Publications by authors named "Mar Petit-Pedrol"

24 Publications

  • Page 1 of 1

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
February 2021

Regulation of membrane NMDA receptors by dynamics and protein interactions.

J Cell Biol 2021 Jan;220(1)

Université de Bordeaux, Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297, Bordeaux, France.

Understanding neurotransmitter system crosstalk in the brain is a major challenge in neurobiology. Several intracellular and genomic cascades have been identified in this crosstalk. However, the discovery that neurotransmitter receptors are highly diffusive in the plasma membrane of neurons, where they form heterocomplexes with other proteins, has profoundly changed our view of neurotransmitter signaling. Here, we review new insights into neurotransmitter crosstalk at the plasma membrane. We focus on the membrane organization and interactome of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) that plays a central role in excitatory synaptic and network physiology and is involved in the etiology of several major neuropsychiatric disorders. The nanoscale organization and dynamics of NMDAR is a key regulatory process for glutamate synapse transmission, plasticity, and crosstalk with other neurotransmitter systems, such as the monoaminergic ones. The plasma membrane appears to be a prime regulatory compartment for spatial and temporal crosstalk between neurotransmitter systems in the healthy and diseased brain. Understanding the molecular mechanisms regulating membrane neurotransmitter receptor crosstalk will likely open research avenues for innovative therapeutical strategies.
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http://dx.doi.org/10.1083/jcb.202006101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754687PMC
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

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

Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2.

Neurol Neuroimmunol Neuroinflamm 2020 03 11;7(2). Epub 2019 Dec 11.

From the Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clínic; Neuroimmunology Program (E.M.-H., B.J., M.P.-P., T.A., L. Sabater, J.D., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (E.M.-H.), Hospital Clinic; Service of Neurology (E.P.-B., L. Salais), Hospital General de Castellón, Spain; Service of Pediatrics (V.F.), Hospital General de Albacete, Spain; Onco-Hematology Unit (M.d.P.), Service of Pediatrics, Hospital General de Albacete; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia, PA.

Objective: To report the presence of a new neuronal surface antibody against the metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in 2 patients with paraneoplastic cerebellar ataxia.

Methods: mGluR2-Abs were initially characterized by immunohistochemistry on the rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluRs, expression of mGluR2 in patients' tumors, and the effects of mGluR2-Abs on cultures of rat hippocampal neurons.

Results: Patient 1 was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients' serum and CSF showed a characteristic immunostaining of the hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients' antibodies only recognized mGluR2. mGluR2-Abs were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias, and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters.

Conclusions: mGluR2-Abs are a novel biomarker of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by downregulation or internalization of neuronal surface mGluR2.
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http://dx.doi.org/10.1212/NXI.0000000000000658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943365PMC
March 2020

Toll-like receptor 3 deficiency in autoimmune encephalitis post-herpes simplex encephalitis.

Neurol Neuroimmunol Neuroinflamm 2019 11 5;6(6). Epub 2019 Sep 5.

From the Neuroimmunology Program (T.A., M.P.-P., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, Spain; Clinical Immunology and Primary Immunodeficiencies Unit (B.J.B., A.D.-M., L.A., A.E.-S.), Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona, Spain; Clinical Immunology Unit (A.V., A.E.-S., R.R.-G., M.J., L.A.), Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Barcelona, Spain; Laboratory of Immunogenetics of Human Diseases (R.P.d.D.), IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain; Innate Immunity Group (R.P.d.D.), IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain; Interdepartmental Group of Immunodeficiencies (R.P.d.D.), Madrid, Spain; Neurology Department (J.D.), University of Pennsylvania, Philadelphia; and Catalan Institute for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

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http://dx.doi.org/10.1212/NXI.0000000000000611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773430PMC
November 2019

LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.

Brain 2018 11;141(11):3144-3159

Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany.

Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that forms a trans-synaptic complex that includes the presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23), which interacts with voltage-gated potassium channels Kv1.1, and the postsynaptic ADAM22, which interacts with AMPA receptors. Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures. Although there is evidence that this disease is immune-mediated, the underlying LGI1 antibody-mediated mechanisms are unknown. Here, we used patient-derived immunoglobulin G (IgG) antibodies to determine the main epitope regions of LGI1 and whether the antibodies disrupt the interaction of LGI1 with ADAM23 and ADAM22. In addition, we assessed the effects of patient-derived antibodies on Kv1.1, AMPA receptors, and memory in a mouse model based on cerebroventricular transfer of patient-derived IgG. We found that IgG from all patients (n = 25), but not from healthy participants (n = 20), prevented the binding of LGI1 to ADAM23 and ADAM22. Using full-length LGI1, LGI3, and LGI1 constructs containing the LRR1 domain (EPTP1-deleted) or EPTP1 domain (LRR3-EPTP1), IgG from all patients reacted with epitope regions contained in the LRR1 and EPTP1 domains. Confocal analysis of hippocampal slices of mice infused with pooled IgG from eight patients, but not pooled IgG from controls, showed a decrease of total and synaptic levels of Kv1.1 and AMPA receptors. The effects on Kv1.1 preceded those involving the AMPA receptors. In acute slice preparations of hippocampus, patch-clamp analysis from dentate gyrus granule cells and CA1 pyramidal neurons showed neuronal hyperexcitability with increased glutamatergic transmission, higher presynaptic release probability, and reduced synaptic failure rate upon minimal stimulation, all likely caused by the decreased expression of Kv1.1. Analysis of synaptic plasticity by recording field potentials in the CA1 region of the hippocampus showed a severe impairment of long-term potentiation. This defect in synaptic plasticity was independent from Kv1 blockade and was possibly mediated by ineffective recruitment of postsynaptic AMPA receptors. In parallel with these findings, mice infused with patient-derived IgG showed severe memory deficits in the novel object recognition test that progressively improved after stopping the infusion of patient-derived IgG. Different from genetic models of LGI1 deficiency, we did not observe aberrant dendritic sprouting or defective synaptic pruning as potential cause of the symptoms. Overall, these findings demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1 signalling, causing neuronal hyperexcitability, decreased plasticity, and reversible memory deficits.
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http://dx.doi.org/10.1093/brain/awy253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202570PMC
November 2018

Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction.

Neuron 2018 10 23;100(1):91-105.e9. Epub 2018 Aug 23.

Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address:

AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
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http://dx.doi.org/10.1016/j.neuron.2018.07.048DOI Listing
October 2018

Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor.

Neurology 2018 04 16;90(16):e1386-e1394. Epub 2018 Mar 16.

From the Clinical and Experimental Neuroimmunology Program, August Pi i Sunyer Biomedical Research Institute, Hospital Clínic (M.H., E.M.-H., H.A., T.A., M.S., M.P.-P., A.S., M.R.R., F.G., J.D.), and Department of Neurology, Sant Joan de Deu Childrens Hospital (T.A., J.D.), University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Japan; University of Lausanne (M.S.), Switzerland; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM -methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis.

Methods: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005.

Results: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia.

Conclusions: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
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http://dx.doi.org/10.1212/WNL.0000000000005329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902781PMC
April 2018

The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis.

Nat Rev Neurol 2017 May 18;13(5):290-301. Epub 2017 Apr 18.

Department of Neurology, Erasmus University Medical Center, 's-Gravendijkwal 230, PO Box 2040, 3000CA Rotterdam, Netherlands.

The discovery, in 2010, of autoantibodies against the extracellular proteins LGI1 and Caspr2 facilitated a change of view regarding the clinical importance of voltage-gated potassium channel (VGKC) antibodies. Currently, these antibodies are all classified as VGKC-complex antibodies, and are commonly considered to have a similar clinical value. However, studies from the past few years show that the immune responses mediated by these antibodies have differing clinical relevance. Here, we review the clinical importance of these immune responses in three settings: patients with anti-LGI1 antibodies, patients with anti-Caspr2 antibodies, and patients with antibodies against the VGKC complex that lack LGI1 and Caspr2 specificity. Antibodies against LGI1 and Caspr2 are associated with different but well-defined syndromes, whereas the clinical importance of VGKC-complex antibodies without LGI1 and Caspr2 specificity is questionable. We describe each of these syndromes, discuss the function of the target antigens and review the limited paediatric literature on the topic. The findings emphasize the importance of defining these disorders according to the molecular identity of the targets (LGI1 or Caspr2), and caution against the use of VGKC-complex antibodies for the diagnosis and treatment of patients without further definition of the antigen.
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http://dx.doi.org/10.1038/nrneurol.2017.43DOI Listing
May 2017

DPPX antibody-associated encephalitis: Main syndrome and antibody effects.

Neurology 2017 Apr 3;88(14):1340-1348. Epub 2017 Mar 3.

From the Clinical and Experimental Neuroimmunology Program (M.H., H.A., M.P.-P., L.S., E.M.-H., M.R.R., F.G., J.D.), August Pi Sunyer Biomedical Research Institute, Hospital Clínic, University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Biomedical Research Networking Centre for Rare Diseases (H.A., J.D., M.P.-P., L.S., E.M.-H., M.R.R.), Valencia, Spain; Departments of Neurology (M.J.T.) and Immunology (M.W.J.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To report the main syndrome of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and the antibody effects on DPPX/Kv4.2 potassium channels.

Methods: A retrospective analysis of new patients and cases reported since 2013 was performed. IgG subclass and effects of antibodies on cultured neurons were determined with described techniques.

Results: Nine new patients were identified (median age 57 years, range 36-69 years). All developed severe prodromal weight loss or diarrhea followed by cognitive dysfunction (9), memory deficits (5), CNS hyperexcitability (8; hyperekplexia, myoclonus, tremor, or seizures), or brainstem or cerebellar dysfunction (7). The peak of the disease was reached 8 months (range 1-54 months) after onset. All patients had both IgG4 and IgG1 DPPX antibodies. In cultured neurons, the antibodies caused a decrease of DPPX clusters and Kv4.2 protein that was reversible on removal of the antibodies. Considering the current series and previously reported cases (total 39), 67% developed the triad: weight loss (median 20 kg; range 8-53 kg)/gastrointestinal symptoms, cognitive-mental dysfunction, and CNS hyperexcitability. Outcome was available from 35 patients (8 not treated with immunotherapy): 60% had substantial or moderate improvement, 23% had no improvement (most of them not treated), and 17% died. Relapses occurred in 8 of 35 patients (23%) and were responsive to immunotherapy.

Conclusions: DPPX antibodies are predominantly IgG1 and IgG4 and associate with cognitive-mental deficits and symptoms of CNS hyperexcitability that are usually preceded by diarrhea, other gastrointestinal symptoms, and weight loss. The disorder is responsive to immunotherapy, and this is supported by the reversibility of the antibody effects in cultured neurons.
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http://dx.doi.org/10.1212/WNL.0000000000003796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379928PMC
April 2017

Investigations in GABA receptor antibody-associated encephalitis.

Neurology 2017 Mar 15;88(11):1012-1020. Epub 2017 Feb 15.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M.S., M.P.-P., T.A., M.R.R., F.G., J.D.), University of Barcelona, Spain; University of Lausanne (UNIL) (M.S.), Switzerland; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (M.P.-P., T.A., M.R.R., J.D., F.G.), Madrid, Spain; Neurology Service (T.A., J.D.), Hospital Sant Joan de Déu, Barcelona, Spain; Neurology Division, Hospital das Clínicas (M.M.S.), São Paulo University, Brazil; Hospital de Base (F.J.C.), Brasília, Brazil; Service of Neurology (M.I.B.A.) and Service of Immunology (M.R.J.B.), University Hospital of Son Espases, Mallorca, Spain; Department of Neurology (L.B., M.G.), Children's Hospital, Boston, MA; Pediatric Neurology Section (A.F.), Vall d'Hebron University Hospital, Barcelona, Spain; Hospital Nacional Edgardo Rebagliati Martins (R.L.C.O.), Lima, Peru; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; Service of Neurology (F.G., J.D.), Hospital Clínic; and Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

Objective: To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABA receptor (GABAR) encephalitis.

Methods: Clinical study of 26 patients, including 17 new (April 2013-January 2016) and 9 previously reported patients. Antibodies to α1, β3, and γ2 subunits of the GABAR were determined using reported techniques.

Results: Patients' median age was 40.5 years (interquartile range 48.5 [13.75-62.35] years; the youngest 2.5 months old; 13 female). Symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%). Comorbidities were identified in 11 (42%) patients, including 7 tumors (mostly thymomas), 2 herpesvirus encephalitis (herpes simplex virus 1, human herpesvirus 6; coexisting with NMDAR antibodies), and 2 myasthenia without thymoma. Brain MRI was abnormal in 23 (88%) patients, showing in 20 (77%) multifocal, asynchronous, cortical-subcortical T2/fluid-attenuated inversion recovery abnormalities predominantly involving temporal (95%) and frontal (65%) lobes, but also basal ganglia and other regions. Immunologic or tumor therapy resulted in substantial improvement in 18/21 (86%) assessable patients; the other 3 (14%) died (2 status epilepticus, 1 sepsis). Compared with adults, children were more likely to have generalized seizures ( = 0.007) and movement disorders ( = 0.01) and less likely to have a tumor ( = 0.01). The main epitope targets were in the α1/β3 subunits of the GABAR.

Conclusions: Anti-GABAR encephalitis is characterized by frequent seizures and distinctive multifocal cortical-subcortical MRI abnormalities that provide an important clue to the diagnosis. The frequency of symptoms and comorbidities differ between children (more viral-related) and adults (more tumor-related). The disorder is severe but most patients respond to treatment.
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http://dx.doi.org/10.1212/WNL.0000000000003713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384834PMC
March 2017

Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome.

Neurology 2016 Aug 27;87(8):759-65. Epub 2016 Jul 27.

From the Neuroimmunology Program (H.A., T.A., M.P.-P., L.S., E.M.-H., M.H., A.S., J.D., F.G.), August Pi Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (E.L., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain.

Objective: We investigated a series of patients with LGI1 antibody (Ab)-related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution.

Methods: We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab-related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18-200).

Results: Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%-49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4-215.6, p = 0.006) and clinical relapses (odds ratio 10.2, 95% CI 1.0-100.1, p = 0.047) that occurred in 13 patients (27%). In all patients, the LGI1 Abs were IgG4 and usually detectable in both serum and CSF (only CSF, 8%). Abs remained positive in serum of 4 of 16 patients with long-term follow-up; 3 of these 4 patients fully recovered and none showed class switch to IgG1.

Conclusions: Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery.
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http://dx.doi.org/10.1212/WNL.0000000000003009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999321PMC
August 2016

Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity.

Ann Neurol 2016 09 2;80(3):388-400. Epub 2016 Aug 2.

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

Objective: To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity.

Methods: One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus.

Results: Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity.

Interpretation: Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388-400.
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http://dx.doi.org/10.1002/ana.24721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832041PMC
September 2016

The clinical spectrum of Caspr2 antibody-associated disease.

Neurology 2016 Aug 1;87(5):521-8. Epub 2016 Jul 1.

From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder.

Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent.

Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses.

Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.
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http://dx.doi.org/10.1212/WNL.0000000000002917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970662PMC
August 2016

Human neurexin-3α antibodies associate with encephalitis and alter synapse development.

Neurology 2016 06 11;86(24):2235-42. Epub 2016 May 11.

From the Neuroimmunology Program, Biomedical Research Institute August Pi i Sunyer (IDIBAPS) (N.G.-A., J.P., M.P.-P., T.A., E.M.-H., F.G., J.D.), and Service of Neurology, Hospital Clínic (F.G.), University of Barcelona, Spain; Department of Neurology (I.K., S.K.), Brain Research Institute, Niigata University, Japan; Division of Pediatric Infectious Diseases (C.A.G.), Kaiser Permanente, Oakland Medical Center and University of California, San Francisco; Neurology Division (M.M.S.), Hospital das Clínicas, São Paulo University (HC/FMUSP), Brazil; Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain. N.G.-A. is currently affiliated with the Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

Objective: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses.

Methods: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques.

Results: Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7-17 to patients' IgG showed a decrease of neurexin-3α clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients' IgG. Neuronal survival, dendritic morphology, and spine density were unaffected.

Conclusion: Neurexin-3α autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3α and alter synapse development.
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http://dx.doi.org/10.1212/WNL.0000000000002775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909558PMC
June 2016

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder.

JAMA Neurol 2016 06;73(6):714-20

Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain7Department of Neurology, University of Pennsylvania, Philadelphia9Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalonia, Spain.

Importance: Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear.

Objective: To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus.

Design, Setting, And Patients: This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015.

Main Outcomes And Measures: Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses.

Results: The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07).

Conclusions And Relevance: In SPSD, symptom severity and presence and type of antibodies are predictors of outcome.
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http://dx.doi.org/10.1001/jamaneurol.2016.0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020136PMC
June 2016

Clinical and Immunological Features of Opsoclonus-Myoclonus Syndrome in the Era of Neuronal Cell Surface Antibodies.

JAMA Neurol 2016 Apr;73(4):417-24

Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain5Service of Neurology, Hospital Clínic, Barcelona, Spain.

Importance: Most studies on opsoclonus-myoclonus syndrome (OMS) in adults are based on small case series before the era of neuronal cell surface antibody discovery.

Objective: To report the clinical and immunological features of idiopathic OMS (I-OMS) and paraneoplastic OMS (P-OMS), the occurrence of antibodies to cell surface antigens, and the discovery of a novel cell surface epitope.

Design, Setting, And Participants: Retrospective cohort study and laboratory investigations of 114 adult patients with OMS at a center for autoimmune neurological disorders done between January 2013 and September 2015.

Main Outcomes And Measures: Review of clinical records. Immunohistochemistry on rat brain and cultured neurons as well as cell-based assays were used to identify known autoantibodies. Immunoprecipitation and mass spectrometry were used to characterize novel antigens.

Results: Of the 114 patients (62 [54%] female; median age, 45 years; interquartile range, 32-60 years), 45 (39%) had P-OMS and 69 (61%) had I-OMS. In patients with P-OMS, the associated tumors included lung cancer (n = 19), breast cancer (n = 10), other cancers (n = 5), and ovarian teratoma (n = 8); 3 additional patients without detectable cancer were considered to have P-OMS because they had positive results for onconeuronal antibodies. Patients with I-OMS, compared with those who had P-OMS, were younger (median age, 38 [interquartile range, 31-50] vs 54 [interquartile range, 45-65] years; P < .001), presented more often with prodromal symptoms or active infection (33% vs 13%; P = .02), less frequently had encephalopathy (10% vs 29%; P = .01), and had better outcome (defined by a modified Rankin Scale score ≤ 2 at last visit; 84% vs 39%; P < .001) with fewer relapses (7% vs 24%; P= .04). Onconeuronal antibodies occurred in 13 patients (11%), mostly Ri/ANNA2 antibodies, which were detected in 7 of 10 patients (70%) with breast cancer. Neuronal surface antibodies were identified in 12 patients (11%), mainly glycine receptor antibodies (9 cases), which predominated in P-OMS with lung cancer (21% vs 5% in patients with OMS without lung cancer; P = .02); however, a similar frequency of glycine receptor antibodies was found in patients with lung cancer without OMS (13 of 65 patients [20%]). A novel cell surface epitope, human natural killer 1 (HNK-1), was the target of the antibodies in 3 patients with lung cancer and P-OMS.

Conclusions And Relevance: Patients with I-OMS responded better to treatment and had fewer relapses than those with P-OMS. Older age and encephalopathy, significantly associated with P-OMS, are clinical clues suggesting an underlying tumor. Glycine receptor antibodies occur frequently in P-OMS with lung cancer, but the sensitivity and specificity are low. The HNK-1 epitope is a novel epitope in a subset of patients with P-OMS and lung cancer.
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http://dx.doi.org/10.1001/jamaneurol.2015.4607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823978PMC
April 2016

Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity.

PLoS One 2015 16;10(3):e0121364. Epub 2015 Mar 16.

Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service of Neurology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.

Antibodies to glutamic acid decarboxylase (GAD-ab) associate to different neurological syndromes. It is unknown if the diversity in syndrome association represents epitopes in different immunodominant domains or co-existence of antibodies to other proteins of the inhibitory synapsis. We examined the serum and CSF of 106 patients with anti-GAD related syndromes (39 cerebellar ataxia, 32 stiff-person syndrome [SPS], 18 epilepsy, and 17 limbic encephalitis [LE]). GAD65-ab titres were quantified by ELISA. Immunoblot was used to determine if the antibody-targeted epitopes of GAD65 and GAD67 were linear. A cell-based assay (CBA) with HEK293 cells expressing the GAD65 N-terminal, central catalytic domain, or C-terminal was used to investigate the immunodominant domains. Antibodies to GAD67, gamma-aminobutyric acid A receptor (GABAaR), glycine receptor (GlyR), GABAaR-associated protein (GABARAP), and gephyrin were determined with CBA. GAD-ab internalization was investigated using cultured rat hippocampal neurons. CSF GAD65-ab titres were higher in patients with cerebellar ataxia and LE compared to those with SPS (p = 0.02). GAD67-ab were identified in 81% of sera and 100% of CSF. GAD65-ab recognized linear epitopes in 98% of the patients and GAD67-ab in 42% (p<0.001). The GAD65 catalytic domain was recognized by 93% of sera, and the three domains by 22% of sera and 74% of CSF (p<0.001). Six patients had GABAaR-ab and another 6 had GlyR-ab without association to distinctive symptoms. None of the patients had gephyrin- or GABARAP-ab. GAD65-ab were not internalized by live neurons. Overall, these findings show that regardless of the neurological syndrome, the CSF immune response against GAD is more widespread than that of the serum and that there is no specific association between clinical phenotype and the presence of antibodies against other proteins of the inhibitory synapsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361655PMC
October 2015

GABAA receptor and LGI1 antibody encephalitis in a patient with thymoma.

Neurol Neuroimmunol Neuroinflamm 2015 Apr 12;2(2):e73. Epub 2015 Feb 12.

Neurology Division (M.M.S., L.H.C., R.N., A.A.Z., L.G.S., G.C.R.F., H.R.S.N.) and Radiology Institute (L.L.), Hospital das Clínicas, São Paulo University, São Paulo, Brazil; August Pi i Sunyer Biomedical Research Institute (IDIBAPS) (M.P.-P., J.O.D.), Barcelona, Spain; Department of Neurology (J.O.D.), University of Pennsylvania, Philadelphia, PA; and Catalan Institution for Research and Advanced Studies (ICREA) (J.O.D.), Barcelona, Spain.

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http://dx.doi.org/10.1212/NXI.0000000000000073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335819PMC
April 2015

Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice.

Brain 2015 Jan 11;138(Pt 1):94-109. Epub 2014 Nov 11.

1 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain 8 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA 9 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
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http://dx.doi.org/10.1093/brain/awu310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285189PMC
January 2015

Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy.

JAMA Neurol 2014 Aug;71(8):1009-16

Neurology Service, Hospital Clínic, Barcelona, Spain2Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.

Importance: Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data.

Objective: To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs.

Design, Setting, And Participants: Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years).

Main Outcomes And Measures: Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, α1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls.

Results: The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P = .047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P = .01). Similar frequencies of serum GAD67-Abs were found in patients with CA (24 of 34 patients [71%]) and in patients with stiff person syndrome (20 of 28 patients [71%]). However, GAD67-Abs were found in all of the cerebrospinal fluid samples examined (22 samples from patients with CA and 17 samples from patients with stiff person syndrome). Glycine receptor antibodies but not other cell surface antibodies were identified in 4 patients with CA. The presence of glycine receptor antibodies did not correlate with any specific clinical feature.

Conclusions And Relevance: In patients with CA and GAD65-Abs, subacute onset of symptoms and prompt immunotherapy are associated with good outcome. Persistent vertigo or brainstem and cerebellar episodes can herald CA and should lead to GAD65-Ab testing, particularly in patients with systemic organ-specific autoimmunities.
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http://dx.doi.org/10.1001/jamaneurol.2014.1011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841264PMC
August 2014

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.

Lancet Neurol 2014 Mar 22;13(3):276-86. Epub 2014 Jan 22.

August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Hospital Clinic, University of Barcelona, Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address:

Background: Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients' antibodies on neuronal cultures.

Methods: In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy.

Findings: Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3-63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2-74 years, median 26.5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients' antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor).

Interpretation: High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable.

Funding: The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.
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http://dx.doi.org/10.1016/S1474-4422(13)70299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838043PMC
March 2014

Autoimmune encephalitis in children.

J Child Neurol 2012 Nov 29;27(11):1460-9. Epub 2012 Aug 29.

Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.

The causes of encephalitis are numerous, and extensive investigations for infectious agents and other etiologies are often negative. The discovery that many of these encephalitis are immune mediated has changed the approach to the diagnosis and treatment of these disorders. Moreover, the broad spectrum of symptoms including, psychosis, catatonia, alterations of behavior and memory, seizures, abnormal movements, and autonomic dysregulation usually requires a multidisciplinary treatment approach. This review focuses in several forms of encephalitis that occur in children, and for which an autoimmune etiology has been demonstrated (eg, anti-N-methyl-d-aspartate receptor encephalitis) or is strongly suspected (eg, Rasmussen encephalitis, limbic encephalitis, opsoclonus-myoclonus). The authors also review several disorders that may be immune mediated, such as the rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome and some encephalopathies with fever and status epilepticus. Recognition of novel immune-mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy.
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http://dx.doi.org/10.1177/0883073812448838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705178PMC
November 2012