All Publications


  • Clinical and Research Readiness for Spinal Muscular Atrophy: The Time Is Now for Knowledge Translation. Physical therapy Krosschell, K. J., Young, S. D., Peterson, I., Curry, M., Mazzella, A., Jarecki, J., Cruz, R. 2022

    Abstract

    : Disease modifying therapies for spinal muscular atrophy (SMA) are rapidly changing the outlook for many individuals by substantially altering the clinical course, phenotypic expression and functional outcomes. Physical therapists have played critical roles in the effective conduct and execution of clinical trials leading to the approval of these therapies. Given the treatment landscape, educating practicing clinicians to understand best practice is of great importance and a timely call to action to facilitate knowledge translation from SMA researchers to clinicians is necessary. The SMA Clinical Trial Readiness Program engaged clinical and research centers, identified physical therapy knowledge gaps related to evaluation and outcomes assessment, and provided educational resources including the development of a SMA Best Practices Clinical Evaluator Toolkit. Toolkit content synthesizes evidence and covers a breadth of issues relevant to practice, including: background on SMA and the drug pipeline; therapist roles and responsibilities related to research; clinical and research evaluation; and useful materials and resources for additional education, training and professional development. Surveys and telephone interviews were conducted with physical therapists managing individuals with SMA to determine their SMA practice experience and educational needs. Their recommendations, along with synthesized SMA research evidence, provided input into toolkit content development and assisted in identifying gaps important to address. Impact was assessed over time via utilization feedback surveys downloaded by clinicians across various settings. Open-ended feedback supported beneficial use of the toolkit for clinicians and researchers working with individuals with SMA. Next steps should include timely dissemination to bring this resource and others into practice in a systematic, efficacious, and engaging manner. As the treatment landscape for SMA evolves the therapist's role in multidisciplinary care and research are of great importance and a "call to action" for the development, implementation, evaluation and reporting of informed knowledge, using evidence-based knowledge translation strategies is critical.IMPACT: Partnership among patient advocacy groups, industry collaborators, and key opinion leaders/experts can optimize essential resource development to address the knowledge gap for best practices in physical therapy. This partnership model can be replicated for other diseases providing an efficient way to support clinical trial readiness and target early development of evidence-based content and resources related to both research and best practice clinical evaluation for physical therapist researchers, clinicians, and patients. While identifying knowledge gaps and resource development are initial steps toward change in SMA practice, a rapidly changing rehabilitation outlook warrants a call to action for enhanced efforts aimed at improving rehabilitation evaluation, assessment, and care for this population. It is critical to forge a timely path forward for development, implementation, and sustainability of effective knowledge translation to practice for SMA.

    View details for DOI 10.1093/ptj/pzac108

    View details for PubMedID 35904447

  • Scoliosis Surgery Significantly Impacts Motor Abilities in Higher-functioning Individuals with Spinal Muscular Atrophy JOURNAL OF NEUROMUSCULAR DISEASES Young, S., Montes, J., Salazar, R., Glanzman, A. M., Pasternak, A., Mirek, E., Martens, W., Finkel, R. S., Darras, B. T., De Vivo, D. C. 2020; 7 (2): 183-192

    Abstract

    Weakness affects motor performance and causes skeletal deformities in spinal muscular atrophy (SMA). Scoliosis surgery decision-making is based on curve progression, pulmonary function, and skeletal maturity. Benefits include quality of life, sitting balance, and endurance. Post-operative functional decline has not been formally assessed.To assess the impact of scoliosis surgery on motor function in SMA types 2 and 3.Prospective data were acquired during a multicenter natural history study. Seventeen participants (12 type 2, 5 type 3 with 4 of the 5 having lost the ability to ambulate) had motor function assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) performed pre-operatively and at least 3 months post-operatively. Independent t-tests determined group differences based on post-operative HFMSE changes, age, and baseline HFMSE scores.Three participants had minimal HFMSE changes (±2 points) representing stability (mean change = -0.7). Fourteen participants lost >3 points, representing a clinically meaningful progressive change (mean change = -12.1, SD = 8.9). No participant improved >2 points. There were no age differences between stable and progressive groups (p = 0.278), but there were significant differences between baseline HFMSE (p = 0.006) and change scores (p = 0.001). Post-operative changes were permanent over time.Scoliosis surgery has an immediate impact on function. Baseline HFMSE scores anticipate post-operative loss as higher motor function scores were associated with worse decline. Instrumentation that includes fixation to the pelvis reduces flexibility, limiting the ability for compensatory maneuvers. These observations provide information to alert clinicians regarding surgical risk and to counsel families.

    View details for DOI 10.3233/JND-190462

    View details for Web of Science ID 000685105100011

    View details for PubMedID 32083590

  • Perceived Fatigue in Spinal Muscular Atrophy: A Pilot Study JOURNAL OF NEUROMUSCULAR DISEASES Young, S., Montes, J., Kramer, S. S., Podwika, B., Rao, A. K., De Vivo, D. C. 2019; 6 (1): 109-117

    Abstract

    Fatigue is a common complaint in spinal muscular atrophy (SMA). Fatigability is well described in ambulatory SMA but the relationship to perceived fatigue has not been evaluated. Understanding this relationship has proven challenging for most disorders.To assess the relationship of perceived fatigue to fatigability, function, and quality of life in SMA.Thirty-two participants with SMA (21.9% type 2, 78.1% type 3) were recruited. Perceived fatigue and fatigability, function, and quality of life were assessed using standardized questionnaires and assessments. Associations were analyzed using Pearson correlation coefficients (p = 0.05). Also, the effects of age, type, and ambulatory status were determined on perceived fatigue.All SMA participants reported fatigue. Perceived fatigue was not associated with function, quality of life, or fatigability in ambulatory SMA patients. Neither age, type, nor ambulatory status influenced perceived fatigue.Perceived fatigue can be quantified in SMA. Interestingly, perceived fatigue did not correlate with fatigability or function, suggesting that cognitive, homeostatic, or psychologic factors may be more relevant as co-morbid factors. Clinical trials targeting perceived fatigue in SMA should focus on these patient-reported assessments. A multilevel approach is required to separate the various mechanisms involved in perceived fatigue.

    View details for DOI 10.3233/JND-180342

    View details for Web of Science ID 000685097900010

    View details for PubMedID 30562906

  • Six-minute walk test is reliable and valid in spinal muscular atrophy MUSCLE & NERVE Young, S., Montes, J., Kramer, S. S., Marra, J., Salazar, R., Cruz, R., Chiriboga, C. A., Garber, C., De Vivo, D. C. 2016; 54 (5): 836-842

    Abstract

    The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA.Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients.Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE.This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016.

    View details for DOI 10.1002/mus.25120

    View details for Web of Science ID 000386699400002

    View details for PubMedID 27015431

  • Physical therapy services received by individuals with spinal muscular atrophy (SMA) JOURNAL OF PEDIATRIC REHABILITATION MEDICINE Dunaway, S., Montes, J., McDermott, M. P., Martens, W., Neisene, A., Glanzman, A. M., Pasternak, A., Riley, S., Sproule, D., Chiriboga, C., Finkel, R., Tennekoon, G., Darras, B., De Vivo, D., Pandya, S. 2016; 9 (1): 35-44

    Abstract

    The consensus statement for standard of care in SMA recommends multidisciplinary medical care including physical therapy (PT) services. To date there are no reports regarding the implementation of these recommendations and the type of care or services received by individuals with SMA. The purpose of this study is to describe the PT services received by individuals with SMA.Interviews were conducted with patients or their caregivers at the Pediatric Neuromuscular Clinical Research (PNCR) Network sites from October 2011 to September 2012. Questions included information about clinical status of the patient, sociodemographic profile of the patient or caregiver, and PT services received in the past year, including the setting, frequency, duration and type of PT, and therapies administered by caregivers.Eighty-six percent of 105 participants reported receiving PT services, some in multiple settings: 62% in the neuromuscular clinic, 38% at school, 34% at home, and 13% in an outpatient clinic. Greater frequency of PT services received was associated with younger age and inability to walk, but not SMA type.This is the first multicenter study documenting PT services received by patients with SMA. Further research is needed to better understand the impact of PT services on the natural history of SMA.

    View details for DOI 10.3233/PRM-160360

    View details for Web of Science ID 000448293800007

    View details for PubMedID 26966799

  • PERFORMANCE OF THE TIMED "UP & GO" TEST IN SPINAL MUSCULAR ATROPHY MUSCLE & NERVE Dunaway, S., Montes, J., Garber, C., Carr, B., Kramer, S. S., Kamil-Rosenberg, S., Strauss, N., Sproule, D., De Vivo, D. C. 2014; 50 (2): 273-277

    Abstract

    The timed "up & go" (TUG) test is a quick measure of balance and mobility. TUG scores correlate with clinical, functional, and strength assessment and decline linearly over time. Reliability and validity have not been tested in spinal muscular atrophy (SMA).Fifteen ambulatory SMA participants performed TUG testing and strength, functional, and clinical assessments. Intraclass correlation coefficients quantified test-retest reliability. Convergent validity was determined using Pearson correlation coefficients.Test-retest reliability was excellent for all participants. TUG was associated significantly with total leg and knee flexor strength, as well as the Hammersmith Functional Motor Scale Expanded, the 10-meter walk/run, and 6-minute walk tests. TUG findings were not associated with knee extensor strength, pulmonary function, or fatigue.In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA.

    View details for DOI 10.1002/mus.24153

    View details for Web of Science ID 000340237500017

    View details for PubMedID 24375426

  • Independent Mobility After Early Introduction of a Power Wheelchair in Spinal Muscular Atrophy JOURNAL OF CHILD NEUROLOGY Dunaway, S., Montes, J., O'Hagen, J., Sproule, D. M., De Vivo, D. C., Kaufmann, P. 2013; 28 (5): 576-582

    Abstract

    Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills.

    View details for DOI 10.1177/0883073812449383

    View details for Web of Science ID 000317683900003

    View details for PubMedID 22772161

  • Spinal Muscular Atrophy Type III: Trying to Understand Subtle Functional Change Over Time-A Case Report JOURNAL OF CHILD NEUROLOGY Dunaway, S., Montes, J., Ryan, P. A., Montgomery, M., Sproule, D. M., De Vivo, D. C. 2012; 27 (6): 779-785

    Abstract

    Spinal muscular atrophy is a relatively stable chronic disease. Patients may gradually experience declines in muscle strength and motor function over time. However, functional progression is difficult to document, and the mechanism remains poorly understood. An 11-year-old girl was diagnosed at 19 months and took a few steps without assistance at 25 months. She was evaluated for 54 months in a prospective multicenter natural history study. Outcome measures were performed serially. From 6 to 7.5 years, motor function improved. From 7.5 to 11 years, motor function declined with increasing growth. Manual muscle testing scores minimally decreased. Motor unit number estimation studies gradually increased over 4.5 years. Compared to the published natural history of spinal muscular atrophy type III, our patient lost motor function over time. However, she walked with assistance 2 years longer than expected. Our report highlights possible precipitating factors that could affect the natural history of spinal muscular atrophy type III.

    View details for DOI 10.1177/0883073811425423

    View details for Web of Science ID 000304143000013

    View details for PubMedID 22156787

  • Reliability of telephone administration of the PedsQL (TM) Generic Quality of Life Inventory (TM) and Neuromuscular Module (TM) in spinal muscular atrophy (SMA) NEUROMUSCULAR DISORDERS Dunaway, S., Montes, J., Montgomery, M., Battista, V., Koo, B., Marra, J., De Vivo, D. C., Hynan, L. S., Iannaccone, S. T., Kaufmann, P. 2010; 20 (3): 162-165

    Abstract

    Clinical research visits are challenging for people with SMA because of limited mobility and intercurrent illnesses. Missing data threaten the validity of research results. Obtaining outcomes remotely would represent a solution. To evaluate reliability of telephone administration of the PedsQL Pediatric Generic Core Quality of Life Inventory 4.0 (Generic) and Neuromuscular Module 3.0 (NM) in SMA, we recruited 21 participants of a Natural History Study for telephone administration of both modules no more than 7 days before or after an in-person study visit. We found excellent reliability between telephone and in-person administration of both modules with the NM slightly better than the Generic. Reliability of the child and parent forms was similar. We concluded that both modules can be administered reliably over the telephone to SMA patients and caregivers, expanding the utility of these tools in clinical trials. Notably, telephone administration is reliable in children as young as 8 years.

    View details for DOI 10.1016/j.nmd.2009.12.002

    View details for Web of Science ID 000276759100002

    View details for PubMedID 20074950

  • Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscular disorders : NMD Coratti, G., Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, A., Pane, M., Albamonte, E., Antonaci, L., Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, E., Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 1800

    Abstract

    The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

    View details for DOI 10.1016/j.nmd.2021.10.009

    View details for PubMedID 34980538

  • Different trajectories in upper limb and gross motor function in spinal muscular atrophy. Muscle & nerve Coratti, G., Pera, M. C., Montes, J., Pasternak, A., Scoto, M., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Mazzone, E. S., Milev, E., Rohwer, A., Civitello, M., Pane, M., Antonaci, L., Frongia, A. L., Sframeli, M., Vita, G. L., D'Amico, A., Mizzoni, I., Albamonte, E., Darras, B. T., Bertini, E., Sansone, V. A., Bovis, F., Day, J., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R., Mercuri, E. 2021

    Abstract

    Ref: Different trajectories in upper limb and gross motor function in spinal muscular atrophy INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 months.METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-month changes also included the analysis of concordance between scales with changes grouped as stable (+2 points), improved (>+2) or declined (>-2).RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2 the point of slope change was 4.1years for the HFMSE and 5.8 for the RULM, while for type 3 it was 6years for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least 2 assessments at 12-month. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups.DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

    View details for DOI 10.1002/mus.27384

    View details for PubMedID 34327716

  • Psychometric properties of the PEDI-CAT for children and youth with spinal muscular atrophy. Journal of pediatric rehabilitation medicine Fragala-Pinkham, M., Pasternak, A., McDermott, M. P., Mirek, E., Glanzman, A. M., Montes, J., Dunaway Young, S., Salazar, R., Quigley, J., Riley, S. O., Chiriboga, C. A., Finkel, R. S., Tennekoon, G., Martens, W. B., De Vivo, D. C., Darras, B. T. 2021

    Abstract

    PURPOSE: The purpose of this study was to examine the psychometric properties of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) in children and youth with Spinal Muscular Atrophy (SMA).METHODS: In this prospective cross-sectional study, caregivers of children and youth with SMA completed the PEDI-CAT Daily Activities and Mobility domains. A subset of caregivers completed a questionnaire about the measure.RESULTS: Mean ranks of scaled scores for Daily Activities (n = 96) and Mobility (n = 95) domains were significantly different across the three SMA types and across the three motor classifications. Normative scores indicated that 85 participants (89.5%) had limitations in Mobility and 51 in Daily Activities (53.1%). Floor effects were observed in≤10.4%of the sample for Daily Activities and Mobility. On average, caregivers completed the Mobility domain in 5.4 minutes and the Daily Activities domain in 3.3 minutes. Most caregivers reported that they provided meaningful information (92.1%), were willing to use the PEDI-CAT format again (79%), and suggested adding content including power wheelchair mobility items.CONCLUSION: Convergent validity was demonstrated for the Daily Activities and Mobility domains. Normative scores detected limitations in Mobility and Daily Activity performance for most participants with SMA. The PEDI-CATwas feasible to administer and caregivers expressed willingness to complete the PEDI-CAT in the future.

    View details for DOI 10.3233/PRM-190664

    View details for PubMedID 34275913

  • Advances in the therapy of Spinal Muscular Atrophy. The Journal of pediatrics Klotz, J., Rocha, C. T., Young, S. D., Duong, T., Buu, M., Sampson, J., Day, J. W. 2021

    View details for DOI 10.1016/j.jpeds.2021.06.033

    View details for PubMedID 34197889

  • Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Annals of clinical and translational neurology Pera, M. C., Coratti, G., Bovis, F., Pane, M., Pasternak, A., Montes, J., Sansone, V. A., Dunaway Young, S., Duong, T., Messina, S., Mizzoni, I., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Morando, S., De Sanctis, R., Sframeli, M., Antonaci, L., Frongia, A. L., Rohwer, A., Scoto, M., De Vivo, D. C., Darras, B. T., Day, J., Martens, W., Patanella, K. A., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E., iSMAC group 2021

    Abstract

    OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83years after nusinersen treatment.RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12months on both HFMSE (1.18 points, p=0.004) and RULM scores (0.58 points, p=0.014) but not on the 6MWT (mean difference=6.65m, p=0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

    View details for DOI 10.1002/acn3.51411

    View details for PubMedID 34165911

  • Nusinersen Treatment in Adults With Spinal Muscular Atrophy. Neurology. Clinical practice Duong, T., Wolford, C., McDermott, M. P., Macpherson, C. E., Pasternak, A., Glanzman, A. M., Martens, W. B., Kichula, E., Darras, B. T., De Vivo, D. C., Zolkipli-Cunningham, Z., Finkel, R. S., Zeineh, M., Wintermark, M., Sampson, J., Hagerman, K. A., Young, S. D., Day, J. W. 2021; 11 (3): e317-e327

    Abstract

    Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA.Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models.Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events.Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA.Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort.

    View details for DOI 10.1212/CPJ.0000000000001033

    View details for PubMedID 34476123

  • Essential competencies for physical therapist managing individuals with spinal muscular atrophy: A delphi study PLOS ONE Timmerberg, J., Krosschell, K. J., Young, S., Uher, D., Yun, C., Montes, J. 2021; 16 (4): e0249279

    Abstract

    With the availability and development of disease-modifying therapies for individuals with spinal muscular atrophy (SMA), new emerging phenotypes must be characterized, and potential new treatment paradigms tested. There is an urgent demand to develop an educational program that provides physical therapists (PTs) worldwide the necessary knowledge and training to contribute to best-practice care and clinical research. A competency based education framework is one that would focus on outcomes not process and where progression of learners would occur only after competencies are demonstrated. The first step toward such a framework is defining outcomes. The purpose of this Delphi study was to develop consensus on those competencies deemed essential within the SMA PT community.Purposive selection and snowball sampling techniques were used to recruit expert SMA PTs. Three web-based survey rounds were used to achieve consensus, defined as agreement among >80% of respondents. The first round gathered demographic information on participants as well as information on clarity and redundancy on a list of competencies; the second round, collected the same information on the revised list and whether or not participants agreed if the identified domains captured the essence of a SMA PT as well as the definitions for each; and the third asked participants to rank their agreement with each competency.Consensus revealed 35 competencies, organized under 6 domains, which were deemed essential for a PT working with persons with SMA.In order to develop a curriculum to meet the physical therapy needs of persons with SMA, it is imperative to establish defined outcomes and to achieve consensus on those outcomes within the SMA community.This study identified essential competencies that will help to provide guidance in development of a formal education program to meet these defined outcomes. This can foster best-practice care and clinical decision-making for all PTs involved in the care of persons with SMA in a clinical and research setting.

    View details for DOI 10.1371/journal.pone.0249279

    View details for Web of Science ID 000644138300133

    View details for PubMedID 33886555

    View details for PubMedCentralID PMC8062020

  • Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen. Neuromuscular disorders : NMD Coratti, G., Pane, M., Lucibello, S., Pera, M. C., Pasternak, A., Montes, J., Sansone, V. A., Duong, T., Dunaway Young, S., Messina, S., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Tacchetti, P., Carnicella, S., Sframeli, M., Antonaci, L., Frongia, A. L., De Vivo, D. C., Darras, B. T., Day, J., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E. 2021

    Abstract

    Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

    View details for DOI 10.1016/j.nmd.2021.03.012

    View details for PubMedID 34099377

  • Gaussian Process Regression for COP Trajectory Estimation in Healthy and Pathological Gait Using Instrumented Insoles Duong, T. H., Uher, D., Young, S., Duong, T., Sangco, M., Cornett, K., Montes, J., Zanotto, D., IEEE IEEE. 2021: 9548-9553
  • Clinical variability in spinal muscular atrophy type III. Annals of neurology Coratti, G., Messina, S., Lucibello, S., Pera, M. C., Montes, J., Pasternak, A., Stat, F. B., Escudero, J. E., Mazzone, E. S., Mayhew, A., Glanzman, A. M., Young, S. D., Salazar, R., Duong, T., Lofra, R. M., de Sanctis, R., Carnicella, S., Milev, E., Civitello, M., Pane, M., Scoto, M., Bettolo, C. M., Antonaci, L., Frongia, A., Sframeli, M., Vita, G. L., D'Amico, A., van den Hauwe, M., Albamonte, E., Goemans, N., Darras, B. T., Bertini, E., Sansone, V., Day, J., Osorio, A. N., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 2020

    Abstract

    OBJECTIVE: We report natural history data in a large cohort of 199 spinal muscular atrophy (SMA) type III patients assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number and functional status.METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments.RESULTS: A break point at age 7 was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type and ambulatory status were significantly associated with changes in mean HFMSE score while sex and SMN2 copy number were not. The increase in response before the break point of age 7 is significant only for SMA IIIA (beta=1.79, p<.0001). After the break point the change in the rate of HFMSE score significantly decrease for both SMA IIIA (beta=1.15, p<.0001) and IIIB (beta=0.69, p=0.002).INTERPRETATION: Our findings contribute to the understanding of the natural history of type III SMA and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.25900

    View details for PubMedID 32926458

  • Age and baseline values predict 12 and 24-month functional changes in type 2 SMA NEUROMUSCULAR DISORDERS Coratti, G., Pera, M. C., Lucibello, S., Montes, J., Pasternak, A., Mayhew, A., Glanzman, A. M., Young, S., Pane, M., Scoto, M., Messina, S., Goemans, N., Osorio, A., Pedemonte, M., Sansone, V., Bertini, E., De Vivo, D. C., Finkel, R., Muntoni, F., Mercuri, E., ISMAC Grp Collaborators 2020; 30 (9): 756-764

    Abstract

    The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA.

    View details for DOI 10.1016/j.nmd.2020.07.005

    View details for Web of Science ID 000573468800009

    View details for PubMedID 32900576

  • Lack of effect on ambulation of dalfampridine-ER (4-AP) treatment in adult SMA patients NEUROMUSCULAR DISORDERS Chiriboga, C. A., Marra, J., LaMarca, N. M., Young, S., Weimer, L. H., Levin, B., McCabe, B. 2020; 30 (8): 693-700

    Abstract

    SMA is a genetically determined motor system disorder that results in muscle weakness, selective motor neuron death, muscle atrophy, and impaired functional mobility. In SMA model systems, long-term treatment with 4-aminopyridine (4-AP) has been shown to improve motor function. To assess tolerability and preliminary efficacy of 4-AP on walking ability, endurance and EMG in adult ambulatory SMA patients, we conducted a double blind, placebo control, crossover pilot study with dalfampridine (4-AP, 10 mg BID). The study is comprised of a short-term (2 weeks) treatment arm with 1-week washout and a long-term (6 weeks) treatment arm with a 2-week washout. The primary outcome measure, for which the study was powered, was the 6 min walk test (6MWT, distance and percent fatigue); secondary outcome measures were the Hammersmith Functional Motor Scale Expanded (HFMSE), Manual Muscle Testing (MMT), Myometry with Hand held Dynamometry, HHD) and Quantitative Gait Analyses. We performed electrophysiology, including CMAP and H-reflex, during the short-term treatment trial. The mean age of the 11 participants enrolled was 37.7 ± 11.9 years; 54.5% were male. Dalfampridine was safe and well tolerated and no patient suffered a serious adverse event related to treatment. We observed no statistically significant positive effects of dalfampridine treatment on our primary functional motor outcome (6MWT distance, fatigue). Dalfampridine had a positive effects on H-reflex and H/M ratio but not on CMAP amplitude. The effect on the H-reflex is of interest, as it suggests dalfampridine may enhance neuronal activity, an effect observed in SMA Drosophila and mouse models at doses (mg/kg) not recommended for clinical use. Larger studies with dalfampridine in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients.

    View details for DOI 10.1016/j.nmd.2020.07.007

    View details for Web of Science ID 000565539700011

    View details for PubMedID 32788051

  • Quantitative gait assessment in children with 16p11.2 syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Goldman, S., McCullough, A. K., Young, S., Mueller, C., Stahl, A., Zoeller, A., Abbruzzese, L., Rao, A. K., Montes, J. 2019; 11 (1): 26

    Abstract

    Neurodevelopmental disorders such as 16p11.2 syndrome are frequently associated with motor impairments including locomotion. The lack of precise measures of gait, combined with the challenges inherent in studying children with neurodevelopmental disorders, hinders quantitative motor assessments. Gait and balance are quantifiable measures that may help to refine the motor phenotype in 16p11.2. The characterization of motor profile is useful to study the trajectories of locomotion performance of children with genetic variants and may provide insights into neural pathway dysfunction based on genotype/phenotype model.Thirty-six children (21 probands with 16p11.2 deletion and duplication mutation and 15 unaffected siblings), with a mean age of 8.5 years (range 3.2-15.4) and 55% male, were enrolled. Of the probands, 23% (n = 6) had a confirmed diagnosis of autism spectrum disorder (ASD) and were all male. Gait assessments included 6-min walk test (6MWT), 10-m walk/run test (10MWR), timed-up-and-go test (TUG), and spatio-temporal measurements of preferred- and fast-paced walking. The Pediatric Evaluation of Disability Inventory-Computer Adaptive Tests (PEDI-CAT), a caregiver-reported functional assessment, was administered. Measures of balance were calculated using percent time in double support and base of support. Analyses of the six children with ASD were described separately.Thirty-six participants completed the protocol. Compared with sibling controls, probands had significantly lower scores on the 6MWT (p = 0.04), 10MWR (p = 0.01), and TUG (p = 0.005). Group differences were also identified in base of support (p = 0.003). Probands had significantly lower PEDI-CAT scores in all domains including the mobility scale (p < 0.001). Using age-matched subsamples, the ASD and non-ASD genetic variant groups had larger base of support compared to the controls. In the fast-paced condition, all participants increased their velocity, and there was a corresponding decrease in percent time in double support compared to the preferred-pace condition in all participants. Only the ASD group presented with upper limb arm/hand stereotypies.Children with 16p11.2, with and without ASD, present with balance impairment during locomotion activities. Probands performed worse on functional assessments, and quantitative measures revealed differences in base of support. These results highlight the importance of using precise measures to differentiate motor dysfunction in children with neurodevelopmental disorders.

    View details for DOI 10.1186/s11689-019-9286-9

    View details for Web of Science ID 000509098000001

    View details for PubMedID 31656164

    View details for PubMedCentralID PMC6816222

  • Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy MUSCLE & NERVE Montes, J., Young, S., Mazzone, E. S., Pasternak, A., Glanzman, A. M., Finkel, R. S., Darras, B. T., Muntoni, F., Mercuri, E., De Vivo, D. C., Bishop, K. M., Schneider, E., Bennett, C., Foster, R., Farwell, W., CS2 Study Grp, CS12 Study Grp 2019; 60 (4): 409-414

    Abstract

    Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied.Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12.Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%).These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA.

    View details for DOI 10.1002/mus.26633

    View details for Web of Science ID 000478182800001

    View details for PubMedID 31298747

    View details for PubMedCentralID PMC6771553

  • Revised upper limb module for spinal muscular atrophy: 12 month changes MUSCLE & NERVE Pera, M., Coratti, G., Mazzone, E. S., Montes, J., Scoto, M., De Sanctis, R., Main, M., Mayhew, A., Lofra, R., Young, S., Glanzman, A. M., Duong, T., Pasternak, A., Ramsey, D., Darras, B., Day, J. W., Finkel, R. S., De Vivo, D. C., Sormani, M., Bovis, F., Straub, V., Muntoni, F., Pane, M., Mercuri, E., Bettolo, C., Civitiello, M., Mirek, E., Salazar, R., Forcina, N., Norcia, G., Carnicella, S., Antonaci, L., ISMAC Consortium Grp 2019; 59 (4): 426–30

    View details for DOI 10.1002/mus.26419

    View details for Web of Science ID 000461232700011

  • Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function PEDIATRIC PHYSICAL THERAPY Salazar, R., Montes, J., Young, S., McDermott, M. P., Martens, W., Pasternak, A., Quigley, J., Mirek, E., Glanzman, A. M., Civitello, M., Gee, R., Duong, T., Mazzone, E. S., Main, M., Mayhew, A., Ramsey, D., Lofra, R., Coratti, G., Fanelli, L., De Sanctis, R., Forcina, N., Chiriboga, C., Darras, B. T., Tennekoon, G. I., Scoto, M., Day, J. W., Finkel, R., Muntoni, F., Mercuri, E., De Vivo, D. C. 2018; 30 (3): 209–15
  • Ambulatory function in spinal muscular atrophy: Age-related patterns of progression PLOS ONE Montes, J., McDermott, M. P., Mirek, E., Mazzone, E. S., Main, M., Glanzman, A. M., Duong, T., Young, S., Salazar, R., Pasternak, A., Gee, R., De Sanctis, R., Coratti, G., Forcina, N., Fanelli, L., Ramsey, D., Milev, E., Civitello, M., Pane, M., Pera, M., Scoto, M., Day, J. W., Tennekoon, G., Finkel, R. S., Darras, B. T., Muntoni, F., De Vivo, D. C., Mercuri, E. 2018; 13 (6): e0199657

    Abstract

    Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

    View details for PubMedID 29944707

  • Pilot study of population-based newborn screening for spinal muscular atrophy in New York state GENETICS IN MEDICINE Kraszewski, J. N., Kay, D. M., Stevens, C. F., Koval, C., Haser, B., Ortiz, V., Albertorio, A., Cohen, L. L., Jain, R., Andrew, S. P., Young, S., LaMarca, N. M., De Vivo, D. C., Caggana, M., Chung, W. K. 2018; 20 (6): 608-613

    Abstract

    PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1.5%. We identified one newborn with a homozygous SMN1 deletion and two copies of SMN2, which strongly suggests the severe type 1 SMA phenotype. The infant was enrolled in the NURTURE clinical trial and was first treated with Spinraza at age 15 days. She is now age 12 months, meeting all developmental milestones, and free of any respiratory issues.ConclusionOur pilot study demonstrates the feasibility of population-based screening, the acceptance by families, and the benefit of newborn screening for SMA. We suggest that SMA be considered for addition to the national recommended uniform screening panel.

    View details for DOI 10.1038/gim.2017.152

    View details for Web of Science ID 000434409000006

    View details for PubMedID 29758563

  • Ambulatory function and fatigue in nusinersen-treated children with spinal muscular atrophy. Montes, J., Young, S., Mazzone, E., Pasternak, A., Glanzman, A., Finkel, R., Darras, B., Muntoni, F., Mercuri, E., De Vivo, D., Bishop, K., Schneider, E., Bennett, F., Foster, R., Farwell, W. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Evaluator Training and Reliability for SMA Global Nusinersen Trials1. Journal of neuromuscular diseases Glanzman, A. M., Mazzone, E. S., Young, S. D., Gee, R., Rose, K., Mayhew, A., Nelson, L., Yun, C., Alexander, K., Darras, B. T., Zolkipli-Cunningham, Z., Tennekoon, G., Day, J. W., Finkel, R. S., Mercuri, E., De Vivo, D. C., Baldwin, R., Bishop, K. M., Montes, J. 2018; 5 (2): 159–66

    Abstract

    BACKGROUND: Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes.METHODS: Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability.RESULTS: Inter and intra-rater reliability were both excellent. Intraclass correlation coefficients (ICC) ranged between 0.906-0.994 across initial training meetings and 0.824-0.996 across annual retraining meetings. This was similar for CHOP INTEND (ICC = 0.824-0.951), HFMSE (ICC = 0.981-0.996), and RULM (ICC = 0.966-0.990). Intra-rater reliability for the CHOP INTEND, HFMSE, and RULM were ICC = 0.895 (95% CI: 0.852-0.926; n = 116), ICC = 0.959 (95% CI: 0.942-0.971; n = 125), and ICC = 0.948 (95% CI: 0.927-0.963; n = 126) respectively.CONCLUSIONS: Rigorous evaluator training ensures reliability of assessment of subjects with spinal muscular atrophy (SMA) in multicenter international trials.

    View details for PubMedID 29865090

  • Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study. Journal of neuromuscular diseases Krosschell, K. J., Bosch, M. n., Nelson, L. n., Duong, T. n., Lowes, L. P., Alfano, L. N., Benjamin, D. n., Carry, T. B., Devine, G. n., Kelley, C. n., Gadekan, R. n., Malkus, E. C., Pasternak, A. n., Provance-Orr, S. n., Roemeiser-Logan, L. n., Nicorici, A. n., Trussell, D. n., Young, S. D., Fetterman, J. R., Montes, J. n., Powers, P. J., Quinones, R. n., Quigley, J. n., Coffey, C. S., Yankey, J. W., Bartlett, A. n., Kissel, J. T., Kolb, S. J. 2018; 5 (4): 509–21

    Abstract

    The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1.To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS).Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with 'expert' consensus scores was examined using Pearson's correlation coefficients.Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with 'expert' consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability.Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

    View details for PubMedID 30223401

  • First international workshop on rehabilitation management and clinical outcome measures for spinal muscular atrophy NEUROMUSCULAR DISORDERS Montes, J., Young, S., Mazzone, E., Main, M., Int Spinal Muscular Atrophy 2017; 27 (10): 964-969
  • GAIT ASSESSMENT WITH SOLESOUND INSTRUMENTED FOOTWEAR IN SPINAL MUSCULAR ATROPHY MUSCLE & NERVE Montes, J., Zanotto, D., Young, S., Salazar, R., De Vivo, D. C., Agrawal, S. 2017; 56 (2): 230-236

    Abstract

    Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied.Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors.The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 ± 9.1%, which corresponded to an average deceleration of 0.37 ± 0.28 mm/s2 . Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle.These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. Muscle Nerve 56: 230-236, 2017.

    View details for DOI 10.1002/mus.25484

    View details for Web of Science ID 000406875000012

    View details for PubMedID 27863443

  • Reliability of functional outcome measures in spinal muscular atrophy: Results from multi-centered, global, phase 3 clinical trials Glanzman, A., Mazzone, E., Young, S., Gee, R., Rose, K., Mayhew, A., Yun, C., Alexander, K., Tennekoon, G., Day, J., Finkel, R., Mercuri, E., De Vivo, D., Bennett, F., Bishop, K., Montes, J. LIPPINCOTT WILLIAMS & WILKINS. 2017
  • Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC neurology Pera, M. C., Coratti, G., Forcina, N., Mazzone, E. S., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Messina, S., Sframeli, M., Main, M., Lofra, R. M., Duong, T., Ramsey, D., Dunaway, S., Salazar, R., Fanelli, L., Civitello, M., De Sanctis, R., Antonaci, L., Lapenta, L., Lucibello, S., Pane, M., Day, J., Darras, B. T., De Vivo, D. C., Muntoni, F., Finkel, R., Mercuri, E. 2017; 17 (1): 39-?

    Abstract

    Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE).First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE.Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2.Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.

    View details for DOI 10.1186/s12883-017-0790-9

    View details for PubMedID 28231823

  • Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PloS one Ramsey, D., Scoto, M., Mayhew, A., Main, M., Mazzone, E. S., Montes, J., De Sanctis, R., Dunaway Young, S., Salazar, R., Glanzman, A. M., Pasternak, A., Quigley, J., Mirek, E., Duong, T., Gee, R., Civitello, M., Tennekoon, G., Pane, M., Pera, M. C., Bushby, K., Day, J., Darras, B. T., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. 2017; 12 (2)

    Abstract

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

    View details for DOI 10.1371/journal.pone.0172346

    View details for PubMedID 28222119

  • RASCH ANALYSIS OF THE PEDIATRIC EVALUATION OF DISABILITY INVENTORY-COMPUTER ADAPTIVE TEST (PEDI-CAT) ITEM BANK FOR CHILDREN AND YOUNG ADULTS WITH SPINAL MUSCULAR ATROPHY MUSCLE & NERVE Pasternak, A., Sideridis, G., Fragala-Pinkham, M., Glanzman, A. M., Montes, J., Dunaway, S., Salazar, R., Quigley, J., Pandya, S., O'Riley, S., Greenwood, J., Chiriboga, C., Finkel, R., Tennekoon, G., Martens, W. B., McDermott, M. P., Fournier, H., Madabusi, L., Harrington, T., Cruz, R. E., Lamarca, N. M., Videon, N. M., De Vivo, D. C., Darras, B. T., Muscle Study Grp MSG, Pediat Neuromuscular Clin Res 2016; 54 (6): 1097-1107

    Abstract

    In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA).PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types.Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types.The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016.

    View details for DOI 10.1002/mus.25164

    View details for Web of Science ID 000389625300019

    View details for PubMedID 27121348

  • Developmental milestones in type I spinal muscular atrophy NEUROMUSCULAR DISORDERS De Sanctis, R., Coratti, G., Pasternak, A., Montes, J., Pane, M., Mazzone, E. S., Young, S., Salazar, R., Quigley, J., Pera, M. C., Antonaci, L., Lapenta, L., Glanzman, A. M., Tiziano, D., Muntoni, F., Darras, B. T., De Vivo, D. C., Finkel, R., Mercuri, E. 2016; 26 (11): 754-759

    Abstract

    The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials.

    View details for DOI 10.1016/j.nmd.2016.10.002

    View details for Web of Science ID 000387626200006

    View details for PubMedID 27769560

    View details for PubMedCentralID PMC5091285

  • Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle & nerve Mazzone, E. S., Mayhew, A., Montes, J., Ramsey, D., Fanelli, L., Dunaway Young, S., Salazar, R., De Sanctis, R., Pasternak, A., Glanzman, A., Coratti, G., Civitello, M., Forcina, N., Gee, R., Duong, T., Pane, M., Scoto, M., Pera, M. C., Messina, S., Tennekoon, G., Day, J. W., Darras, B. T., De Vivo, D. C., Finkel, R., Muntoni, F., Mercuri, E. 2016

    Abstract

    There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/mus.25430

    View details for PubMedID 27701745

  • Characterization of Gait and Fatigue in Children and Adults with Spinal Muscular Atrophy Using Instrumented Footwear Montes, J., Zanotto, D., Dunaway, S., Salazar, R., De Vivo, D., Agrawal, S. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Gait Assessment in Children with Known Genetic Neurodevelopmental Disorders with and without Autism Spectrum Disorders Goldman, S., Dunaway, S., Mueller, C., Boehme, A., Sherwood, G., Stahl, A., Zoeller, A., Abbruzzese, L., Rao, A., Montes, J. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials NEUROMUSCULAR DISORDERS Mercuri, E., Finkel, R., Montes, J., Mazzone, E. S., Sormani, M., Main, M., Ramsey, D., Mayhew, A., Glanzman, A. M., Dunaway, S., Salazar, R., Pasternak, A., Quigley, J., Pane, M., Pera, M., Scoto, M., Messina, S., Sframeli, M., Vita, G., D'Amico, A., van den Hauwe, M., Sivo, S., Goemans, N., Kaufmann, P., Darras, B. T., Bertini, E., Muntoni, F., De Vivo, D. C. 2016; 26 (2): 126-131

    Abstract

    The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients.

    View details for DOI 10.1016/j.nmd.2015.10.006

    View details for Web of Science ID 000371652100002

    View details for PubMedID 26776503

    View details for PubMedCentralID PMC4762230

  • SPINAL MUSCULAR ATROPHY FUNCTIONAL COMPOSITE SCORE: A FUNCTIONAL MEASURE IN SPINAL MUSCULAR ATROPHY MUSCLE & NERVE Montes, J., Glanzman, A. M., Mazzone, E. S., Martens, W. B., Dunaway, S., Pasternak, A., Riley, S. O., Quigley, J., Pandya, S., De Vivo, D. C., Kaufmann, P., Chiriboga, C. A., Finkel, R. S., Tennekoon, G. I., Darras, B. T., Pane, M., Mercuri, E., Mcdermott, M. P., Pediat Neuromuscular Clinical Res, Muscle Study Grp, SMA Europe 2015; 52 (6): 942-947

    Abstract

    With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA).Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores.The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component.This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients.

    View details for DOI 10.1002/mus.24670

    View details for Web of Science ID 000368260600004

    View details for PubMedID 25846132

  • Single-Blind, Randomized, Controlled Clinical Trial of Exercise in Ambulatory Spinal Muscular Atrophy: Why are the Results Negative? Journal of neuromuscular diseases Montes, J., Garber, C. E., Kramer, S. S., Montgomery, M. J., Dunaway, S., Kamil-Rosenberg, S., Carr, B., Cruz, R., Strauss, N. E., Sproule, D., De Vivo, D. C. 2015; 2 (4): 463-470

    Abstract

    BACKGROUND: The benefits of exercise on long-term health and well-being are well established. The possible benefits of exercise in Spinal Muscular Atrophy (SMA) have not been explored in a controlled clinical trial format.OBJECTIVE: To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients.METHODS: Fourteen participants, ages 10-48 years, were randomized to control and exercise cohorts after a 1 month lead-in period. The exercise group received 6 months of intervention. Thereafter, both groups received the intervention for the remaining 12 months. Participants were monitored for a total of 19 months. Exercise included individualized home-based cycling and strengthening. The primary outcome measure was distance walked during the six-minute walk test (6MWT). Secondary outcomes included strength, function, exercise capacity, quality of life and fatigue.RESULTS: Twelve participants completed the first 7 months of the study, and 9 completed all 19 months. At baseline, the groups were similar on all clinical variables. There were no group changes at any time point in the 6MWT, fatigue, or function. Percent-predicted VO2 max improved 4.9% in all participants in 6 months (p = 0.036) (n = 10).CONCLUSION: Daily exercise is safe in ambulatory SMA and should be encouraged. We did not uncover any deleterious effects on strength, function, or fatigue. Our study documented a reduction in oxidative capacity and a blunted conditioning response to exercise possibly representing an important insight into underlying pathophysiological mechanisms. These findings also may be linked causally to mitochondrial depletion in SMA and warrant further study.

    View details for PubMedID 27858749

  • Old measures and new scores in spinal muscular atrophy patients MUSCLE & NERVE Mazzone, E., Montes, J., Main, M., Mayhew, A., Ramsey, D., Glanzman, A. M., Dunaway, S., Salazar, R., Pasternak, A., Quigley, J., Pane, M., Pera, M. C., Scoto, M., Messina, S., Sframeli, M., D'amico, A., Van Den Hauwe, M., Sivo, S., Goemans, N., Darras, B. T., Kaufmann, P., Bertini, E., De Vivo, D. C., Muntoni, F., Finkel, R., Mercuri, E. 2015; 52 (3): 435-437

    Abstract

    A recent Rasch analysis performed on the Hammersmith Functional Motor Scale-Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items.We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients.The mean 12-month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar.The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items.

    View details for DOI 10.1002/mus.24748

    View details for Web of Science ID 000359671800017

    View details for PubMedID 26111847

  • Observational study of spinal muscular atrophy type I and implications for clinical trials NEUROLOGY Finkel, R. S., McDermott, M. P., Kaufmann, P., Darras, B. T., Chung, W. K., Sproule, D. M., Kang, P. B., Foley, A., Yang, M. L., Martens, W. B., Oskoui, M., Glanzman, A. M., Flickinger, J., Montes, J., Dunaway, S., O'Hagen, J., Quigley, J., Riley, S., Benton, M., Ryan, P. A., Montgomery, M., Marra, J., Gooch, C., De Vivo, D. C. 2014; 83 (9): 810-817

    Abstract

    Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02).Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.

    View details for DOI 10.1212/wnl.0000000000000741

    View details for Web of Science ID 000341096100010

    View details for PubMedID 25080519

    View details for PubMedCentralID PMC4155049

  • Leg muscle function and fatigue during walking in spinal muscular atrophy type 3 MUSCLE & NERVE Montes, J., Dunaway, S., Garber, C., Chiriboga, C. A., De Vivo, D. C., Rao, A. K. 2014; 50 (1): 34-39

    Abstract

    Spinal muscular atrophy (SMA) causes muscle weakness and fatigue. Better understanding of the relationship between weakness and fatigue may help identify potential targets for rehabilitation.Gait and surface electromyography (EMG) from 4 muscle groups were measured during the Six-Minute Walk Test (6MWT) in 10 ambulatory participants, aged 9-49 years. Average root mean square amplitude (RMS) of muscle activity was calculated. Strength was assessed using manual and quantitative methods.RMS, stride length, and velocity decreased during the 6MWT. Knee flexor and hip abductor strength was associated with fatigue-related changes; overall strength correlated with disease duration; and leg strength was associated with 6MWT distance.Clinical measures are valid in assessing fatigue and function in SMA, and these assessments can be enhanced by use of gait analysis and EMG. Disease duration and strength measures may represent further stratification refinements when enrolling patients in clinical trials.

    View details for DOI 10.1002/mus.24081

    View details for Web of Science ID 000337639600004

    View details for PubMedID 24122959

  • A Randomized, Controlled Clinical Trial of Exercise in Patients with Spinal Muscular Atrophy: Methods and Baseline Characteristics. Journal of neuromuscular diseases Montes, J., Garber, C. E., Kramer, S. S., Montgomery, M. J., Dunaway, S., Kamil-Rosenberg, S., Carr, B., Strauss, N. E., Sproule, D., De Vivo, D. C. 2014; 1 (2): 151-161

    Abstract

    BACKGROUND: Spinal Muscular Atrophy (SMA) is a recessively-inherited neuromuscular disease characterized by weakness and muscle atrophy. Although anecdotal benefits from exercise have been noted, and despite promising pre-clinical and pilot reports, the effect of exercise has not been addressed in a controlled trial in SMA.OBJECTIVE: To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients.METHODS/DESIGN: An evaluator-blinded, randomized, controlled trial of aerobic and strengthening exercise in 14 ambulatory SMA patients aged 8-50 years. Patients will be randomized to either the exercise or control arm after the 1 month lead in period. During the first 6-months, the exercise group will receive the intervention while the other group serves as a control. After those 6 months, both groups will receive the intervention. The last 6-months of the study are designed to mimic real-world conditions where all participants are encouraged to continue on their own. Participants will be monitored throughout this 19 month study and will have in-person visits every three months. The primary outcome measure is the change in the total distance walked over 6-months on the six minute walk test (6MWT). Secondary outcome measures include maximal oxygen uptake (VO2 max), functional and strength assessments, pulmonary function, fatigue, and quality of life.DISCUSSION: The result of this prospective, single blinded, randomized and controlled clinical trial of exercise on an established functional outcome measure will have impact on clinical practice by providing important guidance to clinical management of SMA patients.

    View details for PubMedID 27858768

  • Weakness and Fatigue in Diverse Neuromuscular Diseases JOURNAL OF CHILD NEUROLOGY Montes, J., Blumenschine, M., Dunaway, S., Alter, A. S., Engelstad, K., Rao, A. K., Chiriboga, C. A., Sproule, D. M., De Vivo, D. C. 2013; 28 (10): 1277-1283

    Abstract

    Weakness and fatigue are captured by the 6-minute walk test, but the relationship between these symptoms is uncertain. Comparison across neuromuscular diseases has not been examined. A cohort study of 114 patients with spinal muscular atrophy, Duchenne/Becker muscular dystrophy, myasthenia gravis, and energy failure syndromes were included. Percent-predicted distance on the 6-minute walk test was computed from normative values to determine weakness. Fatigue was determined by the decrement in distance from the first to sixth minute. Weakness was seen across all groups (61.9%) but significant fatigue was seen only in spinal muscular atrophy (21.0%). Other groups showed little fatigue. Correlation between weakness and fatigue was significant only in spinal muscular atrophy (R = -0.71; P < .001). Longitudinally, distance walked declined only in Duchenne/Becker muscular dystrophy. In spinal muscular atrophy, weakness did not change, but fatigue increased significantly. These findings suggest independent mechanisms underlying weakness and fatigue in diverse neuromuscular conditions.

    View details for DOI 10.1177/0883073813493663

    View details for Web of Science ID 000324399300014

    View details for PubMedID 23847297

  • Falls and spinal muscular atrophy: Exploring cause and prevention MUSCLE & NERVE Montes, J., McIsaac, T. L., Dunaway, S., Kamil-Rosenberg, S., Sproule, D., Garber, C. E., De Vivo, D. C., Rao, A. K. 2013; 47 (1): 118-123

    Abstract

    Falls can cause injury and may compromise function in spinal muscular atrophy (SMA) patients. Weakness and gait variability are associated with falls in other neurological disorders, and fatigue is well documented in SMA. The relationship of weakness, fatigue, and gait variability to falls has never been investigated.Seven ambulatory patients with SMA completed a falls history questionnaire, 6MWT, gait analysis, and strength testing. Pearson correlation coefficients were used to examine associations between these variables.All 7 subjects reported falls in the previous year. Stride-length variability was significantly associated with falls, unlike strength, fatigue, or other gait variables.Stride-length variability was the key variable associated with falls. Preventive strategies to avoid falls should be incorporated into patient management plans. Gait analysis provides actionable information not revealed by standard assessments and should be included in clinical trials designed to address the prevention of falls in the SMA population.

    View details for DOI 10.1002/mus.23656

    View details for Web of Science ID 000312657200019

    View details for PubMedID 23042039

  • Prospective cohort study of spinal muscular atrophy types 2 and 3 NEUROLOGY Kaufmann, P., McDermott, M. P., Darras, B. T., Finkel, R. S., Sproule, D. M., Kang, P. B., Oskoui, M., Constantinescu, A., Gooch, C. L., Foley, A., Yang, M. L., Tawil, R., Chung, W. K., Martens, W. B., Montes, J., Battista, V., O'Hagen, J., Dunaway, S., Flickinger, J., Quigley, J., Riley, S., Glanzman, A. M., Benton, M., Ryan, P. A., Punyanitya, M., Montgomery, M. J., Marra, J., Koo, B., De Vivo, D. C., Muscle Study Grp MSG, Pediat Neuromuscular Clinical Res 2012; 79 (18): 1889-1897

    Abstract

    To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning.We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data.In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up.The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.

    View details for DOI 10.1212/WNL.0b013e318271f7e4

    View details for Web of Science ID 000310579900015

    View details for PubMedID 23077013

    View details for PubMedCentralID PMC3525313

  • Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) PEDIATRIC PHYSICAL THERAPY Glanzman, A. M., McDermott, M. P., Montes, J., Martens, W. B., Flickinger, J., Riley, S., Quigley, J., Dunaway, S., O'Hagen, J., Deng, L., Chung, W. K., Tawil, R., Darras, B. T., Yang, M., Sproule, D., De Vivo, D. C., Kaufmann, P., Finkel, R. S., Pediat Neuromuscular Clinical Res, Muscle Study Grp MSG 2011; 23 (4): 322-326

    Abstract

    Preliminary validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) for motor skill assessment in spinal muscular atrophy type I.A total of 27 subjects 3 to 260 months old (mean = 49, SD = 69) with spinal muscular atrophy-I were evaluated with the CHOP INTEND. Subjects were evaluated as part of a multicenter natural history study.CHOP INTEND scores and age were significantly correlated (r = -0.51, P = .007; 2 survival of the motor neuron [SMN] 2 gene copies, n = 16, r = -0.60, 3 SMN2 gene copies, n = 9, r = -0.83). Respiratory support and CHOP INTEND scores were correlated (r = -0.74, P < .0001, n = 26). The CHOP INTEND and age regression in patients with 2 copies versus 3 copies of SMN2 approached significance (P = .0711, n = 25). Subjects who required respiratory support scored significantly lower (mean = 15.5, SD = 10.2 vs mean = 31.2, SD = 4.2, P < .0001, n = 27). Correlation with motor unit number estimation and combined motor unit activation were not significant.The CHOP INTEND reflects measures of disease severity and supports continued exploration of the CHOP INTEND.

    View details for DOI 10.1097/PEP.0b013e3182351f04

    View details for Web of Science ID 000300557700002

    View details for PubMedID 22090068

  • Validation of the Expanded Hammersmith Functional Motor Scale in Spinal Muscular Atrophy Type II and III JOURNAL OF CHILD NEUROLOGY Glanzman, A. M., O'Hagen, J. M., McDermott, M. P., Martens, W. B., Flickinger, J., Riley, S., Quigley, J., Montes, J., Dunaway, S., Deng, L., Chung, W. K., Tawil, R., Darras, B. T., De Vivo, D. C., Kaufmann, P., Finkel, R. S., Pediat Neuromuscular Clin Res, MSG 2011; 26 (12): 1499-1507

    Abstract

    The relationships between the Expanded Hammersmith Functional Motor Scale (HFMSE) and genotype and motor and respiratory outcomes were examined in patients with spinal muscular atrophy types II and III (n = 70). The correlation between the HFMSE and Gross Motor Function Measure was r = 0.98. Correlations between HFMSE and forced vital capacity (percentage of predicted normal) (n = 56) and a functional rating (n = 57) were r = 0.87 and r = 0.92, respectively. Correlations with strength were as follows: knee extension, r = 0.74 (n = 60); elbow flexion, r = 0.77 (n = 61); and knee flexion, r = 0.74 (n = 58). The HFMSE differentiated patients by SMN2 copy number (P = .0007); bi-level positive airway pressure use, <8 versus ≥8 hours/day (P < .0001); ambulatory status (P < .0001); and spinal muscular atrophy type (P < .0001). The HFMSE demonstrates significant associations with established measures of function, strength, and genotype, and discriminates patients based on function, diagnostic category, and bi-level positive airway pressure need. Time of administration averaged 12 minutes. The HFMSE is a valid, time-efficient outcome measure for clinical trials in spinal muscular atrophy types II and III.

    View details for DOI 10.1177/0883073811420294

    View details for Web of Science ID 000297312100005

    View details for PubMedID 21940700

  • Thigh Muscle Volume Measured by Magnetic Resonance Imaging Is Stable Over a 6-Month Interval in Spinal Muscular Atrophy JOURNAL OF CHILD NEUROLOGY Sproule, D. M., Montgomery, M. J., Punyanitya, M., Shen, W., Dashnaw, S., Montes, J., Dunaway, S., Finkel, R., Darras, B., De Vivo, D. C., Kaufmann, P. 2011; 26 (10): 1252-1259

    Abstract

    Changes in thigh muscle volume over 6 months were assessed using magnetic resonance imaging in 11 subjects aged 6 to 47 years with spinal muscular atrophy (4 type 2 and 7 type 3; 4 ambulatory and 3 nonambulatory). Muscle volume with normal and abnormal signal was measured using blinded, semiautomated analysis of reconstructed data. Volumes at baseline and 6 months were correlated with clinical function at each epoch. There was minimal increase in normal (0.3 ± 1.4 mL/cm) and total (0.1 ± 1.3 mL/cm) muscle. Muscle volume correlated closely with clinical function. Minimal interval change in muscle volume is consistent with the established clinical history of minimal disease progression over intervals shorter than 1 year. Relative constancy of muscle volume estimation and correlation with established functional measures suggest a role for segmental magnetic resonance imaging as a biomarker of treatment effect in future therapeutic trials.

    View details for DOI 10.1177/0883073811405053

    View details for Web of Science ID 000295736500005

    View details for PubMedID 21572051

  • Observational Study of Spinal Muscular Atrophy Type 2 and 3 Functional Outcomes Over 1 Year ARCHIVES OF NEUROLOGY Kaufmann, P., McDermott, M. P., Darras, B. T., Finkel, R., Kang, P., Oskoui, M., Constantinescu, A., Sproule, D., Foley, R., Yang, M., Tawil, R., Chung, W., Martens, B., Montes, J., O'Hagen, J., Dunaway, S., Flickinger, J. M., Quigley, J., Riley, S., Glanzman, A. M., Benton, M., Ryan, P. A., Irvine, C., Annis, C. L., Butler, H., Caracciolo, J., Montgomery, M., Marra, J., Koo, B., De Vivo, D. C., Muscle Study Grp 2011; 68 (6): 779-786

    Abstract

    To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA.A comprehensive multicenter, longitudinal, observational study.The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites.Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated.We collected demographic and medical history information and determined the SMN 2 copy number.Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function.There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function.Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.

    View details for DOI 10.1001/archneurol.2010.373

    View details for Web of Science ID 000291546100013

    View details for PubMedID 21320981

    View details for PubMedCentralID PMC3839315

  • FATIGUE LEADS TO GAIT CHANGES IN SPINAL MUSCULAR ATROPHY MUSCLE & NERVE Montes, J., Dunaway, S., Montgomery, M. J., Sproule, D., Kaufmann, P., De Vivo, D. C., Rao, A. K. 2011; 43 (4): 485-488

    Abstract

    Impaired mobility and fatigue are common in ambulatory spinal muscular atrophy (SMA) patients. The 6-minute walk test (6MWT) is a reliable measure of fatigue in SMA patients. To further evaluate fatigue, we used quantitative gait analysis during the 6MWT.Nine subjects with SMA and 9 age- and gender-matched, healthy controls were evaluated. Gait parameters of speed and dynamic balance were correlated with 6MWT distance. Performance during the first and last 25 meters of the 6MWT was compared.Speed-related gait parameters and support base correlated with 6MWT distance. Walking performance was worse for SMA patients. The deterioration in stride length during the 6MWT was greater in SMA patients than in controls.Gait analysis detects fatigue, and the decrement in stride length may reflect selective muscle involvement in SMA. Further understanding of the mechanisms underlying fatigue may suggest additional targets for future therapeutic interventions.

    View details for DOI 10.1002/mus.21917

    View details for Web of Science ID 000288462400004

    View details for PubMedID 21404286

  • Bioelectrical Impedance Analysis Can Be a Useful Screen for Excess Adiposity in Spinal Muscular Atrophy JOURNAL OF CHILD NEUROLOGY Sproule, D. M., Montes, J., Dunaway, S. L., Montgomery, M., Battista, V., Shen, W., Punyanitya, M., De Vivo, D. C., Kaufmann, P. 2010; 25 (11): 1348-1354

    Abstract

    Accurate, noninvasive measures of body composition are needed for management of patients with spinal muscular atrophy. Fat mass index (fat mass/height(2) in kg/m(2)) was measured in 16 subjects with spinal muscular atrophy using 5 bioelectrical impedance analysis equations and compared with a reference method, dual-energy x-ray absorptiometry. The machine default equation, validated by Cordain, was the primary analysis. Fat mass index calculated by impedance measures differed by between -2.5 kg/m(2) and 1.7 kg/m(2) from the reference mean (8.3 ± 5.0 kg/m(2)). The Cordain equation provided the smallest difference (-0.4 ± 2.0 kg/m(2)), with correlation coefficient of 0.92. The Cordain equation showed high sensitivity (85.7%) and specificity (100%) for prediction of ''at risk for overweight'' (fat mass index > 85th percentile for age and gender). Although insufficiently accurate for use as a research tool, bioelectrical impedance can have application as a well-tolerated, noninvasive, easily used screening tool for excess adiposity in patients with spinal muscular atrophy.

    View details for DOI 10.1177/0883073810365185

    View details for Web of Science ID 000284155600007

    View details for PubMedID 20388937

  • Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy NEUROMUSCULAR DISORDERS Sproule, D. M., Montes, J., Dunaway, S., Montgomery, M., Battista, V., Koenigsberger, D., Martens, B., Shen, W., Punyanitya, M., Benton, M., Butler, H., Caracciolo, J., Mercuri, E., Finkel, R., Darras, B., De Vivo, D. C., Kaufmann, P. 2010; 20 (7): 448-452

    Abstract

    The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith functional motor scale, expanded score into three cohorts: low-functioning non-ambulatory (type 2 with Hammersmith score < 12, n=19), high-functioning non-ambulatory (type 2 with Hammersmith score > or = 12 or non-ambulatory type 3, n=17), and Ambulatory (n=17). Lean and fat mass was estimated using dual-energy X-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg/stature in m(2)) and fat (fat mass in kg/stature in m(2)) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the high-functioning non-ambulatory cohort (10.4+/-4.5) compared with both the ambulatory (7.2+/-2.1, P=0.013) and low-functioning non-ambulatory (7.6+/-3.1, P=0.040) cohorts. 12 of 17 subjects (71%) in the high-functioning non-ambulatory cohort had fat mass index > 85th percentile for age and gender (connoting "at risk of overweight") versus 9 of 19 subjects (47%) in the low-functioning non-ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA.

    View details for DOI 10.1016/j.nmd.2010.05.013

    View details for Web of Science ID 000280285000004

    View details for PubMedID 20610154

    View details for PubMedCentralID PMC2902766

  • An Integrated Motion Capture System for Evaluation of Neuromuscular Disease Patients Gamarnik, V., Pan, S., Malke, J., Chiu, C., Koo, B., Montes, J., Yeager, K., Marra, J., Dunaway, S., Montgomery, M., Strauss, N., De Vivo, D. C., Kaufmann, P., Morrison, B., Konofagou, E., IEEE IEEE. 2009: 218-+

    Abstract

    There currently exist a variety of methods for evaluating movement in patients suffering from neuromuscular diseases (NMD). These tests are primarily performed in the clinical setting and evaluated by highly trained individuals, rather than evaluating patient in their natural environments (i.e., home or school). Currently available automated motion capture modalities offer a highly accurate means of assessing general motion, but are also limited to a highly controlled setting. Recent advances in MEMS technology have introduced the possibility of robust motion capture in uncontrolled environments, while minimizing user interference with self-initiated motion, especially in weaker subjects. The goal of this study is to design and evaluate a MEMS-sensor-based system for motion capture in the NMD patient population. The highly interdisciplinary effort has led to significant progress toward the implementation of a new device, which is accurate, clinically relevant, and highly affordable.

    View details for DOI 10.1109/IEMBS.2009.5334475

    View details for Web of Science ID 000280543600058

    View details for PubMedID 19964732

  • Design and Evaluation of a Hybrid Passive and Active Gravity Neutral Orthosis (GNO) Koo, B., Montes, J., Gamarnik, V., Yeager, K., Marra, J., Dunaway, S., Montgomery, M., De Vivo, D. C., Strauss, N., Konofagou, E., Kaufmann, P., Morrison, B., IEEE IEEE. 2009: 1573-+

    Abstract

    Neuromuscular diseases (NMD), including Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), result in progressive muscular weakness that often leaves patients functionally dependent on caregivers for many activities of daily living (ADL) such as eating, bathing, grooming (touching the face and head), reaching (grabbing for objects), and dressing. In severe cases, patients are unable to perform even the simplest of activities from exploring their 3D space to touching their own face. The ability to move and initiate age appropriate tasks, such as playing and exploration, are considered to be of vital importance to both their physical and cognitive development. Therefore, to improve quality of life and reduce dependence on caregivers in children and young adults with NMD, we designed, built and evaluated an assistive, active orthosis to support arm function. The goal of this project is the development and evaluation of a mechanical arm orthosis to both encourage and assist functional arm movement while providing the user a sense of independence and control over one's own body.

    View details for DOI 10.1109/IEMBS.2009.5332578

    View details for Web of Science ID 000280543601124

    View details for PubMedID 19963513