
Copper is an essential trace element and is required by all life forms. It is a component of key metalloenzymes that have a critical role in the structure and function of the nervous system. Cytochrome c oxidase is a component of the mitochondrial respiratory chain, superoxide dismutase is an important antioxidant, and dopamine β-hydroxylase is important in the catecholamine biosynthetic pathway. Copper deficiency is known to cause an ataxic myelopathy in ruminants called swayback.6 Veterinary reports of enzootic ataxia (swayback) in lambs support the role of copper deficiency as an etiology for myelopathy.7
In humans, the well recognized disorders of copper deficiency are Menkes disease8 and the occipital horn syndrome.9 In Menkes disease, copper deficiency10 results from a failure to mobilize copper absorbed into the mucosal cells.11 Neuropathologic studies have shown similarity between Menkes in humans and swayback in lambs.12 Decreased activity of a copper metalloenzyme has been shown in swayback13 and Menkes disease.14
The hematologic manifestations of copper deficiency are well described,15 but literature on the neurologic manifestations of acquired copper deficiency in humans is limited. The first report of copper deficiency myelopathy was of a 46-year-old woman with previous gastrectomy.2 A prior report described neurologic deficits attributed to demyelination in two patients with hypocupremia and hyperzincemia3; one of these patients had been reported earlier as having the deficits possibly due to zinc toxicity.16 We1,5⇓ and others17 have reported individual cases of myeloneuropathy in association with copper deficiency. A severe progressive peripheral neuropathy and optic neuritis have also been described in association with copper deficiency.4
Hematologic manifestations have been associated with most of the reported neurologic cases.2–5,17⇓⇓⇓⇓ Evidence of anemia or leukopenia was present in 10 of our 13 patients. Six patients at presentation had a normal hemoglobin, and nine had a normal white blood count. We conclude that neurologic manifestations of copper deficiency can be present in the absence of hematologic manifestations.
Copper deficiency in humans can result from various causes.18 Because of copper’s ubiquitous distribution and low daily requirement, dietary copper deficiency is rare. Neonatal copper deficiency,19 copper deficiency secondary to zinc therapy,20 and copper deficiency in patients on parenteral nutrition21 have led to increased awareness of acquired copper deficiency. Excessive zinc consumption was the cause of decreased copper in Case 1. Zinc induces the synthesis of metallothionein in the enterocytes. Copper has a higher affinity for metallothionein than zinc and gets sloughed off into the intestinal tract when it remains bound to metallothionein. Serum zinc levels were elevated or near the upper limit of the normal range in 7 of the 11 patients in whom this information was available. Eight of 10 patients in whom information on urinary zinc excretion was available had elevated rates of urinary zinc excretion, despite the fact that only 1 patient was consuming excessive amounts of zinc. Despite improvement in serum copper, the serum and urinary zinc remained elevated in the four patients in whom this information was available. It has recently been suggested that myeloneuropathy in the setting of copper deficiency and hyperzincemia may represent an unrecognized zinc overload syndrome.17 Patients with similar manifestations in the setting of low copper and normal serum zinc levels have been described by us5 and others.2 Elevated plasma zinc has also been described as a heritable anomaly with no clinical manifestations.22 High plasma copper levels with low zinc levels have been reported in patients with sickle cell anemia23 and among zinc-deficient dwarfs.24 The role of zinc is not clear, as one of our patients (Case 8) and two other patients reported in the literature3 (see table 5) have shown some improvement despite persisting hyperzincemia.
The exact site of copper absorption in humans is unclear. Animal studies suggest that copper absorption takes place at varying degrees along the entire upper gastrointestinal tract.25,26⇓ Serum copper levels were reported to be normal or near normal in 20 patients after partial or total gastrectomy27; however, the first reported patient with a copper deficiency myelopathy had a history of gastric surgery,2 as did four of our patients (Cases 3 to 6). Anemia and neutropenia due to copper deficiency secondary to malabsorption have been described in a patient with antrectomy.28 There was evidence of malabsorption in two of our patients (Cases 7 and 8), suggesting that a decreased copper absorption may have been the reason for the hypocupremia.
The absence of an obvious cause of hypocupremia in most of our cases suggests that unidentified defects in copper uptake or trafficking may be responsible for the hypocupremia. Studies in yeast have shown that reduced copper is transported across the membrane by the high-affinity copper transporter Ctr1 and three different proteins transport copper to cytochrome c oxidase, copper–zinc superoxide dismutase, and the post-Golgi compartment for insertion into a multicopper oxidase essential for high-affinity iron uptake.29 These are high-affinity pathways, active in conditions of low copper concentration, and increasing the concentration of copper may result in the pathways being bypassed.29 If copper deficiency is due to a defect in this pathway, it may be possible to bypass the defect by increasing ingested copper. This might explain why we were able to achieve normal or near-normal copper levels with oral copper alone in seven patients.
We believe that the neurologic manifestations of acquired copper deficiency in adults constitute an underrecognized syndrome. When we became aware of this entity, further cases were prospectively acquired in little over a year. Clinical findings that should raise suspicion include sensory ataxia, lower limb spasticity, and acral paresthesias. The clinical presentation mimics vitamin B12 deficiency in many ways. It also appears that neurologic manifestations due to copper deficiency may occur in the absence of hematologic manifestations. Prompt recognition of copper deficiency may prevent further neurologic injury.
Addendum.
One additional patient with a similar syndrome was recently reported (Greenberg SA, Briemberg HR. A neurological and hematological syndrome associated with zinc excess and copper deficiency. J Neurol 2004;251:111–114). Clinical details of Cases 2, 5, and 9 were recently published (Kumar N, Crum B, Petersen RC, Vernino SA, Ahlskog JE, Cooper deficiency myelopathy. Arch Neurol 2004;61:762–766).
- Received February 5, 2004.
- Accepted March 10, 2004.
References
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