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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 30-39 |
| Number of pages | 10 |
| Journal | JAMA neurology |
| Volume | 80 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2023 |
ASJC Scopus subject areas
- Clinical Neurology
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Flanagan, E. P., Geschwind, M. D., Lopez-Chiriboga, A. S., Blackburn, K. M., Turaga, S., Binks, S., Zitser, J., Gelfand, J. M., Day, G. S., Dunham, S. R., Rodenbeck, S. J., Clardy, S. L., Solomon, A. J., Pittock, S. J., McKeon, A., Dubey, D., Zekeridou, A., Toledano, M., Turner, L. E., ... Irani, S. R. (2023). Autoimmune Encephalitis Misdiagnosis in Adults. JAMA neurology, 80(1), 30-39. https://doi.org/10.1001/jamaneurol.2022.4251
Autoimmune Encephalitis Misdiagnosis in Adults. / Flanagan, Eoin P.; Geschwind, Michael D.; Lopez-Chiriboga, A. Sebastian et al.
In: JAMA neurology, Vol. 80, No. 1, 01.01.2023, p. 30-39.
Research output: Contribution to journal › Comment/debate › peer-review
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 2023, 'Autoimmune Encephalitis Misdiagnosis in Adults', JAMA neurology, vol. 80, no. 1, pp. 30-39. https://doi.org/10.1001/jamaneurol.2022.4251
Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, Blackburn KM, Turaga S, Binks S et al. Autoimmune Encephalitis Misdiagnosis in Adults. JAMA neurology. 2023 Jan 1;80(1):30-39. doi: 10.1001/jamaneurol.2022.4251
Flanagan, Eoin P. ; Geschwind, Michael D. ; Lopez-Chiriboga, A. Sebastian et al. / Autoimmune Encephalitis Misdiagnosis in Adults. In: JAMA neurology. 2023 ; Vol. 80, No. 1. pp. 30-39.
@article{86b9758aed754ac4a7d801a4dfa192cb,
title = "Autoimmune Encephalitis Misdiagnosis in Adults",
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.",
author = "Flanagan, {Eoin P.} and Geschwind, {Michael D.} and Lopez-Chiriboga, {A. Sebastian} and Blackburn, {Kyle M.} and Sanchit Turaga and Sophie Binks and Jennifer Zitser and Gelfand, {Jeffrey M.} and Day, {Gregory S.} and Dunham, {S. Richard} and Rodenbeck, {Stefanie J.} and Clardy, {Stacey L.} and Solomon, {Andrew J.} and Pittock, {Sean J.} and Andrew McKeon and Divyanshu Dubey and Anastasia Zekeridou and Michel Toledano and Turner, {Lindsey E.} and Steven Vernino and Irani, {Sarosh R.}",
year = "2023",
month = jan,
day = "1",
doi = "10.1001/jamaneurol.2022.4251",
language = "English (US)",
volume = "80",
pages = "30--39",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "1",
}
TY - JOUR
T1 - Autoimmune Encephalitis Misdiagnosis in Adults
AU - Flanagan, Eoin P.
AU - Geschwind, Michael D.
AU - Lopez-Chiriboga, A. Sebastian
AU - Blackburn, Kyle M.
AU - Turaga, Sanchit
AU - Binks, Sophie
AU - Zitser, Jennifer
AU - Gelfand, Jeffrey M.
AU - Day, Gregory S.
AU - Dunham, S. Richard
AU - Rodenbeck, Stefanie J.
AU - Clardy, Stacey L.
AU - Solomon, Andrew J.
AU - Pittock, Sean J.
AU - McKeon, Andrew
AU - Dubey, Divyanshu
AU - Zekeridou, Anastasia
AU - Toledano, Michel
AU - Turner, Lindsey E.
AU - Vernino, Steven
AU - Irani, Sarosh R.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
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FAQs
What mimics autoimmune encephalitis? ›
Diagnostic mimics of autoimmune encephalitis are far more prevalent than autoimmune encephalitis, including toxic/metabolic encephalopathies, functional neurological disorders, primary psychiatric disease, neurodegenerative disorders, neoplasms, and epilepsy.
What is the differential diagnosis for autoimmune encephalitis? ›The most frequent differential diagnoses are herpes simplex virus encephalitis and other CNS infections. Importantly, CSF herpes simplex virus PCR can be negative if done too early (eg, within 24 h), and this test should be repeated if the clinical suspicion remains high.
How do you rule out autoimmune encephalitis? ›- A spinal tap (lumbar puncture) to withdraw a sample of cerebrospinal fluid, the liquid that surrounds your brain and spinal cord. ...
- Blood tests to look for antibodies that may indicate autoimmune encephalitis.
- MRI (magnetic resonance imaging) scans of your brain to identify signs of the disease.
In patients with anti-NMDAR encephalitis the brain MRI is normal in approximately 60% of the patients and shows nonspecific findings in the rest including, cortical-subcortical FLAIR changes in brain or posterior fossa, transient meningeal enhancement, or areas of demyelination.
How do you confirm encephalitis? ›- Neuroimaging, such as a brain MRI or CT scan.
- A lumbar puncture (spinal tap) to check for signs of infection in the brain or spinal cord.
- Electroencephalogram (EEG) to look for seizures or specific patterns of electrical activity in the brain.
Encephalitis and meningitis are both infections of the brain, but they affect different parts of the brain. Meningitis is an infection in the membranes surrounding the brain and spinal cord, called the meninges, while encephalitis is inflammation of brain tissues.
Can you have encephalitis with a normal MRI? ›The brain MRI is normal in approximately 60% of patients with anti-NMDAR encephalitis. Very few studies have systematically investigated neuroimaging in all-cause encephalitis.
Why is encephalitis often difficult to diagnosis? ›How is encephalitis diagnosed? Encephalitis can be difficult to diagnose. This is because other things such as meningitis, stroke and sometimes brain tumours can cause similar symptoms. Therefore, you may have various tests before encephalitis can be diagnosed.
What does autoimmune encephalitis look like on MRI? ›Imaging features of striatal autoimmune encephalitis on MRI include hyperintense T2/FLAIR abnormalities in the basal ganglia, often bilateral, with sparing of the mesial temporal lobes. Diffusion restriction is usually absent which helps differentiate AE from the most common differential diagnoses in this location.
When should you suspect autoimmune encephalitis? ›A diagnosis of pediatric AE should be considered in previously healthy children who present with acute or subacute (less than 3 months) onset of new focal or diffuse neurologic deficits, cognitive difficulties, developmental regression, movement abnormalities, psychiatric symptoms, and/or seizures.
Is there a blood test for autoimmune encephalitis? ›
NMDA Receptor Antibody, IgG, CSF with Reflex to Titer [RCNMDA] is the preferred first-line test for autoimmune encephalitis.
Is autoimmune encephalitis hard to diagnose? ›Autoimmune encephalitis is a difficult clinical diagnosis due to the similarities in the clinical, imaging and laboratory findings of many forms of autoimmune and infectious encephalitis. Patients generally have impaired memory and cognition over a period of days or weeks.
What organ is inflamed when one has encephalitis? ›Encephalitis (en-sef-uh-LIE-tis) is inflammation of the brain. There are several causes, including viral infection, autoimmune inflammation, bacterial infection, insect bites and others. Sometimes there is no known cause.