Malnutrition in Spinal Muscular Atrophy Type I: Case Report of a Novel Nutritional Intervention With Improved Growth and Function While Receiving Parallel Gene Splicing Therapies.

Children with spinal muscular atrophy (SMA) frequently experience feeding intolerance and diminished growth. Although splicing modulators to prevent symptoms are available worldwide, adequate nutrition to support growth, development, and improved quality of life remains essential. We present a case study of a one-year-old malnourished male with SMA type I who achieved improved growth and feeding tolerance with a human milk (HM)-derived nutrition intervention. Despite feeding with appropriately balanced semielemental formula, he remained severely malnourished after two months of hospitalization. Feeds were partially replaced with HM-based diet plus a HM-based fat modular. Feeding tolerance, fecal calprotectin levels, and z scores for weight and length improved while receiving the HM-based intervention. We hypothesize that the HM-based feeding reduced intestinal inflammation by diminishing pathogenic elements of his microbiome. Owing to their aberrant fatty acid metabolism, patients with SMA are uniquely positioned to benefit from HM-based nutrient acquisition even while receiving splicing modulators to stabilize the disease process.

Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1.

The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades, the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life and creating new challenges and goals. Many nutritional problems, gastrointestinal disorders and metabolic and endocrine alterations are commonly identified in patients affected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidisciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.

[Audiovisual stimulation in children with severely limited motor function: does it improve their quality of life?]. / Estimulacion audiovisual en niños con limitacion grave de la motricidad: mejora su calidad de vida?

INTRODUCTION: Children with neurological diseases that impose severe limitations on their mobility have a deficient quality of life (QL). AIMS: To study whether the QL of such patients improves with the application of a programme of audiovisual stimulation. PATIENTS AND METHODS: A prospective study was conducted on nine children, six of whom were males (mean age: 42.6 ± 28.6 months), with severely limited mobility and who had been hospitalised for long periods. Two audiovisual stimulation programmes were produced and applied, together with videos, by means of a specially designed structure. The stimulus was applied twice a day for 10 minutes over 20 days. The first ten days the stimulus was carried out in a passive manner and the second block of ten days it was performed with the guidance of the observer. Biological, behavioural and cognitive variables were recorded and an adapted QL survey was applied. RESULTS: Three cases of spinal muscular atrophy, two of congenital muscular dystrophy, two of myopathy and two with other conditions were diagnosed. Eight patients completed the follow-up. From the baseline point of view, they presented a regular QL (7.2 ± 1.7 points; median: 7.0; range: 6-10), which improved to good on finishing the therapy (9.4 ± 1.2 points; median: 9.0; range: 8-11), with an intra-individual difference of 2.1 ± 1.6 (median: 2.5; range: -1 to 4; CI 95% = 0.83-3.42; p = 0.006). Improved cognition and a favourable perception in the caregivers were detected. No changes took place in the biological or behavioural variables. CONCLUSIONS: Audiovisual stimulation can be used to enhance the quality of life of children with severely limited mobility.

TITLE: Estimulacion audiovisual en niños con limitacion grave de la motricidad: mejora su calidad de vida?Introduccion. Los niños con enfermedades neurologicas que condicionan una limitacion grave de la movilidad tienen una calidad de vida (CV) deficiente. Objetivo. Estudiar si la CV de dichos pacientes mejora con la aplicacion de un programa de estimulacion audiovisual. Pacientes y metodos. Estudio prospectivo en nueve niños, seis de ellos varones (edad media: 42,6 ± 28,6 meses), con limitacion grave de la movilidad, hospitalizados de manera prolongada. Se elaboraron dos programas de estimulo audiovisual que, junto con videos, se aplicaron mediante una estructura especialmente diseñada. La frecuencia fue de dos veces al dia, por 10 minutos, durante 20 dias. Los primeros diez dias se llevo a cabo de manera pasiva y los segundos diez con guia del observador. Se registraron variables biologicas, conductuales, cognitivas y se aplico una encuesta de CV adaptada. Resultados. Se diagnosticaron tres casos de atrofia muscular espinal, dos de distrofia muscular congenita, dos de miopatia y dos con otros diagnosticos. Ocho pacientes completaron el seguimiento. Desde el punto de vista basal, presentaron CV regular (7,2 ± 1,7 puntos; mediana: 7,0; rango: 6-10), que mejoraba a buena al finalizar (9,4 ± 1,2 puntos; mediana: 9,0; rango: 8-11), con diferencia intraindividual de 2,1 ± 1,6 (mediana: 2,5; rango: ­1 a 4; IC 95% = 0,83-3,42; p = 0,006). Se detecto mejoria en cognicion y percepcion favorable de los cuidadores. No hubo cambio en las variables biologicas ni conductuales. Conclusion. Mediante la estimulacion audiovisual es posible mejorar la calidad de vida de niños con limitacion grave de la movilidad.

Perspectives on clinical trials in spinal muscular atrophy.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.

Evaluation of therapeutic electrical stimulation to improve muscle strength and function in children with types II/III spinal muscular atrophy.

The study aimed to evaluate the effect of low-intensity night-time therapeutic electrical stimulation (TES) on arm strength and function in children with intermediate type spinal muscular atrophy (SMA). The design was a randomized controlled trial with a 6-month baseline control period. Children were evaluated at baseline, 6, and 12 months. TES was applied from 6 to 12 months to the deltoid and biceps muscle, of a randomly selected arm with the opposite arm receiving a placebo stimulator. Thirteen individuals with SMA between 5 to 19 years of age were recruited into the study and eight completed the 12-month assessment. No statistically significant differences between the treatment and control arm were found at baseline, 6, and 12 months for elbow flexors, or shoulder abductors on quantitative myometry or manual muscle testing. There was no significant change in excitable muscle mass assessed by M-wave amplitudes, nor function on the Pediatric Evaluation of Disability Inventory (self-care domain). Therefore, in this study there was no evidence that TES improved strength in children with SMA.

[Pulsed magnetic fields--their possibilities in pediatric neurology]. / Pulzní magnetické pole--jeho moznosti v detské neurologii.

The author reviews information on the use of a pulsatile magnetic field with defined parameters in some child diseases of the CNS according to his experience assembled during the past five years. PMP was applied in 17 cases with spinal amyotrophy type M. Werdnig-Hoffman and in 16 cases with DMO. In both diseases treatment was previously only symptomatic. PMP frequencies of alpha EEG waves were used during application on the area of the head and a different frequency for whole body treatment focused on muscular dystonia. The author draws attention to the specificity of biotropic parameters of the applied magnetic field.