Abstract
Chief Complaint and Presenting Problem
History of Present Illness and Initial Presentation
Parents reported that B.'s symptoms began abruptly three months prior to presentation. On the first day, B. experienced a low-grade fever (99.8 degrees Fahrenheit) and was observed to be more quiet than usual. The fever was not alarming, and B. went to school that day. The following day, B. again experienced a fever (101 degrees Fahrenheit). She returned home from school with her mother, and the family again noted her to be quiet and withdrawn. She did not interact normally with her siblings or parents, and was not laughing and talking as she usually did. B. was observed to vomit. That day, B. reportedly spent a considerable amount of time in the bathroom, sitting on the toilet in the dark wearing all her clothes. She was later unwilling to change her clothes and had difficulty sleeping, wanting to remain in her parents' room that night. B. was reported by her parents to be oppositional and defiant, which was unusual for her. She reported to her family that other students at school had been talking about her, calling her “gay” and a “prostitute” and saying that she was “high on drugs.”
Parents reported being concerned about B.'s behavior, and they were especially worried about the possibility of a trauma such as sexual abuse, molestation, or rape. They took B. to the emergency room that night, where she endorsed auditory hallucinations of voices engaged in talking in a dialogue about her. On the third day, B. was admitted to an inpatient psychiatric unit where she remained for five days. A preliminary diagnosis of a psychotic disorder was discussed with B.'s parents, and treatment with aripiprazole was recommended. B.'s parents did not believe that medication management was necessary at that time, and they were not convinced that B. had a psychotic condition. She was therefore discharged from the hospital.
The following day, B.'s parents brought her back to the hospital. They were more convinced that she exhibited signs and symptoms of a psychotic disorder. B. continued to be quiet, withdrawn, and antisocial with her family. She did not laugh or engage with them. She insisted on drawing the curtains in her room so others could not see her. She was again sitting in the bathroom in the dark, and she admitted to hearing voices. She was unable to sleep in her room as in the past.
Because of their concerns about the possibility of a sexual trauma, B.'s parents had her evaluated by a gynecologist. There were reportedly no concerning findings on gynecological examination. B.'s parents deny that B. had a current or past history of significantly depressed mood, visual hallucinations, generalized anxiety, panic attacks, obsessions, compulsions, known trauma, social anxiety, enuresis, encopresis, abnormal movements such as tics, selective mutism, separation anxiety, homicidal ideation, suicidal ideation, or manic symptoms such as grandiosity.
B. was re-hospitalized for approximately two weeks. She was discharged with a diagnosis of psychotic disorder, not otherwise specified, on risperidone 1 mg in the morning and 1.5 mg in the evening and benztropine 0.5 mg twice a day. B. was subsequently placed in a partial hospital program for one week. Upon discharge from the partial program, B.'s care was referred to a psychologist and a psychiatrist, and she continued on the combination of risperidone and benztropine.
Past Psychiatric History
B. had no prior psychiatric evaluation or treatment until symptoms abruptly began three months before presenting at the clinic. She was initially evaluated in the psychiatric emergency room a day after her fever began. She had a 5-day inpatient psychiatric hospitalization the following day. A second hospitalization occurred on the inpatient psychiatric unit for 12 days, and B. was subsequently transferred to a partial hospital program at a local hospital for one week.
Developmental History, Including Pregnancy, Birth, and Early Childhood
B.'s mother reported a full-term, uncomplicated pregnancy with spontaneous vaginal labor and delivery at 36 weeks gestation. Birth weight was 8 pounds 2 ounces, and there were no complications during the neonatal period.
B. reached developmental milestones on a normal trajectory, walking and talking by approximately 13 months of age and toilet trained by about 2 years of age. B.'s parents reported no known physical or sexual abuse or neglect.
Educational History
B. was described as a good student who had been on the Honor Roll every year, earning mostly A and B grades with a rare C. During her first semester this year, she did very well, earning A and B grades and one C+. B.'s grades declined after her hospitalizations.
Social History
B. is described as very social and has had numerous friends. This changed in the context of her recent illness; she has been much more withdrawn and much less social with peers. B. used to play the violin, and she continues to express a significant interest in fashion and fashion design.
Family History
Parents reported no significant family medical or psychiatric history.
Medical History
Medical history is significant only for ear infections with placement of bilateral Eustachian tubes in the past. There is no other significant past medical history, including accidents, injuries, cardiac, endocrinologic, or neurological problems.
There is no history of head trauma, loss of consciousness, seizures, frequent headaches, or frequent lightheadedness or dizziness. Hearing and vision are intact.
B. has no known allergies.
Mental Status Exam
B. appeared her stated age, and presented with good hygiene and grooming and was appropriately attired. She was visibly slowed and oddly related. Her affect was significantly blunted. Eye contact was piercing at times. She appeared psychomotorically retarded. B. maintained her composure and was calm throughout the evaluation. Speech was limited but goal directed. B. was alert and oriented to all spheres. Mood was reported to be "okay." Thought process was goal directed with poverty of thought. Thought content was devoid of homicidal ideation, suicidal ideation, obsessions, compulsions, phobias, or grandiosity. B. denied paranoid thoughts. B. denied auditory or visual hallucinations; however, she appeared somewhat internally preoccupied. Cognition was grossly intact. B. was not significantly impulsive. No abnormal movements were noted. Insight was poor and judgment was fair.
Outpatient Treatment Course and Medication History
Upon review of her treatment course to date, including initial emergency room evaluation and subsequent inpatient, partial hospital, and outpatient treatment, it became apparent that B. had not received a thorough medical evaluation. She had not received an electroencephalogram (EEG), head magnetic resonance imaging (MRI), a complete set of labs including Lyme titers, or a neurologic consultation. A comprehensive medical workup was recommended.
Subsequent medical work-up, including laboratory chemistry, hematological profile, head MRI with and without contrast, EEG, and neurologic exam, was within normal limits. Neuropsychological testing conducted during the course of treatment indicated average IQ with a delayed processing speed and poverty of thought.
At presentation to the clinic, B. was described as doing a bit better. Parents reported that B. was no longer as active as she used to be. She continued to be concerned about others looking at her, for example, when she was playing tennis. Parents reported that B. did not move normally, and was described as keeping her arms close to her body, not appearing to have a natural arm swing. B. appeared slowed, tired, and sedated. Parents report that when others spoke to her, they need to repeat what they were saying. B. was resistant to going to school or going anywhere outside the home. For example, parents reported that when eating in a restaurant, she asked again and again "Can we leave now?"
B. was reported to have difficulty awakening in the morning, and due to her slowness, took much longer than usual to prepare for school. She was reported to be worried about missing the bus but was more often resistant to the idea of getting on the bus or going to school at all. B.'s workload was overwhelming, and she was reportedly given only two weeks to remediate the work she missed as a result of her absence. B. was observed to be much less social with her friends and more self-conscious. B. also reportedly experienced a decreased ability to concentrate and increased forgetfulness. Sleep was described to be within normal limits, and her mood appeared to be tranquil.
At four month follow up, B. showed improvement and was more related during her appointment. She was reportedly more interactive and social with her family members, though much less so outside the family. She had completed the eighth grade and graduated from middle school. However, B. was reportedly not engaged in the classroom as she had been prior to the onset of illness and struggled with the academic and social demands of high school. Risperidone was gradually increased to 1.5 mg in the morning and 2 mg in the evening for persistent paranoid thoughts and social withdrawal. She continued on 0.5 mg benztropine twice a day. Despite some improvements in her psychotic symptoms, B. developed a host of adverse effects of risperidone, including a 20-lb weight gain. In addition, she experienced cognitive dulling, daytime sedation, and mild Parkinsonism, including bradykinesia, stiffness, and loss of normal arm swing while walking.
B. also developed menstrual irregularities and heavy vaginal bleeding. This was followed by two months of amenorrhea. A serum prolactin level was found to be significantly elevated at 195.8 ng/mL. B. was referred to a pediatric endocrinologist, who confirmed hyperprolactinemia secondary to risperidone. A brain MRI with pituitary views was found to be normal. Despite tapering of risperidone, symptoms persisted, and prolactin level rose to 217.3 ng/mL. Treatment with a D2 receptor agonist, cabergoline 0.25 mg twice a week, was therefore initiated to reverse the symptomatic hyperprolactinemia. After one month of cabergoline, prolactin levels decreased to 97.4 ng/mL, and she began experiencing a normal menstrual cycle. After two months of treatment, the prolactin level was 63.1 ng/mL, and cabergoline was discontinued. Five months later, B. continued to experience a normal menstrual cycle, and her prolactin level was measured to be 58.6 ng/mL.
Simultaneous to endocrinologic interventions, B.'s benztropine was tapered and discontinued, and risperidone was further tapered to 0.5 mg twice a day. Aripiprazole 2 mg once a day was initiated. After the change in medication, B. lost some of the weight gained on risperidone, became more engaged with her family, normalized her affect, and became less anxious and more social with those outside her immediate nuclear family. Risperidone was discontinued, and aripiprazole was titrated to 5 mg daily, at which dose the patient has been stable, without psychotic or any adverse symptoms.
Brief Formulation
In summary, B. presented as a 13-year-old African-East Indian girl with a new-onset psychosis that began abruptly following a fever, without other physical signs or symptoms of medical illness. B. reported paranoid thoughts, auditory hallucinations, and engaged in disorganized behaviors. Her clinical presentation was consistent with a schizophreniform disorder. Schizophrenia, paranoid type cannot be ruled out.
When psychotic symptoms are clearly present for more than a month, but less than six months, a diagnosis of schizophreniform disorder is made. Schizophrenia does not usually begin abruptly; there is generally a prodrome over months to years of increased social withdrawal and isolation prior to the onset of psychotic symptoms, such as hallucinations and delusional thinking. When symptoms are present for more than 6 months, schizophrenia is diagnosed. When hallucinations and delusional thoughts are present, the disorder is further classified as paranoid type.
When psychotic symptoms begin abruptly and in the context of physical signs or symptoms such as fever, an underlying medical etiology must be considered; differential diagnosis includes psychotic disorder due to a general medical condition. A comprehensive medical work-up was pursued with no significant findings.
B.'s treatment course was characterized by development of several intolerable adverse effects while on risperidone, including daytime sedation, cognitive dulling, Parkinsonism, and symptomatic, severe hyperprolactinemia. Treatment of a D2 agonist was indicated for her symptomatic hyperprolactinemia. Switch to aripiprazole, an atypical partial dopamine agonist, was beneficial, both in treatment of her psychotic symptoms and reduction of the hyperprolactinemia.
B. will benefit from continued medication treatment, supportive therapy, and parent education and guidance.
Multi-Axial Diagnoses
Discussion
This interesting case illustrates several of the common challenges clinicians face in treatment of psychotic disorders in young children and adolescents. Despite two hospitalizations and initial presentation following a fever, a comprehensive medical workup had not been undertaken in the evaluation of this child. First onset psychosis in all patients, especially children and younger adolescents, requires comprehensive neurological, metabolic, infectious, and toxic screen evaluation, including head imaging. B.'s workup was entirely within normal limits; however, close medical monitoring is indicated, given there is no reported family history of psychiatric illness
Another challenge that clinicians face is the development of adverse effects in association with effective treatments. Risperidone, a frequently prescribed second-generation antipsychotic, is indicated for the treatment of psychosis in youth. There is a considerable evidence basis for its efficacy, and a body of literature on adverse effects (Roke et al. 2009; Correll and Carlson 2006). It has several indications for use in the pediatric population, including schizophrenia, mania, Tourette's disorder, and behavioral problems associated with autistic disorder. It is often the first line antipsychotic used to treat psychotic disorders. There is no question that in moderate doses it was beneficial in B.'s initial treatment.
Unfortunately, B. developed several known adverse effects of risperidone in association with her treatment that rendered discontinuation of the drug necessary. Given both D2 dopamine and 5-HT blocking properties, second generation antipsychotics can be associated with extrapyramidal and metabolic adverse effects. Sedation and cognitive dulling can occur, as can prolactin elevation. Hyperprolactinemia occurs as a result of blockade of the D2 receptor in the anterior lobe of the pituitary in the tuberoinfundibular dopamine system. This can lead to reduction in gonadotropin production (Halbreich et al. 2003; Haddad and Wieck 2004).
Hyperprolactinemia in association with antipsychotics may be more frequent in young patients than in adults because there is greater density of D2 dopamine receptors in the central nervous system (Seeman et al. 1987; Roke et al. 2009). Elevated prolactin levels are associated with gynecomastia, irregular menstrual cycles, galactorrhea, and amenorrhea in females. There is individual variation in levels at which symptoms appear; some authors suggest an upper limit of 15 ng/mL in adults, and slightly lower in children (Roke et al. 2009). Amenorrhea usually appears at prolactin levels greater than 60 ng/mL. (Haddad and Wieck 2004; Roke et al. 2009). Pappagallo and Silva (2004) reported an overall rate of 20% in a review of 14 studies. Roke and colleagues reported, in a recent review of 29 studies, a rate of 80% for risperidone (Roke et al. 2009). They reported that all antipsychotics, except clozapine, ziprasidone, and quetiapine, increased prolactin levels from baseline levels of 8 ng/mL after 4–8 weeks of treatment.
Given that B. is an early adolescent, potential effects on pubertal development are of interest. Roke and colleagues report that to date, only two studies with greater than one year duration studied progression of puberty in association with risperidone (Roke et al. 2009). No effect was found on progression of Tanner stages after one year of follow-up. However, one year of follow up may not be of adequate duration to delineate the effects. Hyperprolactinemia due to prolactinoma is associated with delayed puberty in patients with extremely high prolactin levels, 200 ng/mL or higher (Patton and Woolf 1983; Sack et al. 1984; Greenspan et al. 1986; Howlett et al. 1989; Kawano et al. 2000; Roke et al. 2009).
Although prolactin levels do not always correlate with clinical signs, B. had both clinical signs and an excessively high prolactin level. Given her excessively elevated level, treatment was considered indicated by the pediatric endocrinologist. Cabergoline is an ergot derivative with a lengthy half-life with efficacy and tolerability at doses in the 0.5 mg–1 mg/week. It was found to be superior to bromocriptine in treating primary and secondary hyperprolactinemia in one study (Cavallaro et al. 2004), and effective and safe in reduction of prolactin levels in 19 adult schizophrenic patients (Cavallaro et al. 2004).
Given B.'s extrapyramidal adverse effects in addition to the hyperprolactinemia, switch to another second generation antipsychotic was indicated in this case. Aripiprazole, a partial D2 agonist, would be appropriate in this situation, given its antipsychotic efficacy and reported effects of reducing symptomatic hyperprolactinemia in psychotic patients (Hoffer et al. 2009). Hoffer and colleagues (2009) reported, in a literature review including 17 studies, that aripiprazole lowered prolactin levels an average of 74%.
Inquiry regarding potential prolactin-related adverse effects should be systematically undertaken in each child/adolescent treated with risperidone. The presence of symptoms is an indication for obtaining a serum level. Correll and colleagues (2006) recommend that if the level is less than 200 ng/mL dosage, reduction or switch to a prolactin-sparing drug is indicated (Correll and Carlson 2006). If the prolactin level is > 200 or persistently elevated with a prolactin sparing drug, MRI scan of the sella turcica is recommended.
Disclosures
Dr. Jummani has no conflicts of interest or financial ties to disclose. Dr. Coffey has received research support from Eli Lilly Pharmaceutical, Tourette Syndrome Association, Bristol-Myers Squibb, and Boehringer Ingelheim.
Footnotes
Acknowledgments
We would like to acknowledge the contribution of Stephanie Samar, M.A. in editing the manuscript.