50 results on '"Spatola M"'
Search Results
2. BENZODIAZEPINE OVER-DOSAGE IN STATUS EPILEPTICUS TREATMENT: ASSESSMENT OF INTUBATION NEED AND HOSPITALIZATION LENGTH: P16
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Spatola, M and Rossetti, AO
- Published
- 2013
3. Encephalitis with mGluR5 antibodies: Symptoms and antibody effects
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Spatola M, Sabater L, Planagumà J, Martínez-Hernandez E, Armangue-Salvador T, Prüss H, Iizuka T, Caparó Oblitas RL, Antoine JC, Li R, Heaney N, Tubridy N, Munteis Olivas E, Rosenfeld MR, Graus F, and Dalmau J
- Abstract
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(3)) 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.
- Published
- 2018
4. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor
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Hara M, Martinez-Hernandez E, Ariño H, Armangue-Salvador T, Spatola M, Petit-Pedrol M, Saiz A, Rosenfeld MR, Graus F, and Dalmau J
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nervous system ,musculoskeletal, neural, and ocular physiology ,mental disorders ,psychological phenomena and processes - Abstract
OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-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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- 2018
5. Investigations in GABA(A) receptor antibody-associated encephalitis
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Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue-Salvador T, Castro FJ, Barcelo Artigues MI, Julià Benique MR, Benson L, Gorman M, Felipe A, Caparó Oblitas RL, Rosenfeld MR, Graus F, and Dalmau J
- Abstract
OBJECTIVE: To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABA(A) receptor (GABA(A)R) encephalitis. METHODS: Clinical study of 26 patients, including 17 new (April 2013-January 2016) and 9 previously reported patients. Antibodies to a1, ß3, and ?2 subunits of the GABA(A)R 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 (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the a1/ß3 subunits of the GABA(A)R. CONCLUSIONS: Anti-GABA(A)R 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.
- Published
- 2017
6. Erratum: Organic chromophores based on a fused bis-thiazole core and their application in dye-sensitized solar cells (European Journal of Organic Chemistry)
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Dessi, A., Barozzino Consiglio, G., Calamante, M., Reginato, G., Mordini, A., Peruzzini, M., Taddei, M., Sinicropi, A., Parisi, M. L., Fabrizi De Biani, F., Basosi, R., Mori, R., Spatola, M., Bruzzi, M., and Zani, L.
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Solar cells ,Synthetic methods ,Photochemistry ,Dyes/pigments ,Fused-ring systems ,Sensitizers - Published
- 2013
7. Interobserver agreement and validity of bedside “positive signs” for functional weakness, sensory and gait disorders in conversion disorder
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Daum, C., primary, Gheorgita, F., additional, Spatola, M., additional, Stojanova, V., additional, Medlin, F., additional, Vingerhoets, F., additional, Berney, A., additional, Maccaferri, G.E., additional, Hubschmid, M., additional, and Aybek, S., additional
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- 2013
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8. A comparison of H323 and SIP based Architectures for VoIP Systems
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Longo, Maurizio, Langone, V., Spatola, M. C., and Arciello, M.
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- 2000
9. 3.1.1 OVERVIEW OF PRIMARY MONOGENIC DYSTONIA
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Spatola, M., primary and Wider, C., additional
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- 2012
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10. DULOXETINE AND ESCITALOPRAM FOR TREATMENT OF HOT FLUSHES IN BREAST CANCER SURVIVORS
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Biglia, N., primary, Sgandurra, P., additional, Peano, E., additional, Moggio, G., additional, Spatola, M., additional, Palmisano, D., additional, Torta, R., additional, and Sismondi, P., additional
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- 2009
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11. [News in neurology 2013]
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Spatola M, Andrea Rossetti, Michel P, Kuntzer T, Benninger D, Nater B, Jf, Démonet, Schluep M, Ra, Du Pasquier, and Vingerhoets F
12. Lumbar spinal stenosis associated with renal osteodystrophy
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Spatola, M A, primary and Apfelbaum, R I, additional
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- 1987
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13. Managing software in the weapon system environment
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SPATOLA, M., primary
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- 1981
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14. Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations
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Sergio Ferrari, F. Perini, Matteo Gastaldi, Raffaele Iorio, Marco Zoccarato, Margherita Nosadini, Amelia Evoli, Stefano Sartori, Bruno Giometto, Marianna Spatola, Sara Mariotto, Luigi Zuliani, Diego Franciotta, Piera De Gaspari, Zuliani, L., Nosadini, M., Gastaldi, M., Spatola, M., Iorio, R., Zoccarato, M., Mariotto, S., De Gaspari, P., Perini, F., Ferrari, S., Evoli, A., Sartori, S., Franciotta, D., and Giometto, B.
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Male ,Adult ,medicine.medical_specialty ,Autoimmune encephalitis, consensus ,Neurology ,Autoimmune encephalitis ,LGI1 ,NMDAR ,NSAb ,NSAE ,Autoantibodies ,Child ,Encephalitis ,Female ,Hashimoto Disease ,Humans ,Dermatology ,03 medical and health sciences ,Autoimmune encephaliti ,0302 clinical medicine ,Encephaliti ,medicine ,030212 general & internal medicine ,Medical diagnosis ,Intensive care medicine ,biology ,business.industry ,General Medicine ,Autoantibodie ,Settore MED/26 - NEUROLOGIA ,Psychiatry and Mental health ,consensus ,biology.protein ,Neurology (clinical) ,Neurosurgery ,Antibody ,business ,030217 neurology & neurosurgery ,Human - Abstract
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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- 2019
15. Biogeographic variability in wildfire severity and post-fire vegetation recovery across the European forests via remote sensing-derived spectral metrics
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Angelo Nolè, Maria Floriana Spatola, Angelo Rita, Marco Borghetti, Nole, A., Rita, A., Spatola, M. F., and Borghetti, M.
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Biogeographic region ,Environmental Engineering ,Spectral indice ,Wildfire ,Forests ,Pollution ,Fires ,Wildfires ,Benchmarking ,Fire severity ,Remote Sensing Technology ,Environmental Chemistry ,Vegetation spectral recovery ,Waste Management and Disposal ,Ecosystem - Abstract
Wildfires have large-scale and profound effects on forest ecosystems, and they force burned forest areas toward a wide range of post-fire successional trajectories from simple reduction of ecosystem functions to transitions to other stable non-forest states. Fire disturbances represent a key driver of changes in forest structure and composition due to post-fire succession processes, thus contributing to modify ecosystem resilience to subsequent disturbances. Here, we aimed to provide useful insights into wildfire severity and post-fire recovery processes at the European continental scale, contributing to improved description and interpretation of large-scale wildfire spatial patterns and their effects on forest ecosystems in the context of climate change. We analyzed fire severity and short-term post-fire vegetation recovery patterns across the European forests between 2004 and 2015 using Corine Land Cover Forest classes and bioregions, based on MODIS-derived spectral metrics of the relativized burn ratio (RBR), normalized difference vegetation index (NDVI) and relative recovery indicator (RRI). The RBR-based fire severity showed geographic differences and interannual variability in the Boreal bioregion compared to that in other biogeographic regions. The NBR-based RRI showed a slower post-fire vegetation recovery rate with respect to the NDVI, highlighting the differential sensitivities of the analyzed remote sensing-spectral metrics. Moreover, the RRI showed a significant decreasing trend during the observation period, suggesting a growing lag in post-fire vegetation recovery across European forests.
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- 2022
16. Interobserver agreement and validity of bedside “positive signs” for functional weakness, sensory and gait disorders in conversion disorder.
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Anonymous, Gheorgita, F., Spatola, M., Stojanova, V., Medlin, F., Vingerhoets, F., Berney, A., Maccaferri, G.E., Hubschmid, M., and Aybek, S.
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- 2013
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17. Investigations in GABAA receptor antibody-associated encephalitis
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Marianna Spatola, Ruben L. Caparó Oblitas, Leslie Benson, Josep Dalmau, Ana Felipe, Thaís Armangue, Francesc Graus, Mark P. Gorman, Mar Petit-Pedrol, Maria I. Barcelo Artigues, Fernanda J. Castro, Mateus Mistieri Simabukuro, Maria R. Julià Benique, Myrna R. Rosenfeld, Institut Català de la Salut, [Spatola M] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. University of Lausanne, Lausanne, Switzerland. [Petit-Pedrol M] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid, Spain. [Simabukuro MM] Neurology Division, Hospital das Clínicas, São Paulo, Brazil. São Paulo University, São Paulo, Brazil. [Armangue T] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid, Spain. Neurology Service, Hospital Sant Joan de Déu, Barcelona, Spain. [Castro FJ] Hospital de Base, Brasília, Brazil. [Barcelo Artigues MI] Service of Neurology, University Hospital of Son Espases, Mallorca, Spain. [Felipe A] Hospital Universitari Vall d'Hebron, Barcelona, Spain., and Vall d'Hebron Barcelona Hospital Campus
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0301 basic medicine ,Male ,Pathology ,Movement disorders ,Antígens ,Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Chloride Channels::Receptors, GABA-A [CHEMICALS AND DRUGS] ,medicine.disease_cause ,0302 clinical medicine ,Interquartile range ,Otros calificadores::Otros calificadores::/inmunología [Otros calificadores] ,Young adult ,Movement Disorders ,biology ,GABA - Receptors ,Brain ,Middle Aged ,Magnetic Resonance Imaging ,Encephalitis ,Human herpesvirus 6 ,Female ,Immunotherapy ,medicine.symptom ,enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::encefalitis [ENFERMEDADES] ,Adult ,medicine.medical_specialty ,Thymoma ,Adolescent ,Consciousness ,Status epilepticus ,Transfection ,Article ,Antibodies ,03 medical and health sciences ,Young Adult ,Seizures ,Other subheadings::Other subheadings::/immunology [Other subheadings] ,medicine ,Animals ,Humans ,Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Encephalitis [DISEASES] ,Retrospective Studies ,business.industry ,Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [CHEMICALS AND DRUGS] ,aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos [COMPUESTOS QUÍMICOS Y DROGAS] ,aminoácidos, péptidos y proteínas::proteínas::proteínas transportadoras::proteínas de transporte de membrana::canales iónicos::canales del cloro::receptores de GABA-A [COMPUESTOS QUÍMICOS Y DROGAS] ,Encefalitis ,medicine.disease ,biology.organism_classification ,Receptors, GABA-A ,Rats ,030104 developmental biology ,Herpes simplex virus ,HEK293 Cells ,Neurology (clinical) ,business ,Cognition Disorders ,030217 neurology & neurosurgery - Abstract
Objective:To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABAA receptor (GABAAR) 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 GABAAR 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 (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the α1/β3 subunits of the GABAAR.Conclusions:Anti-GABAAR 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.
- Published
- 2017
18. Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection.
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Spatola M, Nziza N, Irvine EB, Cizmeci D, Jung W, Van LH, Nhat LTH, Ha VTN, Phu NH, Ho DTN, Thwaites GE, Lauffenburger DA, Fortune S, Thuong NTT, and Alter G
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- Humans, Male, Adult, Female, Middle Aged, Antibodies, Bacterial blood, Antibodies, Bacterial immunology, Antibodies, Bacterial cerebrospinal fluid, Brain immunology, Young Adult, Mycobacterium tuberculosis immunology, Tuberculosis, Meningeal immunology, Tuberculosis, Pulmonary immunology
- Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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19. Mechanisms of autoimmune encephalitis.
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Papi C, Milano C, and Spatola M
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- Humans, Animals, Receptors, N-Methyl-D-Aspartate immunology, Receptors, N-Methyl-D-Aspartate metabolism, Hashimoto Disease immunology, Intracellular Signaling Peptides and Proteins immunology, Intracellular Signaling Peptides and Proteins metabolism, Proteins immunology, Proteins metabolism, Encephalitis immunology, Autoantibodies immunology
- Abstract
Purpose of Review: To provide an overview of the pathogenic mechanisms involved in autoimmune encephalitides mediated by antibodies against neuronal surface antigens, with a focus on NMDAR and LGI1 encephalitis., Recent Findings: In antibody-mediated encephalitides, binding of IgG antibodies to neuronal surface antigens results in different pathogenic effects depending on the type of antibody, IgG subclass and epitope specificity. NMDAR IgG1 antibodies cause crosslinking and internalization of the target, synaptic and brain circuitry alterations, as well as alterations of NMDAR expressing oligodendrocytes, suggesting a link with white matter lesions observed in MRI studies. LGI1 IgG4 antibodies, instead, induce neuronal dysfunction by disrupting the interaction with cognate proteins and altering AMPAR-mediated signaling. In-vitro findings have been corroborated by memory and behavioral changes in animal models obtained by passive transfer of patients' antibodies or active immunization. These models have been fundamental to identify targets for innovative therapeutic strategies, aimed at counteracting or preventing antibody effects, such as the use of soluble ephrin-B2, NMDAR modulators (e.g., pregnenolone, SGE-301) or chimeric autoantibody receptor T cells (CAART) in models of NMDAR encephalitis., Summary: A deep understanding of the pathogenic mechanisms underlying antibody-mediated encephalitides is crucial for the development of new therapeutic approaches targeting brain autoimmunity., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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20. Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses.
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Spatola M, Nziza N, Jung W, Deng Y, Yuan D, Dinoto A, Bozzetti S, Chiodega V, Ferrari S, Lauffenburger DA, Mariotto S, and Alter G
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- Female, Humans, Aged, SARS-CoV-2, Post-Acute COVID-19 Syndrome, Prospective Studies, Immunoglobulin G, Immunoglobulin M, COVID-19
- Abstract
Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs. In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an 'original antigenic sin' (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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21. Humoral signatures of MOG-antibody-associated disease track with age and disease activity.
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Spatola M, Chuquisana O, Jung W, Lopez JA, Wendel EM, Ramanathan S, Keller CW, Hahn T, Meinl E, Reindl M, Dale RC, Wiendl H, Lauffenburger DA, Rostásy K, Brilot F, Alter G, and Lünemann JD
- Subjects
- Animals, Humans, Myelin-Oligodendrocyte Glycoprotein metabolism, Mammals metabolism, Receptors, IgG, Immunoglobulin G
- Abstract
Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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22. Functional Compartmentalization of Antibodies in the Central Nervous System During Chronic HIV Infection.
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Spatola M, Loos C, Cizmeci D, Webb N, Gorman MJ, Rossignol E, Shin S, Yuan D, Fontana L, Mukerji SS, Lauffenburger DA, Gabuzda D, and Alter G
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- Central Nervous System, HIV Antibodies, Humans, Neurocognitive Disorders complications, HIV Infections, HIV-1
- Abstract
The central nervous system (CNS) has emerged as a critical HIV reservoir. Thus, interventions aimed at controlling and eliminating HIV must include CNS-targeted strategies. Given the inaccessibility of the brain, efforts have focused on cerebrospinal fluid (CSF), aimed at defining biomarkers of HIV-disease in the CNS, including HIV-specific antibodies. However, how antibodies traffic between the blood and CNS, and whether specific antibody profiles track with HIV-associated neurocognitive disorders (HAND) remains unclear. Here, we comprehensively profiled HIV-specific antibodies across plasma and CSF from 20 antiretroviral therapy (ART) naive or treated persons with HIV. CSF was populated by IgG1 and IgG3 antibodies, with reduced Fc-effector profiles. While ART improved plasma antibody functional coordination, CSF profiles were unaffected by ART and were unrelated to HAND severity. These data point to a functional sieving of antibodies across the blood-brain barrier, providing previously unappreciated insights for the development of next-generation therapeutics targeting the CNS reservoir., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2022
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23. Human Metabotropic Glutamate Receptor 5 Antibodies Alter Receptor Levels and Behavior in Mice.
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Maudes E, Mannara F, García-Serra A, Radosevic M, Mellado A, Serafim AB, Planagumà J, Sabater L, Dalmau J, and Spatola M
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- Animals, Autoantibodies, Humans, Immunoglobulin G, Memory Disorders, Mice, Neurons, Encephalitis, Receptor, Metabotropic Glutamate 5
- Abstract
Ophelia syndrome or encephalitis with antibodies against the metabotropic glutamate receptor 5 (mGluR5) manifests with behavioral changes, memory deficits, and anxiety. To study the antibody pathogenicity, mice received continuous cerebroventricular infusion of patients' or controls' immunoglobulin G (IgG) for 14 days, followed by a 15-day washout. The effects on hippocampal mGluR5 clusters were determined by confocal microscopy. Animals infused with patients' IgG, but not controls' IgG, showed memory impairment, increased anxiety, and decreased neuronal surface mGluR5 clusters. After antibody clearance, both behavioral and molecular changes reversed to baseline conditions. These findings support the pathogenicity of these antibodies in anti-mGluR5 encephalitis. ANN NEUROL 2022;92:81-86., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2022
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24. Diagnostic challenges in patients with temporal lobe seizures and features of autoimmune limbic encephalitis.
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Ismail FS, Spatola M, Woermann FG, Popkirov S, Jungilligens J, Bien CG, Wellmer J, and Schlegel U
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- Autoantibodies, Autoimmune Diseases, Humans, Magnetic Resonance Imaging methods, Memory Disorders complications, Seizures complications, Seizures etiology, Temporal Lobe diagnostic imaging, Epilepsy, Temporal Lobe complications, Epilepsy, Temporal Lobe diagnostic imaging, Limbic Encephalitis diagnosis, Limbic Encephalitis diagnostic imaging
- Abstract
Background and Purpose: Consensus criteria for autoimmune limbic encephalitis (ALE) allow for a diagnosis even without neuronal antibodies (Abs), but it remains unclear which clinical features should prompt neuronal Ab screening in temporal lobe epilepsy patients. The aim of the study was to investigate whether patients with temporal lobe seizures associated with additional symptoms or signs of limbic involvement may harbor neuronal Abs, and which clinical features should prompt neuronal Ab screening in these patients., Methods: We identified 47 patients from a tertiary epilepsy center with mediotemporal lobe seizures and additional features suggestive of limbic involvement, including either memory deficits, psychiatric symptoms, mediotemporal magnetic resonance imaging (MRI) hyperintensities or inflammatory cerebrospinal fluid (CSF). Neuronal Ab testing was carried out at two independent reference laboratories (Bielefeld-Bethel, Germany, and Barcelona, Spain). All brain MRI scans were assessed by two reviewers independently., Results: Temporal lobe seizures were accompanied by memory deficits in 35/46 (76%), psychiatric symptoms in 27/42 (64%), and both in 19/42 patients (45%). Limbic T2/fluid-attenuated inversion recovery signal hyperintensities were found in 26/46 patients (57%; unilateral: n = 22, bilateral: n = 4). Standard CSF studies were abnormal in 2/37 patients (5%). Neuronal Abs were confirmed in serum and/or CSF in 8/47 patients (17%) and were directed against neuronal cell-surface targets (leucine-rich glioma inactivated protein 1: n = 1, contactin-associated protein-2: n = 1, undetermined target: n = 3) or glutamic acid decarboxylase in its 65-kD isoform (n = 3, all with high titers). Compared to Ab-negative patients, those who harbored neuronal Abs were more likely to have uni- or bilateral mediotemporal MRI changes (8/8, 100% vs. 18/38, 47%; p = 0.01, Fisher's exact test)., Conclusions: In patients with temporal lobe seizures and additional limbic signs, 17% had neuronal Abs affirming ALE diagnosis. Mediotemporal MRI changes were found in all Ab-positive cases and had a positive likelihood ratio of 2.11 (95% confidence interval 1.51-2.95)., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2022
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25. Neonatal Fc Receptor-Targeted Therapies in Neurology.
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Nelke C, Spatola M, Schroeter CB, Wiendl H, and Lünemann JD
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- Humans, Immunoglobulin G, Neurology, Nervous System Diseases drug therapy, Receptors, Fc antagonists & inhibitors, Receptors, Fc chemistry
- Abstract
Autoantibodies are increasingly recognized for their pathogenic potential in a growing number of neurological diseases. While myasthenia gravis represents the prototypic antibody (Ab)-mediated neurological disease, many more disorders characterized by Abs targeting neuronal or glial antigens have been identified over the past two decades. Depletion of humoral immune components including immunoglobulin G (IgG) through plasma exchange or immunoadsorption is a successful therapeutic strategy in most of these disease conditions. The neonatal Fc receptor (FcRn), primarily expressed by endothelial and myeloid cells, facilitates IgG recycling and extends the half-life of IgG molecules. FcRn blockade prevents binding of endogenous IgG to FcRn, which forces these antibodies into lysosomal degradation, leading to IgG depletion. Enhancing the degradation of endogenous IgG by FcRn-targeted therapies proved to be a powerful therapeutic approach in patients with generalized MG and is currently being tested in clinical trials for several other neurological diseases including autoimmune encephalopathies, neuromyelitis optica spectrum disorders, and inflammatory neuropathies. This review illustrates mechanisms of FcRn-targeted therapies and appraises their potential to treat neurological diseases., (© 2022. The Author(s).)
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- 2022
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26. Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis.
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Spatola M, Petit Pedrol M, Maudes E, Simabukuro M, Muñiz-Castrillo S, Pinto AL, Wandinger KP, Spiegler J, Schramm P, Dutra LA, Iorio R, Kornblum C, Bien CG, Höftberger R, Leypoldt F, Titulaer MJ, Sillevis Smitt P, Honnorat J, Rosenfeld MR, Graus F, and Dalmau J
- Subjects
- Adult, Aged, Animals, Atrophy pathology, Autoimmune Diseases of the Nervous System complications, Cells, Cultured, Cerebellar Diseases etiology, Cerebellar Diseases pathology, Child, Embryo, Mammalian, Encephalitis complications, Female, Follow-Up Studies, Hippocampus cytology, Humans, Immunoglobulin G classification, Immunotherapy, Magnetic Resonance Imaging, Male, Middle Aged, Neurons, Prognosis, Rats, Autoantibodies immunology, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System immunology, Cerebellar Diseases diagnosis, Cerebellar Diseases immunology, Encephalitis diagnosis, Encephalitis immunology, Receptors, Metabotropic Glutamate immunology
- Abstract
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., (© 2020 American Academy of Neurology.)
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- 2020
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27. Placental transfer of NMDAR antibodies causes reversible alterations in mice.
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García-Serra A, Radosevic M, Pupak A, Brito V, Ríos J, Aguilar E, Maudes E, Ariño H, Spatola M, Mannara F, Pedreño M, Joubert B, Ginés S, Planagumà J, and Dalmau J
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- Animals, Behavior, Animal, Female, Humans, Immunoglobulin G, Maternal-Fetal Exchange, Mice, Mice, Inbred C57BL, Placenta, Pregnancy, Pregnancy Complications, Autoantibodies toxicity, Brain pathology, Prenatal Exposure Delayed Effects
- Abstract
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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2020
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28. GABA A receptor autoimmunity after alemtuzumab treatment for multiple sclerosis.
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Maniscalco GT, Mariotto S, Höftberger R, Capra R, Servillo G, Manzo V, Napolitano M, Candelaresi P, Gerevini S, Ferrari S, Bozzetti S, Spatola M, and Florio C
- Subjects
- Aged, Autoimmune Diseases of the Nervous System immunology, Autoimmune Diseases of the Nervous System physiopathology, Autoimmune Diseases of the Nervous System therapy, Autoimmunity immunology, B-Lymphocytes, Electroencephalography, Encephalitis immunology, Encephalitis physiopathology, Encephalitis therapy, Epilepsia Partialis Continua chemically induced, Epilepsia Partialis Continua immunology, Epilepsia Partialis Continua physiopathology, Epilepsia Partialis Continua therapy, Glucocorticoids therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Factors therapeutic use, Lymphocyte Activation, Magnetic Resonance Imaging, Male, Methylprednisolone therapeutic use, Seizures immunology, Seizures physiopathology, Seizures therapy, Status Epilepticus chemically induced, Status Epilepticus immunology, Status Epilepticus physiopathology, Status Epilepticus therapy, T-Lymphocytes, Alemtuzumab adverse effects, Autoantibodies immunology, Autoimmune Diseases of the Nervous System chemically induced, Encephalitis chemically induced, Multiple Sclerosis, Relapsing-Remitting drug therapy, Receptors, GABA-A immunology, Seizures chemically induced
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- 2020
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29. On the Need for Greater Political Action by Neurosurgeons.
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Spatola M
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- Humans, Neurosurgical Procedures, Politics, Neurosurgeons, Neurosurgery
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- 2020
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30. Contributions to the Neurosurgery Political Action Committee (NeurosurgeryPAC): A Historical Perspective.
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Agarwal N, Agarwal P, Taylor TM, Mortimer AR, Stacy JD, Spatola M, Mazzola CA, Orrico KO, and Heary RF
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- Education, Medical, Graduate legislation & jurisprudence, History, 21st Century, Humans, Liability, Legal, Public Policy, Reimbursement Mechanisms legislation & jurisprudence, United States, Fund Raising history, Neurosurgery, Politics, Societies, Medical
- Abstract
Background: The political action committee (PAC) of the American Association of Neurological Surgeons, known as NeurosurgeryPAC, was formed in August 2005 to strengthen neurosurgical advocacy efforts. Since its establishment, NeurosurgeryPAC has made nonpartisan, direct campaign contributions to hundreds of candidates for the U.S. Senate and U.S. House of Representatives., Methods: Historical contribution data for 2005-2018 was obtained from NeurosurgeryPAC. Data analyzed by year, and a 2-year election cycle included total amount raised, number of contributors, average donation, and percent participation. NeurosurgeryPAC contribution amounts for election cycles were also compared with those of other physician PACs., Results: NeurosurgeryPAC has raised $2,953,870 since its inception in 2005, for an average of $210,991 per year. For this fundraising, the average annual donation amount is $796 per donor. The number of unique contributors per cycle has varied from 316-504, with an average of 389 individuals per annum and a participation rate of 7.8%. To date, the total amount raised in election years ($1,605,940) is 16.1% higher than that raised in nonelection years ($1,347,930). Among 28 physician PACs, NeurosurgeryPAC has ranked as high as 13 and as low as 17 in total hard money contributions. The orthopedic, neurology and general surgery PACs have consistently ranked higher than NeurosurgeryPAC, whereas the otolaryngology, spine, and plastic surgery PACs have ranked lower., Conclusions: Since its creation, NeurosurgeryPAC has collected a steady stream of donations to support political candidates. These donations have helped lawmakers who are supportive of policy issues important to neurosurgery, particularly physician reimbursement, medical liability reform, and graduate medical education. However, there remains a significant opportunity to increase the neurosurgeon participation rate in this vital organization. It is truly through advocacy that we will be able to positively affect the future of neurologic surgery in the United States., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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31. Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.
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Zuliani L, Nosadini M, Gastaldi M, Spatola M, Iorio R, Zoccarato M, Mariotto S, De Gaspari P, Perini F, Ferrari S, Evoli A, Sartori S, Franciotta D, and Giometto B
- Subjects
- Adult, Autoantibodies immunology, Child, Encephalitis immunology, Female, Hashimoto Disease immunology, Humans, Male, Encephalitis therapy, Hashimoto Disease therapy
- Abstract
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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- 2019
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32. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.
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Petit-Pedrol M, Sell J, Planagumà J, Mannara F, Radosevic M, Haselmann H, Ceanga M, Sabater L, Spatola M, Soto D, Gasull X, Dalmau J, and Geis C
- Subjects
- ADAM Proteins metabolism, Animals, Autoimmune Diseases immunology, Brain cytology, Brain metabolism, Disks Large Homolog 4 Protein metabolism, Female, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Kv1.1 Potassium Channel ultrastructure, Limbic Encephalitis immunology, Male, Memory drug effects, Mice, Nerve Tissue Proteins metabolism, Neuronal Plasticity drug effects, Neurons drug effects, Neurons ultrastructure, Protein Binding drug effects, Protein Domains drug effects, Proteins metabolism, Synapses drug effects, Synapses physiology, Synapses ultrastructure, Immunoglobulin G pharmacology, Kv1.1 Potassium Channel metabolism, Memory physiology, Neuronal Plasticity physiology, Neurons physiology, Proteins immunology, Receptors, AMPA metabolism
- Abstract
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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- 2018
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33. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.
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Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, and Dalmau J
- Subjects
- Adolescent, Adult, Aged, Animals, Autoantibodies metabolism, Child, Child, Preschool, Cohort Studies, Encephalitis cerebrospinal fluid, Encephalitis diagnostic imaging, Encephalitis, Herpes Simplex cerebrospinal fluid, Encephalitis, Herpes Simplex diagnostic imaging, Female, Glutamate Decarboxylase metabolism, Hashimoto Disease cerebrospinal fluid, Hashimoto Disease diagnostic imaging, Hippocampus metabolism, Hippocampus pathology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Rats, Receptors, N-Methyl-D-Aspartate immunology, Risk Factors, Statistics, Nonparametric, Young Adult, Encephalitis epidemiology, Encephalitis etiology, Encephalitis, Herpes Simplex complications, Encephalitis, Herpes Simplex epidemiology, Hashimoto Disease epidemiology, Hashimoto Disease etiology
- Abstract
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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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34. N-methyl-D-aspartate receptor encephalitis: laboratory diagnostics and comparative clinical features in adults and children.
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Gastaldi M, Nosadini M, Spatola M, Sartori S, and Franciotta D
- Subjects
- Age Factors, Animals, Autoantibodies blood, Autoantibodies immunology, Autoimmunity, Diagnosis, Differential, Encephalitis immunology, Encephalitis metabolism, Encephalitis therapy, Hashimoto Disease diagnosis, Hashimoto Disease immunology, Humans, Neoplasms complications, Prognosis, Receptors, N-Methyl-D-Aspartate metabolism, Recurrence, Schizophrenia complications, Symptom Assessment, Virus Diseases complications, Encephalitis diagnosis, Encephalitis etiology, Receptors, N-Methyl-D-Aspartate immunology
- Abstract
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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- 2018
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35. Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients.
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Jézéquel J, Johansson EM, Dupuis JP, Rogemond V, Gréa H, Kellermayer B, Hamdani N, Le Guen E, Rabu C, Lepleux M, Spatola M, Mathias E, Bouchet D, Ramsey AJ, Yolken RH, Tamouza R, Dalmau J, Honnorat J, Leboyer M, and Groc L
- Subjects
- Adult, Animals, Autoantibodies blood, Autoantibodies metabolism, Calcium metabolism, Ephrin-B2 metabolism, Female, Glutamic Acid metabolism, HEK293 Cells, Hippocampus cytology, Hippocampus metabolism, Humans, Long-Term Potentiation immunology, Male, Mice, Middle Aged, Neurons, Rats, Receptors, N-Methyl-D-Aspartate metabolism, Schizophrenia blood, Single Molecule Imaging, Synapses immunology, Synaptic Transmission immunology, Young Adult, Autoantibodies immunology, Receptors, N-Methyl-D-Aspartate immunology, Schizophrenia immunology, Synapses metabolism
- Abstract
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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- 2017
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36. Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis.
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Spatola M and Dalmau J
- Subjects
- Demyelinating Autoimmune Diseases, CNS complications, Demyelinating Autoimmune Diseases, CNS epidemiology, Encephalitis epidemiology, Epilepsy epidemiology, Hashimoto Disease epidemiology, Humans, Inflammation complications, Inflammation epidemiology, Risk, Seizures epidemiology, Encephalitis complications, Epilepsy etiology, Hashimoto Disease complications, Seizures etiology
- Abstract
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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- 2017
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37. Investigations in GABA A receptor antibody-associated encephalitis.
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Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, Julià Benique MR, Benson L, Gorman M, Felipe A, Caparó Oblitas RL, Rosenfeld MR, Graus F, and Dalmau J
- Subjects
- Adolescent, Adult, Animals, Brain metabolism, Cognition Disorders etiology, Consciousness, Encephalitis metabolism, Encephalitis therapy, Female, HEK293 Cells, Humans, Immunotherapy, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders etiology, Rats, Receptors, GABA-A genetics, Receptors, GABA-A metabolism, Retrospective Studies, Seizures etiology, Transfection, Young Adult, Antibodies blood, Antibodies cerebrospinal fluid, Encephalitis immunology, Receptors, GABA-A immunology
- Abstract
Objective: To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABA
A receptor (GABAA R) 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 GABAA R 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 ( p = 0.007) and movement disorders ( p = 0.01) and less likely to have a tumor ( p = 0.01). The main epitope targets were in the α1/β3 subunits of the GABAA R., Conclusions: Anti-GABAA R 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., (© 2017 American Academy of Neurology.)- Published
- 2017
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38. Serum and CSF GQ1b antibodies in isolated ophthalmologic syndromes.
- Author
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Spatola M, Du Pasquier R, Schluep M, and Regeniter A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers blood, Biomarkers cerebrospinal fluid, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunotherapy, Male, Middle Aged, Miller Fisher Syndrome complications, Miller Fisher Syndrome immunology, Miller Fisher Syndrome therapy, Ophthalmoplegia etiology, Ophthalmoplegia immunology, Ophthalmoplegia therapy, Optic Neuritis etiology, Optic Neuritis immunology, Optic Neuritis therapy, Retrospective Studies, Sensitivity and Specificity, Young Adult, Gangliosides immunology, Immunoglobulin G metabolism, Immunoglobulin M metabolism, Miller Fisher Syndrome diagnosis, Ophthalmoplegia diagnosis, Optic Neuritis diagnosis
- Abstract
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%)., (© 2016 American Academy of Neurology.)
- Published
- 2016
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39. Status epilepticus of inflammatory etiology: a cohort study.
- Author
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Spatola M, Novy J, Du Pasquier R, Dalmau J, and Rossetti AO
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Inflammation complications, Inflammation diagnosis, Inflammation epidemiology, Male, Middle Aged, Prospective Studies, Registries, Retrospective Studies, Status Epilepticus epidemiology, Young Adult, Status Epilepticus diagnosis, Status Epilepticus etiology
- Abstract
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., (© 2015 American Academy of Neurology.)
- Published
- 2015
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40. PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.
- Author
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Spatola M, Wider C, Kuntzer T, and Croquelois A
- Subjects
- Adult, Female, Humans, LEOPARD Syndrome complications, Mutation, Neuralgia etiology, Peripheral Nervous System Diseases etiology, LEOPARD Syndrome genetics, Neuralgia physiopathology, Peripheral Nervous System Diseases pathology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
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.
- Published
- 2015
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41. Interobserver agreement and validity of bedside 'positive signs' for functional weakness, sensory and gait disorders in conversion disorder: a pilot study.
- Author
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Daum C, Gheorghita F, Spatola M, Stojanova V, Medlin F, Vingerhoets F, Berney A, Gholam-Rezaee M, Maccaferri GE, Hubschmid M, and Aybek S
- Subjects
- Adult, Aged, Diagnostic and Statistical Manual of Mental Disorders, Female, Humans, Male, Middle Aged, Observer Variation, Pilot Projects, Reproducibility of Results, Conversion Disorder diagnosis, Gait Disorders, Neurologic diagnosis, Muscle Weakness diagnosis, Point-of-Care Systems, Sensation Disorders diagnosis
- Abstract
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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
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42. Serial brain ¹⁸FDG-PET in anti-AMPA receptor limbic encephalitis.
- Author
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Spatola M, Stojanova V, Prior JO, Dalmau J, and Rossetti AO
- Subjects
- Adult, Electroencephalography, Female, Humans, Limbic Encephalitis diagnostic imaging, Positron-Emission Tomography, Autoantibodies metabolism, Brain diagnostic imaging, Fluorodeoxyglucose F18, Limbic Encephalitis pathology, Receptors, AMPA immunology
- Abstract
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., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
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43. [News in neurology 2013].
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Spatola M, Rossetti AO, Michel P, Kuntzer T, Benninger D, Nater B, Démonet JF, Schluep M, Du Pasquier RA, and Vingerhoets F
- Subjects
- Central Nervous System Agents therapeutic use, Cerebrovascular Disorders drug therapy, Deep Brain Stimulation, Epilepsy drug therapy, Headache Disorders drug therapy, Humans, Movement Disorders therapy, Neurology methods, Neuromuscular Diseases drug therapy, Nitriles, Pyridones therapeutic use, Neurology trends
- Abstract
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.
- Published
- 2014
44. Genetics of Parkinson's disease: the yield.
- Author
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Spatola M and Wider C
- Subjects
- Genome-Wide Association Study, Humans, Risk Factors, Genetic Predisposition to Disease, Parkinson Disease genetics
- Abstract
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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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45. Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
- Author
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Spatola M, Alvarez V, and Rossetti AO
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Dose-Response Relationship, Drug, Female, Humans, Length of Stay statistics & numerical data, Male, Middle Aged, Respiration Disorders chemically induced, Retrospective Studies, Anticonvulsants adverse effects, Benzodiazepines adverse effects, Hospitalization statistics & numerical data, Intubation, Intratracheal, Status Epilepticus drug therapy, Status Epilepticus nursing
- Abstract
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., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)
- Published
- 2013
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46. Effect of vagus nerve stimulation in an adult patient with Dravet syndrome: contribution to sudden unexpected death in epilepsy risk reduction?.
- Author
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Spatola M, Jeannet PY, Pollo C, Wider C, Labrum R, and Rossetti AO
- Subjects
- Humans, Male, Risk Reduction Behavior, Treatment Outcome, Young Adult, Death, Sudden etiology, Epilepsies, Myoclonic complications, Epilepsies, Myoclonic therapy, Vagus Nerve Stimulation
- Abstract
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., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2013
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47. Overview of primary monogenic dystonia.
- Author
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Spatola M and Wider C
- Subjects
- Animals, Dystonic Disorders therapy, Humans, Dystonic Disorders diagnosis, Dystonic Disorders genetics
- Abstract
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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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48. Transcallosal, transventricular approach to a basilar apex aneurysm.
- Author
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de los Reyes RA, Kantrowitz AB, Boehm FH, and Spatola MA
- Subjects
- Adult, Cerebral Angiography, Cerebral Ventricles, Corpus Callosum, Humans, Intracranial Aneurysm diagnostic imaging, Male, Tomography, X-Ray Computed, Basilar Artery surgery, Intracranial Aneurysm surgery
- Abstract
A new approach to the basilar apex in a patient with a megadolichobasilar anomaly and an abnormally rostral basilar apex aneurysm is described. The details of the surgical approach and the advantages and limitations of this transcallosal, interseptal approach are described.
- Published
- 1992
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49. Treatment of dolichoectasia of the middle cerebral artery with bypass and exclusion.
- Author
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de los Reyes RA, Boehm FH Jr, Spatola MA, Goodrich JT, Moser FG, Llena JF, and Spiro AJ
- Subjects
- Adolescent, Cerebral Angiography, Female, Humans, Intracranial Arteriovenous Malformations diagnostic imaging, Cerebral Revascularization methods, Intracranial Arteriovenous Malformations surgery
- Published
- 1989
50. Electrophrenic respiration following anastomosis of phrenic with branchial nerve in the cat.
- Author
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Krieger AJ, Danetz I, Wu SZ, Spatola M, and Sapru HN
- Subjects
- Animals, Brachial Plexus physiology, Cats, Diaphragm innervation, Female, Male, Nerve Regeneration, Phrenic Nerve physiology, Spinal Cord Injuries physiopathology, Brachial Plexus surgery, Electric Stimulation, Phrenic Nerve surgery, Respiration, Artificial, Spinal Cord Injuries therapy
- Abstract
Patients with high spinal cord injuries may be totally dependent on artificial ventilation. Prolonged use of mechanical devices requires intensive care, which restricts the mobility of these patients. Electrophrenic respiration has been used with success to overcome this difficulty. However, a prerequisite for electrophrenic respiration is a viable phrenic nerve. Patients with spinal cord injuries at the C-3 to C-5 levels do not have a viable phrenic nerve due to gradual degeneration of axons in these nerves. In the present study on cats, the authors caused degeneration in one of the phrenic nerves by sectioning it low in the neck. Then the distal end of the phrenic nerve was anastomosed to the proximal segment of a sectioned brachial nerve. Sixteen to 32 weeks were allowed for the growth of brachial axons into the anastomosed phrenic nerve. Each cat served as its own control because one of the phrenic nerves was left intact. It was observed that pacing of the anastomosed phrenic nerve produced respiration comparable to spontaneous respiration or to respiration induced by pacing the intact phrenic nerve. Lack of rhythmic bursts of electrical activity in the anastomosed phrenic nerve and electromyographic activity in the ipsilateral hemidiaphragm confirmed that the anastomosed phrenic nerve remained disconnected from the respiratory motoneurons. Abundance of collagen matrix in the electron micrographs of the anastomosed phrenic nerve indicated that degeneration of the axons of phrenic motoneurons had occurred and the brachial nerve had grown into the phrenic nerve stump. These results indicate that electrophrenic respiration may be possible in patients with spinal cord injuries at the C-3 to C-5 vertebral levels if the phrenic nerve is kept viable by anastomosing it to a branch of the brachial nerve.
- Published
- 1983
- Full Text
- View/download PDF
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