Severe Ataxia, Myelopathy, and Peripheral Neuropathy Due to Acquired Copper Deficiency in a Patient With History of Gastrectomy

The patient is a 74-year-old man with a history of peptic ulcer disease requiring a partial gastrectomy in the 1970s. He has had several surgical revisions over the ensuing few years, subsequently leading to a de facto total gastrectomy with a Roux-en-Y esophagojejunostomy. The patient received long-term enteral nutrition via a feeding jejunostomy tube for over 25 years. He received Jevity 1 Cal (Ross, Div. of Abbott Laboratories, Abbott Park, IL) at 8 cans per day, which provided 2000 kcal, 83.2 g protein, and 2.96 mg copper (0.37 mg Cu/8-oz can). The RDA for copper is 1.2 mg/d.

His initial neurologic presentation occurred in April 2005, with a 1-year history of progressive numbness in his legs that eventually rose to the level of his waist. He developed a progressive gait disturbance with worsening ataxia that left him wheelchair-bound. He noted word-finding difficulty and decreased mentation. He also developed paresthesias in his hands and arms. These symptoms had not improved with intramuscular vitamin B12 injections. Review of systems was negative for nausea, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, skin changes, hair changes, or symptoms of congestive heart failure.

Neurologic examination at the Lahey Clinic on April 25, 2005, demonstrated the presence of a "stocking/ glove" sensory loss, particularly compromising vibratory and proprioceptive modalities, a positive Romberg's sign (the inability to stand steadily with eyes closed, suggestive of a loss of proprioception), as well as severe truncal, limb, and gait ataxia.

Laboratory studies (Table I) demonstrated a normocytic anemia and a normal platelet count. Liver function tests were within normal limits. C-reactive protein was within normal limits. Antiendomysial antibody was normal. Nutrition laboratories are summarized in Table II. Extensive cerebrospinal fluid (CSF) studies demonstrated normal cell count, protein, and glucose levels. CSF cytology was negative, with no signs of bacterial infection, including tuberculosis, Lyme disease, syphilis, or Cryptococcus, as well as negative angiotensin-converting enzyme level and paraneoplastic panel. Copper studies (Table III) revealed a severely decreased serum copper level of 4 µg/dL and ceruloplasmin. Twenty-four-hour urinary copper excretion was undetectable. Zinc level was elevated.

Because of this patient's constellation of symptoms, failure to improve with vitamin B12 repletion, and the prominent laboratory signs of diminished copper stores, a diagnosis of copper deficiency was suspected. In addition to the nearly 3 mg/d of copper in our patient's tube feedings, he was supplemented orally with 2.5 mg of elemental copper in the form of copper sulfate, as well as an additional vitamin/mineral supplement providing an additional 4 mg/d of copper, for a total of nearly 10 mg/d of copper. Over 2 months of follow-up, serum copper levels increased from 4 µg/dL to 20 µg/dL (70-150 µg/dL), and ceruloplasmin increased from 6 mg/dL to 8 mg/dL (14-58 mg/dL), with no significant change in zinc level from 81 µ/dL to 89 µg/dL (Table III). He has had no further progression of his neurologic symptoms. He will be followed up long term to see if he has any significant improvement in his neuropathy symptoms.

DISCUSSION

Review of Literature

Copper is a trace metal that is essential to many biologic functions. It is a key component of many metalloenzymes involved in hematopoiesis, catecholamine synthesis, vascular and skeletal tissues, as well as the structure and function of the nervous system.1-4 Major copper-dependent enzymes include cytochrome c oxidase (oxidative phosphorylation), superoxide dismutase (antioxidant), ceruloplasmin (iron and copper metabolism), tyrosinase (melanin synthesis), and dopamine B-monooxygenase (catecholamine synthesis)2,3,5,6 (Table IV). Copper deficiency has been well described as a cause of neutropenia and anemia due to its effects on hematopoiesis.1,3,5,6

Copper deficiency is thought to be extremely rare due to its low daily requirements and ubiquitous nature in the environment. 1-3,5 Sources of copper include seeds, grains, nuts, beans, shellfish, and liver.3 Patients requiring long-term enteral feedings into the proximal and mid-jejunum seem to be at risk for developing copper deficiency. There are a variety of other clinical settings that negatively affect copper stores. These include malnutrition, nephritic syndrome, prematurity, excess zinc, treatment with penicillamine and alkali agents, parenteral feeding with insufficient copper, and gastrointestinal surgery. Prior studies have estimated that the safe and adequate dietary intake of copper is approximately 1.5-3.0 mg/d.7,8 Higuchi et al have estimated the minimum dietary copper to maintain a normal serum copper concentration to be 1.5 µg/kg/d.7

Neurologic dysfunction secondary to copper deficiency, known as "swayback," is well defined in ruminant animals.1,2,4 This is characterized by Wallerian degeneration (segmentation of the myelin sheath, with resultant atrophy and destruction of the axon), as well as microcavitation of the peripheral and central nervous system white matter.4 Acquired copper deficiency leading to neurologic dysfunction in human adults is a rare disorder that has only recently been recognized. The literature is slowly expanding as more cases are described. It classically mimics the posterior column and dorsal root ganglion dysfunction so typical of vitamin B12 deficiency. Neurologic symptoms include dorsal column symptoms, with loss of proprioception and vibratory sensation and severe ataxia, as well as peripheral neuropathy. These symptoms mimic the severe combined degeneration of vitamin B12 deficiency and may elude diagnosis initially.

Kumar et al2,4 have described copper deficiency in the most detail. In 1 report, 2 patients underwent gastric resection. They subsequently developed severe sensory ataxia and peripheral neuropathy. Extensive workup for neuropathy was negative, except for the copper-deficient state. Both improved with parenteral copper, but the result was not sustained with oral repletion. Paresthesias improved, but paresis did not.1 In another report, 3 patients were described with copper deficiency. All 3 had severe myelopathy and peripheral neuropathy, and 2 had increased signal intensity in the posterior columns on T2-weighted MRI images of the spine.2 These reports supported the existence of a progressive neurologic syndrome with clinical, electrophysiologic, and radiographie evidence of myelopathy, with predilection for the posterior columns and corticospinal tracts.2 A review of the essential findings in this rare condition was presented by Kumar and colleagues2'4 in a study of 13 patients. All presented with gait instability and severe sensory ataxia, dorsal column symptoms, and severe lower-limb spasticity.

Laboratory findings were also reviewed. Ten of 13 patients with primary neurologic dysfunction had anemia or leukopenia; however, 6 had normal hemoglobin levels and 9 had normal WBC counts, suggesting that the neurologic symptoms could present in the absence of hematologic symptoms.5 Zinc levels were normal or elevated in 7 of 11 patients that had zinc levels checked.5 Dorsal column findings were seen on MRIs of 3 patients.5 Oral copper replacement restored serum copper levels in 7 of 12 patients who had adequate follow-up data, and parenteral copper restored serum copper levels to normal or near normal in an additional 3 patients.5 This appeared to decrease progression of neurologic symptoms, but degree of response was variable.5 Clinically, results were improved with parenteral copper when compared with oral copper.1 These symptoms mimicked the subacute combined degeneration of vitamin B12 deficiency but worsened despite significant vitamin B12 repletion.1,5 This may not have been recognized in the past because copper and ceruloplasmin levels have not been a regular part of the diagnostic workup for ataxia.5

Copper deficiency has also been reported in patients with hyperzincemia.1,2,4 Kumar et al4 reported a 65-year-old man with 5 years of progressive gait disturbance. He had severe sensory ataxia, decreased vibratory sense, and lower-limb spasticity. He had been taking 15-30 times the daily required allowance of zinc in the form of zinc gluconate to prevent colds. Cessation of zinc and oral copper replacement resolved his paresthesias and improved gait. Somatosensory evoked potentials (SSEPs) also improved. Prodan et al10 presented 2 cases of idiopathic copper deficiency and hyperzincemia with hematologic changes of copper deficiency and CNS demyelination. Both had mild zinc elevations and were thought to be elevated secondary to copper deficiency. The patients' full hematologic recovery with oral copper supplementation despite a persistently elevated zinc level supported an intestinal copper uptake abnormality as the primary defect.10

Zinc and copper are both absorbed in the proximal small intestine. Copper has a higher affinity for metallothionein than zinc, so it displaces zinc and remains in the enterocytes, which are sloughed off. This has been used as a treatment strategy in Wilson's disease.4 Zinc also up-regulates metallothionein, which increases copper uptake in the enterocyte and a net loss of copper when the enterocytes are sloughed.1,2,5,10

There is also a very rare form of a genetically determined human copper deficiency, Menkes' disease. It primarily occurs in childhood; it is characterized by intestinal malabsorption of copper, resulting in failure to thrive, subsequent intellectual deterioration, seizures, excessive hair kinkiness, and connective tissue abnormalities. A deficiency of a copper metalloenzyme is found in both swayback and Menkes' disease. Surgery to the proximal gut directly or bypassing the proximal gut may mimic Menkes' disease with its intestinal malabsorption of copper and can similarly manifest as intellectual deterioration, failure to thrive, seizures, connective tissue abnormalities, and neurologic dysfunction.

Various animal models have shown that the duodenum is the primary site of copper absorption, and to a lesser extent the stomach and distal small bowel.11 Once absorbed, copper becomes bound to ceruloplasmin in the liver and then transported throughout the body. Copper, unlike iron and zinc, is not stored in significant quantities. Most copper is excreted in the bile, with minimal urinary losses.12 Therefore, it is reasonable to postulate that surgery affecting the upper gastrointestinal tract may affect copper absorption, leading to copper deficiency and its related hematologic and neurologic consequences.

Copper deficiency may shed further light on prior reports of neurologic complications without identifiable cause in patients undergoing gastric surgery. In the Cooperative Veterans Administration Study on Peptic Ulcer, 97 patients had subtotal gastrectomies or Billroth II gastric resections. There were 15 cases of peripheral neuropathy, 1 case each of Parkinsonism, myelopathy, and midline cerebellar degeneration.6,13-15 Neurologic complications were reported in 23 of 500 patients who underwent gastric restriction surgery for obesity, 13 with polyneuropathy, 2 with burning feet syndrome, 2 with Wernicke-Korsakoff syndrome, 3 with meralgia paresthetica, 2 with myelopathy, and 1 with myotonic syndrome.6 Serum copper and ceruloplasmin were not reported in these previous series of patients with neurologic symptoms after gastric surgery.

We postulate that our patient has had significant malabsorption secondary to the extensive surgery to his proximal gut, with the subsequent malabsorption of copper. His tube feeding supplementation contained the recommended RDA of copper, but he may have needed supraphysiologic doses and may even require parenteral copper repletion in the future to maintain an adequate serum copper.

CONCLUSIONS

Enterai feeding is increasingly being used, with some health care institutions describing a 20%-25% per year increase in use.7 Indications such as anorexia due to cancer, chronic illness, dysphagia due to cerebrovascular accidents, and esophageal obstructions due to cancer are increasingly being treated with enterai feeding. Although gastric surgery for peptic ulcer disease is rare in the era of proton-pump inhibitors, there is increased use of bariatric surgery. This physiologically isolates the stomach, duodenum, and proximal jejunum, the preferred sites for copper absorption, from the enterai stream of nutrients. This may place an ever-growing number of patients at risk for copper deficiency, with significant hematologic and neurologic consequences. Over the next several years, the number of patients who will have undergone gastric bypass surgery will approach 1 million, with an annual incidence exceeding 100,000 procedures per year.16 Gastric bypass surgery is both a restrictive and a malabsorptive method for weight reduction and results in micronutrient deficiencies. These patients require vitamin and mineral supplementation and periodic assessment.

Currently, copper status is not routinely supplemented or checked. Early complications such as vomiting and dumping syndrome will likely be recognized by the surgeon, but the patients will likely be lost to follow-up from the surgeon long term and will be followed by other physicians who will continue to monitor their status down the road. Nutritional problems such as vitamin B12 deficiency and iron deficiency have been well recognized.16 After 1 year, between 36% and 70% of patients have vitamin B12 deficiency.16 Ataxia and myelopathy manifestations of B12 deficiency may mimic copper deficiency. The bariatric surgery literature is only recently starting to report nonsurgical complications due to malabsorption of vitamins and micronutrients. For example, beriberi due to thiamine deficiency has been reported, as well as ocular complications such as xerophthalmia, keratitis, and corneal scarring due to hypovitaminosis A.17,18 In all patients, not just bariatric surgery patients, it is important to recognize that multiple micronutrient deficiencies can result in a variety of neurologic complaints (Table V).

Therefore, we recommend that trace elements such as copper be monitored on a regular basis in patients receiving long-term enteral feeding or who have had major upper gastrointestinal surgery. Serum copper and ceruloplasmin should also be checked in patients with peripheral neuropathy and symptoms of vitamin B12 deficiency, such as severe ataxia, especially when therapy with vitamin B12 does not resolve symptoms. Empiric repletion of copper cannot be recommended at this time as not all patients who undergo bariatric surgery develop copper deficiency. However, at this time, in the absence of prospective study, it is unclear how to best replete copper and to what levels.

This case and the few other reported cases in the literature stress the need for early recognition of copper deficiency and eventual therapy with oral or parenteral copper. Our case report and another recent case series in abstract form by Deppe et al,19 of 5 patients with Roux-en-Y gastric bypass, suggest that surgery to the proximal gut will adversely affect copper metabolism. Further prospective studies may be in order, particularly in patients who have undergone bariatric procedures. We are in the process of prospectively studying the effects of Roux-en-Y gastric bypass on copper metabolism in order to identify those patients at risk of biochemical and or symptomatic copper deficiency. This is important because early copper replacement therapy may slow progression or reverse symptoms and prevent irreversible neurologic damage. The current standard of care in post-gastric bypass patients is to monitor several micronutrients such as iron, vitamin D, and vitamin B12. Copper status is not routinely assessed. With increasing awareness of the clinical manifestations of copper deficiency and by identifying those patients at risk, they can be treated earlier, possibly preventing permanent neurologic damage.