Anti-NMDA Receptor Encephalitis in a 12-Year-Old Girl

Anti-N-methyl-d-aspartate (NMDA) receptor (anti-NMDA-R) encephalitis has been an increasingly recognized cause of psychiatric symptoms since it was first identified in 2007. It is an autoimmune disease in which the body creates antibodies against NMDA receptors in the central nervous system, resulting in psychosis, impaired cognition, impaired memory, disordered speech, loss of consciousness, disordered movements, seizures, and autonomic dysfunction (1). It is often paraneoplastic, with ovarian teratoma as the most common associated neoplasm, although neoplasm frequency estimates vary widely (2). First-line treatment of the underlying pathology is immunotherapy, including intravenous (IV) steroids, IV immunoglobulin (IVIg), or plasmapheresis. If a tumor is involved, it is surgically removed, and the patient is treated with chemotherapy or radiation or both, if the tumor is cancerous (1, 2).

Despite this progress, there is a dearth of knowledge, especially in pediatric patients, of the optimal management of behavioral sequelae and psychotic symptoms, even though they are the most common symptoms in the first month of disease (2). Behavioral and psychotic symptoms contribute to morbidity, may complicate treatment, and may persist for months or years (3). Here we report a case of anti-NMDA-R encephalitis in a 12-year-old female, who experienced cognitive and behavioral issues that persisted following immunotherapy and surgery. We discuss management of psychiatric sequelae of pediatric anti-NMDA-R encephalitis in the acute and chronic phases.

Case Presentation

Ms. J was a previously healthy 12-year-old female who was brought to the emergency department (ED) because of agitation and suicidal ideation. Presentation was preceded by 2 weeks of mood, cognitive, and behavioral disturbances, including sadness, withdrawal from family, increased daytime sleepiness, disorientation, and loss of ability to independently perform activities of daily living. She also referred to herself by her sister’s name, had delusions that she was pregnant, and engaged in strange, repetitive movements.

In the ED, vital signs, physical examination, computed tomography of the head, and extensive lab work—including complete blood count, comprehensive metabolic panel, toxicology, and urinalysis—were unremarkable, except for leukocytosis of 16 cells/µL. A pediatric neurology consultation noted that she was oriented only to person and hospital, she struggled with two-step commands and naming, and she demonstrated poor delayed recall and recall of personal information. Her patellar reflexes and upper-extremity tone were asymmetric, her plantar reflexes were flexor bilaterally, and she demonstrated intermittent writhing and twitching of the chest and legs.

Ms. J was admitted to the pediatric intensive care unit. Magnetic resonance imaging (MRI) of the brain showed mild right cerebellar tonsillar ectopia approximately 3.5 mm below the foramen magnum but was otherwise normal. MRI of the cervical, thoracic, and lumbar spine was normal. Continuous electroencephalogram was nonspecific, with slow posterior-dominant rhythm for age. Cerebrospinal fluid and serum were positive for antinuclear antibodies at 1:320 and anti-NMDA-R antibodies, but infectious and autoimmune meningitis and encephalitis panels were otherwise negative. A rheumatic antibody panel, ordered after a pediatric rheumatology consultation, was negative. Once anti-NMDA-R encephalitis was suggested, a left adnexal mass was discovered via abdominal ultrasound and pelvic MRI and was surgically removed, without complication. Pathology confirmed a mature, nonmalignant teratoma.

Once diagnosed, Ms. J received pulse-dose methylprednisolone for 5 days, followed by IVIg treatment over 2 days, and a weekly steroid taper over 7 weeks. Pediatric psychiatry was consulted on admission day 3 for fluctuating mental status and agitation that had persisted despite a regimen of intravenous dexmedetomidine, intramuscular midazolam, and twice daily oral doses of quetiapine 25 mg and olanzapine 5 mg. On mental status examination, Ms. J was alert and oriented to person, place, month, and year and participated in the interview through yes-no responses, otherwise saying, “I don’t know.” Ms. J’s mother described Ms. J crying and becoming physically aggressive at nighttime and said Ms. J’s cognition would fluctuate between barely speaking and speaking in full sentences. The psychiatry consultation recommended that quetiapine be increased to 25 mg in the morning and 50 mg at night. To reduce polypharmacy, olanzapine and midazolam were discontinued in favor of lorazepam 1 mg as needed for agitation. Delirium precautions and sleep hygiene were reinforced, and psychiatry provided follow-up through discharge.

Ms. J’s agitation improved on this regimen, and she was discharged after a 2-week admission on quetiapine 25 mg as needed for agitation. She was fully oriented, with attention and recall having progressively improved but with continued flat affect and occasional confusion.

At her second follow-up appointment at 5 months postdischarge, she demonstrated full range of affect and intact recent and remote memory and attention. She continues to struggle with irritability, concentration, and academics. She has taken 25 mg of quetiapine at bedtime once since hospital discharge. Longer-term follow-up would be needed to consider other pharmacological options, such as a selective serotonin reuptake inhibitor for ongoing irritability.

Discussion

Ms. J presented with 2 weeks of rapid, progressive, cognitive and behavioral decline and was diagnosed as having anti-NMDA-R encephalitis and treated with IVIg and IV steroid treatment and surgery. By 5 months postdischarge, her psychiatric symptoms had improved but not to baseline.

NMDA receptors play a large role in mediating glutamatergic activity and therefore memory, cognition, and behavior. Anti-NMDA-R encephalitis results from immunoglobulin G autoantibodies targeting the GluN1 subunit of NMDA receptors, with a preference for hippocampal neurons. This results in internalization of receptors via antibody crosslinking, and reduction of surface NMDA-R density on inhibitory neurons results in excitotoxicity of downstream neurons (4). This excitotoxicity is a significant contributor to impulsivity, psychotic symptoms, and seizures. Reduced activity of NMDA receptors at cortical GABAergic neurons is also implicated in psychotic symptoms (5, 6). Recovery from anti-NMDA-R encephalitis is slow, given the role of NMDA receptors in synaptic plasticity.

Treating confusion and psychosis in anti-NMDA-R encephalitis is complex, and thus it is helpful to use delirium as a model for understanding the pathophysiology, presentation, and treatment of anti-NMDA-R encephalitis. The psychiatric sequelae of anti-NMDA-R encephalitis and delirium share certain neurophysiological underpinnings, although delirium often exists on a shorter time scale and has heterogeneous etiologies. Glutamatergic excitotoxicity has been implicated as a contributor to delirium, with extracellular glutamate potentiating further release of intracellular glutamate via depolarization and calcium (Ca2+) influx, leading to activation of voltage-dependent NMDA receptors. Various neurotransmitter cells are affected by Ca2+ influx; particularly important with regard to widespread neuronal overstimulation, dopamine (DA) release is upregulated, exacerbating the combined neurotoxic effects of both glutamate and DA. The behavioral observations in delirious patients are attributed to increases in DA. This may underlie the role of DA antagonists in treating glutamate-precipitated and dopamine-mediated neuronal injury and behavioral disturbances (7).

Antipsychotic drugs are the mainstay of pharmacological treatment of psychiatric sequelae in delirium and anti-NMDA-R encephalitis, but duration of treatment and tolerability are particularly difficult issues in anti-NMDA-R encephalitis (3, 8). In a 2018 systematic literature review on the management of anti-NMDA-R encephalitis among 633 identified patients, 41.7% of patients fully recovered within 7 to 8 months, and 29.9% partially recovered (9). Because the principal psychiatric symptoms included agitation-aggression (55.5%), unspecified psychosis (45.8%), delusions specifically (20.5%), and hallucinations specifically (31.3%), antipsychotics were frequently used: haloperidol (36.5%), risperidone (25.8%), olanzapine (23.3%), quetiapine (13.2%), aripiprazole (6.9%), and one or more antipsychotics (39%). Neuroleptic malignant syndrome (NMS) was suspected in 26% of cases in which antipsychotics were involved (9), although the rate of NMS among patients receiving second-generation antipsychotics for other psychosis has been shown to be 6.4 per 1,000 patients per year (10).

Given the dangerousness of certain antipsychotics in anti-NMDA-R encephalitis, second-generation antipsychotics may be preferred because of lower binding affinity for D2 receptors, limiting risk of extrapyramidal symptoms and NMS, and higher binding affinity for 5-HT2A receptors, potentially mitigating NMDA-mediated neurotoxicity (11, 12). Use of drugs with higher potency at D2 receptors could exacerbate dyskinetic and dystonic movements, which are already sometimes present in patients with anti-NMDA-R encephalitis, and thus prevent clinicians from distinguishing anti-NMDA-R encephalitis from NMS. Kayser and Dalmau (12) recommended starting with quetiapine to treat agitation and psychosis in patients with anti-NMDA-R encephalitis. Our patient’s agitation and confusion were treated in the hospital with scheduled quetiapine and lorazepam as needed, with no signs of NMS or other side effects.

Patients may be continued on both scheduled and as-needed second-generation antipsychotics on hospital discharge (13). In our case, scheduled antipsychotics were found to be unnecessary following discharge, because the patient’s agitation and psychosis had largely resolved. This could be because her psychiatric symptoms during hospitalization were sometimes due to anti-NMDA-R encephalitis and sometimes due to delirium resulting from medical complexity. High-dose steroids in the hospital could have contributed to her agitation because steroids are infamous for causing agitation as a side effect when utilized to treat various medical illnesses; however, our patient’s agitation began resolving with an antipsychotic medication before the steroids were tapered and discontinued. This case illustrates the value of considering antipsychotics with low D2 potency for inpatient management of psychiatric complications of anti-NMDA-R encephalitis and delirium. Future research could consider which second-generation antipsychotics are most effective and cause the fewest side effects when treating psychiatric complications of anti-NMDA-R encephalitis, the role of these medications in outpatient management, and the role of other sedative agents, such as benzodiazepines.

Key Points/Clinical Pearls