Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

Longitudinal Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories.

Background and Objectives: The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes. Methods: We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction. Results: We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the Capn3 gene, 47 patients in the Dysf gene, 24 patients in the Fkrp gene, 19 in the Ano5 gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, FKRP was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. Fkrp and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, p < 0.001 and p = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up. Discussion: Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the Fkrp and sarcoglycan genes.

Validation of the North Star Assessment for Limb-Girdle Type Muscular Dystrophies.

OBJECTIVE: The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes. METHODS: Assessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children's Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data "fit" with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity. RESULTS: The NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981-0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of rs(134) = .92). CONCLUSION: Although LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings. IMPACT: Recent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings.

It is vital students are looked after safely.

Not all mentors have the skills proposed by the Nursing and Midwifery Council for newly qualified nurses, so who is going to look after students' safely?

Improving highly accelerated fat fraction measurements for clinical trials in muscular dystrophy: origin and quantitative effect of R2* changes.

Purpose To investigate the effect of R2* modeling in conventional and accelerated measurements of skeletal muscle fat fraction in control subjects and patients with muscular dystrophy. Materials and Methods Eight patients with Becker muscular dystrophy and eight matched control subjects were recruited with approval from the Newcastle and North Tyneside 2 Research Ethics Committee and with written consent. Chemical-shift images with six widely spaced echo times (in 3.5-msec increments) were acquired to correlate R2* and muscle fat fraction. The effect of incorporating or neglecting R2* modeling on fat fraction magnitude and variance was evaluated in a typical three-echo protocol (with 0.78-msec increments). Accelerated acquisitions with this protocol with 3.65×, 4.94×, and 6.42× undersampling were reconstructed by using combined compressed sensing and parallel imaging and fat fraction maps produced with R2* modeling. Results Muscle R2* at 3.0 T (33-125 sec(-1)) depended on the morphology of fat replacement, the highest values occurring with the greatest interdigitation of fat. The inclusion of R2* modeling removed bias, which was greatest at low fat fraction, but did not increase variance. The 95% limits of agreement of the accelerated acquisitions were tight and not degraded by R2* modeling (1.65%, 1.95%, and 2.22% for 3.65×, 4.94×, and 6.42× acceleration, respectively). Conclusion Incorporating R2* modeling prevents systematic errors in muscle fat fraction by up to 3.5% without loss of precision and should be incorporated into all muscular dystrophy studies. Fat fraction measurements can be accelerated fivefold by using combined compressed sensing and parallel imaging, modeling for R2* without loss of fidelity.

Outcomes following the conservative management of patients with non-radicular peripheral neuropathic pain.

STUDY DESIGN: Prospective cohort. INTRODUCTION: There is limited evidence for conservative management of patients with non-radicular peripheral neuropathic pain (PNP). PURPOSE: To investigate the effectiveness of a comprehensive treatment approach on pain and disability in patients with non-radicular PNP and to determine if improvements are maintained following the discontinuation of therapy. METHODS: Patients received a multi-modal therapeutic intervention. Outcome measures were the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QDASH), Numeric Pain Rating Scale (NPRS), and grip strength. Follow-up data were collected 5 ± 2 months post-discharge. RESULTS: There was a significant improvement in the QDASH and mean pain (p < .001). There was no significant change in grip strength (p > .13). Follow-up data suggest that pain and disability scores are maintained (p < .001). CONCLUSION: A comprehensive, conservative treatment program has a positive and lasting effect on pain and disability scores in patients with non-radicular PNP. LEVEL OF EVIDENCE: IIIa.

Investigating the quantitative fidelity of prospectively undersampled chemical shift imaging in muscular dystrophy with compressed sensing and parallel imaging reconstruction.

PURPOSE: Fat fraction measurement in muscular dystrophy has an important role to play in future therapy trials. Undersampled data acquisition reconstructed by combined compressed sensing and parallel imaging (CS-PI) can potentially reduce trial cost and improve compliance. These benefits are only gained from prospectively undersampled acquisitions. METHODS: Eight patients with Becker muscular dystrophy were recruited and prospectively undersampled data at ratios of 3.65×, 4.94×, and 6.42× were acquired in addition to fully sampled data: equivalent coherent undersamplings were acquired for reconstruction with parallel imaging alone (PI). Fat fraction maps and maps of total signal were created using a combined compressed sensing/parallel imaging (CS-PI) reconstruction. RESULTS: The CS-PI reconstructions are of sufficient quality to allow muscle delineation at 3.65× and 4.94× undersampling but some muscles were obscured at 6.42×. When plotted against the fat fractions derived from fully sampled data, non-significant bias and 95% limits of agreement of 1.58%, 2.17% and 2.41% were found for the three CS-PI reconstructions, while a 3.36× PI reconstruction yields 2.78%, 1.8 times worse than the equivalent CS-PI reconstruction. CONCLUSION: Prospective undersampling and CS-PI reconstruction of muscle fat fraction mapping can be used to accelerate muscle fat fraction measurement in muscular dystrophy.

Natural history of pulmonary function in collagen VI-related myopathies.

The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.