A 57-year-old man developed numbness and tingling in his toes, which progressed over 3 to 4 months to involve his legs, hands, and lower torso. He then developed trouble walking owing to imbalance and had increasingly frequent falls. His hands felt clumsy, and he began dropping objects. He reported several instances of urinary incontinence in the weeks before presentation, but no bowel symptoms. He denied focal weakness or changes in speech, swallowing, or breathing. His sisters brought him to the emergency room after a fall in which he hit his head on a kitchen stool, and he was admitted to the neurology service for further evaluation.
The patient's medical history included long-standing tobacco use, chronic obstructive pulmonary disease, and low back pain. In addition, 5 months before the onset of his paresthesias, he was discovered to have a macrocytic anemia that did not respond to treatment with vitamin B12 and folate. He was subsequently treated with periodic blood transfusions.
The general physical examination was unremarkable. On neurologic examination, the patient's mental status and cranial nerves were normal. A motor examination revealed spasticity without weakness in the legs. There was severe loss of vibratory and joint position sensation in the upper and lower extremities in a stocking-glove distribution; pain and temperature sensation were relatively spared. Reflexes were normal to brisk throughout, and there was no extensor toe sign. Finger tapping and toe tapping were mildly slowed. The Romberg sign was present. The patient's gait was slow, stiff-appearing, and ataxic, with a widened base and marked truncal instability. The constellation of lower extremity–predominant spasticity and proprioceptive defects suggested an abnormality in the region of the cervical spinal cord.
QUESTIONS TO CONSIDER
What is in the differential diagnosis of a noncompressive myelopathy?
What are some causes of macrocytic anemia?
Could the excessive use of dental adhesive contribute to the patient's symptoms?.
A laboratory workup on the patient's admission revealed macrocytic anemia (Table 1). The vitamin B12 concentration was in the upper part of the reference interval, and the concentrations of cobalamin pathway metabolites homocysteine and methylmalonic acid were within reference intervals. Despite the normal B12 concentration, B12 repletion was instituted, but symptoms did not improve. An MRI evaluation of the spinal cord excluded compression but identified abnormal T2 signal along the posterior regions of the cervical and upper thoracic cord. Nerve-conduction studies showed a mild sensory peripheral neuropathy. Further questioning revealed that the patient had worn dentures for 10 years and that family members frequently chided him for excessive use of denture adhesive to the extent that it sometimes accumulated at the corners of his mouth.
The patient's brisk reflexes, spastic gait, proprioceptive loss, and history of urinary incontinence were clues toward a predominantly spinal cord localization of his symptoms (i.e., a myelopathy). The differential diagnosis of acquired noncompressive myelopathies is broad, including toxic, nutritional, infectious, autoimmune, vascular, and structural causes (Table 2). The prominent sensory ataxia with only mild motor findings pointed toward a lesion of the posterior columns. This finding, in conjunction with a history of macrocytic anemia, suggested the subacute combined degeneration syndrome of vitamin B12 deficiency. This patient's anemia persisted, however, and his neurologic syndrome worsened while he was receiving B12 supplementation.
Owing to the patient's excessive use of denture adhesive, which contains zinc, serum concentrations of copper and zinc were measured. The patient's serum zinc concentration was 1.42 μg/mL (21.7 μmol/L) (reference interval, 0.66–1.1 μg/mL), and his copper concentration was <0.1 μg/mL (<1.6 μmol/L) (reference interval, 0.75–1.45 μg/mL). The patient was diagnosed with copper deficiency myeloneuropathy due to zinc toxicity from his denture adhesive. Intravenous copper repletion with cupric sulfate (2 mg/day) was administered for 5 days, followed by long-term oral copper gluconate supplementation (2 mg/day). The patient also began using a different brand of denture cream. At follow-up 2 months later, the patient's blood cell counts, mean corpuscular volume, and copper concentration had completely normalized, while the zinc concentration remained slightly increased. He reported near-resolution of his paresthesias and bladder symptoms, and on examination his gait was markedly steadier.
Over the last decade, the relationship between acquired copper deficiency and neurologic disease has become firmly established. Myeloneuropathies with a varying combination of sensory and motor involvement have now been described. A spastic ataxia syndrome with prominent posterior column findings mimicking cobalamin deficiency (1) remains the archetypal and probably the most common neurologic presentation of copper deficiency. In about half of such cases, neuroimaging reveals a pattern of abnormal T2 signal in the midline and posterior columns of the cervical and thoracic spine that is nearly identical to the radiographic findings in B12 deficiency (2). Although minor subjective and objective responses are not uncommon, clinically significant neurologic improvement after copper treatment is atypical; most patients experience a stabilization of their disease. Several variant neurologic presentations of copper deficiency have now been reported in detail (3,–,7). In all of these cases, neurologic findings stabilized or slightly improved with treatment.
A variety of reversible hematologic abnormalities— such as anemia (macrocytic, normocytic, and microcytic), leukopenia, neutropenia, and thrombocytopenia, as well as pancytopenia—may result from copper deficiency. These abnormalities typically, but not always, occur in the context of neurologic presentations. Among the cases described in the neurology literature, swift and complete reversal of accompanying hematologic abnormalities is the norm. Halfdanarson and colleagues (8) reviewed 40 cases of acquired copper deficiency with low hematologic indices, with 22 (55%) of the patients having no other identifiable potential causes for their cytopenia. Of the patients for whom treatment data were available, 89% had complete or partial normalization of hematologic parameters after copper supplementation. Bone marrow biopsies from 23 patients showed characteristic patterns of granulocytic hypoplasia (100%), vacuolization in myeloid precursor cells, erythroid hyperplasia, increased iron staining within macrophages and plasma cells, and ringed sideroblasts. In many cases, biopsies were initially interpreted as reflecting myelodysplastic or toxic syndromes, again attesting to the tendency of copper deficiency to masquerade as a different, better-known entity.
The etiology of acquired copper deficiency ultimately derives from impaired copper absorption from the gastrointestinal tract. Dietary copper is absorbed into enterocytes of the stomach and duodenum via the CTR1 copper import protein and possibly via DMT1 (divalent metal transporter 1) or other less well-characterized transmembrane routes (9). Intracellular copper binds to various cytosolic chaperone proteins and then is pumped into the trans-Golgi endoplasmic reticulum via the copper transporter ATP7A (copper-transporting ATPase 1). From there it is distributed to cuproenzymes or secreted across the basolateral membrane and into the portal circulation, where it is taken up by the liver and either incorporated into ceruloplasmin or excreted (via ATP7B) into bile and ultimately feces. The most commonly identified mechanism of acquired copper deficiency relates to an altered gastroduodenal anatomy, such as occurs after bariatric or peptic ulcer surgery, in which the surface area for copper absorption is reduced. More recently, malabsorption of copper due to celiac disease has also been reported (10). In any potential malabsorption scenario, other concomitant vitamin and mineral deficiencies should be investigated, such as vitamins B1, B6, B12, D, and E, folic acid, and iron. Copper-deficiency states also lead to a reduction in serum ceruloplasmin, and concentrations of this protein may be monitored as a marker of the therapeutic response once copper repletion has begun.
In the presence of a normal anatomy, a second well-described mechanism of copper malabsorption relates to excess zinc intake causing a secondary hypocupremia. Cytosolic zinc within enterocytes causes upregulation of metallothioneins, which are chelators that normally serve to scavenge excess copper but that lead to intracellular copper sequestration and functional malabsorption when overproduced (9), with copper-sequestering enterocytes eventually sloughing off. As with the present patient, many reported cases of acquired copper deficiency feature a concomitant hyperzincemia that is presumably causal. Perhaps the most common way for excess zinc ingestion to occur is through overzealous use of denture adhesives, which contain high concentrations of zinc (6), although some cases have been attributed to excessive zinc ingestion for dubious purported health benefits (e.g., warding off colds). There are also a few reported cases of patients with the dual hit of having undergone gastric bypass and having taken zinc (but not copper) supplementation in a well-meaning attempt to avoid post-bypass nutritional deficiencies. Interestingly, a large fraction of copper-deficiency cases (including some with associated hyperzincemia) remains idiopathic, emphasizing our incomplete knowledge of the etiology of this disorder.
POINTS TO REMEMBER
Copper deficiency can be a treatable cause of neurologic syndromes, including ataxia, neuropathy, spasticity, optic neuropathy, and motor neuron degeneration resembling amyotrophic lateral sclerosis.
Copper deficiency is caused by copper malabsorption secondary to altered gastrointestinal tract anatomy (e.g., after bariatric surgery) or upregulation of copper-chelating proteins by excess zinc (e.g., from denture adhesive), although a significant percentage of cases remain idiopathic.
A history of gastrointestinal surgery, as well as of denture adhesive use or zinc supplementation, should be routinely obtained in evaluating patients with sensorimotor neurologic disorders.
Serum copper should also be measured in patients with unexplained cytopenia or a suspected myelodysplastic syndrome.
Zinc and ceruloplasmin concentrations should also be checked when copper deficiency is suspected.
When copper deficiency is identified in a patient with a history of gastrointestinal resection, other concomitant nutritional deficiencies should also be investigated.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication September 3, 2010.
- Accepted for publication October 26, 2010.
- © 2011 The American Association for Clinical Chemistry