Recognition and Treatment of Neurologic Wilson's Disease
Recognition and Treatment of Neurologic Wilson's Disease
Wilson's disease is a condition that can be effectively treated. Unfortunately, the average time from symptom onset to treatment is long, ~ 12 months. Diagnostic delay appears clinically significant as treatment outcomes have been demonstrated to be better in those with a short diagnostic delay. Free copper is toxic whereas copper bound to ceruloplasmin or metallothionein is not, thus the aim of treatment is to reduce the amount of toxic-free copper. Treatment can be divided into initial therapy, maintenance therapy, and treatment of the presymptomatic patient. Available pharmacologic agents include penicillamine, trientine, and zinc acetate. Tetrathiomolybdate has also been used, but is not approved by the Food and Drug Administration (FDA).
Neurologic worsening following initiation of penicillamine therapy is a concern. The risk of neurologic worsening may be as high as ~ 50% when penicillamine is used as initial treatment of neurologic Wilson's disease, and 50% of those who deteriorate never recover to their prepenicillamine baseline. It has been suggested that mobilization of large hepatic copper stores raise blood free-copper levels leading to increased toxic copper exposure to the brain, and subsequent worsening.
Because of concern for neurologic worsening in those treated with penicillamine, use of other agents have been recommended for initial treatment of neurologic Wilson's disease. If penicillamine is used, the standard starting dose is 250 mg four times a day, or 500 mg twice a day. It has been suggested that starting with lower doses, 250 to 500 mg per day for a few weeks may lessen side effects. When initiated, the patient should be carefully monitored for toxicities, including to the bone marrow and kidney. An acute hypersensitivity reaction occurs in ~ 25% of patients, which may respond to corticosteroid therapy or withdrawal of the drug and readministration in very low doses.
Trientine is a chelator that like penicillamine promotes urinary excretion of copper and causes neurologic worsening in ~ 25%. Trientine is used in doses of 500 to 1,500 mg for initial therapy and 500 mg to 1000 mg for maintenance therapy, divided into two or three times per day dosing. It should be given 1 hour before or 2 hours after meals.
While on trientine, urine copper is a reflection of enhanced urinary copper excretion and total body copper load. Upon initial treatment with trientine, 24-hour urinary copper excretion may be 1000 to 3000 μg (normal 20–50 μg/24 h). After a few weeks, urinary copper decreases to 500 to 1000 μg per 24 hours, and after ~ 1 year of therapy levels should decrease to 200 to 500 μg per 24 hours. Nonceruloplasmin-bound copper, free copper, is a useful measure for monitoring efficacy of trientine and can be calculated by the formula: (Total serum copper in μg/mL) × 100 - (ceruloplasmin in mg/dL × 3) = free copper (normal range is 5–15 μg/dL). Another way that free copper can be accurately estimated is by subtracting 3 μg for every 1 mg/dL of ceruloplasmin from the serum copper, expressed as μg/dL. During the maintenance phase of trientine therapy, a free copper below 25 mg is the goal.
Zinc acetate therapy has been used successfully as preventative therapy in presymptomatic patients as initial treatment for neurologic Wilson's disease, and as maintenance therapy following an initial course of decoppering. Zinc induces intestinal cell metallothionein, a protein that complexes intestinal food copper or endogenously secreted copper in saliva and gastric secretions. The complex is not able to be absorbed into the blood and as intestinal cells die, they along with the complex are sloughed into the stool resulting in a negative copper balance. The net effect of zinc therapy is an intestinal blockade of zinc absorption.
The decoppering effect of zinc is slow. A period of 4 to 8 months of treatment is required to reduce copper to nontoxic levels. In symptomatic individuals, the natural course of the disease continues during this period and can lead to permanent worsening. To avoid potential toxicities of trientine and penicillamine, some have successfully used zinc in the initial treatment of neurologic Wilson's disease. An advantage of zinc is its lack of serious significant side effects and safety in long-term use. Approximately 10% experience gastric discomfort or nausea upon initiation of zinc therapy. The use of zinc acetate compared with zinc sulfate reduces gastric discomfort. Generally, gastric symptoms subside within days to weeks. For maintenance and prophylactic therapy in adults, 50 mg of zinc three times a day is recommended. It is important to separate the zinc from food by at least an hour. For maintenance therapy, zinc is favored over penicillamine or trientine because although all three drugs are effective, zinc has a superior side-effect profile and does not appear to be cause neurologic worsening. Because zinc therapy does not induce urinary excretion of copper, as do trientine or penicillamine, urine copper is an accurate reflection of body copper stores. Following a year of zinc therapy, a 24-hour copper of ~50 to 100 μg is a reflection of good copper control. Compliance with zinc can be assessed by monitoring 24-hour urine zinc excretion, which should be above 2 mg.
For the initial treatment of patients presenting with neurologic or psychiatric disease, the use of TM followed by zinc maintenance therapy has been suggested to provide a good best balance of efficacy and side effects, but TM is not yet FDA approved.
In patients who present with liver disease, if the disease if fulminant, hepatic transplant may be the only way to save the patient's life. However, in cases of mild hepatic failure, a picture of chronic cirrhosis or a picture of mild hepatitis, medical treatment can be quite effective. Orthotopic liver transplant is not recommended as a treatment for neurologic Wilson's disease.
In those studies reporting on the effect of treatment, the largest degree of improvement was observed between 6 months and 2 years of adequate copper control, with some benefit reported to occur for up to 3 years. The response to treatment is variable. Those who do not respond to treatment tend to have a more severe neurologic disease, with more frequent dysarthria and dystonia. Tremor is generally more treatment responsive than dystonia and dysarthria.
Symptomatic treatment of the movement disorders found in Wilson's patients has not been carefully studied and response to treatment is inconsistent. L-Dopa and dopamine agonists do not appear to provide reliable relief of parkinsonism. β-blockers and primidone, medications used to treat essential tremor, can be tried in those with limiting essential tremor-like tremor, but their benefit is limited. Artane, baclofen, and valium can be used in symptomatic therapy of dystonia. Speech and physical therapy can provide a great deal of benefit. Psychiatric manifestations of Wilson's disease also have a variable response to treatment.
Over the years, considerable attention has been paid to diet in Wilson's disease. In the United States, only liver and shellfish are high enough in copper to be of concern. Because animals are fed high levels of minerals, the liver can be very high in copper and should not be ingested during the decoppering period and after that only in small amounts. Shellfish are intermediately high in copper and should not be ingested during the decoppering period and not ingested more often than once a week during maintenance therapy. Other foods are not restricted because the content of copper is not high enough to be of concern. Occasionally, drinking water samples will be found to be high in copper. If the level is higher than ~0.1 ppm the patient should use an alternative source of drinking water.
Treatment
Wilson's disease is a condition that can be effectively treated. Unfortunately, the average time from symptom onset to treatment is long, ~ 12 months. Diagnostic delay appears clinically significant as treatment outcomes have been demonstrated to be better in those with a short diagnostic delay. Free copper is toxic whereas copper bound to ceruloplasmin or metallothionein is not, thus the aim of treatment is to reduce the amount of toxic-free copper. Treatment can be divided into initial therapy, maintenance therapy, and treatment of the presymptomatic patient. Available pharmacologic agents include penicillamine, trientine, and zinc acetate. Tetrathiomolybdate has also been used, but is not approved by the Food and Drug Administration (FDA).
Neurologic worsening following initiation of penicillamine therapy is a concern. The risk of neurologic worsening may be as high as ~ 50% when penicillamine is used as initial treatment of neurologic Wilson's disease, and 50% of those who deteriorate never recover to their prepenicillamine baseline. It has been suggested that mobilization of large hepatic copper stores raise blood free-copper levels leading to increased toxic copper exposure to the brain, and subsequent worsening.
Because of concern for neurologic worsening in those treated with penicillamine, use of other agents have been recommended for initial treatment of neurologic Wilson's disease. If penicillamine is used, the standard starting dose is 250 mg four times a day, or 500 mg twice a day. It has been suggested that starting with lower doses, 250 to 500 mg per day for a few weeks may lessen side effects. When initiated, the patient should be carefully monitored for toxicities, including to the bone marrow and kidney. An acute hypersensitivity reaction occurs in ~ 25% of patients, which may respond to corticosteroid therapy or withdrawal of the drug and readministration in very low doses.
Trientine is a chelator that like penicillamine promotes urinary excretion of copper and causes neurologic worsening in ~ 25%. Trientine is used in doses of 500 to 1,500 mg for initial therapy and 500 mg to 1000 mg for maintenance therapy, divided into two or three times per day dosing. It should be given 1 hour before or 2 hours after meals.
While on trientine, urine copper is a reflection of enhanced urinary copper excretion and total body copper load. Upon initial treatment with trientine, 24-hour urinary copper excretion may be 1000 to 3000 μg (normal 20–50 μg/24 h). After a few weeks, urinary copper decreases to 500 to 1000 μg per 24 hours, and after ~ 1 year of therapy levels should decrease to 200 to 500 μg per 24 hours. Nonceruloplasmin-bound copper, free copper, is a useful measure for monitoring efficacy of trientine and can be calculated by the formula: (Total serum copper in μg/mL) × 100 - (ceruloplasmin in mg/dL × 3) = free copper (normal range is 5–15 μg/dL). Another way that free copper can be accurately estimated is by subtracting 3 μg for every 1 mg/dL of ceruloplasmin from the serum copper, expressed as μg/dL. During the maintenance phase of trientine therapy, a free copper below 25 mg is the goal.
Zinc acetate therapy has been used successfully as preventative therapy in presymptomatic patients as initial treatment for neurologic Wilson's disease, and as maintenance therapy following an initial course of decoppering. Zinc induces intestinal cell metallothionein, a protein that complexes intestinal food copper or endogenously secreted copper in saliva and gastric secretions. The complex is not able to be absorbed into the blood and as intestinal cells die, they along with the complex are sloughed into the stool resulting in a negative copper balance. The net effect of zinc therapy is an intestinal blockade of zinc absorption.
The decoppering effect of zinc is slow. A period of 4 to 8 months of treatment is required to reduce copper to nontoxic levels. In symptomatic individuals, the natural course of the disease continues during this period and can lead to permanent worsening. To avoid potential toxicities of trientine and penicillamine, some have successfully used zinc in the initial treatment of neurologic Wilson's disease. An advantage of zinc is its lack of serious significant side effects and safety in long-term use. Approximately 10% experience gastric discomfort or nausea upon initiation of zinc therapy. The use of zinc acetate compared with zinc sulfate reduces gastric discomfort. Generally, gastric symptoms subside within days to weeks. For maintenance and prophylactic therapy in adults, 50 mg of zinc three times a day is recommended. It is important to separate the zinc from food by at least an hour. For maintenance therapy, zinc is favored over penicillamine or trientine because although all three drugs are effective, zinc has a superior side-effect profile and does not appear to be cause neurologic worsening. Because zinc therapy does not induce urinary excretion of copper, as do trientine or penicillamine, urine copper is an accurate reflection of body copper stores. Following a year of zinc therapy, a 24-hour copper of ~50 to 100 μg is a reflection of good copper control. Compliance with zinc can be assessed by monitoring 24-hour urine zinc excretion, which should be above 2 mg.
For the initial treatment of patients presenting with neurologic or psychiatric disease, the use of TM followed by zinc maintenance therapy has been suggested to provide a good best balance of efficacy and side effects, but TM is not yet FDA approved.
In patients who present with liver disease, if the disease if fulminant, hepatic transplant may be the only way to save the patient's life. However, in cases of mild hepatic failure, a picture of chronic cirrhosis or a picture of mild hepatitis, medical treatment can be quite effective. Orthotopic liver transplant is not recommended as a treatment for neurologic Wilson's disease.
In those studies reporting on the effect of treatment, the largest degree of improvement was observed between 6 months and 2 years of adequate copper control, with some benefit reported to occur for up to 3 years. The response to treatment is variable. Those who do not respond to treatment tend to have a more severe neurologic disease, with more frequent dysarthria and dystonia. Tremor is generally more treatment responsive than dystonia and dysarthria.
Symptomatic treatment of the movement disorders found in Wilson's patients has not been carefully studied and response to treatment is inconsistent. L-Dopa and dopamine agonists do not appear to provide reliable relief of parkinsonism. β-blockers and primidone, medications used to treat essential tremor, can be tried in those with limiting essential tremor-like tremor, but their benefit is limited. Artane, baclofen, and valium can be used in symptomatic therapy of dystonia. Speech and physical therapy can provide a great deal of benefit. Psychiatric manifestations of Wilson's disease also have a variable response to treatment.
Over the years, considerable attention has been paid to diet in Wilson's disease. In the United States, only liver and shellfish are high enough in copper to be of concern. Because animals are fed high levels of minerals, the liver can be very high in copper and should not be ingested during the decoppering period and after that only in small amounts. Shellfish are intermediately high in copper and should not be ingested during the decoppering period and not ingested more often than once a week during maintenance therapy. Other foods are not restricted because the content of copper is not high enough to be of concern. Occasionally, drinking water samples will be found to be high in copper. If the level is higher than ~0.1 ppm the patient should use an alternative source of drinking water.
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