ABSTRACT
Introduction: Evaluation of quality of life (QOL) has become essential in healthcare. Currently no MG‐specific QOL measure exists in French. The aim of this study was to translate, ...culturally adapt, and evaluate the psychometric properties of the French version of the 15‐Item Myasthenia Gravis Quality of Life Scale (MG‐QOL15) scale for French myasthenia patients. Methods: Translation and cross‐cultural adaption of the MG‐QOL15 was performed, followed by reliability and validity evaluations. Results: One hundred and twenty‐five patients were included. Internal consistency was excellent (Cronbach α = 0.92) as was test–retest reliability (ICC = 0.92, 95% CI 0.86–0.96). Concurrent validity was good for both clinical scores (myasthenic muscle score: ρ = –0.52, P < 0.001; Myasthenia Gravis–Activities of Daily Living scale score: ρ = 0.62, P < 0.001). Correlations were strongest for overall QOL (ρ = 0.62, P < 0.001) and physical health (ρ = 0.67, P < 0.001) on the World Health Organization Quality of Life short score (WHO‐QOL BREF). Conclusion: The French version of the MG‐QOL15 is valid and reliable and is now available for use with French‐speaking patients. Muscle Nerve, 2016 Muscle Nerve 55: 639–645, 2017
Objective
The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5–29 years. Secondary aims were to test the effect of mutation, ...ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength.
Methods
The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age.
Results
For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again.
Interpretation
Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.
The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in ...clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD.
Degenerative muscle changes may be associated with changes in muscle mechanical properties. Shear wave elastography (SWE) allows direct quantification of muscle shear modulus (MSM). The aim of this ...study was to evaluate the feasibility and reliability of SWE in the severely disordered muscle as observed in inclusion body myositis. To explore the clinical relevance of SWE, potential relationships between MSM values and level muscle impairments (weakness and ultrasound-derived muscle thickness and echo intensity) were investigated. SWE was performed in the biceps brachii at 100°, 90°, 70° and 10° elbow flexion in 34 patients with inclusion body myositis. MSM was assessed before and after five passive stretch-shortening cycles at 4°/s from 70° to 10° elbow angle and after three maximal voluntary contractions to evaluate potential effects of muscle pre-conditioning. Intra-class correlation coefficients and standard errors of measurements were >0.83 and <1.74 kPa and >0.64 and <1.89 kPa for within- and between-day values, respectively. No significant effect of passive loading-unloading and maximal voluntary contractions was found (all p values >0.18). MSM correlated to predicted muscle strength (all Spearman correlation coefficients (ρ) > 0.36; all p values < 0.05). A significant correlation was found between muscle echo intensity and muscle shear modulus at 70° only (ρ = 0.38, p <0.05). No correlation was found between muscle thickness and MSM (all ρ values > 0.23 and all p values > 0.25, respectively). Within- and between-day reliability of muscle SWE was satisfactory and moderate, respectively. SWE shows promise for assessing changes in mechanical properties of the severely disordered muscle. Further investigations are required to clarify these findings and to refine their clinical value.
Objective
Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for ...prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.
Methods
We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.
Results
The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline.
Interpretation
The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short‐term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978
ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of ...inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment.
This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline.
Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period.
ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD.
Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.
cognitive deterioration and reductions of bone health coincide with increasing age. We examine the relationship between bone composition and plasma markers of bone remodelling with measures of ...cognitive performance in healthy adults.
this cross-sectional study included 225 old (52% women, mean age: 74.4 ± 3.3 years) and 134 young (52% women, mean age: 23.4 ± 2.7 years) adult participants from the MyoAge project. Whole body bone mineral density was measured by dual-energy X-ray absorptiometry. Blood analyses included a panel of bone-related peptides (dickkopf-1, osteoprotegerin, osteocalcin (OC), osteopontin, sclerostin, parathyroid hormone and fibroblast growth factor 23), as well as serum calcium and 25-hydroxy vitamin D assays. A selection of cognitive domains (working memory capacity, episodic memory, executive functioning and global cognition) was assessed with a standardised neuropsychological test battery.
adjusting for covariates and multiple testing revealed that plasma OC levels were positively associated with measures of executive functioning (β = 0.444, P < 0.001) and global cognition (β = 0.381, P = 0.001) in the older women.
these correlative results demonstrate a positive association between OC, a factor known to regulate bone remodelling, with cognitive performance in older non-demented women. Further work should address possible mechanistic interpretations in humans.
Objective
The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) ...with a view to propose objective monitoring markers for future clinical trials.
Methods
Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables.
Results
Significant functional decline was observed based on SMAFRS (
p
= 0.019), pinch and knee flexion strength (
p
= 0.030 and 0.027), MUNIX and MUSIX value in the ADM (
p
= 0.0006 and 0.043) and in TA muscle (
p
= 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (
p
= 0.0005, SRM = −1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials.
Conclusions
Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.
ABSTRACT
Introduction: In this study we evaluated the role of an electrodiagnostic provocative test (long exercise test) in McArdle disease. Methods: Twenty‐five McArdle patients and 2 control groups ...underwent an electrodiagnostic protocol with long exercise test (LET), consisting of recording the compound muscle action potential (CMAP) before and after 5 minutes of isometric contraction. Results: The LET disclosed a postexercise decrease in CMAP amplitude in 23 of 25 McArdle patients. The immediate and long‐lasting decrease differentiated McArdle patients from controls. Patients with a normal LET demonstrated milder symptoms and/or residual myophosphorylase activity. Discussion: The LET is a sensitive, safe, and noninvasive provocative test that may guide clinicians toward molecular analysis of the myophosphorylase gene. The abnormalities observed on LET point toward complex biochemical mechanisms determined by the absence of myophosphorylase, beyond simple glycolytic blockade (ionic pump dysfunction, sarcolemmal inexcitability). The normal LET in patients with milder symptoms indicates a relationship of the LET with clinical severity, thus identifying it as a potential outcome measure. Muscle Nerve 58: 64–71, 2018
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