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Recognition of Wilson disease (WD) is sometimes difficult because of its diverse manifestations. Peripheral neuropathy is rarely reported in the context of WD.
To report an unusual patient with WD whose initial manifestation was peripheral neuropathy.
Neurology department in a tertiary referral center.
A 17-year-old man, who was eventually diagnosed with WD, was initially seen with polyneuropathy at least 6 months prior to developing more typical symptoms of WD. Electrophysiological and pathological studies suggested a neuropathy of mixed type. Treatment for WD resulted in clinical and electrophysiological improvement.
Wilson disease may initially appear as a treatable polyneuropathy.
Wilson disease (WD) is an autosomal recessive disorder of abnormal copper metabolism caused by mutations in the ATP7B gene encoding a putative copper-transporting P-type adenosine triphosphatase and usually manifests with progressive liver cirrhosis, neurologic impairment, and Kayser-Fleischer rings and/or renal malfunction.1,2 Early recognition of the disease is important because there are effective treatments and delayed diagnosis will lead to irreversible brain and liver damage. However, WD may elude early recognition because of its diverse manifestations.
Peripheral neuropathy has rarely been reported in the context of WD,3- 5 and the pathological findings of such an entity have not been clarified yet. We herein report a patient with WD whose initial manifestation was polyneuropathy (PN), which improved clinically and electrophysiologically with treatment of WD.
A 17-year-old man visited us because of intermittent paresthesia and weakness in both hands and feet. The symptoms began several months previously and worsened gradually. He had no remarkable medical or family history of liver disease, psychiatric illness, or movement disorders. He was not a habitual alcohol or drug abuser. He was alert and oriented with intact cognitive function. Cranial nerve examination results were normal. The abductor pollicis brevis, first dorsal interosseous, other intrinsic hand muscles, and toe and feet muscles were weak (Medical Research Council [MRC] grade IV+/IV+) bilaterally, while the power of the other muscles in the proximal arms and legs was normal. Muscle bulk and tone were normal. The sensory examination results for soft touch, pain, temperature, vibration, and proprioception were normal. Deep tendon reflexes were symmetrically decreased in the biceps, triceps, knee, and ankle. Ataxia, tremor, and gait abnormalities were not noted.
A nerve conduction study (NCS) was performed using standard techniques6 of surface stimulation and recording (Nicolet Viking IV; Nicolet Biomedical Instruments, Madison, Wis). Skin temperatures were maintained higher than 32.0°C. Distal motor latency, F-wave latency, motor nerve conduction velocity, and compound motor action potential were measured in the median, ulnar, peroneal, and posterior tibial nerves. Sensory nerve conduction velocity and sensory nerve action potential were obtained in the median, ulnar, and sural nerves. Distal motor latency and F-wave latency were prolonged in the majority of motor nerves, and motor nerve conduction velocity and sensory nerve conduction velocity were slightly decreased. Compound motor action potential and sensory nerve action potential were relatively preserved without conduction block or temporal slowing (Table). Electromyography showed positive sharp waves in the abductor pollicis brevis, first dorsal interosseous, and tibialis anterior muscles with giant motor unit potentials and reduced interference patterns. Nerve biopsy results showed a destruction of the myelin sheath associated with axonal damage (Figure 1).
Pathological examination of the left sural nerve. A, There is no inflammatory cell infiltration (hematoxylin-eosin, original magnification × 100). B, Photograph shows high-magnification views of a fascicle in the longitudinal section (Luxol fast blue, original magnification × 400). The myelinated fibers appear normal except for a single fiber (arrowhead), which may contain either 2 myelin ovoids next to each other or may simply be a node of Ranvier. C and D, Ultrastructural examination disclosed a cross-sectioned nerve. Accumulations of organelles are frequently noted in the axons. Destruction of the myelin sheath is associated with axonal damage (arrows).
Hemoglobin A1C, aspartate aminotransferase and alanine aminotransferase, bilirubin, coagulation factors, iron and ferritin, vitamin B12, folate, thyroid hormone, and immunoelectrophoresis test result values were within normal limits. Cerebrospinal fluid was acellular with normal protein and glucose levels. Rheumatoid factor and anti–double-stranded, antinuclear, and anti–smooth muscle antibodies were absent. Abdominal sonography showed mild fatty liver. The patient was diagnosed with sensorimotor PN of undetermined cause and was followed up with amitriptyline hydrochloride and multivitamin administration.
At least 6 months from the development of neuropathy symptoms, dysarthria and involuntary movement in the right leg developed gradually. On the follow-up neurologic examination 1 year after the first evaluation, the patient showed slurred, somewhat hypokinetic, speech, blepharospasm, dystonic posturing, abnormal co-contraction of limb muscles, and limb ataxia. The weakness of both distal muscles was worse (MRC grade IV−/IV−) with mild muscle wasting. Sensory examination showed hypesthesia to pain, temperature, vibration, and position sense in the hands and feet. The NCS was followed up by the same examiner with the same protocol. Subsequent testing showed worsening of the earlier electrophysiological abnormalities (Table). Slitlamp examination showed Kayser-Fleischer rings. Serum copper and ceruloplasmin levels were 18 μg/dL (2.83 μmol/L) (reference range, 70-155 μg/dL [10.99-24.34 μmol/L]) and 3 μg/dL (reference range, 15-40 μg/dL), respectively. The urine copper level was 1007 μg/d (reference range, 15-30 μg/d). T2-weighted brain magnetic resonance imaging revealed high signal intensity lesions in the basal ganglia and periaqueductal gray matter (Figure 2). Liver sonography showed a coarse echogenicity and tiny nodules suggestive of hepatic cirrhosis while liver enzyme and bilirubin levels were within normal limits and serological markers for hepatitis were negative. A liver biopsy was not performed.
Brain magnetic resonance images. Brain T2-weighted (A) and fluid-attenuated inversion recovery (B and C) images reveal bilateral hyperintensities in the basal ganglia (arrows [A]) and periaqueductal gray matter (C) (arrowhead). The dilatation of the fourth ventricle and a moderate degree of cerebellar atrophy are also evident (D).
The patient was treated orally with penicillamine (1000 mg/d) and zinc sulfate (65 mg/d). Vitamin B6 (50 mg/d) was given for the prophylaxis of penicillamine-induced pyridoxine deficiency. The treatment ameliorated the dystonic movement and improved the distal muscle weakness (MRC grade IV+/IV+) and the hypesthesia to vibration and position sense. The third NCS at 6 months after the treatment (at 1.5 years after the first evaluation) showed a clear improvement (Table).
Polyneuropathy in WD should be cautiously interpreted because penicillamine itself can be the cause of neuropathy7,8 and severe hepatic diseases are frequently associated with neuropathy.9 In our case, PN was present prior to the use of penicillamine, and there was only mild fatty liver with normal liver function at the time of diagnosis of PN. Polyneuropathy was improved clinically with penicillamine, zinc sulfate, and vitamin B6 administration, and the improvement was supported by serial electrophysiological studies. Therefore, PN in our patient seems to be a manifestation of WD itself. This report suggests that peripheral neuropathy, though uncommon, should raise the neurologist’s suspicion of WD in younger patients.
Polyneuropathy in WD has been rarely reported,3- 5 and, to our knowledge, pathological studies have been performed just in 2 studies.3,4 The widespread myelin loss with secondary axonal degeneration was documented in the peripheral nerves of the first autopsy case.3 However, 2 later reports4,5 suggested the axonal degeneration of the peripheral nerves in WD. The NCS in a patient with WD and PN, cerebellar ataxia, and hepatocellular carcinoma showed axonal degeneration, though autopsy showed only small areas of demyelination in the peripheral nerves.4 The electrophysiological study done in 3 patients with WD documented the axonal degeneration of the peripheral nerves.5 However, in these reports, significant liver disease existed at the time of recognition of PN and other potential causes of PN were not excluded. Furthermore, the response to penicillamine treatment was not tracked.
In our patient, the NCS showed that the initial features were demyelinating with prolonged distal and F-wave latencies and mildly slowed conduction velocities. Subsequent testing after 1 year showed worsening of the earlier mild demyelinating features in all nerves (conduction velocities less than 70% of the lower limit of normal, which meets standard criteria for a demyelinating neuropathy) with the addition of axonal features that were much milder in comparison. However, the electromyographic findings suggested axonal involvement given the active denervation potentials found as well as evidence of chronic denervation with reinnervation. Pathological examination demonstrated the destruction of the myelin sheath and axon. Wilson disease was likely to have a neuropathy of mixed type.
Similar pathological features can occur in chronic liver disease or other metabolic disorders.9- 11 However, the circumstances of our patient suggest that abnormal copper metabolism is directly or indirectly related to the occurrence of PN. Further studies are needed to disclose a plausible mechanism for abnormal copper metabolism causing a neuropathy with individual difference. Remarkably, penicillamine administration improved PN in our case, though penicillamine was frequently reported as a causative agent in the development of treatment-related neuropathy.7,8 Whether zinc sulfate or vitamin B6 treatment overcomes the detrimental effect of penicillamine or the “true” benefit of penicillamine exists remains to be clarified.
Correspondence: Beom S. Jeon, MD, PhD, Department of Neurology, Seoul National University Hospital, Yongon-dong 28, Chongno-gu, 110-744 Seoul, South Korea (firstname.lastname@example.org).
Accepted for Publication: November 2, 2004.
Author Contributions:Study concept and design: Jung, Ahn, and Jeon. Acquisition of data: Jung. Analysis and interpretation of data: Jung. Drafting of the manuscript: Jung. Critical revision of the manuscript for important intellectual content: Ahn and Jeon. Administrative, technical, and material support: Jung and Jeon. Study supervision: Jeon.
Jung K, Ahn T, Jeon BS. Wilson Disease With an Initial Manifestation of Polyneuropathy. Arch Neurol. 2005;62(10):1628-1631. doi:10.1001/archneur.62.10.1628