Abstract
Chief Complaint and Presenting Problem
E
History of Present Illness
E.'s onset of illness began in the first two years of life when her parents began to note delays in her speech and motor functions; she received early intervention and speech therapy at school. She was subsequently evaluated by a behavioral neurologist for perseveration of routines, poor relatedness, and limited social imitative play which resulted in a diagnosis of PDD NOS. She received specialized educational instruction.
Around puberty, E. had demonstrated a pattern of worsening irritability, decreased need for sleep, hyperkinetic behavior, and increased productivity two to four days prior to menses with resolution of symptoms within the first few days of menses. At the age of 13, E. was first hospitalized for the management of abrupt mental status changes, and possible mania, and treated with risperidone 1.5 mg daily. During this 5-day hospitalization, E. reportedly had an adverse reaction to risperidone, which resulted in catatonic-like features, rigidity, and autonomic dysregulation suggestive of neuroleptic malignant syndrome (NMS). Organic etiologies were ruled out and a diagnosis of BD was made. She was discharged on lorazepam 1 mg twice daily and diphenhydramine 50 mg at bedtime with outpatient follow-up.
At age 15, E. was re-hospitalized for acute mania characterized by global insomnia, irritability, distractibility, increased goal-directed activity, and pressured speech. During the hospitalization her manic symptoms reduced significantly with an increase of lamotrigine to 100 mg daily from 75 mg daily, reinitiation of oral contraceptives for menstrual mood variations, reduction of aripiprazole from 5 mg to 2.5 mg, and addition of quetiapine at 100 mg at bedtime. Following discharge, E. returned to her functional baseline.
A few months later, E.'s psychopharmacologist discontinued quetiapine and lamotrigine due to excessive sedation. E. remained only on oral contraceptives, given a previously noted pattern of premenstrual exacerbation of manic symptoms beginning a few days prior to menses with remission early in menses. She was subsequently manic-symptom free for over a year.
Three days prior to the current admission E. was brought to the emergency department by her mother for a precipitous exacerbation of her manic symptoms. Mother reported that E. experienced episodic agitation, refusal of food and fluids, global insomnia with increased goal-directed activity, distractibility, motoric hyperactivity, increased quantity and rate of speech, and affective lability. These symptoms and aggressive behavior of hitting her mother represented a marked departure from her functional baseline. E.'s symptoms did not remit despite a rapid increase of quetiapine to 400 mg and lorazepam 1 mg three times a day by her outpatient psychopharmacologist. Precipitants of this episode included recent placement in the residential program of her school, possibly resulting in altered sleep-cycle, and recent verbal bullying at school by peers due to her frequent expression of her love for her boyfriend. E. was also noted to be in the luteal phase of her menstrual cycle during this time.
Mother denied E. had any known history of self-injurious behavior, aggressive behaviors outside of manic episodes, or suicide attempts.
Past Psychiatric History
E. had a history of two prior hospitalizations for similar presentations consistent with mania as described above. She does not have a history of suicidal, homicidal, or paranoid ideation. Psychological testing performed at age 10 revealed an IQ of 54 and deficits in abstract thinking, receptive language, planning, and reasoning, leading to her diagnosis of intellectual disability.
Developmental History
E. was the product of an uneventful, full-term pregnancy. Mother denied in-utero exposure to recreational drugs or alcohol. At age two, E.'s family began to note delays in her speech and motor functions for which she received early intervention and speech therapy at school. Eventually a diagnosis of PDD NOS was made when E. was in preschool.
Educational History
E. received early intervention services in preschool. She currently has an Individualized Education Plan and is a ninth grader in a school for children with specialized disabilities.
Social History
E. lives with her mother, father, and three brothers. E.'s interests include playing basketball, cheerleading, arts, and music. When well, she is reported to be calm, happy, and loving. She requires her mother's assistance for the completion of activities of daily living (ADLs) and instrumental activities of daily living (iADLs). E. had been verbally bullied by male classmates several times within the past school year. E. was in a relationship with an intellectually disabled 16-year-old boy classmate; she frequently expressed her love for him and desire to marry him.
Family History
E. has a maternal family history of unipolar depression and completed suicide. She has a paternal family history of alcohol abuse, Werdnig-Hoffman syndrome, and unknown psychiatric disorders.
Medical History
E. has no chronic medical problems, hospitalizations, or surgery. She had no history of any major childhood illnesses and had received all her appropriate vaccinations. E. had normal growth and development and reached menarche at age 11.
Medication History
E. had had previous trials of risperidone, aripiprazole, quetiapine, and lamotrigine. She reportedly experienced an adverse reaction to risperidone at 1.5 mg daily with catatonic features resembling neuroleptic malignant syndrome, leading to its discontinuation within the first week of initiation. Aripiprazole up to 5 mg daily, quetiapine up to 400 mg daily, and lamotrigine up to 100 mg daily were discontinued gradually within 4 months of initiation due to lack of efficacy and excessive sedation.
Mental Status Examination on Admission to Hospital
E. was an adequately groomed adolescent girl. Her behavior was notable for scant eye contact, fair relatedness, and moderate motoric hyperactivity evidenced by fidgeting and impulsively slapping the emergency department nurse. There was no evidence of tremor or tics. Speech was notable for increased production, dulled tonality, and impaired pragmatics of language. She reported a “sad” mood with labile affect. Her stream of mental activity was concrete and tangential. There was no evidence of overt psychotic symptoms, although at times E. appeared to be talking to herself. There were no self-injurious behaviors, perceptual disturbances, thoughts of self-harm or violent ideation. Insight and judgment were significantly compromised.
Hospital and Treatment Course
Upon admission, E. was taking quetiapine 400 mg at bedtime and lorazepam 1 mg three times a day, which had been initiated by her outpatient psychiatrist one week prior to admission to target mania. Due to lack of response, her medication was switched to olanzapine and valproic acid, and gradually titrated upward to therapeutic effect which was achieved at doses of 20 mg daily and 1750 mg daily, respectively. During the medication change E. continued to exhibit erratic sleep, episodic agitation, aggression toward staff, and affective lability. Clonazepam 1 mg twice daily and benztropine 1 mg twice daily were initiated with minimal improvement for akathisia and muscle rigidity.
Olanzapine was initially increased to 20 mg daily; however, due to significant akathisia, rigidity, and new onset hyperprolactinemia, it was reduced to 5 mg at bedtime; these adverse effects eventually resolved. However, as olanzapine was reduced, E.'s manic symptoms, including insomnia, hyper-productivity and agitation, recurred. Valproic acid (VPA) was increased to 1750 mg daily with some improvement in her manic symptoms; however E. subsequently developed a rash, and VPA was discontinued. E.'s persistent manic symptoms were complicated by daytime and nighttime enuresis and encopresis secondary to mania. At that point, E. was restarted on quetiapine, which was quickly increased to 800 mg daily.
Over the course of her two-month hospitalization, the frequency and intensity of E.'s outbursts decreased and her compliance with directions and participation in group therapy increased. Her oral contraceptive was continued to minimize affective variations during her menstrual cycle with moderate effect. E. demonstrated her prior pattern of worsening irritability, decreased need for sleep, hyperkinetic behavior, and increased productivity two to four days prior to menses and resolution of symptoms within the first few days of menses during the hospitalization.
Improvements in her excessive activity, sleep, and speech symptoms were noted on discharge; however, residual episodic agitation persisted. It was felt that much of E.'s behavioral disturbance was due to environmental causes, such as noise level on the unit, change in routine, and lack of suitable activities, rather than untreated mania; this was confirmed when E. went on long passes off the unit and demonstrated better behavioral control.
During the hospitalization, E. experienced episodes of dysautonomia marked by tachycardia, hypertension, pupillary dilation, confusion, and slurred speech. VPA toxicity was ruled out, given sub-therapeutic VPA levels, normal liver function tests, and normal serum ammonia. Neurology and endocrinology consultants pursued secondary causes of dysautonomia, such as autoimmune/inflammatory disease, thyroid disturbance, heavy metal toxicity, and pheochromocytoma. E.'s medical workup was unremarkable. At discharge, the etiology of these symptoms remained unclear, although her underlying mania was presumed to be the most likely cause.
Brief Formulation
In summary, E. is a 16-year-old adolescent girl with a history of PPD NOS, ID and BD and a consistent pattern of premenstrual exacerbation of manic symptoms and aggressive behavior leading to hospitalization. Her history was notable for a pattern of rigidity related to transitions, impaired sensory stimulus regulation, and receptive language deficits. Her coping mechanisms were limited and maladaptive. Her family history conferred a genetic diathesis for affective illness. Precipitating factors of her current hospitalization included her transition to a residential environment, experience of verbal bullying, and a change in teachers. Despite symptoms of autistic spectrum disorder (ASD), E. had demonstrated significant developmental progress. She had many strengths including a supportive family, a romantic relationship, capacity for play, and a positive self-concept.
Multi-Axial Diagnoses
Discussion
This case represents the challenges in diagnosis and management of acute mania in adolescents with bipolar disorder in the context of ASD and significant menstrual variability. E.'s presentation of marked affective lability, behavioral dysregulation, neuroleptic refractoriness, development of medication adverse effects and dysautonomia in the course of treatment were complex phenomenology and comorbidity. As a result, it was difficult to disentangle symptomatology and prioritize evidence-based treatment, given a paucity of information and lack of systematic study of this subset of the adolescent population. An additional challenge in the treatment of mania in this population is the patient's inability to articulate mood symptoms or side effects, as well as the task of differentiating affective and behavioral fluctuations caused by the underlying autistic disorder versus her mood disorder.
Children with ASD experience a greater burden of comorbid mental illness than the neurotypical population (Simonoff et al., 2008). Family and genome wide association studies have suggested that ASD and BD share common genetic underpinnings (Lee et al., 2013). The prevalence of bipolar disorder in children with autism has not been clearly described, although several authors have found high rates of co-occurrence (Frazier et al., 2002; Munesue et al., 2008). In one recent study of second generation antipsychotic treatment of youth with comorbid bipolar disorder and ASD, of the 151 BD subjects, 15% (n=23) met criteria for comorbid ASD (Joshi et al., 2012). Secondary analysis of similarly designed 8-week open-label trials of risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole revealed no differences in the rate of antimanic response (YMRS change ≥30% or CGI-Improvement≤2: 65% vs. 69%; p=0.7) in the presence of comorbid ASD. The authors concluded that there was no difference in the rate of antimanic response or tolerability of second generation antipsychotics in the presence of ASD comorbidity.
The impact of hormonal fluctuation during the menstrual cycle on the course of BD is also poorly understood, especially in the adolescent population. Steroid hormones have been shown to affect the regulation of multiple neurotransmitters (Steiner et al., 2003). An increase in steroid hormones, such as estrogen during puberty, can alter the sensitivity of neurotransmitters leading to symptoms such as irritability and dysphoria (Steiner et al., 2003). Premenstrual exacerbation of BD has been reported in up to 65% of women in prospective studies, but little is known about the clinical implications of this association (Dias et al., 2011). A longitudinal follow-up study from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that adult women with BD and premenstrual exacerbation had a worse course of illness, as evidenced by more frequent relapses, more severe symptoms, and a poorer therapeutic response (Dias et al., 2011). An increased susceptibility of mood to fluctuating hormone levels in BD may result in mood destabilization, although direct causal information is not available. Another possibility is that insomnia associated with premenstrual dysphoric disorder (PMDD) results in mania precipitation during the luteal phase of the menstrual cycle (Strine et al., 2005). This widely prevalent, albeit understudied and heterogeneous phenomenon has significant implications on the long-term management of these patients. Several case studies have shown reduction in menstrual mood fluctuations by use of adjunctive oral contraceptives (OCPs) in patients with PMDD and BD (Frey & Minuzzi, 2012). Further studies implementing prospective mood and menstrual cycle charting are needed to determine if hormone stabilization through continuous OCP use in this population would result in reduction in illness severity.
Given the diagnostic complexity of E.'s case, psychopharmacologic treatment was aimed at stabilizing her mood with quetiapine, and hormonal variation with combination oral contraceptive therapy. More studies of the role menstrual mood fluctuation plays in the context of major affective illness are needed in the adolescent population. Replication of results of pharmacotherapy studies in youth with comorbid bipolar disorder and ASD in larger and controlled trials is needed to delineate predictors and moderators of treatment response, to factors associated with treatment refractoriness, and adverse effect sensitivity in this population.
Footnotes
Disclosures
Drs. Vijapura and Maneta and Mrs. Schofield have no conflicts of interest or financial ties to disclose. Dr. Coffey has received research support from Eli Lily Pharmaceutical, NIMH, NINDS, Tourette Syndrome Association, Otsuka, Shire, Bristol-Myers, Pfizer, and Boehringer Ingelheim.
Acknowledgments
We would like to acknowledge and thank Laura Ibanez Gomez, Zoey Shaw, and Natasha Kostek for their assistance in review and preparation of the manuscript.