Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD. METHODS: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI. RESULTS: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001). DISCUSSION: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.

Development of an Infantile GM2 Clinical Rating Scale: Remote Assessment of Clinically Meaningful Health-Related Function.

GM2 gangliosidoses (GM2) are a group of rare lysosomal storage disorders in which accumulation of GM2 gangliosides results in progressive central nervous system damage. The infantile GM2 phenotype is characterized by delays in milestones by 6 months of age, followed by rapid loss of motor, cognitive, and visual function. Advancements in early diagnosis and pharmacotherapies provide promise for improved outcomes. However, the lack of feasible and clinically meaningful clinical outcome assessments for GM2 poses a challenge to characterizing GM2 natural history and selecting clinical trial endpoints. The purpose of this study was to develop a remotely administered infantile GM2 rating scale to measure health-related function in children with infantile GM2. A 2-phase mixed methods design was employed. In phase 1 of the study, 8 families of children with Infantile GM2 completed a natural history survey and a 1:1 semistructured interview to provide caregiver perspectives on the impacts of GM2 on health-related function. In phase 2 of the study, 8 expert clinicians provided feedback via surveys and participated in videoconference-hosted focus groups to refine scale administration and scoring procedures. These methods guided the development of 16 scale items to assess function in 5 health-related function domains: vision, hand and arm use, communication, gross motor, and feeding. This study used caregiver perspectives and expert clinician feedback to develop a remotely administered clinical outcome assessment of clinically meaningful health-related function in children with infantile GM2. Future studies will further evaluate the feasibility, reliability, and validity of the Infantile GM2 Clinical Rating Scale.

A Virtual Reality Exergame: Clinician-Guided Breathing and Relaxation for Children with Muscular Dystrophy.

This study introduces a VR-based breathing and relaxation exergame tailored for individuals with Duchenne muscular dystrophy (DMD). DMD is a rare neuromuscular disease that leads to respiratory muscle dysfunction with anxiety being a common comorbidity. Clinical management requires frequent visits to rare disease specialists to manage symptom progression. Limited availability and/or proximity of rare disease experts present challenges to care and can lead to missed care opportunities and reduced quality of life. We propose a breathing and relaxation exergame with remote telehealth applicability that incorporates shared patient-clinician VR interaction, and physiological sensors that provide both real-time feedback to the patient and health analytics for the clinician. The game focuses on two key aspects of DMD clinical care that can be mediated through control of breathing: relaxation/mindfulness training and respiratory muscle exercise. The system was evaluated among 13 individuals, including 4 participants with DMD. Feedback surveys, interviews, and focus group discussions with participants, accompanying family members, and clinicians demonstrated the feasibility of this VR tool for telehealth or as part of a home exercise program.

Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis.

As trials and treatments for spinal muscular atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n = 56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.

Implications of circulating neurofilaments for spinal muscular atrophy treatment early in life: A case series.

This longitudinal cohort study aimed to determine whether circulating neurofilaments (NFs) can monitor response to molecular therapies in newborns with spinal muscular atrophy (SMA; NCT02831296). We applied a mixed-effect model to examine differences in serum NF levels among healthy control infants (n = 13), untreated SMA infants (n = 68), and SMA infants who received the genetic therapies nusinersen and/or onasemnogene abeparvovec (n = 22). Increased NF levels were inversely associated with SMN2 copy number. SMA infants treated with either nusinersen or onasemnogene abeparvovec achieved important motor milestones not observed in the untreated cohort. NF levels declined more rapidly in the nusinersen cohort as compared with the untreated cohort. Unexpectedly, those receiving onasemnogene abeparvovec monotherapy showed a significant rise in NF levels regardless of SMN2 copy number. In contrast, symptomatic SMA infants who received nusinersen, followed by onasemnogene abeparvovec within a short interval after, did not show an elevation in NF levels. While NF cannot be used as the single marker to predict outcomes, the elevated NF levels observed with onasemnogene abeparvovec and its absence in infants treated first with nusinersen may indicate a protective effect of co-therapy during a critical period of vulnerability to acute denervation.

Assessing Physical Function and Mobility following Pediatric Traumatic Brain Injury with the NIH Toolbox Motor Battery: A Feasibility Study.

AIMS: Traumatic brain injury (TBI) can impair physical function in children. The NIH Toolbox Motor Battery (NIHTB-M) was designed to be a brief assessment of physical function, but no studies have examined its use in children with TBI. This study aims to describe the feasibility of using the NIHTB-M to assess children with TBI. METHODS: The NIHTB-M was administered to children with TBI 2 weeks (n = 22) and/or 6 months (n = 23) following injury. This descriptive study summarizes participant performance, administration challenges, and the association between NIHTB-M scores, participant characteristics, and subjective report of physical function. RESULTS: Of the NIHTB-M domains, deficits in endurance and balance were most prevalent. Children aged 5 to 16 years could complete the assessment per administration guidelines, except for a few cases (n = 3) where orthopedic injuries limited participation. Younger children (aged 3 to 4) had difficulty following the NIHTB-M directions. Technological issues impacted balance assessment in several cases (n = 6). CONCLUSION: The NIHTB-M is brief to administer, generally well tolerated by school-aged children and, despite occasional technological challenges, is a feasible performance-based battery for assessment of children with TBI for clinical and research purposes. Additional investigation of psychometric properties and ceiling and floor effects is needed.

Assimilation of the Pediatric Essential Core Competencies by Professional Physical Therapist Education Programs.

PURPOSE: This study examined the degree to which pediatric essential core competencies (ECCs) are meeting their intended purpose to provide guidance to pediatric educators in professional physical therapy (PT) education programs and to determine facilitators, barriers, and recommendations to implementation of ECCs in curricula. METHODS: Pediatric PT educators from professional PT education programs were recruited to participate in a survey. Descriptive statistics were used to analyze close-ended questions for frequency of responses and content analysis to generate themes. RESULTS: Of the 162 completed surveys, most participants were aware of the ECCs (96%) and used them to inform pediatric curriculum (88%). A mean proportion (86%-95%) of participants perceived their program curricula addressed the ECCs very or moderately well. Multiple themes of facilitators/barriers/recommendations to ECC implementation were determined. CONCLUSIONS: Most pediatric educators are aware of and using the ECCs to guide pediatric education to prepare graduates for pediatric patients/clients.

Stander Use in Spinal Muscular Atrophy: Results From a Large Natural History Database.

PURPOSE: The purpose of this study was to describe stander use in a natural history cohort of drug therapy-naïve children with spinal muscular atrophy (SMA) who are not walking and identify factors associated with consistent stander use. METHODS: Data from 397 children with SMA types 1 and 2 characterized the prevalence and frequency of stander use. Predictors of consistent stander use explored were SMA type, survival motor neuron 2 gene (SMN2) copy number, respiratory support, and motor performance. RESULTS: Prevalence of consistent stander use was 13% in type 1 and 68% in type 2. SMA type, SMN2 copy number, respiratory support, and head rotation control each predicted consistent stander use. CONCLUSIONS: Findings characterize stander use in children with SMA who are not walking, address important safety considerations, identify factors that may inform physical therapists' clinical decision-making related to standing program prescription, and provide guidance for future prospective studies.

Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy.

BACKGROUND: The impact of nusinersen therapy on outcomes in adults with Spinal Muscular Atrophy (SMA) remains uncertain. OBJECTIVE: To demonstrate whether nusinersen therapy, at currently prescribed doses, can stabilize or improve motor function in adults with SMA using existing outcome measures. METHODS: A single-center prospective cohort study of 6 adults with SMA type 3, with inclusion/exclusion criteria intended to optimize the ability to demonstrate change using established outcome measures. Primary outcomes were the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Measure (RULM). Secondary outcomes were the PedsQL Fatigue scale, the SMA Functional Rating Scale (SMAFRS), and the 6-minute and 10-meter walk tests (6 MWT and 10 MWT). Estimates of change in HFMSE and RULM mean scores across visits were calculated using a linear mixed effects model. Change from baseline was used for other outcome measures. RESULTS: HFMSE and RULM scores over 12 months were stable or improved in all participants, with a mean increase of 2 points in each. Other measures showed high intra-individual variability. Adverse events related to the primary diagnosis, including injury and infection, significantly impacted the ability to reliably perform walk tests in the four ambulatory participants. CONCLUSIONS: HFMSE and RULM show potential as responsive outcome measures of motor function in ambulatory and non-ambulatory adults with SMA type 3. A time-dependent accrual of benefit of nusinersen on motor function was apparent in this cohort. More sensitive alternative measures of quality of life, fatigue, exercise tolerance, stability and ADLs are clearly needed for adults with SMA.

Monitoring Outcome after Hospital-Presenting Milder Spectrum Pediatric Traumatic Brain Injury Using the Glasgow Outcome Scale-Extended, Pediatric Revision.

The Glasgow Outcome Scale, Pediatric Revision (GOSE-P) is an assessment of "global outcome" designed as a developmentally appropriate version of the Glasgow Outcome Scale-Extended for use in clinical trials of children with traumatic brain injury (TBI). Initial testing describes validity across a wide age and injury severity spectrum, yet the GOSE-P's utility for monitoring children with milder injuries is less clear. We examined the level of agreement between the GOSE-P and the Health and Behavior Inventory (HBI), a TBI-related symptom checklist used to assess children with mild TBI for clinical and research purposes. Participants included children and adolescents 3-16 years of age (n = 50) who presented to two level 1 trauma centers within 24 h of injury, with a GCS of 13-15, who underwent clinical neuroimaging. Outcome was assessed 2 weeks and 3 months following injury. We examined the severity of TBI-related symptoms across disability categories identified using the GOSE-P, and the level of agreement between the two measures in identifying deficits 2 weeks following injury and improvement from 2 weeks to 3 months. Using the GOSE-P, 62% had deficits at 2 weeks, and 42% improved from 2 weeks to 3 months. Agreement between the GOSE-P and HBI was fair 2 weeks after TBI (k = 0.24-0.33), and poor for identifying subsequent improvement (k = 0.10-0.16). Modest agreement between the GOSE-P and the HBI may reflect restricted participation from diverse causes, including TBI, other bodily injuries, and prescribed activity restrictions, and highlights the need for multi-dimensional outcome batteries.

Traumatic Brain Injury-Related Symptoms Reported by Parents: Clinical, Imaging, and Host Predictors in Children with Impairments in Consciousness Less than 24 Hours.

This study examined the relationship between acute neuroimaging, host and injury factors, and parent-reported traumatic brain injury (TBI)-related symptoms in children with noncritical head injury at two weeks and three months after injury. Data were collected prospectively on 45 subjects aged three to 16 years old enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. Subjects had rapid recovery of mental status (Glasgow Coma Score [GCS] = 15 within 24 h), and had no clinical need for neurosurgical intervention. Intra- or extra-axial magnetic resonance imaging (MRI) lesions were categorized using Common Data Elements (CDE) definitions. Host and acute injury factors including neurobehavioral history, race, extracranial injuries, loss of consciousness (LOC), and GCS were analyzed while controlling for pre-injury symptoms, age, sex, and socioeconomic status. Parent-reported cognitive and somatic symptoms were measured by the Health and Behavior Inventory (HBI). Forty-nine percent of children had MRI lesions, most of which were relatively small. LOC predicted increased cognitive and somatic symptoms at two weeks. At three months, pre-injury neurobehavioral history predicted increased cognitive and somatic symptoms. Neuroimaging findings did not predict parent-reported symptom severity, except at three months where extra-axial lesions were associated with less severe cognitive symptoms. While structural MRI lesions do not predict increased parent-reported symptoms in this population, age-specific child performance measures may be more sensitive outcome measures and require further study. Children with pre-injury neurobehavioral problems have more severe symptoms at three months and thus may benefit from longer follow-up and monitoring after traumatic brain injury.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Supported Standing in Boys With Duchenne Muscular Dystrophy.

PURPOSE: To evaluate the safety, tolerability, and efficacy of supported standing in a small sample of boys with Duchenne muscular dystrophy (DMD). METHODS: Four 12- to 15-year-old boys with DMD engaged in a home-based supported standing program for 6 to 12 months. A single-subject design was employed to examine muscle length. Bone mineral density was assessed at 4-month intervals using dual-energy x-ray absorptiometry. RESULTS: Upright, sustained supported standing was tolerated in 3 of the 4 boys. Mean weekly stand times ranged from 1.3 to 3.3 hours. Improved hip or knee flexor muscle length was seen in 3 of the 4 boys. No boys showed improved plantar flexor muscle length or increased lumbar bone mineral density. CONCLUSIONS: Findings offer preliminary empirical evidence addressing the safety, tolerability, and efficacy of standing in boys with DMD. Additional research with an emphasis on better program adherence is indicated.

Effects of AFO use on walking in boys with Duchenne muscular dystrophy: a pilot study.

PURPOSE: Although bracing in the late ambulatory stage of Duchenne muscular dystrophy (DMD) has been described, the effects of ankle-foot orthoses (AFOs) in earlier stages have not been evaluated. The aim of this pilot study was to describe the effects of dynamic response AFO (DR-AFO) use in boys with DMD who are ambulatory. METHODS: Using a crossover design, 3 boys were randomly assigned to either a 2-week DR-AFO or a placebo intervention. Phases were separated by a 1-week washout period. Primary outcomes were time to walk 10 m and a 6-Minute Walk Test. RESULTS: With DR-AFO use, declines in 10-m walk time (median decline = 0.8 s) and 6-Minute Walk Distance (median = 25.0 m) occurred. Parental report suggested that the use of DR-AFOs increased falls in 2 of 3 participants. CONCLUSION: This pilot study does not support the use of DR-AFOs by boys with DMD who are ambulatory.

Truncal fat distribution correlates with decreased vital capacity in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder associated with progressive muscle weakness and respiratory failure. Oral corticosteroids are the mainstay of treatment, but are associated with obesity with a central distribution. This study is designed to determine the relationship between body mass index, central adiposity, and lung function in subjects with DMD. METHODS: Retrospective fat distribution data was obtained in boys with DMD from studies using dual X-ray absorptiometry (DXA). Fat distribution data was reviewed at two tertiary academic institutions and compared with concurrent height, weight, body mass index (BMI), measures of lung function, and sleep study data when available. Truncal fat mass used as a measure of central adiposity. RESULTS: Forty-four subjects (age 12.0 ± 3.4 years) were included. Mean BMI was 22.1 ± 5.9 kg/m(2) . Sixty-eight percent (30 patients) were on corticosteroid therapy. Truncal fat mass percentage was inversely correlated with forced vital capacity (% predicted FVC) (Pearson coefficient -0.37, P = 0.01). Linear regression showed that truncal fat distribution, but not total fat mass, age or corticosteroid use negatively predicted FVC (r(2) = 0.24, P = 0.048). BMI had a positive effect (P = 0.04). However, fat distribution did not predict the rate of change of lung function in a smaller sample. Fat distribution, BMI, or age did not predict measures of sleep disordered breathing. CONCLUSIONS: Truncal fat distribution is a significant predictor of lower vital capacity in boys with DMD, whereas BMI has a positive effect.

Lower leg muscle involvement in Duchenne muscular dystrophy: an MR imaging and spectroscopy study.

OBJECTIVE: To describe the involvement of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) by using MR imaging (MRI) and spectroscopy (MRS) correlated to indices of functional status. SUBJECTS AND METHODS: Nine boys with DMD (mean age, 11 years) and eight healthy age- and BMI-matched boys (mean age, 13 years) prospectively underwent lower leg MRI, 1H-MRS of tibialis anterior (TA) and soleus (SOL) for lipid fraction measures, and 31P-MRS for pH and high-energy phosphate measures. DMD subjects were evaluated using the Vignos lower extremity functional rating, and tests including 6 min walk test (6MWT) and 10 m walk. RESULTS: DMD subjects had highest fatty infiltration scores in peroneal muscles, followed by medial gastrocnemius and soleus. Compared to controls, DMD boys showed higher intramuscular fat (P = 0.04), lipid fractions of TA and SOL (P = 0.02 and 0.003, respectively), pH of anterior compartment (P = 0.0003), and lower phosphocreatine/inorganic phosphorus ratio of posterior compartment (P = 0.02). The Vignos rating correlated with TA (r = 0.79, P = 0.01) and SOL (r = 0.71, P = 0.03) lipid fractions. The 6MWT correlated with fatty infiltration scores of SOL (r = -0.76, P = 0.046), medial (r = -0.80, P = 0.03) and lateral (r = -0.84, P = 0.02) gastrocnemius, intramuscular fat (r = -0.80, P = 0.03), and SOL lipid fraction (r = -0.89, P = 0.007). Time to walk 10 m correlated with anterior compartment pH (r = 0.78, P = 0.04). CONCLUSION: Lower leg muscles of boys with DMD show a distinct involvement pattern and increased adiposity that correlates with functional status. Lower leg MRI and 1H-MRS studies may help to noninvasively demonstrate the severity of muscle involvement.

Medial temporal lobe memory in childhood: developmental transitions.

The medial temporal lobes (MTL) support declarative memory and mature structurally and functionally during the postnatal years in humans. Although recent work has addressed the development of declarative memory in early childhood, less is known about continued development beyond this period of time. The purpose of this investigation was to explore MTL-dependent memory across middle childhood. Children (6 -10 years old) and adults completed two computerized tasks, place learning (PL) and transitive inference (TI), that each examined relational memory, as well as the flexible use of relational learning. Findings suggest that the development of relational memory precedes the development of the ability to use relational knowledge flexibly in novel situations. Implications for the development of underlying brain areas and ideas for future neuroimaging investigations are discussed.