Autoimmune encephalitis misdiagnosis in adults

Courtesy of a colleague

Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, Blackburn KM, Turaga S, Binks S, Zitser J, Gelfand JM, Day GS, Dunham SR, Rodenbeck SJ, Clardy SL, Solomon AJ, Pittock SJ, McKeon A, Dubey D, Zekeridou A, Toledano M, Turner LE, Vernino S, Irani SR. Autoimmune Encephalitis Misdiagnosis in Adults. JAMA Neurol. 2023 Jan 1;80(1):30-39. doi: 10.1001/jamaneurol.2022.4251. PMID: 36441519; PMCID: PMC9706400.

Abstract

Importance: Autoimmune encephalitis misdiagnosis can lead to harm.

Objective: To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.

Design, setting, and participants: This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.

Main outcomes and measures: Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.

Results: A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 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 from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]).

Conclusions and relevance: When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Dalmau J, Graus F. Autoimmune Encephalitis-Misdiagnosis, Misconceptions, and How to Avoid Them. JAMA Neurol. 2023 Jan 1;80(1):12-14. doi: 10.1001/jamaneurol.2022.4154. PMID: 36441535.

No abstract. From the article.

How can we prevent misdiagnoses? (1) Become familiar with the syndromes and favor clinical reasoning over antibody results. (2) Use CSF and serum testing; if forced to pick one, use CSF. (3) Be aware that a positive test result does not always mean presence of antibodies; thus, request antibody confirmation by at least 2 techniques (brain tissue immunohistochemistry and CBA). (4) Doubt any positive serum result that in the context of suspected AE is accompanied by negative CSF antibodies. An exception is the antibodies against myelin oligodendrocyte glycoprotein (MOG) that are more frequently detected in serum and can associate with symptoms of AE.14 Even for anti-LGI1 encephalitis, the concept that antibodies occur more frequently in serum is inaccurate; virtually all patients have LGI1 antibodies in CSF if properly studiedwith brain immunohistochemistry and CBA expressing LGI1 with one of its natural ligands (ADAM23).15 Therefore, diagnostic laboratories should strongly consider including a warning message in their reports, indicating that a positive serum result for antibodies against neuronal surface proteins mandates the confirmation of antibodies in CSF, as the risk for clinical misdiagnosis of AE dramatically increases if the CSF status is negative or unknown. 

Flanagan and colleagues suggest the misdiagnosis of AEs can be lessened by educating physicians; for example, most of the brain MRI images provided should have raised a red flag against AEs. However, a critical analysis of what is occurring in the fields of autoimmune neurology and immunopsychiatry uncovers a more fundamental problem: the education provided has not been adequate. Ifmisdiagnoses are frequent, it is because the clinical-immunological concepts derived from many investigations are not solid, favoring antibody testing over clinical judgment. A careful clinical differential diagnosiswith better selection of cases for antibody studies and appropriate biological samples and techniques would represent a colossal step to prevent the misdiagnosis of AEs