The state of the art in therapeutic administration of botulinum toxin in children with cerebral palsy: an integrative review.

OBJECTIVE: To describe the current state of the art in the therapeutic administration of botulinum toxin with indications, efficacy, and safety profile for children and adolescents with cerebral palsy. DATA SOURCE: An integrative review was conducted. The MEDLINE/PubMed database was searched twice within the last decade using distinct terms, and only studies written in the English language were included. The study population was limited to those aged 0-18 years. Articles that were duplicates or lacked sufficient methodology information were excluded. DATA SYNTHESIS: We found 256 articles, of which 105 were included. Among the included studies, most were conducted in developed countries. Botulinum toxin demonstrated good safety and efficacy in reducing spasticity, particularly when administered by a multidisciplinary rehabilitation team. It is primarily utilized to improve gait and upper limb function, facilitate hygiene care, reduce pain, prevent musculoskeletal deformities, and even decrease sialorrhea in patients without a functional prognosis for walking. CONCLUSIONS: The administration of botulinum toxin is safe and efficacious, especially when combined with a multi-professional rehabilitation team approach, which increases the probability of functional improvement. It can also be beneficial for patients with significant functional impairments to help with daily care tasks, such as hygiene, dressing, and reducing sialorrhea. Pediatricians must be familiar with this treatment and its indications to attend to and refer patients promptly when necessary, and to exploit their neuroplasticity. Further research on this topic is required in developing countries.

Opioid prescription patterns among commercially insured children with and without cerebral palsy.

PURPOSE: This study aimed to describe opioid prescription patterns for children with vs. without cerebral palsy (CP). METHODS: This cohort study used commercial claims from 01/01/2015-12/31/2016 and included children aged 2-18 years old with and without CP. Opioid prescription patterns (proportion exposed, number of days supplied) were described. A zero-inflated generalized linear model compared the proportion exposed to opioids in the follow-up year (2016) and, among those exposed, the number of days supplied opioids between cohorts before and after adjusting for age, gender, race, U.S. region of residence, and the number of co-occurring neurological/neurodevelopmental disabilities (NDDs). RESULTS: A higher proportion of children with (n = 1,966) vs. without (n = 1,219,399) CP were exposed to opioids (12.1% vs. 5.3%), even among the youngest age group (2-4 years: 9.6% vs. 1.8%), and had a greater number of days supplied (median [interquartile range], 8 [5-13] vs. 6 [4-9] days; P < 0.05). Comparing children with opioid exposure with vs. without CP, a greater number of days supplied was identified for older age, Asian race/ethnicity, and without co-occurring NDDs, and a lower number of days supplied was observed for Black race/ethnicity and with ≥1 co-occurring NDDs. CONCLUSION: Children with CP are more likely to be exposed to opioids and have a higher number of days supplied.

Short-Term Effects of Botulinum Toxin-A Injection on the Medial Gastrocnemius Histological Features in Ambulant Children with Cerebral Palsy: A Longitudinal Pilot Study.

Botulinum toxin-A (BoNT-A) injection is known to exert beneficial effects on muscle tone, joint mobility and gait in children with cerebral palsy (CP). However, recent animal and human studies have raised the concern that BoNT-A might be harmful to muscle integrity. In CP-children, the impact of BoNT-A on muscle structure has been poorly studied, and inconsistent results have been reported. This study was aimed at determining the time course effect of a single BoNT-A administration on medial gastrocnemius (MG) morphology in CP-children. MG microbiopsies from 12 ambulant and BoNT-A-naïve CP-children (age, 3.4 (2.3) years, ranging from 2.5 to 7.8 years; seven boys and five girls; GMFCS I = 5, II = 4 and III = 3) were collected before and 3 and 6 months after BoNT-A treatment to analyze the fiber cross-sectional area (fCSA) and proportion; capillarization; and satellite cell (SC) content. Compared with the baseline, the fCSA decreased at 3 months (-14%, NS) and increased at 6 months (+13%, NS). Fiber size variability was significantly higher at 3 months (type I: +56%, p = 0.032; type IIa: +37%, p = 0.032) and 6 months (type I: +69%, p = 0.04; type IIa: +121%, p = 0.032) compared with the baseline. The higher type I proportion seen at 3 months was still present and more pronounced at 6 months (type I: +17%, p = 0.04; type IIx: -65%, p = 0.032). The capillary fiber density was reduced at 3 months (type I: -43%, NS; type II: -44%, p = 0.0320) but normalized at 6 months. There was a non-significant increase in SC/100 fibers at 3 months (+75%, NS) and 6 months (+40%, NS) compared with the baseline. These preliminary data suggest that BoNT-A induced alterations in the MG of children with CP, which were still present 6 months after BoNT-A injection but with signs of muscle recovery.

Evaluating the Safety and Efficacy of Erythropoietin Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Erythropoietin (EPO) is a proposed drug for the treatment of neonatal hypoxic-ischemic encephalopathy (HIE). Multiple studies have linked its use, either as a monotherapy or in conjunction with therapeutic hypothermia (TH), with improved neonatal outcomes including death and neurodisability. However, there is also evidence in the literature that raises concerns about its efficacy and safety for the treatment of neonatal encephalopathy (NE). METHODS: We searched MEDLINE, Cochrane CENTRAL, and Embase for both observational studies and randomized controlled trials (RCTs) investigating the effectiveness of EPO in treating NE. Only studies in which at least 300 U/kg of EPO was used and reported any one of the following outcomes: death, death or neurodisability, and cerebral palsy, were included. RESULTS: Seven studies with 903 infants with the diagnosis of NE were included in our meta-analysis. EPO did not reduce the risk of death or neurodisability (risk ratio 0.68 [95% confidence interval [CI]: 0.43 to 1.09]) (P = 0.11). Similarly, the risk of cerebral palsy was not reduced by the administration of EPO (risk ratio 0.68 [95% CI: 0.33 to 1.40]) (P = 0.30). The risk of death was also not reduced at any dose of EPO regardless of the use of TH. CONCLUSIONS: The results of our meta-analysis do not support the use of EPO for the treatment of neonatal encephalopathy. However, future large-scale RCTs are needed to strengthen these findings.

Cannabidiol Use Patterns and Efficacy for Children Who Have Cerebral Palsy.

Cannabidiol (CBD)-containing supplements are used by children with cerebral palsy (CP), but the prevalence and efficacy of their use have not been studied. We sought to describe CBD use patterns and perceived efficacy in the pediatric population with CP, evaluating any association between CBD use and health-related quality of life. Patients with CP were prospectively enrolled, and caregivers were offered the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) Questionnaire and a survey assessing CBD use. Of 119 participants, 20 (16.8%) endorsed CBD use (CBD+) and 99 (83.2%) denied it (CBD-). Participants in the CBD+ group had worse functional status (85% Gross Motor Function Classification System level IV-V for CBD+ vs 37.4% for CBD-, P<.001) and lower health-related quality of life (mean CPCHILD score of 49.3 for CBD+ vs 62.2 for CBD-, P=.001). Spasticity was the rationale most cited for CBD use (29%), followed by pain and anxiety (both 22.6%). CBD was perceived to be most effective for improving emotional health, spasticity, and pain. Fifty percent of the patients in the CBD+ group underwent surgery in the previous 2 years and most endorsed a general benefit in the postoperative setting. The most common side effects noted were fatigue and increased appetite (both 12%). Most participants endorsed no side effects (60%). CBD may serve as a useful adjunct for some children with CP, especially those with worse disease severity. Caregivers perceive CBD as offering some benefits, particularly in the domains of emotional health, spasticity, and pain. We found no evidence of severe adverse events in our small cohort. [Orthopedics. 2024;47(1):52-56.].

Time course of surface electromyography during walking of children with spastic cerebral palsy treated with botulinum toxin type A and its rehabilitation implications.

BACKGROUND: The timing of the effects of botulinum toxin A on spastic muscles is not yet fully clarified. The goal of this study was to follow the temporal changes of surface electromyographic activity of lower limb muscles during walking, after a therapeutic dose of botulinum toxin A injected into the calf muscles of children with spastic cerebral palsy. METHODS: A group of children with spastic equinus foot was administered botulinum toxin A into the gastrocnemius medialis and lateralis muscles. Surface electromyographic activity of the tibialis anterior, gastrocnemius medialis, rectus femoris and medial hamstrings, was recorded before botulinum toxin A injections and after 4, 8, and 16 weeks. Children walked on ground and on a treadmill at an incline of 0% and 12%. The area of electromyographic activity and the index of muscle co-contraction were calculated for specific segments of gait cycle. FINDINGS: Botulinum toxin A did not modify the speed of gait on ground. ANOVA showed significant differences in electromyography during the stance phase segments with a maximum decrease between 4 and 8 weeks' post botulinum toxin A and a full recovery at 16 weeks. A significant co-contraction of rectus femoris/gastrocnemius medialis, between 0 and 20% and 35-50% of the gait cycle, was observed from the 4th to the 8th week post- botulinum toxin A for both treadmill settings. INTERPRETATION: The temporal identification of deterioration/recovery of electromyographic activity as well as of muscle co-contractions, could be key elements in a rehabilitation program planning combined with botulinum toxin A.

Baclofen pumps do not increase risk of complications following spinal fusion.

PURPOSE: To assess the complication risks associated with intrathecal baclofen (ITB) pumps in cerebral palsy (CP) patients undergoing posterior spinal fusion (PSF) and to determine if timing of pump implantation before or during PSF impacts the risk of complications. METHODS: A prospectively collected multicenter database was retrospectively reviewed to identify CP patients undergoing PSF from 2008 to 2023. Patients were divided into 2 cohorts: those with an ITB pump (ITB cohort) and those without (non-ITB cohort). The ITB cohort was further categorized by placement of the pump prior to or during PSF. Cohorts were then compared in terms of postoperative complications, perioperative complications, and need for revision surgery. RESULTS: Four hundred six patients (ITB n = 79 [53 prior to, 26 during PSF], non-ITB n = 326) were included in this analysis. At an average follow-up of 4.0 years (range 2-10 years), there were no significant differences between the ITB and non-ITB cohorts in the rate of perioperative complications (5.0% vs 6.5%, p = 0.80), revision surgeries (2.5% vs 4.6%, p = 0.54), or any complication type, regardless of whether pumps were placed prior to or during PSF, aside from longer surgical times in the latter group. CONCLUSION: Complication rates are similar for ITBs placed prior to and during PSF. Patients with spastic CP may safely be treated with ITB pumps without increased risks of complication or further reoperation/revision following PSF. LEVEL OF EVIDENCE: Level III.

Maintenance of the synergistic effects of cord blood cells and erythropoietin combination therapy after additional cord blood infusion in children with cerebral palsy: 1-year open-label extension study of randomized placebo-controlled trial.

BACKGROUND: This 1-year open-label extension study aimed to identify the persistent synergistic effects of allogeneic umbilical cord blood (UCB) cells and erythropoietin (EPO) in children with cerebral palsy (CP) for up to 2 years. METHODS: This open-label extension study followed children with CP who were enrolled in the previous randomized, double blind, placebo-controlled trial. The following groups from the first trial were maintained: (A) UCB + EPO, (B) UCB, (C) EPO, and (D) only placebo, and all the participants had continued active rehabilitation. This extended study started 3 months after termination of the first trial, which had a 1-year follow-up duration. All subjects received single additional UCB intravenous infusion at the extension baseline regardless of their initial allocation. Outcome measures were the gross motor performance measure (GMPM), gross motor function measure-66 (GMFM-66), and Bayley scales of infant development-II (BSID-II), which were followed at 3, 6, and 12 months after the extension baseline. Changes in the outcome scores from the baseline values of the previous trial and this study were analysed. RESULTS: Sixty-nine children (4.29 ± 1.28 years, M:F = 34:35) were included in this study. Each group showed improvements in the outcome measures at 12 months after additional UCB infusion compared to the baseline scores, except for GMFM and GMPM in Group C which were elevated at 3 and 6 months post-therapy. Total subject analyses did not show significant differences in the outcome measures between the four different groups at 3, 6 and 12 months after additional UCB therapy. However, patients with severe dysfunction, whose GMFCS levels were IV and V, revealed a larger improvement of the GMPM score in Group A than in Group D (Ps < 0.05) from the baseline value of the previous trial. The changes in BSID-II mental scale scores were positively correlated with the number of administered total nucleated cells per unit body weight during this one-year extension study period (r = 0.536, P = 0.001). CONCLUSIONS: These results suggest that when administering UCB to treat patients with CP, combination therapy with EPO is more effective, and the effect might last as long as 2 years, especially in patients with severe impairments. TRIAL REGISTRATION: CHA Bundang Medical Center IRB, No. 2015-06-093, approved on July 29, 2015, ( https://www.e-irb.com:3443/devlpg/nlpgS200.jsp ), ClinicalTrials.gov, NCT03130816, retrospectively registered on April 27, 2017 ( https://clinicaltrials.gov/ct2/show/NCT03130816?term=NCT03130816&draw=2&rank=1 ).

Efficacy and safety of medical cannabinoids in children with cerebral palsy: a systematic review.

INTRODUCTION: The increasing popularity of cannabinoids for treating numerous neurological disorders has been reported in various countries. Although it reduces tetrahydrocannabinol psychoactivity, it helps patients tolerate higher doses and complements the anti-spasmodic effects of tetrahydrocannabinol. One of the most important potential of cannabinoids are related to its potential to help children with cerebral palsy, a contributor of lifelong disability. Therefore, this systematic review aimed to assess the efficacy and safety of medical cannabinoids in children with cerebral palsy. METHODS: This review adhered to The Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 guidelines. Seven databases, namely, Scopus, PubMed, EBSCO Host, ProQuest, Google Scholar, Semantic Scholar, and JSTOR, were used to identify relevant studies. Studies examining pediatric patients with cerebral palsy and reporting the efficacy and safety of medical cannabinoids through clinical trials, observational cross-sectional studies, or cohort designs were included. The outcomes of the studies included the efficacy of medical cannabinoids administered for spasticity, motor components, pain control, sleep difficulties, adverse effects, and seizure control. RESULTS: Of 803 identified articles, only three met the inclusion criteria for data synthesis. One study exhibited a moderate risk-of-bias. A total of 133 respondents, mainly from Europe, were investigated. Overall effectiveness and safety were considered good. However, the results are inconsistent, especially regarding spasticity treatment variables. CONCLUSION: The anti-spasticity, anti-inflammatory, and anti-seizure properties of cannabinoids might be beneficial for patients with cerebral palsy, although their effectiveness has not been widely studied. Further studies with larger sample sizes and various ethnicities are warranted. Prospero database registration: (www.crd.york.ac.uk/prospero) under ID CRD42022358383.

Characteristics of Changes in Intrathecal Baclofen Dosage over Time due to Causative Disease.

Intrathecal baclofen (ITB) therapy effectively treats spasticity caused by brain or spinal cord lesions. However, only a few studies compare the course of treatment for different diseases. We investigated the change in daily dose of baclofen per year and its associated adverse events in patients presenting with the three most common etiologies at our institute: hereditary spastic paraplegia, cerebral palsy, and spinal cord injury. The ITB pumps were implanted from July 2007 to August 2019, with a mean follow-up period of 70 months. In patients with hereditary spastic paraplegia, baclofen dosage was reduced after eight years following ITB introduction, and the treatment was terminated in one patient owing to disease progression. In patients with cerebral palsy, the dosage increased gradually, and became constant in the 11th year. Patients with spinal cord injury gradually increased their baclofen dosage throughout the entire observation period. Severity and adverse event rates were higher in patients with cerebral palsy than in others. The degree and progression of spasticity varied depending on the causative disease. Understanding the characteristics and natural history of each disease is important when continuing ITB treatment.

Does Botulinum Toxin Injection Exacerbate Sarcopenia and Bone Mass in Individuals With Cerebral Palsy?

BACKGROUND: Botulinum toxin (BoNT) causes sarcopenia and low bone mass in animal studies. Whether such effect exists in children and adolescents with spastic cerebral palsy (CP) is not clear yet. To investigate the influences of BoNT on grip strength (GS), skeletal muscle mass, and bone mineral density (BMD) in children and adolescents with spastic CP, we conducted this uncontrolled longitudinal study. METHODS: The body composition of individuals with spastic CP were measured by dual-energy X-ray absorptiometry at preinjection and at 12 and 24 weeks after BoNT intervention. Sarcopenia was defined as meeting both decreased GS and low muscle mass. Twenty-five participants were enrolled (mean age 8.5 years). RESULTS: Before BoNT intervention, four adolescents had sarcopenia and low bone mass. When the body composition was analyzed as four limbs, trunk, and head, the skeletal muscle mass of the injected limbs, appendicular skeletal muscle mass, and total body less head BMD increased significantly over 24-week follow-up period (P = 0.0117, 0.0032, 0.0229), whereas the GS remained unchanged. When the body composition was analyzed as segments derived from bilateral arms, forearms, hands, thighs, and lower legs, the skeletal muscle mass (P = 0.0113) but not BMD of the injected segments increased significantly over the 24 weeks. The prevalence of low muscle mass, decreased GS, sarcopenia, and low bone mass did not change over 24 weeks. CONCLUSIONS: The present study showed that BoNT does not exacerbate sarcopenia and low bone mass in individuals with spastic CP.

Botulinum Toxin Treatment of Adult Muscle Stem Cells from Children with Cerebral Palsy and hiPSC-Derived Neuromuscular Junctions.

Botulinum neurotoxin type-A (BoNT) injections are commonly used as spasticity treatment in cerebral palsy (CP). Despite improved clinical outcomes, concerns regarding harmful effects on muscle morphology have been raised, and the BoNT effect on muscle stem cells remains not well defined. This study aims at clarifying the impact of BoNT on growing muscles (1) by analyzing the in vitro effect of BoNT on satellite cell (SC)-derived myoblasts and fibroblasts obtained from medial gastrocnemius microbiopsies collected in young BoNT-naïve children (t0) compared to age ranged typically developing children; (2) by following the effect of in vivo BoNT administration on these cells obtained from the same children with CP at 3 (t1) and 6 (t2) months post BoNT; (3) by determining the direct effect of a single and repeated in vitro BoNT treatment on neuromuscular junctions (NMJs) differentiated from hiPSCs. In vitro BoNT did not affect myogenic differentiation or collagen production. The fusion index significantly decreased in CP at t2 compared to t0. In NMJ cocultures, BoNT treatment caused axonal swelling and fragmentation. Repeated treatments impaired the autophagic-lysosomal system. Further studies are warranted to understand the long-term and collateral effects of BoNT in the muscles of children with CP.

Botulinum toxin type A for spasticity in cerebral palsy patients: Which impact on popliteal angle to hamstring length? A proof-of-concept study.

BACKGROUND: Cerebral palsy (CP) is the most common physical disability in childhood. It is a heterogeneous condition in terms of etiology, motor type and severity of impairments. Clinical impairments, such as increased muscle tone (spasticity), muscle weakness and joint stiffness contribute to the abnormal development of functional activities, including gait. OBJECTIVE: The objective of this study was to investigate the popliteal angle to hamstring length after ultrasound guided Incobotulinum toxin A injections for spasticity in CP patients. METHODS: In this proof-of-concept study, we included outpatients with CP and crouch gait correlated to hamstrings spasticity referred to the Pediatric Rehabilitation outpatient clinic of Umberto I University Hospital, Sapienza University of Rome, in the period between February and October 2018. METHODS: Modified Ashworth Scale (MAS) of hamstring muscles, Popliteal Angle and Modified Popliteal Angle, Passive Knee Extension and 10 Meter Walk Test (10MWT) were assessed at baseline (T0) and three weeks after ultrasound guided injection (T1) of Incobotulinum Toxin A (dose weight and site dependent). RESULTS: Thirteen patients (5 male and 8 female), mean aged 9.91 ± 3.59, were included. The clinical evaluation at T0 showed hamstring muscles spasticity, with MAS of 2.4 ± 0.6, popliteal angle -51.7∘± 11.0∘, modified popliteal angle of -39.5∘± 11.0∘, passive knee extension of -14.0∘± 8.7∘ and 10MWT of 14.3 ± 4.6 seconds. At T1, hamstring muscles MAS mean value was 1.7 ± 0.6 (p< 0.01), popliteal angle 41.3∘± 7.0∘ (p< 0.001), modified popliteal angle -32.9∘± 10.4∘ (p< 0.001), passive knee extension -4.0∘± 4.2∘ (p< 0.05) and 10MWT 12.6 ± 4.8 seconds (p< 0.05). None of the treated patients reported any adverse event related to Incobotulinum Toxin A injection. CONCLUSION: Incobotulinum toxin A treatment has been proven to be safe and effective for hamstring muscles spasticity management in CP patients. Further studies with larger samples and longer follow-up are warranted to assess the efficacy of this treatment on the popliteal angle.

Serotonin syndrome from combination hydrocodone and cyclobenzaprine in a patient with cerebral palsy.

Aim: Serotonin syndrome (SS) is a life-threatening syndrome that occurs with the use of serotonergic drugs, most commonly due to two or more agents. Cerebral palsy is associated with mood disorders, and more commonly pain, with a prevalence of up to 50-80%. Case presentation: A 58-year-old female with cerebral palsy, metastatic malignancy and mood disorder who presented to the emergency department with acute-on-chronic pain, and signs of SS. She was initiated on iv. dilaudid, titrated off oral medications and scheduled for a left-sided sacroiliac joint injection. Results: It was suspected that due to additional doses of hydrocodone and cyclobenzaprine, she developed moderate-SS. Conclusion: Physicians need to be cognizant of comorbidities and uncommon pain medications that can predispose patients to SS.

Treatment of pediatric spasticity, including children with cerebral palsy, with Botox (onabotulinumtoxinA): Development, insights, and impact.

Spasticity is a velocity-dependent increase in muscle tone that has a negative effect on quality of life and hinders the ability of others to provide care. In children, most cases are caused by cerebral palsy. Traditionally, many children are treated with surgery, sometimes performed before their limbs had grown sufficiently to permit long-term success. Nonsurgical treatment comprises oral pharmacological options, but their efficacy is limited and side effects such as drowsiness and decreased short-term memory are common; nerve block procedures can cause painful dysesthesias and muscle scarring. OnabotulinumtoxinA was first approved for the treatment of pediatric lower limb spasticity in Europe in the 1990s and is now licensed for use in pediatric patients in over 80 countries worldwide, based on a large body of clinical evidence demonstrating its efficacy and safety. In 2019 the U.S. Food and Drug Administration approved onabotulinumtoxinA for the treatment of pediatric patients with upper or lower limb spasticity. This approval represents 3 decades of work to refine the dose, measurements, patient selection, and muscle selection. The availability of onabotulinumtoxinA as a treatment for pediatric spasticity can have a substantial impact on a patient's quality of life. The use of onabotulinumtoxinA in combination with orthoses and occupational/physical therapy can postpone corrective surgery until growth is nearly complete and minimize the number of corrective surgeries.

Intracerebroventricular baclofen therapy improves function and quality of life in a child with severe cerebral palsy.

Limited therapies are available for severe cerebral palsy children (CP) with complex movement disorders, especially when both dystonia and spasticity are present. In this publication, we present the improvement of a child with severe CP after intracerebroventricular baclofen therapy. The treatment can impact not just the movement disorders but also on the quality of life of the child and caregivers. Global functional improvements can be observed on the 6-month follow-up.