Copper deficiency myeloneuropathy

INTRODUCTION — Copper deficiency-associated myelopathy has been well described in various animal species, in particular ruminants, in which it is called swayback or enzootic ataxia. Acquired copper deficiency has been recognized to cause a myelopathy in humans relatively recently [1,2]; however, cases of myelopathy described among zinc-smelter workers in the 19^th century are now felt likely to be due to copper deficiency myelopathy [3]. The neurologic manifestations of copper deficiency are often accompanied by hematologic derangements of anemia and leukopenia.

This topic discusses the neurologic manifestations of acquired copper deficiency. The physiologic and biochemical functions of dietary copper and the dietary requirements of copper are discussed in detail separately. (See "Overview of dietary trace elements", section on 'Copper'.)

A brief overview of Menkes disease, a congenital X-linked disorder of severe copper deficiency, is also discussed separately. (See "Overview of dietary trace elements", section on 'Menkes disease'.)

EPIDEMIOLOGY — The age range of reported cases of copper deficiency myeloneuropathy is 30 to 82 years [4,5]. More cases in women than in men are reported.

PATHOPHYSIOLOGY — The mechanism underlying neurologic damage in individuals with copper deficiency is uncertain. Copper is a component of enzymes that have a critical role in the structure and function of the nervous system [6-12]. It permits electron transfer in key enzymatic pathways. These include cytochrome-c-oxidase for electron transport and oxidative phosphorylation, copper/zinc superoxide dismutase for antioxidant defense, tyrosinase for melanin synthesis, dopamine beta-hydroxylase for catecholamine biosynthesis, lysyl oxidase for crosslinking of collagen and elastin, peptidylglycine alpha-amidating monooxygenase for neuropeptide and peptide hormone processing, monoamine oxidase for serotonin synthesis, and ceruloplasmin for brain iron homeostasis.

There are limited pathologic studies in individuals with acquired copper deficiency [13-15]. A few reports of nerve biopsies in patients confirm the presence of axonal degeneration [1,16-19]. A single postmortem examination in one patient revealed significant degeneration in the dorsal and lateral columns of the spinal cord [13]. Similar pathologic findings were reported in two other cases; however, in these patients, other nutrient deficiencies (folate and selenium) were also present [14,15]. In animals, neuronal loss in the cerebellum and spinal tracts with extensive demyelination is reported [20].

CAUSES OF ACQUIRED COPPER DEFICIENCY — Although rare, acquired copper deficiency has been well documented in humans [6,20]. The most common causes are malabsorption and zinc ingestion:

●Gastrointestinal surgery is the most common cause of acquired copper deficiency, underlying approximately half of reported cases [1,4,16,21-37]. Typically, neurologic manifestations are delayed by years, at times decades, following gastrointestinal surgery. (See "Bariatric surgery: Postoperative nutritional management", section on 'Copper'.)

●Excessive zinc ingestion is another cause of copper deficiency [3,32,33,38-42]. Copper and zinc are competitively absorbed from the gastrointestinal tract. In addition to overuse of zinc supplements [43,44], ingestion of denture cream [13,39-41,45] and parenteral or oral zinc overloading in patients undergoing chronic hemodialysis [46,47] have also been linked to copper deficiency myelopathy.

●Dietary copper deficiency is rare but has been described in premature infants receiving milk formulas without adequate copper supplementation [6,48]. Copper deficiency has been reported in at least one patient with alcohol use disorder [49]. Copper deficiency may also be a complication of prolonged total or partial parenteral nutrition, in particular when copper supplementation is withheld due to cholestasis [8,14,15,33,50]. One case report notes copper deficiency in a child on a ketogenic diet [51].

●Enteropathies associated with malabsorption, such as cystic fibrosis, celiac disease, and inflammatory bowel disease, may be associated with copper deficiency [1,6,20,33,52,53]. In some cases the neurologic manifestations have occurred in the absence of gastrointestinal symptoms [52,54,55]. Bacterial overgrowth has also been implicated as a cause of copper deficiency in a patient with a prior history of gastric surgery [25].

Prolonged use of proton pump inhibitors was speculated to contribute to impaired intestinal absorption of copper and subsequent copper deficiency and myeloneuropathy in a series of patients without another known cause for copper deficiency [56].

●Overtreatment of Wilson disease with zinc and chelators has only rarely been reported to cause copper deficiency-related neurologic manifestations [57-62]. In one report, copper deficiency was diagnosed in a patient with Wilson disease in the absence of zinc toxicity; malabsorption or reduced oral intake due to dysphagia may have been responsible [63].

The antiparasitic agent, clioquinol, is a copper chelator and was linked to many cases of myelo-optico-neuropathy (a syndrome similar to copper deficiency myeloneuropathy) in Japan in the 1960s [64-66]. Another copper chelator, tetrathiomolybdate, has been associated with copper deficiency [67].

The coexistence of multiple causes of copper deficiency increases the risk of a clinically significant deficiency state [68]. In some cases, the cause of copper deficiency is not evident even after extensive investigation [1,4,5,18,30,69].

These and other risk factors for copper deficiency are discussed in more detail separately. (See "Overview of dietary trace elements", section on 'Risk factors'.)

CLINICAL MANIFESTATIONS

Neurologic — The most common neurologic manifestation of acquired copper deficiency is that of a myelopathy or myeloneuropathy [1,2,5,21,22,38,41,52,54,70]. Patients typically present with a subacute gait disorder with prominent sensory ataxia and/or spasticity. Examination reveals long tract signs with spasticity in the legs and Babinski response, along with impaired vibration and position sense and a positive Romberg sign. Bladder dysfunction is relatively uncommon, but can occur [2,5,31]. This pattern of neurologic deficits reflects involvement of the dorsal columns of the spinal cord and is similar to that seen in patients with subacute combined degeneration secondary to vitamin B₁₂ deficiency. (See "Anatomy and localization of spinal cord disorders", section on 'Dorsal (posterior) cord syndrome' and "Disorders affecting the spinal cord", section on 'Subacute combined degeneration'.)

Symptoms and signs suggesting an associated peripheral neuropathy are common [41]. The neuropathy may take different forms. A complaint of lower limb paresthesias is present in nearly all patients, and most demonstrate a stocking distribution of impaired sensation to pain and temperature [1,2,22]. Superimposed neuropathy may lead to suppressed reflexes in the legs, although many patients have brisk reflexes instead, reflecting the myelopathy [1,2]. A common finding is brisk knee jerks with depressed or absent ankle jerks. Less common peripheral nerve manifestations include a wrist or foot drop [1]; asymmetric sensory symptoms of the face and trunk as well as limbs, suggesting a sensory ganglionopathy [18]; and a progressive, asymmetric weakness with electrodiagnostic evidence of denervation suggesting lower motor neuron disease [17,40]. In most cases, the associated neuropathy develops along with the myelopathy; however, in some cases, these develop before the myelopathy [16] or in the absence of a myelopathic symptoms [29,30,39,57,71]. Not all of the cases of reported isolated neuropathy in this setting were confirmed by careful neurologic examination; the association between copper deficiency and an isolated neuropathy requires further study.

Optic nerve involvement of varying severity has been reported as part of this syndrome in a number of patients [25,29,31,72], although not in most. Affected patients typically have subacute onset of bilateral vision loss, without optic disc edema.

Rare neurologic symptoms associated with copper deficiency in isolated case reports include myopathy (along with myelopathy) [55], myelo-optico-neuropathy with hyposmia and hypogeusia [25], and cognitive impairment [40]. However, the precise significance of these reported associations is unclear and needs further confirmation.

Hematologic — The hematologic hallmark of copper deficiency is anemia and leukopenia; these are present in most, but not all, patients with associated neurologic deficits [1,2,4,19,30,32,33,38,41,73-75]. The anemia may be microcytic, macrocytic, or normocytic. Thrombocytopenia and pancytopenia are relatively rare. Typical bone marrow findings include a left shift in granulocytic and erythroid maturation with cytoplasmic vacuolization in erythroid and myeloid precursors and the presence of ringed sideroblasts or hemosiderin-containing plasma cells [30,33,39,76]. Erythroid hyperplasia with decreased myeloid-to-erythroid ratio and dyserythropoiesis including megaloblastic changes may be seen. In some cases, patients with copper deficiency were initially given a diagnosis of sideroblastic anemia, myelodysplastic syndrome, or aplastic anemia.

Other — One case series and a case report describe hepatic iron overload and/or cirrhosis in five patients with copper deficiency myeloneuropathy [32,77]. The authors speculated that this was caused by the secondary deficiency of ceruloplasmin, which is responsible for oxidizing iron for binding to transferrin, which facilitates iron mobilization.

Clinical signs and symptoms of Menkes disease, a congenital x-linked disorder of severe copper deficiency, are discussed separately. (See "Overview of dietary trace elements", section on 'Menkes disease'.)

DIFFERENTIAL DIAGNOSIS — Other causes of myelopathy, particularly syndromes affecting the dorsal spinal cord, should be considered in the differential diagnosis of this clinical presentation. (See "Anatomy and localization of spinal cord disorders" and "Disorders affecting the spinal cord".)

In particular, the subacute combined degeneration resulting from vitamin B₁₂ deficiency can have a very similar neurologic presentation. Some diagnoses of copper deficiency myeloneuropathy were made only after vitamin B₁₂ supplementation failed to halt neurologic progression [1,4,22,28,39,72]. Copper and vitamin B₁₂ deficiency may also coexist, particularly in patients with a history of gastric surgery [1,2,4,39,78]. (See "Disorders affecting the spinal cord", section on 'Subacute combined degeneration' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Neuropsychiatric changes'.)

Nitrous oxide abuse can also lead to subacute combined degeneration, by inactivation of vitamin B₁₂ [79-81]. (See "Inhalant misuse in children and adolescents", section on 'Nitrous oxide'.)

Other causes of a dorsal cord syndrome include multiple sclerosis (more typically the primary progressive form), tabes dorsalis, Friedreich ataxia, vascular malformations, epidural and intradural extramedullary tumors, cervical spondylotic myelopathy, and atlantoaxial subluxation [82]. Adrenomyeloneuropathy and hereditary spastic paraplegia should also be considered in some cases. These entities are described in detail separately. (See "Disorders affecting the spinal cord" and "Cervical spondylotic myelopathy".)

DIAGNOSIS AND EVALUATION — The diagnosis of copper deficiency myeloneuropathy is made in patients with the characteristic clinical syndrome and laboratory indicators of copper deficiency.

Patients who present with a myelopathy should also have imaging studies (usually magnetic resonance imaging [MRI]) of the spinal cord to exclude other conditions. Vitamin B₁₂ levels should be checked to exclude the alternative or comorbid diagnosis of vitamin B₁₂ deficiency.

While not essential in the evaluation of copper deficiency myeloneuropathy, some patients will have electrophysiology studies or a lumbar puncture.

Laboratory studies — Laboratory indicators of copper deficiency include a decrease in serum copper or ceruloplasmin levels (more than 90 percent of circulating copper is bound to ceruloplasmin). Measurement of 24-hour urinary copper excretion is a less sensitive marker for copper deficiency [33,83].

All described cases of copper deficiency myeloneuropathy have had low serum copper levels [2,4,19,70]. However, in marginal copper deficiency, serum copper levels may be normal [8,84]. Ceruloplasmin is an acute phase reactant and may be elevated in the presence of inflammatory conditions and also at times in pregnancy, oral contraceptive use, liver disease, malignancy, hematologic disease, myocardial infarction, infections, smoking, diabetes, and uremia. It is possible that in these settings, levels of serum copper and ceruloplasmin may be normal, even while stores of copper are low, and a copper deficiency could be masked. Copper levels are commonly low in the absence of copper deficiency in patients with Wilson disease or in heterozygous carriers of the Wilson disease gene [85]. The toxicity in Wilson disease is due to elevation in free serum copper and tissue copper deposition. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

When excessive zinc ingestion is suspected or when the cause of copper deficiency is unknown, serum zinc and 24-hour urinary zinc excretion levels should be obtained. A significant elevation in these should prompt an investigation for an exogenous source of zinc. However, zinc levels have been reported to be modestly elevated in some patients with copper deficiency myeloneuropathy in the absence of known excessive zinc ingestion [33].

Vitamin B₁₂ levels should be checked, as vitamin B₁₂ deficiency may coexist with copper deficiency, particularly in cases of prior gastric surgery [4]. Measurement of methylmalonic acid and homocysteine, which are elevated in vitamin B₁₂ deficiency, increases the sensitivity of laboratory testing and should be performed in high-risk patients. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Serum vitamin B12 and folate levels' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Additional testing for selected individuals'.)

Neuroimaging — Imaging of the spinal cord, usually with MRI, should be undertaken as part of the initial evaluation in all patients with a myelopathy. (See "Anatomy and localization of spinal cord disorders", section on 'Diagnosis'.)

MRI of the spine may be normal [1,2,4,16,19,25,41,54,55,86,87], but many patients have increased T2 signal involving the dorsal column in either the cervical or thoracic cord, or both (image 1) [1,2,4,18,19,21,41,70,74,88,89]. The signal change may also involve the central cord or lateral column [88], and also may extend into the brainstem [90]. Contrast enhancement is typically absent. These findings are similar to those reported in patients with vitamin B₁₂ deficiency [4]. After treatment, the signal abnormality may resolve [4,89].

In some patients who have had brain MRI, nonspecific areas of increased signal involving the subcortical white matter have been reported [1,2,40,54]. In some cases, the subcortical white matter changes appear confluent or cluster in the periventricular region and suggest demyelination [1,25,41,86,87]. The significance of these changes and their association with copper deficiency is uncertain.

Electrophysiology — Nerve conduction studies and other electrophysiologic tests are not essential in the diagnosis or evaluation of patients with copper deficiency myeloneuropathy but may be ordered in the initial evaluation of a patient's complaints.

In patients with copper deficiency myeloneuropathy, nerve conduction studies typically reveal an axonal sensorimotor polyneuropathy of varying severity [1,2,16,18,19,25,30,38,43,54,55,57,70]. Myopathic potentials are rarely seen on electromyography [2,88]. Rare patients with copper deficiency myeloneuropathy have prominent reduction in motor action potentials along with denervation suggesting lower motor neuron disease [17,40].

Evoked potential studies may provide electrophysiologic evidence of posterior column dysfunction [2,19]. Somatosensory evoked potentials, in particular, appear to be abnormal in many patients with copper deficiency myeloneuropathy [1,2,4,18,19,25,54]. Visual evoked potentials may also be prolonged [25].

Cerebrospinal fluid analysis — Lumbar puncture and cerebrospinal fluid (CSF) analysis are not routinely indicated. When performed, a slight, nonspecific elevation in the CSF protein may be seen in this disorder, but no other abnormalities are generally reported [1,18,25,40,41,43,46,57].

TREATMENT — There have been no studies that address the most appropriate dose, duration, route, and form of copper supplementation, and many regimens have been used successfully. Commonly used copper salts include copper gluconate, copper sulphate, and copper chloride. For oral replacement, we typically use elemental copper. In high-risk populations, routine monitoring has been suggested [36].

●Copper replacement: dosing and administration – Because of the need for long-term replacement, parenteral therapy is not preferred and is not required in most patients. Some clinicians use initial parenteral administration followed by oral administration [31]. Copper supplements may not be adequately absorbed when administered through a jejunostomy tube necessitating parenteral therapy [91]. Other situations in which parenteral therapy may be preferred or required include severely depleted patients or significant malabsorption. Subcutaneous and intramuscular supplementation have also been employed.

The standard dose is 2 mg of elemental copper per day. This dose of elemental copper may be given intravenously; a commonly used regimen is 2 mg of elemental copper administered intravenously (over two hours) daily for five days and periodically thereafter. Some patients require higher doses, particularly if administered orally and in the setting of malabsorption. In our practice, we give 8 mg of elemental copper each day orally for a week, 6 mg for the second week, 4 mg for the third week, and 2 mg thereafter. When copper salts are used, the dosing should be adjusted to make sure that the elemental copper is at least 2 mg. Replacement doses are empiric; periodic assessment of serum copper is essential to determine adequacy of replacement and to decide on the most appropriate long-term administration strategy. In one report, overtreatment of copper deficiency (up to 8 mg per day over 10 years) resulted in hepatic copper overload with cirrhosis that required liver transplantation; genetic testing for ATPase copper transporting beta (ATP7B) mutations was negative [92].

●Discontinue zinc – In those patients in whom excess zinc ingestion is the likely cause, stopping zinc supplementation may suffice and no additional copper supplementation may be required. However, copper supplementation is generally started at least initially in addition to stopping zinc supplementation [38].

●Treat other deficiencies – Copper deficiency in gastrointestinal disease may be accompanied by deficiencies of zinc, vitamin B₁₂, vitamin D, vitamin E, and iron [53]; these should be supplemented as well when appropriate. However, iron therapy in a patient with anemia of indeterminate cause may decrease copper absorption.

Copper supplementation in the setting of bariatric surgery is discussed separately. (See "Bariatric surgery: Postoperative nutritional management", section on 'Copper'.)

PROGNOSIS — Copper supplementation generally prevents further neurologic deterioration, but improvement of neurologic signs and symptoms is variable, often subjective, and limited to sensory symptoms [1,2,4,5,25,26,28,35,38,39,41,43,52,70,74,89]. Most patients have residual deficits [2,16,17,21,31]. However, there are reports of substantive improvement in the neurologic deficits, along with abnormalities of nerve conduction studies, evoked potential studies, and MRI signal change with normalization of serum copper [1,2,4,54,60]. The duration and severity of symptoms prior to supplementation may influence prognosis [93].

By contrast, response of the hematologic parameters (including bone marrow findings) is prompt and often complete [1,2,5,19,30,39,41,73]. Hematologic recovery may be accompanied by reticulocytosis.

The natural history of this disorder is not well known, but it is likely that symptoms will continue to progress in the absence of treatment. In one exceptional case of copper deficiency myeloneuropathy related to excessive zinc ingestion that was not diagnosed for several months, neurologic disability progressed to include diaphragmatic weakness and, ultimately, fatal aspiration [13].

SUMMARY AND RECOMMENDATIONS

●Causes of acquired copper deficiency – Gastric surgery is the most common cause of acquired copper deficiency. Other causes include excessive zinc ingestion, dietary copper deficiency, malabsorption syndromes, and chelation therapy in Wilson disease. (See 'Causes of acquired copper deficiency' above.)

●Clinical syndrome

•Neurologic manifestations – The most common neurologic manifestation of acquired copper deficiency is that of a myeloneuropathy. Patients typically present with a subacute onset of a gait disturbance. Examination reveals long tract signs with spasticity in the legs and Babinski response, along with impaired vibration and position sense and a positive Romberg sign. (See 'Neurologic' above.)

•Hematologic manifestations – The hematologic hallmark of copper deficiency is anemia and leukopenia; these are present in most, but not all, patients with associated neurologic deficits. (See 'Hematologic' above.)

●Differential diagnosis – The subacute combined degeneration resulting from vitamin B₁₂ deficiency has a very similar neurologic presentation and may be comorbid with copper deficiency myeloneuropathy. Other causes of a dorsal spinal cord syndrome (eg, multiple sclerosis, tabes dorsalis, Friedreich ataxia, and others) should be considered in the differential diagnosis. (See 'Differential diagnosis' above.)

●Evaluation and diagnosis – The diagnosis of copper deficiency myeloneuropathy is made in a patient with the characteristic clinical syndrome and laboratory indicators of copper deficiency. (See 'Diagnosis and evaluation' above.)

Testing in patients with this clinical syndrome should include:

•MRI of the spine.

•Serum copper and ceruloplasmin levels.

•Vitamin B₁₂ levels along with methylmalonic acid and homocysteine levels in patients with a history of gastric surgery. Other potentially coexisting nutrient deficiencies (eg, folate or vitamin E deficiency) should also be investigated.

•Zinc levels when excessive zinc ingestion is suspected or when the cause of copper deficiency is unknown.

•Serologic testing for celiac disease.

●Treatment – Many different regimens of copper replacement have been used with success. (See 'Treatment' above.)

•For most patients with copper deficiency myeloneuropathy, we use 8 mg of elemental copper each day orally for a week, 6 mg for the second week, 4 mg for the third week, and 2 mg thereafter

•Parenteral administration may be required in some patients

•Periodic assessment of serum copper is essential to determine adequacy of replacement and to decide on the most appropriate long-term administration strategy

•Zinc supplementation should be stopped

●Prognosis – Copper supplementation generally prevents further neurologic deterioration, but improvement of neurologic signs and symptoms is variable; most patients have some residual deficits. (See 'Prognosis' above.)