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Slioui A, Tammam G, Vanoli F, Marina AD, Vohanka S, Gilhus NE, Moroni I, Leite MI, Piehl F, Antozzi C, Pini J, Stascheit F, Attarian S, Santos E, Verschuuren J, Canonge L, Garcia J, Perriard C, Cortés-Vicente E, Mantegazza R, Meisel A, Sacconi S. Toward European harmonization of national myasthenia gravis registries: modified Delphi procedure-based expert consensus on collectable data. Orphanet J Rare Dis 2025; 20:115. [PMID: 40069719 PMCID: PMC11895382 DOI: 10.1186/s13023-024-03520-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 12/18/2024] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Myasthenia gravis (MG) is a rare autoimmune disorder. Several new treatment concepts have emerged in recent years, but access to these treatments varies due to differing national reimbursement regulations, leading to disparities across Europe. This highlights the need for high-quality data collection by stakeholders to establish MG registries. A European MG registry could help bridge the treatment access gap across different countries, offering critical data to support regulatory decisions, foster international collaborations, and enhance clinical and epidemiological research. Several national MG registries already exist or are in development. To avoid duplication and ensure harmonization in data collection, a modified Delphi procedure was implemented to identify essential data elements for inclusion in national registries. RESULTS Following a literature review, consultations with patient associations and pharmaceutical companies, and input from multiple European MG experts, 100 data elements were identified. Of these, 62 reached consensus for inclusion and classification, while only 1 item was agreed for exclusion. 30 items failed to reach the ≥ 80% agreement threshold and were excluded. Among the 62 accepted items, 21 were classified as mandatory data elements, 32 optional, and 9 items pertained to the informed consent form. CONCLUSIONS Through a modified Delphi procedure, consensus was successfully achieved. This consensus-based approach represents a crucial step toward harmonizing MG registries across Europe. The resulting dataset will facilitate the sharing of knowledge and enhance European collaborations. Furthermore, the harmonized data may assist in regulatory or reimbursement decisions regarding novel therapies, as well as address treatment access disparities between European countries.
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Affiliation(s)
- Abderhmane Slioui
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France
| | - Giulia Tammam
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France
- Department of Brain and Behavioral Sciences, University of Pavia, IRCCS Mondino Foundation, Pavia, Italy
| | - Fiammetta Vanoli
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
| | - Adela Della Marina
- Department of Pediatric Neurology, Centre for Neuromuscular Disorders, C-TNBS, University Duisburg-Essen, Essen, Germany
| | - Stanislav Vohanka
- Department of Neurology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Nils Erik Gilhus
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Isabella Moroni
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Maria Isabel Leite
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Fredrik Piehl
- Departments of Clinical Neuroscience, Karolinska Institutet, and Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Carlo Antozzi
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- Immunotherapy and Apheresis Departmental Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Jonathan Pini
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France
| | - Frauke Stascheit
- Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Department of Neurology With Experimental Neurologie, Neuroscience Clinical Research Center, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Shahram Attarian
- Reference Center for Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, Marseille, France
| | - Ernestina Santos
- Neurology Department, Centro Hospitalar Universitário de Santo António; Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Jan Verschuuren
- Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lou Canonge
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France
- ESIEE PARIS School, Gustave Eiffel University, Paris, France
| | - Jeremy Garcia
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France
| | - Caroline Perriard
- Reference Center for Neuromuscular Disorders, Lenval Pediatric Hospitals of Nice University Hospital, Nice, France
| | - Elena Cortés-Vicente
- Neuromuscular Diseases Unit, Hospital de La Santa Creu I Sant Pau, Barcelona, Spain
| | - Renato Mantegazza
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Andreas Meisel
- Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Department of Neurology With Experimental Neurologie, Neuroscience Clinical Research Center, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Sabrina Sacconi
- Peripheral Nervous System and Muscle Department, Reference Center for Neuromuscular Disorders, Pasteur 2 Hospital, Centre Hospitalier, Universitaire de Nice, Nice University Hospital, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France.
- Institute for Research On Cancer and Aging of Nice, CNRS, INSERM, Côte d'Azur University, SNPM - Hôpital Pasteur 2 - 30 voie Romaine, 06001, Nice CEDEX, France.
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Loser V, Vicino A, Théaudin M. Autoantibodies in neuromuscular disorders: a review of their utility in clinical practice. Front Neurol 2024; 15:1495205. [PMID: 39555481 PMCID: PMC11565704 DOI: 10.3389/fneur.2024.1495205] [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: 09/12/2024] [Accepted: 10/23/2024] [Indexed: 11/19/2024] Open
Abstract
A great proportion of neuromuscular diseases are immune-mediated, included myasthenia gravis, Lambert-Eaton myasthenic syndrome, acute- and chronic-onset autoimmune neuropathies (anti-MAG neuropathy, multifocal motor neuropathy, Guillain-Barré syndromes, chronic inflammatory demyelinating polyradiculoneuropathy, CANDA and autoimmune nodopathies), autoimmune neuronopathies, peripheral nerve hyperexcitability syndromes and idiopathic inflammatory myopathies. The detection of autoantibodies against neuromuscular structures has many diagnostic and therapeutic implications and, over time, allowed a better understanding of the physiopathology of those disorders. In this paper, we will review the main autoantibodies described in neuromuscular diseases and focus on their use in clinical practice.
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Affiliation(s)
- Valentin Loser
- Department of Clinical Neurosciences, Nerve-Muscle Unit, Service of Neurology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Su M, Luo Q, Wu Z, Feng H, Zhou H. Thymoma-associated autoimmune encephalitis with myasthenia gravis: Case series and literature review. CNS Neurosci Ther 2024; 30:e14568. [PMID: 38421083 PMCID: PMC10850820 DOI: 10.1111/cns.14568] [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: 03/31/2023] [Revised: 11/20/2023] [Accepted: 12/02/2023] [Indexed: 03/02/2024] Open
Abstract
OBJECTIVES This comprehensive review aimed to compile cases of patients with thymoma diagnosed with both autoimmune encephalitis (AE) and myasthenia gravis (MG), and describe their clinical characteristics. METHODS Clinical records of 3 AE patients in the first affiliated hospital of Sun Yat-sen University were reviewed. All of them were diagnosed with AE between 1 November 2021 and 1 March 2022, and clinical evidence about thymoma and MG was found. All published case reports were searched for comprehensive literature from January 1990 to June 2022. RESULTS A total of 18 cases diagnosed with thymoma-associated autoimmune encephalitis (TAAE) and thymoma-associated myasthenia gravis (TAMG) were included in this complication, wherein 3 cases were in the first affiliated hospital of Sun Yat-sen University and the other 15 were published case reports. 5/18 patients had alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody (AMPAR-Ab) in their serum and cerebrospinal fluid (CSF). All of them had positive anti-acetylcholine receptor antibody (AChR-Ab). And 12/18 patients showed a positive response to thymectomy and immunotherapy. Besides, thymoma recurrences were detected because of AE onset. And the shortest interval between operation and AE onset was 2 years in patients with thymoma recurrence. CONCLUSIONS There was no significant difference in the clinical manifestations between these patients and others with only TAMG or TAAE. TAAE was commonly associated with AMPAR2-Ab. Significantly, AE more commonly heralded thymoma recurrences than MG onset. And the intervals of thymectomy and MG or AE onset had different meanings for thymoma recurrence and prognoses of patients.
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Affiliation(s)
- Miao Su
- Department of NeurologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Qiuyan Luo
- Department of NeurologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
- Department of NeurologyGuangzhou Women and Children's Medical CenterGuangzhouChina
| | - Zichao Wu
- Department of NeurologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Huiyu Feng
- Department of NeurologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Hongyan Zhou
- Department of NeurologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
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Iorio R, Lennon VA. Paraneoplastic autoimmune neurologic disorders associated with thymoma. HANDBOOK OF CLINICAL NEUROLOGY 2024; 200:385-396. [PMID: 38494291 DOI: 10.1016/b978-0-12-823912-4.00008-6] [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: 03/19/2024]
Abstract
Thymoma is often associated with paraneoplastic neurologic diseases. Neural autoantibody testing is an important tool aiding diagnosis of thymoma and its autoimmune neurologic complications. Autoantibodies specific for muscle striational antigens and ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily are the most prevalent biomarkers. The autoimmune neurologic disorders associating most commonly with thymoma are myasthenia gravis (MG), peripheral nerve hyperexcitability (neuromyotonia and Morvan syndrome), dysautonomia, and encephalitis. Patients presenting with these neurologic disorders should be screened for thymoma at diagnosis. Although they can cause profound disability, they usually respond to immunotherapy and treatment of the thymoma. Worsening of the neurologic disorder following surgical removal of a thymoma may herald tumor recurrence. Prompt recognition of paraneoplastic neurologic disorders is critical for patient management. A multidisciplinary approach is required for optimal management of neurologic autoimmunity associated with thymoma.
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Affiliation(s)
- Raffaele Iorio
- Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Vanda A Lennon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States; Department of Neurology, Mayo Clinic, Rochester, MN, United States; Department of Immunology, Mayo Clinic, Rochester, MN, United States
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Guo Q, Huang Y, Wang F, Fang L. Case Report: Telitacicept in severe myasthenia gravis: a case study with multiple autoantibodies. Front Immunol 2023; 14:1270011. [PMID: 38124751 PMCID: PMC10731252 DOI: 10.3389/fimmu.2023.1270011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023] Open
Abstract
Multi-antibody-positive myasthenia gravis (MG) presentations are relatively rare, often found in older patients, and generally predict a poor prognosis. We report a case of a female patient with generalized MG, testing positive for Titin antibodies (Titin-Ab), ryanodine receptor antibodies (RyR-Ab), and acetylcholine receptor antibodies (AChR-Ab), and resistant to acetylcholinesterase inhibitors. Following unsuccessful traditional therapies, she received Telitacicept, leading to significant improvements. This case underscores Telitacicept's potential efficacy for similar patients and offers insights into the clinical characteristics of multi-antibody MG.
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Affiliation(s)
- Qian Guo
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yusen Huang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Fangruyue Wang
- The Third Bethune Hospital of Jilin University, Changchun, China
| | - Le Fang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
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Sobierajski T, Lasek-Bal A, Krzystanek M, Gilhus NE. Diagnosis and therapy of myasthenia gravis-the patients' perspective: a cross-sectional study. Front Neurol 2023; 14:1214041. [PMID: 37602258 PMCID: PMC10437051 DOI: 10.3389/fneur.2023.1214041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 07/25/2023] [Indexed: 08/22/2023] Open
Abstract
The survey aimed to explore patients' perspectives with myasthenia gravis (MG) toward the diagnosis made and the therapy used to treat MG. The survey was conducted with a quantitative method, using the CAWI technique. A total of 321 people participated in the survey. More than half of the respondents (56.4%) had suffered from MG for less than 10 years. In three out of 10 cases (30.9%), the diagnosis of MG lasted 3 years or longer. The diagnostic delay was significantly longer in female respondents than in the males (p = 0.029). Cholinergic drugs were used in 92.9% of cases initially, and as maintenance therapy in 84.3% of cases. Corticosteroids were used in initiating therapy (45.8%) and as maintenance therapy (46.4%). One in four respondents (25.5%) reported experiencing very strong and strong side effects after using steroids. The side effects from steroid therapy very strong or strong affected overall physical health in 55.9% of respondents, very strong or strong affected self-acceptance in 52%, to a very large or large extent on mental health in 47.1%, and to a very strong or strong extent influenced the performance of daily activities in 28.2%. More than half of the respondents (57.0%) had had a thymectomy. Seven out of 10 respondents (72.0%) declared that the therapy they were on at the time of the survey allowed them (to varying degrees) to control their course of MG. Low therapy acceptance and less well controlled MG was associated with a preference for non-tablet therapies (p = 0.045). Regular follow-up and cooperation with the specialist health care system should improve MG symptoms, activities of daily living, and quality of life.
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Affiliation(s)
- Tomasz Sobierajski
- The Center of Sociomedical Research, Faculty of Applied Social Sciences and Resocialization, University of Warsaw, Warsaw, Poland
| | - Anetta Lasek-Bal
- Department of Neurology, School of Health Sciences, Medical University of Silesia in Katowice, Katowice, Poland
- Department of Neurology, Upper-Silesian Medical Center of the Medical University of Silesia in Katowice, Katowice, Poland
| | - Marek Krzystanek
- Department and Clinic of Psychiatric Rehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice, Poland
| | - Nils E. Gilhus
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Neurology, Haukeland University Hospital, Bergen, Norway
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Shelly S, Mills JR, Dubey D, McKeon A, Zekeridou A, Pittock SJ, Harper CM, Naddaf E, Milone M, Mandrekar J, Klein CJ. Clinical Utility of Striational Antibodies in Paraneoplastic and Myasthenia Gravis Paraneoplastic Panels. Neurology 2021; 96:e2966-e2976. [PMID: 33903199 DOI: 10.1212/wnl.0000000000012050] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/15/2021] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To critically assess the clinical utility of striational antibodies (StrAbs) within paraneoplastic and myasthenia gravis (MG) serologic evaluations. METHODS All Mayo Clinic patients tested for StrAbs from January 1, 2012, to December 31, 2018, utilizing Mayo's Unified Data Platform (UDP) were reviewed for neurologic diagnosis and cancer. RESULTS A total of 38,502 unique paraneoplastic evaluations and 1,899 patients with MG were tested. In paraneoplastic evaluations, the StrAbs positivity rate was higher in cancer vs without cancer (5% [321/6,775] vs 4% [1,154/31,727]; p < 0.0001; odds ratio [OR] 1.35; confidence interval [CI] 1.19-1.53), but receiver operating characteristic (ROC) analysis indicated no diagnostic accuracy in cancer (area under the ROC curve [AUC] 0.505). No neurologic phenotype was significantly associated with StrAbs in the paraneoplastic group. Positivity was more common in all MG cancers compared to paraneoplastic cancers (p < 0.0001). In MG evaluations, the StrAbs positivity rate was higher in those with cancer vs without (46% [217/474] vs 26% [372/1,425]; p < 0.0001; OR 2.39, CI 1.9-2.96), with ROC analysis indicating poor diagnostic accuracy for thymic cancer (AUC 0.634, recommended cutoff = 1:60, sensitivity = 56%, specificity = 71%), with worse accuracy for extrathymic cancers (AUC 0.543). In paraneoplastic or MG evaluations, the value of antibody positivity did not improve cancer predictions. Paraneoplastic evaluated patients with positive StrAbs were more likely to obtain CT (p = 0.0001), with cancer found in 3% (12/468). CONCLUSION Despite a statistically significant association with cancer, an expansive review of performance in clinical service demonstrates that StrAbs are neither specific nor sensitive in predicting malignancy or neurologic phenotypes. CT imaging is overutilized with positive StrAbs results. Removal of StrAbs from paraneoplastic or MG evaluations will improve the diagnostic characteristics of the current MG test. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that the presence of StrAbs does not accurately identify patients with malignancy or neurologic phenotypes.
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Affiliation(s)
- Shahar Shelly
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - John R Mills
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN.
| | - Divyanshu Dubey
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Andrew McKeon
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Anastasia Zekeridou
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Sean J Pittock
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - C Michel Harper
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Elie Naddaf
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Margherita Milone
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Jay Mandrekar
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN
| | - Christopher J Klein
- From the Departments of Neurology (S.S., D.D., A.M., A.Z., S.J.P., C.M.H., E.N., M.M., C.J.K.), Laboratory Medicine and Pathology (S.S., J.R.M., D.D., A.M., A.Z., S.J.P., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic, Rochester MN.
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Gastaldi M, Scaranzin S, Businaro P, Mobilia E, Benedetti L, Pesce G, Franciotta D. Improving laboratory diagnostics in myasthenia gravis. Expert Rev Mol Diagn 2021; 21:579-590. [PMID: 33970749 DOI: 10.1080/14737159.2021.1927715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Myasthenia gravis (MG) is a prototypical autoimmune disease, characterized by pathogenic autoantibodies targeting structures of the neuromuscular junction. Radioimmunoprecipitation assays (RIPAs) represent the gold standard for their detection. However, new methods are emerging to complement, or overcome RIPAs, also with the perspective of eliminating the use of radioactive reagents.Areas covered: We discuss advances in laboratory methods, prompted especially by cell-based assays (CBAs), for the detection of the autoantibodies of MG diagnostics, above all those to the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low molecular-weight receptor-related low-density lipoprotein-4 (LRP4).Expert opinion: CBA technology makes AChRs aggregate on cell membranes, thus allowing to detect autoantibodies to clustered AChRs, with reduction of seronegative MG cases. The diagnostic relevance of RIPA/CBA-measurable LRP4 antibodies is still unclear, in Caucasian patients at least. Live CBAs for the detection of AChR, MuSK, and LRP4 antibodies might represent an alternative to RIPAs, but first require full validation. CBAs could be used as screening tests, limiting RIPAs for antibody quantification. To this end, ELISAs might be an alternative.Fixation procedures preserving enough degree of antigen conformationality could yield AChR and MuSK CBAs suitable for a wide use in clinical-chemistry laboratories.
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Affiliation(s)
- Matteo Gastaldi
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Silvia Scaranzin
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Pietro Businaro
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Emanuela Mobilia
- Autoimmunity Laboratory, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Luana Benedetti
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Giampaola Pesce
- Autoimmunity Laboratory, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Department of Internal Medicine (Dimi), University of Genova, Genova, Italy
| | - Diego Franciotta
- Autoimmunity Laboratory, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Spagni G, Todi L, Monte G, Valentini M, Di Sante G, Damato V, Marino M, Evoli A, Lantieri F, Provenzano C. Human Leukocyte Antigen Class II associations in late-onset Myasthenia Gravis. Ann Clin Transl Neurol 2021; 8:656-665. [PMID: 33547763 PMCID: PMC7951107 DOI: 10.1002/acn3.51309] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/26/2020] [Accepted: 01/13/2021] [Indexed: 01/09/2023] Open
Abstract
Objective Genetic factors predisposing to late‐onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome‐wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup. Methods This study consecutively enrolled anti‐acetylcholine receptor antibody‐positive, non‐thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA‐DRB1 and ‐DQB1 genotyping and serum titin antibody testing were performed in this population. Results A total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50‐92) were included. We found a positive association with HLA‐DRB1*07 (P = 1.1 × 10‐5), HLA‐DRB1*14 (P = 0.0251) and HLA‐DQB1*02 (P = 0.0095). HLA‐DRB1*03, HLA‐DRB1*11, and HLA‐DQB1*03 were protective alleles (P = 7.9 × 10‐5, P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA‐DRB1*07‐DQB1*02 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80‐5.99; P = 6.01 × 10‐11). The mean age at onset was 73.4 years in DRB1*07 homozygotes, 69.7 years in heterozygotes, and 66.6 in non‐carriers (P = 0.0488). DRB1*07 carriers and non‐carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics. Interpretation In our study, we identified the HLA DRB1*07‐DQB1*02 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.
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Affiliation(s)
- Gregorio Spagni
- Dipartimento di Neuroscienze, Sezione di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Laura Todi
- Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy
| | - Gabriele Monte
- Dipartimento di Neuroscienze, Sezione di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Mariagrazia Valentini
- Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy
| | - Gabriele Di Sante
- Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy
| | - Valentina Damato
- Dipartimento di Neuroscienze, Sezione di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,U.O.C. di Neurologia, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - Mariapaola Marino
- Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy
| | - Amelia Evoli
- Dipartimento di Neuroscienze, Sezione di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,U.O.C. di Neurologia, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - Francesca Lantieri
- Dipartimento di Scienze della Salute, Università degli Studi di Genova, Genova, Italy
| | - Carlo Provenzano
- Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy
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10
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Lazaridis K, Tzartos SJ. Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management. Front Neurol 2020; 11:596981. [PMID: 33329350 PMCID: PMC7734299 DOI: 10.3389/fneur.2020.596981] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/30/2020] [Indexed: 12/11/2022] Open
Abstract
Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction, characterized by skeletal muscle weakness and fatigability. It is caused by autoantibodies targeting proteins of the neuromuscular junction; ~85% of MG patients have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 5% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). In the remaining about 10% of patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG). Since serological tests are relatively easy and non-invasive for disease diagnosis, the improvement of methods for the detection of known autoantibodies or the discovery of novel autoantibody specificities to diminish SN-MG and to facilitate differential diagnosis of similar diseases, is crucial. Radioimmunoprecipitation assays (RIPA) are the staple for MG antibody detection, but over the past years, using cell-based assays (CBAs) or improved highly sensitive RIPAs, it has been possible to detect autoantibodies in previously SN-MG patients. This led to the identification of more patients with antibodies to the classical antigens AChR and MuSK and to the third MG autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), while antibodies against other extracellular or intracellular targets, such as agrin, Kv1.4 potassium channels, collagen Q, titin, the ryanodine receptor and cortactin have been found in some MG patients. Since the autoantigen targeted determines in part the clinical manifestations, prognosis and response to treatment, serological tests are not only indispensable for initial diagnosis, but also for monitoring treatment efficacy. Importantly, knowing the autoantibody profile of MG patients could allow for more efficient personalized therapeutic approaches. Significant progress has been made over the past years toward the development of antigen-specific therapies, targeting only the specific immune cells or autoantibodies involved in the autoimmune response. In this review, we will present the progress made toward the development of novel sensitive autoantibody detection assays, the identification of new MG autoantigens, and the implications for improved antigen-specific therapeutics. These advancements increase our understanding of MG pathology and improve patient quality of life by providing faster, more accurate diagnosis and better disease management.
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Affiliation(s)
| | - Socrates J Tzartos
- Tzartos NeuroDiagnostics, Athens, Greece.,Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece
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11
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Paraneoplastic neurological syndromes with onconeural antibodies: A single center retrospective study. J Neurol Sci 2020; 418:117103. [DOI: 10.1016/j.jns.2020.117103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/01/2020] [Accepted: 08/18/2020] [Indexed: 12/16/2022]
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12
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Lazaridis K, Tzartos SJ. Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics. Front Immunol 2020; 11:212. [PMID: 32117321 PMCID: PMC7033452 DOI: 10.3389/fimmu.2020.00212] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatiguability of skeletal muscles. It is an antibody-mediated disease, caused by autoantibodies targeting neuromuscular junction proteins. In the majority of patients (~85%) antibodies against the muscle acetylcholine receptor (AChR) are detected, while in 6% antibodies against the muscle-specific kinase (MuSK) are detected. In ~10% of MG patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG), making the improvement of methods for the detection of known autoantibodies or the discovery of novel antigenic targets imperative. Over the past years, using cell-based assays or improved highly sensitive immunoprecipitation assays, it has been possible to detect autoantibodies in previously SN-MG patients, including the identification of the low-density lipoprotein receptor-related protein 4 (LRP4) as a third MG autoantigen, as well as AChR and MuSK antibodies undetectable by conventional methods. Furthermore, antibodies against other extracellular or intracellular targets, such as titin, the ryanodine receptor, agrin, collagen Q, Kv1.4 potassium channels and cortactin have been found in some MG patients, which can be useful biomarkers. In addition to the improvement of diagnosis, the identification of the patients' autoantibody specificity is important for their stratification into respective subgroups, which can differ in terms of clinical manifestations, prognosis and most importantly their response to therapies. The knowledge of the autoantibody profile of MG patients would allow for a therapeutic strategy tailored to their MG subgroup. This is becoming especially relevant as there is increasing progress toward the development of antigen-specific therapies, targeting only the specific autoantibodies or immune cells involved in the autoimmune response, such as antigen-specific immunoadsorption, which have shown promising results. We will herein review the advances made by us and others toward development of more sensitive detection methods and the identification of new antibody targets in MG, and discuss their significance in MG diagnosis and therapy. Overall, the development of novel autoantibody assays is aiding in the more accurate diagnosis and classification of MG patients, supporting the development of advanced therapeutics and ultimately the improvement of disease management and patient quality of life.
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Affiliation(s)
| | - Socrates J Tzartos
- Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece.,Tzartos NeuroDiagnostics, Athens, Greece
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13
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Yildiz Celik S, Durmus H, Yilmaz V, Saruhan Direskeneli G, Gulsen Parman Y, Serdaroglu Oflazer P, Deymeer F. Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome. Acta Neurol Belg 2020; 120:133-140. [PMID: 31811563 DOI: 10.1007/s13760-019-01252-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 11/25/2019] [Indexed: 01/08/2023]
Abstract
Late-onset myasthenia gravis (LOMG) is a unique MG subgroup. More information is needed on its subgroups such as non-thymomatous generalized LOMG. We evaluated the effect of demographic, clinical, and serological factors as well as different immunosuppressive modalities on outcome in generalized non-thymomatous LOMG with onset ≥ 50 years. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, MGFA postintervention score (MGFA PIS) and MG Composite scores were obtained to define the severity of disease and clinical outcome. In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive. In those who received immunosuppressives and provided the clinical scores (84 patients), 50 (60%) had favorable outcome (MGFA PIS categories of complete stable remission, pharmacological remission and minimal manifestations) at the end of 3 years. Use of prednisone + azathioprine had significantly positive effect on outcome. The presence of anti-titin antibodies had no significant effect on severity and outcome. Five anti-MuSK-positive patients had favorable outcome. In conclusion, the presence of neither anti-titin nor anti-MuSK antibodies points to unfavorable outcome. Prednisone and azathioprine combination has beneficial effects in non-thymomatous generalized LOMG.
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Affiliation(s)
- Senay Yildiz Celik
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - Hacer Durmus
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Vuslat Yilmaz
- Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Yesim Gulsen Parman
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Feza Deymeer
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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14
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Nguyen-Cao TM, Gelinas D, Griffin R, Mondou E. Myasthenia gravis: Historical achievements and the "golden age" of clinical trials. J Neurol Sci 2019; 406:116428. [PMID: 31574325 DOI: 10.1016/j.jns.2019.116428] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/17/2019] [Accepted: 08/14/2019] [Indexed: 02/07/2023]
Abstract
Since the death of Chief Opechankanough >350 years ago, the myasthenia gravis (MG) community has gained extensive knowledge about MG and how to treat it. This review highlights key milestones in the history of treatment and discusses the current "golden age" of clinical trials. Although originally thought by many clinicians to be a disorder of hysteria and fluctuating weakness without observable cause, MG is one the most understood autoimmune neurologic disorders. However, studying it in clinical trials has been challenging due to the fluctuating nature of the medical condition which impacts MG clinical outcomes. Clinical trials must also account for the possibility of a placebo effect. Because MG is a rare incurable autoimmune disorder, it limits the number of potential patients available to participate in clinical trials. In the last 15 years, however, significant progress has been made with MG randomized clinical trials, resulting in a new drug (eculizumab) for physicians' treatment repertoire and an old technique (thymectomy) confirmed effective for MG. Some of the therapies (eg, thymectomy, corticosteroids, plasma exchange, and intravenous immunoglobulin [IVIg]) have survived the test of time. Others (eg, eculizumab and neonatal Fc receptor inhibitor) are novel and hold promise.
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Affiliation(s)
- Tam M Nguyen-Cao
- Scientific and Medical Affairs, Grifols, 79 TW Alexander Drive 4101 Research Commons, Research Triangle Park, NC 27709, USA.
| | - Deborah Gelinas
- Scientific and Medical Affairs, Grifols, 79 TW Alexander Drive 4101 Research Commons, Research Triangle Park, NC 27709, USA.
| | - Rhonda Griffin
- Grifols Bioscience Research Group, Grifols, 79 TW Alexander Drive 4201 Research Commons, Research Triangle Park, NC 27709, USA.
| | - Elsa Mondou
- Grifols Bioscience Research Group, Grifols, 79 TW Alexander Drive 4201 Research Commons, Research Triangle Park, NC 27709, USA.
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15
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Abstract
Myasthenia gravis (MG) is an immune-mediated disease of the neuromuscular junction mediated by anti-acetylcholine receptor (AChR) antibodies (Ab). Granulomatous Myositis (GrM) is a histological diagnosis characterized by the presence of epithelioid granuloma in striated muscles. Few cases describing the presence of concomitant thymoma and non-thymoma-related MG with GrM have been reported. This present case is an addition to the literature describing the presence of concomitant thymoma and non-thymoma-related MG with GrM. The patient described is a 77-year-old male who started developing weakness and atrophy involving the musculature of the bilateral lower and upper extremities. Initial laboratory workup showed an elevated level of serum creatine phosphokinase (CPK) of 1,231 U/ L (reference range: 22 to 198 U/L). The right quadriceps muscle biopsy performed showed inflammatory infiltrates containing eosinophils, plasma cells, and lymphocytes forming multinucleate giant cells consistent with a diagnosis of GrM. Detailed laboratory and imaging work conducted to rule out an underlying cause of GrM showed elevated titers of AChR Ab (79.50 nmol/L, reference range: <0.02 nmol/L) and striational Ab (titer: 1:320, reference range < 1:120). A positive repetitive nerve stimulation test for the left ulnar nerve (decrement in the amplitude of muscle action potential by 13%) further confirmed the diagnosis of MG concomitant with GrM. Computed tomography of the chest was negative for the presence of a thymoma. The patient was started on treatment with oral prednisone and mycophenolate mofetil, which resulted in an improvement of symptoms and the downward trending of serum CPK level.
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Affiliation(s)
- Shumaila M Iqbal
- Internal Medicine, University at Buffalo / Sisters of Charity Hospital, Buffalo, USA
| | - Linda Burns
- Rheumatology, Buffalo Rheumatology, Buffalo, USA
| | - Cassandra Zhi
- Internal Medicine, Drexel University College of Medicine, Philadelphia, USA
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16
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Paraneoplastic and Therapy-Related Immune Complications in Thymic Malignancies. Curr Treat Options Oncol 2019; 20:62. [DOI: 10.1007/s11864-019-0661-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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17
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Salem S, Saad I, Alamri R. Thymoma associated myasthenia gravis with atypical presentation of lipomatous tongue atrophy: a case report. Pan Afr Med J 2019; 32:38. [PMID: 31143343 PMCID: PMC6522161 DOI: 10.11604/pamj.2019.32.38.17768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 01/15/2019] [Indexed: 11/20/2022] Open
Abstract
A 28-year-old female patient came to the outpatient dental clinic for multiple teeth extractions and full mouth rehabilitation suffer from myasthenia gravis (MG) primary presentation as tongue atrophy and facial muscles weakness and the symptoms became worries, the patient unable to speak as well and change her voice and complaining of dysphagia and dysarthria. Oral symptoms, treatment schedule and protocol, the selection, prescription and impacts of medications, and prevention of myasthenic crisis are all important; aspects should be considered by dentists and oral health care providers. Weakness of facial and oropharyngeal muscle is considered very popular at disease onset and therefore oral health providers are often the first medical professionals to observe these patients. Myasthenic patients seek particular approach and consultation in order to ensure ideal and proper dental management.
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Affiliation(s)
- Suzan Salem
- Qassim University, College of Dentistry, Department of Oral Surgery, Maxillofacial and Diagnostic Science, Kingdom of Saudi Arabia
| | - Islam Saad
- Qassim University, College of Dentistry, Periodontology and Oral Medicine, Kingdom of Saudi Arabia
| | - Rana Alamri
- Saudi Board of Orthodontic, Kingdom of Saudi Arabia
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18
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Usmani A, Kwan L, Wahib-Khalil D, Trivedi J, Nations S, Sarode R. Excellent response to therapeutic plasma exchange in myasthenia gravis patients irrespective of antibody status. J Clin Apher 2019; 34:416-422. [DOI: 10.1002/jca.21694] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/30/2018] [Accepted: 12/03/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Amena Usmani
- Department of Pathology; University of Texas Southwestern Medical Center; Dallas Texas
| | - Laura Kwan
- Department of Pathology; University of Texas Southwestern Medical Center; Dallas Texas
| | - Dina Wahib-Khalil
- Department of Pathology; University of Texas Southwestern Medical Center; Dallas Texas
| | - Jaya Trivedi
- Department of Neurology; University of Texas Southwestern Medical Center; Dallas Texas
| | - Sharon Nations
- Department of Neurology; University of Texas Southwestern Medical Center; Dallas Texas
| | - Ravi Sarode
- Department of Pathology; University of Texas Southwestern Medical Center; Dallas Texas
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19
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Abstract
OBJECTIVE To evaluate transcervical and transsternal thymectomy benefits in large myasthenia gravis (MG) cohort. METHOD We retrospectively evaluated MG patients (n = 184) who had undergone thymectomy between 2004 and 2015 at National Institute of Mental Health and Neurosciences, Bangalore (India). Myasthenia gravis foundation of America guidelines were followed to assess clinical outcome. Anti-acetylcholine receptors (AChR) antibodies, repetitive nerve stimulation (RNS) and Neostigmine tests were performed at pre and post-thymectomy stage. RESULTS Most of the patients were fell under MG grade IIA (82 of 184, 44.56%) and grade IIB (61 of 184, 33.15%). Thymoma and thymic hyperplasia was established in 64 (34.78%) and 89 (48.37%) patients respectively. Other thymic abnormalities such thymic atrophy, cysts and lipoma were established in 31 (16.85%) patients. MG patients were treated either with transcervical (n = 79) or (n = 105) transsternal thymectomy. At the pre-thymectomy stage, the majority of the patients were positive for anti-AChR antibodies (179 of 184, 97.28%), RNS (170 of 184, 92.4%), and Neostigmine (175 of 184, 95.11%). At the post-thymectomy stage, a significant reduction observed in anti-AChR antibodies positivity (p < 0.022) and RNS positivity (p < 0.015). Overall, benefits were observed in 61.41% (113 of 184) of patients. Clinical benefits (complete stable remission, pharmacological remission, minimal manifestation, and improvement) of transcervical and transsternal thymectomy observed in 69.62% (55 of 79) and 55.24% (58 of 105) of patients respectively. MG patients with thymoma showed the least improvement compared to thymic hyperplasia. DISCUSSION Transcervical and transsternal thymectomy showed clinical benefits, however, there was no significant difference between them.
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Affiliation(s)
- Suresh C Bokoliya
- a Department of Neuromicrobiology , National Institute of Mental Health and Neurosciences , Bangalore , India
| | - Shripad A Patil
- a Department of Neuromicrobiology , National Institute of Mental Health and Neurosciences , Bangalore , India
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20
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Abstract
Acquired Myasthenia Gravis (MG) is a neuromuscular disease caused by autoantibodies against components of the neuromuscular junction. It is a prototype organ-specific autoimmune disease with well-defined antigenic targets mainly the nicotinic acetylcholine receptor (AChR). Patients suffer from fluctuating, fatigable muscle weakness that worsens with activity and improves with rest. Various therapeutic strategies have been used over the years to alleviate MG symptoms. These strategies aim at improving the transmission of the nerve impulse to muscle or at lowering the immune system with steroids or immunosuppressant drugs. Nevertheless, MG remains a chronic disease and symptoms tend to persist in many patients, some being or becoming refractory over time. In this review, based on recent experimental data on MG or based on results from clinical trials for other autoimmune diseases, we explore new potential therapeutic approaches for MG patients, going from non-specific approaches with the use of stem cells with their anti-inflammatory and immunosuppressive properties to targeted therapies using monoclonal antibodies specific for cell-surface antigens or circulating molecules.
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Affiliation(s)
- Anthony Behin
- APHP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile-de-France, Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.,AIM, Institut de Myologie, Paris, France
| | - Rozen Le Panse
- INSERM U974, Paris, France.,UPMC Sorbonne Université, Paris, France.,AIM, Institut de Myologie, Paris, France
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21
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Romi F, Hong Y, Gilhus NE. Pathophysiology and immunological profile of myasthenia gravis and its subgroups. Curr Opin Immunol 2017; 49:9-13. [PMID: 28780294 DOI: 10.1016/j.coi.2017.07.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 07/07/2017] [Indexed: 01/11/2023]
Abstract
Myasthenia gravis (MG) is an autoimmune antibody-mediated disease characterized by muscle weakness and fatigability. It is believed that the initial steps triggering humoral immunity in MG take place inside thymic tissue and thymoma. The immune response against one or several epitopes expressed on thymic tissue cells spills over to neuromuscular junction components sharing the same epitope causing humoral autoimmunity and antibody production. The main cause of MG is acetylcholine receptor antibodies. However, many other neuromuscular junction membrane protein targets, intracellular and extracellular proteins are suggested to participate in MG pathophysiology. MG should be divided into subgroups based on clinical presentation and immunology. This includes onset age, clinical characteristics, thymic pathology and antibody profile. The immunological profile of these subgroups is determined by the antibodies present.
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Affiliation(s)
- Fredrik Romi
- Department of Neurology, Haukeland University Hospital, Norway.
| | - Yu Hong
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Nils Erik Gilhus
- Department of Neurology, Haukeland University Hospital, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway
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22
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Xue L, Wang L, Dong J, Yuan Y, Fan H, Zhang Y, Wang Q, Ding J. Risk factors of myasthenic crisis after thymectomy for thymoma patients with myasthenia gravis†. Eur J Cardiothorac Surg 2017; 52:692-697. [DOI: 10.1093/ejcts/ezx163] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 04/25/2017] [Indexed: 11/14/2022] Open
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23
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Cordts I, Bodart N, Hartmann K, Karagiorgou K, Tzartos JS, Mei L, Reimann J, Van Damme P, Rivner MH, Vigneron A, Weis J, Schulz JB, Tzartos SJ, Claeys KG. Screening for lipoprotein receptor-related protein 4-, agrin-, and titin-antibodies and exploring the autoimmune spectrum in myasthenia gravis. J Neurol 2017; 264:1193-1203. [DOI: 10.1007/s00415-017-8514-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/24/2017] [Accepted: 05/08/2017] [Indexed: 01/09/2023]
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24
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Grisold W, Grisold A, Löscher WN. Neuromuscular complications in cancer. J Neurol Sci 2016; 367:184-202. [PMID: 27423586 DOI: 10.1016/j.jns.2016.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 05/08/2016] [Accepted: 06/01/2016] [Indexed: 12/11/2022]
Abstract
Cancer is becoming a treatable and even often curable disease. The neuromuscular system can be affected by direct tumor invasion or metastasis, neuroendocrine, metabolic, dysimmune/inflammatory, infections and toxic as well as paraneoplastic conditions. Due to the nature of cancer treatment, which frequently is based on a DNA damaging mechanism, treatment related toxic side effects are frequent and the correct identification of the causative mechanism is necessary to initiate the proper treatment. The peripheral nervous system is conventionally divided into nerve roots, the proximal nerves and plexus, the peripheral nerves (mono- and polyneuropathies), the site of neuromuscular transmission and muscle. This review is based on the anatomic distribution of the peripheral nervous system, divided into cranial nerves (CN), motor neuron (MND), nerve roots, plexus, peripheral nerve, the neuromuscular junction and muscle. The various etiologies of neuromuscular complications - neoplastic, surgical and mechanic, toxic, metabolic, endocrine, and paraneoplastic/immune - are discussed separately for each part of the peripheral nervous system.
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Affiliation(s)
- W Grisold
- Department of Neurology, Kaiser Franz Josef Hospital, Vienna, Austria.
| | - A Grisold
- Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - W N Löscher
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Stergiou C, Lazaridis K, Zouvelou V, Tzartos J, Mantegazza R, Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, Brenner T, Vaknin A, Berrih-Aknin S, Behin A, Sharshar T, De Baets M, Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, Maniaol A, Gilhus NE, Casasnovas Pons C, Pitha J, Jakubíkova M, Hanisch F, Bogomolovas J, Labeit D, Labeit S, Tzartos SJ. Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen. J Neuroimmunol 2016; 292:108-15. [PMID: 26943968 DOI: 10.1016/j.jneuroim.2016.01.018] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 01/25/2016] [Indexed: 12/11/2022]
Abstract
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.
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Affiliation(s)
- C Stergiou
- Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece
| | | | - V Zouvelou
- Neurology Department, Aeginition Hospital, Athens, Greece
| | - J Tzartos
- Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece
| | - R Mantegazza
- Neurological Institute "C. Besta", Milano, Italy
| | - C Antozzi
- Neurological Institute "C. Besta", Milano, Italy
| | - F Andreetta
- Neurological Institute "C. Besta", Milano, Italy
| | - A Evoli
- Institute of Neurology, Catholic University, Rome, Italy
| | - F Deymeer
- Istanbul University, Istanbul, Turkey
| | | | - H Durmus
- Istanbul University, Istanbul, Turkey
| | - T Brenner
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - A Vaknin
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - A Behin
- UPMC and INSERM, Paris, France
| | - T Sharshar
- Raymond Poincaré Hospital, Garches, France
| | - M De Baets
- School for Mental Health and Neuroscience, Maastricht University, The Netherlands
| | - M Losen
- School for Mental Health and Neuroscience, Maastricht University, The Netherlands
| | - P Martinez-Martinez
- School for Mental Health and Neuroscience, Maastricht University, The Netherlands
| | - K A Kleopa
- The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | | | - T Kyriakides
- The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | | | - P Szczudlik
- Department of Neurology, Medical University of Warsaw, Poland
| | - B Szyluk
- Department of Neurology, Medical University of Warsaw, Poland
| | - D Lavrnic
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - I Basta
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - S Peric
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - C Tallaksen
- Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway; Faculty of Medicine, Olso University, Norway
| | - A Maniaol
- Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway
| | - N E Gilhus
- Department of Clinical Medicine, University of Bergen, Norway
| | | | - J Pitha
- Department of Neurology and Clinical Neuroscience Center, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic
| | - M Jakubíkova
- Department of Neurology and Clinical Neuroscience Center, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic
| | - F Hanisch
- Universitätsklinikum Halle, Halle, Germany
| | - J Bogomolovas
- Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany
| | - D Labeit
- Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany; Myomedix GmbH, 69151 Neckargemuend, Germany
| | - S Labeit
- Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany
| | - S J Tzartos
- Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece.
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Kumar R. Myasthenia gravis and thymic neoplasms: A brief review. World J Clin Cases 2015; 3:980-983. [PMID: 26677446 PMCID: PMC4677085 DOI: 10.12998/wjcc.v3.i12.980] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 07/09/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
Thymoma is the most common mediastinal tumor. They have varied presentation ranging from asymptomatic incidental mediastinal masses to locally extensive tumor with compressive symptoms and distant metastases. They have frequent association with various paraneoplastic syndromes (PNS). The most common PNS associated with thymoma is myasthenia gravis (MG). Patients of thymoma with MG have a favourable outcome due to early disclosure of the disease. Histologically they are classified into five subtypes and Masaoka-Koga staging system is used for staging. Surgery, chemotherapy and radiotherapy play an important role along with anti-myasthenia drugs. This review would like to highlight the association of thymoma with MG and associated clinical and therapeutic issues.
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Wang Z, Chen Y, Xu S, Yang Y, Wei D, Wang W, Huang X. Aberrant decrease of microRNA19b regulates TSLP expression and contributes to Th17 cells development in myasthenia gravis related thymomas. J Neuroimmunol 2015; 288:34-9. [PMID: 26531692 DOI: 10.1016/j.jneuroim.2015.08.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 08/11/2015] [Accepted: 08/19/2015] [Indexed: 12/24/2022]
Abstract
Myasthenia gravis (MG) is an organ-specific autoimmune disease. The imbalance of T helper type 17 cells (Th17) plays a key role in the pathogenesis of thymomatous MG. But the regulatory mechanism for Th17 cell development in MG-related thymoma remains undefined. Here we demonstrated that thymic stromal lymphopoietin (TSLP) is significantly decreased in thymomas. We also proved that TSLP was post-trancriptionally regulated by microRNA-19b. The expression of microRNA-19b was negatively correlated with the expression of TSLP mRNA and protein in thymomas. This study indicated that the elevation of microRNA-19b suppressed TSLP expression and then influenced T cell development in thymomatous MG.
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Affiliation(s)
- Zhongkui Wang
- Department of Neurology, Chinese PLA General Hospital, Beijing 100853, China; Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Yuping Chen
- Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Shengjie Xu
- Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Yanhua Yang
- Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Dongning Wei
- Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Wei Wang
- Department of Neurology, The 309th Hospital of Chinese PLA, Beijing 100091, China
| | - Xusheng Huang
- Department of Neurology, Chinese PLA General Hospital, Beijing 100853, China
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Szczudlik P, Szyluk B, Lipowska M, Ryniewicz B, Kubiszewska J, Dutkiewicz M, Gilhus NE, Kostera-Pruszczyk A. Antititin antibody in early- and late-onset myasthenia gravis. Acta Neurol Scand 2014; 130:229-33. [PMID: 24947881 DOI: 10.1111/ane.12271] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2014] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against neuromuscular junction proteins, 85% of patients have antibodies against acetylcholine receptor (AChR-MG). Antititin antibodies are present in a subset of patients with MG. We aimed to determine the value of antititin antibodies as severity markers and thymoma predictors in early- and late-onset MG. MATERIALS & METHODS Two-hundred and ninety-five consecutive MG patients (188 F and 107 M) aged 12-89 years (mean 50y) were included. 164 patients had early-onset (EOMG, ≤50 years of age), 131 had late-onset MG (LOMG). Twenty-six patients had thymoma. symptoms, severity graded with MGFA scale, thymus histology, medications, and treatment results were analyzed. RESULTS Antititin antibodies were present in 81 (27%) of all patients: 54% of thymoma MG, 0.6% of non-thymomatous EOMG, and 55% of LOMG, with proportion of titin-positive patients increasing linearly from 40% in the 6th to 88% in the 9th decade of life. Titin-positive patients had more bulbar symptoms (P = 0.003). Severity of MG, need for immunosuppression, myasthenic crisis risk or treatment results were not related to its presence. Antititin antibodies had 56% sensitivity, 99% specificity, 90% positive predictive value (PPV), and 95% negative predictive value (NPV) for thymoma diagnosis in EOMG, and 50% sensitivity, 75% specificity, 71% PPV and 55% NPV in LOMG. CONCLUSIONS Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort.
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Affiliation(s)
- P. Szczudlik
- Department of Neurology; Medical University of Warsaw; Warsaw Poland
| | - B. Szyluk
- Department of Neurology; Medical University of Warsaw; Warsaw Poland
| | - M. Lipowska
- Department of Neurology; Medical University of Warsaw; Warsaw Poland
| | - B. Ryniewicz
- Department of Neurology; Medical University of Warsaw; Warsaw Poland
| | - J. Kubiszewska
- Department of Neurology; Medical University of Warsaw; Warsaw Poland
| | - M. Dutkiewicz
- Department of Immunology, Biochemistry and Nutrition; Medical University of Warsaw; Warsaw Poland
| | - N. E. Gilhus
- Department of Neurology; Haukeland University Hospital; Bergen Norway
- Department of Clinical Medicine; University of Bergen; Bergen Norway
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Wu H, She S, Liu Y, Xiong W, Guo Y, Fang H, Chen H, Li J. Protective effect of Sijunzi decoction on neuromuscular junction ultrastructure in autoimmune myasthenia gravis rats. J TRADIT CHIN MED 2014; 33:669-73. [PMID: 24660594 DOI: 10.1016/s0254-6272(14)60040-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To investigate the protective role of Sijunzi decoction in neuromuscular junction (NMJ) and muscle cell mitochondria ultrastructure; as well as its effects on the amount of adenosine triphosphate (ATP) and the activities of mitochondrial respiratory chain complexes I, II, III, and IV in autoimmune myasthenia gravis rats. METHODS An experimental autoimmune myasthenia gravis (EAMG) rat model was established by inoculating rats with acetylcholine receptors extracted from Torpedo. Rats were divided into three groups: model, prednisone, and Sijunzi decoction, and were fed physiological saline, prednisone, or Sijunzi decoction, respectively. NMJ and muscle cell mitochondria ultrastructure were observed by transmission electron microscope. The amount of ATP was assessed by high performance liquid chromatography. The activities of mitochondrial respiratory chain complexes I, II, III, and IV was determined using the Clark oxygen electrode method. RESULTS In the model group, there were sparse muscle fibers, with decreased mitochondria, and sparse, diffluent, or absent NMJ folds. After intervention with Sijunzi decoction, the above pathology changes were improved: muscle fiber structure was clear and complete; the mitochondria count was higher; and the NMJ structure was close to normal. Gastrocnemius muscle mitochondria in the model group produced significantly less ATP than those in the prednisone group (P < 0.01). Conversely, the ATP of Sijunzi decoction group was significantly higher than prednisone group (P < 0.01). The activities of gastrocnemius muscle mitochondrial respiratory chain complexes I, II, III, and IV in both the prednisone and Sijunzi decoction groups was dramatically higher compared with the model group (P < 0.05). The activities of complexes I and III in the Sijunzi decoction group were significantly higher than those in the prednisone group (P < 0.05), but there was no obvious difference in complex II or IV activities between the two groups (P > 0.05). CONCLUSION Sijunzi decoction improved pathological changes in muscle mitochondria and NMJ, enhanced the amount of ATP in gastrocnemius muscle mitochondria, and improved the activities of respiratory chain complexes I, II, III, and IV (especially I and III) of the EAMG rats.
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Alkhawajah NM, Oger J. Late-onset myasthenia gravis: A review when incidence in older adults keeps increasing. Muscle Nerve 2013; 48:705-10. [DOI: 10.1002/mus.23964] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2013] [Indexed: 01/26/2023]
Affiliation(s)
- Nuha M. Alkhawajah
- Division of Neurology, Department of Medicine and Brain Research Centre, UBC Hospital; University of British Columbia; 2211 Westbrook Mall Vancouver British Columbia V6T 2B5 Canada
| | - Joel Oger
- Division of Neurology, Department of Medicine and Brain Research Centre, UBC Hospital; University of British Columbia; 2211 Westbrook Mall Vancouver British Columbia V6T 2B5 Canada
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Berrih-Aknin S, Le Panse R. [Myasthenia gravis and autoantibodies: Pathophysiology of the different subtypes]. Rev Med Interne 2013; 35:413-20. [PMID: 24156976 DOI: 10.1016/j.revmed.2013.09.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 09/23/2013] [Indexed: 10/26/2022]
Abstract
Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are directed against the acetylcholine receptor (AChR). Recently, other targets have been described, such as muscle-specific kinase protein (MuSK) or lipoprotein related protein 4 (LRP4). The origin of the autoimmune response is not known, but thymic abnormalities and defects in immune regulation certainly play a major role in patients with anti-AChR antibodies. Genetic predisposition probably influences the occurrence of the disease. Sex hormones seem to play a role in the early form of the disease. Muscle weakness is fluctuating and worsens with exercise. Myasthenia gravis could be classified according to the location of the affected muscles (ocular versus generalized), the age of onset of symptoms, thymic abnormalities and profile of autoantibodies. These criteria are used to optimize the management and treatment of patients. In this review, we analyze the latest concepts of the pathophysiology of myasthenia gravis according to the different subgroups of the disease, including a description of the role of immunological, genetic and environmental factors. The potential viral hypothesis of this disease is discussed. Finally, we also discuss the biological assays available to validate the diagnosis.
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Affiliation(s)
- S Berrih-Aknin
- Unité mixte de recherche (UMR), CNRS UMR7215/Inserm U974/UPMC UM76/AIM, thérapie des maladies du muscle strié, groupe hospitalier Pitié-Salpêtrière, 105, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
| | - R Le Panse
- Unité mixte de recherche (UMR), CNRS UMR7215/Inserm U974/UPMC UM76/AIM, thérapie des maladies du muscle strié, groupe hospitalier Pitié-Salpêtrière, 105, boulevard de l'Hôpital, 75651 Paris cedex 13, France
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Decroos EC, Hobson-Webb LD, Juel VC, Massey JM, Sanders DB. Do acetylcholine receptor and striated muscle antibodies predict the presence of thymoma in patients with myasthenia gravis? Muscle Nerve 2013; 49:30-4. [DOI: 10.1002/mus.23882] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2013] [Indexed: 11/10/2022]
Affiliation(s)
- Emily Choi Decroos
- Neuromuscular Section, Division of Neurology, Department of Medicine; Duke University Medical Center; DUMC 3403 Durham North Carolina 27710 USA
| | - Lisa D. Hobson-Webb
- Neuromuscular Section, Division of Neurology, Department of Medicine; Duke University Medical Center; DUMC 3403 Durham North Carolina 27710 USA
| | - Vern C. Juel
- Neuromuscular Section, Division of Neurology, Department of Medicine; Duke University Medical Center; DUMC 3403 Durham North Carolina 27710 USA
| | - Janice M. Massey
- Neuromuscular Section, Division of Neurology, Department of Medicine; Duke University Medical Center; DUMC 3403 Durham North Carolina 27710 USA
| | - Donald B. Sanders
- Neuromuscular Section, Division of Neurology, Department of Medicine; Duke University Medical Center; DUMC 3403 Durham North Carolina 27710 USA
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Berrih-Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev 2013; 12:885-93. [DOI: 10.1016/j.autrev.2013.03.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2013] [Indexed: 12/19/2022]
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Abstract
OBJECTIVES To find the characteristic phenotypes of 3 different types of myasthenia gravis (MG). METHODS The clinical and electrophysiological features among 15 cases of muscle-specific kinase antibody positive (MuSK Ab+) MG, 59 cases of double seronegative (DSN) MG, and 161 cases of acetylcholine receptor antibody (AChR Ab)+ MG in the University of Alabama at Birmingham were compared. RESULTS AChR Ab was positive in 69% of cases and MuSK Ab in 6% of cases. MuSK Ab+ MG was more common (14%) in African Americans compared with whites (4%). AChR Ab+ MG is characterized by male predominance, later onset, a fewer cases of ocular MG, and a higher association with thymoma. DSN-MG is characterized by a greater prevalence of ocular MG, milder forms of MG with less number of crisis, and fewer abnormalities in the repetitive nerve stimulation test. MuSK Ab+ MG is characterized by younger age at onset, severe and bulbar forms of MG, predominant faciobulbar neck weakness, and a poor response to edrophonium, anticholinesterase, and intravenous immunoglobulin. Long-term outcome showed no difference among 3 types of MG. CONCLUSIONS AChR Ab+ MG and DSN-MG are similar, with the exception of less severity in the latter. MuSK Ab+ MG has distinct clinical and electrophysiological features.
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Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmun Rev 2013; 12:924-30. [PMID: 23537507 DOI: 10.1016/j.autrev.2013.03.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2013] [Indexed: 10/27/2022]
Abstract
Myasthenia gravis (MG) is the most common immune-mediated disorder of the neuromuscular junction with a prevalence of 200-300/million population and its study has established paradigms for exploring other antibody-mediated diseases. Most MG patients (~85%) have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 6% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). Until recently no autoantibodies could be detected in the remaining patients (seronegative MG). Probably, the most sensitive assays for the detection of the autoantibodies in MG sera have been the radioimmunoprecipitation assays (RIPA) for both types of MG. However, with recent novel methods, not yet used routinely, it has been shown that the "seronegative" MG group includes patients with low levels of autoantibodies or of low affinity, against the known autoantigens, or even with antibodies to recently identified autoantigens. Since MG is heterogeneous in terms of pathophysiology, depending on the autoantigen targeted and on other factors (e.g. presence of thymoma), the serological tests are crucial in verifying the initial clinical diagnosis, whereas frequent measurement of autoantibody levels is important in monitoring the course of the disease and the efficacy of treatment. In addition, in AChR-MG, autoantibodies against the muscle proteins titin and ryanodin receptor have been identified; these antibodies are useful for the classification of MG, indicating the concomitant presence of thymoma, and as prognostic markers.
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Santoro F, Russo AR, Lupo P, De Gennaro L, Gianfrancesco D, Biase MD, Brunetti ND. Paraaortic Thymoma with Pericardial Effusion Diagnosed by Transthoracic Echocardiography in a Woman with Myasthenia Gravis. Echocardiography 2013; 30:E141-2. [DOI: 10.1111/echo.12108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Affiliation(s)
| | | | - Pierluigi Lupo
- Radiology Department; University of Foggia; Foggia; Italy
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Gressner AM, Arndt T. A. LEXIKON DER MEDIZINISCHEN LABORATORIUMSDIAGNOSTIK 2013. [PMCID: PMC7123472 DOI: 10.1007/978-3-642-12921-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol 2012; 8:427-38. [PMID: 22882218 DOI: 10.1586/eci.12.34] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. A number of molecules, including ion channels and other proteins at the neuromuscular junction, may be targeted by autoantibodies leading to abnormal neuromuscular transmission. In approximately 85% of patients, autoantibodies, directed against the postsynaptic nicotinic acetylcholine receptor can be detected in the serum and confirm the diagnosis, but in general, do not precisely predict the degree of weakness or response to therapy. Antibodies to the muscle-specific tyrosine kinase are detected in approximately 50% of generalized myasthenia gravis patients who are seronegative for anti-acetylcholine receptor antibodies, and levels of anti-muscle-specific tyrosine kinase antibodies do appear to correlate with disease severity and treatment response. Antibodies to other muscle antigens may be found in the subsets of myasthenia gravis patients, potentially providing clinically useful diagnostic information, but their utility as relevant biomarkers (measures of disease state or response to treatment) is currently unclear.
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Affiliation(s)
- Matthew N Meriggioli
- Department of Neurology and Rehabilitation, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA.
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Gradolatto A, Nazzal D, Foti M, Bismuth J, Truffault F, Panse RL, Berrih-Aknin S. Defects of immunoregulatory mechanisms in myasthenia gravis: role of IL-17. Ann N Y Acad Sci 2012; 1274:40-7. [DOI: 10.1111/j.1749-6632.2012.06791.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Maniaol AH, Elsais A, Lorentzen ÅR, Owe JF, Viken MK, Sæther H, Flåm ST, Bråthen G, Kampman MT, Midgard R, Christensen M, Rognerud A, Kerty E, Gilhus NE, Tallaksen CME, Lie BA, Harbo HF. Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLoS One 2012; 7:e36603. [PMID: 22590574 PMCID: PMC3348874 DOI: 10.1371/journal.pone.0036603] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/03/2012] [Indexed: 11/18/2022] Open
Abstract
Background Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. Methodology/Principal Findings This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described. No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. Conclusion The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
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Affiliation(s)
- Angelina H Maniaol
- Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.
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Canalopathies auto-immunes. Rev Med Interne 2011; 32:742-50. [DOI: 10.1016/j.revmed.2011.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2010] [Revised: 02/24/2011] [Accepted: 04/09/2011] [Indexed: 01/18/2023]
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Romi F. Thymoma in myasthenia gravis: from diagnosis to treatment. Autoimmune Dis 2011; 2011:474512. [PMID: 21860784 PMCID: PMC3155972 DOI: 10.4061/2011/474512] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 06/24/2011] [Indexed: 12/28/2022] Open
Abstract
One half of cortical thymoma patients develop myasthenia gravis (MG), while 15% of MG patients have thymomas. MG is a neuromuscular junction disease caused in 85% of the cases by acetylcholine receptor (AChR) antibodies. Titin and ryanodine receptor (RyR) antibodies are found in 95% of thymoma MG and 50% of late-onset MG (MG onset ≥50 years), are associated with severe disease, and may predict thymoma MG outcome. Nonlimb symptom profile at MG onset with bulbar, ocular, neck, and respiratory symptoms should raise the suspicion about the presence of thymoma in MG. The presence of titin and RyR antibodies in an MG patient younger than 60 years strongly suggests a thymoma, while their absence at any age strongly excludes thymoma. Thymoma should be removed surgically. Prethymectomy plasmapheresis/iv-IgG should be considered before thymectomy. The pharmacological treatment does not differ from nonthymoma MG, except for tacrolimus which is an option in difficult thymoma and nonthymoma MG cases with RyR antibodies.
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Affiliation(s)
- Fredrik Romi
- Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
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Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Grisold W, Honnorat J, Sillevis Smitt PAE, Tanasescu R, Vedeler CA, Voltz R, Verschuuren JJGM, European Federation of Neurological Societies. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011; 18:19-e3. [PMID: 20880069 PMCID: PMC3086523 DOI: 10.1111/j.1468-1331.2010.03220.x] [Citation(s) in RCA: 327] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. OBJECTIVES an overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. METHODS many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A-C were possible, but good practice points were agreed by consensus. RECOMMENDATIONS the nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3-6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.
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Affiliation(s)
- M J Titulaer
- Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
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Abstract
The diagnostic use of antibodies is dependent on sensitivity and specificity of the methods of antibody detection, which have been developed and improved over the years. Here, we review the different methods for the detection of acetylcholine receptor and muscle-specific kinase antibodies, which are, so far, the only antibodies recognised as pathogenic in myasthenia gravis (MG). Seronegative MG patients will benefit from more sensitive methods of antibody detection. The most recent developments in antibody detection assays, particularly those based on cells expressing target antigens, allow rapid and reliable identification of autoantibodies, improving the diagnosis and treatment of MG patients. The same approaches to antibody detection are now being applied to a wide range of other autoantigens and other autoimmune diseases.
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Affiliation(s)
- M Isabel Leite
- Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, West Wing OX3 9DS, UK
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Vrolix K, Fraussen J, Molenaar PC, Losen M, Somers V, Stinissen P, De Baets MH, Martínez-Martínez P. The auto-antigen repertoire in myasthenia gravis. Autoimmunity 2010; 43:380-400. [PMID: 20380581 DOI: 10.3109/08916930903518073] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Myasthenia Gravis (MG) is an antibody-mediated autoimmune disorder affecting the postsynaptic membrane of the neuromuscular junction (NMJ). MG is characterized by an impaired signal transmission between the motor neuron and the skeletal muscle cell, caused by auto-antibodies directed against NMJ proteins. The auto-antibodies target the nicotinic acetylcholine receptor (nAChR) in about 90% of MG patients. In approximately 5% of MG patients, the muscle specific kinase (MuSK) is the auto-antigen. In the remaining 5% of MG patients, however, antibodies against the nAChR or MuSK are not detectable (idiopathic MG, iMG). Although only the anti-nAChR and anti-MuSK auto-antibodies have been demonstrated to be pathogenic, several other antibodies recognizing self-antigens can also be found in MG patients. Various auto-antibodies associated with thymic abnormalities have been reported, as well as many non-MG-specific auto-antibodies. However, their contribution to the cause, pathology and severity of the disease is still poorly understood. Here, we comprehensively review the reported auto-antibodies in MG patients and discuss their role in the pathology of this autoimmune disease.
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Affiliation(s)
- Kathleen Vrolix
- Division of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
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Twork S, Wiesmeth S, Klewer J, Pöhlau D, Kugler J. Quality of life and life circumstances in German myasthenia gravis patients. Health Qual Life Outcomes 2010; 8:129. [PMID: 21070628 PMCID: PMC2994799 DOI: 10.1186/1477-7525-8-129] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 11/11/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Myasthenia gravis (MG) is a chronic neuromuscular disease. Advances in medical therapy have continuously increased the life expectancy of MG patients, without definitively curing the disease. To analyze life circumstances and quality of life (QoL), a large German MG cohort was investigated. METHODS AND SAMPLE In cooperation with the German Myasthenia Association, 2,150 patients with confirmed MG were asked to respond to a mailed questionnaire. The standardized questions related to demographic data, impairments, therapeutic course, use of complementary therapies, illness-related costs, and quality of life (SF-36). In total, 1,518 patients participated, yielding a response rate of 70.6%. The average age was 56.7 years, and the proportion of females 58.6%. RESULTS Despite receiving recommended therapy, many patients still suffered from MG-related impairments. In particular, mobility and mental well-being were reduced; moreover, quality of life was markedly reduced. Stepwise linear regression analysis revealed illness stability, impairments, mental conditions, comorbid diseases, and employment to be determinants of QoL. CONCLUSION Results indicate that despite prolonged life expectancy among MG patients, health-related quality of life is low. This outcome resulted mainly from impaired mobility and depression. Physical and mental well-being might be improved by additional therapy options. Additionally, health care resources could be used more efficiently in these patients.
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Affiliation(s)
- Sabine Twork
- Department of Health Sciences/Public Health, Faculty of Medicine "Carl Gustav Carus" at the University of Technology Dresden, Germany
| | - Susanne Wiesmeth
- Department of Health Sciences/Public Health, Faculty of Medicine "Carl Gustav Carus" at the University of Technology Dresden, Germany
| | - Jörg Klewer
- Department of Health Sciences/Public Health, Faculty of Medicine "Carl Gustav Carus" at the University of Technology Dresden, Germany
| | - Dieter Pöhlau
- Department of Neurology, Kamillus-Hospital, Asbach, Germany
| | - Joachim Kugler
- Department of Health Sciences/Public Health, Faculty of Medicine "Carl Gustav Carus" at the University of Technology Dresden, Germany
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Abstract
Current therapy for myasthenia gravis is directed towards generalized modulation and suppression of the immune system. These approaches have been extensively studied and are effective in many patients with myasthenia, but at the cost of significant adverse effects due to the global effects on the immune system. Future directions in therapy are geared towards focused immunotherapies that aim to improve outcomes while lessening the burden of side effects. This paper reviews both the current accepted treatments for myasthenia gravis as well as promising targeted therapies in development.
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Affiliation(s)
- Hans D Katzberg
- Department of Neurology, Stanford University, Palo Alto, CA, USA
| | - Vera Bril
- University Health Network, University of Toronto, Toronto, Canada
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Barritt AW, Bacsi AM, Tschuchnigg M, Sharpe D, Kiernan MC. Myasthenia gravis seven years after removal of an invasive thymoma. J Clin Neurosci 2009; 16:966-8. [PMID: 19342243 DOI: 10.1016/j.jocn.2008.09.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Revised: 09/10/2008] [Accepted: 09/16/2008] [Indexed: 10/21/2022]
Abstract
This report describes a 59-year-old male who developed myasthenia gravis 92 months following excision of an invasive thymoma, in the absence of tumour recurrence. This report highlights the importance of prolonged clinical surveillance in post-thymectomy patients.
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Affiliation(s)
- Andrew W Barritt
- Medical Eye Unit, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, United Kingdom.
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Affiliation(s)
- G O Skeie
- Department of Neurology, Haukeland University Hospital, Bergen, Norway
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