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1
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Stancu P, Sanda N, Lovblad KO, Guinand N, Kleinschmidt A, Paredes JBE. Area postrema syndrome as the only sign of medullary infarction adjacent to area postrema. eNeurologicalSci 2025; 39:100563. [PMID: 40176800 PMCID: PMC11964542 DOI: 10.1016/j.ensci.2025.100563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/04/2025] Open
Abstract
Area postrema syndrome (APS) is characterized by acute or subacute intractable nausea, vomiting, and/or hiccups lasting for at least 48 h. These symptoms can occur individually or in combination and are typically linked to periventricular brainstem lesions, particularly involving the area postrema (AP). The AP, a highly vascularized circumventricular organ located in the dorsal medulla oblongata, is supplied by the anterior spinal artery and perforating branches of the posterior inferior cerebellar artery (PICA), making it susceptible to pathological processes that can lead to APS. APS rarely occurs in stroke patients, but has been seen with ischemic lesions in the medial brachium pontis. The underlying pathophysiology of APS remains unclear, but remote lesions from the AP suggest involvement of an autonomic network of neuronal structures. This article reports a rare case of APS caused by ischemic stroke near the area postrema, without accompanying neurological impairments. The case highlights the importance of vascular investigation in intractable APS cases, even without focal neurological symptoms, and supports the role of neuronal structures connected to the AP in APS development.
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Affiliation(s)
- Patrick Stancu
- Department of Clinical Neurosciences, University Hospital, Geneva, Switzerland
| | - Nicolae Sanda
- Department of Clinical Neurosciences, University Hospital, Geneva, Switzerland
| | - Karl-Olof Lovblad
- Department of Neuroradiology, University Hospital, Geneva, Switzerland
| | - Nils Guinand
- Division of Otorhinolaryngology, University Hospital, Geneva, Switzerland
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2
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Bradl M, Yu Q, Takai Y. The immunological processes behind aquaporin 4-antibody seropositive neuromyelitis optica spectrum disorders. Semin Immunol 2025; 78:101945. [PMID: 40154151 DOI: 10.1016/j.smim.2025.101945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 04/01/2025]
Abstract
Ever since the discovery of pathogenic aquaporin 4-specific antibodies in the serum of patients with neuromyelitis optica spectrum disorders current knowledge about clinical observations and diagnosis, and about the underlying pathology and resulting therapies have been put forward in excellent reviews and primary publications. However, in order to further develop novel strategies for the treatment of this disease, there is an urgent need to understand the immunological processes associated with the formation of the pathogenic antibodies, and with aberrant immune responses observed in affected patients. In this review, we will highlight and evaluate important studies on these processes.
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Affiliation(s)
- Monika Bradl
- Medical University Vienna, Center for Brain Research, Division of Neuroimmunology, Austria.
| | - Qian Yu
- Medical University Vienna, Center for Brain Research, Division of Neuroimmunology, Austria
| | - Yoshiki Takai
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Pathology, Tohoku University Hospital, Sendai, Japan
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3
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Afzali AM, Ulianov O, Eckardt L, Stas I, Seeholzer L, Steiger K, Merkler D, Korn T. AQP4-specific T cells determine lesion localization in the CNS in a model of NMOSD. Acta Neuropathol Commun 2025; 13:27. [PMID: 39934927 PMCID: PMC11817536 DOI: 10.1186/s40478-025-01947-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a paradigmatic autoimmune disease of the central nervous system (CNS), in which the water channel protein Aquaporin-4 (AQP4) is targeted by a self-reactive immune response. While the immunopathology of human NMOSD is largely dependent on antibodies to astrocytic AQP4, the role of AQP4-specific T cells for the localization and quality of NMOSD lesions in the CNS is not known. Only recently, we established that thymic B cells express and present AQP4 in the context of MHC class II molecules to purge the naive T cell receptor repertoire of AQP4-specific clones. Here, we exploited this finding to investigate the lesion localization in the CNS of B cell conditional AQP4-deficient (Aqp4ΔB) mice, which harbor AQP4-specific precursors in their naive T cell repertoire and can be sensitized to mount a strong AQP4(201-220)-specific CD4+ T cell response. Sensitization of Aqp4ΔB mice with AQP4(201-220) was sufficient to induce clinical disease. The spatiotemporal lesion distribution and the glial cell response in AQP4(201-220)-induced experimental autoimmune encephalomyelitis (EAE) was compared to classical MOG(35-55)-induced EAE in Aqp4ΔB mice. In contrast to MOG-EAE, AQP4(201-220)-induced EAE was characterized by midline lesions in the brain, retinal pathology, and lesions at the grey matter/white matter border zone in the spinal cord. Therefore, we conclude that antigen-specific T cells dictate the localization of NMOSD-lesions in the CNS.
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Affiliation(s)
- Ali Maisam Afzali
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany
- Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany
| | - Oleksii Ulianov
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany
| | - Luise Eckardt
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany
- Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany
| | - Ingrid Stas
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany
- Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany
| | - Lea Seeholzer
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Trogerstr. 18, 81675, Munich, Germany
| | - Doron Merkler
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, Centre Médical Universitaire, 1, Rue Michel Servet, 1211, Geneva, Switzerland
| | - Thomas Korn
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany.
- Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany.
- Munich Cluster for Systems Neurology, Feodor-Lynen-Str. 17, 81377, Munich, Germany.
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4
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Segal Y, Soltys J, Clarkson BDS, Howe CL, Irani SR, Pittock SJ. Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets. Neuron 2025; 113:345-379. [PMID: 39809275 DOI: 10.1016/j.neuron.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/26/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025]
Abstract
Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.
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Affiliation(s)
- Yahel Segal
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - John Soltys
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Benjamin D S Clarkson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Charles L Howe
- Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Division of Experimental Neurology, Mayo Clinic, Rochester, MN, USA
| | - Sarosh R Irani
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Sean J Pittock
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
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5
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Chatterjee P, Chakravarty S, Biswas NK, Trivedi S, Datta A, Mukhopadhyay D. Small RNA sequencing of differentiated astrocytoma exposed to NMOSD patient sera reveals perturbations in neurodegenerative signaling. Exp Cell Res 2025; 444:114375. [PMID: 39662661 DOI: 10.1016/j.yexcr.2024.114375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/06/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
The signaling pathways behind severe astrocytic lysis with Aquaporin4 auto-antibody (AQP4-IgG) seropositivity, and reactive astrocytosis with myelin oligodendrocyte glycoprotein auto-antibody (MOG-IgG) seropositivity, remain largely unexplored in Neuromyelitis optica spectrum disorder (NMOSD), while almost no molecular details being known about double-seronegative (DN) patients. Recent discovery of glial fibrillary acidic protein (GFAP) in DN NMOSD patients' cerebrospinal fluid, akin to AQP4-IgG + ve cases, suggests astrocytopathy. Here, we aim to study small non coding RNA (sncRNA) signature alterations in astrocytes exposed to AQP4-IgG + ve and MOG-IgG + ve patient sera, and their potential resemblance with DN-NMOSD. Next Generation Sequencing (NGS) revealed differential expression of several microRNAs with notable alterations in hsa-miR-6824-3p, hsa-miR-324-5p and hsa-miR-4466 respectively upon sera treatment. Results with DN-NMOSD patient sera are majorly similar to that of AQP4+ve sera. Strikingly, in all three treatments, hsa-miR-200b-3p was significantly upregulated. Functional enrichment analysis revealed that Hippo and FoxO signaling pathways were primarily impacted in AQP4-IgG + ve and double negative sera treated cells whereas, MOG-IgG + ve sera treatment perturbed the PI3K-Akt and MAPK signaling pathways. Furthermore, NGS also revealed differential expression of several piRNAs in cells upon treatment with AQP4-IgG + ve and MOG-IgG + ve sera and VEGF signaling was identified as the common target of differentially expressed piRNAs of both the groups. This study, for the first time, revealed that the molecular pathophysiology of double-seronegative NMOSD might involve astrocytopathy akin to AQP4+ve NMOSD, thus pointing towards the possible existence of unidentified astrocytic autoimmune targets and identified the major alterations in intracellular sncRNAs and the associated overall cellular signaling pathways that potentially contribute to the fate of astrocytes during the progression of the disease.
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Affiliation(s)
- Pallavi Chatterjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, A CI of Homi Bhabha National Institute, Kolkata, 700 064, West Bengal, India
| | - Shouvik Chakravarty
- Biotechnology Research and Innovation Council - National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Biotechnology Research and Innovation Council - Regional Centre for Biotechnology (BRIC-RCB), Faridabad, India
| | - Nidhan K Biswas
- Biotechnology Research and Innovation Council - National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Biotechnology Research and Innovation Council - Regional Centre for Biotechnology (BRIC-RCB), Faridabad, India
| | - Santosh Trivedi
- Department of Neurology, Institute of Neurosciences, Kolkata, 700017, West Bengal, India
| | - Ashis Datta
- Department of Neurology, Institute of Neurosciences, Kolkata, 700017, West Bengal, India
| | - Debashis Mukhopadhyay
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, A CI of Homi Bhabha National Institute, Kolkata, 700 064, West Bengal, India.
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Zhang L, Verkhratsky A, Shi FD. Astrocytes and microglia in multiple sclerosis and neuromyelitis optica. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:133-145. [PMID: 40148041 DOI: 10.1016/b978-0-443-19102-2.00001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Multiple sclerosis and neuromyelitis optica are autoimmune neurodegenerative diseases primarily targeting myelin sheath and neuroglia. In multiple sclerosis, autoantibodies destroy oligodendrocytes and myelin, which underlies primary neurologic symptoms. Focal damage to myelin triggers reactive astrogliosis and microgliosis, which contribute to and to a large extent define the disease progression. In neuromyelitis optica, autoantibodies against water channel aquaporin 4 (AQP4), which are localized at astrocytic endfeet mediate damage of the glia limitans thus facilitating infiltration of blood-borne molecules and cells that propagate the damage to nerves and neurons. This primary astrocytopathy recruits microglia, which contribute to the neuroinflammatory response. Neuroglial cells therefore are potential targets for cell-specific therapies.
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Affiliation(s)
- Linjie Zhang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Bizkaia, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Fu-Dong Shi
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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7
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Noori H, Marsool MDM, Gohil KM, Idrees M, Subash T, Alazzeh Z, Prajjwal P, Jain H, Amir O. Neuromyelitis optica spectrum disorder: Exploring the diverse clinical manifestations and the need for further exploration. Brain Behav 2024; 14:e3644. [PMID: 39135307 PMCID: PMC11319236 DOI: 10.1002/brb3.3644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/22/2024] [Accepted: 07/12/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by inflammatory assaults on the central nervous system (CNS), particularly on the optic nerves and spinal cord. In recent years, a wider range of clinical manifestations of this complex disease have been observed, emphasizing the importance of gaining a more profound understanding beyond optic neuritis (ON) and transverse myelitis (TM). CURRENT KNOWLEDGE This study explores the many clinical symptoms of NMOSD, including common and uncommon presentations. Distinctive aspects of ON, TM, and diencephalic/brainstem syndromes are examined, highlighting their unique characteristics in contrast to conditions such as multiple sclerosis. We also discuss extra-CNS involvement, such as unusual signs, including muscle involvement, retinal injury, auditory impairment, and rhinological symptoms. AIMS AND OBJECTIVES Our study intends to highlight the wide range and complexity of NMOSD presentations, emphasizing the significance of identifying unusual symptoms for precise diagnosis and prompt management. The specific processes that contribute to the varied clinical presentation of NMOSD are not well understood despite existing information. This emphasizes the necessity for more study to clarify the mechanisms that cause different symptoms and discover new treatment targets for this complex autoimmune disorder. CONCLUSION It is essential to acknowledge the complex and varied clinical manifestations of NMOSD to enhance diagnosis, treatment, and patient results. By enhancing our comprehension of the fundamental processes and investigating innovative therapeutic approaches, we may aim to enhance the quality of life for persons impacted by this illness.
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Affiliation(s)
- Hamid Noori
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
| | | | - Krutika Mahendra Gohil
- Hinduhridaysamrat Balasaheb Thackeray Medical College and Dr. Rustom Narsi Cooper Municipal General HospitalMumbaiIndia
| | | | - Tushar Subash
- Medical CollegeThe Aga Khan UniversityKarachiPakistan
| | - Zainab Alazzeh
- College of MedicineJordanian University of Science and TechnologyIrbidJordan
| | | | - Hritvik Jain
- All India Institute of Medical SciencesJodhpurIndia
| | - Omniat Amir
- Almanhal Academy for ScienceManhal UniversityKhartoumSudan
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8
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Pestchanker C, Bertado Cortez B, Lana Peixoto MA, Gortari JI, Castro Suarez S, Caparo Zamalloa C, Galiana G, Peñalver F, Daccach Marques V, Messias K, Galleguillos L, García F, Rojas JI, Patrucco L, Cristiano E, Tkachuk V, Liwacki S, Correale J, Marrodan M, Ysraelit MC, Vrech C, Deri N, Leguizamon F, Tavolini D, Mainella C, Zanga G, Alonso Serena M, Ciampi E, Neto HRS, Lopez P, Carnero Contentti E. Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings. J Neurol 2024; 271:4292-4299. [PMID: 38630312 DOI: 10.1007/s00415-024-12371-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 04/03/2024] [Accepted: 04/04/2024] [Indexed: 07/10/2024]
Abstract
INTRODUCTION We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.
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Affiliation(s)
- Claudia Pestchanker
- Neurology Department, Dr. Ramón Carrillo Central Hospital, San Luis, Argentina
| | - Brenda Bertado Cortez
- Clínica de Enfermedades Desmielinizantes (CED) del Centro Médico Nacional Siglo XXI, del Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Marco A Lana Peixoto
- CIEM MS Research Center, Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil
| | | | - Sheila Castro Suarez
- Centro Básico de Investigación en Demencia y Enfermedades Desmielinizantes del Sistema Nervioso, National Institute of Neurological Science, Lima, Peru
| | - Cesar Caparo Zamalloa
- Centro Básico de Investigación en Demencia y Enfermedades Desmielinizantes del Sistema Nervioso, National Institute of Neurological Science, Lima, Peru
| | | | | | - Vanesa Daccach Marques
- Hospital das Clínicas da Faculda de de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
| | - Katharina Messias
- Hospital das Clínicas da Faculda de de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
| | | | - Fernando García
- Neurology Department, Santo Tomás Hospital, Universidad Interamericana de Panamá, Panama City, Panama
| | - Juan I Rojas
- Centro Esclerosis Múltiple Buenos Aires (CEMBA), Buenos Aires, Argentina
| | - Liliana Patrucco
- Centro Esclerosis Múltiple Buenos Aires (CEMBA), Buenos Aires, Argentina
| | - Edgardo Cristiano
- Centro Esclerosis Múltiple Buenos Aires (CEMBA), Buenos Aires, Argentina
| | - Verónica Tkachuk
- Neuroimmunology Unit, Neurology Department, Hospital de Clínicas, Buenos Aires, Argentina
| | - Susana Liwacki
- Neurology Unit, Hospital Córdoba, Córdoba, Argentina
- Clínica Universitaria Reina Fabiola, Córdoba, Argentina
| | - Jorge Correale
- Servicio de Neuroinmunología y Enfermedades Desmielinizantes, Departamento de Neurología, Fleni, Buenos Aires, Argentina
| | - Mariano Marrodan
- Servicio de Neuroinmunología y Enfermedades Desmielinizantes, Departamento de Neurología, Fleni, Buenos Aires, Argentina
| | - María C Ysraelit
- Servicio de Neuroinmunología y Enfermedades Desmielinizantes, Departamento de Neurología, Fleni, Buenos Aires, Argentina
| | - Carlos Vrech
- Neurology Department, Sanatorio Allende, Córdoba, Argentina
| | - Norma Deri
- CENyR, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | | | | | | | - Gisela Zanga
- Unidad Asistencial César Milstein, Buenos Aires, Argentina
| | - Marina Alonso Serena
- Área de Investigación en Medicina Interna, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Ethel Ciampi
- Hospital Dr. Sótero del Río y Universidad Católica de Chile, Santiago, Chile
| | | | - Pablo Lopez
- Neuroimmunology Unit, Department of Neurosciences, Hospital Aleman, Buenos Aires, Argentina
| | - Edgar Carnero Contentti
- Neuroimmunology Unit, Department of Neurosciences, Hospital Aleman, Buenos Aires, Argentina.
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9
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Segal Y, Zekeridou A. Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery. Curr Opin Neurol 2024; 37:295-304. [PMID: 38533672 DOI: 10.1097/wco.0000000000001261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
PURPOSE OF REVIEW The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. RECENT FINDINGS In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. SUMMARY Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.
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Affiliation(s)
- Yahel Segal
- Department of Laboratory Medicine and Pathology
| | - Anastasia Zekeridou
- Department of Laboratory Medicine and Pathology
- Department of Neurology
- Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, USA
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10
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Rees JH, Rempe T, Tuna IS, Perero MM, Sabat S, Massini T, Yetto JM. Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Magn Reson Imaging Clin N Am 2024; 32:233-251. [PMID: 38555139 DOI: 10.1016/j.mric.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
For over two centuries, clinicians have been aware of various conditions affecting white matter which had come to be grouped under the umbrella term multiple sclerosis. Within the last 20 years, specific scientific advances have occurred leading to more accurate diagnosis and differentiation of several of these conditions including, neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody disease. This new understanding has been coupled with advances in disease-modifying therapies which must be accurately applied for maximum safety and efficacy.
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Affiliation(s)
- John H Rees
- Neuroradiology, Department of Radiology, University of Florida College of Medicine.
| | - Torge Rempe
- UF Multiple Sclerosis / Neuroimmunology Fellowship, Department of Neurology, University of Florida, College of Medicine
| | | | | | | | | | - Joseph M Yetto
- University of Florida at Gainesville, Gainesville, FL, USA
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11
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Abdel-Mannan O, Hacohen Y. Pediatric inflammatory leukoencephalopathies. HANDBOOK OF CLINICAL NEUROLOGY 2024; 204:369-398. [PMID: 39322390 DOI: 10.1016/b978-0-323-99209-1.00001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased signal on T2-weighted images. In children, ADS may occur as a monophasic illness or as a relapsing condition, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Almost all young people with MS have a relapsing-remitting course with clinical relapses. Important strides have been made in delineating MS from other ADS subtypes. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and aquaporin 4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) were once considered variants of MS; however, studies in the last decade have established that these are in fact distinct entities. Although there are clinical phenotypic overlaps between MOGAD, AQP4-NMOSD, and MS, cumulative biologic, clinical, and pathologic evidence allows discrimination between these conditions. There has been a rapid increase in the number of available disease-modifying therapies for MS and novel treatment strategies are starting to appear for both MOGAD and AQP4-NMOSD. Importantly, there are a number of both inflammatory and noninflammatory mimics of ADS in children with implications of management for these patients in terms of treatment.
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Affiliation(s)
- Omar Abdel-Mannan
- Department of Neuroinflammation, Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom; Department of Neurology, Great Ormond Street Hospital, London, United Kingdom.
| | - Yael Hacohen
- Department of Neuroinflammation, Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom; Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
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12
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Lowe MC, Money KM, Matthews E, Pastula DM, Piquet AL. case of autoimmune GFAP astrocytopathy with eosinophils in the cerebrospinal fluid. J Neuroimmunol 2023; 385:578249. [PMID: 37992587 DOI: 10.1016/j.jneuroim.2023.578249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 11/24/2023]
Abstract
Cerebrospinal fluid (CSF) eosinophilia is associated with a narrow differential, primarily including parasitic and fungal infections, neoplasm, and chemical meningitis. It has rarely been reported in neuroinflammatory conditions including as a finding of CSF cytology in two autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy cases. Here we describe a case of autoimmune GFAP astrocytopathy with classic clinical and radiographic features as well as presence of eosinophils in the CSF. This case highlights a potential association of eosinophils in the CSF with autoimmune GFAP astrocytopathy, which may suggest its inclusion in the differential diagnosis of eosinophilic meningitis, encephalitis, or myelitis.
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Affiliation(s)
- Mallory C Lowe
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Kelli M Money
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Elizabeth Matthews
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Daniel M Pastula
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America; Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, United States of America; Department of Epidemiology, Colorado School of Public Health, Aurora, CO, United States of America
| | - Amanda L Piquet
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States of America.
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13
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Siriratnam P, Huda S, Butzkueven H, van der Walt A, Jokubaitis V, Monif M. A comprehensive review of the advances in neuromyelitis optica spectrum disorder. Autoimmun Rev 2023; 22:103465. [PMID: 37852514 DOI: 10.1016/j.autrev.2023.103465] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 10/13/2023] [Indexed: 10/20/2023]
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing neuroinflammatory autoimmune astrocytopathy, with a predilection for the optic nerves and spinal cord. Most cases are characterised by aquaporin-4-antibody positivity and have a relapsing disease course, which is associated with accrual of disability. Although the prognosis in NMOSD has improved markedly over the past few years owing to advances in diagnosis and therapeutics, it remains a severe disease. In this article, we review the evolution of our understanding of NMOSD, its pathogenesis, clinical features, disease course, treatment options and associated symptoms. We also address the gaps in knowledge and areas for future research focus.
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Affiliation(s)
- Pakeeran Siriratnam
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Saif Huda
- Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Helmut Butzkueven
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Anneke van der Walt
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Vilija Jokubaitis
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Mastura Monif
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia; Department of Neurology, The Royal Melbourne Hospital, Parkville, VIC, Australia.
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14
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Miyagishima D, Anezaki T, Fukuda A, Watanabe H, Hata M, Eguchi M. Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A Rare Case of Advanced Breast Cancer with Intractable Nausea and Vomiting. AMERICAN JOURNAL OF CASE REPORTS 2023; 24:e941808. [PMID: 37933098 PMCID: PMC10642718 DOI: 10.12659/ajcr.941808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/27/2023] [Accepted: 09/14/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating disease of the central nervous system that includes the triad of transverse myelitis, optic neuritis, and area postrema syndrome (APS), characterized by intractable nausea and vomiting. NMOSD can be part of a paraneoplastic syndrome and is associated with seropositivity to aquaporin-4 (AQP-4). We present a patient with uncontrollable nausea and vomiting who developed herpes zoster and acute myelitis and was finally diagnosed with paraneoplastic NMOSD due to breast cancer. CASE REPORT A 51-year-old woman was hospitalized due to 2 weeks of intractable nausea and vomiting. Although contrast-enhanced thoracoabdominal computed tomography (CT) on day 4 suggested breast cancer in her left breast, the etiology of her symptoms remained unknown. On day 13, she developed herpes zoster, followed by acute myelitis on day 25. Magnetic resonance imaging (MRI) showing longitudinal extensive transverse myelitis and an elevated serum AQP-4 antibody level led to the diagnosis of NMOSD. Brain MRI detected a small lesion in the dorsal medulla oblongata, which explained the preceding APS. After starting intravenous methylprednisolone pulse therapy, her nausea and vomiting rapidly subsided. Breast cancer was resected on day 63, and immunohistochemical staining revealed overexpression of AQP-4 in the tumor cells, suggesting paraneoplastic NMOSD. CONCLUSIONS This report has highlighted the presentation and diagnosis of NMOSD and supports the possibility that this can present as part of a paraneoplastic syndrome. In addition, diagnosis of NMOSD preceded by APS requires meticulous history taking and careful interpretation of MRI in the dorsal medulla oblongata.
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Affiliation(s)
- Daisuke Miyagishima
- Department of Gastroenterology and Hepatology, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Toshiharu Anezaki
- Department of Neurology, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Akiyo Fukuda
- Department of Surgery, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Hiroki Watanabe
- Department of Surgery, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Maki Hata
- Department of Dermatology, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Masanobu Eguchi
- Department of Pathology, Numazu City Hospital, Numazu, Shizuoka, Japan
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15
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Berhanu D, Leal Rato M, Messina S, Leite MI, Geraldes R, Palace J. The effect of smoking on MRI lesion resolution in NMOSD-AQP4 and MOGAD. Mult Scler 2023; 29:1250-1256. [PMID: 37528605 PMCID: PMC10503243 DOI: 10.1177/13524585231188485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/13/2023] [Accepted: 06/30/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND The effect of smoking on the resolution of magnetic resonance imaging (MRI) lesions in patients with neuromyelitis optica spectrum disorders with aquaporin-4 positive antibody (NMOSD-AQP4) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has not been studied before. OBJECTIVE We aimed to determine the effect of smoking on lesion resolution in MRI and assess its correlation with clinical recovery after a relapse. METHODS We conducted a cohort study including NMOSD-AQP4 and MOGAD patients with acute and follow-up MRI scans. We collected demographic, clinical, imaging and smoking data. Logistic regression models were fitted to predict the effect of smoking on lesion resolution and to assess whether clinical recovery was associated with MRI lesion resolution. RESULTS A total of 105 patients were included (57 with NMOSD-AQP4 and 48 with MOGAD). Current and past smoking was associated with a higher risk of persistent lesions in NMOSD-AQP4 and MOGAD (risk ratio (RR) = 3.4, 95% confidence interval (CI) = 2.5-4.7, p < 0.001). Additionally, the presence of lesion resolution was associated with better clinical recovery (RR = 1.9, 95% CI = 1.7-2.2, p < 0.001). CONCLUSION Smoking is associated with worse MRI lesion resolution in patients with NMOSD-AQP4 and MOGAD, and lesion resolution correlates with clinical recovery. Our findings suggest a detrimental effect of smoking in inflammatory central nervous system (CNS) diseases.
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Affiliation(s)
- David Berhanu
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Serviço de Imagiologia Neurológica, Centro Hospitalar Universitário Lisboa Norte, EPE, Lisboa, Portugal
| | - Miguel Leal Rato
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Serviço de Imagiologia Neurológica, Centro Hospitalar Universitário Lisboa Norte, EPE, Lisboa, Portugal
| | - Silvia Messina
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Department of Neurology, Frimley Health NHS Foundation Trust, Frimley, UK
| | - Maria Isabel Leite
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Department of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK
| | - Ruth Geraldes
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Department of Neurology, Frimley Health NHS Foundation Trust, Frimley, UK
| | - Jacqueline Palace
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Department of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK
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16
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Pozzato M, Dilena R, Rogani G, Beretta G, Torreggiani S, Lanni S, Tozzo A, Andreetta F, Cavalcante P, Triulzi F, Martinelli Boneschi F, Minoia F, Filocamo G. Can early-onset acquired demyelinating syndrome (ADS) hide pediatric Behcet's disease? A case report. Front Pediatr 2023; 11:1175584. [PMID: 37425262 PMCID: PMC10327559 DOI: 10.3389/fped.2023.1175584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/30/2023] [Indexed: 07/11/2023] Open
Abstract
Behcet's disease (BD) is a rare vasculitis characterized by multisystemic inflammation. Central nervous system (CNS) involvement is rare and heterogeneous, particularly in the pediatric population. A diagnosis of neuro-Behcet could be highly challenging, especially if neurological manifestations precede other systemic features; however, its timely definition is crucial to prevent long-term sequelae. In this study, we describe the case of a girl who, at 13 months of age, presented with a first episode of encephalopathy compatible with acute disseminated encephalomyelitis, followed, after 6 months, by a neurological relapse characterized by ophthalmoparesis and gait ataxia, in association with new inflammatory lesions in the brain and spinal cord, suggesting a neuromyelitis optica spectrum disorder. The neurological manifestations were successfully treated with high-dose steroids and intravenous immunoglobulins. In the following months, the patient developed a multisystemic involvement suggestive of Behcet's disease, characterized by polyarthritis and uveitis, associated with HLA-B51 positivity. The challenge presented by this unique case required a multidisciplinary approach involving pediatric neurologists, neuro-radiologists, and pediatric rheumatologists, with all of these specialists creating awareness about early-onset acquired demyelinating syndromes (ADSs). Given the rarity of this presentation, we performed a review of the literature focusing on neurological manifestations in BD and differential diagnosis of patients with early-onset ADS.
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Affiliation(s)
- Mattia Pozzato
- Neurology Unit & MS Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Robertino Dilena
- Neuropathophysiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Greta Rogani
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
| | - Gisella Beretta
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
| | - Sofia Torreggiani
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Lanni
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
| | - Alessandra Tozzo
- Infantile Neuropsychiatry Unit, Pediatric Neuroscience Department, IRCCS Fondazione Istituto Neurologico “C. Besta”, Milan, Italy
| | - Francesca Andreetta
- Neurology 4 - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Paola Cavalcante
- Neurology 4 - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Fabio Triulzi
- Neuroradiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Filippo Martinelli Boneschi
- Clinical Neurology, Department of Health Science CRC “Aldo Ravelli” for Experimental Brain Therapeutics, Hospital San Paolo ASST Santi Paolo e Carlo Milan and University of Milan, Milan, Italy
| | - Francesca Minoia
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Filocamo
- Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, Milan, Italy
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17
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Thangaleela S, Sivamaruthi BS, Radha A, Kesika P, Chaiyasut C. Neuromyelitis Optica Spectrum Disorders: Clinical Perspectives, Molecular Mechanisms, and Treatments. APPLIED SCIENCES 2023; 13:5029. [DOI: 10.3390/app13085029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disorder affecting the central nervous system (CNS), specifically the optic nerve and the spinal cord, with severe clinical manifestations, including optic neuritis (ON) and transverse myelitis. Initially, NMO was wrongly understood as a condition related to multiple sclerosis (MS), due to a few similar clinical and radiological features, until the discovery of the AQP4 antibody (NMO-IgG/AQP4-ab). Various etiological factors, such as genetic-environmental factors, medication, low levels of vitamins, and others, contribute to the initiation of NMO pathogenesis. The autoantibodies against AQP4 target the AQP4 channel at the blood–brain barrier (BBB) of the astrocyte end feet, which leads to high permeability or leakage of the BBB that causes more influx of AQP4-antibodies into the cerebrospinal fluid (CSF) of NMO patients. The binding of AQP4-IgG onto the AQP4 extracellular epitopes initiates astrocyte damage through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Thus, a membrane attack complex is formed due to complement cascade activation; the membrane attack complex targets the AQP4 channels in the astrocytes, leading to astrocyte cell damage, demyelination of neurons and oligodendrocytes, and neuroinflammation. The treatment of NMOSD could improve relapse symptoms, restore neurological functions, and alleviate immunosuppression. Corticosteroids, apheresis therapies, immunosuppressive drugs, and B cell inactivating and complement cascade blocking agents have been used to treat NMOSD. This review intends to provide all possible recent studies related to molecular mechanisms, clinical perspectives, and treatment methodologies of the disease, particularly focusing on recent developments in clinical criteria and therapeutic formulations.
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Affiliation(s)
- Subramanian Thangaleela
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | | | - Arumugam Radha
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620024, India
| | - Periyanaina Kesika
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chaiyavat Chaiyasut
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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18
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Yick LW, Ma OKF, Chan EYY, Yau KX, Kwan JSC, Chan KH. T follicular helper cells contribute to pathophysiology in a model of neuromyelitis optica spectrum disorders. JCI Insight 2023; 8:161003. [PMID: 36649074 PMCID: PMC9977492 DOI: 10.1172/jci.insight.161003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory autoimmune disorders of the CNS. IgG autoantibodies targeting the aquaporin-4 water channel (AQP4-IgGs) are the pathogenic effector of NMOSD. Dysregulated T follicular helper (Tfh) cells have been implicated in loss of B cell tolerance in autoimmune diseases. The contribution of Tfh cells to disease activity and therapeutic potential of targeting these cells in NMOSD remain unclear. Here, we established an autoimmune model of NMOSD by immunizing mice against AQP4 via in vivo electroporation. After AQP4 immunization, mice displayed AQP4 autoantibodies in blood circulation, blood-brain barrier disruption, and IgG infiltration in spinal cord parenchyma. Moreover, AQP4 immunization induced motor impairments and NMOSD-like pathologies, including astrocytopathy, demyelination, axonal loss, and microglia activation. These were associated with increased splenic Tfh, Th1, and Th17 cells; memory B cells; and plasma cells. Aqp4-deficient mice did not display motor impairments and NMOSD-like pathologies after AQP4 immunization. Importantly, abrogating ICOS/ICOS-L signaling using anti-ICOS-L antibody depleted Tfh cells and suppressed the response of Th1 and Th17 cells, memory B cells, and plasma cells in AQP4-immunized mice. These findings were associated with ameliorated motor impairments and spinal cord pathologies. This study suggests a role of Tfh cells in the pathophysiology of NMOSD in a mouse model with AQP4 autoimmunity and provides an animal model for investigating the immunological mechanisms underlying AQP4 autoimmunity and developing therapeutic interventions targeting autoimmune reactions in NMOSD.
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19
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Smith AD, Moog TM, Burgess KW, McCreary M, Okuda DT. Factors associated with the misdiagnosis of neuromyelitis optica spectrum disorder. Mult Scler Relat Disord 2023; 70:104498. [PMID: 36610360 DOI: 10.1016/j.msard.2023.104498] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/05/2022] [Accepted: 01/01/2023] [Indexed: 01/04/2023]
Abstract
BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition that is associated with severe disability. Approximately 40% of individuals are misdiagnosed with multiple sclerosis (MS) or other diseases. We aimed to define factors that influence the misdiagnosis of people with NMOSD and provide strategies for reducing error rates. METHODS A retrospective study was performed involving all people with a confirmed diagnosis of NMOSD within a single academic institution. Comprehensive clinical timelines were constructed for each individual that included presenting symptoms, provider type and timing of evaluations, aquaporin 4-IgG (AQP4) results, and MRI scans. Two-sample comparisons of continuous and categorial variables were performed for people accurately diagnosed with NMOSD and those originally misdiagnosed with another medical condition. A subanalysis of only AQP4-IgG positive people was also performed. RESULTS The study cohort included 199 people fulfilling International Panel criteria for NMOSD with 71 people (62 female; mean age at first symptom presentation (standard deviation (SD)) = 32.8 years (y) (SD 16.1)) being initially misdiagnosed and 128 people (106 female; 41.14y (SD 15.41)) who were accurately diagnosed. Of the 199 people with NMOSD, 166 had a positive serostatus. Identified factors associated with misdiagnosis, regardless of AQP4-IgG serostatus, were the presence of protracted nausea/vomiting/hiccups without any accompanying neurological symptoms, 23 (32.4%) versus 16 (12.5%) (p = 0.001), a longer median (range) time to see a neuroimmunology specialist 4.2y (0.14-31.8) versus 0.5y (0.0-21.2) (p<0.0001), and a delay in acquiring an MRI study, 4.7y (0.0-27.3) versus 0.3y (0.0-20.2) (p<0.0001). A greater proportion of people misdiagnosed were identified with a negative live-cell based AQP4-IgG serum test result, 13/13 (100%) versus 22/114 (19.3%) (p<0.0001). Additionally, the mean (SD) time between a first negative and successive live-cell based AQP4-IgG positive test result was greater for people misdiagnosed with another condition, 3.9y (SD 5.0) versus 1.5y (SD 2.1) (p = 0.01). Although not significant between groups, a rash was also reported in 63/199 people with NMOSD, with 31/63 having an anti-nuclear antibody titer ≥ 1:160. CONCLUSION Defined factors can help guide both generalists and specialists in the pursuit of strategies aimed at efficiently diagnosing those with NMOSD such that effective care can be delivered.
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Affiliation(s)
- Alexander D Smith
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tatum M Moog
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Katy W Burgess
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Morgan McCreary
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Darin T Okuda
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
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20
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Liu T, Li L, Guo X, Li Q, Jia D, Ma L. Clinical analysis of neuromyelitis optica spectrum disease with area postrema syndrome as the initial symptom. Eur J Med Res 2022; 27:315. [PMID: 36582004 PMCID: PMC9798654 DOI: 10.1186/s40001-022-00949-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 12/13/2022] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The objective of this study was to report and discuss clinical analysis, including the diagnosis and treatment of 4 cases of neuromyelitis optica spectrum disease (NMOSD) with area postrema syndrome (APS) as the first symptom. METHODS Four patients with intractable nausea, vomiting, and confirmed NMOSD were included in the final analysis. All of these patients were initially misdiagnosed and mismanaged. RESULTS Among the 4 patients, 3 were admitted to the department of gastroenterology at the onset of the disease, and 2 were not correctly diagnosed and treated promptly due to misdiagnosis. Therefore, their symptoms worsened, and they were transferred to Intensive Care Unit (ICU) for life support. No obvious early medulla lesions were found in one patient. One patient was treated with intravenous immunoglobulin, methylprednisolone, and plasma exchange, but there was no significant clinical improvement, after which the disease relapsed during the treatment with low-dose rituximab. CONCLUSION The clinical manifestations of NMOSD are complex and diverse, and the initial symptoms, onset age of the patient, and magnetic resonance imaging (MRI) findings can influence the final diagnosis. Early identification of the APS and timely therapy can prevent visual and physical disabilities, even respiratory failure, coma, and cardiac arrest. Therefore, it is necessary to identify specific and sensitive serum and imaging markers for predicting the prognosis and recurrence of the disease.
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Affiliation(s)
- Ting Liu
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
| | - Lijuan Li
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
| | - Xiaopeng Guo
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
| | - Qifu Li
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
| | - Dandan Jia
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
| | - Lin Ma
- grid.443397.e0000 0004 0368 7493Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan China
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21
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Deng B, Wang J, Yu H, Jin L, Qiu Y, Liu X, Wang P, Zhang X, Chen X. Area Postrema Syndrome in Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy. NEUROLOGY - NEUROIMMUNOLOGY NEUROINFLAMMATION 2022; 9:9/6/e200029. [PMID: 36163176 PMCID: PMC9513980 DOI: 10.1212/nxi.0000000000200029] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/01/2022] [Indexed: 11/18/2022]
Abstract
Background and Objectives To report the frequency of area postrema syndrome (APS) in glial fibrillary acidic protein-immunoglobulin G (GFAP-IgG)–positive patients and emphasize the importance of APS among the phenotypes in autoimmune GFAP astrocytopathy. Methods Eight GFAP-IgG–positive cases with APS were retrospectively identified during 2015–2021. The APS phenotypes were described. A literature review of 8 previously reported cases was also included in analysis. Results A total of 8 patients (11%) (1 woman, 7 men; mean age: 52.4 ± 18.4 years) presented with APS in a cohort of 74 GFAP-IgG–positive patients, 3 of whom (4%) had disease onset with APS. All patients had hiccups, and hiccups was the unique symptom of APS in 5 patients. The median time from disease onset to APS occurrence was 2 days (range 0–20), and the mean duration of APS episodes was 23.6 ± 11.4 days. No patient had isolated APS attack. All episodes were completely resolved with a mean duration of 9.3 ± 5.4 days after immunotherapy. APS manifestations of 8 cases in previous studies showed similar features with our cases. In total, coexisting aquaporin-4-IgG was only detected in one of the 16 cases. Discussion APS could be an early, but not isolated clinical manifestation of autoimmune GFAP astrocytopathy. Hiccups was the predominant symptom of APS in this disorder. APS attacks of autoimmune GFAP astrocytopathy have good response to immunotherapy.
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Affiliation(s)
- Bo Deng
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Jingguo Wang
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Hai Yu
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Lei Jin
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Yue Qiu
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Xiaoni Liu
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Pengyu Wang
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Xiang Zhang
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China
| | - Xiangjun Chen
- From the Department of Neurology (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.), Huashan Hospital and Insitute of Neurology, Fudan University; National Center for Neurological Disorders (B.D., J.W., H.Y., L.J., Y.Q., X.L., P.W., X.Z., X.C.); and Human Phenome Institute (X.C.), Fudan University, Shanghai, China.
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West PK, Viengkhou B, Campbell IL, Hofer MJ. Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α. Front Immunol 2022; 13:1036799. [PMID: 36389783 PMCID: PMC9650248 DOI: 10.3389/fimmu.2022.1036799] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/13/2022] [Indexed: 12/10/2023] Open
Abstract
Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.
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Affiliation(s)
| | | | | | - Markus J. Hofer
- School of Life and Environmental Sciences, Charles Perkins Centre and the Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW, Australia
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Shrestha R, Kharel G. A case report on recurrent area postrema syndrome in AQP4-IgG-positive NMOSD. Oxf Med Case Reports 2022; 2022:omac109. [PMID: 36299670 PMCID: PMC9589462 DOI: 10.1093/omcr/omac109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 12/04/2022] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition of the central nervous system caused by severe immune-mediated demyelination and axonal destruction, mainly affecting optic nerves and the spinal cord. We describe a 26-year-old Nepalese woman with recent onset of headache, nausea, vomiting and hiccups indicative of Area Postrema Syndrome (APS). The antibody test for aquaporin-4 was strongly positive. Brain magnetic resonance imaging (MRI) showed a bilateral hyperintense signal in the area postrema (AP). The patient started on methylprednisolone, and then azathioprine was added. However, the patient was readmitted because of tingling in her right upper extremity and sudden onset of tremors. An MRI scan showed an enlarged lesion in AP. Rituximab was started on top of the previous treatment, and a second dose was given after 2 weeks. The patient had been monitored regularly and symptom-free for 5 months. Hence, we emphasize the immediate need for a diagnostic approach for NMOSD management.
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Affiliation(s)
- Ramesh Shrestha
- Correspondence address. Department of Neurology, Upendra Devkota Memorial National Institute of Neurological and Allied Sciences, Kathmandu, 44600, Nepal. Tel +9779863856230; E-mail:
| | - Ghanshyam Kharel
- Department of Neurology, Upendra Devkota Memorial National Institute of Neurological and Allied Sciences, Kathmandu, Nepal
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24
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Okuda DT, Stanley T, McCreary M, Smith AD, Burgess KW, Wilson A, Guo X, Moog TM. Dorsal medulla surface texture: Differentiating neuromyelitis optica spectrum disorder from multiple sclerosis. J Neuroimaging 2022; 32:1090-1097. [PMID: 36181675 DOI: 10.1111/jon.13059] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND PURPOSE The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease-modifying therapies may result in permanent neurological disability. METHODS Standardized 3-Tesla 3-dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross-sectionally and longitudinally. An ideal introverted planar triangle threshold separating groups with NMOSD and MS was accomplished using the highest Youden's J statistic. For the classification of NMOSD, out-of-sample and in-sample measurements of the following were acquired: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS The study cohort included 60 people with NMOSD, 100 people with MS, 12 with other neurological diseases, and five healthy controls. Significantly higher cross-sectional median introverted triangle counts were observed when the NMOSD (median [interquartile range]: 100 [23.5]) group was compared to MS (65 [20.25]; p < .0001) and other neurological diseases (66 [13.75]; p < .0001). Distinct spatial dissemination patterns of triangles extending craniocaudally at the region of interest within the dorsal medulla was also seen between groups with NMOSD and MS (p < .0001). For the identification of NMOSD, out-of-sample sensitivity (83%), specificity (100%), PPV (100%), and NPV (60%) were achieved. CONCLUSIONS Cross-sectional and longitudinal dorsal medulla surface texture differences within selective regions of vulnerability differentiate NMOSD from MS.
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Affiliation(s)
- Darin T Okuda
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Thomas Stanley
- Department of Computer Science, University of Texas at Dallas, Dallas, Texas, USA
| | - Morgan McCreary
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Alexander D Smith
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Katy W Burgess
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Andrew Wilson
- Department of Computer Science, University of Texas at Dallas, Dallas, Texas, USA
| | - Xiaohu Guo
- Department of Computer Science, University of Texas at Dallas, Dallas, Texas, USA
| | - Tatum M Moog
- Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
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Dang J, Lei S, Chen J. Autoimmune glial fibrillary acidic protein astrocytopathy presented as isolated area postrema symdrome: a case report. BMC Neurol 2022; 22:271. [PMID: 35858856 PMCID: PMC9297591 DOI: 10.1186/s12883-022-02802-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 07/15/2022] [Indexed: 11/22/2022] Open
Abstract
Background Area postrema syndrome (APS) as the isolated manifestation in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy has been rarely reported. Case presentation A 61-year-old male patient presented with intractable hiccup. He was first admitted to the department of Gastroenterology because he had no symptoms other than hiccup. Then he was diagnosed with possible digestive system disease and started on treatment. 2 weeks later, his symptom didn’t improve at all. After consultation, the patient was referred to our department. Cerebrospinal fluid (CSF) analysis revealed lymphocytes pleocytosis, elevated protein level. Cell-based assays demonstrated GFAP antibodies in blood and CSF. His symptom improved with steroid pulse therapy (methylprednisolone, 1 g for 5 days), followed by a gradual tapering of oral prednisolone. Three months after the initial presentation, he showed no relapses. Conclusions We report atypical manifestation of autoimmune GFAP astrocytopathy which presented as APS, suggesting that autoimmune GFAP astrocytopathy should be added to the list of possible cause of APS.
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Affiliation(s)
- Jing Dang
- The Department of Neurology, Chenzhou No.1 People's Hospital, Chenzhou, Hunan, 423000, People's Republic of China.
| | - Shengsuo Lei
- The Department of Neurology, Chenzhou No.1 People's Hospital, Chenzhou, Hunan, 423000, People's Republic of China
| | - Jihua Chen
- The Department of Neurology, Chenzhou No.1 People's Hospital, Chenzhou, Hunan, 423000, People's Republic of China
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Ranjan A, Mudassir S, Sinha N, Panjwani A, Kumar A. Area postrema syndrome: An initial presentation of double Seropositive AQP4 and MOG Antibody: A case report. Neurol Clin Pract 2022; 12:e82-e84. [DOI: 10.1212/cpj.0000000000200065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 06/13/2022] [Indexed: 11/15/2022]
Abstract
Abstract:Objectives:Area postrema syndrome (APS) is one of the core clinical feature of neuromyelitis optic spectrum disorder (NMOSD). APS is mostly associated with neuromyelitis optica (NMO) and rarely reported in myelin oligodendrocyte glycoprotein antibody disease (MOGAD). We herein report a case of area postrema syndrome as the initial presentation of double seropositive aquaporin-4 (AQP-4) and myelin oligodendrocyte glycoprotein (MOG)antibody.Methods:The patient fulfilled the NMOSD diagnostic criteria. MRI brain, CSF studies, electrophysiological test and serum NMO and MOG antibody testing were done.Results:An elderly female initially presented in Gastroenterology outpatient department with a history of nausea, vomiting and hiccups for 3 weeks. Detailed medical evaluation including upper gastrointestinal endoscopy was normal with no improvement with symptomatic therapy. Neurological examination showed bilateral nystagmus, postural imbalance and gait ataxia. MRI brain showed T2/FLAIR hyperintensity in dorsal medulla involving area postrema. Both anti NMO and MOG antibodies were found to be positive in serum. She was treated with intravenous methyl prednisolone with complete symptomatic resolution.Discussion:Double seropositive APS-onset NMOSD has not been previously reported in literature. Early diagnosis and treatment results in resolution of APS- related symptoms and prevents further progression of disease.
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Sechi E, Cacciaguerra L, Chen JJ, Mariotto S, Fadda G, Dinoto A, Lopez-Chiriboga AS, Pittock SJ, Flanagan EP. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management. Front Neurol 2022; 13:885218. [PMID: 35785363 PMCID: PMC9247462 DOI: 10.3389/fneur.2022.885218] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/06/2022] [Indexed: 01/02/2023] Open
Abstract
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.
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Affiliation(s)
- Elia Sechi
- Neurology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Laura Cacciaguerra
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy
- Department of Neurology and Center for Multiple Sclerosis and Autoimmune Neurology Mayo Clinic, Rochester, MN, United States
| | - John J. Chen
- Department of Neurology and Center for Multiple Sclerosis and Autoimmune Neurology Mayo Clinic, Rochester, MN, United States
- Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States
| | - Sara Mariotto
- Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy
| | - Giulia Fadda
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Alessandro Dinoto
- Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy
| | | | - Sean J. Pittock
- Department of Neurology and Center for Multiple Sclerosis and Autoimmune Neurology Mayo Clinic, Rochester, MN, United States
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Eoin P. Flanagan
- Department of Neurology and Center for Multiple Sclerosis and Autoimmune Neurology Mayo Clinic, Rochester, MN, United States
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Eoin P. Flanagan
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Ji Q, Dong H, Lee H, Liu Z, Tong Y, Elkin K, Haddad Y, Geng X, Ding Y. Clinical Characteristics and Outcomes of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder With Brainstem Lesions as Heralding Prodrome. Front Neurol 2022; 13:836337. [PMID: 35614913 PMCID: PMC9124782 DOI: 10.3389/fneur.2022.836337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
ObjectiveThe present study sought to differentiate multiple sclerosis and neuromyelitis optica spectrum disorder patients at their first attack by describing and distinguishing their clinical features, radiographic characteristics, and immunologic characteristics of serum and cerebrospinal fluid.MethodsWe retrospectively studied 58 patients with multiple sclerosis (MS) and 52 patients with neuromyelitis optica spectrum disorder (NMOSD) by referencing brainstem lesions as the prodromal events. Their demographics and presentation at the time of the first attack was evaluated including their gender, age, clinical features of the first attack, the expanded disability status scale (EDSS), brainstem lesion(s) by head MRI, and immunological indices of serum and cerebrospinal fluid.ResultsThe NMOSD group had more female patients (4.8 vs. 1.9, p < 0.05), and was older than the MS group (37.81 ± 16.60 vs. 27.57 ± 11.17, p <0.001). NMOSD patients also had a significantly higher association with autoimmune diseases or positive autoimmune antibodies (p < 0.01). There was no significant difference in the EDSS scores between the two groups (p = 0.420). Central hiccups, vomiting, and pyramidal tract signs were more common in the NMOSD group than the MS group (p < 0.001, p < 0.001, p < 0.01), while eye movement abnormalities were more common with MS (p < 0.01). There were no significant differences in other clinical manifestations such as vertigo, diplopia, limb weakness, numbness, and eating difficulty. MS patients were more likely to have midbrain and pons imaging lesions (p < 0.001, p < 0.001), while NMOSD patients had more lesions in the medulla oblongata (p < 0.001). The lesions in the MS group were mostly located in the periphery, while those in the NMOSD group were centrally located (p < 0.001, p < 0.001). Patchy lesions were more common in MS patients (p < 0.001), while large lesions were more common in the NMOSD group (p < 0.001). Finally, serum AQP4 Ab was found only in the NMOSD group (p < 0.001).ConclusionPatients with MS and NMOSD have differentiating clinical manifestations at the time of their first brainstem lesions which include central hiccups, vomiting, pyramidal tract signs, and abnormal eye movements. Additionally, distinct imaging manifestations such as lesion location(s) and morphology may also aid in the development of pathognomonic criteria leading to timely initial diagnosis of MS and NMOSD.
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Affiliation(s)
- Qiling Ji
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Huiqing Dong
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- *Correspondence: Huiqing Dong
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
| | - Zheng Liu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yanna Tong
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Kenneth Elkin
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
| | - Yazeed Haddad
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
| | - Xiaokun Geng
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
- Xiaokun Geng
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
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The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes. J Neuroinflammation 2022; 19:96. [PMID: 35429976 PMCID: PMC9013466 DOI: 10.1186/s12974-022-02441-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Background Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. Methods Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. Results We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer’s disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. Conclusions Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02441-x.
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Foo R, Yau C, Singhal S, Tow S, Loo JL, Tan K, Milea D. Optic Neuritis in the Era of NMOSD and MOGAD: A Survey of Practice Patterns in Singapore. Asia Pac J Ophthalmol (Phila) 2022; 11:184-195. [PMID: 35533337 DOI: 10.1097/apo.0000000000000513] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE The Optic Neuritis Treatment Trial was a landmark study with implications worldwide. In the advent of antibody testing for neuromyelitis optica spectrum disease (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), emerging concepts, such as routine antibody testing and management, remain controversial, resulting mostly from studies in White populations. We evaluate the practice patterns of optic neuritis investigation and management by neuro-ophthalmologists and neurologists in Singapore. DESIGN 21-question online survey consisting of 4 clinical vignettes. METHODS The survey was sent to all Singapore Medical Council- registered ophthalmologists and neurologists who regularly manage patients with optic neuritis. RESULTS Forty-two recipients (17 formally trained neuro-ophthalmol-ogists [100% response rate] and 25 neurologists) responded. Participants opted for routine testing of anti-aquaporin-4 antibodies (88.1% in mild optic neuritis and 97.6% in severe optic neuritis). Anti-MOG antibodies were frequently obtained (76.2% in mild and 88.1% in severe optic neuritis). Plasmapheresis was rapidly initiated (85.7%) in cases of nonresponse to intravenous steroids, even before obtaining anti-aquaporin-4 or anti-MOG serology results. In both NMOSD and MOGAD, oral mycophenolate mofetil was the preferred option if chronic immunosuppression was necessary. Steroids were given for a longer duration and tapered more gradually than in idiopathic optic neuritis cases. CONCLUSIONS Serological testing for NMOSD and MOGAD is considered as a routine procedure in cases of optic neuritis in Singapore, possibly due to local epidemiological features of these conditions. Chronic oral immunosuppression is preferred for the long term, but further research is necessary to establish the efficacy and cost-effectiveness of these practices.
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Affiliation(s)
- Reuben Foo
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
| | - Christine Yau
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
| | - Shweta Singhal
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
- Singapore Eye Research Institute, Singapore City, Singapore
- Duke-NUS Medical School, Singapore City, Singapore
| | - Sharon Tow
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
- Duke-NUS Medical School, Singapore City, Singapore
| | - Jing-Liang Loo
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
- Singapore Eye Research Institute, Singapore City, Singapore
- National University Hospital, Singapore City, Singapore
| | - Kevin Tan
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Neurology, National Neuroscience Institute, Singapore City, Singapore
| | - Dan Milea
- Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore City, Singapore
- Singapore Eye Research Institute, Singapore City, Singapore
- Duke-NUS Medical School, Singapore City, Singapore
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Parthasarathy D, Lily Therese K, Ambika S, Krishnan S, Priyadarshini Santhakumar D. Simultaneous screening for antibodies to myelin oligodendrocyte glycoprotein and aquaporin-4 in patients with optic neuritis using cell-based assay. CURRENT JOURNAL OF NEUROLOGY 2022; 21:29-34. [PMID: 38011487 PMCID: PMC9527861 DOI: 10.18502/cjn.v21i1.9359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/19/2021] [Indexed: 11/24/2022]
Abstract
Background: This study was aimed to test simultaneous detection of antibodies to myelin oligodendrocyte glycoprotein (MOG)/aquaporin4 (AQP4) in serum samples of patients with clinically-diagnosed optic neuritis (ON), by fixed cell-based immunofluorescence assay (CBIFA). Methods: The study involved 237 serum samples of patients with ON which were tested for MOG and AQP4 antibodies using fixed CBIFA kit which utilizes AQP4 or MOG protein transfected cells as a substrate. Results: Of 237 serum samples, 22 (9%) were positive for AQP4, 66 (28%) were positive for MOG, and 138 (58%) were negative for both AQP4 and MOG antibodies. 11 (5%) patients with clinically-diagnosed multiple sclerosis (MS) were negative for both antibodies. None of the samples were positive for both AQP4 and MOG. Among 237, 132 women [18 (13.6%) and 37 (28%)] and 105 men [4 (3.8%) and 29 (27.6%)] were positive for AQP4/MOG antibodies and remaining percentage belonged to double negative and MS. Seropositivity rate was higher in women than men. Antibodies to MOG were significantly higher than AQP4 antibodies and evenly found in all age groups. There was no ambiguous result encountered in the study. Conclusion: In this study, the seropositivity for antibodies to MOG is more than AQP4 antibody in patients with ON. Fixed CBIFA is a useful tool for laboratory diagnosis of ON in the clinical setting of neuro-ophthalmology to plan the next line of treatment management effectively.
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Affiliation(s)
- Durgadevi Parthasarathy
- L&T Microbiology Research Centre, Kamal Nayan Bajaj Building for Research in Vision and Opthalmology, Vision Research Foundation, Chennai, India
| | - Kulandai Lily Therese
- L&T Microbiology Research Centre, Kamal Nayan Bajaj Building for Research in Vision and Opthalmology, Vision Research Foundation, Chennai, India
| | - Selvakumar Ambika
- Department of Neuro-ophthalmology, Sankara Nethralaya Hospital, Medical Research Foundation, Chennai, India
| | - Selvi Krishnan
- L&T Microbiology Research Centre, Kamal Nayan Bajaj Building for Research in Vision and Opthalmology, Vision Research Foundation, Chennai, India
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Sokhor N, Yasniy O. A case report of neuromyelitis optica spectrum disorder with lesions of the medulla oblongata. Zh Nevrol Psikhiatr Im S S Korsakova 2022; 122:121-125. [DOI: 10.17116/jnevro2022122031121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Khedr EM, Farweez HM, Abo Elfetoh N, Badawy ER, Hassanein S, Mahmoud DM, Nasreldein A. Area postrema syndrome in neuromyelitis optica spectrum disorder: diagnostic challenges and descriptive patterns. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2021. [DOI: 10.1186/s41983-021-00390-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Although area postrema syndrome (APS) is one of the core clinical features of neuromyelitis optic spectrum disorder (NMOSD), it is frequently misdiagnosed as gastrointestinal or systemic disorders. In this study, we describe the diagnostic challenges in NMOSD patients with APS and their characteristic clinical and radiological features. All patients who attended our university hospitals during the period from March 2019 to August 2020 with a diagnosis of NMOSD according to the latest diagnostic criteria were admitted and evaluated clinically, radiologically with gadolinium-enhanced brain and spinal MRI, measures of serum Anti-Aquaporin 4 (Anti-AQP4) and clinical status using the Expanded Disability Status Scale (EDSS) scores. APS was diagnosed if there was a history of intractable nausea, vomiting, or hiccups (INVH) that had lasted longer than 1 week with the exclusion of other etiologies, or less than 48 h if associated with a lesion in the dorsal medulla on MRI scan.
Results
Twenty out of 90 (22.2%) identified patients with a diagnosis of NMOSD had a history of unexplained intractable nausea, vomiting or hiccoughs lasting an average of 20 days. Seventeen patients were anti-Aquaporin 4 seropositive. Seven patients (35%) presented initially with isolated clinical features of APS and were diagnosed only after subsequent relapse. Patients with APS preceding other core clinical presentations (13 cases, 65%) were diagnosed after development of motor manifestations. All patients developed acute myelitis during the course of illness. Brain and spinal MRI scans showed that 13 had a linear lesion in the dorsal tegmentum of the medulla oblongata adjacent to the fourth ventricle. Otherwise, longitudinally extensive transverse myelitis was found in 80%, while 35% showed extension of the cord lesion to the AP.
Conclusions
APS as a core clinical characteristic of NMOSD is not a rare presentation as was previously thought and can occur in both AQP4-seropositive and seronegative NMOSD.
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Lohmann L, Klotz L, Wiendl H. [Neuromyelitis Optica Spectrum Disorders - Present Insights and Recent Developments]. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE 2021; 89:516-530. [PMID: 34666391 DOI: 10.1055/a-1556-7008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The achievements of the last 15 years have essentially shaped the diagnostic methods and therapy of Neuromyelitis optica spectrum disorders (NMOSD): from discovery of aquaporin 4 antibodies and further development of diagnostic criteria the path has led to the approval of eculizumab and satralizumab as first disease modifying treatments in Europe. This article should give an overview on the present insights and future treatment options.
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Lin TY, Chien C, Lu A, Paul F, Zimmermann HG. Retinal optical coherence tomography and magnetic resonance imaging in neuromyelitis optica spectrum disorders and MOG-antibody associated disorders: an updated review. Expert Rev Neurother 2021; 21:1101-1123. [PMID: 34551653 DOI: 10.1080/14737175.2021.1982697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein IgG antibody-associated disorders (MOGAD) comprise two groups of rare neuroinflammatory diseases that cause attack-related damage to the central nervous system (CNS). Clinical attacks are often characterized by optic neuritis, transverse myelitis, and to a lesser extent, brainstem encephalitis/area postrema syndrome. Retinal optical coherence tomography (OCT) is a non-invasive technique that allows for in vivo thickness quantification of the retinal layers. Apart from OCT, magnetic resonance imaging (MRI) plays an increasingly important role in NMOSD and MOGAD diagnosis based on the current international diagnostic criteria. Retinal OCT and brain/spinal cord/optic nerve MRI can help to distinguish NMOSD and MOGAD from other neuroinflammatory diseases, particularly from multiple sclerosis, and to monitor disease-associated CNS-damage. AREAS COVERED This article summarizes the current status of imaging research in NMOSD and MOGAD, and reviews the clinical relevance of OCT, MRI and other relevant imaging techniques for differential diagnosis, screening and monitoring of the disease course. EXPERT OPINION Retinal OCT and MRI can visualize and quantify CNS damage in vivo, improving our understanding of NMOSD and MOGAD pathology. Further efforts on the standardization of these imaging techniques are essential for implementation into clinical practice and as outcome parameters in clinical trials.
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Affiliation(s)
- Ting-Yi Lin
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Claudia Chien
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Angelo Lu
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Friedemann Paul
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Hanna G Zimmermann
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Treatment of Neuromyelitis Optica Spectrum Disorders. Int J Mol Sci 2021; 22:ijms22168638. [PMID: 34445343 PMCID: PMC8395403 DOI: 10.3390/ijms22168638] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/29/2021] [Accepted: 07/31/2021] [Indexed: 12/11/2022] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory disorder that can lead to serious disability and mortality. Females are predominantly affected, including those within the reproductive age. Most patients develop relapsing attacks of optic neuritis; longitudinally extensive transverse myelitis; and encephalitis, especially brainstem encephalitis. The majority of NMOSD patients are seropositive for IgG autoantibodies against the water channel protein aquaporin-4 (AQP4-IgG), reflecting underlying aquaporin-4 autoimmunity. Histological findings of the affected CNS tissues of patients from in-vitro and in-vivo studies support that AQP4-IgG is directly pathogenic in NMOSD. It is believed that the binding of AQP4-IgG to CNS aquaporin-4 (abundantly expressed at the endfoot processes of astrocytes) triggers astrocytopathy and neuroinflammation, resulting in acute attacks. These attacks of neuroinflammation can lead to pathologies, including aquaporin-4 loss, astrocytic activation, injury and loss, glutamate excitotoxicity, microglial activation, neuroinflammation, demyelination, and neuronal injury, via both complement-dependent and complement-independent pathophysiological mechanisms. With the increased understanding of these mechanisms underlying this serious autoimmune astrocytopathy, effective treatments for both active attacks and long-term immunosuppression to prevent relapses in NMOSD are increasingly available based on the evidence from retrospective observational data and prospective clinical trials. Knowledge on the indications and potential side effects of these medications are essential for a clear evaluation of the potential benefits and risks to NMOSD patients in a personalized manner. Special issues such as pregnancy and the coexistence of other autoimmune diseases require additional concern and meticulous care. Future directions include the identification of clinically useful biomarkers for the prediction of relapse and monitoring of the therapeutic response, as well as the development of effective medications with minimal side effects, especially opportunistic infections complicated by long-term immunosuppression.
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Iorio R, Papi C. Neuromyelitis optica, aquaporin-4 antibodies, and neuroendocrine disorders. HANDBOOK OF CLINICAL NEUROLOGY 2021; 181:173-186. [PMID: 34238456 DOI: 10.1016/b978-0-12-820683-6.00013-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system that preferentially affects the optic nerve and the spinal cord. In around 80% of NMO patients, autoantibodies binding to aquaporin-4 (AQP4) are detected. AQP4-IgG unifies a spectrum of disorders (NMOSD) that include not only optic neuritis, longitudinally extensive transverse myelitis but also syndromes caused by lesion of the diencephalic region and the circumventricular organs (CVOs). The distinctive immunopathological characteristics of NMOSD lesions, occurring in regions where AQP4 is highly expressed, supports a central role for AQP4-IgG in disease pathogenesis. AQP4 expression is concentrated in CVOs and in the hypothalamus, mainly in the dorsal hypothalamic area, dorsomedial hypothalamic nucleus and suprachiasmatic nucleus. Several neuroendocrine disorders caused by inflammatory lesions involving the diencephalic region have been described in patients with NMOSD, including syndrome of inappropriate antidiuresis, sleep disorders, and other endocrinopathies caused by hypothalamic injury. Focus of this chapter is the involvement of hypothalamus and CVOs in AQP4 autoimmunity.
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Affiliation(s)
- Raffaele Iorio
- Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Claudia Papi
- Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore, Rome, Italy
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Clarke L, Arnett S, Lilley K, Liao J, Bhuta S, Broadley SA. Magnetic resonance imaging in neuromyelitis optica spectrum disorder. Clin Exp Immunol 2021; 206:251-265. [PMID: 34080180 DOI: 10.1111/cei.13630] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 12/30/2022] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) associated with antibodies to aquaporin-4 (AQP4), which has distinct clinical, radiological and pathological features, but also has some overlap with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease. Early recognition of NMOSD is important because of differing responses to both acute and preventive therapy. Magnetic resonance (MR) imaging has proved essential in this process. Key MR imaging clues to the diagnosis of NMOSD are longitudinally extensive lesions of the optic nerve (more than half the length) and spinal cord (three or more vertebral segments), bilateral optic nerve lesions and lesions of the optic chiasm, area postrema, floor of the IV ventricle, periaqueductal grey matter, hypothalamus and walls of the III ventricle. Other NMOSD-specific lesions are denoted by their unique morphology: heterogeneous lesions of the corpus callosum, 'cloud-like' gadolinium (Gd)-enhancing white matter lesions and 'bright spotty' lesions of the spinal cord. Other lesions described in NMOSD, including linear periventricular peri-ependymal lesions and patch subcortical white matter lesions, may be less specific. The use of advanced MR imaging techniques is yielding further useful information regarding focal degeneration of the thalamus and optic radiation in NMOSD and suggests that paramagnetic rim patterns and changes in normal appearing white matter are specific to MS. MR imaging is crucial in the early recognition of NMOSD and in directing testing for AQP4 antibodies and guiding immediate acute treatment decisions. Increasingly, MR imaging is playing a role in diagnosing seronegative cases of NMOSD.
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Affiliation(s)
- Laura Clarke
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia.,Department of Neurology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Simon Arnett
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia.,Department of Neurology, Gold Coast University Hospital, Southport, QLD, Australia
| | - Kate Lilley
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia.,Department of Neurology, Gold Coast University Hospital, Southport, QLD, Australia
| | - Jacky Liao
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia
| | - Sandeep Bhuta
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia.,Department of Radiology, Gold Coast University Hospital, Southport, QLD, Australia
| | - Simon A Broadley
- Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Nathan, QLD, Australia.,Department of Neurology, Gold Coast University Hospital, Southport, QLD, Australia
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Repulsive Guidance Molecule-a and Central Nervous System Diseases. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5532116. [PMID: 33997000 PMCID: PMC8112912 DOI: 10.1155/2021/5532116] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Repulsive guidance molecule-a (RGMa) is a member of glycosylphosphatidylinositol- (GPI-) anchored protein family, which has axon guidance function and is widely involved in the development and pathological processes of the central nervous system (CNS). On the one hand, the binding of RGMa and its receptor Neogenin can regulate axonal guidance, differentiation of neural stem cells into neurons, and the survival of these cells; on the other hand, RGMa can inhibit functional recovery of CNS by inhibiting axonal growth. A number of studies have shown that RGMa may be involved in the pathogenesis of CNS diseases, such as multiple sclerosis, neuromyelitis optica spectrum diseases, cerebral infarction, spinal cord injury, Parkinson's disease, and epilepsy. Targeting RGMa can enhance the functional recovery of CNS, so it may become a promising target for the treatment of CNS diseases. This article will comprehensively review the research progression of RGMa in various CNS diseases up to date.
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40
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Farges V, Hannoun S, Benini T, Marignier R, Cotton F. MRI to detect and localize the area postrema in multiple sclerosis: The role of 3D-DIR and 3D-FLAIR. J Neuroimaging 2021; 31:701-705. [PMID: 33930239 DOI: 10.1111/jon.12867] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Area postrema (AP) is a highly vascularized paired 2 mm-long anatomical structure, localized on the dorsal inferior surface of the medulla oblongata, at the caudal end of the fourth-ventricle. AP is principally affected in AP syndrome, which is commonly associated with autoimmune inflammatory diseases, including essentially neuromyelitis optica spectrum disorder (NMOSD). The aim of this study is to assess the best cerebral MRI sequences and planes for AP detection in order to assist or aid in the diagnosis of difficult NMOSD cases. METHODS 3DT1, 2DT2, 3D-fluid-attenuated inversion recovery (3DFLAIR), and 3D-double inversion recuperation (3DDIR), routinely used in inflammatory diseases, were analyzed and scored based on quality (0-2), and ability to detect AP in each plane (0 = no detection, 1 = probable detection, 2 = obvious detection). Based on image availability, subjects were divided into three groups: Group-1, including 100 randomly selected subjects with 3DT1 and 3DFLAIR, Group-2, including 30 multiple sclerosis (MS) patients from the "Observatoire Français de la Sclérose En Plaques" (OFSEP) with 3DT1, 3DFLAIR, and 3DDIR, and Group-3, including 164 OFSEP MS patients with 3DFLAIR and 2DT2. RESULTS AP was undetectable on 3DT1 and 2DT2. AP was detected in 87% of 3DFLAIR in Group-1, 90% in Group-2, and 90% in Group-3. AP was also detected in 100% of 3DDIR images in the axial plane. CONCLUSIONS As evidenced, AP was easily assessed on 3DDIR and 3DFLAIR emphasizing the importance of adding these sequences to NMOSD MRI-protocols. Moreover, the most effective imaging plane in identifying AP was the axial plane.
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Affiliation(s)
- Valentine Farges
- Faculty of Medicine, Claude Bernard Lyon 1 University, Lyon, France
| | - Salem Hannoun
- Medical Imaging Sciences Program, Division of Health Professions, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon
| | - Théo Benini
- Faculty of Medicine, Claude Bernard Lyon 1 University, Lyon, France
| | - Romain Marignier
- Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France
| | - François Cotton
- Radiology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France.,CREATIS - CNRS UMR 5220 - INSERM U1294, Université Lyon 1, Villeurbanne, France
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Du L, Chang H, Xu W, Zhang X, Yin L. Elevated chemokines and cytokines for eosinophils in neuromyelitis optica spectrum disorders. Mult Scler Relat Disord 2021; 52:102940. [PMID: 33930716 DOI: 10.1016/j.msard.2021.102940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/27/2021] [Accepted: 04/02/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND Eosinophil infiltration is one of the distinctive features in neuromyelitis optica spectrum disorders (NMOSD) but not in other demyelinating diseases including multiple sclerosis (MS). Eosinophils express the chemokine receptor CCR3, which is activated by eotaxins (eotaxin-1, -2, and -3) and monocyte chemoattractant protein (MCP)-4. We aimed to investigate the role of MCPs (MCP-1, -2, -3, and -4) and eotaxins in the acute phase of NMOSD. METHODS Levels of serum and cerebrospinal fluid (CSF) eotaxins, MCPs, interleukin (IL)-5, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-6 were measured using the cytokine multiplex assay from 26 patients with NMOSD (13 with immunotherapy, 13 without immunotherapy), 9 patients with MS, and 9 patients with other noninflammatory neurological diseases (OND). Glial fibrillary acidic protein was assessed using ELISA. RESULTS Serum MCP-1 and CSF MCP-2 levels were significantly higher in patients with NMOSD than in OND. Moreover, serum MCP-4 and CSF eotaxin-2 and -3 levels were significantly higher in NMOSD patients compared to MS and OND. Serum MCP-1, -4 and CSF eotaxin-2, -3 levels were significantly correlated with the Expanded Disability Status Scale in NMOSD. TNF-α and GM-CSF, which stimulate the above chemokines, were higher in patients with NMOSD than those in OND. Moreover, serum MCP-1 and -4 were significantly increased by IL-5 and GM-CSF stimulation, but not by TNF-α and IL-6. Only CSF eotaxin-2 was significantly increased by GM-CSF. There were no significant differences in serum MCP-1 and -4 levels between NMOSD patients with and without immunotherapy. CONCLUSION These findings suggest that the elevated serum MCP-1, -4 and CSF eotaxin-2, -3 may be a key step in eosinophil recruitment in the acute phase of NMOSD.
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Affiliation(s)
- Li Du
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Haoxiao Chang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Wangshu Xu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xinghu Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China.
| | - Linlin Yin
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China.
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Sawai S, Mori M, Makino T, Nakano Y, Kuwabara S, Kamitsukasa I. Severe orthostatic hypotension associated with lesions of the area postraema in neuromyelitis optica spectrum disorder. eNeurologicalSci 2021; 23:100335. [PMID: 33763606 PMCID: PMC7973318 DOI: 10.1016/j.ensci.2021.100335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/05/2021] [Accepted: 03/06/2021] [Indexed: 11/25/2022] Open
Abstract
Hiccups, nausea and vomiting are known as the clinical manifestations of neuromyelitis optica spectrum disorder (NMOSD) linked to lesions of the area postraema in the medullary tegmentum. Here, we describe a 74-year-old male patient with NMOSD who presented with recurrent syncope due to severe orthostatic hypotension (OH) following symptoms of hiccups, nausea and vomiting. Brain magnetic resonance imaging revealed the lesion of the area postraema and it could be responsible for the symptom of OH. Considering the numerous related reports, we suspect that the prevalence of OH is underreported in the patients with NMOSD. OH may transition into more serious conditions, so it should be evaluated carefully in all patients with NMOSD, particularly when there is a lesion of the area postraema.
The area postraema is frequently affected in Neuromyelitis optica spectrum disorder. A Neuromyelitis optica spectrum disorder patient presented orthostatic hypotension. The lesion of the area postraema could be responsible for orthostatic hypotension.
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Affiliation(s)
- Setsu Sawai
- Department of Neurology, Chibaken Saiseikai Narashino Hospital, 1-1-1 Izumi-cho, Narashino City, Chiba 275-8580, Japan.,Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan
| | - Masahiro Mori
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan
| | - Takahiro Makino
- Department of Neurology, Chibaken Saiseikai Narashino Hospital, 1-1-1 Izumi-cho, Narashino City, Chiba 275-8580, Japan
| | - Yoshikazu Nakano
- Department of Neurology, Chibaken Saiseikai Narashino Hospital, 1-1-1 Izumi-cho, Narashino City, Chiba 275-8580, Japan
| | - Satoshi Kuwabara
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan
| | - Ikuo Kamitsukasa
- Department of Neurology, Chibaken Saiseikai Narashino Hospital, 1-1-1 Izumi-cho, Narashino City, Chiba 275-8580, Japan
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Han W, de Araujo IE. Nausea and the Brain: The Chemoreceptor Trigger Zone Enters the Molecular Age. Neuron 2021; 109:391-393. [PMID: 33539771 DOI: 10.1016/j.neuron.2021.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Area postrema in brainstem has long been known to trigger emesis by detecting blood-borne toxins and pathogens. In this issue, Zhang and colleagues provide a single-cell molecular atlas of this region, opening new possibilities for harnessing its neurons in vivo.
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Affiliation(s)
- Wenfei Han
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ivan E de Araujo
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Pharmacology and Therapeutics Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Abstract
The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.
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Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG- and MOG-IgG-associated diseases. Curr Opin Neurol 2021; 33:362-371. [PMID: 32304439 DOI: 10.1097/wco.0000000000000813] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW This review summarizes recent insights into the pathogenesis and therapeutic options for patients with MOG- or AQP4-antibodies. RECENT FINDINGS Although AQP4-IgG are linked to NMOSD, MOG-IgG-associated diseases (MOGAD) include a broader clinical spectrum of autoimmune diseases of the central nervous system (CNS). Details of membrane assembly of AQP4-IgG required for complement activation have been uncovered. Affinity-purified MOG-IgG from patients were shown to be pathogenic by induction of demyelination when the blood--brain barrier (BBB) was breached and by enhancement of activation of cognate T cells. A high-affinity AQP4-IgG, given peripherally, could induce NMOSD-like lesions in rats in the absence of BBB breach. Circulating AQP4-specific and MOG-specific B cells were identified and suggest differences in origin of MOG-antibodies or AQP4-antibodies. Patients with MOG-IgG show a dichotomy concerning circulating MOG-specific B cells; whether this is related to differences in clinical response of anti-CD20 therapy remains to be analyzed. Clinical trials of AQP4-IgG-positive NMOSD patients showed success with eculizumab (preventing cleavage of complement factor C5, thereby blocking formation of chemotactic C5a and membrane attack complex C9neo), inebilizumab (depleting CD19 + B cells), and satralizumab (anti-IL-6R blocking IL-6 actions). SUMMARY New insights into pathological mechanisms and therapeutic responses argue to consider NMOSD with AQP4-IgG and MOGAD as separate disease entities.
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Sharma J, Bhatti MT, Danesh-Meyer HV. Neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein IgG associated disorder: A comprehensive neuro-ophthalmic review. Clin Exp Ophthalmol 2021; 49:186-202. [PMID: 33426799 DOI: 10.1111/ceo.13863] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/13/2020] [Accepted: 09/19/2020] [Indexed: 11/26/2022]
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system that involves the optic nerves, spinal cord, and often other specific brain regions such as area postrema of the medulla. NMOSD was formerly classified as a variant of multiple sclerosis (MS), given the similar symptomatology and relapsing course but is now considered to have distinct clinical, paraclinical, immunological and prognostic features. The discovery of aquaporin 4 (AQP4) immunoglobulin G (IgG) has improved the ability to diagnose NMOSD. AQP4-IgG targets the astrocytic AQP4 water channel leading to complement activation and increased blood-brain barrier permeability. Accurate and early diagnosis is crucial as timely treatment may result in mitigation of long-term disability. Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorder (MOGAD) is a distinct nosologic entity, which has been more recently described. Its clinical spectrum partly overlaps that of seronegative NMOSD and MS. Although it is considered to have fewer relapses and better prognosis than NMOSD, the clinical course and outcome of MOGAD has not been fully characterized.
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Affiliation(s)
- Jaya Sharma
- Department of Ophthalmology, University of Auckland, New Zealand
| | - M Tariq Bhatti
- Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.,Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Tarulli A. Multiple Sclerosis. Neurology 2021. [DOI: 10.1007/978-3-030-55598-6_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Akaishi T, Fujimori J, Takahashi T, Misu T, Takai Y, Nishiyama S, Kaneko K, Ogawa R, Abe M, Ishii T, Aoki M, Fujihara K, Nakashima I. Seasonal variation of onset in patients with anti-aquaporin-4 antibodies and anti-myelin oligodendrocyte glycoprotein antibody. J Neuroimmunol 2020; 349:577431. [PMID: 33147540 DOI: 10.1016/j.jneuroim.2020.577431] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/24/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
This study aimed to determine the seasonal impact on the clinical onset of inflammatory neurological diseases of the central nervous system by analyzing the onset month with information on clinical manifestations in Japanese patients. As a result, patients with anti-aquaporin-4 antibodies (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSD) showed spring-summer predominance of the clinical onset. Conversely, patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease showed autumn-winter predominance of the clinical onset. Both seasonal variations were irrespective of the clinical manifestation. Environmental factors with seasonal variation influence the development of neurological conditions related to AQP4-IgG and MOG-IgG.
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Affiliation(s)
- Tetsuya Akaishi
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan.
| | - Juichi Fujimori
- Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Toshiyuki Takahashi
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology, National Hospital Organization Yonezawa National Hospital, Yonezawa, Japan
| | - Tatsuro Misu
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiki Takai
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shuhei Nishiyama
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kimihiko Kaneko
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryo Ogawa
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Abe
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Tadashi Ishii
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuo Fujihara
- Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan
| | - Ichiro Nakashima
- Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
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Zhou C, Liao L, Sun R, Wang J, Di W, Zhu Y, He Y. Area postrema syndrome as initial manifestation in neuromyelitis optica spectrum disorder patients: A retrospective study. Rev Neurol (Paris) 2020; 177:400-406. [PMID: 33081997 DOI: 10.1016/j.neurol.2020.07.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 04/16/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Area postrema syndrome (APS) is recognized as a core feature in neuromyelitis optica (NMO) diagnosis. Isolated APS can occur at NMO onset and frequently results in a delay of diagnosis, along with devastating secondary neurologic deficits. To date, few studies have characterized APS-onset neuromyelitis optica spectrum disorder (APSO-NMOSD). OBJECTIVE We aimed to describe the clinical and radiologic features of patients with APSO-NMOSD who are initially misdiagnosed in a cohort of patients from Zhengzhou, China. MATERIALS AND METHODS We identified 15 patients who presented with APS as an initial manifestation, based on the 2015 international consensus diagnostic criteria for NMOSD, and reviewed their demographic, clinical, laboratory, and magnetic resonance imaging (MRI) data. RESULT Fifteen patients (3 men, 12 women) aged 14-50 years old were included in our study. All patients presented with APS that included intractable nausea, vomiting, or hiccups (INVH) as the initial manifestation; many experienced a delay in diagnosis. Serum AQP4 was positive in eleven patients and myelin oligodendrocyte glycoprotein (MOG) in one patient. All patients had a linear medullary lesion or a linear medulla-spinal lesion on sagittal MRI. An "inverted V sign" on axial medulla oblongata images, representing a lesion involving the area postrema, was noted in seven patients in this study. CONCLUSIONS APS can occur as a sole and initial manifestation of NMOSD, often leading to misdiagnosis in the early process of disease. Identifying patients with an "inverted V" sign and a linear medullary lesion upon MRI examination can help to quickly identify APS patients and avoid further diagnostic delays.
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Affiliation(s)
- C Zhou
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - L Liao
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - R Sun
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - J Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - W Di
- Department of Neurology, affiliated hospital of Hebei university, Hebei, China.
| | - Y Zhu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
| | - Y He
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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Sanchez JMS, McNally JS, Cortez MM, Hemp J, Pace LA, Clardy SL. Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology. Front Neurol 2020; 11:787. [PMID: 32849234 PMCID: PMC7412790 DOI: 10.3389/fneur.2020.00787] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 06/25/2020] [Indexed: 12/11/2022] Open
Abstract
The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.
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Affiliation(s)
- John Michael S. Sanchez
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT, United States
| | - J. Scott McNally
- Department of Radiology, Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, UT, United States
| | - Melissa M. Cortez
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
| | - James Hemp
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Laura A. Pace
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Stacey L. Clardy
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, United States
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