Management of COVID-19 Infection-Associated Flare in an Adolescent with Pediatric Acute Neuropsychiatric Syndrome and Obsessive-Compulsive Disorder

Chief Complaint and Presenting Problem

K. was a 14-year-old adolescent boy initially referred by his rheumatologist at 9 years of age for psychiatric evaluation of temper tantrums.

History of Present Illness

Parents reported that since very early childhood K. had had a history of poor eye contact; sensitivity to sounds, textures, and food; and social difficulty, especially engaging with other children, as he perseverated on his interests. In addition, parents reported that K. had exhibited inattention symptoms since he started kindergarten. K. had been diagnosed with autism spectrum disorder (ASD) at age 19 months, and attention-deficit/hyperactivity disorder (ADHD), inattentive presentation, and seizure disorder at age 7 years by a pediatric neurologist.

In addition, K. had been diagnosed with autoimmune encephalitis at age 8 years when he started to wring his hands, lost his ability to write, developed tics, and started to urinate on himself. He was treated with intravenous immunoglobulin (IVIG) and azithromycin that resulted in significant improvement in these symptoms.

In this context, K. was initially referred for psychiatric evaluation at age 9 years for temper tantrums, anxiety, perfectionism, intrusive thoughts, obsessions, and compulsions. Parents reported that symptoms had become apparent abruptly after his diagnosis of autoimmune encephalitis 1 year before referral. They reported that he was losing his temper four to five times daily, occurring mainly at home with his brother and with neighbors; he was occasionally becoming physically aggressive and had bitten, punched, and hit other kids, mostly triggered by something not going in his way.

Parents reported K. had developed intrusive thoughts such as worries that they would be kidnapped or that “black holes” were coming; obsessions about perfectionism, for example, grades had to be stellar; and compulsions of checking, seeking reassurance, counting, and skipping.

Psychiatric evaluation of K. at age 9 years had yielded diagnoses of obsessive-compulsive disorder (OCD) after an abrupt onset after autoimmune encephalitis, pediatric acute neuropsychiatric syndrome (PANS), ADHD, inattentive presentation, and ASD. He was started on sertraline 25 mg po daily for OCD symptoms with a plan to titrate the dose as tolerated and was referred for applied behavioral analysis therapy.

Psychiatric History

Parents report K. had received physical, occupational, and speech therapy in the past for ASD. He was currently receiving individual psychotherapy and had participated in play groups at school. There was a plan for parents to start family counseling at school.

Developmental History

K. was born preterm through cesarean section at 30 weeks gestational age to a nurse who worked in a nuclear catheterization laboratory until 8.5 weeks of pregnancy. K. had had a twin with fetal demise.

Birth weight was 1.5 kg. K. required oxygen for the first 48 hours, developed mild jaundice, and stayed in the neonatal intensive care unit (NICU) for ∼6 weeks. He experienced mild delays in fine motor and speech development. As a toddler, he had displayed limited eye contact and difficulties in two-way conversation, focusing on his own interests. He was also reported to align cars and trains, spin wheels for hours, and flap his hands. He was sensitive to certain food textures and sounds. Toilet training was delayed and occurred ∼4.5 years of age.

Parents report that K. was able to catch up on his developmental milestones after receiving intensive physical, occupational, and speech therapy.

Educational History

K. had been enrolled in the life skills and education for students with autism and pervasive behavioral challenges program at age 2 years that reportedly facilitated a relatively smooth transition to kindergarten and elementary school. He was currently in eighth grade in a public school and had been successful academically, receiving all A's.

Social History

K. was born and raised by both parents in an urban area. He was living with both parents and a brother 2 years younger. Parents denied K. had used illicit drugs, alcohol, or nicotine, and denied any history of sexual, physical, or emotional trauma. K. did not report a current romantic relationship.

Family History

Each parent had been diagnosed with anxiety and depression. K.'s brother was diagnosed with dyslexia and delayed speech. Mother had also been diagnosed with polycystic ovarian syndrome, unspecified allergies, and mixed connective tissue disease, a rare autoimmune disorder.

Medical History

K. had no history of loss of consciousness, or traumatic brain injury. K. was diagnosed with a seizure disorder at age 7 years and had been treated with levetiracetam 300 mg bid for prophylaxis. He had been diagnosed with autoimmune encephalitis at age 8 years; he required treatment with IVIG and azithromycin that resulted in significant improvement in symptoms.

K. had had an inguinal hernia repair, tonsillectomy and adenoidectomy, and myringotomy. He was known to be allergic to dexmedetomidine and oxcarbazepine. Vaccinations were up to date.

Medication History

K. was treated with methylphenidate extended-release (ER) 18 mg daily for ADHD symptoms. He was receiving IVIG monthly, levetiracetam 300 mg twice daily, azithromycin 250 mg daily, a multivitamin, vitamin C, vitamin D3, probiotics, and lactoferrin.

Mental Status Examination

On initial mental status examination, K. was casually dressed, appeared his stated age with appropriate grooming and hygiene, and displayed no dysmorphic features. His sensorium was intact with full orientation to time, place, and person. He intermittently made eye contact. His speech was clear, and coherent but with limited prosody. He was cooperative but was easily distracted. He was anxious with constricted affect. He displayed linear and organized thought process with content significant for excessive worries, perfectionism, intrusions, obsessions, and compulsions. He denied any perceptual disturbances and did not appear to be responding to internal stimuli. K. denied suicidal or homicidal ideation. He exhibited fair insight and judgment.

Formulation

In summary, K. was a 14-year-old adolescent boy with history of ASD, ADHD, and seizure disorder who was initially referred to child and adolescent psychiatry for evaluation of temper tantrums, anxiety, perfectionism, intrusive thoughts, obsessions, and compulsions at age 9 years after an episode of autoimmune encephalitis that yielded diagnoses of OCD and PANS.

Predisposing factors included a history of premature birth in the context of suspected intrauterine radiation exposure and a protracted NICU stay, and delays in fine motor and social development. Medical predisposing factors included a seizure disorder, autoimmune encephalitis, and genetic vulnerability as evidenced by a family history of autoimmune disease and psychiatric disorders. Precipitating factors included new onset PANS symptoms, perpetuated by the chronic fluctuating course and nature of PANS that required long-term IVIG treatment. Protective factors included a normal neurological examination, success in academic tasks, strong social support from well-educated parents, and adherence with treatment recommendations.

Multiaxial Diagnoses

Axis I: OCD

ADHD, inattentive presentation

Autistic spectrum disorder (ASD)

Unspecified anxiety disorder

Axis II: No suspicion of intellectual disability or personality disorder

Axis III: Seizure disorder

PANS

Autoimmune encephalitis, past

Inguinal hernia repair, past

Tonsillectomy and adenoidectomy, past

Myringotomy, past

Axis IV: Family history of autoimmune disease and psychiatric disorder

Suspected intrauterine exposure to radiation

Axis V: 31 on initial encounter; 70 on latest follow-up

Treatment Course

During initial follow-up visits at 9 years of age, K. showed gradual improvement in anxiety, obsessions, and compulsions, as sertraline was titrated up to 75 mg daily within 4 weeks and maintained for ∼6 months. He also received continued treatment for PANS with IVIG 100 g monthly, azithromycin 250 mg daily, and prednisone 20 mg daily for few days when receiving IVIG.

K. had a flare in his OCD symptoms that initially began with a period of upper respiratory infection. Sertraline was gradually increased to 125 mg daily with good response in anxiety and OCD symptoms for several months. However, he started to develop worsening psychiatric symptoms monthly or every other month lasting roughly about a week, characterized by breakthrough anxiety and worsening OCD and inattention. He was started on buspirone 5 mg daily as needed during days with increased symptoms with some reported benefit.

K.'s neurologist switched his methylphenidate ER 18 mg/day for worsening inattention to lisdexamfetamine 20 mg/day and titrated it to 30 mg daily with good response. His rheumatologist started him on mycophenolate mofetil 1500 mg daily for better control of PANS symptoms. K.'s anxiety and OCD symptoms were well controlled in between flares for the following 9 months.

When K. was 11 years old at the beginning of the school year, he experienced another severe flare. He was reported to be moody, loud, crying, and agitated, and frustrated since he was not able to remember skills he had just mastered in the past school year. His handwriting deteriorated and he developed severe insomnia.

K. underwent several additional psychopharmacological treatments including melatonin, hydroxyzine, diphenhydramine, clonidine, and trazodone at appropriate doses and durations. Among them only clonidine 0.1 mg bedtime and trazodone 100 mg at bedtime resulted in some benefit and he continued both as needed. Mother subsequently reported observing upper respiratory symptoms that suggested repeated exposure to viruses, raising concerns about flares of PANS. K.'s rheumatologist discontinued mycophenolate mofetil and started rituximab for PANS, and his neurologist increased levetiracetam dose to 400 mg twice daily. K. eventually was switched to home schooling 2 days a week.

Despite improvements in some symptoms, K.'s OCD symptoms were not well controlled with sertraline 125 mg daily. Sertraline was cross-titrated and switched to fluoxetine; the dose was gradually titrated up to 60 mg/day for 4 months and K. showed some improvement during the following 15 months of treatment.

To achieve further symptom relief of OCD and anxiety symptoms, several pharmacological strategies were considered. Augmentation with fluvoxamine 25 mg was subsequently initiated, then increased to 50 mg/day, resulting in a “greater than ever” good effect on OCD symptoms per mother.

K. remained on fluoxetine 60 mg/day, fluvoxamine 50 mg/day, and trazodone 50 mg bedtime for ∼10 more months with well-controlled symptoms and good functioning. He also continued on IVIG 100 g monthly, azithromycin 250 mg daily, levetiracetam 400 mg twice daily, and prednisolone 10 or 20 mg for a few days when receiving IVIG.

K.'s rheumatologist tried to decrease IVIG gradually from 100 to 70 g per month during this stable period. K. was functioning very well until family members developed COVID-19 infection, and later he himself tested positive for COVID-19. He was symptomatic with mild upper respiratory symptoms and developed another flare of extreme anxiety, crying spells, intrusive thoughts, and worsening obsessions. Mother described this flare as an acute departure from his baseline and described it as the “the worst attack ever.”

Although increasing his selective serotonin reuptake inhibitor (SSRI) dose or augmentation with a second-generation antipsychotic had been considered, they were not initiated due to concerns about serotonergic syndrome and side effects, respectively. The IVIG dose was increased to 100 g monthly per his rheumatologist and he was started on clonazepam 0.25 mg daily. K. showed dramatic improvement in his symptoms and was back to his baseline functioning within 2 weeks. Repeat COVID-19 polymerase chain reaction test was negative at the resolution of symptoms.

On his last visit, K. was on fluoxetine 60 mg/day, fluvoxamine 50 mg/day, trazodone 50 mg bedtime, clonazepam 0.25 mg daily as needed, IVIG 100 g monthly, azithromycin 250 mg daily, levetiracetam 400 mg twice daily, and prednisolone 10 or 20 mg for few days around IVIG infusions. He was clinically stable and had been functioning well in all daily activities.

Discussion

It is crucial to recognize the relationship between autoimmune processes and neuropsychiatric symptoms in the pediatric population. PANS is conceptualized as potentially having multiple etiologies, including underlying neurological, endocrine, or metabolic disorders, and postinfectious autoimmune and neuroinflammatory disorders (Swedo et al. 2017). K., who had an already known underlying neuroinflammatory condition, demonstrated PANS symptom exacerbation in temporal association with COVID-19 infection, suggesting SARS-CoV-2 as one of the multiple etiologies.

Neuropsychiatric sequelae related to COVID-19 have been demonstrated, more commonly in the acute phase of infection. Recent data suggest that acutely, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm (Tang et al. 2021). K.'s worsening psychiatric symptoms after COVID-19 infection suggest another link between inflammatory processes and neuropsychiatric disorders.

Neuropsychiatric symptoms may be related to microbial infection in the presence of dysregulated inflammatory/immune responses; data suggests that IVIG may reveal superior therapeutic effects in such conditions over antibiosis (Hersh et al. 2006). K.'s significant improvement in neuropsychiatric symptoms with IVIG dose increase appears to be consistent with this approach.

Although further studies are indicated, the link between autoimmune processes and family history may follow the pattern of genetic predisposition known as familial autoimmunity. K. had a maternal family history of mixed connective tissue disease that is a rare, however potentially important, predisposing factor that might have played a role in inheritance of neuronal vulnerability to inflammatory processes. Although nongenetic factors may influence familial aggregation, shared genetic factors, in fact, may be the more likely cause for this aggregation (Cárdenas-Roldán et al. 2013)^.

Diagnostic criteria for ASD, ADHD, and OCD intersect (Fairchild 2020). Interestingly, some data suggest a genetic link between ASD and OCD, through “shared genetic susceptibility” that might at least be partially responsible for the phenotypic overlap and frequent comorbidity of both disorders reported in epidemiological data on cross-disorder risk (Guo et al. 2017). K.'s psychiatric symptoms may be an example of this shared genetic susceptibility.

In addition, there is emerging evidence that intrauterine exposure to carcinogens such as radiation can lead to harmful effects on fetal development and early childhood. As highlighted in this case, fetal or neonatal exposure to radiation may be associated with an increased incidence of autism (Kane 2004).

It has been shown that neural projections from basal ganglia may influence frontal cortex that can sometimes present as frontal lobe seizures (Kane 2004). Our patient was diagnosed with a seizure disorder almost 2 years before his autoimmune encephalitis. However, it is unclear whether having a seizure disorder rendered him more vulnerable to the development of autoimmune encephalitis or PANS.

Treatment of comorbid PANS, tics, and OCD can be challenging due to the complexity of the course of the illness. A study by Thienemann et al. showed some improvement in OCD symptoms with antidepressant treatment, and it was preferable in comparison to antipsychotic treatment. Antipsychotic treatment can have many adverse effects if doses are increased too quickly, according to the study, and clinicians should be cautious about the changes in medications (Thienemann et al. 2021). Future studies are needed to investigate the role of antipsychotics or benzodiazepines independent of other treatments such as corticosteroids, cognitive behavioral therapy (CBT), and tonsillectomy in PANS treatment.

Currently antipsychotics and benzodiazepines play some role for mainly symptomatic relief of anxiety/OCD-related symptoms resistant to SSRIs and CBT. Addition of low-dose clonazepam, in combination with IVIG dose adjustment, was helpful in achieving symptomatic relief in our case.

Physicians treating cases with PANS, including patients exhibiting neuropsychiatric symptoms after COVID-19 infection, should be aware of recent recommendations for first-line treatments, as well as some off-label approaches. One line of research suggested that immunomodulatory therapies, such as IVIG, may lead to rapid and sustained symptom improvement in some patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)/PANS (Williams et al. 2016). IVIG dose adjustment and addition of low-dose clonazepam proved to be helpful in our case. However, it is important to note that there is a lack of established evidence base for treatment of PANS currently (Sigra et al. 2018).

In summary, this case highlights the complex interplay between autoimmune processes and neuropsychiatric symptoms in the context of maternal exposure to radiation during pregnancy, ASD, and ADHD. Prospective studies of larger patient populations are needed.