The Spectrum of Psychiatric Symptoms in Wilson’s Disease: Treatment and Prognostic Considerations

Case Presentation

A psychiatric consultation was requested by the internal medicine inpatient service for a 39-year-old woman with no past psychiatric illness who presented with several days of disorganized behavior.

History of Present illness

Nine months earlier, the patient had presented to her primary care provider with mild neurological complaints. The course of her physical symptoms and laboratory tests leading to the diagnosis of Wilson’s disease are summarized in Table 1, in the entries for months 0–8. For her Wilson’s disease, the patient was started on a combination of the copper chelator trientine and zinc. She soon developed colitis, which was thought to be a side effect of the trientine. To treat the colitis, prednisone was initiated at 40 mg/day, and trientine was discontinued.

The psychiatric symptoms for which the formal evaluation was requested began approximately 3 days after prednisone was started: the patient began exhibiting insomnia, increased energy, and delusions of thought control. She had been staying up at night working on two computers and cooking at the same time. She claimed to be a famous movie star. She was admitted via the emergency department to the medical service.

Mental Status Examination and Pertinent Physical Findings

Our psychiatric consultation team examined the patient within 2 hours of admission. She appeared to be a groomed woman looking her stated age, hyperactive, with bizarre movements that she called “my special dance.” Her affect was excessive, bizarre, and labile. She had loose associations and delusions of thought insertion. She could not participate in formal cognitive testing, but she was oriented to person, time, and place and there were no fluctuations in alertness. The neurological evaluation revealed limitation of upward gaze, mild ptosis, reduced blink frequency, axial rigidity of the neck, reduced smooth-pursuit eye movements, and a slight tilt of the neck with the chin down and to the left. There was no glabellar reflex, and no cogwheel rigidity. She had Kayser-Fleischer rings.

Psychosocial History

The patient was married and had two children. She had completed postgraduate education and had been working as a freelance designer until she became ill. There was no family history of psychiatric illness.

Laboratory Data

Basic serum chemistry values were within normal limits. CBC was notable for a WBC count of 13.5×1000/μL, a hemoglobin level of 13.3 g/dL, a hematocrit of 40.1%, and a platelet count of 345×1000/μL. Liver functions tests were notable for normal direct and total bilirubin levels, an AST level of 47 U/L, an ALT level of 159 U/L, and an ALP level of 185 U/L. The patient’s albumin level was 3.1 g/dL and total protein 6.7 g/dL. Her prothrombin time was 11.8 seconds, and her INR (international normalized ratio) was 1.12. Repeated copper studies consistent with her diagnosis of Wilson’s disease were ceruloplasmin levels <2 mg/dL, a total serum copper level of 0.25 μg/dL, and a 24-hour urinary copper level of 187 μg. A brain MRI showed nonspecific foci of increased signal in the last centrum semiovale and white matter of the right parietal lobe.

Treatment Course

A presumptive diagnosis of steroid-induced psychosis was made. Prednisone was tapered off over the next 2 days and the patient was given one dose of olanzapine, 2.5 mg, after which she developed significant neck dystonia. The olanzapine was discontinued and quetiapine was started. The patient tolerated 25 mg/day of quetiapine, although when the dosage was increased to 50 mg/day, she developed orthostatic hypotension and sedation, and the dosage was reduced to 12.5 mg/day. She continued to be psychotic and grandiose (she had plans to buy $50,000 worth of stocks and claimed she was the CEO of a company). Over 5 days, the quetiapine was titrated to a total dosage of 75 mg/day, and her psychiatric condition improved: she became calmer and cooperative. She was discharged home.

While at home, the patient continued to be disorganized and tangential; she developed paranoid delusions, hallucinations, and pressured speech. She became aggressive, which prompted readmission 3 weeks after discharge. She had been off steroids for 6 weeks and had continued the zinc for Wilson’s disease. Over the next 2 weeks, the quetiapine dosage was increased to 400 mg/day, with intermittent adherence. The patient remained disorganized, incoherent, and paranoid. She developed Capgras syndrome and had vague thoughts of hurting her family. She was deemed psychiatrically disabled and was committed to the psychiatric inpatient unit. In parallel, trientine was resumed and added to the zinc for treatment of Wilson’s disease after a sigmoidoscopy and biopsy showed no active colitis.

After the patient was transferred to the psychiatric unit, quetiapine was discontinued and haloperidol was initiated at 20 mg/day. The patient developed parkinsonian symptoms (Table 1, month 10). After 4 days of psychiatric hospitalization, she returned to the medicine service for bloody diarrhea, and trientine-induced colitis was confirmed by endoscopy. She was started on prednisone at 10 mg/day for 1 week, without worsening of her psychosis. Her paranoia began to resolve. Her thought process remained tangential. Over the next month, her psychotropic medications were adjusted (Table 1, month 10), initially on the medical unit and later on an outpatient basis, to address her psychosis and haloperidol-induced parkinsonism.

Over the next 5 months the thought disorder and parkinsonian symptoms slowly resolved while quetiapine and clonazepam were continued (Table 1, months 11–16). Nine months after the start of the psychotic symptoms, the patient showed no evidence of psychosis, had no mood symptoms, and had resumed her freelance work. Her family described her as being as fully engaged with them as she had been before her illness. Her copper and ceruloplasmin levels were consistent with treated Wilson’s disease (Table 1, month 17). In the subsequent 3 months, clonazepam was tapered and discontinued, and shortly thereafter, quetiapine was tapered and discontinued. Approximately 13 months after the beginning of her psychotic episode, the patient presented with moderate depressive symptoms triggered by the realization of the “time lost due to the big W” (the nickname the patient uses for Wilson’s disease). Sertraline was prescribed for 6 months and discontinued when her symptoms resolved.

Four years after her initial psychiatric evaluation and 3 years after her last depressive episode, the patient has remained asymptomatic off psychotropic medications. She has continued to take zinc as maintenance treatment for her Wilson’s disease.

Discussion

Background: Psychiatric Manifestations in Wilson’s Disease

Wilson’s disease is an autosomal recessive illness attributed to a defect of the gene ATP7B (on chromosome 13) leading to excessive accumulation of copper in liver, brain, and other tissues. Its lifetime prevalence is estimated at 1:30,000 (1).

A vast range of psychiatric symptoms has been described in patients with Wilson’s disease, so many that the illness has been called “a great masquerader” (2). In Wilson’s 1912 monograph describing the disease for the first time, eight of 12 cases had psychiatric symptoms (3). Psychiatric symptoms have a higher prevalence among patients with Wilson’s disease than in the general population (4). Psychosis has been described at various points in the course of Wilson’s disease (5–8). Cases have been reported of patients carrying a diagnosis of schizophrenia for years before being diagnosed with Wilson’s disease (9).

The mechanism of psychiatric symptoms in Wilson’s disease is not clear. Because symptoms can occur at the start of the illness, they are not fully explained by the psychosocial impact of a medical condition. Initially it was thought that basal ganglia abnormalities led to various psychiatric symptoms through dopamine dysregulation. More recent studies have explored the role of copper and other microelements in schizophrenia and bipolar illness (10, 11).

Our patient’s initial presentation suggested steroid-induced mania, with onset within days after starting prednisone and a clinical picture that included elevated energy, decreased need for sleep, and grandiosity. Other manic features, however, such as pressured speech, flight of ideas, and psychomotor agitation, were lacking. Over the course of the first month, the psychotic symptoms became predominant, with delusions of being controlled, Capgras syndrome, posturing, and tangential thought process. Three factors suggest that steroids were not the primary cause of her psychiatric illness. First, the psychosis persisted months after the steroids were discontinued, whereas 90% of cases of steroid-induced mania resolve within 6 weeks after discontinuation of steroids (12). Second, there were no side effects with a second steroid challenge (albeit with a lower dosage of prednisone). Third, our patient did not exhibit any cognitive deficits, which occur in over 70% of cases of steroid-induced neuropsychiatric side effects (13). The late onset of psychosis, good premorbid psychosocial functioning, and lack of prodromal symptoms militate against a chronic primary psychotic disorder, and therefore a diagnosis of psychosis secondary to a medical condition (Wilson’s disease) was formally established.

Treatment and Prognosis of Psychiatric Manifestations of Wilson’s Disease

Although it is well recognized that Wilson’s disease often presents with psychiatric problems, little is known about the treatment or the prognosis of these clinical manifestations. Two treatment approaches to psychiatric symptoms in Wilson’s disease patients have been described: 1) primary treatment of Wilson’s disease directed at removal of pathological copper deposition (chelation therapy or treatment with zinc) alone leads to an improvement in psychiatric symptoms (14, 15); 2) psychotropic medication or psychotherapy is used to address specific psychiatric presentations independent of medical therapy for Wilson’s disease. Trials of various psychotropic medications have been reported, including lithium, haloperidol, tricyclic antidepressants, benzodiazepines, quetiapine, risperidone, and clozapine, as well as trials of ECT (4, 8, 16, 17).

Our case illustrates three important aspects of treating psychiatric symptoms in patients with Wilson’s disease.

Sensitivity to antipsychotic medications.

High incidences of neurological side effects caused by psychotropic medications have been reported in patients with Wilson’s disease (e.g., 18). Our patient developed significant side effects with minimal dosages of atypical antipsychotics and severe parkinsonism with haloperidol, which lasted weeks after haloperidol was discontinued. Thus, our case supports the practice of selecting antipsychotics that are less likely to cause extrapyramidal symptoms (such as quetiapine) and titrating the dosage slowly.

The setting where treatment is provided for psychiatric symptoms.

Patients with Wilson’s disease may have active medical problems (in our case ileitis-colitis) requiring prompt management that psychiatric units often are not equipped to provide. Close collaboration with the medical team is essential in the long-term management of these patients. Often a psychiatrist in a consultative role follows patients with Wilson’s disease when they are hospitalized on a medical unit. We were fortunate to be able to continue the multidisciplinary treatment in the outpatient setting, in our Wilson’s Disease Center for Excellence. Co-located models of care have been reported to improve the quality of life of patients with liver (19) and neurological disease (20). This model, which implies the presence of mental health professionals in the medical clinic, needs to be considered for Wilson’s disease because of the high prevalence of psychiatric symptoms.

For our patient, strong family support allowed her to avoid extended hospitalization despite disabling psychiatric symptoms. Psychoeducation and/or referral to support organizations, such as the Wilson Disease Association, can ease the burden on caregivers.

Duration and goal of treatment.

For our patient, remission of psychiatric symptoms was achieved after 9 months of treatment. This slow recovery may have been due to the slow reduction of copper levels in the brain, but it may also be attributable to the fact that the patient’s psychotropic medications could only be adjusted slowly because of her sensitivity.

Full remission, once achieved, was maintained for 3 years without psychotropic medications while continuing treatment for Wilson’s disease. There are no data to guide the duration of treatment with psychotropics in Wilson’s disease, since there have been no systematic studies of the correlation of biological markers with psychiatric symptoms in the disorder. We advocate close ongoing observation to identify when the psychiatric symptoms resolve and the disease markers are normalized. At that time, attempts should be made to discontinue the psychotropic medications to reduce short- and long-term side effects. The association of Wilson’s disease with irreversible cognitive decline is no longer the rule in the context of effective medical therapy for the disorder. Our case supports the notion that the goal of treatment for patients with Wilson’s disease who develop psychotic symptoms is total remission and return to previous functioning.

Conclusions

Treatment of psychiatric symptoms in Wilson’s disease may require slower titration of psychotropic medications and should accompany therapy for Wilson’s disease directed at the prevention of accumulation and the removal of copper. Even when severe psychosis is present, the aim of care should be full recovery, since patients may maintain remission for years after psychotropic medications have been discontinued.