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.

Towards automated video-based assessment of dystonia in dyskinetic cerebral palsy: A novel approach using markerless motion tracking and machine learning.

Introduction: Video-based clinical rating plays an important role in assessing dystonia and monitoring the effect of treatment in dyskinetic cerebral palsy (CP). However, evaluation by clinicians is time-consuming, and the quality of rating is dependent on experience. The aim of the current study is to provide a proof-of-concept for a machine learning approach to automatically assess scoring of dystonia using 2D stick figures extracted from videos. Model performance was compared to human performance. Methods: A total of 187 video sequences of 34 individuals with dyskinetic CP (8-23 years, all non-ambulatory) were filmed at rest during lying and supported sitting. Videos were scored by three raters according to the Dyskinesia Impairment Scale (DIS) for arm and leg dystonia (normalized scores ranging from 0-1). Coordinates in pixels of the left and right wrist, elbow, shoulder, hip, knee and ankle were extracted using DeepLabCut, an open source toolbox that builds on a pose estimation algorithm. Within a subset, tracking accuracy was assessed for a pretrained human model and for models trained with an increasing number of manually labeled frames. The mean absolute error (MAE) between DeepLabCut's prediction of the position of body points and manual labels was calculated. Subsequently, movement and position features were calculated from extracted body point coordinates. These features were fed into a Random Forest Regressor to train a model to predict the clinical scores. The model performance trained with data from one rater evaluated by MAEs (model-rater) was compared to inter-rater accuracy. Results: A tracking accuracy of 4.5 pixels (approximately 1.5 cm) could be achieved by adding 15-20 manually labeled frames per video. The MAEs for the trained models ranged from 0.21 ± 0.15 for arm dystonia to 0.14 ± 0.10 for leg dystonia (normalized DIS scores). The inter-rater MAEs were 0.21 ± 0.22 and 0.16 ± 0.20, respectively. Conclusion: This proof-of-concept study shows the potential of using stick figures extracted from common videos in a machine learning approach to automatically assess dystonia. Sufficient tracking accuracy can be reached by manually adding labels within 15-20 frames per video. With a relatively small data set, it is possible to train a model that can automatically assess dystonia with a performance comparable to human scoring.

Attainment of personal goals in the first year of intrathecal baclofen treatment in dyskinetic cerebral palsy: a prospective cohort study.

PURPOSE: To assess attainment of individual treatment goals one year after intrathecal baclofen (ITB) pump implantation in individuals with dyskinetic cerebral palsy (CP). MATERIALS AND METHODS: A multi-center prospective cohort study was conducted including 34 non-walking individuals with severe dyskinetic CP, classified as Gross Motor Function Classification System (GMFCS) IV/V, aged 4-24 years, 12 months after pump implantation. The main outcome measure was Goal Attainment Scaling (GAS). Predictors of GAS results were analyzed. Complications were registered systematically. RESULTS: Seventy-one percent of individuals with dyskinetic CP fully achieved one or more treatment goals. One or more treatment goals were partially achieved in 97% of individuals. Two factors were found to be associated with attainment of goals: Dyskinesia Impairment Scale (DIS) score at baseline and the difference in pain score between baseline and follow-up. These two variables explain 30% of the variance in the outcome. CONCLUSIONS: Intrathecal baclofen is effective in achieving individual treatment goals in children and young adults with dyskinetic CP after nine to 12 months of ITB treatment. A positive outcome on treatment goals is, for a small part, associated with higher severity of dystonia at baseline and with improvement of pain during treatment. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, number NTR3642.Implications for rehabilitationIntrathecal baclofen treatment is effective in attainment of personal treatment goals, one year after pump implantation in patients with dyskinetic cerebral palsy.A positive outcome on treatment goals is, for a small part, related to higher severity of dystonia at the start and on improvement of pain during treatment.

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.

The Impact of Frame Running on Quality of Life in Young Athletes With Mobility Limitations.

Purpose: The para-athletic sport Frame Running is developed for persons with neurological impairments causing severe limitations of walking ability. Participating in sports can contribute to a better quality of life (QoL). It is unknown if participation in Frame Running contributes to QoL in children with mobility limitations. This study aims to explore the changes in QoL in children and youth who started Frame Running. Materials and Methods: We conducted a cross-sectional study amongst young Frame Running athletes with mobility limitations due to various underlying causes, aged 6-19 years, who are members of one of the Frame Running groups in the Netherlands. For 62 athletes, parents completed the Psychosocial Impact of Assistive Devices Scale (PIADS) questionnaire (subscales: competence, adaptability, and self-esteem). For six athletes, parents were interviewed to obtain more in-depth insight in the perceived changes in the QoL of their children. Results: Parents (of 58% boys, mean age 12 years 4 months; SD 3 years 3 months; 52% supported walkers) reported a significant positive change on all three subscales of the PIADS questionnaire since their children started Frame Running. Most change was experienced in the items performance, the ability to participate, happiness and self-confidence. Quotes of the parents who were interviewed elucidated these changes. Conclusion: Frame Running increased QoL in young athletes with a mobility limitation. Frame Running may therefore be advised for these children and youth to improve QoL.

[Dystonia in cerebral palsy; what are the treatment options?] / Dystonie bij cerebrale parese.

Cerebral palsy (CP) is the most common cause of motor disability in children. The largest group of children with CP present with spasticity. Dystonia is estimated to be present in approximately 15% of children with CP, referred to as dyskinetic CP. Still, dystonia in CP remains underdiagnosed. Dystonia and spasticity can occur together in a subgroup of children with CP as well. Dystonia is characterized by fluctuating hypertonia and involuntary movement and postures. Dystonia in children with CP can interfere with motor function, caregiving and comfort. It is important to recognize dystonia in children with CP as specific treatment is indicated. In this paper we describe three cases of children with dystonia in CP and we review the pharmacological treatment options for dystonia in CP and the surgical options including intrathecal baclofen pump and deep brain stimulation.

Surgical complications of intrathecal baclofen in children: A single centre, 20-year retrospective cohort study.

INTRODUCTION: Complications of intrathecal baclofen treatment (ITB) with an implanted pump can be severe and require surgery. Surgical implantation techniques and catheter materials for continuous ITB treatment have improved over the past years with the aim to reduce complications. OBJECTIVE: To assess: 1) the type and rate of complications of ITB that require surgical intervention, 2) which risk factors influence the occurrence of complications, and, specifically, 3) whether complication rate is influenced by type of catheter used. METHODS: A retrospective cohort study was conducted including all children (<18 years old) in one university medical center with pump implantation between 2001 and 2017. All complications requiring surgery were recorded. Risk factors for surgical intervention were determined using multiple logistic regression analysis. Catheter related complications between two types of catheters (silicone vs coated) were compared. RESULTS: In total, 88 complications of ITB treatment requiring surgery were found in 47 (36.2%) out of 130 children. These included catheter-related complications (55.7% of all complications), infections (21.6%), cerebrospinal fluid leakage (14.8%), and pump-related complications (7.9%). The silicone catheter type, used until 2012, was found to be a significant risk factor for complications (Odds Ratio 3.75; 95% CI: 1.30-10.83). Since the introduction of the coated catheter type, in 2012, the rate of catheter-related complications decreased, from 0.15 to 0.10 complications per pump year. CONCLUSION: The rate of surgical complications of intrathecal baclofen in children is high, and most frequently catheter-related. The number of complications decreased since the introduction of a new, coated, catheter in 2012. This study helps to inform children and their caregivers about the risk of possible complications of ITB, and to identify directions for future improvement of ITB care.

Instrumented assessment of motor function in dyskinetic cerebral palsy: a systematic review.

BACKGROUND: In this systematic review we investigate which instrumented measurements are available to assess motor impairments, related activity limitations and participation restrictions in children and young adults with dyskinetic cerebral palsy. We aim to classify these instrumented measurements using the categories of the international classification of functioning, disability and health for children and youth (ICF-CY) and provide an overview of the outcome parameters. METHODS: A systematic literature search was performed in November 2019. We electronically searched Pubmed, Embase and Scopus databases. Search blocks included (a) cerebral palsy, (b) athetosis, dystonia and/or dyskinesia, (c) age 2-24 years and (d) instrumented measurements (using keywords such as biomechanics, sensors, smartphone, and robot). RESULTS: Our search yielded 4537 articles. After inspection of titles and abstracts, a full text of 245 of those articles were included and assessed for further eligibility. A total of 49 articles met our inclusion criteria. A broad spectrum of instruments and technologies are used to assess motor function in dyskinetic cerebral palsy, with the majority using 3D motion capture and surface electromyography. Only for a small number of instruments methodological quality was assessed, with only one study showing an adequate assessment of test-retest reliability. The majority of studies was at ICF-CY function and structure level and assessed control of voluntary movement (29 of 49) mainly in the upper extremity, followed by assessment of involuntary movements (15 of 49), muscle tone/motor reflex (6 of 49), gait pattern (5 of 49) and muscle power (2 of 49). At ICF-CY level of activities and participation hand and arm use (9 of 49), fine hand use (5 of 49), lifting and carrying objects (3 of 49), maintaining a body position (2 of 49), walking (1 of 49) and moving around using equipment (1 of 49) was assessed. Only a few methods are potentially suitable outside the clinical environment (e.g. inertial sensors, accelerometers). CONCLUSION: Although the current review shows the potential of several instrumented methods to be used as objective outcome measures in dyskinetic cerebral palsy, their methodological quality is still unknown. Future development should focus on evaluating clinimetrics, including validating against clinical meaningfulness. New technological developments should aim for measurements that can be applied outside the laboratory.

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.

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.

Intrathecal baclofen treatment in dystonic cerebral palsy: a randomized clinical trial: the IDYS trial.

BACKGROUND: Dystonic cerebral palsy is primarily caused by damage to the basal ganglia and central cortex. The daily care of these patients can be difficult due to dystonic movements. Intrathecal baclofen treatment is a potential treatment option for dystonia and has become common practice. Despite this widespread adoption, high quality evidence on the effects of intrathecal baclofen treatment on daily activities is lacking and prospective data are needed to judge the usefulness and indications for dystonic cerebral palsy. The primary aim of this study is to provide level one clinical evidence for the effects of intrathecal baclofen treatment on the level of activities and participation in dystonic cerebral palsy patients. Furthermore, we hope to identify clinical characteristics that will predict a beneficial effect of intrathecal baclofen in an individual patient. METHODS/DESIGN: A double blind placebo-controlled multi-center randomized clinical trial will be performed in 30 children with dystonic cerebral palsy. Patients aged between 4 and 25 years old with a confirmed diagnosis of dystonic cerebral palsy, Gross Motor Functioning Classification System level IV or V, with lesions in the cerebral white matter, basal ganglia or central cortex and who are eligible for intrathecal baclofen treatment will be included. Group A will receive three months of continuous intrathecal baclofen treatment and group B will receive three months of placebo treatment, both via an implanted pump. After this three month period, all patients will receive intrathecal baclofen treatment, with a follow-up after nine months. The primary outcome measurement will be the effect on activities of and participation in daily life measured by Goal Attainment Scaling. Secondary outcome measurements on the level of body functions include dystonia, spasticity, pain, comfort and sleep-related breathing disorders. Side effects will be monitored and we will study whether patient characteristics influence outcome. DISCUSSION: The results of this study will provide data for evidence-based use of intrathecal baclofen in dystonic cerebral palsy.

Long-term follow-up on continuous intrathecal Baclofen therapy in non-ambulant children with intractable spastic Cerebral Palsy.

BACKGROUND: Little is known about the long-term effects of Continuous intrathecal Baclofen (CITB) therapy in non-ambulant children with intractable spastic Cerebral Palsy (CP). AIM: To determine whether short-term beneficial effects of CITB therapy are present at the long-term, and whether caregivers would choose CITB therapy for their child again considering the advantages and disadvantages encountered over the years. METHODS: Long-term follow-up data were obtained of the children whom had previously participated in a RCT on CITB by the Dutch Study Group on Spasticity. Quality of life (QoL) was assessed by the Child Health Questionnaire (CHQ), current satisfaction with CITB was measured by use of a Visual Analogue Scale regarding previously set treatment goals, functioning in daily living was determined by a questionnaire concerning functioning of the child, and possible detrimental effects of CITB therapy encountered over the years were noted. All data were acquired via interview of the caregivers. RESULTS: All 17 children of the former trial participated in this study. Previously identified significant positive effects on pain (CHQ 46.8 vs. 74.38, p = 0.002; VAS 2.4 vs. 8.01, p = 0.02), ease of care (VAS 2.0 vs. 7.26, p = 0.00), and mental health (CHQ 67.2 vs. 75.94, p = 0.010) were still present at the end of the trial. Novel significant positive effects were noted at six to nine years follow-up, i.e. significantly improved scores on the Parent Impact - Emotional subscale (CHQ 66.0 vs. 78.2, p = 0.008), Parent Impact - Time subscale (CHQ 68.9 vs. 91.72, p = 0.002), and the Physical Summary (CHQ 17.6 vs. 27.4, p = 0.019) compared to baseline. Ninety-four percent of the caregivers would choose CITB treatment again for their child again. CONCLUSION: The beneficial effects of CITB are present at the long term and caregiver satisfaction is high.

Intrathecal baclofen for progressive neurological disease in childhood: a systematic review of literature.

BACKGROUND: Intrathecal baclofen (ITB) treatment is frequently used for individuals with severe, but non-progressive, spasticity refractory to oral treatment. However, experiences with ITB in patients with progressive neurological disorders of childhood causing spasticity are limited. AIM: To investigate whether ITB is an option in patients with progressive neurological disorders causing spasticity in childhood. DESIGN: A systematic literature search in Embase, Pubmed and the Cochrane Library was performed. RESULTS: We identified six eligible studies considering patients with progressive neurological disease in childhood and receiving ITB treatment. The studies included a total of seven paediatric patients and four adult patients. Improvement was reported in spasticity, spasms, pain, gait, activities of daily life and providing care. High satisfaction is described. CONCLUSIONS: ITB has beneficial effects in paediatric patients with progressive neurological disease. However, the level of evidence is limited due to the small number of available studies and due to the poor quality of these studies.

Effects of intrathecal baclofen on daily care in children with secondary generalized dystonia: a pilot study.

AIM: Treatment options for dystonic cerebral palsy (CP) are limited. Our aims were to determine whether intrathecal baclofen (ITB) improves daily care, decreases dystonia and decreases pain in patients with dystonic CP. METHODS: Patients received randomized blinded treatment with ITB or placebo. Scores on problems of daily care were recorded and dystonia, pain and comfort were assessed. RESULTS: Four patients (three males, average age 12 years 6 months) were included (all Gross Motor Function Classification System level V). During the trial period problem scores and dystonia scores decreased in all four patients. CONCLUSION: In this pilot study we report positive functional effects of ITB trial treatment in four patients with dystonic CP. A randomized trial with a larger cohort is needed to verify these results.