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Background and Objectives: To develop a valid, disease-specific, patient-reported outcome (PRO) measure for adolescents and adults with Friedreich ataxia (FA) for use in therapeutic trials., Methods: We conducted semistructured qualitative interviews and a national cross-sectional study of individuals with FA to determine the most prevalent and burdensome symptoms and symptomatic themes to this population. These symptoms and symptomatic themes were included as questions in the first version of the Friedreich's Ataxia-Health Index (FA-HI). We subsequently used factor analysis, beta interviews with 17 individuals with FA, and test-retest reliability assessments with 20 individuals with FA to evaluate, refine, and optimize the FA-HI. Finally, we determined the capability of the FA-HI to differentiate between subgroups of FA participants with varying levels of disease severity., Results: Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden., Discussion: Initial evaluation of the FA-HI supports its validity and reliability as a PRO for assessing how individuals with FA feel and function., Competing Interests: J. Seabury reports no disclosures relevant to the manuscript; D. Alexandrou reports no disclosures relevant to the manuscript; C. Engebrecht reports no disclosures relevant to the manuscript; N. Dilek reports no disclosures relevant to the manuscript; B. Greco reports no disclosures relevant to the manuscript; J. Heatwole reports no disclosures relevant to the manuscript; J. Larkindale is a paid employee of PepGen Inc.; D.R. Lynch receives grant support from the NIH, FDA, Friedreichs Ataxia Research Alliance, Reata Pharmaceuticals, Retrotope, PTC Therapeutics, Design Pharmaceuticals; C. Park reports no disclosures relevant to the manuscript; S. Rosero reports no disclosures relevant to the manuscript; S. Subramony receives research support from the NIH, FDA, Wyck, Friedreichs Ataxia Research Alliance, Muscular Dystrophy Association, Facioscapulohumeral Muscular Dystrophy Society, National Ataxia Foundation, Reata, PTC, Retrotope, Biohaven, Takeda, Acceleron, Pharnext, Avidity, and Reneo. He has provided consultation or served on advisory boards for Dyne, Avidity, Reata, and Avexis; A. Varma reports no disclosures relevant to the manuscript; E. Wagner reports no disclosures relevant to the manuscript; S. Walther reports no disclosures relevant to the manuscript; J. Weinstein reports no disclosures relevant to the manuscript; M. Wells reports no disclosures relevant to the manuscript; C. Zizzi has provided consultation to Recursion Pharmaceuticals; C. Heatwole receives royalties for the use of multiple disease-specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation. He receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, SwanBio Therapeutics, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreichs Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2023 American Academy of Neurology.)

Background and Objectives: To determine the prevalence and relative importance of symptoms experienced by children and adults with Friedreich ataxia (FA) and to identify factors associated with a higher burden of disease., Methods: We conducted qualitative interviews with individuals with FA and caregivers of pediatric individuals with FA to identify potential symptoms of importance to those living with FA. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in FA and to determine which factors are associated with a higher burden of disease., Results: Thirty-nine participants provided 2,527 quotes regarding the symptomatic burden of FA. Two hundred two individuals (153 individuals with FA and 49 caregivers) participated in a subsequent cross-sectional study. Individuals with FA and caregivers identified impaired coordination, limitations with mobility and walking, inability to do activities, fatigue, and lower extremity weakness as the most prevalent and life-altering symptomatic themes in FA. Muscle stiffness and functional staging for ataxia were associated with the prevalence of symptomatic themes in FA. In addition, the length of smaller GAA expansion and the mean length of both GAA expansions were strongly associated with the onset of symptoms in FA., Discussion: There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions., (© 2022 American Academy of Neurology.)

Objective: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1)., Methods: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months., Results: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants., Conclusions: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period., Classification of Evidence: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months., (© 2020 American Academy of Neurology.)

Objective: To determine the frequency and relative importance of the most meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to identify the demographic and clinical features that are associated with the greatest disease burden in this population., Methods: We performed a cross-sectional study involving 328 participants with FSHD. Collectively, participants reported the prevalence and relative importance of 274 symptoms and 15 symptomatic themes. We assessed the association between symptomatic theme prevalence and participants' age, sex, disease duration, pain level, employment status, and education., Results: Participants answered >48,000 questions regarding their disease burden. The symptomatic themes with the highest prevalence in our sample were problems with shoulders or arms (96.9%), limitations with activities (94.7%), core weakness (93.8%), fatigue (93.8%), limitations with mobility and walking (93.6%), changed body image due to the disease (91.6%), and pain (87.7%). Problems with shoulders and arms and limitations with mobility and walking had the greatest effect on participants' lives. Employment status and the report of pain had the most extensive association with the prevalence of symptoms, with employment being associated with 8 of 15 of the symptomatic themes and pain being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD experienced a similar prevalence of all symptomatic themes., Conclusions: Adults with FSHD experience a variety of symptoms that play an important role in their disease burden. These symptoms have a variable prevalence and importance in the FSHD population and are associated with disease duration, employment status, and pain level., (© 2019 American Academy of Neurology.)

Purpose of Review: Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist., Recent Findings: The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients., Summary: The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit., Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations., Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

Objective: To determine the frequency and relative importance of symptoms experienced by adults with spinal muscular atrophy (SMA) and to identify factors that are associated with a higher burden of disease in this population., Methods: We conducted a cross-sectional study of 359 adults with SMA using the International SMA Patient Registry. Participants provided input regarding 20 symptomatic themes and 207 symptoms that potentially affect adults with SMA. Participants were asked about the relative importance of each symptom, and analysis was conducted to determine how age, sex, SMA type, education, mobility, and employment status relate to symptom prevalence., Results: Limitations with mobility or walking (98.6%) and the inability to do activities (98.6%) were the 2 themes with the highest prevalence in the study sample. Limitation with mobility or walking was the theme that was identified as having the greatest effect on the lives of adults with SMA. Employment status was associated with the prevalence of 4 of 20 themes and a reliance on an assistive device was associated with 7 of 20 themes. The prevalence of breathing difficulties, choking or swallowing difficulties, and communication difficulties differed among those with different SMA types., Conclusions: There are many symptomatic themes that affect the lives of adults with SMA. These themes vary in prevalence and relative importance in the adult SMA population., (© 2018 American Academy of Neurology.)

Objective: Inclusion body myositis (IBM) is the most common form of idiopathic inflammatory myopathy in adults older than 50 years. Few studies have focused on the functional, physical, and social limitations of this disease. This study identifies pertinent symptoms that impact the health and daily function of patients with IBM., Methods: We used semistructured interviews with 10 biopsy-confirmed adults with IBM to identify the psychological, physical, and functional limitations that have the greatest impact on the lives of patients with IBM., Results: Participants with IBM provided 644 direct quotes identifying issues that have the greatest effect on their lives. Two hundred nine individual symptoms and 17 symptomatic themes were identified by patients as having a significant impact on their lives. The symptomatic themes mentioned most frequently involved mobility and ambulation, emotional distress, and activity impairment., Conclusions: Identifying critical issues to patients with IBM is potentially useful for clinicians whose aim is to provide optimal care to patients with IBM.

Objective: Herein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood., Methods: Children with CDM and age-matched controls aged 0 to 13 years were enrolled. Participants were divided into cohorts based on the following age groups: 0-2, 3-6, and 7-13 years. Each cohort received age-appropriate evaluations including functional testing, oral facial strength testing, neuropsychological testing, quality-of-life measurements, and ECG. Independent-samples t test or Wilcoxon 2-sample test was used to compare the differences between children with CDM and controls. Probability values less than 0.05 are reported as significant., Results: Forty-one participants with CDM and 29 healthy controls were enrolled. The 6-minute walk was significantly different between CDM (258.3 m [SD 176.0]) and control participants (568.2 m [SD 73.2]). The mean lip force strength was significantly different in CDM (2.1 N [SD 2.8)] compared to control participants (17.8 N [SD 7.6]). In participants with CDM, the mean IQ (65.8; SD 18.4) was 3 SDs below the mean compared to standardized norms. Measurements of grip strength, sleep quality, and quality of life were also significantly different. Strength measures (oral facial strength, grip strength, and 6-minute walk) correlated with each other but not with participant IQ., Conclusions: This work identifies important phenotypes associated with CDM during childhood. Several measures of strength and function were significantly different between participants with CDM and controls and may be useful during future therapeutic trials., (© 2016 American Academy of Neurology.)

Objective: To determine the frequency and relative importance of the most life-affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms., Methods: We conducted a cross-sectional study of adult patients with DM2 from a National Registry of DM2 Patients to assess the prevalence and relative importance of 310 symptoms and 21 symptomatic themes. Participant responses were compared by age categories, sex, educational attainment, employment status, and duration of symptoms., Results: The symptomatic themes with the highest prevalence in DM2 were the inability to do activities (94.4%), limitations with mobility or walking (89.2%), hip, thigh, or knee weakness (89.2%), fatigue (89.2%), and myotonia (82.6%). Participants identified the inability to do activities and fatigue as the symptomatic themes that have the greatest overall effect on their lives. Unemployment, a longer duration of symptoms, and less education were associated with a higher average prevalence of all symptomatic themes (p < 0.01). Unemployment, a longer duration of symptoms, sex, and increased age were associated with a higher average effect of all symptomatic themes among patients with DM2 (p < 0.01)., Conclusions: The lives of patients with DM2 are affected by a variety of symptoms. These symptoms have different levels of significance and prevalence in this population and vary across DM2 subgroups in different demographic categories., (© 2015 American Academy of Neurology.)

Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence., Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors., Results and Recommendations: Available genetic testing for FSHD type 1 is highly sensitive and specific. Although respiratory insufficiency occurs rarely in FSHD, patients with severe FSHD should have routine pulmonary function testing. Routine cardiac screening is not necessary in patients with FSHD without cardiac symptoms. Symptomatic retinal vascular disease is very rare in FSHD. Exudative retinopathy, however, is potentially preventable, and patients with large deletions should be screened through dilated indirect ophthalmoscopy. The prevalence of clinically relevant hearing loss is not clear. In clinical practice, patients with childhood-onset FSHD may have significant hearing loss. Because undetected hearing loss may impair language development, screening through audiometry is recommended for such patients. Musculoskeletal pain is common in FSHD and treating physicians should routinely inquire about pain. There is at present no effective pharmacologic intervention in FSHD. Available studies suggest that scapular fixation is safe and effective. Surgical scapular fixation might be cautiously offered to selected patients. Aerobic exercise in FSHD appears to be safe and potentially beneficial. On the basis of the evidence, patients with FSHD might be encouraged to engage in low-intensity aerobic exercises., (© 2015 American Academy of Neurology.)

Objectives: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population., Methods: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist., Results: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model., Conclusions: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden., (© 2015 American Academy of Neurology.)

Objective: To compare the short-term financial costs of treating a patient in myasthenia gravis crisis with intravenous immunoglobulin (IVIG) versus plasma exchange., Methods: An itemized comparative cost-minimization analysis of IVIG versus plasma exchange for myasthenia gravis crisis was performed. Calculations were based on each therapy's implementation cost, associated hospitalization times, and predicted cost to treat known complications. A cost superiority determination was proposed based on the total cost profile of each therapy., Results: The difference in total cost favored IVIG over plasma exchange with an average savings of $22,326 per patient. Sensitivity analysis demonstrated that overall costs are highly dependent on IVIG dosing, hospital lengths of stay, and the number of plasma exchange days required., Conclusions: The use of IVIG for myasthenia gravis crisis may be a short-term cost minimizing therapy compared with plasma exchange. Additional prospective studies are required to evaluate the extended cost profile and efficacy of these therapies.