Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.

OBJECTIVE: To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments. METHODS: Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient-reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential [CMAP], single motor unit potential [SMUP], motor unit number estimation [MUNE]) were collected. RESULTS: dEMG MUAP amplitudes were higher in ambulatory versus control and non-ambulatory groups and were higher in controls versus non-ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non-ambulatory and control groups but similar between non-ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test-retest reliability. INTERPRETATION: dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.

Cardiac MRI with late gadolinium enhancement shows cardiac involvement 3-6 months after severe acute COVID-19 similar to or worse than PIMS.

Background: Coronavirus disease 2019 (COVID-19) in children is rarely severe. However, severe courses occur, especially in the presence of risk factors. A minority of children develop pediatric inflammatory multisystem syndrome (PIMS) with substantial morbidity. While the importance of cardiac involvement after PIMS is well established, its role after severe acute COVID-19 remains unclear. We aim to compare cardiac sequelae of children after severe acute COVID-19 using cardiac MRI and compare them with patients after PIMS. Methods: For this prospective cohort study, we recruited patients with acute COVID or PIMS in a single center. Clinical follow-up, lab work, ECG, and echocardiography were done within 2 days after disease onset and 3-6 months after discharge. At the last visit 3-6 months later, cardiac MRI (CMR) with late gadolinium enhancement (LGE) was performed to evaluate cardiac sequelae and compare both groups. Results: Data were obtained from n = 14 patients with PIMS and n = 7 patients with severe acute COVID-19. At the start of the respective disease, left ventricular (LV) ejection fraction was reduced in seven patients with PIMS but none in the acute COVID-19 group. Transient mitral valve insufficiency was present in 38% of patients, of whom PIMS accounted for 7/8 cases. Eight patients (38%) with PIMS presented coronary artery abnormalities, with normalization in 7/8 patients. A significant decrease in LV mass index 3-6 months after disease onset was observed in both groups. MRI follow-up revealed non-ischemic myocardial pattern of LGE in 12/21 patients- in all (6/6) after severe acute COVID-19 and in less than half (6/14) after PIMS. Normal body weight-adjusted stroke volumes and end-diastolic volumes were found in 20/21 patients. Conclusions: We show that children suffering from severe acute COVID-19 have a similar, or worse, cardiac risk profile as patients with PIMS. Both patient groups should therefore receive close pediatric cardiac follow-up examinations. Cardiac MRI is the technique of choice, as most patients presented with delayed LGE as a sign of persistent cardiac injury despite normalization of laboratory and echocardiographic findings.

Psychometric evaluation of modified spinal muscular atrophy functional rating scale (SMAFRS) in adult patients using Rasch analysis.

INTRODUCTION/AIMS: The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models. METHODS: A total of 253 responses from 41 adult patients with ambulatory and non-ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item-person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning. RESULTS: Most items had good fitting with the exception of "toileting" and "respiratory." There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni-dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non-ambulatory populations. DISCUSSION: Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non-ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.

Video game rehabilitation for outpatient stroke (VIGoROUS): A multi-site randomized controlled trial of in-home, self-managed, upper-extremity therapy.

BACKGROUND: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach. METHODS: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850. RESULTS: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%. INTERPRETATION: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life. FUNDING: PCORI, NIH.

Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen.

OBJECTIVE: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. METHODS: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3-5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n = 6). For patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. RESULTS: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p = 0.0013; pNfH p = 0.0035) and an increase in CSF NfL in controls (p = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r = -0.822, p = 0.04), upper extremity strength (r = -0.828, p = 0.042), lower extremity strength (r = -0.860, p = 0.028), and total strength (r = -0.870, p = 0.024). CONCLUSIONS: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population.

Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen.

OBJECTIVE: Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA. METHODS: Participants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement. RESULTS: Data from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (-14.2%±11.5%, n=17) vs baseline (-11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (-13.9%±6.7%) vs baseline (-16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration. CONCLUSION: Adults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA.

Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology. Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment. Results: Six women, seven men (mean age: 37 ± 11, range: 18-59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable. Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy.

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA). Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded. Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21-64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable. Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

Predicting Improved Daily Use of the More Affected Arm Poststroke Following Constraint-Induced Movement Therapy.

BACKGROUND: Constraint-induced movement therapy (CI therapy) produces, on average, large and clinically meaningful improvements in the daily use of a more affected upper extremity in individuals with hemiparesis. However, individual responses vary widely. OBJECTIVE: The study objective was to investigate the extent to which individual characteristics before treatment predict improved use of the more affected arm following CI therapy. DESIGN: This study was a retrospective analysis of 47 people who had chronic (> 6 months) mild to moderate upper extremity hemiparesis and were consecutively enrolled in 2 CI therapy randomized controlled trials. METHODS: An enhanced probabilistic neural network model predicted whether individuals showed a low, medium, or high response to CI therapy, as measured with the Motor Activity Log, on the basis of the following baseline assessments: Wolf Motor Function Test, Semmes-Weinstein Monofilament Test of touch threshold, Motor Activity Log, and Montreal Cognitive Assessment. Then, a neural dynamic classification algorithm was applied to improve prognostic accuracy using the most accurate combination obtained in the previous step. RESULTS: Motor ability and tactile sense predicted improvement in arm use for daily activities following intensive upper extremity rehabilitation with an accuracy of nearly 100%. Complex patterns of interaction among these predictors were observed. LIMITATIONS: The fact that this study was a retrospective analysis with a moderate sample size was a limitation. CONCLUSIONS: Advanced machine learning/classification algorithms produce more accurate personalized predictions of rehabilitation outcomes than commonly used general linear models.

Improved quality of life following constraint-induced movement therapy is associated with gains in arm use, but not motor improvement.

BACKGROUND: Constraint-induced movement therapy (CI therapy) is one of few treatments for upper extremity (UE) hemiparesis that has been shown to result in motor recovery and improved quality of life in chronic stroke. However, the extent to which treatment-induced improvements in motor function versus daily use of the more affected arm independently contribute to improved quality of life remains largely unexplored. OBJECTIVE: The objective of this study is to identify whether motor function or daily use of a hemiparetic arm has a greater influence on quality of life after CI therapy. METHODS: Two cohorts of participants with chronic stroke received either in-person CI therapy (n = 29) or video-game home-based CI therapy (n = 16). The two cohorts were combined and the motor-related outcomes (Wolf Motor Function Test, Action Research Arm Test, Motor Activity Log [MAL]) and quality of life (Stroke-Specific Quality of Life) were jointly modeled to assess the associations between outcomes. RESULTS: The only outcome associated with improved quality of life was the MAL. Improvements in quality of life were not restricted to motor domains, but generalized to psychosocial domains as well. CONCLUSIONS: Results suggest that improved arm use during everyday activities is integral to maximizing quality of life gains during motor rehabilitation for chronic post-stroke UE hemiparesis. In contrast, gains in motor function were not associated with increases in quality of life. These findings further support the need to implement techniques into clinical practice that promote arm use during daily life if improving quality of life is a main goal of treatment. ClinicalTrials.gov Registration Numbers: NCT01725919 and NCT03005457.

Ethics and adolescent care: an international perspective.

PURPOSE OF REVIEW: This update reviews the concepts underlying ethical issues in various contexts and countries, highlighting the evolution in the use of the core values underpinning the field and practice of bioethics as applied to healthcare. RECENT FINDINGS: It stresses the specific position of the adolescent as being a unique individual searching for autonomy and, most of the time, being competent to make decisions regarding the adolescent's own health. It briefly outlines the principles of a 'deliberative' approach in which the practitioner, while keeping in mind the legal context of the country where the practitioner is working, assesses to what extent the adolescent can be considered as competent, and then discusses with the adolescent the medical and psychosocial aspects of the various actions to be taken in a situation, as well as the basic ethical values linked with each of the various options available. The deliberation can involve relevant stakeholders, provided the issues concerning confidentiality have been fully discussed with the adolescent. SUMMARY: This process forces the practitioner, the adolescent patient and those who care for the adolescent patient to look outside their usual frameworks and make a decision that is in the best interest of the young person, and is informed by various ethical values.

Moving beyond the function of the health behaviour: the effect of message frame on behavioural decision-making.

Health messages that provide gain- or loss-framed arguments have a differential impact on behavioural decision-making (Rothman & Salovey, 1997). Typically, gain-framed messages more effectively promote preventive health behaviours, which maintain health and minimise the risk of a health problem, whereas loss-framed messages more effectively promote detection behaviours, which involve the risk of finding a health problem. Two experiments tested the thesis that the risk implications of the behaviour are an important determinant of the persuasive impact of gain- and loss-framed appeals. Results revealed that when the risk associated with a health behaviour (either a prevention behaviour in Experiment 1 or a detection behaviour in Experiment 2) was low, participants responded more favourably to gain-framed messages. However, when the risk associated with the health behaviour (either prevention or detection) was high, participants responded more favourably to loss-framed messages. Discussion focuses on the importance of taking into account how individuals construe a behaviour when constructing framed appeals.

Girls with social and/or attention deficits: a descriptive study of 100 clinic attenders.

OBJECTIVE: Examine clinical correlates and distinguishing features of autism spectrum disorders (ASD), ADHD, and tic disorders in girls referred for social impairment, attention/academic deficits, and/or tics. METHOD: One hundred 3- to 18-year-old girls referred for social impairment and attention symptoms were assessed in detail. Sixty of these girls, 7 to 16 years of age (IQ >or= 80) were compared with age-matched girls (IQ >or= 80) from the community. RESULTS: Main diagnoses of ASD, ADHD, tic disorders, and "other psychiatric disorder" were made in 46, 46, 3, and 5, respectively, of the referred girls. The ASD and ADHD groups (mean age at diagnosis 8.8 and 13.0 years, respectively) had the same types and high rates of psychiatric comorbidity. Girls with ASD had more problems with global functioning and adaptive levels of daily living skills than girls with ADHD. Differences between these girls referred for investigation and the community sample of girls were very considerable across a range of factors. CONCLUSIONS: Girls referred for social and/or attention deficits usually meet diagnostic criteria for either ASD or ADHD. They have severe psychiatric comorbidities and low global levels of functioning.

Reading comprehension, word decoding and spelling in girls with autism spectrum disorders (ASD) or attention-deficit/hyperactivity disorder (AD/HD): performance and predictors.

BACKGROUND: Difficulties with aspects of literacy are often seen in children with autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (AD/HD). The bases of the connections between these disorders and literacy difficulties are poorly understood. Furthermore, it is not clear if existing research is representative for girls. AIMS: There were three aims: (1) to compare performance in reading comprehension, word decoding, and spelling in girls with ASD (n = 20), AD/ HD (n = 36), and community girls with typical developing (girls; n = 54); (2) to assess rates of reading and writing disorders within groups; and (3) to examine the predictive value of measures of autistic and AD/HD symptomatology to reading comprehension in the whole girl sample. METHODS & PROCEDURES: Participants were aged between 8 and 17 years, and had a full scale IQ>70. Standardized tests of literacy, oral vocabulary, and non-verbal ability were administered. Parent ratings of degree of autistic symptomatology and both parent and teacher ratings of AD/HD symptomatology were collected for all girls. OUTCOMES & RESULTS: Girls with diagnosed ASD could not be separated significantly from typically developing girls or girls with AD/HD on average performance on any literacy test. However, among girls with ASD, 40% had at least one reading and writing disorder. Girls with AD/HD performed lower than typically developing girls in reading comprehension, word decoding, and spelling, and 56% had at least one reading and writing disorder. In regression analysis, using the total sample, both degrees of autistic and AD/HD symptomatology negatively contributed to the variance in reading comprehension after controlling for oral vocabulary, word decoding, and non-verbal ability. Whereas AD/HD contributed to the variance in reading comprehension once autistic symptomatology was controlled for, the opposite was not true. However, a large bivariate correlation between autistic and AD/HD symptomatology somewhat complicates the interpretation of that result. CONCLUSIONS & IMPLICATIONS: The findings highlight the importance of monitoring and supporting the literacy development in girls with ASD or AD/HD. Results from regression analyses suggested that word decoding and/or oral vocabulary training may not be sufficient for the girls fully to overcome difficulties in the important skill of reading comprehension.

Addressing ethical dilemmas in the clinical care of adolescents: an international view.

This chapter reviews some basic concepts underlying ethical issues in adolescence and provides a step-by-step procedure to address ethical dilemmas involving minor adolescents, based on a deliberative approach. "Deliberation" with the patient, along with involving the opinion of relevant stakeholders if possible, allows for a careful, multidisciplinary examination of all options, the medical and psychosocial consequences, and the moral values stressed by each option. Although the final decision regarding which ethical option should be chosen usually belongs to the health care providers and his or her patient, the deliberative approach provides the ingredients for sound, unbiased decision-making.

Efficacy of a screening procedure to identify potentially disruptive participants in an immersion program for the treatment of adolescent obesity.

BACKGROUND: This study examined the efficacy of the red flag screening procedure, an approach used in a largescale immersion program for the treatment of adolescent obesity (Wellspring Camps). The intention of the red flag screening was to screen out potentially highly disruptive applicants, provide an impetus for additional support when high-risk campers were admitted, and help parents develop appropriate expectations. When compared to non-flagged peers, red-flagged campers who attended camp were expected to be sent home early more frequently. METHODS: Wellspring's admissions coordinators 'red-flagged' potential campers whose enrollment forms showed evidence of a history of psychological distress, major medical challenges, and/or developmental delays; a licensed psychologist then determined whether or not to admit the child after talking with the identified applicant, parents, and health care providers. 554 overweight young people attended three Wellspring Camps in the summer of 2007 (445 females, 109 males, mean age = 15.8 years, mean BMI = 35.6 kg/m(2), mean % overweight = 66.7%). RESULTS: 8.7% of applicants were red-flagged (n = 48), and 8% of all of the campers (n = 44) were dismissed prematurely. As expected, a much higher percentage of red-flagged campers who were admitted to camp were dismissed prematurely (31,3% of the red-flagged campers) than were non-flagged campers (5,1%; p < 0.0005). CONCLUSION: These findings support the efficacy of Wellspring's red flag screening procedure. While further improvements can be made, such a tool may be useful to other immersion programs.