Clinical Characterization and Long-Term Outcome of Children and Adults with Anti-AMPA Receptor Encephalitis
Chiara Milano1, Ezgi Saylam2, Claudia Papi3, Laura Marmolejo Alcaide4, Alexandra Sankovic2, Jerome Honnorat5, Takahiro Iizuka6, Romana Höftberger7, Raphael Reinecke7, Maarten Titulaer8, Jeroen Kerstens8, Mateus Simabukuro9, Marie Benaiteau5, Bastien Joubert5, Matteo Gastaldi10, Livia Almeida Dutra11, Frank Leypoldt12, Mareike Jansen13, Izumi Kawachi14, Eugenia Martinez-Hernandez4, Thais Armangue15, Francesc Graus16, Josep Dalmau4, Setty Magana2, Marianna Spatola4
1Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; La Caixa Research Institute, Barcelona, Spain; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 2Department of Pediatrics, Division of Neurology, Nationwide Children's Hospital, Columbus, OH, USA, 3Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; La Caixa Research Institute, Barcelona, Spain; Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy, 4Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; La Caixa Research Institute, Barcelona, Spain, 5Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MELIS institute UMR Inserm 1314, CNRS 5284, Université Claude Bernard Lyon 1, Lyon, France, 6Department of Neurology, Kitasato University School of Medicine, Japan, 7Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria, 8Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands, 9Division of Neurology, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; Instituto do Cancer do Estado de Sao Paulo (ICESP), Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 10Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy, 11Hospital Israelita Albert Einstein, São Paulo, Brazil, 12Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Germany; Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany, 13Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Germany, 14Department of Neurology, Brain Research institute, Niigata University, Japan, 15Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain; La Caixa Research Institute, Barcelona, Spain; Sant Joan de Deu Hospital, Barcelona, Spain, 16Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain
Objective:
To describe the neurological manifestations and long-term outcome of children and adults with anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) encephalitis.
Background:
Anti-AMPAR encephalitis manifests as limbic encephalitis (LE) in adults, and is frequently associated with cancer. Although a few studies suggest it occurs also in children, clinical features in younger patients and long-term outcome in both children and adults are unknown.
Design/Methods:
Clinical information was retrospectively obtained from medical records, together with data from previously published pediatric patients.
Results:
We identified 115 patients, of which 84 (71 adults, 13 children) had AMPAR antibodies alone and 31 (27 adults, 4 children) had additional neuronal antibodies. Considering patients with AMPAR antibodies alone, tumors were only identified in adults (37/71 (52%) vs 0/13 (0%), p<0.0001). Compared to adults, children were more likely to show behavioral/psychiatric symptoms at onset (5/13, 39% vs 8/71, 11%, p=0.026), cerebellar dysfunction (6/13, 46% vs 7/68, 10% p= 0.005) or movement disorders (5/13, 39% vs 8/67, 12%, p=0.032) during the disease course, and extratemporal brain MRI abnormalities (4/9, 44% vs. 5/44, 11%, p=0.035).
A follow-up >24 months was available from 34 alive patients (30 adults, 4 children): 23 (68%), all adults, had neurological sequelae and 11 had full recovery. At multivariate analysis, failure to respond to first-line immunotherapy was the only predictor of bad outcome (i.e. modified Rankin scale [mRS]>2 (OR 8.8, 95%CI 1.3–59.5, p=0.025). Among the 31 patients with additional neuronal autoantibodies, 22 (79%) had an associated tumor; those with high-risk antibodies had higher mortality (p= 0.009).
Conclusions:
Children with anti-AMPAR encephalitis have different clinical-radiological features compared to adults. Neurological sequelae are frequent in adults, and failure to respond to first-line immunotherapy predicts worse outcome. Additional high-risk antibodies are associated with higher mortality.
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