Efficacy and safety of onabotulinumtoxinA with standardized physiotherapy for the treatment of pediatric lower limb spasticity: A randomized, placebo-controlled, phase III clinical trial

BACKGROUND: Spasticity is common in cerebral palsy and can result in pain and diminished health-related quality of life. OBJECTIVE: To evaluate the safety and efficacy of onabotulinumtoxinA for lower limb spasticity treatment in children with cerebral palsy. METHODS: In this registrational phase 3, multinational, randomized, double-blind, placebo-controlled trial (NCT01603628), children (2–< 17 years) with cerebral palsy and ankle spasticity (Modified Ashworth Scale-Bohannon [MAS] score≥2) were randomized 1 : 1:1 to standardized physical therapy and onabotulinumtoxinA (4 or 8 U/kg), or placebo. Primary endpoint was average change from baseline at weeks 4 and 6 in MAS ankle score. Secondary endpoints included the Modified Tardieu Scale (MTS) and Global Attainment Scale (GAS). RESULTS: 381 participants were randomized. MAS scores averaged at weeks 4 and 6 were significantly reduced with both onabotulinumtoxinA doses (8 U/kg: –1.06, p = 0.010; 4 U/kg: –1.01, p = 0.033) versus placebo (–0.8). Significant improvements in average dynamic component of spasticity, measured by MTS, and in function, measured by GAS, were observed at several time points with both onabotulinumtoxinA doses versus placebo. Most adverse events were mild or moderate. CONCLUSIONS: OnabotulinumtoxinA was well tolerated and effective in reducing lower limb spasticity and improving functional outcomes versus placebo in children.

A Meta-Analysis: Whether Repetitive Transcranial Magnetic Stimulation Improves Dysfunction Caused by Stroke with Lower Limb Spasticity

Objective. To evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving lower limb spasticity after stroke. Methods. The PubMed, Web of Science, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM) disc, China Science and Technology Journal Database (VIP), and Wanfang databases were searched online from their inception to May 2021 for randomized controlled trials (RCTs) involving repetitive transcranial magnetic stimulation for lower extremity spasticity after stroke. Valid data were extracted from the included literature, and the quality evaluation was conducted with the Cochrane Handbook for Systematic Reviews of Interventions along with the Physiotherapy Evidence Database scale (PE-Dro scale). The data that met the quality requirements were systematically analysed using Review Manager 5.4 software. Results. A total of 554 patients from seven articles (nine studies) were quantitatively analysed. Outcomes included the Modified Ashworth Scale (MAS), Fugl–Meyer Assessment of Lower Extremity (FMA-LE), Modified Barthel Index (MBI), and Timed Up and Go (TUG), measured as the effect of rTMS compared with controls conditions after treatment. The systematic review showed that rTMS reduced MAS and increased MBI scores, respectively (SMD = −0.24, 95% CI [−0.45, −0.03], P = 0.02; MD = 6.14, 95% CI [−3.93,8.35], P ＜ 0.00001), compared with control conditions. Low-frequency rTMS (LF-rTMS) significantly improved FMA-LE scores (SMD = 0.32, 95% CI [0.13, 0.51], P = 0.001). However, there was no significant difference in FMA-LE scores when using high-frequency rTMS (HF-rTMS) ( P > 0.1) and in TUG times ( P > 0.1) between the treatment and control groups. Conclusions. rTMS was effective in improving spasticity and activities of daily living. LF-rTMS has positive clinical effects on enhancing motor function in patients who experience lower extremity spasticity after stroke. To better validate the above conclusions, more multicentre, high-quality, and double-blind randomized controlled trials are needed.

Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity.Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

Is botulinum toxin type A more effective and safer than other treatments for the management of lower limb spasticity in children with cerebral palsy? A Cochrane Review summary with commentary

BACKGROUND: Botulinum toxin A (BoNT-A) is a well-accepted treatment for the medical management of spasticity in children with cerebral palsy (CP). OBJECTIVE: To assess the efficacy and safety of BoNT-A compared with other treatment options in managing lower limb spasticity in children with CP. METHODS: A summary of the Cochrane Review update by Blumetti et al. (2019), with comments. RESULTS: This review included 31 randomized controlled trials (1508 participants). Compared with usual care/physiotherapy, the evidence is very uncertain about the effect of BoNT-A on gait, function, ankle joint range of motion (ROM), satisfaction, and ankle spasticity in children with CP. Compared with placebo/sham, BoNT-A probably benefits these same outcomes, although the results for function are contradictory. BoNT-A may not be more effective than serial casting at improving gait, function, ankle ROM and spasticity at any time point. However, it may be more effective than an orthosis at medium-term follow-up for hip ROM and adductor spasticity, but not function. The rate of adverse events with BoNT-A is similar to placebo/sham and serial casting. CONCLUSIONS: Evidence for the effectiveness and safety of BoNT-A for the management of lower limb spasticity in children with CP is uncertain, with better quality evidence available from studies of placebo/sham than non-placebo controls. To produce high-quality evidence, future studies need to improve their methodological quality and increase sample sizes.

IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study

PURPOSE: Investigate the efficacy and safety of multipattern incobotulinumtoxinA injections in children/adolescents with lower-limb cerebral palsy (CP)-related spasticity. METHODS: Phase 3 double-blind study in children/adolescents (Gross Motor Function Classification System – Expanded and Revised I–V) with unilateral or bilateral spastic CP and Ashworth Scale (AS) plantar flexor (PF) scores ⩾ 2 randomized (1:1:2) to incobotulinumtoxinA (4, 12, 16 U/kg, maximum 100, 300, 400 U, respectively) for two 12- to 36-week injection cycles. Two clinical patterns were treated. Pes equinus (bilateral or unilateral) was mandatory; if unilateral, treatment included flexed knee or adducted thigh. Endpoints: Primary: AS-PF change from baseline to 4 weeks; Coprimary: investigator-rated Global Impression of Change Scale (GICS)-PF at 4 weeks; Secondary: investigator’s, patient’s, and parent’s/caregiver’s GICS, Gross Motor Function Measure-66 (GMFM-66). RESULTS: Among 311 patients, AS-PF and AS scores in all treated clinical patterns improved from baseline to 4-weeks post-injection and cumulatively across injection cycles. GICS-PF and GICS scores confirmed global spasticity improvements. GMFM-66 scores indicated better motor function. No significant differences between doses were evident. Treatment was well-tolerated, with no unexpected treatment-related adverse events or neutralising antibody development. CONCLUSION: Children/adolescents with lower-limb spasticity experienced multipattern benefits from incobotulinumtoxinA, which was safe and well-tolerated in doses up to 16 U/kg, maximum 400 U.

Using Surface Electromyography to Evaluate the Efficacy of Governor Vessel Electroacupuncture in Poststroke Lower Limb Spasticity: Study Protocol for a Randomized Controlled Parallel Trial

Background. Lower limb spasticity is a common complication after stroke, which seriously affects the quality of life and rehabilitation of patients. There are different treatment methods for poststroke spasticity. It has been found in clinical practice that governor vessel electroacupuncture (GV-EA) can effectively relieve poststroke upper extremity spasticity, but the efficacy of treatment of lower extremity spasticity needs to be further verified. This study aims to design a randomized controlled trial to evaluate the efficacy of GV-EA in the treatment of poststroke lower limb spasticity. Methods/Design. This is a randomized, controlled trial. Patients (N = 177) will be randomized to receive routine therapeutic drug and rehabilitation treatment plus GV-EA (experimental group) or routine therapeutic drug and rehabilitation treatment plus EA (control group 1) or routine therapeutic drug and rehabilitation treatment (control group 2). All patients will receive 20 sessions of treatment for 4 weeks. The primary outcomes are the RMS value and the Modified Ashworth Scale. Secondary outcomes include the Fugl–Meyer Assessment for Lower Extremity (FMA-LE) and the Modified Barthel Index score. All outcome measures will be evaluated at the beginning and after the intervention (4 weeks). Discussion. This trial will observe the clinical effect of GV-EA on lower extremity spasticity after stroke, especially its influence on surface electromyography characteristics, and provide high-quality experimental evidence for the clinical application of GV-EA based on surface electromyography in the treatment of poststroke lower limb spasticity. Trial Registration. China Clinical Trials Registry No. ChiCTR1900027969. Registered on 7 December 2019.