Effectiveness of conservative non-pharmacological interventions in people with muscular dystrophies: a systematic review and meta-analysis.

INTRODUCTION: Management of muscular dystrophies (MD) relies on conservative non-pharmacological treatments, but evidence of their effectiveness is limited and inconclusive. OBJECTIVE: To investigate the effectiveness of conservative non-pharmacological interventions for MD physical management. METHODS: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched Medline, CINHAL, Embase, AMED and Cochrane Central Register of Controlled Trial (inception to August 2022). Effect size (ES) and 95% Confidence Interval (CI) quantified treatment effect. RESULTS: Of 31,285 identified articles, 39 studies (957 participants), mostly at high risk of bias, were included. For children with Duchenne muscular dystrophy (DMD), trunk-oriented strength exercises and usual care were more effective than usual care alone in improving distal upper-limb function, sitting and dynamic reaching balance (ES range: 0.87 to 2.29). For adults with Facioscapulohumeral dystrophy (FSHD), vibratory proprioceptive assistance and neuromuscular electrical stimulation respectively improved maximum voluntary isometric contraction and reduced pain intensity (ES range: 1.58 to 2.33). For adults with FSHD, Limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD), strength-training improved dynamic balance (sit-to-stand ability) and self-perceived physical condition (ES range: 0.83 to 1.00). A multicomponent programme improved perceived exertion rate and gait in adults with Myotonic dystrophy type 1 (DM1) (ES range: 0.92 to 3.83). CONCLUSIONS: Low-quality evidence suggests that strength training, with or without other exercise interventions, may improve perceived exertion, distal upper limb function, static and dynamic balance, gait and well-being in MD. Although more robust and larger studies are needed, current evidence supports the inclusion of strength training in MD treatment, as it was found to be safe.

A pilot study of a single intermittent arm cycling exercise programme on people affected by Facioscapulohumeral dystrophy (FSHD).

For patients affected by Facioscapulohumeral dystrophy (FSHD), alternate methods for increasing physical activity engagement that may benefit shoulder function and wider health are needed. Arm cycling has been proposed as a potential method for achieving this although dosage parameters and evidence is limited. The aim of this study was to conduct a pilot study evaluating the effect of a single intermittent arm cycling exercise programme on people affected by FSHD. People with confirmed genetic diagnosis of FSHD between the ages 18-60 years were recruited to attend a single session for the exercise intervention (5 exercise efforts lasting 2 minutes each with 30 seconds of rest between each effort). Prior to exercise, measures of shoulder function (Oxford shoulder score), strength and range of movement were recorded. During the exercise participants were video recorded to quantify range of movement and extract movement profile features. Participants comments were recorded and followed up four days later to check for adverse events. Fifteen participants, (6F:9M) were recruited with median (IQR) Oxford Shoulder Scores of 25 (18 to 39). All participants successfully completed the exercise intervention with only transient symptoms consistent with exercise being reported and achieving a median (IQR) rate of perceived exertion scores of 13 (12 to 13). Movement profile data was available for 12 out of 15 participants and suggests that exercise intensity did not compromise movement. An association between strength and shoulder function (R2 = 0.5147), Rate of perceived exertion (RPE) of the final effort against shoulder function and strength (R2 = 0.2344 and 0.1743 respectively) was identified. Participant comments were positive regarding the exercise intervention. Our study demonstrates that an intermittent arm cycling programme is feasible for people affected by FSHD. Further work is needed to evaluate physiological responses to exercise across variations in programme variables and equipment set up in a larger sample of people affected by FSHD.

Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy.

OBJECTIVE: The North Star Ambulatory Assessment (NSAA) is a validated 17-item functional rating scale and widely used to assess motor function in boys with Duchenne muscular dystrophy (DMD). The SARS-CoV-2 pandemic and subsequent Government 'lockdown' resulted in no face-to-face clinic visits hence the motor abilities were not monitored. The aim was to investigate whether the NSAA was feasible and reliable by video assessment. METHOD: Ten ambulant DMD boys were selected from the electronic hospital records. Two physiotherapists scored the boys' NSAA independently and the intraclass correlation coefficient was used to assess agreement. The video scores were compared to two previous NSAA in-clinic scores. RESULTS: Mean scores (SD) for clinic visit one were 22.6 (4.19) and clinic visit two 21.8 (5.3). The two physiotherapists video mean scores were 20.6 (5.66) for physiotherapist 1 and 20.6 (6.53) for physiotherapist 2. The intraclass correlation coefficient was 0.98 (95% CI 0.93-1.00) for the total NSAA and 1.00 (95% CI 1.00 to 1.00) for the rise time. The mean decline in score from clinic visit one (-12 months) to video assessment was 2.0 (2.8SD). CONCLUSION: The results from the study suggest that video NSAA is partially feasible and reliable.

High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients.

Duchenne muscular dystrophy (DMD) is an incurable disease caused by out-of-frame DMD gene deletions while in frame deletions lead to the milder Becker muscular dystrophy (BMD). In the last decade several antisense oligonucleotides drugs have been developed to induce a partially functional internally deleted dystrophin, similar to that produced in BMD, and expected to ameliorate the disease course. The pattern of dystrophin expression and functionality in dystrophinopathy patients is variable due to multiple factors, such as molecular functionality of the dystrophin and its distribution. To benchmark the success of therapeutic intervention, a clear understanding of dystrophin expression patterns in dystrophinopathy patients is vital. Recently, several groups have used innovative techniques to quantify dystrophin in muscle biopsies of children but not in patients with milder BMD. This study reports on dystrophin expression using both Western blotting and an automated, high-throughput, image analysis platform in DMD, BMD, and intermediate DMD/BMD skeletal muscle biopsies. Our results found a significant correlation between Western blot and immunofluorescent quantification indicating consistency between the different methodologies. However, we identified significant inter- and intradisease heterogeneity of patterns of dystrophin expression in patients irrespective of the amount detected on blot, due to variability in both fluorescence intensity and dystrophin sarcolemmal circumference coverage. Our data highlight the heterogeneity of the pattern of dystrophin expression in BMD, which will assist the assessment of dystrophin restoration therapies.

Upper Limb Rehabilitation in Facioscapulohumeral Muscular Dystrophy: A Patients' Perspective.

OBJECTIVE: To identify (1) what exercise modalities people living with facioscapulohumeral muscular dystrophy (FSHD) are undertaking in the community as a part of their ongoing rehabilitation and (2) what future research projects would gain the support of people with FSHD. DESIGN: An online questionnaire composed of open and closed questions. Conventional content analysis was used for open questions, and quantitative analysis was used for closed questions. SETTING: Online questionnaire distributed to a United Kingdom FSHD registry. PARTICIPANTS: A total of 232 patients on the United Kingdom FSHD registry (N=232). INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: A response rate of 43.6% was achieved with 232 of 532 patients completing the survey. Despite 85.8% (n=199) of patients experiencing shoulder instability that affects daily living, only 44.4% (n=103) engaged with exercises targeting the upper body. The themes from the data were understanding of disease mechanism shaping exercise choice, lack of understanding about the condition and the benefit of exercise, support from professionals, barriers to exercise, and thoughts about future research. Participants (92.2%, n=214) agreed additional research into upper limb exercises is needed and felt a 3-month arm cycling intervention with monthly clinical visits and magnetic resonance imaging would be appropriate. CONCLUSIONS: Exercise selection was variable among patients with FSHD, and lack of information, pain, fatigue, availability and access to facilities, cost, and time were identified as barriers to exercise. This may account for the limited engagement with upper limb rehabilitation despite the high percentage of shoulder instability in patients with FSHD. Further research is needed to develop evidence-based exercise interventions, and guidance for upper limb exercise prescription in FSHD, and patients are supportive of this.

Healthcare utilisation in children with SMA type 1 treated with nusinersen: a single centre retrospective review.

BACKGROUND: Nusinersen has been used to treat spinal muscular atrophy type 1 (SMA1) in the UK since 2017. While initial trials showed neuromuscular benefit from treating SMA1, there is little information on the respiratory effects of nusinersen. We aimed to look at the respiratory care, hospital utilisation and associated costs in newly treated SMA1. METHODS: We reviewed the medical records of all children within the West Midlands with SMA1 treated with nusinersen at Royal Stoke University Hospital. Baseline demographics and hospital admission data were collected including: the reason for admission, total hospital days, days of critical care, days intubated, discharge diagnosis, doses of nusinersen and treatment complications. RESULTS: 11 children (six girls) received nusinersen between May 2017 and April 2019. Their median (range) age was 29 (7-97) months. The median (range) number of nusinersen doses per child was 6 (4-8). All children were receiving long-term ventilatory support; this was mask ventilation in nine and tracheostomy ventilation in two. The total number of hospital days since diagnosis was 1101 with a median (range) of 118 (7-235) days per child. This included general paediatric ward days 0 (0-63), High Dependency Unit 79 (7-173) days and Paediatric Intensive Care Unit 13 (0-109) days per child. This equated to a median (range) of 20 (2-72) % of their life in hospital. The estimated cost of this care was £2.2M. CONCLUSION: Patients with SMA1 treated with nusinersen initially spend a considerable proportion of their early life in hospital. Parents should be counselled accordingly. These data suggest that for every 10 children started on nusinersen an extra HDU bed is required. This has a significant cost implication.

Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case.

Immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition.

Women's experiences of sexuality after spinal cord injury: a UK perspective.

STUDY DESIGN: Cross-sectional phenomenological qualitative study. OBJECTIVES: To investigate women's experience of sexuality after spinal cord injury (SCI) with a focus on rehabilitation and manging practical impact. SETTING: Women with SCI living in the community in United Kingdom (UK). METHODS: Participants were recruited via three UK SCI centres, ensuring tetraplegia, paraplegia and cauda equina syndrome representation. Single semi-structured interviews exploring individual's experiences around sexuality following SCI were recorded and transcribed for thematic analysis. RESULTS: Twenty-seven women aged 21-72 years, sexually active since SCI were interviewed, each lasting 17-143 min (mean 55 min). Six key themes emerged: physical change, psychological impact, dependency, relationships and partners, post injury sexual life and sexuality rehabilitation. CONCLUSIONS: Sexuality remains an important, valued aspect of female identity following SCI; sexual activity continues and though altered remains enjoyable and rewarding. Sexuality rehabilitation should commence early, preparing women for altered sexual sensation, disclosure of altered sexual function to partners, and encouraging early self-exploration. Techniques optimising continence management in preparation for and during sex should be taught. Participants identified a need for women-only education and support groups, increased peer support, self-esteem, communication and social skills training and even fashion advice and pampering sessions during rehabilitation. Support and education for partners are needed. Staff require support to be knowledgeable and confident in addressing women's sexuality needs. Use of the Ex-PLISSIT model for psychosexual support could help staff to better meet these needs.

Two Cases of Spinal Muscular Atrophy Type II with Eosinophilic Oesophagitis.

Although primarily characterised by loss of motor neurons from the anterior horn of spinal cord and muscle atrophy, spinal muscular atrophy (SMA) is now recognised as a multi-systemic disorder. Here, we report two SMA Type II patients with eosinophilic oesophagitis (EoE), a rare, chronic immune/antigen-mediated condition. One patient presented with dysphagia and poor weight gain, and the second patient had symptoms of gastro-oesophageal reflux (GOR) and poor weight gain. In both patients, macroscopic observations during gastroscopy indicated typical signs of EoE, which were verified during histological examination of oesophageal biopsies. Given that there is a specific treatment strategy for EoE, these cases highlight the importance of considering this condition in clinical investigations - especially for patients with SMA - who have GOR, discomfort, and oral aversion.

Spinal cord infarction in a sick neonate from predominant haemorrhagic aetiology: a case report.

INTRODUCTION: Spinal cord injuries in new born infants following a traumatic delivery or umbilical cord catheterisation due to thromboembolism are well known. Cases with atraumatic acute onset of neonatal paraplegia have also been described in preterm babies or babies born small for gestational age with a stormy postnatal course related to ischaemic aetiology. We describe a rare case of infarction of the spinal cord from a predominant haemorrhagic aetiology. CASE PRESENTATION: A term female baby, first child of unrelated parents, was born by normal vaginal delivery. She had meconium aspiration at birth, leading to severe respiratory distress, requiring neonatal intensive care admission. At 2 weeks, she developed new flaccid paraplegia. MRI scan of the spine showed haemorrhagic infarction of the spinal cord from the level of thoracic inlet, vertebral level C7-T1. A follow-up MRI scan at 11 months revealed severe atrophy of the cord distal to C6. At 3 years of age, she had good upper-limb function, diaphragmatic breathing and flaccid paralysis of lower limbs. DISCUSSION: In an acutely unwell term infant with symptoms of paralysis or spinal cord damage, haemorrhagic infarction needs to be considered in the differential diagnosis. To our knowledge, this is the first reported case of spinal cord injury in a term infant with a haemorrhagic lesion, and it helps to understand the pathogenesis of nontraumatic insult.

A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness.

Myosin heavy chain (MyHC) is a major structural component of the striated muscle contractile apparatus. In adult human limb skeletal muscle, there are three major MyHC isoforms, slow/beta cardiac MyHC, MyHC IIa and MHC IIx, which are important for the functional characteristics of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression dependent on the mutated isoform, and also the type and location of the mutation. Myosin myopathy with external ophthalmoplegia is associated with mutations in MYH2, encoding for MyHC IIa that is mainly expressed in type 2A muscle fibers and is inherited in dominant as well as recessive manner. We present a family with myopathy with early onset proximal muscle weakness, facial muscle involvement and ophthalmoplegia. Muscle biopsy demonstrated lack of type 2A muscle fibers and genetic work up demonstrated that the disease was caused by a novel recessive MYH2 mutation: c.1009-1G>A resulting in skipping of exon 12, which is predicted to result in a frame shift and introducing at premature stop codon at position 347 (p.Ser337Leufs*11).