Treatment Ideally, treatment should be started before the appearance of neurologic signs; if this can be implemented, neurologic deterioration can be prevented to a large extent. Treatment consists of (1) reduction of dietary copper to less than 1 mg/d, which can usually be accomplished by avoidance of copper-rich foods (liver, mushrooms, cocoa, chocolate, nuts, and shellfish), and (2) administration of the copper chelating agent d-penicillamine (1 to 3 g/d) by mouth, in divided doses. Pyridoxine 25 mg/d should be added in order to prevent anemia. The use of d- penicillamine is associated with a number of problems. Sensitivity reactions to the drug (rash, arthralgia, fever, leukopenia) develop in 20 percent of patients and require a temporary reduction of dosage or a course of prednisone to bring them under control. Reinstitution of drug therapy should then be undertaken, using low dosages (250 mg daily) and, later, small, widely spaced increases. If the patient is still sensitive to d-penicillamine or if severe reactions (lupus-like or nephrotic syndromes or myasthenia gravis) occur, the drug should be discontinued and another chelating agent, triethylene tetramine (trientine) or ammonium tetrathiomolybdate may be substituted. Zinc, which blocks the intestinal absorption of copper, is also a suitable treatment, but ineffective alone. It is given as zinc acetate, 100 to 150 mg daily in 3 to 4 divided doses at least 1 h before meals (Hoogenraad et al). The appropriate drug must then be continued for the patient’s lifetime. Some women report improvement in neurologic symptoms during pregnancy, although there is no apparent change in copper metabolism during this time. In most patients, neurologic signs improve in response to decoppering agents. The Kayser-Fleischer rings disappear and liver function tests may return to normal, although the abnormalities of copper metabolism remain unchanged. In moderately severe and advanced cases, clinical improvement may not begin for several months despite full doses of d-penicillamine, and it is important to resist discontinuing the drug during this latent period.
It is also well known that the institution of treatment with penicillamine may induce an abrupt worsening of neurologic signs, and we have witnessed several such instances, including one that culminated fatally from a cardiac arrhythmia. Furthermore, in many of these patients, the lost function is never retrieved. Presumably this deterioration is a result of the rapid mobilization of copper from the liver and its redistribution to the brain. The slow introduction of penicillamine may avoid this complication. The additional use of zinc or one of the newer agents mentioned above should be instituted as soon as neurologic deterioration becomes evident. In at least one reported case, new lesions of Wilson disease (shown by MRI) developed while the patient was receiving full doses of d-penicillamine and excellent decoppering of the liver had occurred (Brewer et al). In the few patients who develop seizures, they may become apparent soon after therapy is begun.
Many wilsonian patients with advanced liver disease have been subjected to liver transplantation, which is curative for the underlying metabolic defect. The degree of neurologic improvement varies; in some it has been remarkable and sustained, confirming that the hepatic defect is primary and that the brain is involved secondarily. According to Schilsky and coworkers, the main indication for transplantation is severe and progressive liver damage, but the operation has been used successfully in some patients with intractable neurologic deterioration and only mild signs of liver disease.