Unilateral rubral tremors in Wilson's disease treated with dimercaprol.

Tremors are reported as the most frequent neurological manifestation of Wilson's disease (WD) in some series. Postural tremors, rest tremors, action tremors and wing-beating (rubral) tremors are the different types of tremors seen in WD. We report a patient of WD with unilateral rubral tremors refractory to 1-year therapy with Penicillamine and anti-tremor medications. The tremors decreased considerably after adding chelation therapy with dimercaprol. Combination of Penicillamine and dimercaprol is an effective decoppering measure in rubral tremors of WD.

Introduction

Tremors, dysarthria, dystonia, Parkinsonism and gait disturbances are the common neurological manifestations of Wilson's disease (WD). In some series tremors are reported as the most frequent neurological manifestation of WD[1] Postural tremors, rest tremors, action tremors and wing-beating (rubral) tremors are the different types of tremors seen in WD.[12] We report a patient of WD with unilateral rubral tremors refractory to Penicillamine and anti-tremor medications. The tremors decreased considerably after chelation therapy with dimercaprol.

Case Report

A 22-year-old right-handed man working in a motor rewinding company presented with tremor of right upper limb since 1 year. The tremor began distally in the right upper limb and progressed over 2 months to involve wrist and elbow. The tremors gradually increased in severity over the next few months and he was unable to work. Examination revealed a Kayser Fleischer (K-F) ring. There were high amplitude postural tremors with flexion extension at wrist. Tremor markedly exacerbated on outstretching of hands and action. In the shoulder abducted and elbow flexed posture wing-beating tremors with upward and downward movement of forearm were seen. The tremors disappeared completely at rest [see video 1 segment 1].

Serum ceruloplasmin levels were 5.16 mg/dl (10-20 mg/dl). Twenty-four-hour urinary copper levels were 756 μg. Magnetic resonance imaging scan of brain showed typical features of Wilson's disease [see Figure 1].

Figure 1

Axial T2 image of MRI Brain showing face of giant panda sign typical of Wilson's disease

He was started on chelation therapy with 250 mg of D-Penicillamine twice a day. Zinc was given in the dose of 200 mg three times a day. Penicillamine was gradually increased to 2 g/day in two divided doses administered in fasting and continued for 1 year. Compliance was closely monitored. Symptomatic anti-tremor therapy with clonazepam, primidone, trihexphenidyl was given. One year after chelation therapy with Penicillamine and symptomatic therapy the tremors persisted. Hence it was decided to give alternative chelation therapy. British antilewisite (BAL, 2, 3 dimercaprol) in dose of 5 mg/kg bolus dose followed by 2.5 mg/kg for 14 days was given intramuscularly along with penicillamine. One month later tremors reduced significantly and the patient was able to function normally [see video 1 segment 2].

Discussion

Rubral tremors in WD can be refractory to chelation with penicillamine and symptomatic anti-tremor treatment. Our patient received penicillamine 2 g/day for 1 year. Tremors persisted after 1 year of penicillamine therapy and he could not function due to the tremors. Hence we decided to use alternative chelation therapy. Trientine, tetrathiomolybdate, dimercaprol are other chelation therapies for WD.[3] Trientine and tetrathiomolybdate are not freely available in India. Hence a combination of dimercaprol which is easily available and penicillamine was given. After a 2-week course of dimercaprol the tremors decreased significantly. Penicillamine in the dose of 1 g/day was continued after dimercaprol therapy. He has minimal tremors and is able to work at 3 months of follow-up after dimercaprol therapy.

Dimercaprol was designed by a team of workers in Oxford as an antidote to arsenical war gas lewisite. Cumings hypothesized that BAL might arrest the progress of WD.[34] Therapy with dimercaprol is effective but the deep intramuscular injections are painful, may not be tolerated and with repeated courses the chelating effect decreases. Hence, oral-chelating agent penicillamine which is well tolerated and effective is favored. Adverse effects with penicillamine though uncommon are serious like SLE and nephropathy. Some patients continue to progress on penicillamine and in these patients a course with dimercaprol can induce remission of symptoms. Intensive therapy with dimercaprol has been used in severely dystonic patients of WD. Conventional chelation with penicillamine can then be continued. Thalamotomy and deep brain stimulation (DBS) have been tried in cases of refractory tremors in WD. A course of dimercaprol with penicillamine is much cheaper than and as effective as thalamotomy or DBS.

Conclusions

Wing-beating tremors in WD may be refractory to Penicillamine therapy. Combination of Penicillamine and dimercaprol is effective in rubral tremors of WD.