Autoimmune Encephalitis Misdiagnosis Can Lead to Harm in Adult Patients

Overinterpretation of positive serum antibodies and misinterpretation of functional/psychiatric or nonspecific cognitive dysfunction as encephalopathy are contributors to autoimmune encephalitis misdiagnosis.

Neurologists should recognize the possibility of misdiagnosis of autoimmune encephalitis and the need to consider a broad differential diagnosis, including common disorders, when assessing suspected cases. These are the findings of a retrospective study published in JAMA Neurology.

Realizing that a misdiagnosis of autoimmune encephalitis can be associated with much harm, researchers sought to determine those diseases misdiagnosed as autoimmune encephalitis and the potential reasons for these misdiagnoses. The study was conducted between January 1, 2014, and December 31, 2020, in 107 patients at several autoimmune encephalitis subspecialty outpatient clinics:

  1. Mayo Clinic (n=44)
  2. University of Oxford (n=18)
  3. University of Texas Southwestern (n=18)
  4. University of California, San Francisco (n=17)
  5. University of Washington in St. Louis (n=6)
  6. University of Utah (n=4)

Study inclusion criteria were age 18 years or older and a previous autoimmune encephalitis diagnosis at a participating center or other medical facility, along with a subsequent alternative diagnosis at a participating center. Among a total of 393 individuals who were referred with a diagnosis of autoimmune encephalitis, 286 patients with true autoimmune encephalitis were excluded from the study.

Overall, 72% (77 of 107) of the misdiagnosed patients did not meet diagnostic criteria for autoimmune encephalitis. The median participant age was 48 years (range, 35.5-60.5 years); 61% of the patients were women. Among individuals misdiagnosed, the correct diagnoses included:

  • functional neurologic disorder (n=27);
  • neurodegenerative disease (n=22);
  • primary psychiatric disease (n=19);
  • cognitive deficits from comorbidities (n=11);
  • cerebral neoplasm (n=10); and
  • other diagnoses (n=18).

The onset was considered “acute/subacute” in 52% (56 of 107) of patients or “insidious” (ie, more than 3 months) in 48% (51 of 107) of patients. Magnetic resonance imaging (MRI) scans of the brain suggested autoimmune encephalitis in 18% (19 of 104) of patients; cerebrospinal fluid (CSF) pleocytosis was reported in 19% (16 of 84) of patients. Additionally, thyroid peroxidase antibodies were elevated in 39% (24 of 62) of patients.

Improved recognition of the clinical, imaging, and serologic red flags in the evaluation of autoimmune encephalitis . . . may lessen the burden of misdiagnosis in the future.

Positive neural antiantibodies were observed more often in serum than in CSF (46% vs 8%, respectively), including 1 or more of GAD65 (n=14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative; n=10), N-methyl-d-aspartate receptor by cell-based assay only (n=10; 6 negative in CSF), and other (n=18). Adverse reactions associated with the use of immunotherapies were reported in 20% (17 of 84) of patients.

Overinterpretation of a nonspecific autoantibody was a frequent contributor to misdiagnosis. An insidious onset of symptoms and the absence of MRI or CSF findings suggestive of neuroinflammation should raise suspicion of an alternative diagnosis.

Prospective studies are warranted to evaluate the frequency of autoimmune encephalitis misdiagnoses, along with the characteristics observed among new referrals to subspecialty clinics who have presumed autoimmune encephalitis. Further, differences in rates of autoimmune encephalitis misdiagnoses across centers are likely indicative of variations in referral patterns.

The researchers concluded that “Improved recognition of the clinical, imaging, and serologic red flags in the evaluation of autoimmune encephalitis . . . may lessen the burden of misdiagnosis in the future.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults.  JAMA Neurol. Published online November 28, 2022. doi:10.1001/jamaneurol.2022.4251