Subacute Combined Degeneration Due to Copper Deficiency Joseph M. Ferrara, MD, Mark B. Skeen, MD, Nancy J. Edwards, Linda Gray, MD, E. Wayne Massey, MD From the Division of Neurology (JMF, MBS, NJE, EWM) and Department of Radiology (LG), Duke University Medical Center,Durham, North Carolina.
ABSTRACT There is growing clinical evidence supporting a connection between copper deficiency and subacute combined degeneration. While nearly half of patients with copper deficiency myelopathy exhibit MRI abnormalities, signal changes are often ill-defined in distribution. We report a patient with sensory ataxia and spastic paraplegia from copper deficiency whose MRI demonstrates abnormal signal restricted to the dorsal and lateral columns, providing clear radiological support of an association between hypocupremia and combined system degeneration.
Keywords: Copper deficiency, myelopathy, subacute combined degeneration. Acceptance: Received December 16, 2006, and in revised form December 16, 2006. Accepted for publication December 19,2006. Correspondence: Address correspondence to Joseph M. Ferrara, MD, Box 2905 – Duke University Medical Center, Durham, NC 27710. E-mail:
[email protected]. J Neuroimaging 2007;17:375-377. DOI: 10.1111/j.1552-6569.2007.00126.x
Case Report A 71-year-old woman presented with a 3-year history of worsening sensory loss, ascending from her feet to the midthorax, accompanied by leg weakness, urinary incontinence, and weight loss. Prior to our evaluation, the patient was treated with vitamin B12 supplementation despite a normal serum cobalamin level. Her vitamin B12 level measured as high as 1146 pg/mL; however, her neurological condition continued to deteriorate. The patient’s medical history was notable for a Billroth II surgery, performed for peptic ulcers in 1980. She had no history of excessive zinc ingestion, nitrous oxide exposure, autoimmune disease, or malignancy. Her family history was negative for neurological disease. On examination, the patient exhibited spastic weakness in both legs. She had markedly reduced proprioception in her lower extremities, including the hip joints, and mildly reduced proprioception in her distal fingers. Vibration sensation was absent at and below the iliac crests and was moderately impaired over her sternum and fingers. Pinprick and temperature sensation were diminished in a stocking-glove distribution in all limbs. She had absent ankle jerks but otherwise diffuse hyperreflexia with patellar clonus and extensor plantar responses. Her gait showed a profound sensory ataxia coupled with spasticity. Routine hematological and biochemical measurements, including her hemoglobin level (13.3 g/dL) and mean corpuscular volume (96 fL), were unremarkable. The following laboratory tests were also normal: vitamin B12, folate, vitamin E, and zinc levels; HIV, HTLV-1, and HTLV-2 serology; antinuclear antibodies; serum protein electrophoreses; RPR; and a paraneoplastic autoantibody panel. Nerve conduction studies revealed a sensorimotor polyneuropathy suggesting both demyelination and axonal loss. Electromyography demonstrated sporadic myopathic motor units in the tibialis anterior muscle.
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Magnetic resonance imaging (MRI) showed abnormal T2 signal in the dorsal and lateral columns extending the entire length of the thoracic spinal cord (Fig 1 and Fig 2). Within the cervical spinal cord abnormal T2 signal was present predominantly within the dorsal columns. Laboratory testing confirmed copper deficiency. Her serum copper was 0.33 mcg/dL (normal, 0.75-1.45), ceruloplasmin was 15 mg/dL (normal, 20-60), and 24hour urinary copper excretion was undetectable (normal, 15-60 mcg/specimen). The patient was treated with copper supplementation. Six weeks following initiation of therapy she noted diminished paresthesias but no improvement in strength.
Discussion Copper is a heavy metal, that, when incorporated into specific enzymes, can alternate between two oxidation states, thereby facilitating electron transfer reactions. Copper-containing enzymes include: cytochrome-c oxidase, which is the final catalyst of the electron-transport chain; dopamine β-hydroxylase, which produces norepinephrine; copper-zinc superoxide dismutase, which detoxifies reactive oxygen species; lysyl oxidase, which cross-links collagen; tyrosinase, which synthesizes melanin; and ceruloplasmin, which oxidizes ferrous iron.1 In 1937, Bennetts and Chapman demonstrated that lambs develop enzootic ataxia as a result of severe copper deficiency, a neurological condition characterized by hindlimb incoordination and pale, brittle wool.2 Believing that enzootic ataxia, or “swayback,” was predominantly a white matter disease, Mandelbrote and his colleagues then tested for copper deficiency in patients with various neurological diseases, predominantly demyelinating conditions. In 1948, they reported no association between copper deficiency and white matter disease in humans. Serendipitously, they did discover that the chelating
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Fig 1. Axial T2-weighted MR imaging of the thoracic spinal cord reveals abnormal signal within the corticospinal tracts and dorsal columns bilaterally. agent dimercaprol induced a striking cupuresis in a patient with Wilson’s disease.3 In 1972, the link between copper deficiency and neurological disease in humans resurfaced when Danks and colleagues noted that the kinky hair of boys with Menkes disease resembled the wool of swayback lambs—an observation that prompted the discovery of severe hypocupremia in these children.4 Menkes disease is an X-linked recessive disorder due to the dysfunction of a P-type ATPase necessary for the intestinal absorption and systemic regulation of copper. In addition to connective tissue abnormalities, Menkes disease shares neu-
Fig 2. Sagittal T2-weighted MR imaging shows increased signal in the spinal cord.
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ropathological features with swayback.5 Despite these studies, physicians failed to recognize the neurological impact of acquired copper deficiency in genetically normal adults until 2001 when Schleper and Stuerenburg described a copper-deficient woman with severe myelopathy.6 Numerous other cases have since confirmed the association between low copper levels and subacute combined degeneration, a syndrome usually tied to vitamin B12 deficiency.7 The hallmark of copper deficiency myelopathy is an unsteady gait with mixed features of sensory ataxia and spasticity produced by posterior and lateral column dysfunction, respectively. Plantar responses are usually extensor and reflexes can either be brisk or absent, varying with the degree of superimposed peripheral neuropathy. With an accompanying neuropathy, patients may also have impaired pinprick sensation in a stocking distribution overlying their marked proprioceptive dysfunction. Other manifestations of the syndrome are paresthesias and urinary bladder dysfunction.7 The etiology of hypocupremia is unknown in approximately one-third of patients with a related myelopathy, but there does appear to be an association with remote gastric surgery and malabsorption.8 Excessive zinc consumption and idiopathic hyperzincemia have also been cited to cause copper deficiency myelopathy,9-13 perhaps by inducing the production of enterocyte metallothioneins (proteins that are known to impede copper absorption). Copper deficiency with hematological—but not neurological—dysfunction has been described in patients taking copper chelating agents and in those who are reliant on parenteral or enteral tube feeding formulas lacking copper. Several patients reported with copper deficiency myelopathy had a history of treated cobalamin deficiency. This association raises the question whether low copper levels are truly pathogenic or merely an indicator of past vitamin B12 deficiency. Observations that support a causal role for copper are: multiple patients without a history of pernicious anemia have developed myelopathy in association with copper deficiency; copper deficiency myelopathy is phenotypically and pathologically similar to enzootic ataxia seen in copper-deficient ruminants; and patients with copper deficiency myelopathy worsen despite cobalamin supplementation and improve or stabilize with copper supplementation.7 Although the pathophysiology of copper deficiency myelopathy remains speculative, it is likely due to cuproenzyme impairment, specifically cytochrome-c oxidase. In the proper clinical setting, one can diagnose copper deficiency myelopathy by revealing hypocupremia while excluding alternative causes of spinal cord dysfunction. Other markers of copper deficiency include low ceruloplasmin levels, reduced 24-hour urine copper excretion, and in some patients, anemia or neutropenia. The differential diagnosis of combined posterior and lateral column degeneration includes nitrous oxide toxicity; HIV infection; and cobalamin or folate deficiency. Recently, Kumar and colleagues documented MRI abnormalities in the spinal cords of 11 of 25 patients with copper deficiency myelopathy, chiefly, increased signal on T2weighted imaging of the cervical cord.8 In their series, the dorsal columns and central cord were most affected. Our case of copper deficiency myelopathy demonstrates abnormal
signal that is clearly restricted to the dorsal columns and corticospinal tracts. Accordingly, it provides neuroimaging evidence that hypocupremia can lead to subacute combined degeneration. The clinical and radiological findings of copper deficiency are similar to—if not indistinguishable from—cobalamin deficiency. Furthermore, subacute combined degeneration resulting from either condition affects a common patient population: those with a history of gastric surgery or malabsorption. As such, we believe that copper deficiency myelopathy is likely underdiagnosed and should be considered in all patients with clinical or radiological features of combined system degeneration.
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