Abstract
Chief Complaint and Presenting Problem
C. was a 16-year-old adolescent boy with a history of autism spectrum disorder (ASD), intellectual disability (ID), and cerebral palsy (CP) who was brought to the emergency department (ED) by his mother due to worsening aggression and erratic behavior.
History of Present Illness
Mother reported that C. had been a quiet and reserved child with an abrupt change in mood and behaviors at the onset of adolescence, around age 12 years, including aggression, impulsivity, and poor frustration tolerance. He had a history of multiple psychiatric inpatient admissions and outpatient treatment including medication management and therapy; however, symptoms had been difficult to control. C's behavior continued to escalate into a more threatening nature, appearing more disorganized, leading to his current referral to the ED.
Mother referred C. for worsening aggression, including punching staff at school, and becoming violent at home, scratching, and hitting family. Mother also reported that C. threatened his outpatient therapist, leading her to terminate care and discharge him from the clinic due to safety concerns.
Upon initial evaluation in the ED, C. was disorganized, hyperverbal, with pressured speech, and flight of ideas. C. frequently changed the topic of conversation, was difficult to interrupt, and spoke of illogical and vague ambitions for the future. Mother reported prior episodes in which C. had reported feeling down and depressed, followed by elevated affect, pressured speech, and apparent decreased need for sleep and goal-directed activity over the past 2 to 3 weeks.
Psychiatric History
Mother reported that C.'s symptoms began around age 12 years, with abrupt changes in mood and behavior. Over the next 6 months, symptoms progressed with outbursts of violent behavior, which progressed to causing physical harm to parents, siblings, and staff at school. At that time, mother noted impulsivity and hypersexuality, reportedly masturbating up to six to eight times per day. Shortly after C. turned 13 years old, he was hospitalized in an inpatient psychiatric unit at an outside facility, which, as per parents, was the first time he was seen by a psychiatrist. He was started on clonidine 0.1 mg po bid for impulsivity and mirtazapine 15 mg po qhs for mood and sleep and was discharged with outpatient follow-up.
Aggressive behavior continued and the patient was admitted 5 weeks later to an academic medical psychiatry inpatient unit. Mirtazapine 15 mg po qhs was continued for mood and sleep; clonidine was discontinued, and he was started on risperidone 1 mg po qhs for aggressive behavior in the context of ASD, ID, and CP. He was discharged to outpatient follow-up.
Over the next 2 years, C. was followed on an outpatient basis at another facility, and symptoms were reported to have been well controlled with medication management and behavior therapy. During this time, lorazepam 1 mg po qhs was added for sleep and anxiety, risperidone was discontinued due to cramps in the right calf, and aripiprazole 5 mg po daily was started. There were no other reported inpatient admissions during this period.
At age 15 years, C. was briefly admitted for observation of worsening aggression with bizarre behavior and paranoia. Mother reported that he had become suspicious and distrustful, felt that family was after him, and became sexually preoccupied with his behavior therapist, and made comments about strangers impregnating his sister. Violence escalated such that C. tore off his mother's shirt sleeve and scratched her, bent her wrist joint backward, and destroyed items around the house. He was subsequently discharged on home medication regimen. During outpatient follow-up with psychiatry, lorazepam dose was decreased to 0.5 mg and zonisamide 50 mg was started for “anger management”; there was no reported history of seizures for which zonisamide was indicated.
C. presented to the academic psychiatry ED 5 weeks later with ongoing symptoms of aggression and was admitted to the inpatient unit for treatment. During admission, mirtazapine was tapered and discontinued; sertraline was started for impulsivity, and hydroxyzine was started for insomnia. C. was discharged to outpatient follow-up on aripiprazole 10 mg po daily, zonisamide 50 mg po daily, sertraline 25 mg po daily, and hydroxyzine 50 mg po qhs. He continued with outpatient follow-up and hydroxyzine and zonisamide were discontinued gradually. However, aggressive symptoms persisted, ultimately leading to the current presentation to the ED and admission to inpatient psychiatry.
Developmental History
C. was the product of an uncomplicated full-term pregnancy. He was born through spontaneous vaginal delivery in Cuba, reportedly weighing 8 pounds, and was subsequently discharged home with parents after a routine 3-day hospital stay. Although attempts to confirm birth records were unsuccessful, recall bias was suspected, as there were no other clinical conditions suggestive of significant fetal macrosomia.
C. was delayed in motor and language milestones. He began to crawl around 9 months, but was noted to drag his legs behind him; he walked at age 4 years, and continues to require support with sitting due to CP. C. was able to first hold a small object in his hands at age 12 months, and transfer from hand-to-hand after 14+ months. Regarding language, he began to babble at 8 months, said his first words around 12–13 months, and began using short phrases after 24 months. C. also experienced social delays, including poor eye contact in the first year of life, which later improved, and limited peer relationships.
Educational History
C. was in the 10th grade at special education private school where he received accommodations for ID and ASD. He received passing grades in all his classes and had no history of school suspensions or expulsions.
Social History
C. was raised in Cuba until age 11 years at which time he moved to the United States. Mother was the primary caregiver as his parents divorced when he was a toddler, though mother later remarried. He was currently living with mother, stepfather, and older sister.
C. had no history of alcohol, nicotine, or illicit drug use and mother denied any history of physical abuse or neglect. She did endorse that C. and his sister had been victims of sexual abuse in Cuba but had no contact with the perpetrator since moving to the United States. C. denied any romantic relationships and was not sexually active at the time of evaluation. His hobbies included spending time with his family, watching movies, and learning about photography and videography.
Family History
Family history was significant for alcohol use disorder in maternal grandfather. There was no other known family history of psychiatric illness and no known history of suicide.
Medical History
C. had a history of CP and a prior surgical history of bilateral medial hamstring lengthening, bilateral Achilles lengthening, and anterior tibial tendon transfers. There was no known history of seizures, loss of consciousness, or traumatic brain injuries. He had no known allergies, and vaccinations were up to date. C. had full range of motion in upper and lower extremities, though with mild tightness in bilateral hips and increased tone of lower extremities. He had good control of neck muscles and fair control of trunk, which improved with sitting.
He had a wide-based crouched gait, with limited heel strike worse on the left side than right. C. was able to ambulate independently and continued to follow-up with physical medicine and rehabilitation for management. Initial laboratory evaluation was unremarkable.
Medication History
C. had been tried on several psychotropic medications for aggression and associated symptoms of mood and impulsivity.
Year 1: C. was hospitalized in August and initiated on mirtazapine 15 mg po qhs and clonidine titrated to 0.1 mg po bid. In September, during an inpatient admission, clonidine was discontinued due to poor effect, mirtazapine was continued at 15 mg po qhs, and risperidone 1 mg po qhs was started for aggressive behavior.
Years 2–3: C. was followed in the outpatient clinic. Risperidone was increased up to 2 mg po qhs, but subsequently discontinued due to side effects of cramps in the right calf, and aripiprazole 5 mg po daily was started for aggressive behavior. Lorazepam 1 mg po qhs was added for sleep and anxiety; mirtazapine 15 mg po qhs was continued. Several months later, lorazepam was decreased to 0.5 mg po qhs due to concerns of disinhibition.
Year 4: Zonisamide was titrated to 50 mg po daily for “anger management.” Several months later during admission, aripiprazole was increased to 10 mg for aggression, and zonisamide 50 mg po daily was continued. Sertraline 25 mg po daily was started for impulsivity and hydroxyzine 50 mg po qhs was started for insomnia. Mirtazapine was discontinued due to poor effect.
C. was discharged to outpatient follow-up on aripiprazole 10 mg po daily, zonisamide 50 mg po daily, sertraline 25 mg po daily, and hydroxyzine 50 mg po qhs. He continued with outpatient follow-up and hydroxyzine and zonisamide were discontinued gradually. However, aggressive symptoms persisted, ultimately leading to the current admission to inpatient psychiatry.
Mental Status Examination
On initial mental status examination, C. appeared his stated age, was well nourished, and well developed, though disheveled and poorly groomed. He was alert and oriented, to person, year (not month and day), and general place (not city or state), as corroborated by mother, and limited by developmental delays and ID. He maintained fair eye contact. His speech was clear and coherent but pressured and hyperverbal. He was pleasant and cooperative, yet easily distracted during the interview.
He had a euphoric mood with restricted affect. Bizarre preoccupations, such as pencil sharpeners, and puberty, and some grandiosity, were elicited. Thought process was disorganized, illogical, characterized by flight of ideas. He denied auditory or visual hallucinations and did not appear internally preoccupied; no paranoia was elicited. He denied suicidal or homicidal ideation. He exhibited poor insight and judgment.
Brief Formulation
In summary, C. was a 16-year-old adolescent boy with a history of ASD, ID, and CP who was referred to the ED for recurrent episodes of worsening aggressive behavior with a threatening quality. C. was noted to be illogical and disorganized on evaluation, with pressured and hyperverbal speech, and difficult to engage. Predisposing factors include CP, which is associated with higher rates of both ASD and mood disorders. Precipitating factors include puberty, with symptom onset and clear changes in mood occurring at age 13 years. Perpetuating factors included multiple previously failed medication trials with recurrent symptom exacerbations requiring inpatient admissions. Protective factors include support from mother, engagement and access to mental health treatment, and hobbies and interests.
Multiaxial Diagnoses
Axis I: ASD
Bipolar disorder
Axis II: Borderline ID
Axis III: CP
Axis IV: Family stressors; history of sexual abuse
Axis V: Global Assessment of Functioning 16 at initial presentation, 60 on most recent visit
Treatment Course
On admission, C. was diagnosed with comorbid bipolar disorder (BD). He was continued on sertraline 25 mg po daily for impulsivity given no clear correlation between current symptoms and initiation of antidepressant medication. Mother recalled prior good effects with risperidone, which had been discontinued due to side effects of cramps in the right calf. It was unclear whether these symptoms were related to the history of CP or extrapyramidal side effects (EPSs) of antipsychotics; however, given prior response, risperidone was restarted at 0.5 mg po qhs as a mood stabilizer and for aggressive behavior. Benztropine 1 mg po daily was added for prevention of EPS. Aripiprazole was discontinued.
Neurology was consulted to rule out organic causes of aggressive behavior given poor response to treatment and recurrent hospitalizations. Laboratory workup, including complete blood panel, complete metabolic panel, thyroid panel, ammonia levels, and sedimentation, was unremarkable.
Medications were optimized and C. was discharged shortly after on a regimen of risperidone 1 mg po daily and 2 mg po qhs, sertraline 50 mg po daily, benztropine 0.5 mg po daily, and 1 mg po qhs.
Three weeks later, C. presented to the ED after grabbing a glass, crushing it, and throwing it at his mother and sister. On evaluation, he was threatening and aggressive, requiring chemical restraints and seclusion for safety. He was readmitted to the inpatient unit and observed to be hypersexual, voicing religious delusions, and with nonsensical thought process. Mother requested social work assistance with group home placement, given frequent readmissions and ongoing aggressive behavior, as she did not feel comfortable with C. returning home on discharge.
During this most recent admission, valproic acid was added for mood stabilization and titrated up to 500 mg po bid, risperidone was increased to 2 mg po bid for aggressive behavior and benztropine was increased to 0.5 mg po bid for EPS prevention. Sertraline was also titrated to 100 mg po daily for impulsivity and trazodone 50 mg po qhs was started for sleep. Throughout admission, psychomotor agitation resolved, and the aggressive behavior and mood lability improved. C. tolerated this medication regimen well and was discharged in stable condition. C. was able to return with outpatient follow-up.
Discussion
This case highlights the importance of keeping a developmental perspective in mind, especially in adolescents who present with difficult-to-treat aggressive behavior in the context of ASD, ID, and CP. Our patient had undergone several different failed medication trials until he was eventually diagnosed with comorbid BD and appropriately treated with a classical mood stabilizer.
Children with ASD have a higher risk of developing comorbid psychiatric disorders than their neurotypical peers (Frazier et al, 2002), and most will develop a co-occurring condition at some point in their lives (Cawkwell et al, 2016; Guinchat et al, 2015; Sapmaz et al, 2018). This co-occurrence increases the disease burden of ASD, not only for the child, but to their caretakers and support network as well. Although there is discrepancy in the literature regarding the prevalence of co-occurring ASD and BD, BD is commonly associated with ASD (Dunalska et al, 2021; Espluga-Frigola et al, 2017; Frazier et al, 2002; Joshi et al, 2013; Skokauskas and Frodl, 2015).
Given the dysfunctions in language and emotional processing frequently seen in patients with ASD, traditional assessment measures commonly used in psychiatric evaluations may be difficult to apply, as was the case with C. At the same time, psychiatric comorbidities may have an atypical presentation in children with ASD, contributing to the difficulty in making an accurate diagnosis (Cawkwell et al, 2016; Vannucchi et al, 2014). Moreover, the diagnosis of BD in children and adolescents with ASD is specifically challenging, as there is a significant overlap in the symptoms of both conditions.
Distractibility, irritability, dysphoric mood, sleeplessness, psychomotor agitation, and poor impulse control, often seen in patients with ASD, are also seen in episodes of mania in patients with BD (Cawkwell et al, 2016; Gutkovich et al, 2007; Limbu et al, 2022; Sapmaz et al, 2018; Skokauskas and Frodl, 2015). Clinical features of the emotional dysregulation and language-processing problems characteristics of ASD may be perceived as mood swings, for example, when a child with ASD becomes upset when overwhelmed with sensory inputs or environmental changes (Gutkovich et al, 2007; Sapmaz et al, 2018). At the same time, mood symptoms may be masked by worsening intrusiveness of behaviors associated with ASD, such as stereotypes, social isolation, aggression, and self-injury.
Aggression is frequently the primary reason for referral for psychiatric evaluation, as with C. He initially responded to pharmacological treatments commonly used for behavioral disturbances, such as second-generation antipsychotics and alpha-1 agonists (Fallah et al, 2019; Joshi et al, 2012; Limbu et al, 2022). However, he also presented with episodic changes in his baseline, with worsening aggression, grandiosity, disorganized speech, and paranoia, which were severe in phenomenology and refractory to the usual treatment.
The emergence of new or worsening behavioral changes in patients with ASD may indicate the occurrence of another comorbid disorder (Cawkwell et al, 2016; Dunalska et al, 2021; Sapmaz et al, 2018; Skokauskas and Frodl, 2015). Since there is no specific pharmacological treatment for the core deficits of ASD, making an accurate diagnosis may help guide treatment choices to improve functioning (Borue et al, 2016).
There is no consensus on the treatment of irritability and aggressive behavior in children with ASD. Many studies showed different results with different classes of medications, including antipsychotics, different classes of antidepressants, stimulants, and others (D'Alò et al, 2020; Fung et al, 2016; Loy et al, 2017; Persico et al, 2021; Pesko et al, 2020; Williams et al, 2013). C.'s behavioral disturbances had responded to different combinations of drugs in different moments of his treatment; however, despite good adherence with the regimen, he experienced intermittent relapses requiring hospitalization for severe decompensation. It was not until the diagnosis of BD was considered, and he was started on a classical mood stabilizer, that he was able to achieve remission of symptoms and stability for a longer period.
It is important to note that the existing literature in treating co-occurrence of BD and ASD is sparse. Some studies have shown success with the use of electroconvulsive therapy for youth with history of BD and ASD (Siegel et al, 2012; Wachtel et al, 2011). Studies focused on psychopharmacological options suggest that second-generation antipsychotics and mood stabilizers, such as lithium and valproic acid, may show some response, but there are not enough data available that favor one medication over another (Amadori et al, 2022; Joshi et al, 2012; Rysstad et al, 2020; Sesso et al, 2022).
Novel treatment options may be available in the future, as studies are exploring effects of different substances and approaches, such as folate and its derivatives, metformin, and stem-cell and gene therapy for psychiatric disorders (Dodd et al, 2022; Lam et al, 2022; Shahcheraghi et al, 2022).
Of note, C. had other risk factors that could be contributing to his difficult-to-manage behavior and psychiatric symptoms, besides underlying comorbid BD. Literature has revealed that children and adolescents with CP have increased risk of developing psychiatric conditions and may present with behavioral disturbances not associated with a co-occurring psychiatric disorder (Belmonte-Darraz et al, 2021; Colver, 2010; Cooper et al, 2022; Parkes et al, 2008; Sigurdardottir et al, 2010). C. also had a history of sexual abuse, for which details have not been able to be clarified.
Many studies have associated behavioral disturbances in children and adolescents with a personal history of different types of abuse, including sexual (Burgić Radmanović, 2020; Connor et al, 2003; Lesmana et al, 2015). Children with IDs who suffered sexual abuse may have a more severe presentation (Rittmannsberger et al, 2020; Smit et al, 2019); biological risk factors, social determinants, previous diagnosis, and comorbid conditions may play a role in presenting symptoms or problematic behavior, so treatment can be tailored accordingly.
As Sir William Osler once said, we “treat the patient that has a disease, not the disease a patient has” It is important to consider a patient's life history, biological risk factors, social determinants, previous diagnosis, and comorbid conditions that play a role in symptom presentation or problematic behavior, so treatment can be tailored accordingly, and better outcomes can be achieved.