Spectrum of ERCC6-Related Cockayne Syndrome (Type B): From Mild to Severe Forms.

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity.

Robotic-assisted locomotor treadmill therapy does not change gait pattern in children with cerebral palsy.

Although robotic-assisted locomotor treadmill therapy is utilized on children with cerebral palsy (CP), its impact on the gait pattern in childhood is not fully described. We investigated the outcome of robotized gait training focusing on the gait pattern modifications and mobility in individuals with CP. An additional intention is to compare our results with the previous literature advancing future solutions. Twenty-four children with diplegic CP (average age 6.4 years old with Gross Motor Functional Classification System range I-IV) received robotized gait training five times per week for 4 weeks. Gait analysis and Gross Motor Function Measurement (GMFM) assessments were performed before and at the end of the treatment. Gait analysis showed inconsistent modifications of the gait pattern. GMFM showed a mild improvement of the dimension D in all subjects, while dimension E changed only in the younger and more severely affected patients. In this study, a detailed investigation comprehensive of electromyography patterns, where previous literature reported only sparse data without giving information on the whole gait pattern, were conducted. We carried on the analysis considering the age of the participants and the severity of the gait function. The findings differentiate the concept of specific pattern recovery (no gait pattern changes) from the concept of physical training (mild GMFM changes).

Minimum Clinically Important Difference of Gross Motor Function and Gait Endurance in Children with Motor Impairment: A Comparison of Distribution-Based Approaches.

OBJECTIVE: The minimum clinically important difference (MCID) is a standard way of measuring clinical relevance. The objective of this work was to establish the MCID for the 6-minute walking test (6minWT) and the Gross Motor Function Measure (GMFM-88) in pediatric gait disorders. METHODS: A cohort, pretest-posttest study was conducted in a hospitalized care setting. A total of 182 patients with acquired brain injury (ABI) or cerebral palsy (CP) performed 20 robot-assisted gait training sessions complemented with 20 sessions of physical therapy over 4 weeks. Separate MCIDs were calculated using 5 distribution-based approaches, complemented with an anonymized survey completed by clinical professionals. RESULTS: The MCID range for the 6minWT was 20-38 m in the ABI cohort, with subgroup ranges of 20-36 m for GMFCS I-II, 23-46 m for GMFCS III, and 24-46 m for GMFCS IV. MCIDs for the CP population were 6-23 m, with subgroup ranges of 4-28 m for GMFCS I-II, 9-19 m for GMFCS III, and 10-27 m for GMFCS IV. For GMFM-88 total score, MCID values were 1.1%-5.3% for the ABI cohort and 0.1%-3.0% for the CP population. For dimension "D" of the GMFM, MCID ranges were 2.3%-6.5% and 0.8%-5.2% for ABI and CP populations, respectively. For dimension "E," MCID ranges were 2.8%-6.5% and 0.3%-4.9% for ABI and CP cohorts, respectively. The survey showed a large interquartile range, but the results well mimicked the distribution-based methods. CONCLUSIONS: This study identified for the first time MCID ranges for 6minWT and GMFM-88 in pediatric patients with neurological impairments, offering useful insights for clinicians to evaluate the impact of treatments. Distribution-based methods should be used with caution: methods based on pre-post correlation may underestimate MCID when applied to patients with small improvements over the treatment period. Our results should be complemented with estimates obtained using consensus- and anchor-based approaches.

Effect of Robot-Assisted Gait Training in a Large Population of Children With Motor Impairment Due to Cerebral Palsy or Acquired Brain Injury.

OBJECTIVE: To evaluate retrospectively the effect of robotic rehabilitation in a large group of children with motor impairment; an additional goal was to identify the effects in children with cerebral palsy (CP) and acquired brain injury (ABI) and with different levels of motor impairment according to the Gross Motor Function Classification System. Finally, we examined the effect of time elapsed from injury on children's functions. DESIGN: A cohort, pretest-posttest retrospective study was conducted. SETTING: Hospitalized care. PARTICIPANTS: A total of 182 children, 110 with ABI and 72 with CP and with Gross Motor Function Classification System (GMFCS) levels I-IV, were evaluated retrospectively. INTERVENTIONS: Patients underwent a combined treatment of robot-assisted gait training and physical therapy. MAIN OUTCOME MEASURES: All the patients were evaluated before and after the training using the 6-minute walk test and the Gross Motor Function Measure. A linear mixed model with 3 fixed factors and 1 random factor was used to evaluate improvements. RESULTS: The 6-minute walk test showed improvement in the whole group and in both ABI and CP. The Gross Motor Function Measure showed improvement in the whole group and in the patients with ABI but not in children with CP. The GMFCS analysis showed that all outcomes improved significantly in all classes within the ABI subgroup, whereas improvements were significant only for GMFCS III in children with CP. CONCLUSIONS: Children with motor impairment can benefit from a combination of robotic rehabilitation and physical therapy. Our data suggest positive results for the whole group and substantial differences between ABI and CP subgroups, with better results for children with ABI, that seem to be consistently related to time elapsed from injury.

Prestatus and status dystonicus in children and adolescents.

AIM: To critically analyse the management of status dystonicus and prestatus dystonicus in children and adolescents, in order to examine clinical features, acute management, and risk of relapse in a paediatric cohort. METHOD: Clinical, demographic, and therapeutic features were analysed according to disease severity. Risk of subsequent relapse was estimated through Kaplan-Meier curves. RESULTS: Thirty-four patients (eight females, 26 males) experiencing 63 episodes of acute dystonia exacerbations at a tertiary referral Italian hospital were identified. Mean age at status dystonicus presentation was 9 years 11 months (11y at inclusion in the study). Onset of dystonia dated back to infancy in most cases. Fourteen patients experienced two or more episodes. Infections were the most common trigger (48%). Benzodiazepines were the most commonly used drugs for acute management. Stereotactic pallidotomy was performed in six cases during status dystonicus, and in two additional patients it was electively performed after medical management. The probability of survival free from status dystonicus relapses was 78% after 4 months and 61% after 27 months. INTERPRETATION: Dystonia exacerbations are potentially life-threating emergencies, with a considerable risk of relapse. Nevertheless, no obvious factors for relapse risk stratification exist. Pallidotomy is a feasible option in medical refractory status dystonicus for patients with limited deep brain stimulation applicability, but the risk of recurrence is elevated. WHAT THIS PAPER ADDS: Acute exacerbations may affect up to 10% of children with dystonia. Infections are the most common precipitant factor. In about 30% of the cases, intensive care unit admission is needed. Subsequent relapses are common, reaching 25% risk at 1 year. Pallidotomy can be considered in medical-refractory cases with no deep brain stimulation applicability.

A study validating the Italian version of the Level of Sitting Scale in children with cerebral palsy.

OBJECTIVES: To assess measurement properties of the Italian version of the Level of Sitting Scale when classifying sitting ability of children with cerebral palsy. DESIGN: Methodological study. SETTING: Children's hospital (inpatients and outpatients). SUBJECTS: Children 18 years of age or younger with cerebral palsy. METHODS: The original English version of the Level of Sitting Scale was translated and culturally adapted for the Italian culture following international guidelines. Examination of reliability and validity of the Italian Level of Sitting Scale was then undertaken. Inter-rater and one-week test-retest reliability were estimated using both intraclass correlation coefficients (ICCs) with 95% confidence intervals and Bland-Altman plots. Construct validity of the Italian Level of Sitting was evaluated using three approaches examining Pearson's correlation coefficient (r) and Mann-Whitney U test (P-value < 0.05). MAIN MEASURES: Italian Level of Sitting Scale and Gross Motor Function Classification System. RESULTS: The Italian Level of Sitting Scale was administered to 109 subjects. Inter-rater reliability and one-week test-retest showed excellent value with ICCs of 0.99 for both. (1) The Pearson correlation coefficient comparing Italian Level of Sitting Scale with Gross Motor Function Classification System was -0.91 and (2) correlation with total amount of adaptive seating components was -0.90. Differences in sitting abilities and use/non-use of wheelchair were found. All reported a statistical significance of P < 0.01. CONCLUSION: Our findings provide evidence of reliability and validity when using the Italian Level of Sitting Scale to classify seated postural abilities in a sample of Italian children with cerebral palsy.

Spasticity Measurement Based on Tonic Stretch Reflex Threshold in Children with Cerebral Palsy Using the PediAnklebot.

Nowadays, objective measures are becoming prominent in spasticity assessment, to overcome limitations of clinical scales. Among others, Tonic Stretch Reflex Threshold (TSRT) showed promising results. Previous studies demonstrated the validity and reliability of TSRT in spasticity assessment at elbow and ankle joints in adults. Purposes of the present study were to assess: (i) the feasibility of measuring TSRT to evaluate spasticity at the ankle joint in children with Cerebral Palsy (CP), and (ii) the correlation between objective measures and clinical scores. A mechatronic device, the pediAnklebot, was used to impose 50 passive stretches to the ankle of 10 children with CP and 3 healthy children, to elicit muscles response at 5 different velocities. Surface electromyography, angles, and angular velocities were recorded to compute dynamic stretch reflex threshold; TSRT was computed with a linear regression through angles and angular velocities. TSRTs for the most affected side of children with CP resulted into the biomechanical range (95.7 ± 12.9° and 86.7 ± 17.4° for Medial and Lateral Gastrocnemius, and 75.9 ± 12.5° for Tibialis Anterior). In three patients, the stretch reflex was not elicited in the less affected side. TSRTs were outside the biomechanical range in healthy children. However, no correlation was found between clinical scores and TSRT values. Here, we demonstrated the capability of TSRT to discriminate between spastic and non-spastic muscles, while no significant outcomes were found for the dorsiflexor muscle.

Working memory and mental imagery in cerebral palsy: a single case investigation.

In this study we describe visuospatial working memory and visual mental imagery of a child with Cerebral Palsy. Beyond a moderate impairment of visuomotor integration skills, cognitive level and memory span, poor performance emerged in figures reconstruction, in memorizing matrix patterns and movements along a path. No such deficits were observed in recalling figures and their positions on a grid and learning groups of words using a visual imagery strategy. This case highlights that impaired action execution impairs performance in imagery tasks as well, but not when alternative strategies (e.g., verbal encoding) can be adopted. Results are discussed considering recent evidence on working memory and visual imagery links, and their role in motor rehabilitation training.

Reduced short term adaptation to robot generated dynamic environment in children affected by Cerebral Palsy.

BACKGROUND: It is known that healthy adults can quickly adapt to a novel dynamic environment, generated by a robotic manipulandum as a structured disturbing force field. We suggest that it may be of clinical interest to evaluate to which extent this kind of motor learning capability is impaired in children affected by cerebal palsy. METHODS: We adapted the protocol already used with adults, which employs a velocity dependant viscous field, and compared the performance of a group of subjects affected by Cerebral Palsy (CP group, 7 subjects) with a Control group of unimpaired age-matched children. The protocol included a familiarization phase (FA), during which no force was applied, a force field adaptation phase (CF), and a wash-out phase (WO) in which the field was removed. During the CF phase the field was shut down in a number of randomly selected "catch" trials, which were used in order to evaluate the "learning index" for each single subject and the two groups. Lateral deviation, speed and acceleration peaks and average speed were evaluated for each trajectory; a directional analysis was performed in order to inspect the role of the limb's inertial anisotropy in the different experimental phases. RESULTS: During the FA phase the movements of the CP subjects were more curved, displaying greater and variable directional error; over the course of the CF phase both groups showed a decreasing trend in the lateral error and an after-effect at the beginning of the wash-out, but the CP group had a non significant adaptation rate and a lower learning index, suggesting that CP subjects have reduced ability to learn to compensate external force. Moreover, a directional analysis of trajectories confirms that the control group is able to better predict the force field by tuning the kinematic features of the movements along different directions in order to account for the inertial anisotropy of arm. CONCLUSIONS: Spatial abnormalities in children affected by cerebral palsy may be related not only to disturbance in motor control signals generating weakness and spasticity, but also to an inefficient control strategy which is not based on a robust knowledge of the dynamical features of their upper limb. This lack of information could be related to the congenital nature of the brain damage and may contribute to a better delineation of therapeutic intervention.

Neurophysiological changes induced by the botulinum toxin type A injection in children with cerebral palsy.

In the last few years botulinum toxin type A (BTX-A) has been widely used in the management of spasticity in children with cerebral palsy in order to reduce hypertonicity and improve functional outcomes enhancing motor skill development. The botulinum toxin injection seems to interact with intrafusal and extrafusal fibers producing a reduction of hypertone both through synaptic blockade and inhibition of stretch reflex loop and these changes may influence not only the spinal cord but also the central nervous system (CNS). The purpose of our study was to determine the neurophysiological changes induced by the BTX-A through an evaluation of cortical somatosensory Evoked Potential (SEP) and Soleus H wave, that is the index of excitability of stretch reflex loop. Eighteen children with Cerebral Palsy (CP), aged between 5 and 12, were recruited at Children's Hospital "Bambino Gesù" of Rome. All children were evaluated with appropriate clinical scales before and 1 month after the BTX-A injection. Neurophysiological measurements were performed before, and 1 month after botulinum toxin injection through lower limb SEPs, M-wave and Soleus H wave recording. After the injection the results showed a statistically significant improvement both of clinical scales and the neurophysiological variables. These findings suggest that spasticity itself can be considered as a factor affecting the cortical SEPs. And even though it seems that BTX-A does not have any direct central effect on sensory pathways we suppose an indirect mechanism on modulation of afferent fibers Ia due to the modification induced by BTX-A to central loop reflex.

Robot-mediated and clinical scales evaluation after upper limb botulinum toxin type A injection in children with hemiplegia.

OBJECTIVE: The aim of this pilot study was to examine changes in different aspects of impairment, including spasticity in the upper limbs, of hemiplegic children following botulinum toxin type A intervention. Progress was assessed using standard clinical measurements and a robotic device. DESIGN: Pre-post multiple baseline. SUBJECTS: Six children with hemiplegia. METHODS: Botulinium toxin type A injections were administered into the affected upper limb muscles. Outcomes were evaluated before and one month after the injection. Outcome assessments included: Melbourne Scale, Modified Ashworth Scale (MAS) and Passive Range of Motion. Furthermore, a robotic device was employed as an evaluation tool. RESULTS: Patients treated with botulinum toxin type A had significantly greater reduction in spasticity (MAS, p < 0.01), which explains an improvement in upper limb function and quality movement measured with the Melbourne Scale (p < 0.01). These improvements are consistent with robot-based evaluation results that showed statistically significant changes (p < 0.01) following botulinum toxin type A injections. CONCLUSION: The upper limb performs a wide variety of movements. The multi-joint nature of the task during the robot-mediated evaluation required active control of joint interaction forces. There was good correlation between clinical scales and robotic evaluation. Hence the robot-mediated assessment may be used as an additional tool to quantify the degree of motor improvement after botulinum toxin type A injections.

Reach-to-grasp interjoint coordination for moving object in children with hemiplegia.

OBJECTIVE: To evaluate interjoint coordination in children with hemiplegia as they reach to grasp objects, in both static and dynamic conditions. An ad hoc robotic device was used to study the dynamic condition. DESIGN: Observational study. PATIENTS: Six children with hemiplegia and 6 young adults. METHODS: Kinematics of the trunk and arm were studied using an optoelectronic system. In the dynamic condition the target object, a cup, was moved by the robotic device along clockwise and counterclockwise circular trajectories. RESULTS: Two main strategies were used to study the onset and offset of shoulder and elbow movements and their maximum velocities. The hand velocity profile was bell-shaped in the static condition and compatible with ramp movements for the more affected side in the dynamic condition. The time to object contact was higher for the more affected side in the dynamic condition. The temporal coordination index illustrated an immature and less flexible behaviour in children's reaching in all the examined conditions. CONCLUSION: Study of the hand velocity profiles, the time to object contact and the temporal coordination index highlighted, first, the dependence of upper limb interjoint coordination on task, context, residual resources and individual solution, and secondly, the sensory-motor deficit characteristics of the children's more affected side during dynamic reaching, raising the prospect of a promising training context in children with hemiplegia.

Foot drop and plantar flexion failure determine different gait strategies in Charcot-Marie-Tooth patients.

OBJECTIVE: To describe the temporal, kinetic, kinematic, electromyographic and energetic aspects of gait in Charcot-Marie-Tooth patients with foot drop and plantar flexion failure. METHODS: A sample of 21 patients fulfilling clinical, electrodiagnostic and genetic criteria for Charcot-Marie-Tooth disease were evaluated by computerized gait analysis system and compared to a group of matched healthy subjects. Patients were classified as having isolate foot drop (group 1) and association of foot drop and plantar flexion failure (group 2). RESULTS: While it was impossible to detect a reliable gait pattern when the group of patients was considered as a whole and compared to healthy subjects, we observed two distinctive gait patterns when patients were subdivided as group 1 or 2. Group 1 showed a gait pattern with some characteristics of the "steppage pattern". The complex motor strategy adopted by this group leads to reduce the swing velocity and to preserve the step length in spite of a high energy consumption. Group 2 displayed a "clumsy pattern" characterized by very slow gait with reduced step length, a broader support area and great reduction in the cadence. This group of patients is characterized by a low energy consumption and greater energy recovery, due above all to the primary deficit and the various compensatory mechanisms. CONCLUSIONS: Such between-group differences in gait pattern can be related to both primary motor deficits and secondary compensatory mechanisms. Foot drop and plantar flexion failure affect the overall gait strategy in Charcot-Marie-Tooth patients.

Peroneus longus muscle activation pattern during gait cycle in athletes affected by functional ankle instability: a surface electromyographic study.

BACKGROUND: Functional ankle instability is a clinical syndrome that may develop after acute lateral ankle sprain. Although several causes of this functional instability have been suggested, it is still unclear what the activation pattern of the peroneus longus muscle is in patients with functional ankle instability. HYPOTHESIS: Peroneus longus activation patterns differ in the injured side and the uninjured side in subjects with functional ankle instability. STUDY DESIGN: Descriptive laboratory study. METHODS: The authors examined 14 subjects with functional ankle instability by using surface electromyography during walking. Activation time of the peroneus longus muscle was expressed as a percentage of the stance phase of the gait cycle. RESULTS: A statistically significant decrease in peroneus longus muscle activity was found in the injured side compared with the uninjured side (22.8% +/- 4.25% vs 37.6% +/- 3.5%, respectively). CONCLUSIONS: Results obtained in this study show a change in peroneus longus muscle activation time after injury. Independent of the origin of this change, which could only be surmised, the decrease in peroneus longus muscle activity may result in reduced protection against lateral sprains. CLINICAL RELEVANCE: The assessment of peroneus longus activation pattern during gait is useful to design an appropriate rehabilitation program in athletes suffering from functional ankle instability.