Wilson Disease: A Case Report of Psychosis Preceding Parkinsonism

Background

A first, acute psychotic episode is one of the most common psychiatric emergencies [1]. In a small proportion of patients, psychosis is due to secondary causes [2]. Wilson disease is a rare, autosomal recessive disorder of copper metabolism due to mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase [3]. The accumulation of copper in the brain can lead to neurological and psychiatric symptoms. Personality changes in patients with Wilson Disease are a common first symptom, whereas the prevalence of acute psychosis ranges from 1.4% to 11.3% [3]. Kayser-Flesicher rings are invariably present in patients with neurological symptoms [2]. Serum copper and caeruloplasmin levels have high positive predictive value for diagnosing Wilson disease in the correct clinical context but are not always performed routinely [2–4].

Advanced, untreated Wilson disease manifesting as parkinsonism can be confused with drug-induced parkinsonism where there is a common history of neuroleptic use. Here, we describe a 48-year-old man with previously undiagnosed Wilson disease who presented with parkinsonism and outline the features on magnetic resonance imaging (MRI) of the brain, which can support a detailed clinical history and examination to clarify the diagnosis [5,6].

Case Report

A 48-year-old man self-presented to the Emergency Department with a 3-month history of worsening mobility, falls, dysarthria, and sialorrhea. He was estranged from family, living in squalor, and subsisting on a diet of porridge.

His past medical history was relevant for psychotic depression, diagnosed 15 years earlier after a suicide attempt. The first psychotic symptoms appeared at age 30 years at a time when the patient was also using cannabis, amphetamines, and other illicit drugs. He was subsequently diagnosed with schizophrenia, having been hospitalized multiple times with personality changes and further episodes of substance abuse and psychotic episodes. Brain imaging at the time of diagnosis was not available. He had been commenced on a paliperidone 100-mg via depot injection 2 years prior to the current presentation. Extrapyramidal features were noted after 18 months of paliperidone therapy, thought to be secondary to drug-induced parkinsonism, and the medication was reduced to 75 mg, and then ceased. The patient was not on any other medications at the time of admission.

Examination revealed hypomimia, risus sardonicus, dysarthria (verging on anarthria) and sialorrhea, a stooped posture with shuffling gait, axial rigidity, bradykinesia, and cogwheeling in both upper limbs. There was no tremor or dystonic posturing, no frontal release signs, and his eye movements were normal. There were no positive features of schizophrenia, such as hallucinations, delusions, or thought disorder, either at presentation or during the admission.

Dedicated ophthalmological examination, requested after initial investigations returned, revealed Kayser-Fleischer rings (Figure 1).

Initial serum testing results, including full blood count, glucose, urea, and electrolytes, were normal. Liver function studies were within normal limits, with only GGT mildly raised (57 U/L, reference range, 5–50). Liver synthetic function and iron studies were normal. Serum copper was 4.3μmol/L (reference range, 12.0–22.0); ceruloplasmin, 0.02 μmol/L (reference range, 0.17–0.31); and 24-h urine copper 2.0μmol (reference range, <1.6). Liver ultrasound showed cirrhotic changes, without evidence of portal hypertension. MRI of the brain showed increased FLAIR/T2 signal in the pons, midbrain, and basal ganglia (Figure 2).

The patient’s paliperidone was suspended, and he was commenced on benztropine therapy while awaiting the results of investigations. On confirmation of Wilson disease, chelation therapy with penacillamine and zinc was initiated. Levodopa therapy was added for the marked parkinsonism. At follow-up 6 months later, there was mild improvement in his gait and rigidity. At 1 year, however, he had deteriorated; the patient was bedbound with tremor in all 4 limbs, dysarthric, and with severe dysphagia leading to malnutrition, requiring percutaneous gastrostomy tube insertion.

Discussion

Psychosis as the primary presenting feature of Wilson disease poses a diagnostic challenge, and serum copper studies are not always included as part of routine first-line investigations [2].

Serum copper and ceruloplasmin levels are easily obtained and should be considered as part of the first-line investigations for all young adult psychiatric patients presenting with extrapyramidal and/or hepatic symptoms [2]. Most patients with Wilson disease have a low serum ceruloplasmin level (<0.2 μmol/L) [11]. However, low ceruloplasmin levels can be seen in other disorders, such as malabsorption and acute or chronic hepatitis; conversely, patients with Wilson disease can have elevated ceruloplasmin levels in the presence of acute hepatitis or pregnancy [5]. Serum copper levels are usually decreased proportionally to the reduction in serum ceruloplasmin [5]. A low serum ceruloplasmin level, with or without a low serum copper level, should prompt confirmatory testing with a formal ophthalmological examination for the presence of Kayser-Fleischer rings and 24-h urinary copper excretion levels [5,6]. Kayser-Fleischer rings are due to copper deposition in Descemet’s membrane and are seen particularly in patients with neuropsychiatric involvement [6].

The patient in our case had been mistakenly diagnosed with depression and schizophrenia and treated with standard anti-psychotic medication. The presence of axial rigidity, bradykinesia, bilateral cogwheeling of the upper limbs, and hypomimia were initially thought to represent drug-induced parkinsonism.

While the most common cause of parkinsonism is idiopathic Parkinson disease, drug-induced parkinsonism, central nervous system malignancy (glioma, lymphoma), Huntington disease, mitochondrial disease, Wilson disease, brain iron accumulation, and toxic-metabolic disorders are important differential diagnoses for early-onset extrapyramidal disorders in a young person [7,8]. Drug-induced parkinsonism usually appears hours to weeks after starting or increasing antipsychotic dosing [9,10]. In our case, symptoms started several months after commencement of paliperidone.

The marked bilateral extrapyramidal features from onset with dysarthria and sialorrhea raised suspicion of an alternative cause to drug-induced parkinsonism. Dysarthria occurs in severe parkinsonism from any cause, but the severity of the dysarthria and sialorrhea was disproportionate to the neuroleptic exposure. In cases in which psychosis precedes parkinsonism, neurodegeneration with brain iron accumulation (NBIA), including neuroferritinopathy, and Wilson disease, should be considered [7].

MRI of the brain can distinguish between NBIA and Wilson disease. NBIA shows characteristic iron deposition in the basal ganglia, particularly in the globus pallidus [12]. Abnormal T2 hyperintensity in the putamina is the most common radiographic finding in Wilson disease, and where there is involvement of the midbrain tegmentum, this can give rise to the pathognomonic “face of a giant panda” [13,14].

The predilection for copper accumulation in the basal ganglia and pons in Wilson disease drives the characteristic neurological manifestations of an akinetic-rigid syndrome, tremor, ataxia, and dysarthria [5]. Involvement of the caudate nucleus manifests clinically as choreoathetosis [6]. Sialorrhea, dystonia, personality changes, and psychosis can also be seen with cortical involvement [6,13]. The brain MRI in the present case demonstrated the classic findings of increased FLAIR/T2 signal in the pons, midbrain, and basal ganglia [14].

Conclusions

Although rare, Wilson disease, if diagnosed early, is a potentially treatable and reversible condition. Serum copper studies should be requested in any patient presenting with new-onset neuropsychiatric disturbance, including first-episode psychosis. When the patient has received neuroleptic medication, radiological changes on brain MRI can support a detailed clinical history and examination to differentiate the disease from drug-induced parkinsonism.