Publications by authors named "Marianna Spatola"

22 Publications

  • Page 1 of 1

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

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

GABA receptor autoimmunity after alemtuzumab treatment for multiple sclerosis.

Neurology 2020 09 10;95(9):399-401. Epub 2020 Jul 10.

From the Department of Neurology and Stroke Unit "A. Cardarelli Hospital" (G.T.M., G.S., V.M., M.N., P.C., C.F.); Multiple Sclerosis Centre "A. Cardarelli Hospital" (G.T.M., C.F.), Naples; Neurology Unit (S.M., S.F., S.B.), Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy; Institute of Neurology (R.H.), Medical University of Vienna, Austria; Multiple Sclerosis Center (R.C.), ASST - Spedali Civili of Brescia, Montichiari; Department of Neuroradiology (S.G.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; and Ragon Institute of Massachusetts General Hospital (M.S.), Massachusetts Institute of Technology and Harvard Medical School, Cambridge.

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http://dx.doi.org/10.1212/WNL.0000000000010310DOI Listing
September 2020

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Neurol Sci 2019 Oct 3;40(10):2017-2030. Epub 2019 Jun 3.

Department of Neurology, Ospedale Santa Chiara, Trento, Italy.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.
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http://dx.doi.org/10.1007/s10072-019-03930-3DOI Listing
October 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

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

Lancet Neurol 2018 09 23;17(9):760-772. Epub 2018 Jul 23.

Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, PA, USA; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address:

Background: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.

Methods: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.

Findings: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).

Interpretation: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.

Funding: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
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http://dx.doi.org/10.1016/S1474-4422(18)30244-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128696PMC
September 2018

Encephalitis with mGluR5 antibodies: Symptoms and antibody effects.

Neurology 2018 05 27;90(22):e1964-e1972. Epub 2018 Apr 27.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (M.S., L.S., J.P., E.M.-H., T.A., M.R.R., F.G., J.D.) and Hospital Clínic, University of Barcelona, Spain; Department of Clinical Neuroscience (M.S.), University of Lausanne, Switzerland; Centro de Investigación Biomédica en Red de Enfermedades Raras (L.S., J.P., E.M.-H., T.A., M.R.R., F.G., J.D.), Valencia; ICFO-Institut de Ciències Fotòniques (J.P.); Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Charité Universitätsmedizin Berlin (H.P.), Experimentelle Neurologie und Klinik und Poliklinik für Neurologie; German Center for Neurodegenerative Diseases (H.P.), Berlin, Germany; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara, Japan; Hospital Nacional Edgardo Rebagliati Martins (R.L.C.O.), Lima, Peru; Department of Neurology (J.-C.A.), University Hospital, Saint-Etienne, France; Pamela Youde Nethersole Eastern Hospital (R.L.), Hong Kong; Beatson West of Scotland Cancer Centre (N.H.), Glasgow, UK; Department of Neurology (N.T.), St. Vincent's University Hospital, Dublin, Ireland; Service of Neurology (E.M.O.), Hospital del Mar, IMIM, Barcelona, Spain; 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 clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters.

Methods: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques.

Results: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95.

Conclusions: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.
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http://dx.doi.org/10.1212/WNL.0000000000005614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980520PMC
May 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

N-methyl-D-aspartate receptor encephalitis: laboratory diagnostics and comparative clinical features in adults and children.

Expert Rev Mol Diagn 2018 02 29;18(2):181-193. Epub 2018 Jan 29.

d Laboratory of Neuroimmunology , IRCCS Mondino Foundation , Pavia , Italy.

Introduction: N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis due to autoantibodies against neuronal surface antigens, can affect both children and adults, leading to neurological and neuropsychological sequelae. However, it is potentially treatable and the prompt start of immunotherapy associates with better prognosis. Conversely, misdiagnosis can be harmful. The detection of NMDAR antibodies in serum and cerebrospinal fluid plays a pivotal role in the diagnostic work-up. Reliable methods for NMDAR antibody detection are thus fundamental to assure accurate diagnosis and allow early treatments. Areas covered: This review recapitulates the pathogenic mechanisms of NMDAR encephalitis as a model of antibody mediated synaptopathy, and gives insights into the related state-of-the-art laboratory testing. The differences in clinical presentations, tumor associations and responses to treatments between adults and children are also described. Expert commentary: The relevance of NMDAR encephalitis has placed neuroimmunology laboratories in a crucial position, but methods for NMDAR antibody detection are awaiting thorough and consensus-based standardizations. In the next few years, this process, along with novel insights into the pathogenic mechanisms, could improve the disease management and clarify the still pending role of NMDAR antibodies in healthy people and in other more common neuropsychiatric disorders.
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http://dx.doi.org/10.1080/14737159.2018.1431124DOI Listing
February 2018

Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients.

Nat Commun 2017 11 27;8(1):1791. Epub 2017 Nov 27.

Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, France.

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.
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http://dx.doi.org/10.1038/s41467-017-01700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702610PMC
November 2017

Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis.

Curr Opin Neurol 2017 06;30(3):345-353

aInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain bUniversity of Lausanne (UNIL), Lausanne, Switzerland cCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Instituto Carlos III, Madrid, Spain dDepartment of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA eCatalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.

Purpose Of Review: The aim of this study was to assess the seizure manifestations and risk of epilepsy in encephalitis associated with antibodies against neuronal cell-surface (autoimmune encephalitis) or myelin-associated antigens, and to review several chronic epileptic disorders, including Rasmussen's encephalitis, fever-induced refractory epileptic syndromes (FIRES) and new-onset refractory status epilepticus (NORSE).

Recent Findings: Seizures are a frequent manifestation of autoimmune encephalitis. Some autoimmune encephalitis may associate with characteristic features: faciobrachial dystonic seizures (anti-LGI1 encephalitis), electroencephalogram extreme delta brush (anti-NMDAR) or multifocal FLAIR-MRI abnormalities (anti-GABAAR). In anti-LGI1 encephalitis, cortical, limbic and basal ganglia dysfunction results in different types of seizures. Autoimmune encephalitis or myelin-antibody associated syndromes are often immunotherapy-responsive and appear to have a low risk for chronic epilepsy. In contrast patients with seizures related to GAD65-antibodies (an intracellular antigen) frequently develop epilepsy and have suboptimal response to treatment (including surgery). Rasmussen's encephalitis or FIRES may occur with autoantibodies of unclear significance and rarely respond to immunotherapy. A study of patients with NORSE showed that 30% developed chronic epilepsy.

Summary: Although seizures are frequent in all types of autoimmune encephalitis, the risk for chronic epilepsy is dependent on the antigen: lower if located on the cell-surface, and higher if intracellular. For other disorders (Rasmussen's encephalitis, FIRES, NORSE), the prognosis remains poor.
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http://dx.doi.org/10.1097/WCO.0000000000000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831325PMC
June 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

Serum and CSF GQ1b antibodies in isolated ophthalmologic syndromes.

Neurology 2016 05 16;86(19):1780-4. Epub 2016 Mar 16.

From the University of Lausanne (UNIL) (M. Spatola), Lausanne, Switzerland; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Hospital Clinic (M. Spatola), Neuroimmunology Program, University of Barcelona, Barcelona, Spain; University Hospital of Lausanne (CHUV) (R.Du Pasquier, M. Schluep), Department of Clinical Neuroscience, Service of Neurology, Lausanne, Switzerland; and University Hospital of Basel (A.Regeniter), Department of Laboratory Medicine, Basel, Switzerland.

Objective: To establish the sensitivity and specificity of serum and CSF antibodies targeting the gangliosides GQ1b (GQ1bAb) in isolated ophthalmologic syndromes, such as acute ophthalmoplegia (AO) and optic neuritis (ON), caused by disorders other than Miller-Fisher syndrome (MFS).

Methods: We measured serum and CSF GQ1bAb in patients with MFS and with AO or ON caused by other disorders than MFS.

Results: Twenty-one patients with AO (21 serum, 9 CSF), 13 with ON (13 serum, 13 CSF), and 12 with MFS (12 serum, 10 CSF) were included in the study. There were no significant differences in age, sex, and CSF findings between the AO and MFS groups. Elevated serum GQ1b titers occurred in 11 of 12 patients with MFS but in only 1 of the 34 patients without MFS. Sensitivity was 92% (95% confidence interval [CI] 62%-100%) and specificity 97% (95% CI 85%-100%). In CSF, GQ1bAb were identified in 2 of 10 patients with MFS but in none with other disorders. Sensitivity was 20% (95% CI 2%-56%) and specificity 100% (95% CI 85%-100%).

Conclusions: Increased serum GQ1bAb are highly specific for MFS. Measurement of GQ1bAb in CSF does not improve diagnosis.

Classification Of Evidence: This study provides Class III evidence that serum GQ1bAb accurately distinguish MFS from other disorders (sensitivity 92%, 95% CI 62%-100%; specificity 97%, 95% CI 85%-100%).
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http://dx.doi.org/10.1212/WNL.0000000000002558DOI Listing
May 2016

Status epilepticus of inflammatory etiology: a cohort study.

Neurology 2015 Aug 19;85(5):464-70. Epub 2015 Jun 19.

From the Service of Neurology (M.S., J.N., R.D.P., A.O.R.), Department of Clinical Neurosciences, CHUV and University of Lausanne, Switzerland; IDIBAPS and Service of Neurology (J.D.), Hospital Clinic, University of Barcelona, Spain; and Department of Neurology (J.D.), University of Pennsylvania, Philadelphia.

Objective: Inflammation-related epilepsy is increasingly recognized; however, studies on status epilepticus (SE) are very infrequent. We therefore aimed to determine the frequency of inflammatory etiologies in adult SE, and to assess related demographic features and outcomes.

Methods: This was a retrospective analysis of a prospective registry of adult patients with SE treated in our center, from January 2008 to June 2014, excluding postanoxic causes. We classified SE episodes into 3 etiologic categories: infectious, autoimmune, and noninflammatory. Demographic and clinical variables were analyzed regarding their relationship to etiologies and functional outcome.

Results: Among the 570 SE consecutive episodes, 33 (6%) were inflammatory (2.5% autoimmune; 3.3% infectious), without any change in frequency over the study period. Inflammatory SE episodes involved younger patients (mean age 53 vs 61 years, p = 0.015) and were more often refractory to initial antiepileptic treatment (58% vs 38%, odds ratio = 2.19, 95% confidence interval = 1.07-4.47, p = 0.041), despite similar clinical outcome. Subgroup analysis showed that, compared with infectious SE episodes, autoimmune SE involved younger adults (mean age 44 vs 60 years, p = 0.017) and was associated with lower morbidity (return to baseline conditions in 71% vs 32%, odds ratio = 5.41, 95% confidence interval = 1.19-24.52, p = 0.043) without any difference in mortality.

Conclusions: Despite increasing awareness, inflammatory SE etiologies were relatively rare; their occurrence in younger individuals and higher refractoriness to treatment did not have any effect on outcome. Autoimmune SE episodes also occurred in younger patients, but tended to have better outcomes in survivors than infectious SE.
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http://dx.doi.org/10.1212/WNL.0000000000001717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534074PMC
August 2015

PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.

BMC Neurol 2015 Apr 16;15:55. Epub 2015 Apr 16.

Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Rue du Bugnon 21, 1011, Lausanne, Switzerland.

Background: LEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized.

Case Presentation: We hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS.

Conclusion: LS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.
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http://dx.doi.org/10.1186/s12883-015-0310-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407356PMC
April 2015

Interobserver agreement and validity of bedside 'positive signs' for functional weakness, sensory and gait disorders in conversion disorder: a pilot study.

J Neurol Neurosurg Psychiatry 2015 Apr 3;86(4):425-30. Epub 2014 Jul 3.

Department of Neurology and Clinical Neurosciences, University Hospital (CHUV), Lausanne, Switzerland.

Background: Conversion disorder (CD) is no longer a diagnosis of exclusion. The new DSM-V criteria highlight the importance of 'positive signs' on neurological examination. Only few signs have been validated, and little is known about their reliability.

Objective: The aim was to examine the clinical value of bedside positive signs in the diagnosis of CD presenting with weakness, gait or sensory symptoms by assessing their specificity, sensitivity and their inter-rater reliability.

Patients And Methods: Standardised video recorded neurological examinations were performed in 20 consecutive patients with CD and 20 'organic' controls. Ten previously validated sensory and motor signs were grouped in a scale. Thirteen additional motor/sensory 'positive signs', 14 gait patterns and 1 general sign were assessed in a pilot validation study. In addition, two blinded independent neurologists rated the video recordings to assess the inter-rater reliability (Cohen's κ) of each sign.

Results: A score of ≥ 4/14 on the sensory motor scale showed a 100% specificity (CI 85 to 100) and a 95% sensitivity (CI 85 to 100). Among the additional tested signs, 10 were significantly more frequent in CD than controls. The interobserver agreement was acceptable for 23/38 signs (2 excellent, 10 good, 11 moderate).

Conclusions: Our study confirms that six bedside 'positive signs' are highly specific for CD with good-excellent inter-rater reliability; we propose to consider them as 'highly reliable signs'. In addition 13 signs could be considered as 'reliable signs' and six further signs as 'suggestive signs' while all others should be used with caution until further validation is available.
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http://dx.doi.org/10.1136/jnnp-2013-307381DOI Listing
April 2015

Serial brain ¹⁸FDG-PET in anti-AMPA receptor limbic encephalitis.

J Neuroimmunol 2014 Jun 16;271(1-2):53-5. Epub 2014 Apr 16.

Service of Neurology, Department of Clinical Neuroscience, CHUV and University of Lausanne, Lausanne, Switzerland. Electronic address:

Immunotherapy-responsive autoimmune CNS syndromes linked to antibodies targeting surface neuronal antigens lack reliable biomarkers of disease activity. We report serial cerebral (18)FDG PET studies in a woman with AMPA receptor (AMPA-R) autoimmune limbic encephalitis. During her follow-up, despite an aggressive immunotherapy, she displayed a persistent, predominantly left hippocampal FDG hypermetabolism, in the absence of CNS inflammatory signs. Brain metabolism abnormalities regressed after increasing antiepileptic treatment, correlating with a moderate clinical improvement. Brain (18)F-FDG PET could thus represent a useful complementary tool to orient the clinical follow-up.
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http://dx.doi.org/10.1016/j.jneuroim.2014.04.002DOI Listing
June 2014

[News in neurology 2013].

Rev Med Suisse 2014 Jan;10(412-413):78-81

Service de Neurologie Département des Neurosciences Cliniques, CHUV, Lausanne.

In 2013, perampanel is approved as an add-on treatment for generalised and focal seizures in pharmaco-resistant epilepsy. New anticoagulants are superior to antivitamin K in stroke secondary prevention in case of atrial fibrillation. DBS remains a valid therapeutic option for advanced Parkinson's disease. Intranasal ketamine seems to reduce the intensity of severe migraine aura. High concentrations of topic capsaicin improve post-herpetic neuralgia. In Alzheimer's disease, statins might deteriorate cognitive functions. Oral immuno-modifing treatments for relapsing remitting multiple sclerosis have shown to slow cerebral atrophy progression at two years.
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January 2014

Genetics of Parkinson's disease: the yield.

Parkinsonism Relat Disord 2014 Jan;20 Suppl 1:S35-8

Department of Clinical Neurosciences, University Hospital of Lausanne, Lausanne, Switzerland.

The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.
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http://dx.doi.org/10.1016/S1353-8020(13)70011-7DOI Listing
January 2014

Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.

Epilepsia 2013 Aug 29;54(8):e99-e102. Epub 2013 May 29.

Department of Clinical Neurosciences, CHUV and University of Lausanne, Lausanne, Switzerland.

Benzodiazepine (BDZ), a widely recognized first-line status epilepticus (SE) treatment, may lead to respiratory depression. This cohort study investigates the effect of BDZ doses in SE patients in terms of morbidity and mortality. It considers incident SE episodes from a prospective registry (2009-2012), comparing patients receiving standard BDZ dose to those receiving exceeding doses (>30% above recommended dose), in terms of likelihood to receive intubation, morbidity, and mortality. Duration of hospitalization was assessed for subjects needing intubation for airways protection (not for refractory SE treatment) versus matched subjects not admitted to the intensive care unit (ICU). We identified 29 subjects receiving "excessive" and 173 "standard" BDZ dose; 45% of the overtreated patients were intubated for airways protection, but only 8% in the standard-dose group (p < 0.001). However, both groups presented similar clinical outcomes: 50% returned to baseline, 40% acquired a new handicap, and 10% died. Orotracheal intubation due to airways protection was associated with significantly longer hospitalization (mean 2 weeks vs. 1 week, p = 0.008). In conclusion, although administration of excessive BDZ doses in SE treatment does not seem to influence outcome, it is related to higher respiratory depression risk and longer hospitalization, potentially exposing patients to additional complications and costs.
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http://dx.doi.org/10.1111/epi.12235DOI Listing
August 2013

Effect of vagus nerve stimulation in an adult patient with Dravet syndrome: contribution to sudden unexpected death in epilepsy risk reduction?.

Eur Neurol 2013 29;69(2):119-21. Epub 2012 Nov 29.

Service de Neurologie, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

We report on a patient who developed, from 5 months of age, multiple seizure types, including myoclonic, associated with severe psychomotor delay, leading to the diagnosis of Dravet syndrome. Over the years, he developed refractory epilepsy and was implanted with a vagus nerve stimulator at the age of 19. After 3 months, he experienced a progressive improvement of partial and generalized seizures, with a >90% reduction, and better alertness. This meaningful clinical improvement is discussed in the light of the sudden unexpected death in epilepsy risk, which is high in this setting, and seems remarkably diminished in our patient in view of the reduction of generalized convulsions.
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http://dx.doi.org/10.1159/000345132DOI Listing
August 2013

Overview of primary monogenic dystonia.

Parkinsonism Relat Disord 2012 Jan;18 Suppl 1:S158-61

Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois (CHUV-UNIL), Lausanne, Switzerland.

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.
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http://dx.doi.org/10.1016/S1353-8020(11)70049-9DOI Listing
January 2012