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Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies. Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begin in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2, have been shown to cause distal myopathy. ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha‐actinin‐2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha‐actinin‐2 is to link actin and titin to the sarcomere Z‐disk. New ACTN2 variants are continuously discovered; however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype–phenotype correlations in ACTN2‐related diseases, actininopathies, persists. Methods: Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies. We assess the genotype–phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results: The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha‐actinin‐2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do form alpha‐actinin‐2 aggregates. Interpretation: The results suggest that alpha‐actinin‐2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein‐extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies. [ABSTRACT FROM AUTHOR]

Introduction/Aims: We developed a patient‐ and physician‐weighted consensus unit called the adverse event unit (AEU) that quantifies and compares adverse event (AE) burden among any group of medications in neurological patients. In this study we evaluated preliminary validity and feasibility of measuring AE burden with the AEU in myasthenia gravis (MG). Methods: This is a single‐center, prospective, 1‐year, observational study of adult MG patients presenting for routine care between April 1, 2021 and March 31, 2022. The MG Activities of Daily Living (MG‐ADL), the 15‐item MG Quality of Life revised (MG‐QOL15r), MG‐Composite, and AEU scores were obtained at all visits. A priori primary feasibility metric was AEU completion rate equal to (within 3.8%, one‐sided 95% confidence interval [CI]) or better than MG‐ADL completion rate. Time to administer AEU and MG‐ADL/MG‐QOL15r, correlation between AEU total score and MG‐QOL15r, and median AEU scores for each MG medication were evaluated. Results: Fifty‐four patients completed 67 study visits; side effects were reported at 75% of the visits. The study met the primary feasibility endpoint; AEU and MG‐ADL were recorded at all visits. Times to administer the AEU (median 5 minutes) and MG‐ADL/MG‐QOL15r were similar. We observed a weak correlation of 0.29 (95% CI 0.03 to 0.51, P =.032) between AEU and MG‐QOL15r scores. Non–statistically significant differences in median AEU scores were observed among MG medications. Discussion: Our data demonstrate preliminary feasibility and validity of using the AEU to measure AE burden in MG. Future studies will compare AE burden among MG treatments and evaluate clinically meaningful AEU scores in MG. See Editorial on pages 1–3 in this issue. [ABSTRACT FROM AUTHOR]

For many years, Neuromuscular Medicine programs lacked a standardized means of handling fellowship applications and offering positions. Programs interviewed applicants and made offers as early as the first half of Post Graduate Year 3 (PGY3), a suboptimal timeline for applicants who may have had little prior exposure to neuromuscular or electrodiagnostic medicine. In 2021, the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) developed the Neuromuscular Fellowship Portal to standardize a later timeline and establish a process for fellowship applications and offers. In its first year, the Neuromuscular Fellowship Portal used a unique one‐way match, in which the portal released serial offers to applicants based on rank order lists submitted by programs. Fifty‐two Neuromuscular Medicine programs and seven electromyography (EMG)‐focused Clinical Neurophysiology programs participated. Sixty‐eight positions were filled, a similar number to previous years. A survey of fellowship directors and applicants following this process showed overwhelming support for the standardized timeline and application portal, but all program directors and most applicants favored moving to a traditional match. To maintain the existing application timeline and minimize costs for all parties, the AANEM Neuromuscular Fellowship Portal will host a two‐way match, based on existing commercial match algorithms, in 2022. A match will afford a fair and efficient process for all involved. Both Neuromuscular Medicine and EMG‐focused Clinical Neurophysiology programs will be encouraged to participate. The process undertaken by the AANEM can stand as an example for other neurologic subspecialties who are interested in standardizing their application timeline. [ABSTRACT FROM AUTHOR]

Rituximab is a chimeric mouse/human anti-CD20 monoclonal immunoglobulin. We reviewed the efficacy and safety of rituximab in 169 myasthenia gravis (MG) patients from case reports and series. Antibodies to the acetylcholine receptor (AChR) were present in 59% and muscle-specific tyrosine kinase (MuSK) in 34%. Modified Myasthenia Gravis Foundation of America postintervention scale of minimal manifestations (MM) or better occurred in 44%, and combined pharmacologic and chronic stable remission in 27% overall; MM or better was achieved in 72% of MuSK MG and 30% of AChR MG (P < 0.001). Posttreatment relapses decreased more in MuSK MG (P = 0.05). Response predictors were MuSK MG, less severe disease, and younger age at treatment. Among a responder subset, 26% of AChR and 82% of MuSK MG patients showed decreased posttreatment antibody titers. Rituximab was generally well tolerated. Detectable serum rituximab and depleted CD20+ B-cells were observed up to 20 and 16 weeks, respectively, after 4 weekly infusions. Muscle Nerve 56: 185-196, 2017. [ABSTRACT FROM AUTHOR]

Non-dystrophic myotonias (NDM) are characterised by muscle stiffness during voluntary movement owing to delayed skeletal muscle relaxation caused by mutations in the chloride (CLCN1) and sodium (SCN4A) skeletal muscle channel genes. Late onset acid maltase deficiency (AMD) is characterised by progressive respiratory and proximal muscle weakness; electrical but not clinical myotonia can be observed. Case report of a unique patient with concurrent NDM and AMD. We describe the clinical presentation and management of a patient with two rare neuromuscular disorders. This case illustrates the importance of reopening the differential diagnosis in patients who do not conform to the typical natural history of a specific disease. [ABSTRACT FROM AUTHOR]

Background and Objectives: Epidemiologic studies suggest increasing incidence and prevalence of myasthenia gravis (MG) among the elderly population outside the United States. We aimed to provide an estimation of MG incidence and prevalence and their trend among the Medicare Fee-For-Service (FFS)-covered elderly US population., Methods: We performed a retrospective longitudinal study using Medicare claims data (2006-2019). Study-eligible beneficiaries were aged 65 years and older, had at least 1 month of FFS Part A/B coverage, and were without any health maintenance organization insurance coverage. Study-eligible beneficiaries were aggregated into 2-year periods from 2006-2007 through 2018-2019. MG cases were ascertained using a validated algorithm of 2 MG claims within each 2-year period, from 2 outpatient office visits or a combination of 1 inpatient admission and 1 outpatient office visit, separated by ≥ 28 days. Period prevalence was calculated from MG-ascertained cases divided by FFS Part A/B beneficiaries and reported as cases per 100,000 population. Incident cases were determined among MG prevalent cases if the initial MG claim occurred in that period after a full calendar year since coverage initiation. Incidence was calculated as case counts per 100,000 at-risk beneficiary person-years (PYs) in each period excluding 2006-2007. Trends of prevalence and incidence over time were examined with Poisson regression. All-cause mortality of each 2-year period was calculated., Results: The period prevalence of MG increased from 81 to 119 per 100,000 FFS A/B population from 2006-2007 to 2018-2019 ( p < 0.001). Increasing trends of prevalence were observed in all sex (male/female), age (65-69/70-74/75-79/80+), race/ethnic (African American/Asian/Hispanics of any race/non-Hispanic White/other), and census region (Northeast/Midwest/South/West) subgroups. MG incidence increased from 12.2 to 13.3 per 100,000 PYs from 2008-2009 to 2018-2019 ( p < 0.05). Increasing incidence trends were significant in the following subgroups: men and women; all age groups except 75-79 years; White non-Hispanic race; Northeast, Midwest, and South census regions. All-cause mortality among MG beneficiaries was stable from 6.26 deaths per 100 PYs in 2006-2007 to 5.67 in 2018-2019 ( p = 0.18)., Discussion: Increasing trends in MG prevalence and incidence in the elderly US population, with variation in rates of certain subgroups, are confirmed in this 14-year period.

Purpose of Review: This article reviews updated diagnostic procedures and currently available treatment modalities for myasthenia gravis (MG)., Recent Findings: Patients with MG can be classified based on antibody status and their clinical presentation; treatment responses may differ based on disease subtypes. Improved diagnostic methods and recognition of new antigenic targets such as lipoprotein-related protein 4 have led to improved diagnostic efficiencies. Corticosteroids remain the first-line immunotherapy, but there is a trend toward minimizing their use at high doses and for long durations. Oral immunosuppressants such as mycophenolate mofetil, azathioprine, and tacrolimus remain useful. An international, multicenter randomized trial comparing thymectomy plus prednisone with prednisone alone demonstrated that thymectomy improves clinical outcomes in selected patients with nonthymomatous MG. Eculizumab, efgartigimod, and ravulizumab have recently been approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor-antibody positive. These drugs take advantage of novel mechanisms of action and expand treatment options for patients with MG. Data on rituximab suggest that it can be a good option, especially for patients with MG who are positive for antibodies against muscle-specific tyrosine kinase (MuSK). The number of clinical trials and drugs in development for MG is steadily increasing., Summary: The diagnosis of MG can generally be made from the patient's history, a neurologic examination, and laboratory and electrodiagnostic testing. Carefully selected treatment improves outcomes in MG. Additional treatment options for MG will likely be available in the near future., (Copyright © 2022 American Academy of Neurology.)

Myasthenia gravis (MG) is a rare disease, but the most common disorder of the neuromuscular junction. It is the prototypic autoimmune disease most commonly caused by antibodies to the acetylcholine receptor (AChR) leading to characteristic fatigable weakness of the ocular, bulbar, respiratory, axial, and limb muscles. The majority of patients with MG first present with ocular symptoms. Most patients with MG will experience at least 1 exacerbation of symptoms throughout the course of their illness. This article will cover the epidemiology, clinical presentation, classification, and natural history of MG., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose of Review: Infections are important, potentially treatable causes of peripheral nervous system disease. This article reviews the clinical presentation and management of several common peripheral nervous system diseases due to viral, bacterial, spirochetal, and parasitic infections., Recent Findings: The clinical presentation and evaluation of infectious peripheral nervous system diseases are well established. Advances in the treatment and, in some cases, the prevention of these diseases are still evolving., Summary: A diverse range of peripheral nervous system diseases, including peripheral neuropathy, radiculopathy, radiculomyelopathy, cranial neuropathy, and motor neuropathy, are caused by numerous infectious agents. In some patients, peripheral neuropathy may be a side effect of anti-infectious drugs. Infectious neuropathies are important to recognize as they are potentially treatable. This article discusses the clinical presentation, evaluation, and treatment of several common peripheral nervous system diseases caused by viral, bacterial, spirochetal, and parasitic infections, as well as some peripheral nerve disorders caused by adverse effects of the treatments of these infectious diseases.