Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria

Abstract

Background and objectives: The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated.

Methods: In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria.

Results: In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; p = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98).

Discussion: AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.

Figure 1. 2016 Clinical Criteria for Autoimmune Encephalitis by Graus et al.

Reprinted with permission from Elsevier.

Figure 2. Proposed Criteria for Probable Anti-LGI1 Encephalitis

Figure 3. Overview of Diagnostic Categories Specified by Age Category (Total Group vs Mimics)

The pie charts on the left represent the specific inflammatory categories (depicted in blue and green) and AE mimics (depicted in red) in the total group (n = 239), adults (n = 179), and children (n = 60). Diagnostic subcategories of AE mimics are demonstrated per age category on the right side. ADEM = acute disseminated encephalomyelitis; AE = autoimmune encephalitis; HE = Hashimoto encephalitis; PNID = probable neuroinflammatory disorder; SN-AE = seronegative autoimmune encephalitis.

Figure 4. Evaluation of Patients According to Diagnostic Algorithm for Autoimmune Encephalitis

Adapted from Graus et al., reprinted with permission from Elsevier. ♦ Anti-MOG was tested in all (n = 21) patients with ADEM; in 10/21 (48%) antibodies were present. *Two patients ultimately diagnosed as probable SN-AE. Three patients fulfilling criteria for definite autoimmune limbic encephalitis were diagnosed as AE mimic after applying diagnostic AE algorithm. † Anti-NMDARE (1), PACNS (1), PML (1), MS (1), and neuro-Sjögren (1). ¥ Encephalitis with unknown cause (3), PNID (3), definite AE (2), and HE (1). Ψ Caspr2 (6), Ma2 (1), and NMDAR (1). Abs = antibodies; ADEM = acute disseminated encephalomyelitis; AE = autoimmune encephalitis; BBE = Bickerstaff brainstem encephalitis; HE = Hashimoto encephalopathy; MOG = myelin oligodendrocyte glycoprotein; NMDARE = anti-NMDA receptor encephalitis; PNID = probable neuroinflammatory disorder; SN-AE = seronegative autoimmune encephalitis.

Figure 5. AE Mimic Examples (Brain MRI)

(A–D) Glioblastoma multiforme (GBM): 47-year-old female patient with subacute working memory deficits and new-onset focal seizures. Left temporal hyperintensities on T2/FLAIR images (A) with subtle left temporal leptomeningeal enhancement (B). Brain MRI after 6 months showed progression of T2/FLAIR hyperintense left temporal lesion (C) and enhancement (D). (E–F) CNS Whipple disease: 69-year-old male patient with rapidly progressive dementia and diarrhea. Bilateral mesiotemporal hyperintensities on T2/FLAIR images (E) and parenchymal enhancement in corresponding regions. (This patient was also published elsewhere by Kloek et al.). (G) Neurofibromatosis type 1 (NF-1): 52-year-old male patient with a chronic course focal epilepsy and cognitive decline. Bilateral mesiotemporal T2/FLAIR hyperintensities, showing no progression for approximately 10 years, regarded as CNS lesion due to NF-1. (H) 3,4-Methyl enedioxy methamphetamine (MDMA) intoxication: 27-year-old male patient with acute amnestic syndrome. No seizures were observed, and hippocampal damage was probably causes by direct MDMA-neurotoxicity, as described earlier.