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Validation of Motor Outcome Measures in Myotonic Dystrophy Type 2.

ABSTRACT: 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.

SUBMITTER: Montagnese F

PROVIDER: S-EPMC7186332 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Validation of Motor Outcome Measures in Myotonic Dystrophy Type 2.

Montagnese Federica F Rastelli Emanuele E Khizanishvili Nina N Massa Roberto R Stahl Kristina K Schoser Benedikt B

Frontiers in neurology 20200421

<b>Introduction:</b> 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). <b>Methods:</b> Sixty ...[more]

PMID: 32373059

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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.

Project description:BackgroundMyotonic Dystrophy 1 (DM1) causes progressive myopathy of extremity muscles. DM1 may also affect muscles of the trunk. The aim of this study was to investigate fat infiltration and muscle size in trunk muscles in DM1 patients, and in an age and gender matched control group. Further, explore how fat infiltration and degree of atrophy in these muscles are associated with motor and respiratory function in DM1 patients.MethodWe measured fat infiltration and trunk muscle size by MRI in 20 patients with genetically confirmed classic form of DM1, and compared these cases with 20 healthy, age and gender matched controls. In the DM1 group, we investigated correlations between MRI findings and clinical measures of muscle strength, mobility and respiration. We used sum scores for fat infiltration and muscle size in trunk flexors and trunk extensors in the analysis of group differences and correlations.ResultsSignificant differences between cases and controls were present for fat infiltration in trunk flexors (p = 0.001) and trunk extensors (p = < 0.001), and for muscle size in trunk flexors (p = 0.002) and trunk extensors (p = 0.030). Fat infiltration in trunk flexors were significant correlated to back extension strength (rho = - 0.523 p = 0.018), while muscle size in trunk flexors was significantly correlated to trunk flexion strength (rho = 0.506 p = 0.023). Fat infiltration in trunk flexors was significantly correlated with lower general mobility (rho = - 0.628, p = 0.003), reduced balance (rho = 0.630, p < 0.003) and forced vital capacity (rho - 0.487 p = 0.040).ConclusionsTrunk muscles in DM1 patients had significant higher levels of fat infiltration and reduced muscle size compared to age and gender matched controls. In DM1 patients, fat infiltration was associated with reduced muscle strength, mobility, balance and lung function, while muscle size was associated with reduced muscle strength and lung function. These findings are of importance for clinical management of the disease and could be useful additional outcome measures in future intervention studies.

Dataset Information

Validation of Motor Outcome Measures in Myotonic Dystrophy Type 2.

Publications

Validation of Motor Outcome Measures in Myotonic Dystrophy Type 2.

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