MIAMI BEACH—Copper deficiency secondary to gastric bypass surgery can cause a myeloneuropathy, according to a new study. Symptoms of the deficiency may occur years after surgery. But not every patient with a copper deficiency myelopathy has had surgery, suggesting that neurologists need to be on the lookout for this condition with patients with an unexplained myelopathy.
Neeraj Kumar, MD, of the Department of Neurology at the Mayo Clinic in Rochester, MN, presented a clinical overview of 25 such patients at the AAN Annual Meeting here in April.
NEUROPATHY, CENTRAL CONDUCTION DELAY
The index case was a 65-year-old man with a five-year history of subacute-onset, slowly progressive gait difficulty, characterized by stiff leg and imbalance. He had distal paresthesias and neurogenic bladder symptoms, with a spastic, ataxic gait, lower limb spasticity, and upper motor neuron weakness. His reflexes were brisk except at the ankle, which was depressed, and he had an extensor plantar response. His perception of vibration was reduced in the distal lower limbs.
He had evidence of an axonal sensory multifocal neuropathy, said Dr. Kumar, “but what was most striking was the presence of central conduction delay on somatosensory evoked potential studies.”
Investigating further, Dr. Kumar discovered the patient had been taking 200 to 400 milligrams of zinc – 20 times the recommended daily allowance – for over two decades, because of the reported benefits of zinc in the prevention of upper respiratory infections.
This was reflected in the elevated serum zinc level of 1.51 micrograms per milliliter, about 40 percent higher than the upper limit of normal. In contrast, his serum copper was dramatically low, at 0.45 mcg/ml, about 50 percent below the lower limit of normal.
Dr. Kumar immediately stopped the zinc supplements and put the patient on copper supplementation. After six weeks, his serum levels of both metals were back to normal. His gait improved, as did the somatosensory evoked potentials. He remains stable at two-year follow-up, Dr. Kumar reported.
SERUM COPPER IS THE BEST TEST
Over the following two years, Dr. Kumar and colleagues identified 24 more patients with copper deficiency myelopathy. In most cases, the cause of copper deficiency could not be determined. Ten patients, though, had received gastric surgery, seven for peptic ulcer disease, and three for obesity. One additional patient reported taking high doses of iron for anemia.
The patients ranged from 36 to 78 years in age, and included 20 women and five men. Their symptoms had begun from two months to 10 years before presentation. The amount of time elapsed between gastric surgery and symptom onset was not clear for most patients, but, Dr. Kumar said, it ranged from months to probably years.
Among these patients, the mean serum copper was 0.134 mcg/ml, and it was undetectable or barely detectable in many patients. In contrast, urinary copper was low in only about half the patients.
“Serum copper is by far the most reliable test,” said Dr. Kumar, since urinary copper at presentation and follow-up were variable. Furthermore, he said, “I don't think there is any role for doing provocative tests” in an attempt to increase the reliability of the urinary copper assessment.
SYMPTOMS: WHAT INVESTIGATORS OBSERVED
Nine patients had urinary symptoms and three had L'Hermitte's sign. As in the index patient, the combination of a brisk knee jerk with a depressed ankle jerk and extensor plantar response were common responses, said Dr. Kumar. Nine patients, most of whom had undergone gastric surgery, had a history of vitamin B deficiency, the symptoms of which are similar to those in this series, but vitamin replacement had not corrected their symptoms. Anemia and leukopenia were seen in about half the patients.
Upon electrophysiologic testing, 21 of 24 patients had clear signs of a peripheral neuropathy. Sensorimotor findings were present in about half, with an exclusive or mainly motor neuropathy in nine patients, and an exclusive or mainly sensory neuropathy in three patients. While most patients had only mild neuropathy, in eight it was classified as severe. Again as in the index case, said Dr. Kumar, “the most striking finding was a delay in central conduction,” seen in 19 of the 20 patients in whom the somatosensory evoked potential was measured.
While the majority of patients had a normal spinal MRI, in 11 patients, there was an elevated T2 signal in either cervical or thoracic regions, or both. Three patients had spinal cord atrophy. There was no evidence of enhancement in the 10 patients given contrast. In at least one patient, the elevated T2 signal normalized with copper nine months later.
NORMAL COPPER LEVEL ACHIEVED
Using oral supplementation, a normal copper level was achieved in 18 of the 20 patients for whom follow-up data were available. The remaining two patients responded to parenteral administration. Residual clinical deficits were present in all patients, but further deterioration was prevented in all but one case.
However, the improvement was more subjective than objective, Dr. Kumar said. “Very often, the patients reported that their paresthesias were less distressing.” The subjective sense of improvement may also be augmented in some patients by the relief of having a diagnosis. However, he said, “I can say with confidence the patients have not deteriorated.”
Dr. Kumar does not yet know the incidence of copper deficiency myelopathy, but at the Mayo Clinic, he reported they are seeing one new patient approximately every two to three weeks.
While the pathophysiology of copper deficiency in this patient is not entirely clear, Dr. Kumar pointed out that copper is an essential trace element, and is a component of many crucial metalloenzymes, including cytochrome C oxidase, Cu/Zn superoxide dismutase, and dopamine beta hydroxylase. Copper deficiency in infancy can cause the neurodegeneration of Menkes disease, and in animals, it leads to the ataxic condition known as swayback. Finally, several suspected cases of copper deficiency myelopathy in humans have been reported.
EVEN LONG-PAST GASTRIC SURGERY IS A RISK
Laurence Kinsella, MD, Associate Professor of Neurology at Saint Louis University, noted that these findings add to the list of nutritional deficiencies the clinician must keep in mind when examining a patient with unexplained myelopathy. Vitamin B12 and vitamin E deficiencies also have similar findings.
“The take-home point for me,” he told Neurology Today, “is that vitamin deficiencies and nutritional syndromes are often induced by things patients are doing to themselves.” Many patients, he said, are poorly educated about dietary supplements such as zinc, which are not regulated by the federal government. “Consumers are left with the wrong impression, that if it's not regulated, it must be good for you, and more must be better.”
Gastric bypass surgery, he also noted, can induce a host of nutritional disturbances, which may lead to neurological symptoms. Indeed, a new syndrome has been recognized, called acute post-gastric reduction surgery neuropathy. While he has not yet seen a copper deficiency myelopathy patient, he said, “copper and ceruloplasmin are now part of my routine evaluation when I have a patient with myelopathy.”
Dr. Kumar reinforced the importance of keeping this diagnosis in mind in patients with myelopathy, including in patients manifesting a vitamin B12 deficiency. “If, despite vitamin replacement, the patient does not improve, copper deficiency should be considered,” he said.
Dr. Kumar noted the risk for copper deficiency after gastric surgery does not disappear after the acute period, and may continue for years. Cynthia Comella, MD, Associate Professor at Rush University Medical Center in Chicago, who chaired the platform session in which the study was presented, noted that the long delay between surgery and symptom onset means “we should be thinking about this as we see patients with any past history of gastric surgery, not necessarily just an acute history.”
ARTICLE IN BRIEF
- ✓ Investigators reported that copper deficiency secondary to gastric bypass surgery can cause a myeloneuropathy.