Brain on Fire: Anti-NMDA Receptor Encephalitis

Public and medical awareness of a rare autoimmune encephalitis increased in 2012 when Susannah Cahalan, a reporter for the New York Post, published a medical memoir called Brain on Fire describing her rapid decline at age 24 into psychosis, seizures, cognitive impairment, and catatonia. Initially diagnosed with bipolar disorder and suspected substance misuse, she did not improve with standard psychiatric treatment. She was ultimately diagnosed with a rare autoimmune condition in which antibodies were attacking the NMDA receptors in her brain. Once she received treatment directed at the underlying immune dysregulation, she recovered.    

Thanks to this widely publicized account, anti-NMDAR autoimmune encephalitis is on the radar screen, and it is vital that psychiatrists and other front-line mental health providers put it in their differential diagnosis when evaluating patients with acute onset of new psychiatric symptoms.

NMDA Receptor Function and Autoimmune Disruption

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that mediate calcium-permeable excitatory neurotransmission and play essential roles in synaptic plasticity, learning, memory, and neuronal development. Anti-NMDA receptor (NMDAR) encephalitis is an antibody-mediated autoimmune disorder caused by IgG antibodies targeting the GluN1 subunit of NMDA receptors, resulting in a characteristic neuropsychiatric syndrome that is treatable with immunotherapy.

Prevalence and Incidence

The prevalence of anti-NMDAR encephalitis was 0.6 per 100,000 in one U.S. population study⁽¹⁾, however, overall  incidence appears to be rising, likely due to increased awareness and testing rather than true increase in disease frequency. Although encephalitis in general is rare, anti-NMDAR encephalitis is significant when compared to other causes of encephalitis. In young individuals, anti-NMDAR encephalitis surpasses the frequency of any individual viral cause of encephalitis, including herpes simplex virus, West Nile virus, and varicella-zoster virus.^(2,3) In one California study, anti-NMDAR encephalitis was identified more than 4 times as frequently as HSV-1, WNV, or VZV in patients aged ≤30 years.⁽³⁾ Among pediatric encephalitis cases with identified etiology, anti-NMDAR encephalitis represented 26% of cases in one Houston study, making it the most common autoimmune cause.⁽⁴⁾

Clinical Presentation

Approximately 90% of patients develop prominent psychiatric or behavioral symptoms at onset, making psychiatrists often the first clinicians to evaluate these patients.⁽⁵⁾ Presenting symptoms include psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%).⁽⁶⁾ Common specific symptoms include delusional thinking (74%), mood disturbances (70%, usually manic), visual or auditory hallucinations, and aggression (57%).^(7,8)

There are key distinguishing features of anti- NMDA autoimmune encephalitis:

1. Ultra rapid onset and dynamic evolution of symptoms (median onset 1 day)
2. Typically evolves sequentially from mood to psychotic to catatonic predominance within 2 weeks.⁽⁹⁾
3. The combination of catatonia-delirium comorbidity, along with tonic-clonic seizures and orolingual dyskinesia, represents a distinctive neurobehavioral phenotype.⁽⁶⁾

From a practical point of view, Psychiatrists should consider anti-NMDAR encephalitis when new psychiatric symptoms are accompanied by:

1. Recent viral prodrome, seizures, or unexplained fever⁽⁷⁾
2. Unusual quality of psychiatric symptoms (e.g., non-verbal auditory hallucinations)⁽⁷⁾
3. Rapid progression with neurological features including abnormal movements (especially orofacial dyskinesias), speech dysfunction (pressured speech, verbal reduction, or mutism), decreased consciousness, or autonomic dysfunction⁽⁵⁾
4. Apparent neuroleptic intolerance e.g. hyperthermia, rigidity,or  rhabdomyolysis.⁽⁵⁾
5. History of encephalitis

Risk Factors

The primary risk factors for anti-NMDA receptor encephalitis are ovarian teratomas and herpes simplex encephalitis, with age, sex, and possibly genetic factors also playing a role. Herpes simplex encephalitis is a confirmed trigger, with 27% of prospectively followed HSV encephalitis patients developing autoimmune encephalitis 2-16 weeks later.⁽⁵⁾

1. Viral neuroinfections
2. Ovarian teratoma in females
3. Testicular germ cell tumors in males
4. Possible association with family or personal autoimmune history
5. Possible links with HLA immune gene variations (HLA-I allele B07:02 and HLA-II allele DRB116:02)

Diagnosis and Treatment for Anti-NMDA Receptor Encephalitis

Diagnosis requires identification of anti-NMDAR IgG antibodies against the GluN1 subunit of NMDA receptors in CSF or serum. CSF testing is preferred as seronegative cases exist. Supportive diagnostic findings include CSF lymphocytic pleocytosis or oligoclonal bands, and EEG showing focal or diffuse slow/disorganized activity, epileptic activity.⁽⁵⁾ All patients should be screened for underlying tumors, particularly ovarian teratomas in females and testicular germ-cell tumors in males, with periodic screening recommended for at least 2 years.

Most patients respond to first-line immunotherapy (corticosteroids, intravenous immunoglobulins, or plasma exchange) and tumor resection when applicable. Second-line treatments (rituximab or cyclophosphamide) are used when first-line therapy fails. For the approximately 10% of patients refractory to first- and second-line therapies, third-line options include tocilizumab or bortezomib. Earlier treatment initiation correlates with better outcomes.

Management of psychiatric symptoms may be necessary for symptomatic relief before or during immunotherapy treatment. Antipsychotics have limited efficacy for core symptoms but can help manage agitation and aggression. While concerns exist about antipsychotic sensitivity, one cohort found no significant increase in neurological or autonomic symptoms with antipsychotic use, though differentiating medication side effects from disease progression remains challenging. Benzodiazepines are preferred for catatonia, with electroconvulsive therapy considered when pharmacological treatment fails.^(10,11)

Prognosis and Follow-up

More than 75% of patients recover completely or have mild sequelae with appropriate treatment.⁽¹¹⁾ Relapse occurs in an estimated 4% of cases and can present with isolated psychiatric symptoms. Over 90% of patients return to similar or better functional levels after relapse treatment.⁽¹²⁾ Long-term immunotherapy with rituximab or IVIG reduces relapse risk.⁽¹³⁾ Nevertheless, residual anxiety, fatigue and cognitive problems can considerably affect the quality of life. 

Conclusion

Psychiatrists should recognize that anti-NMDA receptor encephalitis is a treatable autoimmune disorder that often presents with the acute onset of prominent psychiatric symptoms. Although it can mimic primary psychiatric illness, distinctive clinical features should prompt appropriate diagnostic testing and timely immunotherapy.