Abstract
Iatrogenic copper deficiency is rare in patients with Wilson’s disease. We present a case of iatrogenic copper deficiency myeloneuropathy secondary to zinc treatment for Wilson’s disease and compare the patient’s clinical features with existing cases. Our study highlights the importance of recognizing subtle clinical manifestations and counselling patients receiving copper-reducing treatment to watch for symptoms of myeloneuropathy. Early biochemical testing, including serum copper, caeruloplasmin and zinc levels, as well as magnetic resonance imaging of the spine and electrophysiological studies, may be helpful in diagnosing copper deficiency-related myeloneuropathy due to zinc treatment. Early detection and treatment of copper deficiency may lead to good recovery of neurological symptoms.
Introduction
Wilson’s disease is an inherited copper metabolic disorder that results in accumulation of copper in multiple organs including liver, brain and cornea. The clinical manifestations are heterogeneous and include hepatic, neurological and psychiatric manifestations. Pharmacological treatment includes chelating agents such as d-penicillamine and trientine, and zinc salts that inhibit the intestinal absorption of copper. 1 Acquired copper deficiency with characteristic neurological manifestations has been reported, and common causes include previous upper gastrointestinal tract surgery, zinc excess from various causes including denture cream, dietary supplements, dialysis and malabsorption syndromes. 2 However, myeloneuropathy resulting from iatrogenic copper deficiency due to treatment of Wilson’s disease is uncommon. We present a case of iatrogenic copper deficiency myeloneuropathy secondary to zinc treatment for Wilson’s disease and compare the patient’s clinical features with existing cases.
Case report
A 67-year-old woman was diagnosed with Wilson’s disease 33 years ago. She had been treated with penicillamine since her diagnosis and was switched to zinc 50 mg three times daily, 2 years prior to her current presentation.
She presented with a 9-months history of progressive paresthesia on the bilateral soles of her feet, lower abdomen and pelvis. On the day of her admission, she was unsteady and could not get out of bed. She also complained of bowel incontinence. She denied falls or trauma. She had no fever, weight loss or loss of appetite. She had no symptoms of liver decompensation, neurological or psychiatric manifestations of Wilson’s disease. She did not consume alcohol or smoke. There were no recent dietary changes.
On physical examination, her biceps, triceps and knee reflexes were brisk. Her plantar responses were flexor bilaterally. Her hip flexors and knee flexors had Medical Research Council grade 4 power, while the remaining lower limb and upper limb muscle groups were normal. Sensory testing showed impaired sensation to fine touch and pinpricks in both lower limbs, trunk and abdomen. Proprioception was impaired in the lower limbs. Vibration sensation was impaired in a length dependent manner over her lower limbs. Sensory testing in the upper limbs was normal. Muscle tone was normal. She had no cerebellar signs. Anal tone was good and there was no saddle anaesthesia. Her clinical examination suggested a mixture of upper and lower motor neuron signs - The hyperreflexia and sensory level suggested spinal cord pathology, while the presence of plantar flexor responses, and length-dependent pattern of vibration loss in the lower limbs suggested concomitant polyneuropathy. She was evaluated for myeloneuropathy.
Magnetic resonance imaging (MRI) showed T2 hyperintensities in the posterior spinal cord at the C3-C6 level, without contrast enhancement. (Figure 1) Her sensory nerve conduction study showed absent sensory nerve amplitude (SNAP) over the right peroneal and sural nerves, whereas the SNAP of the right radial, median and ulnar nerves showed reduced amplitudes with normal latency. Her motor nerve conduction study showed reduced compound muscle action potential (CMAP) of the right tibial nerve with normal latency and absent CMAP over the peroneal nerve. Right ulnar nerve showed reduced CMAP with normal latency. These nerve conduction study findings were suggestive of a length dependent sensorimotor, axonal polyneuropathy. Axial (a) and Sagittal (b) planes of MRI cervical spine showing raised T2 hyperintensities in the posterior aspect of the cord from the level of C3-C6 (white arrows).
On admission, her serum vitamin B12, folic acid, thyroid function test, liver function test, electrolyte levels and ammonia were normal. Her infection markers were normal. Syphilis and HIV serologies were negative. Her serum total copper was undetectable (<3.3 ug/dL) [normal reference value: 73.4–171.4 ug/dL ] and 24-h urine free copper concentration was very low (1.7 mg/day). Serum caeruloplasmin concentration was also significantly reduced (<6.0 mg/dL) [normal reference value: 15–45 mg/dL]. She had markedly elevated serum zinc concentrations (214 ug/dL) [normal reference value: 72.4–124.4 ug/dL].
She was diagnosed with iatrogenic copper deficiency due to zinc treatment, resulting in myeloneuropathy. Her zinc sulphate tablets were discontinued and she was given oral copper replacement of 500 mg/day. At the 4-months follow-up, her total serum copper level increased to 6.9 mg/dL and zinc level decreased to 77.9 mg/dL. There was mild improvement in her numbness and gait, and she was able to ambulate with assistance. However, there was persistent sensory loss to pinpricks, vibration and proprioception in the lower limbs. A repeat MRI scan after 4 months showed persistent hyperintensity of the dorsal column of the cervical cord.
Discussion
Summary of the demographic background, clinical features, investigations and outcomes of patients with Wilson’s disease and copper deficiency myeloneuropathy related to zinc treatment.
Copper deficiency-related myelopathy is similar to subacute combined degeneration of the spinal cord caused by vitamin B12 deficiency, leading to dorsal column deficits in cervical and/or thoracic cord. 12 MRI spine often shows increased T2 signals involving the dorsal column, and electrophysiological studies often indicate sensorimotor axonal polyneuropathy. 13 This is consistent with our study, seven patients (77.8%) had MRI findings which showed posterior column T2 hyperintensities, while most patients (70%) had abnormal nerve conduction studies. Four of the seven patients had sensorimotor polyneuropathy, while two patients had purely sensory involvement and one had motor neuropathy. Furthermore, most patients in our review had low serum copper, serum caeruloplasmin (88.9%) and high serum zinc levels (77.8%). These findings suggest the importance of MRI, nerve conduction study, serum copper, caeruloplasmin and zinc levels in determining copper deficiency myeloneuropathy related to zinc treatment.
In our review, the median duration between onset of neurological symptoms and diagnosis was 4 months (2 months - 1 year). This is consistent with observation by Gabreyes et al. in which the median duration was 12 months. 14 Our study identified possible reasons for delayed diagnosis of patients with copper deficiency. Firstly, delayed diagnosis due to delayed presentation. In our review, three of the patients presented only after a prolonged duration of their symptoms. This highlights the importance of counselling of these patients to watch for symptoms of myeloneuropathy and seek early medical attention. Secondly, the investigation was delayed due to subtle neurological symptoms. Two patients had initially presented with paresthesias in the distal extremities and were only evaluated when their deficits had progressed. Considering that copper deficiency causes predominantly sensory polyneuropathy and dorsal column dysfunction, sensory complaints can be an early sign of copper deficiency and it is important to consider this diagnosis, even if the neurological complaints are subtle. Furthermore, in one patient, the diagnosis was delayed because the symptoms were attributed to poor nutritional status. Although poor nutrition is also a cause of copper deficiency, it would be prudent for clinicians to evaluate for copper deficiency due to zinc overtreatment in Wilson’s disease as a cause of neurological symptoms. This would allow clinicians to provide immediate treatment with discontinuation of copper-reducing drugs and copper supplementation as needed.
To date, there are no standard guidelines for copper replacement in the context of Wilson’s disease. In our review, copper-inhibiting drugs were discontinued in all patients, while four patients (40%) received oral copper replacement. However, discontinuation of anti-copper drugs and initiation of oral or parenteral coper supplementation must be carefully considered, as excessive copper supplementation may also lead to an exacerbation of the underlying Wilson’s disease. Our review showed variable neurological recovery, eight patients (88.9%) had persistent residual symptoms or deficits. Only one patient (patient 3) had complete neurological recovery with no residual symptoms. Interestingly, this was also the only patient for whom there was no delay in diagnostic evaluation and treatment when she presented with symptoms of myeloneuropathy. This suggests that prompt diagnosis and treatment of copper deficiency may be essential for achieving favorable neurological outcomes. However, larger and prospective studies are needed to conclude the association between delay in diagnosis and neurological outcomes, and to determine the optimal treatment strategies in this clinical entity.
In conclusion, iatrogenic copper deficiency is rare in patients with Wilson’s disease. Our study highlights the importance of recognizing subtle clinical manifestations and counselling patients receiving copper-reducing treatment to watch for symptoms of myeloneuropathy. Early biochemical testing, including serum copper, caeruloplasmin and zinc levels, as well as MRI imaging and electrophysiological studies, may be helpful in diagnosing copper deficiency-related myeloneuropathy due to zinc treatment. Early detection and treatment of copper deficiency may lead to good recovery of neurological symptoms, although future larger, prospective studies are required to provide further clarity.
Footnotes
Author contributions
Chloe Pawa had contributed to the initial patient care, management and the writing of the case report manuscript. Kexin Ang had contributed to the acquisition of data and editing of manuscript. Yi Rong Chiew had contributed to the review and editing of the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical statement
Data availability statement
We documented the patient’s data reported in the article. We will share the de-identified data on reasonable request. To request the data, please contact the corresponding author.