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Practice Lesson of the Week

Copper deficiency as a treatable cause of poor balance

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c508 (Published 12 April 2010) Cite this as: BMJ 2010;340:c508
  1. Zhaleh Khaleeli, neurology registrar1,
  2. Daniel G Healy, consultant neurologist2,
  3. Anthony Briddon, prinicipal clinical scientist3,
  4. Michael P Lunn, consultant neurologist 2,
  5. Mary M Reilly, consultant neurologist 2,
  6. John Land, consultant in clinical biochemistry3,
  7. Gavin Giovannoni, neurology professor 4
  1. 1Department of Neurology, National Hospital for Neurology and Neurosurgery, London WC1N 3BG
  2. 2MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG
  3. 3Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG
  4. 4Department of Clinical Neurosciences, Barts and the London School of Medicine and Dentistry, London E1 2AT
  1. Correspondence to: G Giovannoni g.giovannoni{at}qmul.ac.uk
  • Accepted 8 December 2009

­­Copper deficiency often goes undiagnosed

Patients presenting with a neurological syndrome typical of B-12 deficiency may actually be manifesting symptoms of copper deficiency, as has been recognised over the past decade.1 Most commonly, they have a progressive spinal cord syndrome resulting in poor balance due to loss of proprioception. The cases we report show that copper deficiency, which has various causes, is more common than previously realised and often goes undiagnosed. Increased awareness of this condition is vital because early diagnosis and treatment can prevent severe disability.

Case 1

A 65 year old man presented in 2006, having fallen in the shower on closing his eyes; he had burning and tightness affecting his feet and had recently lost weight. Over six months he became bedbound due to poor balance. He had undergone partial gastrectomy in 1973 for a duodenal ulcer. Three years before the neurological symptoms developed, he was diagnosed with asymptomatic B-12 deficiency, which was successfully treated.

Initial examination showed a positive Romberg test and an inability to walk heel-to-toe. Cranial nerve examination was unremarkable. Tone and power were normal, ankle jerks were depressed, and one plantar reflex was extensor. Over six months he developed spastic weakness in his legs (hip flexion MRC grade 4), hyper-reflexia, and bilateral extensor plantar reflexes. Sensory disturbance suggested greater abnormality in the posterior columns; vibration sense was reduced to the costal margins, proprioception to the ankle, and pinprick to mid-foot level.

Magnetic resonance imaging showed T2 signal abnormality in the posterior cervical cord at C2-4 (figure ). Electrophysiology found lower limb motor abnormalities consistent with a motor neuronopathy, but sensory nerve action potentials were normal. Central motor conduction to the limbs (a method for examining the central motor pathways, in which the difference between the latency of motor evoked potentials and peripheral conduction time is determined) indicated corticospinal disease. There was evidence of normochomic normocytic anaemia, thrombocytosis, and relative lymphopenia. Serum copper and caeruloplasmin were both low (table ). He was treated with intravenous copper acetate solution equivalent to 2 mg a day for 10 days, followed by oral copper acetate 8 mg a day, reduced to a maintenance dose of 2 mg, which he continues to take. One year later he had regained his normal weight, he walked without an aid, and performance on the Romberg test was improved. His pain and other neurological signs did not improve, but the abnormalities in his full blood count and biochemical profile resolved fully (table).

Figure1

Fig 1 T2 weighted MRI shows high signal in the cervical cords of both patients

Investigations before and after copper replacement

View this table:

Case 2

A 37 year old man presented in 1999, at another hospital, with poor balance in the dark and tingling and burning in his toes. Over the following year, his sensory symptoms ascended to his chest, hands, and forearms. Examination showed a positive Romberg’s sign. Visual acuity was reduced to 6/12 (right) and 6/18 (left) after pinhole correction, but otherwise cranial nerve examination, including fundoscopy, was normal. He had full power and flexor plantar reflexes. Light touch and pinprick sensation were impaired in his legs, distally in his arms, and in a shield-like distribution over his chest. Vibration sense was absent up to the jaw. Joint position sense was impaired in the toes and fingers.

Investigations at first presentation identified anaemia, with vitamin B-12 and folate deficiency, but when these were corrected by his general practitioner he continued to deteriorate. He was referred to our unit for a second opinion in 2002. On close questioning we discovered that for several years he had consumed more than four litres of a cola drink per day. He had lost his teeth, and his dentures were anchored with dental cement (Super Poligrip Ultra Fresh denture adhesive cream, GlaxoSmithKline), which he used in large amounts (a 68 g tube every three days). By this time he had developed mild weakness of ankle dorsiflexion, and the abnormality of light touch and pinprick sensation had progressed to C2 level, sparing his face and a narrow strip over the middle of his back. Investigations found microcytic anaemia, neutropenia, and lymphopenia. B-12 and folate concentrations were now in the normal range. Serum copper was low, with low caeruloplasmin and raised serum zinc (table). Magnetic resonance imaging showed extensive T2 signal abnormality in the posterior aspect of the entire cervical cord (figure). Electrophysiology suggested a pure sensory neuropathy or neuronopathy. Visual evoked potentials were delayed in the left optic nerve.

He was treated with 2 mg of intravenous copper chloride in 250 ml of normal saline on three consecutive days, and for five days after one and four months. After the third treatment his haemoglobin concentration and white cell count became normal, and after further oral copper replacement his copper, caeruloplasmin, and zinc concentrations were also normal (table). His symptoms have not improved but he is neurologically stable. Oral copper supplementation has been stopped, and his copper and zinc concentrations remain normal.

Discussion

Copper is an essential component of proteins and metalloenzymes in the central nervous system. Copper deficient sensory ataxia, called swayback disease, has been recognised for decades in ruminant animals but only recently in humans.2 Over the past decade a wide variety of neurological syndromes secondary to acquired copper deficiency have been reported.3 Malabsorption secondary to gastric surgery is the commonest cause,4 followed by hyperzincaemia (zinc excess causes up-regulation of the metallothionein transporter, for which zinc competes with copper; copper has a higher affinity for metallothionein, remains bound to it, and is shed into the intestinal tract5).

In case 1, gastrectomy—which was widely performed for peptic ulcer disease before the 1990s—is the likely cause of hypocupraemia. Recognised complications of gastrectomy, which may occur acutely or decades after surgery,6 include B-12 deficiency, but hypocupraemia is rarely considered. The mildly raised serum zinc and markedly raised urinary zinc concentrations, in the absence of an exogenous source of zinc, are in keeping with other studies and may be a secondary manifestation.7 8 9

In case 2 the high levels of zinc raised the possibility of an external source. Our laboratory analysis of the cola drink did not find high zinc content; the only exogenous source of zinc identified was the dental cement, which contained polymethylvinylethermaleic acid, a calcium-zinc salt. After he switched to a dental adhesive with lower zinc content (Super Poligrip Free, GlaxoSmithKline), the patients’ indices became normal even though oral copper was stopped. Hyperzincaemia and hypocupraemia have been associated with overuse of dental cement,7 10 and four patients reportedly developed neurological symptoms after using dental cement in similar quantities to case 2, which is far in excess of the recommended daily zinc intake.11 Whether the association between hyperzincaemia and dental cement is widespread remains difficult to prove.

We also considered whether the cola drink contributed to the symptoms of hypocupraemia in case 2. An association with the sugars used in soft drinks has been reported in rats,12 but a link has not been proved in humans.13

Copper is necessary for the integrity of the red blood cell membrane, and as a caeruloplasmin component it is vital for oxidation and transport of ferrous iron,14 hence the hypocaeruloplasminaemia and anaemia seen in our patients, and the abnormal results of iron studies and bone marrow findings in case 2. Neutropenia, and rarely pancytopenia,15 as well as thrombocytosis,16 have also been described, although the mechanisms remain unclear. Although both patients had low concentrations of vitamin B-12 initially, case 1 had been treated before the onset of neurological symptoms, and in case 2 symptoms did not improve with treatment. B-12 deficiency commonly coexists with hypocupraemia,17 and both result in myeloneuropathy. In addition, both our patients had similar features on magnetic resonance imaging, typical of B-12 myelopathy.18 This underlines the importance of considering hypocupraemia in patients with symptomatic B-12 deficiency who do not improve with treatment.8 Further neurological deterioration is prevented by copper replacement, and limited improvement is seen in some cases.2 8 9 10 19

Given the number of gastrectomies performed, and the multiple potential sources of zinc ingestion, copper deficiency may be underdiagnosed. Cases of copper deficiency have been reported when zinc has been used to treat acrodermatitis hepatica and sickle cell anaemia, and when it has been taken prevent common colds.7 20 21 Zinc is also used to promote ulcer healing7 and in multivitamin preparations. Practitioners should measure serum copper levels in all patients presenting with predominantly posterior column spinal cord dysfunction (disproportionate loss of joint position and vibration sense). Peripheral neuropathy, leg spasticity, altered full blood count, and a history of B-12 deficiency may also be present. Greater recognition of this syndrome is vital to prevent irreversible disability.

Notes

Cite this as: BMJ 2010;340:c508

Footnotes

  • Competing interests: None declared.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References