Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol.

BACKGROUND: Hereditary spinal muscular atrophy (SMA) is a motor neuron disorder with a wide range in severity in children and adults. Two therapies that alter splicing of the Survival Motor Neuron 2 (SMN2) gene, i.e. nusinersen and risdiplam, improve motor function in SMA, but treatment effects vary. Experimental studies indicate that motor unit dysfunction encompasses multiple features, including abnormal function of the motor neuron, axon, neuromuscular junction and muscle fibres. The relative contributions of dysfunction of different parts of the motor unit to the clinical phenotype are unknown. Predictive biomarkers for clinical efficacy are currently lacking. The goals of this project are to study the association of electrophysiological abnormalities of the peripheral motor system in relation to 1) SMA clinical phenotypes and 2) treatment response in patients treated with SMN2-splicing modifiers (nusinersen or risdiplam). METHODS: We designed an investigator-initiated, monocentre, longitudinal cohort study using electrophysiological techniques ('the SMA Motor Map') in Dutch children (≥ 12 years) and adults with SMA types 1-4. The protocol includes the compound muscle action potential scan, nerve excitability testing and repetitive nerve stimulation test, executed unilaterally at the median nerve. Part one cross-sectionally assesses the association of electrophysiological abnormalities in relation to SMA clinical phenotypes in treatment-naïve patients. Part two investigates the predictive value of electrophysiological changes at two-months treatment for a positive clinical motor response after one-year treatment with SMN2-splicing modifiers. We will include 100 patients in each part of the study. DISCUSSION: This study will provide important information on the pathophysiology of the peripheral motor system of treatment-naïve patients with SMA through electrophysiological techniques. More importantly, the longitudinal analysis in patients on SMN2-splicing modifying therapies (i.e. nusinersen and risdiplam) intents to develop non-invasive electrophysiological biomarkers for treatment response in order to improve (individualized) treatment decisions. TRIAL REGISTRATION: NL72562.041.20 (registered at https://www.toetsingonline.nl . 26-03-2020).

A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.

A novel variant of unknown significance c.8A > G (p.Glu3Gly) in TPM3 was detected in two unrelated families. TPM3 encodes the transcript variant Tpm3.12 (NM_152263.4), the tropomyosin isoform specifically expressed in slow skeletal muscle fibers. The patients presented with slowly progressive muscle weakness associated with Achilles tendon contractures of early childhood onset. Histopathology revealed features consistent with a nemaline rod myopathy. Biochemical in vitro assays performed with reconstituted thin filaments revealed defects in the assembly of the thin filament and regulation of actin-myosin interactions. The substitution p.Glu3Gly increased polymerization of Tpm3.12, but did not significantly change its affinity to actin alone. Affinity of Tpm3.12 to actin in the presence of troponin ± Ca2+ was decreased by the mutation, which was due to reduced interactions with troponin. Altered molecular interactions affected Ca2+-dependent regulation of the thin filament interactions with myosin, resulting in increased Ca2+ sensitivity and decreased relaxation of the actin-activated myosin ATPase activity. The hypercontractile molecular phenotype probably explains the distal joint contractions observed in the patients, but additional research is needed to explain the relatively mild severity of the contractures. The slowly progressive muscle weakness is most likely caused by the lack of relaxation and prolonged contractions which cause muscle wasting. This work provides evidence for the pathogenicity of the TPM3 c.8A > G variant, which allows for its classification as (likely) pathogenic.

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = -0.56 and -0.59; both P < .001) whereas for fat fraction values are τ = -0.50 and -0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.

Drug treatment for spinal muscular atrophy types II and III.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES: To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA: We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS: Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.

Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests.

BACKGROUND: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity. METHODS: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons (N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15). RESULTS: Fatigability in SMA was operationalised as the decline in physical performance. The following test criteria were established; one method of testing for patients with SMA type 2-4, a set of outcome measures that mimic daily life activities, a submaximal test protocol of repetitive activities over a longer period; external regulation of pace. The scoping review did not generate suitable outcome measures. We therefore adapted the Endurance Shuttle Walk Test for ambulatory patients and developed the Endurance Shuttle Box and Block Test and the - Nine Hole Peg Test for fatigability testing of proximal and distal arm function. Content validity was established through input from experts and patients. Pilot testing showed that the set of endurance tests are comprehensible, feasible and meet all predefined test criteria. CONCLUSIONS: The development of this comprehensive set of endurance tests is a pivotal step to address fatigability in patients with SMA.

Drug treatment for spinal muscular atrophy type I.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a point mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. By definition, children with SMA type I are never able to sit without support and usually die or become ventilator dependent before the age of two years. There have until very recently been no drug treatments to influence the course of SMA. We undertook this updated review to evaluate new evidence on emerging treatments for SMA type I. The review was first published in 2009 and previously updated in 2011. OBJECTIVES: To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. We also searched two trials registries to identify unpublished trials (October 2018). SELECTION CRITERIA: We sought all randomised controlled trials (RCTs) or quasi-RCTs that examined the efficacy of drug treatment for SMA type I. Included participants had to fulfil clinical criteria and have a genetically confirmed deletion or mutation of the SMN1 gene (5q11.2-13.2). The primary outcome measure was age at death or full-time ventilation. Secondary outcome measures were acquisition of motor milestones, i.e. head control, rolling, sitting or standing, motor milestone response on disability scores within one year after the onset of treatment, and adverse events and serious adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1 gene replacement with viral vectors are out of the scope of this review. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We identified two RCTs: one trial of intrathecal nusinersen in comparison to a sham (control) procedure in 121 randomised infants with SMA type I, which was newly included at this update, and one small trial comparing riluzole treatment to placebo in 10 children with SMA type I. The RCT of intrathecally-injected nusinersen was stopped early for efficacy (based on a predefined Hammersmith Infant Neurological Examination-Section 2 (HINE-2) response). At the interim analyses after 183 days of treatment, 41% (21/51) of nusinersen-treated infants showed a predefined improvement on HINE-2, compared to 0% (0/27) of participants in the control group. This trial was largely at low risk of bias. Final analyses (ranging from 6 months to 13 months of treatment), showed that fewer participants died or required full-time ventilation (defined as more than 16 hours daily for 21 days or more) in the nusinersen-treated group than the control group (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.32 to 0.89; N = 121; a 47% lower risk; moderate-certainty evidence). A proportion of infants in the nusinersen group and none of 37 infants in the control group achieved motor milestones: 37/73 nusinersen-treated infants (51%) achieved a motor milestone response on HINE-2 (risk ratio (RR) 38.51, 95% CI 2.43 to 610.14; N = 110; moderate-certainty evidence); 16/73 achieved head control (RR 16.95, 95% CI 1.04 to 274.84; moderate-certainty evidence); 6/73 achieved independent sitting (RR 6.68, 95% CI 0.39 to 115.38; moderate-certainty evidence); 7/73 achieved rolling over (RR 7.70, 95% CI 0.45 to 131.29); and 1/73 achieved standing (RR 1.54, 95% CI 0.06 to 36.92; moderate-certainty evidence). Seventy-one per cent of nusinersen-treated infants versus 3% of infants in the control group were responders on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) measure of motor disability (RR 26.36, 95% CI 3.79 to 183.18; N = 110; moderate-certainty evidence). Adverse events and serious adverse events occurred in the majority of infants but were no more frequent in the nusinersen-treated group than the control group (RR 0.99, 95% CI 0.92 to 1.05 and RR 0.70, 95% CI 0.55 to 0.89, respectively; N = 121; moderate-certainty evidence). In the riluzole trial, three of seven children treated with riluzole were still alive at the ages of 30, 48, and 64 months, whereas all three children in the placebo group died. None of the children in the riluzole or placebo group developed the ability to sit, which was the only milestone reported. There were no adverse effects. The certainty of the evidence for all measured outcomes from this study was very low, because the study was too small to detect or rule out an effect, and had serious limitations, including baseline differences. This trial was stopped prematurely because the pharmaceutical company withdrew funding. Various trials and studies investigating treatment strategies other than nusinersen, such as SMN2 augmentation by small molecules, are ongoing. AUTHORS' CONCLUSIONS: Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I. It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and CHOP INTEND). The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty. It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence. Future trials could provide more high-certainty, longer-term evidence to confirm this result, or focus on comparing new treatments to nusinersen or evaluate them as an add-on therapy to nusinersen.

Social participation of adult patients with spinal muscular atrophy: Frequency, restrictions, satisfaction, and correlates.

INTRODUCTION: In this study we assessed social participation in 62 adults with spinal muscular atrophy (SMA) types 1c-4. METHODS: The outcome measure used was the Utrecht Scale of Evaluation Rehabilitation-Participation (USER-P) with Frequency, Restrictions, and Satisfaction scores, and a hierarchical regression analysis. RESULTS: Early-onset (types 1, 2, and 3a) and late-onset (types 3b and 4) SMA patients reported similar frequency and satisfaction scores. "Age," "motor skills," "pain," and "feelings of depression" correlated with frequency; "motor skills" and "feelings of depression" correlated with restrictions; and "level of education," "fatigue," and "feelings of depression" correlated with satisfaction. "Motor skills" and "feelings of depression" explained 33% of variance in frequency of participation. "Motor skills" explained 26% of variance of restrictions in participation. "Fatigue" and "feelings of depression" explained 50% of variance in satisfaction with participation. DISCUSSION: Motor skills, feelings of depression and fatigue are correlates of participation in daily life. This knowledge can be used to optimize care for SMA patients. Muscle Nerve 58:805-811, 2018.

Correlates of health related quality of life in adult patients with spinal muscular atrophy.

INTRODUCTION: To improve care for patients with spinal muscular atrophy (SMA), we assessed the physical and mental quality of life (QoL) in 62 adult patients with SMA. METHODS: Physical component scores (PCS) and mental component scores (MCS) of the Short Form-36 Health Survey (SF-36) were obtained. Correlations with demographics, disease severity, and emotional distress were assessed. We used hierarchical multiple regression analysis to identify determinants of QoL. RESULTS: PCS scores were lower, and MCS scores higher than in the healthy reference population. Patients with milder SMA types reported lower scores on several MCS domains. Motor skills scores and emotional distress explained 16% of the variance in PCS. SMA type and emotional distress explained 10% and 45% of the variance of MCS, respectively. CONCLUSIONS: Patients with milder forms of SMA tend to have a reduced mental QoL. Psychological interventions to reduce emotional distress may improve both mental and physical QoL. Muscle Nerve 54: 850-855, 2016.

Exploring functional strength changes during nusinersen treatment in symptomatic children with SMA types 2 and 3.

The Hammersmith Functional Motor Scale-Expanded (HFMSE) is a validated outcome measure for monitoring changes in functional strength in patients with spinal muscular atrophy (SMA). The objective of this study was to explore changes in HFMSE item-scores in children with SMA types 2 and 3a treated with nusinersen over a period of six to twenty months. We stratified patients according to motor ability (sitting and walking), and calculated numbers and percentages for each specific improvement (positive score change) or decrease (negative score change) for the total group and each subgroup and calculated frequency distributions of specific score changes. Ninety-one percent of the children showed improvement in at least 1 item, twenty-eight percent showed a score decrease in 1 or more items. In the first six to twenty months of nusinersen treatment motor function change was characterized by the acquisition of the ability to perform specific tasks with compensation strategies (score changes from 0 to 1). Children with the ability to sit were most likely to improve in items that assess rolling, whilst children with the ability to walk most likely improved in items that assess half-kneeling. The ability most frequently lost was hip flexion in supine position.

Monitoring Nusinersen Treatment Effects in Children with Spinal Muscular Atrophy with Quantitative Muscle MRI.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA. OBJECTIVE: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect. METHODS: We used a quantitative MRI protocol before start of treatment and following the 4th and 6th injection of nusinersen in 8 children with SMA type 2 and 3 during the first year of treatment. The MR protocol allowed DIXON, T2 mapping and diffusion tensor imaging acquisitions. We also assessed muscle strength and motor function scores. RESULTS: Fat fraction of all thigh muscles with the exception of the m. adductor longus increased in all patients during treatment (+3.2%, p = 0.02). WaterT2 showed no significant changes over time (-0.7 ms, p = 0.3). DTI parameters MD and AD demonstrate a significant decrease in the hamstrings towards values observed in healthy muscle. CONCLUSIONS: Thigh muscles of children with SMA treated with nusinersen showed ongoing fatty infiltration and possible normalization of thigh muscle microstructure during the first year of nusinersen treatment. Quantitative muscle MRI shows potential as biomarker for the effects of SMA treatment strategies.

Natural History of Mandibular Function in Spinal Muscular Atrophy Types 2 and 3.

Background: Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. Objective: In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3. Methods: We included 44 patients with SMA types 2 and 3 (mean age was 33.6 (95% CI 28.4;38.9) and re-examined them after on average 4 years. None were treated with SMN-modulating treatments before or during the course of this study. Longitudinal assessments included a questionnaire on mandibular and bulbar function, the Mandibular Function Impairment Questionnaire (MFIQ), and a clinical examination of masticatory performance, maximum voluntary bite force, and mandibular movements including the active maximal mouth opening. Results: We found significant higher MFIQ scores and a significant decrease of all mandibular movements in patients with SMA type 2 (p < 0.001), but not in SMA type 3. Masticatory performance and maximum voluntary bite force did not change significantly. Mean reduction of active maximal mouth opening at follow-up was 3.5 mm in SMA type 2 (95% CI: 2.3; 4.7, p < 0.001). SMA type 2 was an independent predictor for a more severe reduction of the mouth opening (ß= -2.0 mm (95% CI: -3.8; -0.1, p = 0.043)). Conclusions: Bulbar functions such as mandibular mobility and active maximum mouth opening decrease significantly over the course of four years in patients with SMA type 2.

Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine.

OBJECTIVE: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). METHODS: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. RESULTS: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. CONCLUSIONS: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. SIGNIFICANCE: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.

Feasibility and tolerability of multimodal peripheral electrophysiological techniques in a cohort of patients with spinal muscular atrophy.

Objective: Electrophysiological techniques are emerging as an aid in identifying prognostic or therapeutic biomarkers in patients with spinal muscular atrophy (SMA), but electrophysiological assessments may be burdensome for patients. We, therefore, assessed feasibility and tolerability of multimodal peripheral non-invasive electrophysiological techniques in a cohort of patients with SMA. Methods: We conducted a single center, longitudinal cohort study investigating the feasibility and tolerability of applying multimodal electrophysiological techniques to the median nerve unilaterally. Techniques consisted of the compound muscle action potential scan, motor nerve excitability tests, repetitive nerve stimulation and sensory nerve action potential. We assessed tolerability using the numeric rating scale (NRS), ranging from 0 (no pain) to 10 (worst possible pain), and defined the protocol to be tolerable if the NRS score ≤ 3. The protocol was considered feasible if it could be performed according to test and quality standards. Results: We included 71 patients with SMA types 1-4 (median 39 years; range 13-67) and 63 patients at follow-up. The protocol was feasible in 98% of patients and was well-tolerated in up to 90% of patients. Median NRS score was 2 (range 0-6 at baseline and range 0-4 at follow-up (p < 0.01)). None of the patients declined follow-up assessment. Conclusions: Multimodal, peripheral, non-invasive, electrophysiological techniques applied to the median nerve are feasible and well-tolerated in adolescents and adults with SMA types 1-4. Significance: Our study supports the use of non-invasive multimodal electrophysiological assessments in adolescents and adults with SMA types 1-4.

Lung function decline preceding chronic respiratory failure in spinal muscular atrophy: a national prospective cohort study.

BACKGROUND: Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure. METHODS: We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PEmax). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure. RESULTS: We analyzed 385 lung function tests from 38 patients with SMA types 1c-3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2-30.1) and median standardized FVC, FEV1 and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PEmax was 35.3 cmH2O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV1, PEF and PEmax were lower in patients who electively started mechanical ventilation (p < 0.001). CONCLUSIONS: Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PEmax remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection.

Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2-4.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2-4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: -1.17-1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00-1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15-0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011-004369-34, NCT02941328.

Drug treatment for spinal muscular atrophy type I.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. OBJECTIVES: To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. SELECTION CRITERIA: We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS: Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS: One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. AUTHORS' CONCLUSIONS: No drug treatment for SMA type I has been proven to have significant efficacy.

Drug treatment for spinal muscular atrophy types II and III.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009. OBJECTIVES: To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). SELECTION CRITERIA: We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. MAIN RESULTS: Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. AUTHORS' CONCLUSIONS: There is no proven efficacious drug treatment for SMA types II and III.