Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study

Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was -0.67 (2.80), -1.15 (3.98), -1.46 (3.37) and -1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was -1.47 (3.73), -2.78 (5.86), -2.95 (4.56) and -4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients

2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items

Upper limb function in Duchenne muscular dystrophy: 24 month longitudinal data

The aim of the study was to establish 24 month changes in upper limb function using a revised version of the performance of upper limb test (PUL 2.0) in a large cohort of ambulant and non-ambulant boys with Duchenne muscular dystrophy and to identify possible trajectories of progression. Of the 187 patients studied, 87 were ambulant (age range: 7\u201315.8 years), and 90 non-ambulant (age range: 9.08\u201324.78). The total scores changed significantly over time (p<0.001). Non-ambulant patients had lower total scores at baseline (mean 19.7) when compared to the ambulant ones (mean 38.4). They also had also a bigger decrease in total scores over 24 months compared to the ambulant boys (4.36 vs 2.07 points). Multivariate model analysis showed that the Performance of Upper Limb changes reflected the entry level and ambulation status, that were independently associated to the slope of Performance of Upper Limb changes. This information will be of help both in clinical practice and at the time of designing clinical trials

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01 mL/m2 , p = 0.03) while for dp116 were correlated with decreased EF (–4.14%, p = Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD

Efficacy and safety of a fixed combination of intramuscular diclofenac 75 mg + thiocolchicoside 4 mg in the treatment of acute low back pain. A phase III, randomized, double blind, controlled trial

Background: The management of acute low back pain (LBP) is directed to obtain early and maximum relief of the local and regional pain, and to improve mobility and physical function. Aim: To evaluate the effects of a 4 mL-volume diclofenac 75mg/thiocolchicoside 4mg fixed dose combination (FDC) for intramuscular (IM) injection (test) compared to the separate injection of the two components (reference). Design: Phase III, randomized, controlled, double-blind (blind-observer), parallel-group. Setting: Twenty-two General Practitioners in Italy. Population: Adult outpatients with acute moderate-severe LBP at rest (≥50 mm at VAS) and stable muscle contracture (increase <5 cm in the distance between the two fingers of the examiner in the Schober test). Methods: Eligible patients were randomized to the test (N.=111) or reference (N.=112) treatment, both given IM once daily for 5 days. The primary efficacy endpoint of the study was the change from baseline in pain VAS score (0-100 mm) measured at rest 96±2 hours (day 5) from the start of treatment, one hour after the last injection. Results: Pain VAS Score markedly improved in both groups and the test was non-inferior to the reference in primary endpoint, i.e. the upper bound of the 95% confidence interval of the adjusted difference was lower than the pre-specified limit of 4 mm. There were no statistically significant differences between groups for improvements of pain measured at all time points before and one hour after injection, time to resolution of pain, improvements from baseline of muscle contracture, and time to first resolution of muscle contracture. Approximately 20% of patients in the two groups used rescue paracetamol for pain relief. Both the test and the reference treatment were well tolerated in terms of adverse effects, laboratory parameters and vital signs. Conclusions: A 5-day treatment with IM diclofenac+thiocolchicoside FDC in a 4-mL volume was as effective and well tolerated as the separate injection of the two components in improving pain symptoms in patients with acute moderate-severe LBP. Clinical Rehabilitation Impact: The new diclofenac+thiocolchicoside FDC formulation may allow treating effectively acute LBP while reducing the number of injections and hence the risk of local adverse reactions, and improving the patient's compliance

Sex differences in cerebral palsy on neuromotor outcome: a critical review

Sex differences have been reported in children with cerebral palsy (CP), with males having a higher risk of developing CP, but it is not entirely clear whether sex may also affect the severity of motor impairment. The aim of the present study was to critically review the existing literature on sex influence on neuromotor outcome in children with CP. The published papers confirm that CP occurs more frequently in males than in females. Within different types of CP or individual level of impairment, however, there was limited evidence that sex also had an effect on their performance

Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?

There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5-17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.(c) 2023 Published by Elsevier B.V

Early assessment of visual function in preterm infants: how early is early?

BACKGROUND: Several studies reported on various aspects of visual function at term age and in the first months after birth but less has been reported in preterm infants before they reach termequivalent age. AIMS: To assess the suitability of a battery of tests of visual function for use in infants born at <33weeks gestation (GA) and assessed before 34weeks post-menstrual age (PMA); to evaluate the distribution of the findings according to GA, and to compare the data with those previously published on preterm infants assessed at 35weeks PMA. STUDY DESIGN: Cross-sectional study. SUBJECTS: Sixty-four preterm infants with a GA <33weeks were studied. OUTCOME MEASURES: We used a battery of visual function tests previously validated at 35 and 40weeks PMA in low-risk preterm infants. All the infants in this current study underwent the same assessment before 34weeks PMA. RESULTS: Before 31weeks PMA most infants could not be reliably assessed because of clinical instability, whilst after 31weeks PMA most infants could be assessed and they showed progressive maturation in their responses with PMA. Some items (spontaneous ocular motility, horizontal tracking, tracking a coloured stimulus, and ocular fixation) showed similar results at 32-33weeks PMA to those found in low-risk preterm at 35weeks PMA. Ocular movements to a target and arc tracking were the items with the most immature responses. CONCLUSIONS: Our results provide further evidence that a structured assessment of visual function can be used in clinical routine and for research purposes in infants as young as 31weeks PMA

Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy.

The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers

Assessing Prevalence and Characteristics of Oro-bulbar Involvement in Children and Adults with SMA Type 2 and 3 Using a Multimodal Approach

Bulbar and jaw muscles are impaired in patients with Spinal Muscular Atrophy (SMA) but the assessment of their severity and progression are limited by the lack of age-appropriate and disease-specific measures. We investigated mastication and swallowing in children and adults with SMA, sitters and walkers. In a 2-year multicentre cross-sectional prospective study, lip and tongue strength (Iowa Oral Performance Instrument), chewing and swallowing (Test of Masticating and Swallowing Solids), active mouth opening (aMMO) were compared to age-appropriate normative data. The perceived burden of oro-bulbar involvement (SMA-Health Index) was recorded. 78 patients were included, 45 children (median age 7.4 years),22 adults (median age 26.8 years) on nusinersen and 11 untreated (median age 32.7 years). Forty-three percent children had reduced mouth opening, 50% had prolonged total time to eat. These issues were more prominent in sitters than in walkers (p = 0.019, p = 0.014). Sixty-six percent needed increased swallows for bolus clearance. Nusinersen treated adults had median aMMO, tongue strength and total time at TOMASS values within normal range (z score: -1.40, -1.22, -1.32, respectively) whereas untreated adults had reduced aMMO (z score: -2.68) and tongue strength (z score: -2.20). Only a minority of children (2/17) and treated adults (5/21) reported burden in swallowing or mastication compared to all untreated adults (5/5). After 16 months, mastication and swallowing were stable in treated children and adults, whether sitters or walkers. The reported multimodal approach to assess oro-bulbar functions demonstrate that swallowing and mastication are impaired in SMA despite patients' perception. These results suggest a trend towards stabilization of oro-bulbar function in patients on long-term treatment with nusinersen