Publications by authors named "Josep Dalmau"

338 Publications

Autoimmune encephalitis or autoimmune psychosis?

Eur Neuropsychopharmacol 2021 Jun 5;50:112-114. Epub 2021 Jun 5.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.euroneuro.2021.05.004DOI Listing
June 2021

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.

Neurol Neuroimmunol Neuroinflamm 2021 Jul 18;8(4). Epub 2021 May 18.

From the Neuroimmunology Program (F.G., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centre de Référence National pour les Syndromes Neurologiques Paranéoplasique (A.V., S.M.-C., J.-C.G.A., V.D., B.J., L.T., J.H.), Hôpital Neurologique, Hospices Civils de Lyon; SynatAc Team (A.V., S.M.-C., V.D., B.J., L.T., J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon; Université Claude Bernard Lyon 1 (A.V., S.M.-C., V.D., B.J., L.T., J.H.), Université de Lyon; Service de Neurologie (J.-C.G.A.), CHU de Saint-Etienne, France; Department of Neurology (D.D., A.M.), Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Neurology Unit (B.G.), Trento Hospital, Azienda Provinciale per I Servizi Sanitari (APSS) di Trento, Italy; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, United Kingdom; Neuroimmunology Section (F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck; German Center for Neurodegenerative Diseases (DZNE) Berlin (H.P.), and Department of Neurology and Experimental Neurology (H.P.), Charité-Universitätsmedizin Berlin, Germany; Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Department of Neurology 2 Mazarin (D.P.), and INSERM U 1127 (D.P.), CNRS UMR 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière Groupe, Hospitalier Pitié-Salpêtriêre et Université Pierre et Marie Curie-Paris 6, AP-HP, France; Department of Neurology (M.J.T.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Clinical Medicine (C.A.V.), University of Bergen; Department of Neurology (C.A.V.), Haukeland University Hospital; Neuro-SysMed-Centre of Excellence for Experimental Therapy in Neurology (C.A.V.), Departments of Neurology and Clinical Medicine, Bergen, Norway; and Neurology Department (J.J.V.), Leiden University Medical Center, the Netherlands.

Objective: The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.

Methods: A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.

Results: The panel proposed to substitute "classical syndromes" with the term "high-risk phenotypes" for cancer and introduce the concept of "intermediate-risk phenotypes." The term "onconeural antibody" was replaced by "high risk" (>70% associated with cancer) and "intermediate risk" (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.

Conclusions: The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.
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http://dx.doi.org/10.1212/NXI.0000000000001014DOI Listing
July 2021

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis.

Neurology 2021 May 12. Epub 2021 May 12.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain;

Objectives: To report the neuropsychiatric features and frequency of N-methyl-d-aspartate receptor (NMDAR) and other neuronal IgG antibodies in patients with first episode psychosis (FEP), and assess the performance of reported warning signs and criteria for autoimmune psychosis (AP).

Methods: Prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed.

Findings: 105 patients were included; median age 30 years (range 14-75), 44 (42%) female. None had neuronal antibodies. Two/105 (2%) had CSF pleocytosis, 4/100 (4%) brain MRI abnormalities, and 3/73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled two sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and non-psychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1159 reported FEP patients, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR-antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR-antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features).

Conclusions: NMDAR-antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurological symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.
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http://dx.doi.org/10.1212/WNL.0000000000012191DOI Listing
May 2021

Horizontal Saccadic Palsy as a Prominent Symptom of Anti-NMDAR Encephalitis.

Neurol Clin Pract 2021 Feb;11(1):e20-e21

Department of Neurology (KD, TC, BD, MS, RL), University Hospitals Leuven, Leuven, Belgium; University Hospitals Leuven (KP), Laboratory Medicine, Leuven, Belgium; KU Leuven (KP), Department of Neurosciences, Laboratory for Molecular Neurobiomarker Research, Leuven, Belgium; KU Leuven (BD), Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium; Department of Neurology (JD), Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology (JD), University of Pennsylvania, Philadelphia, PA; Institució Catalana de Recerca i Estudis Avançats (ICREA) (JD), Barcelona, Spain; Department of Neurosciences (RL), KU Leuven-University of Leuven, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; and VIB (RL), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.

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http://dx.doi.org/10.1212/CPJ.0000000000000750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101314PMC
February 2021

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

Mov Disord 2021 May 6. Epub 2021 May 6.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1002/mds.28597DOI Listing
May 2021

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

Ann Neurol 2021 May 5. Epub 2021 May 5.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Objective: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects.

Methods: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells.

Results: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization.

Interpretation: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26098DOI Listing
May 2021

Absence of GluD2 Antibodies in Patients With Opsoclonus-Myoclonus Syndrome.

Neurology 2021 02 21;96(7):e1082-e1087. Epub 2020 Dec 21.

From the Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M.P.-P., M.G., T.A., A.S., F.G., J.D.), and Neurology Service (M.G., T.A., A.S., J.D.), Hospital Clínic, and Pediatric Neuroimmunology Unit, Department of Pediatric Neurology (T.A., C.L.), and Department of Haematology and Oncology (A.M.L.M.), Sant Joan de Déu Children Hospital, Universitat de Barcelona; Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER) (M.P.-P., M.G., T.A., J.D.), Valencia; Developmental Tumor Biology Laboratory (C.L.), Sant Joan de Déu Research Institute, Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. M.P.P. is currently affiliated with the Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, France.

Objective: A recent study showed glutamate receptor delta 2 antibodies (GluD2-ab) in sera of patients with opsoclonus-myoclonus syndrome (OMS). Inconsistencies between cerebellar immunoreactivity and expression of GluD2 led us to hypothesize that these antibodies are not biomarkers of OMS.

Methods: Serum of 45 children with OMS (10 [22%] with neuroblastoma), 158 adults with OMS (53 [34%] with tumors), and 172 controls including 134 patients with several types of neurologic disorders, 18 with neuroblastoma without OMS, and 20 healthy participants were investigated. Antibodies were determined with 3 different techniques: (1) rat brain immunohistochemistry, (2) a live cell-based assay using a standard secondary antibody (2-step CBA), and (3) a similar CBA with a secondary and tertiary antibodies (3-step CBA). Two plasmids were used in the CBA studies. Three commercial GluD2-ab and 2 human sera with GluD2-ab served as controls for expression of GluD2.

Results: The 3 commercial GluD2-ab showed predominant reactivity with the molecular and Purkinje cell layers (where GluD2 is highly enriched), and were also positive with the indicated CBAs. Substantially milder reactivity with brain tissue and CBA was obtained with the 2 control human sera containing GluD2-ab. None of the 203 patients with OMS and 172 controls showed immunoreactivities consistent with GluD2-abs. Compared with a standard 2-step CBA, the 3-step assay did not improve antibody detection and showed more frequent nonspecific reactivity that was not immunoabsorbed with GluD2.

Conclusion: We did not find GluD2-ab in a large cohort of patients with OMS. GluD2-ab should not be considered diagnostic biomarkers of OMS.
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http://dx.doi.org/10.1212/WNL.0000000000011410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055333PMC
February 2021

year in review.

Neurol Neuroimmunol Neuroinflamm 2021 01 18;8(1). Epub 2020 Dec 18.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (J.D.), Hospital Clínic, Universitat de Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Department of Neurology (J.D., D.L.K.), University of Pennsylvania, Philadelphia; Neuroimmunology Unit (M.C.D.), National and Kapodistrian University of Athens Medical School, Greece; Thomas Jefferson University (M.C.D.), Philadelphia, PA; Charité-Universitätsmedizin Berlin und Max Delbrueck Center for Molecular Medicine (F.P.), Germany; and Department of Neurology (S.S.Z.), Weill Institute for Neurosciences and Program in Immunology, University of California, San Francisco.

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http://dx.doi.org/10.1212/NXI.0000000000000925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757781PMC
January 2021

Author response: Hashimoto encephalopathy in the 21st century.

Neurology 2020 12;95(23):1068

(Barcelona, Spain).

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http://dx.doi.org/10.1212/WNL.0000000000011101DOI Listing
December 2020

Sleep disorders in autoimmune encephalitis.

Lancet Neurol 2020 12;19(12):1010-1022

Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Sleep disorders in people with autoimmune encephalitis have received little attention, probably overshadowed by the presence of other neurological and psychiatric symptoms in this group of conditions. However, sleep disorders are frequent, often severe, and usually persist beyond the acute disease stage, interfering with patients' recovery and quality of life. Because autoimmune encephalitis can affect any brain network involved in sleep initiation and regulation, all types of sleep disorders can occur, with varying distinct associations, frequency, and intensity. Anti-IgLON5 and anti-NMDA receptor encephalitis exemplify two diseases in which sleep disorders are prominent. In anti-IgLON5 disease, sleep disorders were the core symptoms that led to the description of this disease, whereas in anti-NMDA receptor encephalitis, sleep disorders vary according to the disease stage along with other neuropsychiatric symptoms. Comprehensive, systematic, multicentre studies are needed to characterise sleep disorders and their mechanisms in autoimmune encephalitis.
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http://dx.doi.org/10.1016/S1474-4422(20)30341-0DOI Listing
December 2020

Placental transfer of NMDAR antibodies causes reversible alterations in mice.

Neurol Neuroimmunol Neuroinflamm 2021 01 10;8(1). Epub 2020 Nov 10.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (A.G.-S., M.R., A.P., V.B., E.A., E.M., H.A., M.S., F.M., M.P., B.J., S.G., J.P., J.D.), Hospital Clínic, Universitat de Barcelona; Departament de Biomedicina (A.P., V.B., S.G.), Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) (A.P., V.B., S.G.), Madrid; Medical Statistics Core Facility (J.R.), IDIBAPS and Hospital Clínic, Barcelona; Biostatistics Unit (J.R.), School of Medicine, Universitat Autònoma de Barcelona; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) (J.D.), Madrid, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.

Objective: To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies.

Methods: Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects.

Results: In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood.

Conclusions: In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy.
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http://dx.doi.org/10.1212/NXI.0000000000000915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713722PMC
January 2021

Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects.

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Nov 3.

From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France.

Objective: To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.

Methods: SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.

Results: In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.

Conclusions: SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
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http://dx.doi.org/10.1212/NXI.0000000000000916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641326PMC
January 2021

A probable case of anti-NMDAR encephalitis from 1830.

Authors:
Josep Dalmau

Neurol Neuroimmunol Neuroinflamm 2020 11 21;7(6). Epub 2020 Oct 21.

From ICREA-IDIBAPS Hospital Clínic, University of Barcelona, Spain; and Department of Neurology, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1212/NXI.0000000000000901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641120PMC
November 2020

StimuliApp: Psychophysical tests on mobile devices.

Behav Res Methods 2020 Oct 9. Epub 2020 Oct 9.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Psychophysical tests are commonly carried out using software applications running on desktop or laptop computers, but running the software on mobile handheld devices such as smartphones or tablets could have advantages in some situations. Here, we present StimuliApp, an open-source application in which the user can create psychophysical tests on the iPad and the iPhone by means of a system of menus. A wide number of templates for creating stimuli are available including patches, gradients, gratings, checkerboards, random-dots, texts, tones or auditory noise. Images, videos and audios stored in files could also be presented. The application was developed natively for iPadOS and iOS using the low-level interface Metal for accessing the graphics processing unit, which results in high timing performance.
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http://dx.doi.org/10.3758/s13428-020-01491-4DOI Listing
October 2020

Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis.

Neurology 2020 12 14;95(22):e3012-e3025. Epub 2020 Sep 14.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (M. Spatola, M.P.P., E.M., M.R.R., F.G., J.D.), Barcelona, Spain; Ragon Institute of MGH, MIT and Harvard Medical School (M. Spatola), Cambridge, MA; Interdisciplinary Institute for Neuroscience (M.P.P.), University of Bordeaux, France; Neurology Division (M. Simabukuro), University of São Paulo, School of Medicine, Brazil; Centre de Référence des Syndromes Neurologiques Paranéoplasiques et des Encéphalites Autoimmunes (S.M.-C., A.L.P., J.H.), Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon1, INMG, Inserm U1217/CNRS UMR 5310, France; Institute of Clinical Chemistry and Department of Neurology (K.-P.W.), Department of Neuropediatrics (J.S.), and Department of Neuroradiology (P.S.), University Hospital Schleswig Holstein, Lübeck, Germany; Faculdade Israelita de Ciências da Saúde Albert Einstein and General Neurology Division (L.A.D.), Federal University of São Paulo, Brazil; Institute of Neurology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS (R.I.), Rome, Italy; Department of Neurology (C.K.), University Hospital Bonn; Epilepsy Center Bethel (C.G.B.), Krankenhaus Mara, Bielefeld, Germany; Division of Neuropathology and Neurochemistry (R.H.), Department of Neurology, Medical University of Vienna, Austria; Neuroimmunology (F.L.), Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany; Department of Neurology (M.J.T., P.S.S.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; University Hospital Clínic (F.G.), University of Barcelona; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To clinically characterize patients with anti-metabotropic glutamate receptor (mGluR) 1 encephalitis, to identify prognostic factors, and to study the immunoglobulin G (IgG) subclasses and effects of antibodies on neuronal mGluR1 clusters.

Methods: Clinical information on new and previously reported patients was reviewed. Antibodies to mGluR1 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays, and their effects on mGluR1 clusters were studied on rat hippocampal neurons.

Results: Eleven new patients were identified (10 adults, 1 child);4 were female. In these and 19 previously reported cases (n = 30, median age 55 years), the main clinical manifestation was a subacute cerebellar syndrome that in 25 (86%) patients was associated with behavioral/cognitive changes or other neurologic symptoms. A tumor was found in 3 of 26 (11%). Brain MRI was abnormal in 7 of 19 (37%) at onset and showed cerebellar atrophy in 10 of 12 (83%) at follow-up. Twenty-five of 30 (83%) patients received immunotherapy. Follow-up was available for 25: 13 (52%) had clinical stabilization; 10 (40%) showed significant improvement; and 2 died. At the peak of the disease, patients with bad outcome at 2 years (modified Rankin Scale score > 2, n = 7) were more likely to have higher degree of initial disability, as reflected by a worse Scale for Assessment and Rating of Ataxia score, and more frequent need of assistance to walk. Antibodies to mGluR1 were mainly IgG1 and caused a significant decrease of mGluR1 clusters in cultured neurons.

Conclusions: Anti-mGluR1 encephalitis manifests as a severe cerebellar syndrome, often resulting in long-term disability and cerebellar atrophy. The antibodies are pathogenic and cause significant decrease of mGluR1 clusters in cultured neurons.
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http://dx.doi.org/10.1212/WNL.0000000000010854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734921PMC
December 2020

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia.

Nat Commun 2020 08 25;11(1):4250. Epub 2020 Aug 25.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Carrer Rosselló 149, 08036, Barcelona, Spain.

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.
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http://dx.doi.org/10.1038/s41467-020-18033-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447775PMC
August 2020

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis.

Brain 2020 09;143(9):2709-2720

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient's CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient's CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.
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http://dx.doi.org/10.1093/brain/awaa195DOI Listing
September 2020

N2 in the time of COVID-19.

Authors:
Josep Dalmau

Neurol Neuroimmunol Neuroinflamm 2020 09 20;7(5). Epub 2020 Aug 20.

From the ICREA-IDIBAPS Hospital Clínic, University of Barcelona, Spain; and Department of Neurology, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1212/NXI.0000000000000858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455311PMC
September 2020

The Diagnostic Value of Onconeural Antibodies Depends on How They Are Tested.

Front Immunol 2020 14;11:1482. Epub 2020 Jul 14.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Detection of onconeural antibodies is important because establishes a definitive diagnosis of paraneoplastic neurological syndrome (PNS). The recommended method for diagnosis of onconeural antibodies is by immunohistochemistry on rodent brain sections and confirmation of results by immunoblot. However, in many diagnostic laboratories samples are only tested with commercial line blots. In this study we inquired whether this change in diagnostic methodology (line blot alone vs. combined immunohistochemistry and line blot) would affect the results. Among 439 samples examined by immunohistochemistry and a commercial line blot (Euroimmun, Lübeck, Germany) 96 (22%) were positive by line blot, and their clinical information was reviewed. Onconeural antibodies were detected by both assays in 46/96 (48%) patients (concordant group) whereas 50 (52%) were only positive by line blot (discordant group). In the concordant group 42/46 (91%) patients had a definite diagnosis of PNS whereas in the discordant group only 4/50 (8%) had PNS ( < 0.00001). None of the 14 patients with ZIC4 antibodies and 1/13 (8%) with Yo antibodies demonstrated only by line blot had PNS. These findings show a robust diagnostic value of combined diagnostic techniques, and both should be used to demonstrate onconeural antibodies, If antibody testing is performed only with line blot assay, positive bands should be confirmed by rodent brain immunohistochemistry. For ZIC4 or Yo antibody testing, line blot positivity with negative immunohistochemistry has no diagnostic significance, and for the rest of onconeural antibodies the predictive diagnostic value is low.
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http://dx.doi.org/10.3389/fimmu.2020.01482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372120PMC
April 2021

Effects of IgLON5 Antibodies on Neuronal Cytoskeleton: A Link between Autoimmunity and Neurodegeneration.

Ann Neurol 2020 11 27;88(5):1023-1027. Epub 2020 Aug 27.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neuronal-specific tau accumulation. Here, we report that patients' IgLON5 IgG, but not other cell-surface antibodies, disrupt the cytoskeletal organization in cultured rat hippocampal neurons, resulting in dystrophic neurites and axonal swelling. Adsorption of IgLON5 IgG with HEK293 cells expressing IgLON5 abrogated the indicated cytoskeletal changes. These findings, along with an increase of levels of neurofilaments in patients' cerebrospinal fluid, suggest that IgLON5 IgG, unlike other cell-surface antibodies, disrupts neuronal cytoskeleton maintenance, providing a link between autoimmunity and neurodegeneration. ANN NEUROL 2020;88:1023-1027.
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http://dx.doi.org/10.1002/ana.25857DOI Listing
November 2020

NMDAR Antibodies Alter Dopamine Receptors and Cause Psychotic Behavior in Mice.

Ann Neurol 2020 09 11;88(3):603-613. Epub 2020 Jul 11.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Objective: The aim was to demonstrate that antibodies from patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic-like features in mice.

Methods: Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic-like behavior), memory, locomotor activity, and the density of cell-surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques.

Results: In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell-surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell-surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic-like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped.

Interpretation: In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti-NMDAR encephalitis cause reversible psychotic-like features accompanied by changes (D1R decrease, D2R increase) in cell-surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603-613.
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http://dx.doi.org/10.1002/ana.25829DOI Listing
September 2020

Sleep disorders in anti-NMDAR encephalitis.

Neurology 2020 08 23;95(6):e671-e684. Epub 2020 Jun 23.

From Clinical and Experimental Neuroimmunology (H.A., A.M.-L., E.M.-H., T.A., M.R.-J., D.E., F.G., G.S., J.C.-F., A.C., J.D., J.S.), Institut d'Investigació Biomèdica August Pi i Sunyer; Departments of Neurology (A.M.-L., E.M.-H., D.E., N.M., J.D., J.S.) and Child and Adolescent Psychiatry and Psychology (T.A., G.S., J.C.-F.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain.

Objective: To describe the sleep disorders in anti-NMDA receptor encephalitis (anti-NMDARe).

Methods: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single-center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment, and neuropsychological evaluation. Age- and sex-matched healthy participants served as controls.

Results: Eighteen patients (89% female, median age 26 years, interquartile range [IQR] 21-29 years) and 21 controls (81% female, median age 23 years, IQR 18-26 years) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia; nightmares occurred in 7. After the acute stage, 14 (78%) had hypersomnia. At study admission (median 183 days after disease onset, IQR 110-242 days), 8 patients still had hypersomnia, 1 had insomnia, and 9 had normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, = 0.02, and Epworth Sleepiness Score, = 0.04). On V-PSG, sleep efficiency was similar in both groups, but patients more frequently had multiple and longer confusional arousals in non-REM (NREM) sleep (videos provided). In addition, 13 (72%) patients had cognitive deficits; 12 (67%) had psychological, social, or occupational disability; and 33% had depression or mania. Compared with controls, patients had a higher body mass index (median 23.5 [IQR 22.3-30.2] vs 20.5 [19.1-21.1] kg/m; = 0.007). Between disease onset and last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) developed hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction.

Conclusions: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), are associated with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.
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http://dx.doi.org/10.1212/WNL.0000000000009987DOI Listing
August 2020

Interplay between persistent activity and activity-silent dynamics in the prefrontal cortex underlies serial biases in working memory.

Nat Neurosci 2020 08 22;23(8):1016-1024. Epub 2020 Jun 22.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative 'activity-silent' substrates. Using monkey and human electrophysiology data, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in the prefrontal cortex (PFC). This interaction allows memory reactivations, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in the PFC. Just before the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model that integrates activity-based and activity-silent mechanisms. Finally, single-pulse transcranial magnetic stimulation applied to the human PFC between successive trials enhanced serial biases, thus demonstrating the causal role of prefrontal reactivations in determining working-memory behavior.
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http://dx.doi.org/10.1038/s41593-020-0644-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392810PMC
August 2020

"Time to recharge".

Authors:
Josep Dalmau

Neurol Neuroimmunol Neuroinflamm 2020 07 11;7(4). Epub 2020 Jun 11.

From the ICREA-IDIBAPS Hospital Clínic, University of Barcelona, Barcelona, Spain; and Department of Neurology, University of Pennsylvania, Pennsylvania.

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http://dx.doi.org/10.1212/NXI.0000000000000779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309523PMC
July 2020

High-Throughput Task to Study Memory Recall During Spatial Navigation in Rodents.

Front Behav Neurosci 2020 15;14:64. Epub 2020 May 15.

Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.

Spatial navigation is one of the most frequently used behavioral paradigms to study memory formation in rodents. Commonly used tasks to study memory are labor-intensive, preventing the simultaneous testing of multiple animals with the tendency to yield a low number of trials, curtailing the statistical power. Moreover, they are not tailored to be combined with neurophysiology recordings because they are not based on overt stereotyped behavioral responses that can be precisely timed. Here we present a novel task to study long-term memory formation and recall during spatial navigation. The task consists of learning sessions during which mice need to find the rewarding port that changes from day to day. Hours after learning, there is a recall session during which mice search for the location of the memorized rewarding port. During the recall sessions, the animals repeatedly poke the remembered port over many trials (up to ∼20) without receiving a reward (i.e., no positive feedback) as a readout of memory. In this task, mice show memory of port locations learned on up to three previous days. This eight-port maze task requires minimal human intervention, allowing for simultaneous and unsupervised testing of several mice in parallel, yielding a high number of recall trials per session over many days, and compatible with recordings of neural activity.
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http://dx.doi.org/10.3389/fnbeh.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243682PMC
May 2020

GAD antibodies in neurological disorders - insights and challenges.

Nat Rev Neurol 2020 Jul 26;16(7):353-365. Epub 2020 May 26.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.

Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff-person syndrome, cerebellar ataxia and epilepsy. These antibodies were first described in 1988, but several controversies about GAD autoimmunity still remain. No criteria exist to establish when a neurological syndrome is pathogenically linked to GAD antibodies, often leading to the assumption that any syndrome in which these antibodies are present is immune mediated, sometimes resulting in misdiagnosis and unnecessary treatment. In this Review, we provide recommendations for assessing the association between a neurological syndrome and the presence of GAD antibodies, and we critically review the evidence on the pathogenicity of GAD antibodies. Given that stiff-person syndrome is usually autoimmune, the presence of GAD antibodies in the cerebrospinal fluid is sufficient to confirm a pathogenic link with GAD autoimmunity. However, for cerebellar ataxia, epilepsy and other syndromes with different aetiologies, we propose that confirmation of a pathogenic link with GAD autoimmunity requires demonstration of intrathecal GAD antibody synthesis. Nevertheless, the evidence that GAD antibodies are directly pathogenic is not yet convincing. Studies in animal models are needed to demonstrate whether neurological syndromes are directly caused by specific disruption of GAD function by GAD antibodies.
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http://dx.doi.org/10.1038/s41582-020-0359-xDOI Listing
July 2020

Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.

Neurology 2020 06 11;94(22):e2302-e2310. Epub 2020 Mar 11.

From the Neuroimmunology Program (E.M.-H., M.G., A.G.-S., E.M., H.A., T.A., A.S., F.G., J.D.), Institut d'Investigacions Biomediques August Pi i Sunyer; Neurology Department (E.M.-H., M.G., H.A., M.S., T.A., A.S., J.D.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Deu Children's Hospital, University of Barcelona; Centro de Investigaciones Biomedicas en Red de Enfermedades Raras (E.M.-H., M.G., T.A., J.D.), Madrid, Spain; Hospital Cayetano Heredia (A.P.R.), San Martin de Porres, Perú; Hadassah-Hebrew University Medical Center (T.B.-H.), Jerusalem, Israel; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To determine the frequency and significance of concurrent glial (glial-Ab) or neuronal-surface (NS-Ab) antibodies in patients with anti-NMDA receptor (NMDAR) encephalitis.

Methods: Patients were identified during initial routine screening of a cohort (C1) of 646 patients consecutively diagnosed with anti-NMDAR encephalitis and another cohort (C2) of 200 patients systematically rescreened. Antibodies were determined with rat brain immunostaining and cell-based assays.

Results: Concurrent antibodies were identified in 42 patients (4% from C1 and 7.5% from C2): 30 (71%) with glial-Ab and 12 (29%) with NS-Ab. Glial-Ab included myelin oligodendrocyte glycoprotein (MOG) (57%), glial fibrillary acidic protein (GFAP) (33%), and aquaporin 4 (AQP4) (10%). NS-Ab included AMPA receptor (AMPAR) (50%), GABAa receptor (GABAaR) (42%), and GABAb receptor (8%). In 39 (95%) of 41 patients, concurrent antibodies were detected in CSF, and in 17 (41%), concurrent antibodies were undetectable in serum. On routine clinical-immunologic studies, the presence of MOG-Ab and AQP4-Ab was suggested by previous episodes of encephalitis or demyelinating disorders (8, 27%), current clinical-radiologic features (e.g., optic neuritis, white matter changes), or standard rat brain immunohistochemistry (e.g., AQP4 reactivity). GFAP-Ab did not associate with distinct clinical-radiologic features. NS-Ab were suggested by MRI findings (e.g., medial temporal lobe changes [AMPAR-Ab], or multifocal cortico-subcortical abnormalities [GABAaR-Ab]), uncommon comorbid conditions (e.g., recent herpesvirus encephalitis), atypical tumors (e.g., breast cancer, neuroblastoma), or rat brain immunostaining. Patients with NS-Ab were less likely to have substantial recovery than those with glial-Ab (5 of 10 [50%] vs 17 of 19 [89%], = 0.03).

Conclusions: Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.
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http://dx.doi.org/10.1212/WNL.0000000000009239DOI Listing
June 2020

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

Lancet Neurol 2020 03 10;19(3):234-246. Epub 2020 Feb 10.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Catalan Institute for Research and Advanced Studies, Barcelona, Spain. Electronic address:

Background: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis.

Methods: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity.

Findings: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59).

Interpretation: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications.

Funding: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.
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http://dx.doi.org/10.1016/S1474-4422(19)30488-0DOI Listing
March 2020