Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland. METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed. RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter. CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

[Understand, assess and manage the pain of children with profound intellectual and multiple disabilities]. / Comprendre, évaluer et traiter la douleur de l'enfant en situation de polyhandicap.

Children with profound intellectual and multiple disabilities are highly vulnerable. It is related to their numerous medical issues, their reliance on complex care as well as support for daily living activities. They also have frequent reason to visit emergent care. The number of caregivers involved is usually understandably high. This combination of numerous medical issues and multiple procedure required, as benevolent as they are meant to be, will expose these children to potential pain. This article will summarize how to recognize and treat the pain in children with multiple disabilities.

Les enfants en situation de polyhandicap présentent une grande vulnérabilité en raison de la variabilité et de l'accumulation de leurs problématiques médicales. Ils ont un besoin élevé en soins, en traitements et en aides à la vie quotidienne. Le nombre d'intervenants impliqués dans leur prise en charge (parents et proches, soignant·e·s, thérapeutes, etc.) est souvent important, sans oublier les situations d'urgences fréquentes. Cette combinaison de problèmes médicaux et d'actes multiples, aussi bienveillants soient-ils, expose ces enfants à de potentielles douleurs qu'il est important de (re)connaître et de traiter.

Co-sleeping in school-aged children with a motor disability: a comparative population-based study.

AIM: To determine the prevalence and determinants of co-sleeping in school-aged children with a motor disability compared with the school-aged general population. METHOD: A questionnaire on demographic characteristics and co-sleeping habits, along with the Sleep Disturbance Scale for Children (SDSC), was sent to parents of children aged between 4 years and 18 years followed in our tertiary paediatric neurorehabilitation clinic, and to school-aged children in a representative sample of state schools. RESULT: We analysed responses for 245 children with motor disability (142 males, 103 females; mean age 10y 6mo, standard deviation [SD] 3y 10mo, range 4-18y) and 2891 of the general population (1484 males, 1497 females; mean age [SD] 9y 6mo [3y 5mo], range 4-18y) (response rates 37% and 26% respectively). Cerebral palsy was the most common diagnosis among children with motor disability. Weekly co-sleeping was significantly more common in children with motor disability than in the general population (11.8% vs 7.9% respectively, p=0.032). Special care of the child with motor disability at night, mainly addressing epilepsy, was reported as a cause of co-sleeping by two-thirds of parents. Factors associated with co-sleeping in the motor disability group were age, housing crowding, severe visual impairment, and pathological sleep according to the SDSC. INTERPRETATION: Co-sleeping is common among children with motor disability. It is influenced by personal and medical factors, as well as the requirements for special care at night. Therefore, health professionals should explore sleeping arrangements in families of children with motor disability.

Mirror therapy in children with hemiparesis: a randomized observer-blinded trial.

AIM: To determine the efficacy of mirror therapy in children with hemiparesis. METHOD: The design was an observer-blinded parallel-group randomized controlled trial (International Standard Randomised Controlled Trial Number 48748291). Randomization was computer-generated, 1:1 allocation to mirror therapy or comparison groups. The settings were home-based intervention and tertiary centre assessments. Participants were 90 children with hemiparesis aged 7 to 17 years. Intervention was 15 minutes per day of simultaneous arm training, 5 days a week, for 5 weeks. The mirror therapy group used a mirror; those in the comparison group looked at their paretic limb. Assessments comprised measures of upper limb strength, function (Melbourne Assessment 2), daily performance (ABILHAND-Kids), and sensory function at weeks 0 (T0 ), 5 (T1 ), and 10 (T2 ). RESULTS: There were no significant differences in outcomes and their progression over time between the mirror therapy and comparison groups. Post-hoc intention-to-treat analyses showed significant improvements in both groups for grasp strength (T0 -T1 +12.6%), pinch strength (T0 -T2 +9.1%), upper limb function in terms of accuracy (T0 -T2 +2.7%) and fluency (T0 -T2 +5.0%), as well as daily performance (T0 -T2 +16.6%). Per protocol analyses showed additional improvements in dexterity (T0 -T2 +4.0%). INTERPRETATION: The use of the mirror illusion during therapy had no significant effect on treatment outcomes. However, 5 weeks of daily simultaneous arm training significantly improved paretic upper limb strength, function, and daily use.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. Methods: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Results: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. Conclusion: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

Chronic Pain in Patients with Spinal Muscular Atrophy in Switzerland: A Query to the Spinal Muscular Atrophy Registry.

Background and Objectives: Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic pain is scarce. Thus, this study assessed the prevalence of chronic pain in children, adolescents, and adults with SMA and investigated the influence of clinical characteristics on chronic pain. Materials and Methods: This study used data from 141 patients, which were collected by the Swiss Registry for Neuromuscular Disorders. Extracted data included information on pain (present yes/no, pain location, and pain medication) and clinical characteristics, such as SMA type, motor function, wheelchair use, scoliosis, and contractures. Results: The analyses revealed that the highest prevalence of chronic pain was observed in adolescents with 62%, followed by adults with 48%, children (6-12 years) with 39%, and children < 6 years with 10%. The legs, back, and hips were most frequently reported as pain locations. Sex (females), age (adolescents), and the presence of contractures and scoliosis (with surgery) were factors that were associated with chronic pain. Conclusions: These findings contribute to a better understanding of pain in SMA, shedding light on its prevalence and characteristics in different age groups, which underscores the importance of assessing and managing pain in patients with SMA.

Rituximab in juvenile myasthenia gravis-an international cohort study and literature review.

Juvenile myasthenia gravis (JMG) is a rare, antibody-mediated disorder of the neuromuscular junction. Treatment strategies in JMG are largely informed by adult MG treatments as the pathophysiology is similar. Rituximab is increasingly considered as a treatment option in refractory JMG but has not yet been systematically investigated in this patient group We conducted a retrospective study from five international centres with expertise in paediatric myasthenia. 10 JMG patients treated with rituximab were identified. Following rituximab treatment all patients had a reduction in JMG-related hospital admissions. At 24 month follow up, 6 patients (60%) had achieved complete stable remission or pharmacological remission and 7 patients were able to reduce immunomodulatory treatment(s). The main side-effect was infusion-related reactions (30%) which resolved in all patients with symptomatic treatment. We compared our cohort to previously reported JMG cases treated with rituximab and noted similar response rates but a slightly higher side-effect profile. Rituximab is a safe and effective treatment option in moderate to severe JMG and most patients have an improvement in MG symptoms post treatment.

Evaluation of real-life outcome data of patients with spinal muscular atrophy treated with nusinersen in Switzerland.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1-44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were <18 months-old at treatment initiation. Two of them did not need ventilation or nutritional support at the last assessment; three had delayed language development and 3 articulation difficulties. 5/21 SMA type 2 patients achieved higher HFMSE scores. All ambulant type 3 patients showed a gain in the 6MWT. Nusinersen is an effective treatment, with gains in motor function occurring particularly in children and SMA type 1, but also in type 2 and 3, adolescents and adults.

Parent-reported sleep disorders in children with motor disabilities: a comparison with the Sleep Disturbance Scale for Children's new norms.

OBJECTIVE: Children with motor disabilities such as cerebral palsy or neuromuscular diseases present more sleep disorders than their typically developing (TD) peers. However, research on these populations has always been performed using historical normative datasets or controls such as siblings. Therefore, we assessed the sleep quality of children with motor disabilities in comparison with a large, contemporary, general population sample. METHODS: Demographic, medical, and the Sleep Disturbance Scale for Children (SDSC) questionnaires were sent to parents of children aged 4-18 years and followed by our tertiary pediatric neurorehabilitation clinic, and to those of school-aged children in regional primary and secondary schools. TD participant data allowed us to set pathological sleep score thresholds (T score ≥70). RESULTS: We collected 245 responses for children with motor disabilities and 2891 for those from the general population (37% and 26% response rates, respectively). Cerebral palsy was the most frequent diagnosis (N = 109, 44.5%). Children with motor disabilities had significantly more frequent pathological sleep reported in their total SDSC score (7% vs 1.9%, odds ratio (OR) 3.98, 95% confidence interval (CI) 2.17-7.27, p < 0.001) and in five subscores. Single-parent households and drug-resistant epilepsy showed significant positive associations with pathological sleep among children with motor disabilities. For TD peers, parental unemployment and parental nationality were positively associated with pathological sleep. CONCLUSION: This population-based study robustly estimated the prevalence of sleep disorders in children with motor disabilities. Sleep disorders were significantly more frequent in children with motor disabilities, but at a lower frequency than previously reported.

Myoglobinuria in two patients with Duchenne muscular dystrophy after treatment with zoledronate: a case-report and call for caution.

Rhabdomyolysis with myoglobinuria is a recognized complication of dystrophinopathies. It can be triggered by infections, exercise or volatile anesthetics. To our knowledge, it has never been reported in boys with Duchenne muscular dystrophy (DMD) after the administration of bisphosphonates. We report two patients with DMD who presented an apparent transient rhabdomyolysis with myoglobinuria after zoledronate administration. Possible mechanisms could involve hypophosphatemia, a known dose-dependent side effect of bisphosphonates, and/or direct myotoxicity of biphosphonates. Physicians and families should be aware of rhabdomyolysis with myoglobinuria as a potential uncommon side effect of bisphosphonates in DMD, in particular of zoledronate.