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Introduction/Aims: The global incidence and prevalence of myasthenia gravis (MG) range between 6–31/million and 10–37/100,000, respectively. Sardinia is a high‐risk region for different immune‐mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)‐immunoglobulin G (IgG) and muscle‐specific tyrosine kinase (MuSK)‐IgG in the district of Sassari (North‐Western Sardinia; population, 325,288). Methods: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK‐IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR‐IgG and/or MuSK‐IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010–December 2019) and prevalence (December 31, 2019) were calculated. Results: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8–39.2)/million, while prevalence was 55.3 (47.7–63.9)/100,000. After age‐standardization to the world population, incidence decreased to 18.4 (14.3–22.5)/million, while prevalence decreased to 31.6 (26.1–37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18–49 (14%), 50–64 (21%), and ≥65 (63%). Discussion: Sardinia is a high‐risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Total thymectomy in addition to medical treatment is an accepted standard therapy for myasthenia gravis (MG). Patients with severe generalized MG present life-threatening events, poor prognosis and higher risk of postoperative myasthenic crisis. The aim of our study is to investigate neurological and surgical results in patients with Myasthenia Gravis Foundation of America (MGFA) class IV and V MG following thymectomy. METHODS Data on 76 MG patients with preoperative MGFA classes IV and V who underwent thymectomy were retrospectively collected. Primary end points included short-term surgical outcomes and long-term neurological results including the achievement of complete stable remission and any improvement as defined by MGFA Post-Intervention Status criteria. RESULTS There were 27 (35.5%) males and 49 (64.5%) females; 53 (69.7%) were classified as MGFA class IV and 23 (30.3%) as class V. Thymectomy was performed through sternotomy in 25 (32.9%) patients, Video-assisted thoracic surgery (VATS) in 5 (6.6%) and Robot-assisted thoracic surgery (RATS) in 46 (60.5%). The median operative time was 120 (interquartile range: 95; 148) min. In-hospital mortality was observed in 1 (1.3%) patient and postoperative complications in 14 (18.4%) patients. The median postoperative hospital stay was 4 (interquartile range: 3; 6) days. Pathological examination revealed 31 (40.8%) thymic hyperplasia/other benign and 45 (59.2%) thymomas. Cumulative complete stable remission and improvement probabilities were 20.6% and 83.7% at 5 years and 66.9% and 97.6% at 10 years, respectively. A significant improvement rate was found in patients with age at the time of thymectomy of ≤50 years (P  = 0.0236), MGFA class V (P  = 0.0154) and acetylcholine receptor antibodies positivity (P  = 0.0152). CONCLUSIONS Thymectomy in patients with severe MG yields good perioperative outcomes and satisfactory long-term neurological improvement, especially for patients younger than 50 years, with MGFA class V and anti-AChR+ MG. [ABSTRACT FROM AUTHOR]

Background: Thymoma‐associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR‐Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR‐Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses. Methods: We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post‐thymectomy status, oncological features and surgical approach. AChR‐Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR‐Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence. Results: The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow‐up time: 4.8 years). The AChR‐Ab titers decreased after first thymectomy (P < 0.001); the decrease was more pronounced in female patients (P = 0.05), in patients diagnosed with MG at an older age (P = 0.003), and in those who had lower MG stage before surgery (P = 0.02) or higher Masaoka‐Koga stage (P = 0.005). The risk of relapse was closely linked with the age of the patient, the Masaoka‐Koga stage and the surgical approach. Conclusions: Presurgery levels of AChR‐Ab or their change after surgery were not associated with thymoma recurrence. The reduction of AChR‐Ab titers after thymectomy confirms an immunological role of thymoma in the pathogenesis of MG. Key points: Significant findings of the study: Young MG patients with an advanced Masaoka staging score of the primary tumor who underwent thymectomy with approaches different from sternotomy and VATS should be monitored for high risk of recurrence.What this study adds: No other study has ever investigated the changes in AChR‐Ab titers before and after thymectomy in a large cohort of TAMG patients. The reduction of AChR‐Ab titers after thymectomy suggests an immunological role of thymoma in the pathogenesis of MG. [ABSTRACT FROM AUTHOR]

Introduction: Epilepsy is significantly more frequent in AD patients than in age-matched controls, even though the true extent of the phenomenon is not clear yet. Areas covered: In this review, we describe in detail the available data on the pharmacological treatment of epilepsy in patients with AD. We also briefly describe general principles of AEDs use in elderly, as well as the potential cognitive profile of AEDs and safety of concomitant psychotropic drugs in patients with epilepsy and AD. Expertcommentary: As some preclinical data suggest a role of epileptiform discharges in cognitive decline in AD, a prompt diagnosis and treatment of seizures in these patients should be pursued. The few data on the use of AEDs in AD patients suggest that newer AEDs (in particular lamotrigine and levetiracetam) might be good choices. Experimental data even support a potential role of some AEDs in modifying the disease course of AD. [ABSTRACT FROM PUBLISHER]

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit ( CHRNA1 ) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit ( CHRNB1 ) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22 , HLA-DQA1/HLA-B , and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis., Competing Interests: Competing interest statement: R.J.B. served as a consultant for NuFactor and Momenta Pharmaceutical and receives research support from PTC Therapeutics, Ra Pharma, Orphazyme, Sanofi Genzyme, FDA OOPD, NIH, and Patient-Centered Outcomes Research Institute (PCORI). M.B. reports grant support from Muscular Dystrophy Association, ALS Association, ALS Recovery Fund, Kimmelman Estate, Target ALS, Eli Lilly and Company, and NIH during the conduct of the study. He also reports grant support from FDA, Centers for Disease Control and Prevention (CDC), and DOD; research support from Alexion Pharmaceuticals, UCB, Cytokinetics, Neuraltus, Biogen, and Orphazyme A/S; and personal fees from NMD Pharma, Ra Pharmaceuticals, Mitsubishi Tanabe, Avexis, UCB, and Denali outside the submitted work. V.C. served as a consultant for review and expert testimony for the Department of Health and Human Services and the Department of Justice under the Vaccine Injury and Compensation Program. Dr. Chaudhry has received a royalty for total neuropathy score (TNS) patented (through Johns Hopkins University) for the license of TNS use from AstraZeneca, Genentech, Seattle Genetics, Calithera Biosciences, Merrimack Pharmaceuticals, Levicept, and Acetylon Pharmaceuticals. M.M.D. serves or recently served as a consultant for Argenx Pharmaceuticals, Catalyst, CSL Behring, Kezar, Momenta, NuFactor, RMS Medical, Sanofi Genzyme, Shire Takeda, and Spark Therapeutics. Dr. Dimachkie received grants from Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, CSL Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association (MDA), NIH, Novartis, Sanofi Genzyme, Octapharma, Orphazyme, Sarepta Therapeutics, Shire Takeda, Spark, UCB Biopharma, Viromed, and TMA. A.E. was a member of the advisory board for Alexion Pharmaceuticals, a scientific award jury member for Grifols, and safety data monitor for UCB. M.F. has received honoraria for serving on advisory boards for Argenx Pharmaceuticals and Alexion Pharmaceuticals. M.F. also has research support from Catalyst, Ra pharma, Amicus, Orphazyme, Alexion Pharmaceuticals, Momenta, and Alnylam. J.F.H. reports research support and grants from Alexion Pharmaceuticals and Argenx Pharmaceuticals, Centers for Disease Control and Prevention, MDA, NIH (including the National Institute of Neurologic Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Disease), PCORI, and Ra Pharmaceuticals (now UCB Biosciences); honoraria from Alexion Pharmaceuticals, Argenx Pharmaceuticals, Immunovant, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from Alexion Pharmaceuticals, Argenx Pharmaceuticals, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia. P.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72 and has received grant funding from the Helsinki University Hospital, Finnish Academy, Sigrid Juselius Foundation, EU Marie Curie action, Biogen Finland, Roche Finland, Merck Finland, Sanofi Genzyme Finland, and Novartis Finland and has made consultations to Alexion Pharmaceuticals, Biogen, Novartis, Orion, Roche, Sanofi Genzyme, Santen, and Teva. H.J.K. is funded by the MDA (508240) and NIH grant U54NS115054; is a consultant for Alnylam Pharmaceuticals, Ra Pharmaceuticals, and UCB Pharmaceuticals; and is CEO of ARC Biotechnology, LLC, which receives support from the NIH (R41NS110331). He serves on the Editorial Board of Experimental Neurology. M.M.M. has received honoraria as a speaker and/or moderator from Alnylam, Akcea, Pfizer, and CSL Behring. She has served on Advisory Boards for Pfizer, Alnylam, and Akcea. She serves as an investigator for clinical trials with Alnylam and Biogen. S.M. has served on advisory board meetings for Alexion Pharmaceuticals and Argenx Pharmaceuticals. M.P. served on the advisory boards for CSL Behring, Alexion Pharmaceuticals, and Argenx Pharmaceuticals and has been a consultant for Momenta Pharmaceuticals. D.P.R. receives research funding from a Sponsored Research Agreement from Cabaletta Bioscience. B.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72 and has received research grants from the Myasthenia Gravis Foundation, the Robert Packard Center for ALS Research, the ALS Association, the Italian Football Federation, the CDC, the MDA, Merck, and Microsoft Research. B.J.T. receives funding through the Intramural Research Program at NIH., (Copyright © 2022 the Author(s). Published by PNAS.)