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Analysis of the functional capacity outcome measures for myotonic dystrophy.

ABSTRACT: OBJECTIVES:Defining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross-sectional analysis and subsequently 98 patients were followed for longitudinal analysis. We aimed to assess: (1) feasibility and best practice; (2) intra-session reliability; (3) validity; and (4) behavior over time, of these tests. RESULTS:OMMYD outcomes proved feasible as 96% of the participants completed at least one trial for all tests and more than half (n = 113) performed all three trials of each test. Body mass index and disease severity associate with functional capacity. There was a significant difference between the first and second trials of each test. There was a moderate to strong correlation between these functional outcomes and muscle strength, disease severity and patient-reported outcomes. All outcomes after 1 year detected a change in functional capacity except the nine-hole peg test. CONCLUSIONS:These tests can be used as a battery of outcomes or independently based on the shown overlapping psychometric features and strong cross-correlations. Due to the large and heterogeneous sample of this study, these results can serve as reference values for future studies.

SUBMITTER: Jimenez-Moreno AC

PROVIDER: S-EPMC6689676 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Analysis of the functional capacity outcome measures for myotonic dystrophy.

Jimenez-Moreno Aura Cecilia AC Nikolenko Nikoletta N Kierkegaard Marie M Blain Alasdair P AP Newman Jane J Massey Charlotte C Moat Dionne D Sodhi Jas J Atalaia Antonio A Gorman Grainne S GS Turner Chris C Lochmüller Hanns H

Annals of clinical and translational neurology 20190722 8

<h4>Objectives</h4>Defining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled ...[more]

PMID: 31402614

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Project description:Introduction: Myotonic dystrophy type 2 (DM2) lacks disease-specific, validated, motor outcome measures (OMs), and patients' reported outcomes (PROs). This represents a limit for the monitoring of disease progression and treatment response. Our aim was to identify the most appropriate OMs to be translated in clinical practice and clinical trials on DM2. This study has been registered on clinicaltrials.gov NCT03603171 (https://clinicaltrials.gov/ct2/show/NCT03603171). Methods: Sixty-six patients with genetically confirmed DM2 underwent a baseline and a follow-up visit after 1 year. The tested OMs included: hand opening time, pressure pain threshold (PPT), manual muscle testing (MMT), hand held dynamometry (HHD), scale for the assessment and rating of ataxia (SARA), quantitative motor function test (QMFT), gait stairs Gowers chair (GSGC), 30-s sit to stand test, functional index 2 (FI-2) and 6MWT. The PROs included DM1-Active-C, Rasch-built Pompe-specific activity scale (R-Pact), fatigue and daytime sleepiness (FDSS), brief pain inventory short form (BPI-sf), myotonia behavior scale (MBS), and the McGill pain questionnaire. Results: All patients completed the MBS and the results correlated well with the hand-opening time. The PPT showed a low reliability, no correlation with pain questionnaires, and did not differentiate patients with or without myalgia. Both muscle strength assessments, MMT and HHD, showed good construct validity. The QMFT showed an acceptable ceiling effect (14.5%), good convergent and differential validity and performed overall better than GSGC. The SARA score showed high flooring effect and is not useful in DM2. 6MWT proved a valid outcome measure in DM2. The 30-s sit to stand is a feasible test with good convergent validity, showing a flooring effect of 20% as it cannot be used in more severely affected patients. The FI-2 is time-consuming and has a high ceiling effect. At the 1-year visit the only assessments able to detect a worsening of DM2 were HHD, QMFT, and 6MWT, which are the most sensitive to change, and therefore clinically meaningful OMs in DM2. Conclusion: The clinical meaningful motor outcome measures that best depict the multifaceted phenotype of DM2 and its slow progression are MBS, MMT, or HHD (depending on the clinical setting), QMFT, and the 6MWT.

Project description:BACKGROUND:Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements. OBJECTIVE:The goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices. METHODS:A group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes. RESULTS:Round one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor. CONCLUSION:With minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.

Project description:BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function.MethodsWe studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures.ResultsThere was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced.ConclusionsAssessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Project description:Background: Central nervous system involvement in myotonic dystrophy type 1 (DM1) is associated with cognitive deficits, impaired social performance and excessive somnolence, which greatly impact quality of life. With the advent of clinical trials in DM1, there is a pressing need to identify outcome measures for quantification of central symptoms that are feasible and valid. In this context, we sought to evaluate neuropsychological and self-reported measures currently recommended by expert consensus, with particular reference to their specificity for central nervous system involvement in a moderate-sized DM1 cohort. Methods: Forty-five adults with DM1 and 20 controls completed neuropsychology assessments and symptom questionnaires. Those without contraindication also underwent MRI brain, from which global gray matter volume and white matter lesion volume were quantified. CTG repeat was measured by small pool PCR, and was screened for the presence of variant repeat sequences. Results: The neuropsychology test battery was well tolerated and detected impairment across various domains in the DM1 group vs. controls. Large effect sizes in the Stroop and Trail Making Tests were however attenuated by correction for basic speed, which could be influenced by dysarthria and upper limb weakness, respectively. Low mood was strongly associated with increased self-reporting of central symptoms, including cognitive impairment. Conversely, self-reported cognitive impairment did not generally predict poorer performance in neuropsychology assessments, and there was a trend toward greater self-reporting of low mood and cognitive problems in those with milder white matter change on MRI. Global gray matter volume correlated with performance in several neuropsychology assessments in a multivariate model with age and sex, while white matter lesion volume was associated with executive dysfunction reported by a proxy. Screening for variant repeats was positive in three individuals, who reported mild muscle symptoms. Conclusions: Identification of outcome measures with good specificity for brain involvement in DM1 is challenging, since complex cognitive assessments may be compromised by peripheral muscle weakness and self-reported questionnaires may be influenced by mood and insight. This highlights the need for further large, longitudinal studies to identify and validate objective measures, which may include imaging biomarkers and cognitive measures not influenced by motor speed.

Dataset Information

Analysis of the functional capacity outcome measures for myotonic dystrophy.

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Analysis of the functional capacity outcome measures for myotonic dystrophy.

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