Abstract
Chief Complaint and Presenting Problem
E.
History of Present Illness
The patient's mother reported that E. was a shy child who liked to stay by himself or hang out with his older brother. He had no history of behavioral or developmental problems that had required clinical attention, and he had done relatively well in school until a few months before his presentation. E. had been exposed to domestic violence in the home between his mother and his father. His mother separated from his father when E. was 6 years old, and his father had been inconsistently present in E.'s life since then. His mother reported that about a year ago, E. and his older brother got into a physical altercation with their father, and as a result, E. had had no contact with him until a few days before his presentation. By that time, his mother also noted that E. had begun smoking marijuana regularly, usually with his older brother. His mother reported that his use peaked about 5 months before this current presentation, and at that time, his school performance started to decline.
Three months before presentation, his mother noticed an acute change in E.'s behavior and mood. He started talking back to others, thinking that people on the street were looking at him, and having frequent mood swings. His mother brought him to the emergency department where his symptoms were attributed to marijuana intoxication, and he was discharged home with a referral to a therapist. No medications were started. After that presentation, E. reportedly stopped smoking marijuana and his behavior returned to baseline, although he continued to struggle at school. He did not, however, adhere to the outpatient treatment plan nor arrange alternative care.
A week before presentation, his mother noticed that E. had started smoking marijuana again (he came home with red eyes), was sleeping and eating less, and was engaging in new activities like yoga, which was out of character for him. He also started having idiosyncratic, bizarre conversations, and saying things such as “everybody is watching and talking about me” and “they know about my life.” Two days before presentation, E. was on his way to summer school when he suddenly started crying, called his mother, and took the train back home. That night, E. started asking his mother whether his father was actually his real father. Due to this change in behavior, E. was referred back to the emergency department. His symptoms were once again attributed to marijuana, and he was discharged home. The following day, he was reported to be crying and saying that he wanted to see his father, which his mother did not allow; his mother instead called his father and told him to come and see E. The next day, E. met with his father and said that he forgave him for everything. His father noted a change in E.'s behavior; he had to return him to his mother after E. unexpectedly ran out of the house. After the encounter with his father, E. again left the house and was found in the middle of the night by his older brother, lying on a bench in the park saying, “I belong on the streets,” “my bed is here,” and “it's my life.” His mother subsequently called an ambulance to bring him to the hospital.
In the emergency department, E. was noted to be disorganized and oddly related, with circumstantial thought process and loose associations. Initial laboratories (complete blood cell count, comprehensive metabolic panel, thyroid stimulating hormone, and urinalysis) were within normal range, but his aspartate aminotransferase (AST) was at the upper limit of normal at 46 U/L (range 15–46 U/L). Urine toxicology was positive for cannabinoids. An electrocardiogram was normal, and magnetic resonance imaging showed no identifiable brain pathology, although E. was moving during the procedure. E. was subsequently admitted to a Child and Adolescent Psychiatry Inpatient Unit.
Psychiatric History
E. had had two previous emergency department evaluations for odd behavior and acute mood changes as described, but had received no formal psychiatric diagnosis or treatment.
Developmental History
E. was the product of an uneventful pregnancy with full prenatal care and no maternal use of alcohol, tobacco, or narcotics. Delivery was uncomplicated. Birth weight was about 3.5 kg. Postnatal history was uneventful. E. met all of his development milestones on time.
Educational History
E. did well academically until a few months before his admission. He was enrolled in a regular education class and had completed his junior year in high school. He had been planning to enroll in a summer school before starting his senior year because of his recent academic decline.
Social History
E. lived with his mother, two brothers (ages 10 and 18), and one sister (age 15) in an inner city neighborhood. E.'s parents separated when he was 6 years old; although his father had been present in E.'s life, their relationship was strained. A year before his hospitalization, E. and his older brother got into a physical altercation with their father. E. had not seen his father since then, until the day before admission. His mother had worked as a receptionist, but lost her job 9 months before his admission and was currently unemployed.
Family History
Maternal grandmother and maternal aunt had a history of schizophrenia. There was no reported family history of substance use disorders. There was no family history of significant medical problems, including Wilson's disease, liver abnormalities, or neurological problems.
Medical History
E. had a history of intermittent asthma that was well controlled with albuterol as needed. He also had seasonal allergies and an allergy to cranberry sauce, manifested as hives. He had no known drug allergies.
Medication History
E. had not been treated with psychotropic medications in the past.
Mental Status Examination
On initial interview, E. was alert, somewhat disheveled, and oddly related. He appeared his age and had two tattoos, one on each forearm, saying “Grandma” and “Grandby.” He was cooperative with the interview, but overall acted childish and disorganized. Psychomotor activation was present and he paced throughout the room. His speech was of normal rate, rhythm, and volume. He described his mood as “good,” but his affect was expansive, labile, and, at times, incongruent to specific situations. He laughed at almost every question when giving his responses. His thought process alternated between linear and goal oriented at certain times and racing, tangential, with loose associations in other instances. He endorsed delusions of grandeur, such as having “special powers” that allowed him to know things about people, ideas of reference, and paranoid ideation. He denied current suicidal or homicidal ideation, but endorsed that he had thought of hurting other people if they did something to him. At one point, he mentioned hearing a tiger “roaring” and seeing its image in his head, but on further questioning, it appeared to have been a dream, which awoke him from sleep. He denied other auditory or visual hallucinations. He was not oriented to time and had impaired concentration, but his language skills were within normal limits. He endorsed feeling more energized and having trouble sleeping. He had limited insight, but was able to recognize that some of his thoughts may have been false. His judgment was poor.
Hospital Course
On physical examination, E. had no evidence of Kayser–Fleischer rings, jaundice, abdominal tenderness or distension, hepatosplenomegaly, or abnormalities on neurological examination.
Laboratory evaluation was remarkably low for ceruloplasmin 15 mg/dL (range 20–60 mg/dL), prompting further work-up for Wilson's disease. Serum copper was low at 65 μg/dL (range 75–187 μg/dL), but 24-hour urine copper excretion was also low at 6 μg/24 h (range 15–60 μg/24 h), making the diagnosis of Wilson's disease less likely, but still a possibility. Urine toxicology screen was positive for cannabinoids.
E. was started on risperidone 0.5 mg BID, which was gradually titrated to 1.5 mg BID. He tolerated the medication well, without any side effects.
E.'s abnormalities in mental status improved sufficiently after ∼2 weeks to permit discharge and referral for ongoing care in the outpatient setting. He continued to endorse some delusions and paranoid ideation, but became more organized and less manic. After several sessions of motivational interviewing, E. committed to stop cannabis use after discharge. His mother was also counseled extensively on ensuring that E. did not have access to marijuana in the home. He was discharged from the hospital to continue care in a substance abuse-specialized outpatient community clinic, and to conclude his evaluation of laboratory abnormalities with his established primary care provider.
Brief Formulation
E. was a 17-year-old adolescent boy with a history of excessive cannabis use who was admitted to a psychiatric inpatient unit after 3 days of bizarre behavior and disorganized thinking, inappropriate and labile affect, delusions, and paranoid ideation. E.'s symptoms were suggestive of psychosis and mania, either due to a primary psychotic disorder, a psychotic and mood disorder, a substance-induced psychotic disorder, or a psychotic disorder secondary to a medical condition. Since E. had had these symptoms for <6 months, a diagnosis of schizophrenia could not be made at that time.
From a biological perspective, E. had a genetic predisposition to psychosis because of a family history of schizophrenia. In addition, his history of heavy cannabis use could have rendered him more vulnerable to the development of psychotic symptoms, given an underlying genetic predisposition. Abnormal laboratory findings of low ceruloplasmin and serum copper were suggestive of Wilson's disease, which may also present with psychotic symptoms.
From a psychological perspective, E. had had little support or resources to facilitate the development of good coping skills. E.'s conflicts with his father appeared to be a manifestation and perhaps the result of his difficulty with modulation of aggression; he had little in the way of a positive male role model around which to identify and work through tasks of mid-adolescence. From a social perspective, E. witnessed domestic violence (although never a victim), as well as likely financial stressors at home, as his mother was recently unemployed.
Diagnoses
AXIS I: Psychotic disorder not otherwise specified
Cannabis use disorder
Rule out psychosis secondary to cannabis use
Rule out psychosis secondary to Wilson's disease
Rule out schizoaffective disorder (bipolar)
Rule out bipolar disorder with psychosis
AXIS II: Deferred
AXIS III: Asthma
Seasonal allergies; cranberry sauce allergy
AXIS IV: Strained relationship with father; academic performance decline; financial hardship (mother currently unemployed)
AXIS V: Global Assessment of Functioning score: 25
Discussion
E. presented with symptoms of psychosis and mania in the context of excessive cannabis use, superimposed on a genetic predisposition for psychiatric disorders. However, in this particular case, the routine work-up for new-onset psychosis revealed a laboratory abnormality of low ceruloplasmin, prompting a more comprehensive investigation into possible Wilson's disease. Wilson's disease is an extremely rare condition with a worldwide prevalence of 1 in 30,000 live births; most cases are diagnosed at a mean age of 12–23 years (Huster 2010).
Wilson's disease is a disorder of copper transport, resulting in organ dysfunction secondary to excessive copper deposition in tissues, most commonly in liver, brain, and cornea. It is inherited in an autosomal recessive manner and is most commonly due to mutations in the ATP7B gene coding for hepatic copper transport protein on chromosome 13, although other genes have also been implicated, and most people are compound heterozygotes (Thomas et al. 1995; Huster 2010). The clinical manifestations are predominately hepatic, neurologic, and psychiatric.
Interestingly, some reports indicate that psychiatric findings are present in up to 100% of patients, and may be the first presenting symptoms. These may sometimes precede hepatic and neurological disease by many years. As a result, treatment is delayed and disease progression can occur (Akil and Brewer 1995). The most common psychiatric and behavioral symptoms include depression, decline in school performance, personality change, and irritability. In addition, labile mood, bipolar, and psychotic symptoms, which E. clearly exhibited, have also been described (Dening and Berrios 1990).
Initial evaluation of patients with suspected Wilson's disease includes serologic testing (liver function tests, complete blood count, and serum ceruloplasmin level), 24-hour evaluation of urinary copper excretion, and ocular examination. E.'s lower than normal ceruloplasmin level and upper limit of normal AST prompted further investigation. On subsequent work-up, E.'s serum copper was also found to be low, providing more supportive evidence for Wilson's disease, since more copper is deposited in the tissues rather than circulating in the blood in this population.
E.'s 24-hour urinary copper excretion was the only test that did not support the Wilson's disease diagnosis, as it was found to be lower than the value described for the majority of Wilson's patients. This finding, however, could have been a false negative, as E. was not always compliant with the urine collection, an essential condition to determine urinary copper excretion (European Association for Study of Liver 2012). For this reason, the 24-hour urinary copper collection should be repeated.
If low urinary copper excretion were confirmed, follow-up and additional work-up would be still indicated. Based on the 2008 consensus guidelines from the American Association for the Study of Liver Disease and the 2012 guidelines from European Association of the Liver, a liver biopsy to stain for copper and to determine hepatic copper concentration or molecular genetic testing for ATP7B mutation is recommended in patients with low ceruloplasmin and low urinary copper excretion (European Association for Study of Liver, 2012; Roberts and Schilsky 2008).
Although most of disease manifestations are seen in homozygotes, it is interesting to note that abnormalities can be seen in individuals who only have one mutated copy of the gene, which is approximately 1%–2% of the population (Das and Ray 2006). About 10%–20% of asymptomatic carriers have serum ceruloplasmin concentration <20 mg/dL, as was the case with E. A recent study of individuals known to have one mutated copy of the ATP7B gene found that heterozygotes had significantly lower serum ceruloplasmin and serum copper, and significantly higher urinary copper excretion than controls (Gromadzka et al. 2010). These individuals were for the most part reported to be healthy and had normal liver enzymes, although a few had a slight head or hand tremor, which could have been attributed to other causes.
No study to date has looked at prevalence of psychiatric findings in carriers for Wilson's disease. It is possible that E. was heterozygous for the disease, in light of the laboratory abnormalities without significant hepatic or neurologic abnormalities; if that were the case, it would be interesting to ascertain how this genetic mutation contributed to the patient's biologic diathesis for the development of psychosis and mania.
It is important to note that although low serum ceruloplasmin is found in 85%–90% of patients with Wilson's disease (Brewer and Yuzbasiyan-Gurkan 1992), it is not specific to this condition. In fact, one study found its positive predictive value to be only 6% (Cauza et al. 1997). Other conditions that have been associated with low ceruloplasmin level are acute viral hepatitis, chronic hepatitis, end-stage liver disease, drug- and alcohol-induced liver disease, malabsorption, nephrotic syndrome, protein-losing enteropathy, copper deficiency, and other rare genetic disorders (i.e., Menkes disease and aceruloplasmonemia), all of which were unlikely in E. because of the absence of other clinical or laboratory findings (Cauza et al. 1997; European Association for Study of Liver 2012).
When the diagnosis of Wilson's disease is confirmed, treatment must be started right away, as this condition is almost universally fatal. However, the prognosis for patients who adhere to the recommended treatment is excellent. Patients are usually treated with
Limited data are available regarding the treatment of psychiatric symptoms in patients with Wilson's disease. Two treatment approaches have been proposed. The first approach is aimed at reducing the copper load as already described. Several case studies have reported improvement in and, in some cases, resolution of psychiatric symptoms with the use of
The second approach is to treat the psychiatric symptoms conventionally. Multiple case studies reported benefit of either initiating or augmenting treatment with psychotropic medications and procedures such as cognitive behavioral therapy and electroconvulsive therapy (Shah and Kumar 1997; Zimbrean and Schilsky 2014). Trials of many psychotropic medications for psychiatric symptoms have been reported, including mood stabilizers, typical and atypical neuroleptics, selective serotonin reuptake inhibitors, tricyclic antidepressants, and benzodiazepines, with good effect (Zimbrean and Schilsky 2014). However, it has been shown that patients with Wilson's disease are especially sensitive to typical neuroleptics, so these medications should be used with caution to prevent extrapyramidal side effects, which can exacerbate neurological symptoms (Zimbrean and Schilsky 2015). For patients with Wilson's disease and psychosis, atypical neuroleptics, such as clozapine and quetiapine, have been used effectively (Kulaksizoglu and Polat 2003). Thus, for E., risperidone was a suitable choice. However, slow titration and careful monitoring are imperative as his ongoing work-up for Wilson's disease unfolds.
Minimal data are available regarding interactions between chelating agents and psychotropic medications. One review article found an increased risk of neutropenia and agranulocytosis with concomitant use of
E.'s case underscores the importance of a comprehensive medical work-up in an adolescent with new-onset psychosis, even when other causes seem more probable, such as substance use. In this case, the work-up unveiled a possible diagnosis of Wilson's disease. The family history of psychiatric disease and mother's denial of any family history of liver or neurological problems did not preclude a Wilson's disease diagnosis. It is also possible that E. is a carrier of the disease, explaining the presence of some but not other findings. Further investigation is indicated to better understand the manifestation of Wilson's heterozygous disease, with special emphasis on psychiatric symptoms, since these are often attributed to something else, delaying diagnosis.
Footnotes
Acknowledgment
We would like to acknowledge and thank Maxwell Luber for his assistance in review and preparation of the article.
Disclosures
No competing financial interests exist.