Abstract
Objective: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute disseminated encephalomyelitis (ADEM) in children, (2) to validate the currently used clinical criteria to diagnose AIE, and (3) to describe pitfalls in the diagnosis of pediatric autoimmune (AI) and inflammatory neurologic disorders.
Methods: This study cohort consists of 3 patient categories: (1) children with antibody-mediated AIE (n = 21), (2) children with ADEM (n = 32), and (3) children with suspicion of an AI etiology of their neurologic symptoms (n = 60). Baseline and follow-up clinical data were used to validate the current guideline to diagnose AIE. In addition, patient files and final diagnoses were reviewed.
Results: One-hundred three of the 113 included patients fulfilled the criteria of possible AIE. Twenty-one children had antibody-mediated AIE, of whom 19 had anti-N-methyl-D-aspartate receptor (NMDAR), 1 had anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and 1 had anti-leucine-rich glioma-inactivated protein 1 encephalitis. Finally, 34 children had ADEM, and 2 children had Hashimoto encephalopathy. Mean incidence rates were 1.54 children/million (95% CI 0.95-2.35) for antibody-mediated AIE and 2.49 children/million (95% CI 1.73-3.48) for ADEM. Of the other 48 children, treating physicians' diagnoses were reviewed. In 22% (n = 6) of children initially diagnosed as having an AI/inflammatory etiology (n = 27), no support for AI/inflammation was found.
Conclusion: Besides anti-NMDAR encephalitis and ADEM, other AIEs are rare in children. The current guideline to diagnose AIE is also useful in children. However, in children with nonspecific symptoms, it is important to review data critically, to perform complete workup, and to consult specialized neuroinflammatory centers.
Brenner J, Ruhe CJ, Kulderij I, Bastiaansen AEM, Crijnen YS, Kret CN, Verkoelen JCP, Tolido AAG, Thomassen B, Kersten LP, de Bruijn MAAM, Olijslagers SHC, Mandarakas MR, Kerstens J, van Steenhoven RW, de Vries JM, Veenbergen S, Schreurs MWJ, Neuteboom RF, Sillevis Smitt PAE, van den Berg E, Titulaer MJ. Long-Term Cognitive, Functional, and Patient-Reported Outcomes in Patients With Anti-NMDAR Encephalitis. Neurology. 2024 Dec 24;103(12):e210109. doi: 10.1212/WNL.0000000000210109. Epub 2024 Nov 20. PMID: 39566012; PMCID: PMC11627176.
Abstract
Background and objectives: Anti-NMDA receptor (anti-NMDAR) encephalitis generally manifests in young adults. Although 80%-90% returns to independence, the majority experience persistent cognitive and psychosocial difficulties. Studies have demonstrated that cognitive recovery may continue for years; the temporal trajectory is largely unknown, as are factors influencing cognitive/psychosocial recovery. Objectives were to (1) describe the cognitive recovery trajectory, (2) assess self-reported outcomes, (3) identify factors relating to outcome, and (4) explore the relation between cognitive and self-reported outcomes, and participation.
Methods: We performed a large-scale cross-sectional and prospective cohort study. We addressed our nationwide cohort, provided they were (1) older than 16 years, (2) independent preillness, and (3) able to perform cognitive tests and/or self-report. Patients completed Patient-Reported Outcome Measures and neuropsychological assessments (memory, language, perception and construction, and attention and executive functions), and functional outcomes were established (modified Rankin Scale [mRS] score and return-to-work/-education). Outcomes were compared with references and between groups based on clinical characteristics and functional outcomes (T-tests for normalized data and nonparametric tests for patient-reported data). Recovery was visualized by plotting outcomes against time-of-assessment.
Results: We included 92 patients (age 29 ± 2 years; 77% female). Cognitive scores improved with time-of-assessment, up to 36 months after diagnosis (R = 0.35, p = 0.022), with the most enhanced improvement in the first 6 months. This result could be reproduced in prospective patients (n = 12). Beyond 36 months (n = 44), 34% of patients had a persistent impairment (z-score <-1.5 SD) and 65% scored below-average (<-1 SD) in 1 or more cognitive domains, despite a "favorable" outcome measured by mRS (≤2) in the majority (91%). Most affected were memory (mean -0.67 ± 0.89 SD, p = 0.25) and language (-0.75 ± 1.06 SD, p = 0.23). Self-reported complaints remained in emotional well-being (mean 72 ± 25 SD vs norm 82 ± 33 SD, p < 0.001), social functioning (73 ± 26 SD vs 84 ± 22 SD, p < 0.001), energy levels (57 ± 19 SD vs 69 ± 19 SD, p < 0.001), and quality of life (0.85 ± 0.14 SD vs 0.93 ± 0.11 SD, p < 0.001). Many patients did not resume school/work (30%) or needed adjustments (18%). Resuming school/work related to processing speed (-0.14 ± 0.78 SD vs -0.84 ± 1.05 SD, p = 0.039) and well-being (EuroQol 5 Dimensions 5 Levels median 0.90 vs 0.81, p = 0.016).
Discussion: Recovery from anti-NMDAR encephalitis may continue for 3 years, with risk of persisting cognitive deficits, notably in memory and language, and sequelae in social functioning, energy levels, and well-being. The frequently applied outcome measure mRS does not fully capture outcomes. Almost half of patients struggled resuming school/work, associated with cognitive deficits and well-being.
Van Steenhoven RW, de Vries JM, Bruijstens AL, Paunovic M, Nagtzaam MM, Franken SC, Bastiaansen AE, De Bruijn MA, Van Sonderen A, Schreurs MWJ, Gardeniers M, Verdijk RM, Balvers RK, Sillevis Smitt PA, Neuteboom RF, Titulaer MJ. Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria. Neurol Neuroimmunol Neuroinflamm. 2023 Aug 15;10(6):e200148. doi: 10.1212/NXI.0000000000200148. Erratum in: Neurol Neuroimmunol Neuroinflamm. 2025 Jan;12(1):e200342. doi: 10.1212/NXI.0000000000200342. PMID: 37582614; PMCID: PMC10427145.
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.
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