Assessing perspectives of disease burden and clinically meaningful changes using the Spinal Muscular Atrophy Health Index in adolescents and young adults.

INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) treatment may increase survival and improve physical function among adolescents and young adults. Validated patient-reported outcome measures are needed to understand which treatment benefits are clinically meaningful and to develop targeted resources for this population. To date, use of the SMA Health Index (SMA-HI) in pediatric and young adult populations has been limited. Here, we report results from a survey of adolescents and young adults with SMA to quantifiably understand individuals' perceptions of disease burden. METHODS: Participants aged 12-25 y with a self-reported diagnosis of SMA completed an online survey containing demographic questions and the SMA-HI, a patient-reported outcome measure that assesses individuals' perceptions of disease burden in 15 symptomatic areas. RESULTS: Eighty-eight participants completed the survey. Total SMA-HI scores and SMA-HI subscale scores including shoulder and arm function; back, chest, and abdominal function; activity participation; hand and finger strength; swallowing function; gastrointestinal function; respiratory function; mobility and ambulation, and total disease burden were significantly higher (greater disease burden) in patients with poorer motor function and severe SMA. SMA-HI total and subscale scores were generally lower in adolescents (12-17 y old) versus adults (18-25 y old), suggesting a possible progression of symptomatic disease burden over time. DISCUSSION: This study demonstrates the utility of the SMA-HI for measuring clinically relevant disease burden in adolescents and young adults with SMA. This study demonstrates how disease burden varies by age, SMA type, and other demographics.

Early Cost-Effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) Treatment for Spinal Muscular Atrophy I in The Netherlands With Relapse Scenarios.

OBJECTIVES: Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. METHODS: An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. CONCLUSIONS: Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

State of the art for motor function assessment tools in spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is a progressive disease characterized by a degeneration of the spinal cord motor neurons. Many clinical trials - planned, in progress, or completed - have chosen motor function as the primary or secondary outcome because motor function assessment tools appeared to be more reliable than quantitative muscle testing in monitoring the course of the disease. Reliable, valid, and responsive outcome measures are needed to be able to capture the effectiveness of the therapeutic approach during clinical trials. Medical staff involved in neuromuscular diseases is faced with increasing pressure regarding the complex issue of choosing the right outcome measure for the objectives they have to assess. This paper provides a narrative literature review of available and validated motor function assessment tools in SMA population based on SMA subtypes, age and ambulant status. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Identifying Opportunities to Provide Family-centered Care for Families With Children With Type 1 Spinal Muscular Atrophy.

STUDY PURPOSE: The purpose of this qualitative study was to understand, from the parent perspective, the experience of the family whose child has Type 1 spinal muscular atrophy (Type 1 SMA), in the emergency center, hospital, and clinical care settings to identify opportunities for improved family-centered care (FCC). DESIGN AND METHODS: This study used a qualitative descriptive design with individual or small group interviews guided by a semi-structured questionnaire. Reviewers used framework analysis to identify gaps in the provision of FCC and opportunities for improvement with respect to services health professionals may provide families of children with Type 1 SMA. RESULTS: Nineteen families with 22 children with Type 1 SMA participated. Results are organized according to eight basic tenets of FCC. Family-to-family interactions strongly impacted participants' decision-making and perceived level of support. Participants valued strong family/provider partnerships, feeling heard and respected by their providers, and receiving complete education regarding disease trajectory. CONCLUSIONS: Our analyses revealed both successful application of FCC and gaps in care where FCC could have been used to benefit families who have children with Type 1 SMA. As a pediatric chronic illness affects the whole family, FCC is important in maintaining the providers' focus on the family during the child's care. PRACTICE IMPLICATIONS: There are opportunities for nursing, social work, care managers and others to engage as care coordinators to explain the family's goals and values to the medical team. Care coordinators help ensure understanding between families and providers, empowering the family to articulate their hopes and concerns.

A double determination of central motor conduction time in the assessment of Hirayama disease.

OBJECTIVE: To investigate central motor conduction time (CMCT) in patients with Hirayama disease (HD) and to analyse the role of motor nerve root lesions in the pathogenesis of HD. METHODS: CMCT measured by F-wave (CMCT-F) and by paravertebral magnetic stimulation (CMCT-M) was performed on both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) in 41 HD patients and 22 controls. All patients underwent neck-flexion magnetic resonance imaging evaluation. RESULTS: Prolonged CMCT (CMCT-F and/or CMCT-M) was recorded in at least one tested muscle from 7/41 (17.1%) HD patients, and 4 cases presented significant prolonged CMCT-M with normal CMCT-F on the side with significant cervical cord forward-shifting. This asymmetric forward-shifting was identified in 13 HD patients, and forward-shifting on the symptomatic side was more obvious. Compared to the controls (ADM: 0.9±0.3ms; APB: 0.8±0.3ms) and the other 28 HD patients (symptomatic side: ADM: 0.8±0.2ms, APB: 0.8±0.3ms), increased nerve root conduction times were demonstrated in these symptomatic sides (ADM: 1.5±0.7ms; APB: 1.2±0.6ms) (P<0.05). CONCLUSIONS: Motor nerve root may be main lesion site in some HD patients, especially on the symptomatic side of patients with asymmetric neck-flexion cervical cord forward-shifting. SIGNIFICANCE: Compared to spinal motor neuron lesions, damage to motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD. Abnormally increased forward traction in shorter nerve roots may be the cause for the main damage in motor nerve root.

Motor unit number estimation in the quantitative assessment of severity and progression of motor unit loss in Hirayama disease.

OBJECTIVE: To investigate motor unit number estimation (MUNE) as a method to quantitatively evaluate severity and progression of motor unit loss in Hirayama disease (HD). METHODS: Multipoint incremental MUNE was performed bilaterally on both abductor digiti minimi and abductor pollicis brevis muscles in 46 patients with HD and 32 controls, along with handgrip strength examination. MUNE was re-evaluated approximately 1year after initial examination in 17 patients with HD. RESULTS: The MUNE values were significantly lower in all the tested muscles in the HD group (P<0.05). Despite abnormally low MUNE values, 54.3% (25/46) of patients with HD had normal ipsilateral grip power. There was a significant inverse correlation between MUNE values and disease duration (P<0.05). A longitudinal follow-up MUNE analysis demonstrated slow progression of motor unit loss in patients with HD within approximately 1year (P<0.05), even in patients with an illness duration >4years. CONCLUSIONS: A reduction in the functioning motor units was found in patients with HD compared with that in controls, even in the early asymptomatic stages. Moreover, the motor unit loss in HD progresses gradually as the disease advances. SIGNIFICANCE: These results have provided evidence for the application of MUNE in estimating the reduction of motor unit in HD and confirming the validity of MUNE for tracking the progression of HD in a clinical setting.

The Quantitative Assessment of Imaging Features for the Study of Hirayama Disease Progression.

OBJECTIVE: To evaluate the forward shifting of cervical spinal cords in different segments of patients with Hirayama disease to determine whether the disease is self-limiting. METHODS: This study was performed on 11 healthy subjects and 64 patients. According to the duration, the patients were divided into 5 groups (≤1 year, 1-2 years, 2-3 years, 3-4 years, and ≥ 4 years). Cervical magnetic resonance imaging (MRI) of flexion and conventional position was performed. The distances between the posterior edge of the spinal cord and the cervical spinal canal (X), the anterior and posterior wall of the cervical spinal canal (Y), and the anterior-posterior (A) and the transverse diameter (B) of spinal cord cross sections were measured at different cervical spinal segments (C4 to T1). RESULTS: In cervical flexion position, a significant increase in X/Y of C4-5 segments was found in groups 2-5, the C5-6 and C6-7 segments in groups 1-5, and the C7-T1 segments in group 5 (P < 0.05). The degree of the increased X/Y and cervical flexion X/Y of C5-6 segments were different among the 5 groups (P < 0.05), which was likely due to rapid increases in X/Y during the course of Hirayama's disease. CONCLUSION: The X/Y change progression indicates that Hirayama disease may not be self-limiting.

Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study.

BACKGROUND: The clinical features of SMA, which range along a spectrum of severity, are relatively well described. In contrast, the literature on how individuals with SMA and their families experience this condition is limited. To address this gap, we undertook a qualitative study with individuals affected by SMA Types I, II and III, parents of those affected, and clinicians. METHODS: We completed 16 focus group sessions and 37 interviews in the US with 96 participants including: 21 with individuals with SMA; 64 parents of individuals affected by SMA; and 11 clinicians who specialize in the care of SMA patients. RESULTS: The Diagnostic Journey: Families reported substantial diagnostic delays owing to: 1) lack of awareness and knowledge about SMA; 2) the difficulty of distinguishing normal from abnormal development; and 3) the challenge of differential diagnosis. Lack of sensitivity in how clinicians communicated this potentially devastating diagnosis compounded parents' negative impressions. Newborn Screening: Parents generally held positive views about adding SMA to newborn screening panels. For example, it would: 1) enable earlier access to care; 2) shorten the diagnostic journey; and 3) give families more time to prepare to care for a disabled child. Some noted negative outcomes such as prematurely affecting a parent's relationship with a child before symptoms are evident. The Psychosocial Impact of Living with SMA: Ten thematic areas characterized the impact: 1) confronting premature death; 2) making difficult treatment choices; 3) fearing the loss of functional ability; 4) coming to terms with lost expectations; 5) loss of sleep and stress; 6) stigma; 7) limitations on social activities; 8) independence; 9) uncertainty and helplessness; and 10) family finances. CONCLUSIONS: The results of this study suggest high levels of burden experienced by individuals with SMA and their families. The difficulties of living with SMA begin with the long and often arduous process of finding a diagnosis for their child. Newborn screening for SMA is seen as an important step toward shortening this journey. The psychosocial effects of coping with SMA are substantial and wide ranging both for the individual living with this condition and family members of affected individuals.

Pathology and prognosis of proximal-type cervical spondylotic amyotrophy: new assessment using compound muscle action potentials of deltoid and biceps brachii muscles.

STUDY DESIGN: Case studies of patients with cervical spondylotic amyotrophy (CSA) used compound muscle action potentials (CMAPs) of deltoid and biceps brachii muscles. OBJECTIVE: To discuss pathology and prognosis from the magnetic resonance imaging (MRI) and CMAPs of deltoid and biceps brachii muscles. SUMMARY OF BACKGROUND DATA: CSA is a rare type of cervical spondylotic disorder. Selective lesions in ventral nerve roots (VNR) or anterior horns (AH) have been proposed to explain the pathology of CSA, but these are not well understood. METHOD: Conservative therapy was performed in 21 patients with the proximal-type CSA. Patients were classified into two groups: 13 with incomplete recovery of deltoid and biceps brachii muscle strength (Group 1) and 8 with complete recovery (Group 2). All underwent MRI. Erb-point-stimulated CMAPs were recorded in the deltoid and biceps. Measurements of CMAPs included negative-peak amplitude from the baseline to peak. The percentage amplitude of CMAPs was calculated in contrast to the opposite side. RESULTS: Sagittal T2-weighted MRI showed spinal cord compression in all patients from Group 1 and in four patients from Group 2. Deltoid muscle CMAPs: Three patients from Group 1 and all eight patients from Group 2 had a CMAPs' amplitude on the normal side that was greater than 10 mV. Biceps brachii muscle CMAPs: four patients from Group 1 and four patients from Group 2 had a CMAPs' amplitude on the normal side that was greater than 10 mV. CONCLUSION: Patients with a CMAPs amplitude on the normal side that exceeded 10 mV had no impingement of the AH. A CMAPs' amplitude that exceeded 10 mV on the normal side and a CMAPs' amplitude of more than 50% on the affected side compared with the normal side indicated slight involvement of VNR. These patients were able to fully recover function.

The cost-effectiveness of prenatal screening for spinal muscular atrophy.

OBJECTIVE: We sought to investigate the cost-effectiveness of prenatal screening for spinal muscular atrophy (SMA). STUDY DESIGN: A decision analytic model was created to compare a policy of universal SMA screening to that of no screening. The primary outcome was incremental cost per maternal quality-adjusted life year. Probabilities, costs, and outcomes were estimated through literature review. Univariate and multivariate sensitivity analyses were performed to test the robustness of our model to changes in baseline assumptions. RESULTS: Universal screening for SMA is not cost-effective at $4.9 million per quality-adjusted life year. In all, 12,500 women need to be screened to prevent 1 case of SMA, at a cost of $5.0 million per case averted. Our results were most sensitive to the baseline prevalence of disease. CONCLUSION: Universal prenatal screening for SMA is not cost-effective. For populations at high risk, such as those with a family history, SMA testing may be a cost-effective strategy.

Physical characteristics and applicability of standard assessment methods in a total population of spinal muscular atrophy type II patients.

The aims of this study were to evaluate muscle strength, functional abilities, contractures and Forced Vital Capacity in a population of 54 spinal muscular atrophy (SMA) type II patients between the ages of 5 and 70, and to evaluate the applicability of conventional assessment methods. The patients were evaluated by means of functional scales, muscles tests, joint motion measurement and Forced Vital Capacity test. There was a significant score difference in functional tests and muscle tests as well as in the sum of contractures between younger individuals (or= 21years). The functional scales were not sensitive enough to differentiate among the most impaired persons. A reduced Manual Muscle Test score of the upper limbs was found to differentiate more precisely among individuals than a total score derived from testing 38 muscle groups. There is a need for clinical tools that can evaluate patients with SMA type II of all ages and with severely reduced functional abilities.

Assessment of liquid microbead arrays for the screening of newborns for spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy is a common neurodegenerative disorder that has recently been considered for inclusion in the next generation of newborn screening regimens. We sought to validate liquid microbead arrays for the identification of affected individuals by direct DNA analysis. METHODS: Assays were created to detect the homozygous deletions in exon 7 of the SMN1 gene found in approximately 95% of affected individuals by use of 2 different microbead chemistries on the Luminex 200: MultiCode-PLx and Tag-It. A series of 367 blood spots including 164 from affected individuals, 46 from known carriers, and 157 from unaffected individuals were then analyzed with each assay. RESULTS: The MultiCode-PLx assay required 4.2 h to perform and provided correct identification of all 164 samples from affected individuals. Correct exclusion was also made for all 46 carrier and 157 unaffected individual samples. The Tag-It assay required 6.8 h, detected all samples from affected individuals, and excluded all but 1 (99.5%) of the samples from carriers and unaffected individuals. Neither method was sensitive to increasing copy numbers of the SMN2 gene. CONCLUSIONS: Both methods showed high sensitivity and specificity for the detection of patients with spinal muscular atrophy. For both methods, ample DNA was extracted from all blood spots for analysis, and SMN2 copy numbers did not interfere. Liquid bead arrays represent a robust method for DNA analysis in newborn screening laboratories.

Spinal muscular atrophy genetic counseling access and genetic knowledge: parents' perspectives.

Spinal muscular atrophy is characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord, which leads to progressive symmetrical muscle weakness and atrophy. Spinal muscular atrophy is the leading fatal autosomal recessive disorder in infancy, and genetic counseling is an essential component of the care of families of these patients. However, little guidance is available in the published literature regarding the process and benefit of genetic counseling for families. Accordingly, the authors designed a questionnaire to assess parents' knowledge of the disease, gauge their access to genetic counseling, and determine how parents use information gained from counseling to guide choices for future pregnancies. The questionnaire specifically targeted when genetic counseling was received, from whom, parental knowledge regarding spinal muscular atrophy genetics, parental choices regarding spinal muscular atrophy and their child, frequency of prenatal testing, perceived relevance of newborn screening, and opinions regarding the disease. Most families clearly received some type of genetic counseling. Yet how and from whom they received the information varied greatly, as did their genetic knowledge of spinal muscular atrophy. The highest percentage of families received counseling from neurologists, who may not be appropriately prepared to provide formal genetic counseling. Many respondents reported having a negative experience with genetic counseling, possibly because it occurred at the time of diagnosis or shortly afterward, a period of great emotional turmoil. These data suggest that a consistent approach for facilitating how and when genetic counseling is received is greatly needed.

A feasibility study for the newborn screening of spinal muscular atrophy.

PURPOSE: The natural history of spinal muscular atrophy suggests that for maximum effect, therapeutics will need to be administered in the earliest phases of the disease. This will require the adoption of techniques for the genetic analysis of affected individuals at the newborn stage. Our objective was to examine the feasibility surrounding the newborn screening for spinal muscular atrophy. METHODS: We investigated the application of real-time polymerase chain reaction technology for newborn screening. A multiplex assay was designed to identify homozygous deletions in SMN1 exon 7 and validated using 266 samples with defined SMN1 and SMN2 copy numbers. Sensitivity and specificity were then evaluated as part of a newborn screening strategy using DNA from 153 blood spots. RESULTS: Real-time technology validation demonstrated correct exclusion of all normal and carrier samples, and identified the homozygous SMN1 exon 7 deletions in all 32 affected samples. In the series of blood spots, all 59 affected samples were correctly identified yielding an analytic sensitivity of 100%; 56 normal and 39 carrier samples were correctly excluded yielding an analytic specificity of 100% for this blood spot series. CONCLUSION: We demonstrate that effective molecular technology exists and that ethics may soon warrant the newborn screening of spinal muscular atrophy.

Infant neurologic assessment.

Infant neurologic assessment reflects the ongoing maturation of the central nervous system. Traditional approaches to assessment cannot be used. Key factors are accurate observation and flexibility in obtaining the data. A case example using a 4-month-old infant illustrates specific approaches to assessment.