Key points What diseases are misdiagnosed as autoimmune encephalitis and what factors contribute to misdiagnosis? Findings In this case series of 107 outpatients misdiagnosed with autoimmune encephalitis, approximately half had functional neurological or psychiatric disorders. An insidious rather than subacute onset and lack of MRI or cerebrospinal fluid findings suggestive of inflammation were clues to misdiagnosis; overinterpretation of nonspecific serum antibodies was a major contributor to misdiagnosis. Meaning A wide range of disorders are misdiagnosed as autoimmune encephalitis and misdiagnosis occurs in many settings, including in the specialty centers participating in this study. |
Autoimmune encephalitis is increasingly a diagnostic consideration in patients with subacute onset of memory loss, altered mental status, and/or psychiatric symptoms, central features of the proposed diagnostic criteria. Detection of autoimmune encephalitis is increasing over time with the discovery of new neuronal autoantibody biomarkers and increased awareness among clinicians, although the diagnosis remains rare overall.
Mimetic diagnoses of autoimmune encephalitis are much more common than autoimmune encephalitis, including toxic/metabolic encephalopathies, functional neurological disorders, primary psychiatric diseases, neurodegenerative disorders, neoplasms, and epilepsy.
Although the discovery of new antineuronal and antiglial autoantibodies has improved diagnostic sensitivity for autoimmune encephalitis, specificity varies depending on antibody type, test methodology, and pretest probability. 4 Therefore, there is a possibility of false-positive autoantibody results in patients with diseases other than autoimmune encephalitis, which may contribute to misdiagnosis.
In much of the autoimmune encephalitis literature, emphasis is placed on patients in whom the diagnosis of autoimmune encephalitis was initially mistakenly missed. However, there are limited data on patients initially incorrectly diagnosed with autoimmune encephalitis and their subsequent correct diagnosis. This is an important issue given the risk of patient harm associated with misdiagnosis, including morbidity from adverse effects of immunotherapies and delay in appropriate treatment.
We present data from an international multicenter study of autoimmune encephalitis misdiagnosis at 6 subspecialty centers to analyze patients misdiagnosed with autoimmune encephalitis and identify potential contributors to the misdiagnosis.
Importance
Misdiagnosis of autoimmune encephalitis can cause harm.
Aim
Determine misdiagnosed diseases such as autoimmune encephalitis and possible reasons for misdiagnosis.
Design, environment and participants
This retrospective multicenter study was conducted from January 1, 2014 to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics, including the Mayo Clinic (n = 44), the University of Oxford (n = 18), the University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4).
Inclusion criteria were adults (age ≥18 years) with a prior diagnosis of autoimmune encephalitis at a participating center or another medical center and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with a diagnosis of autoimmune encephalitis, and of these, 286 patients with true autoimmune encephalitis were excluded.
Main results and measures
Data were collected on clinical characteristics, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and adverse reactions to immunotherapy.
Results
A total of 107 patients were misdiagnosed with autoimmune encephalitis and 77 (72%) did not meet the diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were women.
Correct diagnoses included functional neurological disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficit due to comorbidities (11 [10%]), brain neoplasia (10 [9.5%]), and others (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%).
Magnetic resonance imaging of the brain suggested 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%). N -methyl- d -aspartate receptor alone by cell-based assay (n = 10; 6 CSF negative) and others (n = 18) .
Adverse reactions to immunotherapies occurred in 17 of 84 patients (20%).
Possible contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of nonspecific functional/psychiatric or cognitive dysfunction as encephalopathy (41 [38%]).
Summary of warning signs in the diagnosis of autoimmune encephalitis Clinical
Magnetic resonance imaging of the brain.
cerebrospinal fluid
Serology
Abbreviations : CASPR2, contactin-associated protein 2-like; CSF, cerebrospinal fluid; GAD65, glutamic acid decarboxylase 65; LGI1, leucine-rich-inactivated-glioma-1; NMDAR, N -methyl- d -aspartate receptor; RIA, radioimmunoprecipitation assay; TPO, thyroid peroxidase. a Normal white blood cell count and absence of single oligoclonal bands in CSF. |
Misdiagnosis of autoimmune encephalitis is problematic for multiple reasons .
- First, misdiagnosis of autoimmune encephalitis increases morbidity by not treating the actual diagnosis.
- Second, immunosuppressive treatments commonly have adverse reactions that can be serious, and in this study included infection, psychosis, avascular necrosis of the hip, and heart failure. Additionally, there are many less serious, although common and bothersome, adverse reactions of corticosteroids, including insomnia, weight gain, and irritability, some of which may not have been captured in this analysis.
- Third, during the COVID-19 pandemic, immunotherapies may increase the risk of severe COVID-19 infection and hinder responses to vaccine and natural infection.
- Finally, increased healthcare costs may arise from the use of expensive immunosuppressants or from unnecessary evaluation of an underlying cancer caused by the detection of nonspecific antibodies.
In summary , neurologists should be aware of the possibility of misdiagnosis of autoimmune encephalitis and consider a broad differential diagnosis that includes common disorders when evaluating suspected cases. Better recognition of clinical, imaging, and serologic red flags in the evaluation of autoimmune encephalitis summarized in the box may decrease the burden of future misdiagnosis.
Conclusions and relevance
When evaluating autoimmune encephalitis, a broad differential diagnosis must be considered, and misdiagnosis occurs in many settings, even in specialized centers. In this study, red flags suggesting alternative diagnoses included insidious onset, positive nonspecific serum antibodies, and failure to meet diagnostic criteria for autoimmune encephalitis. Misdiagnosis of autoimmune encephalitis leads to morbidity from unnecessary immunotherapies and delay in treatment of the correct diagnosis.
