Abstract

INTRODUCTION

Wilson disease is a metabolic disorder involving copper metabolism and is associated with abnormal liver functions. It occurs more frequently in males and usually between the ages of 6 and 20 years. Neuropsychiatric and behavioral disturbances are commonly reported in patients with Wilson's disease with lifetime prevalence estimated to be in the range of 20-100%.[1,2] The most common psychiatric manifestations in patients with Wilson's disease include sudden and changeable mood swings, anger outbursts, personality changes, depression, anxiety and cognitive impairment.[1,2]

Compared to other psychiatric manifestations, psychotic disorders are less commonly reported. In the initial description of 12 cases of the disease, Wilson described presence of schizophrenia-like psychosis in two of his cases.[3] However, over the years the accumulating data suggests that prevalence of schizophreniform disorders, catatonia, and hallucinations in patients with Wilson's disease are similar to that seen in the general population.[4,5] However, the prevalence of psychosis and catatonia is higher in patients with neurological manifestations of Wilson's disease.[6]

Most of the literature, describing psychiatric manifestations in patients with Wilson's disease is limited to young adults, with occasional case series/reports describing psychiatric manifestations in children and adolescents.[7,8] In this report, we present the case of a boy who developed psychotic features, within few days of being diagnosed with Wilson's Disease and review the existing literature with respect to psychosis in patients with Wilson's disease.

CASE REPORT

A 12-year-old boy presented to the hospital with symptoms of abdominal distension associated with dull aching continuous pain for 1 month. About a week following the onset of pain in the abdomen, parents noticed changes in the patient's behavior. He developed irritability, delusion of reference, delusion of persecution associated with marked dysfunction in the form of refusal to attend school, secondary to the psychotic symptoms. Over the next few days, the psychotic symptoms became more pervasive and systematized; following which he was found to keep all his belonging under lock and key. Additionally he developed lability of mood and reduced appetite. All these symptoms were not associated with any altered sensorium, hallucinations in any modality, thought disorder, depressive cognitions, cognitive disturbances, head injury or substance abuse. There was no family history of any psychiatric illness and developmental milestones were reportedly normal.

He was brought to the hospital primarily for the continuous abdominal pain. During the initial evaluation, his routine investigations in the form of hemogram, renal function test and liver function test did not reveal any abnormality. However, ultrasound examination of the abdomen revealed parenchymal liver disease with portal hypertension and ascites. In view of the evidence of parenchymal liver disease, serum ceruloplasmin was estimated and was found to be low, that is, 8.1 mcg/dl (normal range 25-63 ug/dl). Serum copper level and total urine copper level were also estimated, reports of which were consistent with a diagnosis of Wilson's disease. Slit lamp examination of the eyes showed the presence of Kayser–Fleischer ring. On the basis of clinical manifestations and laboratory findings, a diagnosis of Wilson's disease was made. He was started on tab penicillamine 250 mg along with zinc acetate 150 mg/day. After a week, tab penicillamine was increased to 500 mg/day, with which his psychiatric symptoms worsened. In addition to the above-mentioned symptoms, the child became very agitated and disinhibited. The abnormal behavior led to the admission into the hepatology unit of the Institute, and psychiatric consultation was sought.

On mental status examination, the boy was found to be conscious and oriented to time, place and person. He had psychomotor agitation, was anxious and fearful. He expressed delusion of reference and persecution. In view of the clinical picture, a diagnosis of organic delusional disorder (F06.2) due to Wilson's disease was considered. As there was some evidence for an increase in psychotic symptoms after increasing the dose of penicillamine, the dose of same was reduced to 250 mg/day. However, this did not lead to abatement of psychotic symptoms and required use of tab risperidone 1 mg/day, with which, within a week the psychotic symptoms resolved, and he was discharged from the hospital.

DISCUSSION

Wilson's disease is an autosomal recessive genetic disorder that is caused by the mutation of the ATP7B gene.[9] This results in abnormalities of copper metabolism and accumulation of copper in various tissues. The disease primarily affects the liver and the central nervous system. The hepatic presentation may be in the form of elevated transaminase levels, chronic hepatitis or cirrhosis; while neurological manifestations may be in the form of tremors, choreiform movements, dysarthria, gait disturbances, etc.

Psychiatric manifestations are common with Wilson's disease and occur in 20-100% of the cases.[1,2,5,10] The psychiatric manifestations span a range of diagnostic entities and most commonly include affective and personality changes.[2] Psychosis and cognitive impairment are other less common forms of presentation.[2] These manifestations are common in the adolescent and well as adult age groups. Patients with primarily hepatic disease usually present earlier than those with neurological disease.[11] The psychiatric manifestations are common at the initial presentation of the disease but seldom are the main cause for treatment seeking.[12,13]

Compared to other psychiatric manifestations, psychosis is less commonly described in patients with Wilson's disease. The commonly reported psychotic manifestations include that of schizophrenia like psychosis and of delusional disorder. A study from India, which evaluated 350 patients with Wilson's disease, reported psychosis in three cases only, which was of schizophreniform type.[14] Other studies have also reported low prevalence of psychosis, viz., 1 out of 31,[15] 8 out of 71 cases,[16] 3 cases of organic delusional disorder out of 45 patients,[4] 2 out of 195 cases[5] and 2 out of 42 cases.[2] However, certain other studies which have reported about the various psychiatric manifestations have not reported a single case of psychosis.[10] Overall the prevalence of psychosis in patients with Wilson's disease varies from 0% to 11.3%.

Since, the early description of Wilson's disease, few case reports have documented the occurrence of psychosis in patients with Wilson's disease.[17,18,19,20] However, over the last two decades, there is the proliferation of case reports/series describing psychosis in patients with Wilson's disease.[2,4,7,8,10,11,12,15,16,21,22,23,24,25,26,27]

A case report described a patient with Wilson's disease who had psychotic episodes at the age of 18, 22 and 23 and was diagnosed with paranoid schizophrenia. However, the diagnosis of Wilson's disease was made after 12 years of the first episode of psychosis.[21] Similarly, a recent case report described a patient who was treated as a case of schizophrenia for 10 years before being diagnosed with Wilson's disease.[22] One report described 3 cases with psychiatric manifestations that were usually misinterpreted as schizophrenia-like disease and lead to delay in the diagnosis. Diagnosis of Wilson's disease was confirmed on the basis of magnetic resonance imaging findings which showed asymmetric cerebral white matter lesions in the frontal lobe.[16] A case series documenting disturbance of circadian rhythm of temperature, pulse, and blood pressure in Wilson's disease described two cases of schizophrenia like psychosis.[28] Another report described a patient with psychosis who developed movement disorders with the use of haloperidol and was later confirmed to have Wilson's disease.[23] Spyridi et al.[24] described a case of delusional disorder presenting with non-persecutory delusional disorder and alcohol abuse in the absence of neurological signs when he discontinued his treatment of Wilson's disease which he was receiving for duration of 3 years. A case report described the resolution of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances in a patient with Wilson's disease after liver transplantation.[25] With regards to treatment of psychosis, two case reports described the use of electroconvulsive therapy in a patient with psychosis and Wilson's disease.[29,30] Another case report described the development of akinetic-rigid syndrome with use of risperidone.[31] Whereas two reports described improvement in psychosis with use of penicillamine and reduction in serum copper levels.[26,27]

What is evident from these case reports/series is that in most cases psychosis is diagnosed prior to diagnosis of Wilson's disease, and the latter is diagnosed later on when the patient developed additional symptoms of Wilson's disease or developed movement related side effects with antipsychotics.

In contrast to many of the previous reports the index case, developed psychosis with onset of abdominal manifestations of Wilson's disease. However, in contrast to some of the previous reports, the index case developed mild worsening of psychosis with increase in the dose of penicillamine. This could be possibly due to worsening of the primary psychiatric illness or may be due to penicillamine. However, the symptoms of psychosis reduced to a certain extent with reduction in the dose of penicillamine, and this possibly suggests an association between the two. But it is also possible that the reduction of psychotic symptoms may be due to the actual effect of penicillamine on serum copper levels. Some of the previous studies support the later hypothesis, which suggest an improvement in psychosis with chelation therapy.[26,27]

Index patient responded to low dose of antipsychotic medication, and this suggests that the use of the chelating agent possibly reduces the need for antipsychotic in patients with Wilson's disease as has been reported in some of the previous reports too.[17]

The case reflects that psychotic symptoms, though rare but may be a presenting feature in patients with Wilson's disease. As is evident from the literature, Wilson's disease must be considered as a possibility in patients who develop psychosis at a young age and the patients must be adequately investigated for the same, which should include ultrasound abdomen, serum ceruloplasmin levels, serum copper level and total urine copper level. Further, when diagnosed with psychosis associated with Wilson's disease, patients should be treated with low dose antipsychotics with close monitoring for extrapyramidal side effects.

Footnotes

REFERENCES