Seizure Evolution and Outcome in Pediatric Autoimmune Encephalitis.

BACKGROUND: Our study aimed to characterize seizure incidence and seizure outcome of pediatric autoimmune encephalitis (AE) focusing on subgroup analysis based on antibody (Ab). METHODS: Among 110 pediatric patients with AE, we compared seizure characteristics and outcomes in 68 patients with seizure, who satisfied the proposed criteria of pediatric AE. Accordingly, patients were classified into three groups, anti-myelin oligodendrocyte glycoprotein (anti-MOG) AE, anti-N-methyl-D-aspartic acid receptor (anti-NMDAR) AE, and Ab-negative AE. Univariate and multivariate analyses were performed to evaluate the risk factors for postencephalitic seizures, defined as persisting seizures six months after onset. RESULTS: Seizure incidence in the anti-NMDAR (88.9%) and Ab-negative (71.1%) groups differed from anti-MOG group (37.8%). Median seizure frequency within six months was higher in the Ab-negative group (6.0, interquartile range [IQR] 3.0 to 13.0) than in the anti-NMDAR group (3.0, IQR 2.0 to 4.5) and anti-MOG group (2.0, IQR 1.0 to 5.0). Patients in the Ab-negative group tended to develop postencephalitic seizures more frequently and have a lower seizure freedom rate than those in the anti-NMDAR and anti-MOG groups. Ab-negative status, high seizure frequency within six months, and the presence of status epilepticus were associated with the development of postencephalitic seizures on univariate analysis. On multivariate analysis, Ab-negative status remained the only significant variable linked with postencephalitic seizure (odds ratio, 4.17; 95% confidence interval, 1.02 to 18.05). CONCLUSIONS: We delineated the seizure incidence, evolution, and outcome of pediatric patients with Ab-positive and Ab-negative AE. Ab-negative status is predictive of higher seizure burden, more frequent development of postencephalitic seizures, and less favorable seizure outcome than anti-NMDAR and anti-MOG Ab-positive status.

The Korean undiagnosed diseases program phase I: expansion of the nationwide network and the development of long-term infrastructure.

BACKGROUND: Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system. RESULTS: During the program (2018-2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration. CONCLUSIONS: The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.

Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis.

BACKGROUND: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. RESULTS: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range 7-78 months) and age at last examination was 7.4 years (range 3.3-16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range 0-75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient's mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. CONCLUSIONS: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

Clinical outcomes of pediatric Anti-NMDA receptor encephalitis.

OBJECTIVE: To investigate the clinical features and long-term outcomes of pediatric Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Thirty-two anti-NMDAR encephalitis patients with positive anti-NMDAR antibody test results were recruited. Clinical outcomes were evaluated using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and the modified Rankin Scale (mRS). RESULTS: The median age of onset was 9.0 years (range, 0.7-17.2 years). Twenty-four patients (75.0%) were female. All patients received first-line immunotherapy including intravenous immunoglobulin and/or steroid therapy. The second-line immunotherapy was administered to 22 patients (68.8%). Clinical outcomes were evaluated in 27 patients who were followed for longer than 6 months after onset, among whom the median follow-up duration was 31.2 months (range, 6.3-82.9 months). The proportion of patients with ≤2 points on the mRS at their 12-month follow-up was 79.2% (19/24). The CASE scores of these 19 patients ranged from 0 to 5, with language and memory deficits accounting for most of these disabilities. When the outcome was assessed according to onset age (<12 years or 12-18 years), the younger group tended to show a slower recovery over their clinical course. CONCLUSIONS: Despite overall favorable clinical outcomes, mild cognitive problems, including language and memory, may persist in pediatric anti-NMDAR encephalitis patients. A specific outcome measure, such as CASE, should be adopted to delineate clinical outcomes and aid the development of individualized treatment plans.

Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-Associated Disease in Korean Children.

BACKGROUND AND PURPOSE: The myelin oligodendrocyte glycoprotein (MOG) antibody is detected at a high rate in childhood acquired demyelinating syndrome (ADS). This study aimed to determine the diagnostic value of the MOG antibody in ADS and the spectrum of MOG-antibody-positive demyelinating diseases in children. METHODS: This study included 128 patients diagnosed with ADS (n=94) or unexplained encephalitis (n=34). The MOG antibody in serum was tested using an in-house live-cell-based immunofluorescence assay. RESULTS: The MOG antibody was detected in 48 patients (46 ADS patients and 2 encephalitis patients, comprising 23 males and 25 females). Acute disseminated encephalomyelitis (ADEM) (35.4%) was the most-common diagnosis, followed by the unclassified form (17.4%), isolated optic neuritis (ON) (15.2%), neuromyelitis optica spectrum disorder (13.0%), multiple sclerosis (MS) (10.8%), other clinically isolated syndromes [monophasic event except ADEM, isolated ON, or transverse myelitis (TM)] (8.7%), and unexplained encephalitis (4.3%). At the initial presentation, 35 out of the 46 patients with ADS had brain lesions detected in magnetic resonance imaging, and 54% of these 35 patients had encephalopathy. Nine of the 11 patients without brain lesions exhibited only ON. Thirty-nine percent of the patients experienced a multiphasic event during the mean follow-up period of 34.9 months (range 1.4-169.0 months). Encephalopathy at the initial presentation was frequently confirmed in the monophasic group (p=0.011). CONCLUSIONS: MOG antibodies were identified in all pediatric ADS phenotypes except for monophasic TM. Therefore, the MOG antibody test is recommended for all pediatric patients with ADS, especially before a diagnosis of MS and for patients without a clear diagnosis.