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An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

ObjectiveTo examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).MethodsThis study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.ResultsPatients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.ConclusionsThymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.Clinicaltrialsgov identifierNCT00294658.Classification of evidenceThis study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

AbstractObjective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3–4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9–4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5–4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers. [ABSTRACT FROM AUTHOR]

Hydrophilic endogenous bile acids ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), and glucourosodeoxycholic acid (GUDCA) have suggested neuroprotective effects. We performed a case–control study to examine the association between ALS diagnosis and serum levels of bile acids. Sporadic and familial ALS patients, age‐ and sex‐matched healthy controls, and presymptomatic gene carriers who donated blood samples were included. Non‐fasted serum samples stored at −80°C were used for the analysis. Serum bile acid levels were measured by liquid chromatography‐mass spectrometry (LC–MS). Concentrations of 15 bile acids were obtained, 5 non‐conjugated and 10 conjugated, and compared between ALS versus control groups (presymptomatic gene carriers + healthy controls) using the Wilcoxon‐Rank‐Sum test. In total, 80 participants were included: 31 ALS (17 sporadic and 14 familial ALS); 49 controls (22 gene carriers, 27 healthy controls). The mean age was 50 years old and 50% were male. In the ALS group, 45% had familial disease with a pathogenic variant in C9orf72 (29%), TARDBP (10%), FUS (3%), and CHCHD10 (3%) genes. In the control group, 43% carried pathogenic variants: C9orf72 (27%), SOD1 (10%), and FUS (6%). The serum levels of UDCA, TUDCA, and GUDCA trended higher in the ALS group compared to controls (median 27 vs. 7 nM, 4 vs. 3 nM, 110 vs. 47 nM, p‐values 0.04, 0.06, 0.04, respectively). No significant group differences were found in other bile acids serum levels. In conclusion, the serum level of UDCA, TUDCA, GUDCA trended higher in ALS patients compared to controls, and no evidence of deficiencies was found. [ABSTRACT FROM AUTHOR]

Objective: High‐caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants. Methods: Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n = 304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total‐score, and tracheostomy‐free survival using linear regression and Cox proportional hazard models. Baseline age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised amyotrophic lateral sclerosis functional rating scale total‐score, and forced vital capacity were included as covariates. Results: Baseline higher glycemic index and load were associated with less decline of revised amyotrophic lateral sclerosis functional rating scale total score at 3‐month follow‐up (β = −0.13, 95% CI −0.2, −0.01, p = 0.03) and (β = −0.01, 95% CI −0.03, −0.0007, p = 0.04), respectively. Glycemic index second‐quartile, third‐quartile, and fourth‐quartile groups were associated with less decline at 3 months by 1.9 (95% CI −3.3, −0.5, p = 0.008), 2.0 (95% CI −3.3, −0.6, p = 0.006), and 1.6 (95% CI −3.0, −0.2, p = 0.03) points compared with the first‐quartile group; the glycemic load fourth‐quartile group had 1.4 points less decline compared with the first‐quartile group (95% CI −2.8, 0.1, p = 0.07). Higher glycemic index was associated with a trend toward longer tracheostomy‐free survival (HR 0.97, 95% CI 0.93, 1.00, p = 0.07). Interpretation: Higher dietary glycemic index and load are associated with slower disease progression in amyotrophic lateral sclerosis. ANN NEUROL 2024;95:217–229 [ABSTRACT FROM AUTHOR]

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated. [ABSTRACT FROM AUTHOR]

A recently published article titled "Higher Glycemic Index and Glycemic Load Diet Is Associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis" found a significant association between dietary glycemic index (GI) and glycemic load (GL) with functional decline and survival in patients with amyotrophic lateral sclerosis (ALS). However, questions have been raised about the potential interaction between riluzole intake, the most commonly used medication for ALS patients, and the association between GI/GL and disease progression. The authors plan to analyze the dataset further to examine whether dietary GI or GL have different associations with functional decline and survival among those with or without riluzole intake. The authors have no conflicts of interest related to the product discussed in the study. [Extracted from the article]

Introduction/aims: Factors associated with coronavirus disease 2019 (COVID‐19) infection among the myasthenia gravis (MG) population are incompletely understood. This study aimed to characterize the behavior of MG patients during the pandemic and to examine risk factors associated with COVID‐19 infection. Methods: A "COVID‐19 Survey" was sent to MG Patient Registry participants in the summer of 2020 (CSS20) and winter of 2021 (CWS21). Survey results were summarized descriptively. Demographics, disease characteristics, medication use, and survey results were compared between those reporting COVID‐19 diagnosis (COVID), COVID‐19 like symptoms without diagnosis (COVID‐Like), and asymptomatic participants. Results: A total of 454 and 665 participants completed the CSS20 and CWS21 surveys respectively; 326 participants completed both. Most continued follow‐up visits and MG treatments. The frequency of COVID‐like symptoms was similar between CSS20 and CWS21, while COVID‐19 exposure (6% vs. 27%), COVID‐19 testing among symptomatic individuals (35% vs. 78%), and COVID‐19 diagnosis (0.2% vs. 6%) were higher in the CWS21. Cough, fever, fatigue, myalgia, anosmia/ageusia, and hospital and intensive care unit (ICU) admissions were more frequent in the COVID compared to the COVID‐Like group. COVID‐19 exposure (odds ratio [OR] 7.88), number of people in the household (OR 1.31), and report of MG exacerbation before the pandemic (OR 2.6) were independently associated with COVID‐19 infection. Discussion: COVID‐19 affected MG patients increasingly through the early pandemic. While face‐to‐face contact with a COVID‐19 infected individual was an obvious risk factor, MG patients who had more people in the household and unstable disease were at elevated risk for COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Background: The extrapolated reference values procedure (E‐Ref) was used to compare data from a single institution with the recently published reference value (RV) for concentric electrode jitter. Methods: Data from voluntarily activated concentric needle jitter studies in the frontalis muscle were obtained using retrospective chart review. All measured signals were reviewed for acceptable quality. Cutoff values for increased jitter were calculated using E‐Ref, and compared with the published RVs. Results: At total of 1501 apparent single‐fiber action potential (ASFAP) pairs were reviewed; 1371 ASFAP pairs were determined to have acceptable quality. The cutoff value identified by E‐Ref from all reviewed ASFAP pairs was 36 microseconds and the cutoff for acceptable pairs was 35 microseconds. Using either of these cutoff values (36 or 35 microseconds) did not result in a significant difference in percentage of jitter recordings considered normal when compared with the recently published RV (38 microseconds). Discussion: The single‐institution jitter cutoff value obtained by E‐Ref gives results that are not significantly different from the reported RV. [ABSTRACT FROM AUTHOR]

Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG).Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected.Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years.Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status. [ABSTRACT FROM AUTHOR]

Introduction: Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scales were compared using the data from the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) study.Methods: Correlation between QMG and MG-ADL raw and change-from-baseline scores was calculated every 3 months for 60 months based on treatment groups and minimal manifestation status (MMS).Results: QMG and MG-ADL change-from-baseline scores correlated significantly, with increasing strength of correlation over time, in both treatment groups. QMG and MG-ADL raw scores correlated significantly in both treatment groups, with increasing correlation only in the prednisone-alone group. Correlation between raw scores was weaker in patients who were in MMS, demonstrating a "floor effect" on the MG-ADL scale. Raw QMG scores could be modeled assuming a normal distribution, whereas raw MG-ADL scores could not be modeled this way.Discussion: The floor effect and skewed distribution of the MG-ADL measure should be taken into account in the design of myasthenia gravis clinical trials. [ABSTRACT FROM AUTHOR]