Potentially Life-Threatening Interaction between Opioids and Intrathecal Baclofen in Individuals with a Childhood-Onset Neurological Disorder: A Case Series and Review of the Literature.

BACKGROUND: Spasticity and dystonia are movement impairments that can occur in childhood-onset neurological disorders. Severely affected individuals can be treated with intrathecal baclofen (ITB). Concomitant use of ITB and opioids has been associated with central nervous system (CNS) depression. This study aims to describe the clinical management of this interaction, based on a case series and review of literature. METHODS: Four individuals with childhood-onset CNS disorders (age 8-24) and CNS-depressant overdose symptoms after the concomitant use of ITB and opioids are described. The Drug Interaction Probability Scale (DIPS) was calculated to assess the cause-relationship (doubtful <2, possible 2-4, probable 5-8, and highly probable >8) of the potential drug-drug interaction. A literature review of similar previously reported cases and the possible pharmacological mechanisms of opioid-baclofen interaction is provided. RESULTS: After ITB and opioid co-administration, three out of four patients had decreased consciousness, and three developed respiratory depression. DIPS scores indicated a possible cause-relationship in one patient (DIPS: 4) and a probable cause-relationship in the others (DIPS: 6, 6, and 8). Discontinuation or adjusting ITB or opioid dosages resulted in clinical recovery. All patients recovered completely. In the literature, two articles describing nine unique cases were found. CONCLUSION: Although the opioid-ITB interaction is incompletely understood, concomitant use may enhance the risk of symptoms of CNS-depressant overdose, which are potentially life-threatening. If concomitant use is desirable, we strongly recommend to closely monitor these patients to detect interaction symptoms early. Awareness and monitoring of the potential opioid-ITB interaction is essential to reduce the risk of severe complications.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively).    Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: • Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. • Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: • Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. • Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Child-to-adult transition: a survey of current practices within the European Reference Network for Rare Neurological Diseases (ERN-RND).

BACKGROUND: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. AIM: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). METHODS: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. RESULTS: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. CONCLUSIONS: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.

Motor function and gait decline in individuals with cerebral palsy during adulthood: a narrative review of potential physiological determinants.

Cerebral palsy (CP) is the most common childhood-onset disability. The evolution of gait according to severity is well known amongst children and thought to peak between 8 and 12 years of age among those walking without assistive devices. However, among adults, clinical experience as well as scientific studies report, through clinical assessments, questionnaires and interviews, increasing walking difficulties leading to an increased dependency of assistive devices in everyday ambulation. For many individuals with CP, this change will occur around 30-40 years, with the risk of losing mobility increasing with age. This narrative review aims to first provide objective evidence of motor function and gait decline in adults with CP when ageing, and then to offer mechanistic hypotheses to explain those alterations. Many studies have compared individuals with CP to the typically developing population, yet the evolution with ageing has largely been understudied. Comorbid diagnoses comprise one of the potential determinants of motor function and gait decline with ageing in people with CP, with the first manifestations happening at an early age and worsening with ageing. Similarly, ageing appears to cause alterations to the neuromuscular and cardiovascular systems at an earlier age than their typically developing (TD) peers. Future studies should, however, try to better understand how the physiological particularities of CP change with ageing that could pave the way for better strategies for maintaining function and quality of life in people with CP.

Surgical treatment options for spasticity in children and adolescents with hereditary spastic paraplegia.

PURPOSE: To provide an overview of outcome and complications of selective dorsal rhizotomy (SDR) and intrathecal baclofen pump implantation (ITB) for spasticity treatment in children with hereditary spastic paraplegia (HSP). METHODS: Retrospective study including children with HSP and SDR or ITB. Gross motor function measure (GMFM-66) scores and level of spasticity were assessed. RESULTS: Ten patients were included (most had mutations in ATL1 (n = 4) or SPAST (n = 3) genes). Four walked without and two with walking aids, four were non-walking children. Six patients underwent SDR, three patients ITB, and one both. Mean age at surgery was 8.9 ± 4.5 years with a mean follow-up of 3.4 ± 2.2 years. Five of the SDR patients were walking. Postoperatively spasticity in the legs was reduced in all patients. The change in GMFM-66 score was + 8.0 (0-19.7 min-max). The three ITB patients treated (SPAST (n = 2) and PNPLA6 (n = 1) gene mutation) were children with a progressive disease course. No complications of surgery occurred. CONCLUSIONS: SDR is a feasible treatment option in carefully selected children with HSP, especially in walking patients. The majority of patients benefit with respect to gross motor function, complication risk is low. ITB was used in children with severe and progressive disease.

Fatigue-related gait adaptations in children with cerebral palsy.

AIM: To obtain insights into the effects of fatigue on the kinematics, kinetics, and energy cost of walking (ECoW) in children with cerebral palsy (CP). METHOD: In this prospective observational study, 12 children with CP (mean age 12 years 9 months, SD 2 years 7 months; four females, eight males) and 15 typically developing children (mean age 10 years 8 months, SD 2 years 4 months; seven females, eight males) followed a prolonged intensity-based walking protocol on an instrumented treadmill, combined with gas analysis measurements. The protocol consisted of consecutive stages, including a 6-minute walking exercise (6MW) at comfortable speed, 2 minutes of moderate-intensity walking (MIW) (with a heart rate > 70% of its predicted maximal), and 4 minutes walking after MIW. If necessary, the speed and slope were incremented to reach MIW. Outcomes were evaluated at the beginning and end of the 6MW and after MIW. RESULTS: With prolonged walking, Gait Profile Scores deteriorated slightly for both groups (p < 0.01). Knee flexion increased during early stance (p = 0.004) and ankle dorsiflexion increased during late stance (p = 0.034) in children with CP only. Negligible effects were found for kinetics. No demonstrable change in ECoW was found in either group (p = 0.195). INTERPRETATION: Kinematic deviations in children with CP are progressive with prolonged walking. The large variation in adaptations indicates that an individual approach is recommended to investigate the effects of physical fatigue on gait in clinical practice.

Brain structural and functional connectivity and network organization in cerebral palsy: A scoping review.

AIM: To explore altered structural and functional connectivity and network organization in cerebral palsy (CP), by clinical CP subtype (unilateral spastic, bilateral spastic, dyskinetic, and ataxic CP). METHOD: PubMed and Embase databases were systematically searched. Extracted data included clinical characteristics, analyses, outcome measures, and results. RESULTS: Sixty-five studies were included, of which 50 investigated structural connectivity, and 20 investigated functional connectivity using functional magnetic resonance imaging (14 studies) or electroencephalography (six studies). Five of the 50 studies of structural connectivity and one of 14 of functional connectivity investigated whole-brain network organization. Most studies included patients with unilateral spastic CP; none included ataxic CP. INTERPRETATION: Differences in structural and functional connectivity were observed between investigated clinical CP subtypes and typically developing individuals on a wide variety of measures, including efferent, afferent, interhemispheric, and intrahemispheric connections. Directions for future research include extending knowledge in underrepresented CP subtypes and methodologies, evaluating the prognostic potential of specific connectivity and network measures in neonates, and understanding therapeutic effects on brain connectivity.

Reliability and validity of the Dutch-language version of the Viking Speech Scale in children with cerebral palsy.

PURPOSE: The Viking Speech Scale is used to classify speech performance in children with cerebral palsy (CP). A Dutch-language version (VSS-NL) has recently become available. This study aimed to determine the reliability and validity of the VSS-NL and the association with motor type of CP, Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS) and Communication Function Classification System (CFCS). METHODS: A total of 90 children with CP, recruited throughout the Netherlands, took part in the study. VSS-NL classifications by speech and language therapists unfamiliar (SLT1) and familiar (SLT2) with the child, parents and physicians were compared. Convergent and discriminant validity were determined with the Intelligibility in Context Scale-Dutch (ICS-NL) and the Computer Based Instrument for Low Motor Language Testing (C-BiLLT). Inter- and intrarater reliability were determined by weighted Kappa (ƙw ). Validity and associations between VSS-NL and GMFCS, MACS and CFCS were determined with Spearman's coefficient. Association between VSS-NL and motor type of CP was determined with Fisher's exact test. RESULTS: Interrater reliability was excellent between SLT1-SLT2 (ƙw  = 0.93, 95% confidence interval [CI] 0.87-0.99), good between SLT1-parent (ƙw = 0.71, 95% CI 0.60-0.83), SLT1-physician (ƙw = 0.70, 95% CI 0.58-0.81), SLT2-parent (ƙw = 0.71, 95% CI 0.57-0.84), SLT2-physician (ƙw = 0.73, 95% CI 0.62-0.85) and parent-physician (ƙ = 0.72, 95% CI 0.60-0.85). Intrarater reliability was excellent for SLTs familiar and unfamiliar to the child (ƙw = 1.00, 95% CI 1.00-1.00), and very good for physicians (ƙw = 0.89, 95% CI 0.75-1.00) and parents (ƙw = 0.72, 95% CI 0.62-1.00). Convergent validity was very strong (r = -0.81, p < 0.001) and discriminant validity moderate (r = -0.56, p < 0.001). Association with motor type of CP was significant (χ2 = 27.558, p < 0.001) and strong with GMFCS (r = 0.62, p < 0.001), MACS (r = 0.63, p < 0.01) and CFCS (r = 0.69, p < 0.001). CONCLUSION: The VSS-NL is a reliable and valid system to classify speech performance in children with cerebral palsy. Classifications can be performed by SLTs, parents and physicians.

Predicting Gait Patterns of Children With Spasticity by Simulating Hyperreflexia.

Spasticity is a common impairment within pediatric neuromusculoskeletal disorders. How spasticity contributes to gait deviations is important for treatment selection. Our aim was to evaluate the pathophysiological mechanisms underlying gait deviations seen in children with spasticity, using predictive simulations. A cluster analysis was performed to extract distinct gait patterns from experimental gait data of 17 children with spasticity to be used as comparative validation data. A forward dynamic simulation framework was employed to predict gait with either velocity- or force-based hyperreflexia. This framework entailed a generic musculoskeletal model controlled by reflexes and supraspinal drive, governed by a multiobjective cost function. Hyperreflexia values were optimized to enable the simulated gait to best match experimental gait patterns. Three experimental gait patterns were extracted: (1) increased knee flexion, (2) increased ankle plantar flexion, and (3) increased knee flexion and ankle plantar flexion when compared with typical gait. Overall, velocity-based hyperreflexia outperformed force-based hyperreflexia. The first gait pattern could mostly be explained by rectus femoris and hamstrings velocity-based hyperreflexia, the second by gastrocnemius velocity-based hyperreflexia, and the third by gastrocnemius, soleus, and hamstrings velocity-based hyperreflexia. This study shows how velocity-based hyperreflexia from specific muscles contributes to different spastic gait patterns, which may help in providing targeted treatment.

Heritable connective tissue disorders in childhood: Decreased health-related quality of life and mental health.

The psychosocial consequences of growing up with Heritable Connective Tissue Disorders (HCTD) are largely unknown. We aimed to assess Health-Related Quality of Life (HRQoL) and mental health of children and adolescents with HCTD. This observational multicenter study included 126 children, aged 4-18 years, with Marfan syndrome (MFS, n = 74), Loeys-Dietz syndrome (n = 8), molecular confirmed Ehlers-Danlos syndromes (n = 15), and hypermobile Ehlers-Danlos syndrome (hEDS, n = 29). HRQoL and mental health were assessed through the parent and child-reported Child Health Questionnaires (CHQ-PF50 and CHQ-CF45, respectively) and the parent-reported Strengths and Difficulties Questionnaire. Compared with a representative general population sample, parent-reported HRQoL of the HCTD-group showed significantly decreased Physical sum scores (p < 0.001, d = 0.9) and Psychosocial sum scores (p = 0.024, d = 0.2), indicating decreased HRQoL. Similar findings were obtained for child-reported HRQoL. The parent-reported mental health of the HCTD-group showed significantly increased Total difficulties sum scores (p = 0.01, d = 0.3), indicating decreased mental health. While the male and female MFS- and hEDS-subgroups both reported decreased HRQoL, only the hEDS-subgroup reported decreased mental health. In conclusion, children and adolescents with HCTD report decreased HRQoL and mental health, with most adverse outcomes reported in children with hEDS and least in those with MFS. These findings call for systematic monitoring and tailored interventions.

Convergent validity of functional communication tools and spoken language comprehension assessment in children with cerebral palsy.

BACKGROUND: The majority of children with cerebral palsy (CP) experience challenges in functional communication from a young age. A pivotal aspect of functional communication is language comprehension. A variety of classification systems and questionnaires are available to classify and describe functional communication skills in children with CP. A better understanding of the convergent validity of (subsections of) these tools, as well as their relationship with spoken language comprehension, will be valuable in both clinical practice and research. AIMS: To investigate the convergent validity of (subsections of) functional communication tools and the relationship with spoken language comprehension in children with CP. METHODS & PROCEDURES: Cross-sectional data on 138 children were subdivided into three developmental stages based on (Dutch) educational phases: ages 18 months-3;11y (n = 59), 4;0-5;11 years (n = 37) and 6;0-8;11 years (n = 42). The following functional communication tools were used to classify and describe functional communication: Communication Function Classification System (CFCS), subscales of the Caregivers Priorities and Child Health Index of Life with Disabilities-Dutch Version (CPCHILD-DV) and the Focus on Communication Under Six-34 (FOCUS-34) questionnaire. Spoken language comprehension was assessed with the Computer-Based instrument for Low motor Language Testing (C-BiLLT). Correlations between the functional communication tools, and with the C-BiLLT, were calculated using Pearson's and Spearman's correlation coefficients. It was hypothesized a priori that correlations of at least 0.60 suggest good convergent validity. OUTCOMES & RESULTS: At all developmental stages, a significant ordered decreasing tendency of communication outcomes was found across CFCS levels; lower CFCS levels were associated with lower scores on the CPCHILD-DV and FOCUS-34, and with a lower level of spoken language comprehension (C-BiLLT). Correlation coefficients of the functional communication tools exceeded 0.60 at all developmental stages. Correlations between C-BiLLT raw scores and the functional communication tools varied between 0.351 and 0.591 at developmental stage 18 months-3;11 years, between 0.781 and 0.897 at developmental stage 4;0-5;11 years, and between 0.635 and 0.659 at developmental stage 6;0-8;11 years. CONCLUSIONS & IMPLICATIONS: The functional communication tools assessed in this study showed convergent validity at all developmental stages. The CFCS, currently most widely used in paediatric rehabilitation, is adequate in the classification of functional communication. However, for more detailed clinical goal setting and evaluation of change in functional communication, the additional use of FOCUS-34 or CPCHILD-DV is recommended. WHAT THIS PAPER ADDS: What is already known on the subject A range of functional communication tools are available that help describe and classify functional communication in children with CP. These include the CFCS, subsections of CPCHILD-DV and FOCUS-34. The CFCS classifies functional communication in daily life with familiar and unfamiliar partners. Specific subsections of the CPCHILD-DV and FOCUS-34 include items that pertain to communicative participation. The innovative C-BiLLT provides a standardized method to assess spoken language comprehension in children with CP and significant motor impairments. What this paper adds to existing knowledge In the present study, convergent validity was confirmed between CFCS and specific subsections of the CPCHILD-DV and FOCUS-34. Correlations between these functional communication tools and the C-BiLLT were moderate to strong. What are the potential or actual clinical implications of this work? For clinical and research purposes (for instance, accurate prescription of augmentative and alternative communication-AAC), healthcare and educational professionals together with parents need to know how functional communication tools converge and how functional communication levels relate to the comprehension of spoken language. The CFCS provides a valid classification of functional communication abilities in children with CP. However, to measure change in functional communication and to evaluate treatment outcomes, use of additional functional communication tools such as the CPCHILD-DV and FOCUS-34 is recommended. When discrepancies are found between communicative abilities and spoken language comprehension, it is strongly recommended that valid tools are used in a more detailed examination of the child's spoken language comprehension skills and functional communication.

Home-Based Measurements of Dystonia in Cerebral Palsy Using Smartphone-Coupled Inertial Sensor Technology and Machine Learning: A Proof-of-Concept Study.

Accurate and reliable measurement of the severity of dystonia is essential for the indication, evaluation, monitoring and fine-tuning of treatments. Assessment of dystonia in children and adolescents with dyskinetic cerebral palsy (CP) is now commonly performed by visual evaluation either directly in the doctor's office or from video recordings using standardized scales. Both methods lack objectivity and require much time and effort of clinical experts. Only a snapshot of the severity of dyskinetic movements (i.e., choreoathetosis and dystonia) is captured, and they are known to fluctuate over time and can increase with fatigue, pain, stress or emotions, which likely happens in a clinical environment. The goal of this study was to investigate whether it is feasible to use home-based measurements to assess and evaluate the severity of dystonia using smartphone-coupled inertial sensors and machine learning. Video and sensor data during both active and rest situations from 12 patients were collected outside a clinical setting. Three clinicians analyzed the videos and clinically scored the dystonia of the extremities on a 0-4 scale, following the definition of amplitude of the Dyskinesia Impairment Scale. The clinical scores and the sensor data were coupled to train different machine learning models using cross-validation. The average F1 scores (0.67 ± 0.19 for lower extremities and 0.68 ± 0.14 for upper extremities) in independent test datasets indicate that it is possible to detected dystonia automatically using individually trained models. The predictions could complement standard dyskinetic CP measures by providing frequent, objective, real-world assessments that could enhance clinical care. A generalized model, trained with data from other subjects, shows lower F1 scores (0.45 for lower extremities and 0.34 for upper extremities), likely due to a lack of training data and dissimilarities between subjects. However, the generalized model is reasonably able to distinguish between high and lower scores. Future research should focus on gathering more high-quality data and study how the models perform over the whole day.

Physiological Response to the 6-Minute Frame Running Test in Children and Adults With Cerebral Palsy.

PURPOSE: To determine the physiological response and association to peak oxygen uptake of the 6-minute Frame Running test (6-MFRT) in persons with cerebral palsy (CP). METHODS: Twenty-four participants with CP, Gross Motor Function Classification System II/III/IV, performed the 6-MFRT. Distance, peak heart rate (HR peak ), peak respiratory exchange ratio (RER peak ), and peak oxygen uptake ( O 2peak ) were measured. RESULTS: HR peak ranged from 146 to 201 beats per minute, RER peak from 0.94 to 1.49, 6-MFRT distance from 179 to 1220 m and O 2peak from 0.62 to 2.18 L/min. HR peak was achieved in 63%, RER peak in 71%. A strong correlation was observed between 6-MFRT and O 2peak . CONCLUSIONS: The 6-MFRT represented a (near) maximum effort for 75% of the participants and the 6-MFRT can be used to estimate oxygen consumption on an individual basis.

Parenting a child with Marfan syndrome: Distress and everyday problems.

Marfan syndrome (MFS) is a multisystemic, autosomal dominant connective tissue disorder that occurs de novo in 25%. In many families, parent and child(ren) are affected, which may increase distress in parents. To assess distress, 42 mothers (29% MFS) and 25 fathers (60% MFS) of 43 affected children, completed the validated screening-questionnaire Distress thermometer for parents of a chronically ill child, including questions on overall distress (score 0-10; ≥4 denoting "clinical distress") and everyday problems (score 0-36). Data were compared to 1,134 control-group-parents of healthy children. Mothers reported significantly less overall distress (2, 1-4 vs. 3, 1-6; p = .049; r = -.07) and total everyday problems (3, 0-6 vs. 4, 1-8; p = .03; r = -.08) compared to control-group-mothers. Mothers without MFS reported significantly less overall distress compared to mothers with MFS, both of a child with MFS (1, 0-4 vs. 3.5, 2-5; p = .039; r = -.17). No significant differences were found between the father-groups, nor between the group of healthy parents of an affected child living together with an affected partner compared to control-group-parents. No differences in percentages of clinical distress were reported between mothers and control-group-mothers (33 vs. 42%); fathers and control-group-fathers (28 vs. 32%); nor between the other groups. Distress was not associated with the children's MFS characteristics. Concluding, parents of a child with MFS did not show more clinical distress compared to parents of healthy children. However, clinical distress was reported in approximately one-third and may increase in case of acute medical complications. We advise monitoring distress in parents of a child with MFS to provide targeted support.

Functional assessment of stretch hyperreflexia in children with cerebral palsy using treadmill perturbations.

BACKGROUND: As hyperactive muscle stretch reflexes hinder movement in patients with central nervous system disorders, they are a common target of treatment. To improve treatment evaluation, hyperactive reflexes should be assessed during activities as walking rather than passively. This study systematically explores the feasibility, reliability and validity of sudden treadmill perturbations to evoke and quantify calf muscle stretch reflexes during walking in children with neurological disorders. METHODS: We performed an observational cross-sectional study including 24 children with cerebral palsy (CP; 6-16 years) and 14 typically developing children (TD; 6-15 years). Short belt accelerations were applied at three different intensities while children walked at comfortable speed. Lower leg kinematics, musculo-tendon lengthening and velocity, muscle activity and spatiotemporal parameters were measured to analyze perturbation responses. RESULTS: We first demonstrated protocol feasibility: the protocol was completed by all but three children who ceased participation due to fatigue. All remaining children were able to maintain their gait pattern during perturbation trials without anticipatory adaptations in ankle kinematics, spatiotemporal parameters and muscle activity. Second, we showed the protocol's reliability: there was no systematic change in muscle response over time (P = 0.21-0.54) and a bootstrapping procedure indicated sufficient number of perturbations, as the last perturbation repetition only reduced variability by ~ 2%. Third, we evaluated construct validity by showing that responses comply with neurophysiological criteria for stretch reflexes: perturbations superimposed calf muscle lengthening (P < 0.001 for both CP and TD) in all but one participant. This elicited increased calf muscle activity (359 ± 190% for CP and 231 ± 68% for TD, both P < 0.001) in the gastrocnemius medialis muscle, which increased with perturbation intensity (P < 0.001), according to the velocity-dependent nature of stretch reflexes. Finally, construct validity was shown from a clinical perspective: stretch reflexes were 1.7 times higher for CP than TD for the gastrocnemius medialis muscle (P = 0.017). CONCLUSIONS: The feasibility and reliability of the protocol, as well as the construct validity-shown by the exaggerated velocity-dependent nature of the measured responses-strongly support the use of treadmill perturbations to quantify stretch hyperreflexia during gait. We therefore provided a framework which can be used to inform clinical decision making and treatment evaluation.

Neuromuscular Control before and after Independent Walking Onset in Children with Cerebral Palsy.

Early brain lesions which produce cerebral palsy (CP) may affect the development of walking. It is unclear whether or how neuromuscular control, as evaluated by muscle synergy analysis, differs in young children with CP compared to typically developing (TD) children with the same walking ability, before and after the onset of independent walking. Here we grouped twenty children with (high risk of) CP and twenty TD children (age 6.5-52.4 months) based on their walking ability, supported or independent walking. Muscle synergies were extracted from electromyography data of bilateral leg muscles using non-negative matrix factorization. Number, synergies' structure and variability accounted for when extracting one (VAF1) or two (VAF2) synergies were compared between CP and TD. Children in the CP group recruited fewer synergies with higher VAF1 and VAF2 compared to TD children in the supported and independent walking group. The most affected side in children with asymmetric CP walking independently recruited fewer synergies with higher VAF1 compared to the least affected side. Our findings suggest that early brain lesions result in early alterations of neuromuscular control, specific for the most affected side in asymmetric CP.

Care Pathway for Foetal Joint Contractures, Foetal Akinesia Deformation Sequence, and Arthrogryposis Multiplex Congenita.

INTRODUCTION: The majority of arthrogryposis multiplex congenita (AMC) and lethal forms of AMC such as foetal akinesia deformation sequence (FADS) cases are missed prenatally. We have demonstrated the additional value of foetal motor assessment and evaluation in a multidisciplinary team for the period 2007-2016. An applied care pathway was developed for foetuses presenting with joint contracture(s) in one anatomic region (e.g., talipes equinovarus [TEV]), more than one body part with non-progressive contractures and motility (AMC) and with deterioration over time (FADS). METHODS: The multidisciplinary team of Amsterdam University Medical Centre Expertise Centre FADS and AMC developed the care pathway. Additional tools are provided including a motor assessment by ultrasound examination and a post-mortem assessment form. RESULTS: An eight-step care pathway is presented with a proposed timing for prenatal sonographic examination, genetic examinations, multidisciplinary meetings, prenatal and postnatal counselling of the parents by a specialist also treating after birth, and the follow-up of prenatal and postnatal findings with counselling for future pregnancies. DISCUSSION/CONCLUSION: The scheduled serial structural and motor sonograpahic assessment together with follow-up examinations and genetic analysis should be tailored per prenatal centre per available resources. The multidisciplinary care pathway may pave the way to increase the detection rate and diagnosis of isolated contracture(s), TEV with underlying genetic causes, and the rare phenotypes AMC/FADS and prompt treatment after birth within expertise teams.

The Effect of Intrathecal Baclofen in Dyskinetic Cerebral Palsy: The IDYS Trial.

OBJECTIVE: Intrathecal baclofen treatment is used for the treatment of dystonia in patients with severe dyskinetic cerebral palsy; however, the current level of evidence for the effect is low. The primary aim of this study was to provide evidence for the effect of intrathecal baclofen treatment on individual goals in patients with severe dyskinetic cerebral palsy. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was performed at 2 university medical centers in the Netherlands. Patients with severe dyskinetic cerebral palsy (Gross Motor Functioning Classification System level IV-V) aged 4 to 24 years who were eligible for intrathecal baclofen were included. Patients were assigned by block randomization (2:2) for treatment with intrathecal baclofen or placebo for 3 months via an implanted microinfusion pump. The primary outcome was goal attainment scaling of individual treatment goals (GAS T score). A linear regression model was used for statistical analysis with study site as a covariate. Safety analyses were done for number and type of (serious) adverse events. RESULTS: Thirty-six patients were recruited from January 1, 2013, to March 31, 2018. Data for final analysis were available for 17 patients in the intrathecal baclofen group and 16 in the placebo group. Mean (standard deviation) GAS T score at 3 months was 38.9 (13.2) for intrathecal baclofen and 21.0 (4.6) for placebo (regression coefficient = 17.8, 95% confidence interval = 10.4-25.0, p < 0.001). Number and types of (serious) adverse events were similar between groups. INTERPRETATION: Intrathecal baclofen treatment is superior to placebo in achieving treatment goals in patients with severe dyskinetic cerebral palsy. ANN NEUROL 2019.

Factors associated with spoken language comprehension in children with cerebral palsy: a systematic review.

AIM: To identify factors that are relevant for spoken language comprehension in children with cerebral palsy (CP), following the International Classification of Functioning, Disability and Health - Children and Youth (ICF-CY) framework. METHOD: A systematic literature search was conducted using the electronic literature databases PubMed, Embase, PsycInfo, and Cochrane Library, from January 1967 to December 2019. Included studies involved children with CP, results regarding spoken language comprehension, and analysis of at least one associated factor. Factors were classified within ICF-CY domains. RESULTS: Twenty-one studies met inclusion criteria. Factors in the ICF-CY domains of body functions and structure were most frequently reported. White brain matter abnormalities, motor type, functional mobility, and intellectual functioning appear to be relevant factors in spoken language comprehension in CP. Factors in the domain of activities and participation, as well as contextual factors, have rarely been studied in the context of spoken language comprehension in CP. INTERPRETATION: Most factors known to be important for spoken language comprehension in typically developing children and/or known to be susceptible to change by interventions are understudied in CP.

Use of the Dyskinesia Impairment Scale in non-ambulatory dyskinetic cerebral palsy.

AIM: To assess the responsiveness, concurrent validity, and feasibility of the Dyskinesia Impairment Scale (DIS) in non-ambulatory patients with dyskinetic cerebral palsy (CP). METHOD: The study is a secondary analysis of data collected in the IDYS trial, a randomized controlled trial on the effects of intrathecal baclofen (ITB). The DIS and Barry-Albright Dystonia Scale (BADS) were conducted at baseline and after 3 months of ITB or placebo treatment. Responsiveness was assessed by comparing the effect sizes and correlation of change after treatment between the DIS and BADS. Concurrent validity was evaluated by assessing the correlations between scales. Feasibility was evaluated for each DIS item by the number of participants who successfully accomplished the item. RESULTS: Thirty-three non-ambulatory patients (9 females, 24 males) with dyskinetic CP (ITB-treated: n=17, mean [SD] age: 14y 1mo [4y 1mo]; placebo-treated: n=16, mean [SD] age: 14y 7mo [4y]) were included in the study. The effect sizes for BADS and DIS were similar in The ITB-treated group (-0.29 and -0.22 respectively). Changes after treatment on the DIS dystonia subscale correlated with changes on the BADS (r=0.64; p<0.001). The DIS dystonia subscale and BADS correlated at baseline and follow-up (r=0.78; p<0.001 and r=0.79; p<0.001). Not all DIS activity items could be performed in this sample of patients. INTERPRETATION: For non-ambulatory patients with dyskinetic CP, the responsiveness of the DIS equalled the responsiveness of BADS. Concurrent validity was adequate. Feasibility for activity items was restricted in patients with severe dyskinetic CP. WHAT THIS PAPER ADDS: The Dyskinesia Impairment Scale (DIS) and Barry-Albright Dystonia Scale showed similar responsiveness in non-ambulatory patients with dyskinetic cerebral palsy (CP). No floor or ceiling effect was observed for DIS in non-ambulatory participants. The concurrent validity of DIS was adequate in non-ambulatory participants. Patients with dyskinetic CP in Gross Motor Function Classification System levels IV and V could not perform all DIS activity items.