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.

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.

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.

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.

Functional recovery in children and adolescents with spinal cord injury.

PURPOSE: To examine functional recovery in mobility and self-care measured using the Pediatric Evaluation of Disability Inventory (PEDI) in children with spinal cord injury (SCI) during an inpatient rehabilitation stay and to identify how demographic and clinical variables relate to functional recovery. METHODS: PEDI scores were collected through retrospective chart review for 32 children and adolescents with SCI (mean age, 10.6 +/- 6.2 years; range, 1-19 years) admitted to an inpatient physical rehabilitation program between 1995 and 2007. RESULTS: Children with SCI showed significantly improved functional skill recovery and reduced caregiver assistance for the PEDI mobility and self-care domains after rehabilitation. Item analyses suggested more recovery in mobility than in self-care skills. Children with incomplete injury gained more independence in self-care than those with complete injury. CONCLUSIONS: Children with SCI showed improved functional skills and reduced need for caregiver assistance as measured by the PEDI during inpatient rehabilitation.

Effects of aquatic aerobic exercise for a child with cerebral palsy: single-subject design.

PURPOSE: The purpose of this study was to evaluate the effects of an aquatic aerobic exercise program for a child with cerebral palsy. METHODS: A 5-year-old girl with spastic diplegia classified at level III on the Gross Motor Function Classification System participated in this single-subject A-B-A design study. The aquatic aerobic exercise intervention was carried out 3 times per week for 12 weeks at an intensity of 50% to 80% of heart rate reserve. The Canadian Occupational Performance Measure, Gross Motor Function Measure, and 6-minute walk test were used as outcomes. RESULTS: Statistically significant improvements were found in the participation, activity, and body function components of the International Classification of Functioning, Disability, and Health model. Improvements in functional abilities and walking endurance and speed were recorded. CONCLUSION: These findings suggest that an aquatic aerobic exercise program was effective for this child with cerebral palsy and support the need for additional research in this area.

Developmental changes in the responses of preterm infants to a painful stressor.

The purpose of this investigation was to examine longitudinally gestational age and developmental differences in preterm infants' self-regulatory abilities in response to a painful stressor, as well as associations between behavioral and cardiovascular responses. Participants included 49 healthy premature infants. Behavioral and cardiovascular responses to a heel stick blood draw were compared between infants of 28-31 and 32-34 weeks' gestation age at birth. Both gestational age groups displayed behavioral and cardiovascular indications of stress in response to the blood draw. However, both shortly after birth and several weeks later, infants born at younger gestational ages (28-31 weeks) were more physiologically reactive. Evidence that the behavioral stress responses of 28-31 weeks' gestation age group preterm infants do not reflect their physiological responses suggests that evaluation of preterm infants' experiences and risk require assessments of both physiology and behavior. The greater stress vulnerability of the 28-31 weeks' gestation group relative to the 32-34 weeks' gestation group and the implications of this for subsequent development are discussed.

Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia.

The hippocampus is injured in both hypoxia-ischemia (HI) and perinatal iron deficiency that are co-morbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were subjected to unilateral HI injury of 15, 30, or 45 mins (n=12 to 13/HI duration) on postnatal day 14. Sixteen metabolite concentrations were measured from an 11 microL volume on the ipsilateral (HI) and contralateral (control) hippocampi 1 week later using in vivo 1H NMR spectroscopy. The concentrations of creatine, glutamate, myo-inositol, and N-acetylaspartate were lower on the control side in the iron-deficient group (P<0.02, each). Magnetic resonance imaging showed hippocampal injury in the majority of the iron-deficient rats (58% versus 11%, P<0.0001) with worsening severity with increasing durations of HI (P=0.0001). Glucose, glutamate, N-acetylaspartate, and taurine concentrations were decreased and glutamine, lactate and myo-inositol concentrations, and glutamine/glutamate ratio were increased on the HI side in the iron-deficient group (P<0.01, each), mainly in the 30 and 45 mins HI subgroups (P<0.02, each). These neurochemical changes likely reflect the histochemically detected neuronal injury and reactive astrocytosis in the iron-deficient group and suggest that perinatal iron deficiency predisposes the hippocampus to greater injury from exposure to a relatively mild HI insult.

Memory in early adolescents born prematurely: a functional magnetic resonance imaging investigation.

This study employed functional magnetic resonance imaging to examine the functional neuroanatomy of the hippocampus and head of the caudate nucleus during 2 different types of memory tasks in a sample of 9 early adolescent children who were born preterm (neonatal intensive care unit [NICU] sample) and a group of 9 age-matched control children who were born at term. The investigation employed delayed match to sample (DMS), delayed nonmatch to sample (DNMS), and spatial memory span tasks, as well as 2 analogous perceptuomotor tasks that placed no demands on memory. The general question examined was whether preterm children show different levels of hippocampal and caudate activation during these tasks when compared to children born at term. The findings indicated that the 2 groups did not differ in functional activation of the hippocampus during the DMS and DNMS tasks. During the encoding phase of the spatial memory span task, the DMS perceptuomotor task, and the spatial memory span perceptuomotor task, the NICU sample showed greater activation change in the right caudate nucleus, and less right caudate activation change during the test phase. During the spatial span perceptuomotor task, the preterm group showed reduced activation change in the left caudate nucleus during both the encoding and test phase. Also, during the DMS perceptuomotor task, the NICU group showed increased activation change in the left caudate nucleus during encoding and decreased activation change at test. The implications of these findings for understanding the functional neuroanatomy of memory deficits are discussed, as is the potential for distinguishing the effects of neural plasticity from those of typical brain maturational processes.

Effects of prenatal betamethasone exposure on regulation of stress physiology in healthy premature infants.

The objective of this study was to examine the effects of prenatal exposure to betamethasone, a corticosteroid, on postnatal stress regulation, particularly activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Effects were assessed by measuring salivary cortisol production at baseline and in response to two potentially stressful events, a heel-stick blood draw and a physical exam, in infants born at 33-34 weeks gestation. Subjects included 9 infants with antenatal betamethasone treatment (2 doses of 12 mg of betamethasone administered intramuscularly to the mother twelve hours apart) and 9 infants without such treatment. Testing took place 3-6 days after delivery. Measures of behavioral distress confirmed that both events were stressful to these premature infants. Infants with betamethasone exposure, however, failed to exhibit increases in cortisol to either stressor. In contrast, infants without betamethasone exposure displayed elevated cortisol to the heel-stick blood draw but not the physical exam. These findings suggest that antenatal corticosteroids suppress infants' HPA response to a stressor typically encountered in a neonatal intensive care situation.

Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus.

Cognitive deficits in human infants at risk for gestationally acquired perinatal iron deficiency suggest involvement of the developing hippocampus. To understand the plausible biological explanations for hippocampal injury in perinatal iron deficiency, a neurochemical profile of 16 metabolites in the iron-deficient rat hippocampus was evaluated longitudinally by 1H NMR spectroscopy at 9.4 T. Metabolites were quantified from an 11-24 microL volume centered in the hippocampus in 18 iron-deficient and 16 iron-sufficient rats on postnatal day (PD) 7, PD10, PD14, PD21 and PD28. Perinatal iron deficiency was induced by feeding the pregnant dam an iron-deficient diet from gestational d 3 to PD7. The brain iron concentration of the iron-deficient group was 60% lower on PD7 and 19% lower on PD28 (P < 0.001 each). The concentration of 12 of the 16 measured metabolites changed over time between PD7 and PD28 in both groups (P < 0.001 each). Compared with the iron-sufficient group, phosphocreatine, glutamate, N-acetylaspartate, aspartate, gamma-aminobutyric acid, phosphorylethanolamine and taurine concentrations, and the phosphocreatine/creatine ratio were elevated in the iron-deficient group (P < 0.02 each). These neurochemical alterations suggest persistent changes in resting energy status, neurotransmission and myelination in perinatal iron deficiency. An altered neurochemical profile of the developing hippocampus may underlie some of the cognitive deficits observed in human infants with perinatal iron deficiency.