Dr. Rahul Chakor Neurologist
Special Interest in Neuroimmunology, Epilepsy

Introduction

Recognition of Wilson disease is credited to S. A. Kinnier Wilson who documented a detailed report on the clinical and pathologic changes of this disease. Wilson disease (WD) is a inherited disease of copper metabolism. It is important to consider WD in any patient with parkinsonism or rest tremor before 40 years of age because WD is a treatable disease and fatal if untreated. The prevalence is 1–3/100,000.

Symptoms

The presentation could be hepatic, neurologic, hematologic or musculoskeletal. The neurologic presentation is discussed here. The presentation of WD is variable and no two patients of WD are similar. This variability of presentation leads to a delay in diagnosis. Hence a high index of suspicion is must for diagnosing WD. Most cases of neurological WD present with slurred speech and a movement disorder in adolescence, often in association with behavioral disturbances. Approximately half of all cases present with neuropsychiatric symptoms, usually between 14 and 20 years of age.

Extrapyramidal manifestation usually a Parkinsonian syndrome is the dominant presentation of WD. Seizures, cognitive disturbance, behavioral problems weakness is also reported. In the ‘pseudosclerotic’ neurological variant the onset is with wing-beating tremor and some ataxia and dysarthria. Akinetic-rigid Parkinsonian syndrome with some dystonia dominates in most patients. Early gait abnormalities are frequent and a mixed movement disorder is common. Change in handwriting and deterioration of school or work performance could be an early symptom of WD. A risus sardonicus with dull look, drooling of saliva, Wilsonian smile and pseudobulbar palsy is commonly seen in advanced cases. Dysarthria is the most common sign, whereas chorea and athetosis affect few patients. All patients with WD presenting with neurological dysfunction have Kayser–Fleischer (K-F) rings on slit-lamp examination. These are caused by copper deposition on the inner surface of the cornea in Descemet’s membrane and have a golden brown or greenish appearance.

Psychiatric symptoms are prominent in WD. These are hyperkinetic behavior, irritability or anger, emotional lability, psychosis, mania, difficulty concentrating, abnormal behavior, personality changes, depression, schizophrenia, intellectual decline. Sometimes these can be a presenting symptom of WD.

Pathogenesis and pathology

Mutation in ATP7B a copper transport protein leads to accumulation of copper in hepatocytes which later spills into the circulation and leads to deposition of copper in various organs notably brain and liver. Excess copper in these organs leads to free radical damage and is responsible for the symptoms of WD.

Diagnosis

Parkinsonism, dystonia or a tremor in an adolescent or young adult with slurred speech should always raise the possibility of WD. A slit lamp examination should be done for KF ring. A low serum ceruloplasmin level is diagnostic of WD K-F rings are present. Urinary copper is elevated in WD. An excretion rate greater than 100 µg/24 hours is diagnostic but levels above 40 µg/24 hours are also significant in a neurological presentation. Brain MRI may show high signal abnormalities on T2 weighted images and low intensity lesions on T1 in the putamen, globus pallidus, thalamus, midbrain, pons and cerebellum. The classic sign of WD on MRI is called as face of the giant Panda sign. White matter abnormalities are also common and cortical atrophic changes may also occur.

Once WD is diagnosed, screening of all first degree relatives for KF ring, serum ceruloplasmin and urinary copper excretion is essential.

Treatment

Chelation therapy is effective if started early, hence the importance of early diagnosis. The various copper chelators available are (BAL) dimercaprol, trientene, tetrathiomolybdate, penicillamine. WD is a disease of copper deposition hence chocolate, liver, nuts, mushrooms and shellfish which contain high levels of copper are avoided in the diet.

Paradoxical worsening of neurological symptoms can occur on initiation of chelation therapy. In these cases very gradual increase in dose is recommended as per the patients neurological condition and tolerance.

For patients with hepatic disease who deteriorate on medical therapy liver transplantation can be life-saving. For refractory or deteriorating neurological disability despite other treatments, a course of intramuscular BAL injections is worth trying. Liver transplantation can be tried for patients with progressive neurological impairment despite adequate chelation.