Wilson Disease with an Initial Manifestation of Polyneuropathy

OBSERVATION Wilson Disease With an Initial Manifestation of Polyneuropathy

Keun-Hwa Jung, MD; Tae-Beom Ahn, MD; Beom S. Jeon, MD, PhD

Background: Recognition of Wilson disease (WD) is Method: Personal observation. sometimes difficult because of its diverse manifestations. Peripheral neuropathy is rarely reported in the con- Result: A 17-year-old man, who was eventually diagnosed text of WD. with WD, was initially seen with polyneuropathy at least 6monthspriortodevelopingmoretypicalsymptomsofWD. Objective: To report an unusual patient with WD whose Electrophysiological and pathological studies suggested a initial manifestation was peripheral neuropathy. neuropathy of mixed type. Treatment for WD resulted in clinical and electrophysiological improvement. Design: Case report. Conclusion: Wilson disease may initially appear as a treat- able polyneuropathy. Setting: Neurology department in a tertiary referral center. Arch Neurol. 2005;62:1628-1631

ILSON DISEASE (WD) hands and feet. The symptoms began sev- is an autosomal re- eral months previously and worsened cessive disorder of gradually. He had no remarkable medical abnormal copper or family history of liver disease, psychiat- metabolism caused ric illness, or movement disorders. He was byW mutations in the ATP7B gene encod- not a habitual alcohol or drug abuser. He ing a putative copper-transporting P- was alert and oriented with intact cogni- type adenosine triphosphatase and usu- tive function. Cranial nerve examination re- ally manifests with progressive liver sults were normal. The abductor pollicis cirrhosis, neurologic impairment, and Kay- brevis, first dorsal interosseous, other in- ser-Fleischer rings and/or renal malfunc- 1,2 trinsic hand muscles, and toe and feet tion. Early recognition of the disease is muscles were weak (Medical Research important because there are effective treat- Council [MRC] grade IVϩ/IVϩ) bilater- ments and delayed diagnosis will lead to ally, while the power of the other muscles irreversible brain and liver damage. How- in the proximal arms and legs was nor- ever, WD may elude early recognition be- mal. Muscle bulk and tone were normal. cause of its diverse manifestations. Peripheral neuropathy has rarely been The sensory examination results for soft reported in the context of WD,3-5 and the touch, pain, temperature, vibration, and pathological findings of such an entity have proprioception were normal. Deep ten- not been clarified yet. We herein report a don reflexes were symmetrically de- patient with WD whose initial manifesta- creased in the biceps, triceps, knee, and tion was polyneuropathy (PN), which im- ankle. Ataxia, tremor, and gait abnormali- proved clinically and electrophysiologi- ties were not noted. cally with treatment of WD. A nerve conduction study (NCS) was Author Affiliations: performed using standard techniques6 of Department of Neurology and surface stimulation and recording (Nico- Clinical Research Institute, REPORT OF A CASE Seoul National University let Viking IV; Nicolet Biomedical Instru- Hospital (Drs Jung and Jeon), ments, Madison, Wis). Skin tempera- Kyung Hee University Hospital A 17-year-old man visited us because of in- tures were maintained higher than 32.0°C. (Dr Ahn), Seoul, South Korea. termittent paresthesia and weakness in both Distal motor latency, F-wave latency, mo-

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Parameter, Right Side Cutoff Value First NCS (0 y) Second NCS (1 y) Third NCS (1.5 y) DML, ms (% of ULN) Median nerve 3.5 (100) 4.7 (134.3) 5.2 (148.6) 4.2 (120.0) Ulnar nerve 2.6 (100) 3.4 (130.0) 5.1 (196.1) 3.9 (150.0) Peroneal nerve 4.9 (100) 5.0 (102.3) 6.4 (130.0) 4.5 (91.8) Posterior tibial nerve 5.4 (100) 5.0 (92.6) 5.2 (96.3) 4.5 (83.3) MNCV, ms (% of LLN) Median nerve 49 (100) 42 (85.7) 33 (67.3) 51 (104.1) Ulnar nerve 49 (100) 43 (87.8) 30 (61.2) 50 (102.0) Peroneal nerve 44 (100) 38 (86.4) 32 (72.7) 47 (106.8) Posterior tibial nerve 41 (100) 34 (82.9) 30 (73.2) 33 (80.5) CMAP, mV Median nerve 7.0 12.6 6.9 10.7 Ulnar nerve 8.0 15.5 7.8 12.3 Peroneal nerve 10.0 14.3 7.7 11.4 Posterior tibial nerve 4.0 6.5 4.4 7.6 F-wave latency Median nerve 24.9 27.0 28.6 27.4 Ulnar nerve 25.6 34.7 41.6 36.6 Peroneal nerve 43.9 57.0 63.5 62.3 Posterior tibial nerve 45.9 56.7 NP 65.6 SNCV, ms (% of LLN) Median nerve 50 (100) 33 (66.0) NP 42 (84.0) Ulnar nerve 50 (100) 29 (58.0) NP 35 (70.0) Sural nerve 40 (100) 29 (72.5) 25 (62.5) 35 (87.5) SNAP, µV Median nerve 12.0 15.8 NP 5.4 Ulnar nerve 20.0 13.2 NP 6.3 Sural nerve 10.0 27.4 4.3 7.8

Abbreviations: CMAP, compound muscle action potential; DML, distal motor latency; LLN, lower limit of normal; MNCV, motor nerve conduction velocity; NCS, nerve conduction study; NP, no potential; SNAP, sensory nerve action potential; SNCV, sensory nerve conduction velocity, ULN, upper limit of normal.

tor nerve conduction velocity, and compound motor ac- At least 6 months from the development of neuropa- tion potential were measured in the median, ulnar, pe- thy symptoms, dysarthria and involuntary movement in roneal, and posterior tibial nerves. Sensory nerve the right leg developed gradually. On the follow-up neu- conduction velocity and sensory nerve action potential rologic examination 1 year after the first evaluation, the were obtained in the median, ulnar, and sural nerves. Dis- patient showed slurred, somewhat hypokinetic, speech, tal motor latency and F-wave latency were prolonged in blepharospasm, dystonic posturing, abnormal co- the majority of motor nerves, and motor nerve conduc- contraction of limb muscles, and limb ataxia. The weak- tion velocity and sensory nerve conduction velocity were ness of both distal muscles was worse (MRC grade IV−/ slightly decreased. Compound motor action potential and IV−) with mild muscle wasting. Sensory examination sensory nerve action potential were relatively preserved showed hypesthesia to pain, temperature, vibration, and without conduction block or temporal slowing (Table). position sense in the hands and feet. The NCS was fol- Electromyography showed positive sharp waves in the lowed up by the same examiner with the same protocol. abductor pollicis brevis, first dorsal interosseous, and tibi- Subsequent testing showed worsening of the earlier elec- alis anterior muscles with giant motor unit potentials and trophysiological abnormalities (Table). Slitlamp exami- reduced interference patterns. Nerve biopsy results nation showed Kayser-Fleischer rings. Serum copper and showed a destruction of the myelin sheath associated with ceruloplasmin levels were 18 µg/dL (2.83 µmol/L) (ref- axonal damage (Figure 1). erence range, 70-155 µg/dL [10.99-24.34 µmol/L]) and Hemoglobin A1C, aspartate aminotransferase and ala- 3 µg/dL (reference range, 15-40 µg/dL), respectively. The nine aminotransferase, bilirubin, coagulation factors, iron urine copper level was 1007 µg/d (reference range, 15-30 and ferritin, vitamin B12, folate, thyroid hormone, and µg/d). T2-weighted brain magnetic resonance imaging re- immunoelectrophoresis test result values were within vealed high signal intensity lesions in the basal ganglia normal limits. Cerebrospinal fluid was acellular with nor- and periaqueductal gray matter (Figure 2). Liver sonog- mal protein and glucose levels. Rheumatoid factor and raphy showed a coarse echogenicity and tiny nodules sug- anti–double-stranded, antinuclear, and anti–smooth gestive of hepatic cirrhosis while liver enzyme and bili- muscle antibodies were absent. Abdominal sonography rubin levels were within normal limits and serological showed mild fatty liver. The patient was diagnosed with markers for hepatitis were negative. A liver biopsy was sensorimotor PN of undetermined cause and was fol- not performed. lowed up with amitriptyline hydrochloride and multivi- The patient was treated orally with penicillamine (1000 tamin administration. mg/d) and zinc sulfate (65 mg/d). Vitamin B6 (50 mg/d)

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C D C D

Figure 1. Pathological examination of the left sural nerve. A, There is no Figure 2. Brain magnetic resonance images. Brain T2-weighted (A) and inflammatory cell infiltration (hematoxylin-eosin, original magnification fluid-attenuated inversion recovery (B and C) images reveal bilateral ϫ100). B, Photograph shows high-magnification views of a fascicle in the hyperintensities in the basal ganglia (arrows [A]) and periaqueductal gray longitudinal section (Luxol fast blue, original magnification ϫ400). The matter (C) (arrowhead). The dilatation of the fourth ventricle and a moderate myelinated fibers appear normal except for a single fiber (arrowhead), which degree of cerebellar atrophy are also evident (D). 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 though autopsy showed only small areas of demyelin- damage (arrows). ation in the peripheral nerves.4 The electrophysiological study done in 3 patients with WD documented the axonal degeneration of the peripheral nerves.5 How- was given for the prophylaxis of penicillamine-induced ever, in these reports, significant liver disease existed at pyridoxine deficiency. The treatment ameliorated the dys- the time of recognition of PN and other potential causes tonic movement and improved the distal muscle weak- of PN were not excluded. Furthermore, the response to ness (MRC grade IVϩ/IVϩ) and the hypesthesia to vi- penicillamine treatment was not tracked. bration and position sense. The third NCS at 6 months In our patient, the NCS showed that the initial fea- after the treatment (at 1.5 years after the first evalua- tures were demyelinating with prolonged distal and F- tion) showed a clear improvement (Table). wave latencies and mildly slowed conduction velocities. Subsequent testing after 1 year showed worsening of the COMMENT earlier mild demyelinating features in all nerves (conduction velocities less than 70% of the lower limit of nor- Polyneuropathy in WD should be cautiously inter- mal, which meets standard criteria for a demyelinating preted because penicillamine itself can be the cause of neuropathy) with the addition of axonal features that were neuropathy7,8 and severe hepatic diseases are frequently much milder in comparison. However, the electromyo- associated with neuropathy.9 In our case, PN was pre- graphic findings suggested axonal involvement given the sent prior to the use of penicillamine, and there was only active denervation potentials found as well as evidence mild fatty liver with normal liver function at the time of of chronic denervation with reinnervation. Pathological diagnosis of PN. Polyneuropathy was improved clini- examination demonstrated the destruction of the my- cally with penicillamine, zinc sulfate, and vitamin B6 ad- elin sheath and axon. Wilson disease was likely to have ministration, and the improvement was supported by se- a neuropathy of mixed type. rial electrophysiological studies. Therefore, PN in our Similar pathological features can occur in chronic patient seems to be a manifestation of WD itself. This re- liver disease or other metabolic disorders.9-11 However, port suggests that peripheral neuropathy, though un- the circumstances of our patient suggest that abnormal common, should raise the neurologist’s suspicion of WD copper metabolism is directly or indirectly related to in younger patients. the occurrence of PN. Further studies are needed to dis- Polyneuropathy in WD has been rarely reported,3-5 and, close a plausible mechanism for abnormal copper to our knowledge, pathological studies have been per- metabolism causing a neuropathy with individual dif- formed just in 2 studies.3,4 The widespread myelin loss ference. Remarkably, penicillamine administration with secondary axonal degeneration was documented in improved PN in our case, though penicillamine was fre- the peripheral nerves of the first autopsy case.3 How- quently reported as a causative agent in the develop- ever, 2 later reports4,5 suggested the axonal degenera- ment of treatment-related neuropathy.7,8 Whether zinc tion of the peripheral nerves in WD. The NCS in a pa- sulfate or vitamin B6 treatment overcomes the detrimen- tient with WD and PN, cerebellar ataxia, and tal effect of penicillamine or the “true” benefit of peni- hepatocellular carcinoma showed axonal degeneration, cillamine exists remains to be clarified.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Accepted for Publication: November 2, 2004. 3. Miyakawa T, Murayama E, Sumiyoshi S, Deshimaru M, Miyakawa K. A biopsy Correspondence: Beom S. Jeon, MD, PhD, Department case of Wilson’s disease: pathological changes in peripheral nerves. Acta Neu- ropathol (Berl). 1973;24:174-177. of Neurology, Seoul National University Hospital, Yongon- 4. Madden JW, Ironside JW, Triger DR, Bradshaw JP. An unusual case of Wilson’s dong 28, Chongno-gu, 110-744 Seoul, South Korea (brain disease. Q J Med. 1985;55:63-73. @snu.ac.kr). 5. Leven B, Fasshauer K. Lesions of the peripheral nerves in Wilson’s disease: Author Contributions: Study concept and design: Jung, electrodiagnostic findings. Fortschr Neurol Psychiatr Grenzgeb. 1978;46:202- Ahn, and Jeon. Acquisition of data: Jung. Analysis and in- 206. 6. Oh SJ. Clinical Electromyography—Nerve Conduction Studies. 2nd ed. Balti- terpretation of data: Jung. Drafting of the manuscript: Jung. more, Md: Williams & Wilkins; 1993. Critical revision of the manuscript for important intellec- 7. Lee AH, Lawton NF. Penicillamine treatment of Wilson’s disease and optic tual content: Ahn and Jeon. Administrative, technical, and neuropathy. J Neurol Neurosurg Psychiatry. 1991;54:746. material support: Jung and Jeon. Study supervision: Jeon. 8. Pedersen PB, Hogenhaven H. Penicillamin-induced neuropathy in rheumatoid arthritis. Acta Neurol Scand. 1990;81:188-190. 9. Chaudhry V, Corse AM, O’Brian R, Cornblath DR, Klein AS, Thuluvath PJ. Auto- REFERENCES nomic and peripheral (sensorimotor) neuropathy in chronic liver disease: a clinical and electrophysiologic study. Hepatology. 1999;29:1698-1703. 1. Schilsky ML. Diagnosis and treatment of Wilson’s disease. Pediatr Transplant. 10. Krarup C, Crone C. Neurophysiological studies in malignant disease with par- 2002;6:15-19. ticular reference to involvement of peripheral nerves J Neurol. 2002;249:651- 2. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease is 661. a putative copper transporting P-type ATPase similar to the Menkes gene. Nat 11. Bolton CF, McKeown MJ, Chen R, Toth B, Remtulla H. Subacute uremic and dia- Genet. 1993;5:327-337. betic polyneuropathy. Muscle Nerve. 1997;20:59-64.

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