Autoimmune Encephalitis Testing Recommendations

Autoimmune encephalitis

Acute and subacute encephalitis are a debilitating group of inflammatory disorders of the brain with a complex differential diagnosis. They often develop as a rapidly progressive encephalopathy, usually in less than 6 weeks, with memory deficits or altered mental status. In the past 10 years, an increasing number of non-infectious, mostly autoimmune, encephalitis cases have been identified. Termed “autoimmune encephalitis”, these conditions have a wide variety of clinical manifestations including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders and seizures.

Within the autoimmune encephalitis category, certain subcategories have been associated with specific antibodies, although identification of the specific antibody is not a requirement for diagnosis.

Conventional neurological evaluation and standard diagnostic tests (MRI, CSF, EEG studies) prevail in the initial assessment of autoimmune encephalitis. The presence of CSF pleocytosis (>5 cells per mm3) can also lend support to the diagnosis. Per most recent guidelines, this must be coupled with exclusion of other causes (i.e. toxicology, metabolic, infectious) for a diagnosis of autoimmune encephalitis to be made. The preliminary diagnosis and decision for initiating treatment of autoimmune encephalitis cases are often not dependent on antibody status. The detection of specific autoantibodies aids in the establishment of a definitive diagnosis of autoimmune encephalitis (versus “possible” or “probable” categories).

Tests available

The University of Washington Laboratory Formulary Committee in combination with the Department of Neurology has recommended starting with focused testing strategies (i.e. specific antibodies) if considering these diagnoses.

NMDA Receptor IgG Antibody with Reflex, CSF (Sendout) [RCNMDA] is the preferred first-line test for autoimmune encephalitis.

The most common (40-60%) of these disorders is NMDA-receptor autoimmune encephalitis. Anti-NMDA receptor encephalitis is associated with CSF IgG antibodies against the GluN1 subunits of the glutamate NMDA receptor. The disease predominantly affects young individuals (95% younger than 45 years) with a female sex predominance of 4:1. Approximately half of women older than 18 years had an underlying tumor, usually an ovarian teratoma.

NMDA Receptor IgG Antibody with Reflex, Serum (Sendout) [RNMDAG] is offered if CSF is unavailable. Serum testing for NMDA-receptor antibodies can have clinical false positives. CSF testing is preferred over serum.

Confirmatory testing for other autoimmune encephalitis syndromes can be conducted by ordering the Autoimmune Encephalitis Panel, CSF (Sendout) [RCAENP] and/or the Autoimmune Encephalitis Panel, Serum (Sendout) [RSAENP]. Both panels test for reactivity to the same 22 autoantigens. False positives can occur. Refer to the online test guide for a list of specific autoantibodies included in the panels. The APE2 (Antibody-Prevalence-in-Epilepsy-and-Encephalitis) Scorecard can be used to guide the use of these panels and is available here: Mayo Antibody Prevalence in Epilepsy and Encephalopathy (APE²) Scorecard. An APE2 score >=4 was shown to have a sensitivity of 99% and specificity of 93% for predicting the presence of neural-specific antibodies (Dubey et al (2018) J Neuroimmunology 323:62).

For details on the individual antibodies included in Mayo's phenotype-specific panels in comparison to the Paraneoplastic Autoantibody Evaluation, Serum (Sendout) [RPNPV] or Paraneoplastic Autoantibody Evaluation, CSF (Sendout), refer to the Autoimmune Neurology Antibody Matrix tool.

Monitoring antibody titers

There is little evidence to support monitoring titers of these antibodies over time. Antibody titers do not necessarily normalize with response to therapy.