Autoimmune Encephalitis: The Surprisingly Common Condition and the Need for Early Recognition

The initial reports of paraneoplastic encephalitis in the late 1960s described adults with breast cancer or small cell lung cancer who developed seizures, psychiatric dysfunction, or dementia.¹  The condition was dubbed limbic encephalitis because of postmortem inflammatory changes in the brain’s limbic system. Almost four decades later, Dalmau and colleagues identified antibodies targeting the brain’s NMDA receptors in a cohort of women with ovarian teratomas, kicking off renewed interest in autoimmune encephalitis.²

As noted by Jafarpour and Santoro in a recent Pediatrics in Review article (10.1542/pir.2021-005096), our understanding of autoimmune encephalitis has improved steadily in the last few years.³ Several additional antibodies targeting brain antigens have now been recognized, although these are identified less often than anti-NMDA receptor antibodies. Patients with a negative antibody assay despite typical clinical findings are not unusual, so it seems likely that additional antibodies targeting the brain will be identified.

Autoimmune encephalitis is surprisingly common. Anti-NMDA receptor antibody encephalitis was the most commonly documented cause of encephalitis in the California Encephalitis Project, occurring far more often than encephalitis due to herpes simplex encephalitis and West Nile virus.⁴ About 40% of the patients with anti-NMDA receptor antibody encephalitis are less than 18 years of age.⁵ Unlike viral encephalitis, autoimmune encephalitis affects females more often than males.

Without treatment, the clinical features of children with autoimmune encephalitis often evolve. A child presenting with seizures, for example, may subsequently develop chorea, dystonia or psychiatric symptoms. Psychiatric manifestations range from personality change to hallucinations and frank psychosis. Only about a third of patients have cerebrospinal fluid pleocytosis. About half of the patients have magnetic resonance imaging abnormalities, and these may be nonspecific and only appear later in the course.⁵ Consequently, diagnosis relies heavily on clinical suspicion followed by antibody testing.

Relatively few children with autoimmune encephalitis have a malignancy, although adolescent girls have a greater likelihood of teratoma than other pediatric patients. Some children develop autoimmune encephalitis following an infection, probably on the basis of molecular mimicry.⁶  Although several systemic infections have been documented prior to the onset of autoimmune encephalitis, it is often difficult to confirm a cause-and-effect relationship given the high frequency of these infections and the rarity of autoimmune encephalitis.  Herpes simplex encephalitis, however, is an accepted risk factor. In one study, 27% of individuals recovering from herpes simplex encephalitis developed autoimmune encephalitis. About two-thirds of these individuals had new anti-NMDA receptor antibodies and one-third had antibodies targeting the GABA_A receptor or other antigens.⁷

Increasing awareness of autoimmune encephalitis has led to more frequent recognition, and commercially available antibody tests now allow definitive confirmation of the diagnosis.  The clinical manifestations of autoimmune encephalitis are protean and the customary diagnostic tests are not always helpful, so the diagnosis often begins with a high level of clinical suspicion.  Early recognition of autoimmune encephalitis is vitally important, because this often-devastating disorder is highly treatable, and earlier treatment is likely to be more effective.

References

1. Corsellis JA, Goldberg GJ, Norton AR. "Limbic encephalitis" and its association with carcinoma. Brain 1968;91:481-496.
2. Dalmau J, Tuzun E, Wu HY et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25-36.
3. Jafarpour, S., Santoro JD. Autoimmune encephalitis (In press). Pediatr Rev
4. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis 2012;54:899-904.
5. Gable M, Glaser C. Anti-N-Methyl-d-Aspartate Receptor Encephalitis Appearing as a New-Onset Psychosis: Disease Course in Children and Adolescents Within the California Encephalitis Project. Pediatr Neurol 2017;72:25-30.
6. Li Q, Fu N, Han Y, Qin J. Pediatric Autoimmune Encephalitis and Its Relationship With Infection. Pediatr Neurol 2021;120:27-32.
7. Armangue T, Spatola M, Vlagea A et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol 2018;17:760-772.