Trends and insights review. Nerve procedures in the management of upper limb spasticity.

This article reviews the recent advances or nerve-oriented surgical procedures in the treatment of the spastic upper limb. The idea to intervene on the nerve is not recent, but new trends have developed in nerve surgery over the past few years, stimulating experiments and research. Specific surgical procedures involving the nerves have been described at different levels from proximal to distal: at the cervical spinal cord and the dorsal root entry zone (rhizotomy), at the level of the roots (contralateral C7 transfer) or in the peripheral nerve, within the motor trunk (selective neurectomy) or as its branches penetrate the muscles (hyperselective neurectomy). All of these neurosurgical procedures are only effective on spasticity but do not address the other deformities, such as contractures and motor deficit. Additional procedures may have to be planned in conjunction with nerve procedures to optimize outcomes.

The upper limb in children with cerebral palsy. Evaluation and treatment.

Management of the upper limb in children with cerebral palsy is often complex and must be carried out by a team experienced in this field. Several clinical parameters must be taken into consideration, such as higher functions, visual problems, overall upper limb function, motor control, sensitivity, presence of hemineglect or synkinesis, limb position at rest and during walking. And last but not least, a complete analysis of the upper limb is required. It is only after this exhaustive assessment - which often includes occupational therapy, physiotherapy and in some cases, video and electromyography evaluations - that a treatment indication can be discussed with the patient's family. Other than baseline treatment consisting of rehabilitation, occupational therapy and bracing, botulinum toxin injections could be an option, targeting specific muscle groups. Surgical treatments, which are often indicated in severe forms with contractures, are proposed after the patient's case is presented at a multidisciplinary meeting. These include selective neurotomy, muscle-tendon release, transfer or lengthening, and procedures on bone and joints (osteotomy, arthrodesis). LEVEL OF EVIDENCE: Expert opinion.

Effects of transcranial combined with peripheral repetitive magnetic stimulation on limb spasticity and resting-state brain activity in stroke patients.

Background and objective: Transcranial magnetic stimulation and peripheral repetitive magnetic stimulation (rPMS), as non-invasive neuromodulation techniques, can promote functional recovery in patients with post-stroke spasticity (PSS), but the effects of transcranial magnetic stimulation combined with peripheral magnetic stimulation on PSS remain largely unknown. Therefore, we examined the effects of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) combined with rPMS on PSS patients and its potential neural correlates to behavioral improvements. Methods: Forty-nine PSS patients were divided randomly into three groups: a combined group (n = 20), a LF-rTMS group (n = 15), and a control group (n = 14). The combined group received LF-rTMS and rPMS treatment, the rTMS group received LF-rTMS treatment, and the control group received only routine rehabilitation. All patients underwent Ashworth Spasm Scale (MAS), upper extremity Fugl-Meyer (FMA-UE), and modified Barthel Index (MBI) assessments before and after intervention. In addition, resting-state functional magnetic resonance imaging data were collected pre- and post-treatment to observe changes in the amplitude of low-frequency fluctuation (ALFF). Results: The MAS score was decreased, FMA-UE score and MBI scores were increased in the three groups after therapy than before therapy (all P < 0.05). In particular, the combined group showed significant effect on improved motor function and relieved spasticity in PSS (P < 0.01). Moreover, the combined treatment increased ALFF values mainly in the right supplementary motor area, right middle frontal gyrus, and right cerebellum, while reduced ALFF values mainly in the right post-central gyrus compared with pre-treatment. Compared with the LF-rTMS and control groups, the combined treatment increased ALFF values in the right cerebellum and reduced ALFF values mainly in the frontoparietal cortex. Improvements in the MAS score were positively correlated with the change in ALFF values in the right cerebellum (r = 0.698, P = 0.001) and the right supplementary motor area (r = 0.700, P = 0.001) after combined treatment. Conclusion: Transcranial combined with peripheral repetitive magnetic stimulation could improve spastic state and motor function in PSS patients, and this effect may be associated with altered cerebellar and frontoparietal cortical activity. Clinical trial registration: http://www.chictr.org.cn/index.aspx, identifier ChiCTR1800019452.

Improvement in Quality-of-Life-Related Outcomes Following Treatment with IncobotulinumtoxinA in Adults with Limb Spasticity: A Pooled Analysis.

A strong correlation has been reported between patient-reported quality of life (QoL) and the investigator-rated Disability Assessment Scale (DAS) in patients with spasticity. The current analysis evaluates the effect of incobotulinumtoxinA on QoL-related outcomes (limb position abnormality, as well as dressing- and hygiene-related disability, measured with the DAS) in adults with upper limb spasticity, using pooled data from six studies. Separate analyses for each DAS domain were performed using data from patients with disabilities for that domain (DAS score ≥1). Results showed that a significantly greater proportion of incobotulinumtoxinA-treated compared with placebo-treated patients achieved a ≥1-point reduction from baseline in each of the DAS domains (improvement) 4 weeks after the first injection. The benefits of incobotulinumtoxinA were observed regardless of the baseline severity of DAS impairment and of the time elapsed since stroke. The effects of incobotulinumtoxinA 4 weeks after injection were maintained or enhanced over multiple injection cycles for all three DAS domains, supporting the use of repeated injection cycles to provide sustained QoL benefit. IncobotulinumtoxinA represents an important treatment option to achieve better QoL-related outcomes for patients with upper limb spasticity, irrespective of the duration of their condition.

Effects of Functional Acupuncture on Upper Limb Spasticity After Ischemic Stroke: A Protocol for a Randomized Controlled Parallel Clinical Trial.

Background: Upper limb spasticity (ULS) is a common complication after stroke, which seriously affects the quality of life and rehabilitation of patients. There are different treatment methods for post-stroke spasticity (PSS). Our group found that functional acupuncture (FA) can effectively improve forearm spasticity and hand dysfunction after stroke, but the efficacy of ULS needs to be further verified. Therefore, this subject has mainly used clinical randomized controlled trials to evaluate the clinical efficacy of FA in the treatment of ULS after ischemic stroke. Method: This is a parallel design and randomized controlled trial. We selected 108 patients who met the predefined criteria and randomized them into two groups, the experimental group and the control group. The experimental group receives FA and routine rehabilitation treatment. The control group received traditional acupuncture (TA) and routine rehabilitation treatment. All patients received 20 courses of treatment for 4 weeks, and the modified Ashworth score (MAS), clinical neurological deficit score (CSS), Fugl-Meyer upper extremity function assessment (FMA-UE), and the Modified Barthel Index (MBI) scores were evaluated before and after treatment. Discussion: This trial is mainly to study the clinical efficacy of FA in the treatment of ULS after ischemic stroke. It will not only provide a new idea for the clinical treatment of upper limb post-stroke spasticity (ULPSS) but also will provide effective experimental support and a theoretical basis for the clinic. Trial registration: China Clinical Trials Registry No. ChiCTR2100050440. Registered on 27 August 27 2021.

The cost-effectiveness of abobotulinumtoxinA (Dysport) and onabotulinumtoxinA (Botox) for managing spasticity of the upper and lower limbs, and cervical dystonia.

OBJECTIVE: To evaluate the costs and benefits associated with the use of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for lower limb spasticity in children, upper and lower limb spasticity in adults, and cervical dystonia in adults. METHODS: This pharmacoeconomic analysis compared aboBoNT-A with onaBoNT-A. A decision tree model with a 1-year time horizon was conducted from a UK National Health Service (NHS) perspective using data from a variety of sources: randomized controlled trials (RCTs), network meta-analyses (NMAs), observational studies, and a physician survey investigating treatment patterns and resource utilization. Four patient populations were included: pediatric patients with lower limb spasticity (PLL), and adults with upper limb spasticity (AUL), lower limb spasticity (ALL), and cervical dystonia (CD). Outcomes included costs, quality-adjusted life years (QALYs) gained, cost per responder, and incremental cost per QALY gained. The effectiveness of each treatment was evaluated as a response to treatment. The base case assumption was that all patients in the model continued to receive botulinum toxin type A (BoNT-A) treatments at regular intervals regardless of treatment response status. Scenario analysis evaluated the impact of discontinuing BoNT-A for patients without a response to the first injection. RESULTS: The model found that aboBoNT-A resulted in greater quality-of-life and lower costs compared with onaBoNT-A for the management of spasticity and CD in all included indications. Across populations, cost savings ranged from £304 to £3,963 and QALYs gained ranged from 0.010 to 0.02 over a 1-year time horizon. Results were robust to scenario analyses and were driven by the impact of treatment response on health-related quality-of-life. CONCLUSIONS: AboBoNT-A was associated with higher treatment response, improved quality-of-life, and reduced costs in spasticity and CD versus onaBoNT-A. These findings could help deliver more effective and efficient healthcare in the NHS.

The objective of this study was to compare the costs and health outcomes associated with abobotulinumtoxinA (aboBoNT-A; Dysport) and onabotulinumtoxinA (onaBoNT-A; Botox) for treating children and adults with a variety of conditions related to limb spasticity and cervical dystonia. Therapies such as aboBoNT-A and onaBoNT-A have been shown to reduce spasticity, deformity, pain, and cervical dystonia symptoms. They can also improve function, movement, and self-care abilities. We estimated the treatment costs for patients with spasticity and patients with cervical dystonia receiving aboBoNT-A and onaBoNT-A in the UK. We also estimated other health-related costs that patients were expected to incur while receiving these treatments, as well as their quality of life.For each indication (spasticity in the upper and lower limbs in adults and children, cervical dystonia in adults), research studies were identified to estimate the likelihood of patient response for aboBoNT-A and onaBoNT-A. Survey studies were assessed to understand use of health services and costs for patients who respond to therapy vs. those who do not. We estimated total costs over one year and expected quality of life for patients. Costs included the costs of aboBoNT-A and onaBoNT-A treatments, as well as other health services.In all identified studies, the likelihood of response was higher for aboBoNT-A than for onaBoNT-A. This was associated with reduced need for other health services (and therefore lower costs), and better quality of life for patients receiving aboBoNT-A. In addition, the cost per year of aboBoNT-A treatment was lower than onaBoNT-A treatment for all indications. Therefore, treatment with aboBoNT-A was consistently associated with lower costs and better quality of life. This outcome is referred to as "economically dominant," meaning that from a health economic perspective, aboBoNT-A would be preferred to onaBoNT-A for treating patients with spasticity or cervical dystonia.

Chronic stroke survivors with upper limb spasticity: linking experience to the ICF.

PURPOSE: To identify the impact of upper limb spasticity on stroke survivors by linking their shared experience to the International Classification of Functioning, Disability, and Health (ICF). METHODS: Ten community dwelling adults with a chronic stroke and spasticity, who had completed an upper limb rehabilitation trial participated in semi-structured interviews. Data were analysed using content analysis and linked to the ICF Comprehensive Core Set for stroke using standard linking rules. RESULTS: Four hundred and thirty-nine meaningful concepts eligible for linking were identified. The majority (n = 178) linked to Body Function, n = 137 to Activities and Participation, n = 115 to Environmental Factors, and n = 9 to Body Structures. Sixty-two of the 130 Comprehensive Core Set categories were used; an additional eight were required to fully represent experience. Stroke survivors with upper limb spasticity use words and discuss topics concentrated around mental functions, functions of the joints and bones, muscles and movements, carrying, moving and handling objects, support and relationships with immediate family and health professionals, products and technology, and health services. CONCLUSIONS: Half of the Comprehensive Core Set categories for stroke were relevant, but to adequately capture experience an additional eight were needed. The ICF category profile may be unique to our participants or may suggest further research is needed to determine if additions to core set categories are required.Implications for rehabilitationOur ICF mapping demonstrated that the Brief Core Set for stroke was not sufficient to capture the range of experience for stroke survivors with upper limb spasticity, instead the Comprehensive Core Set for stroke supplemented with eight clinical-cohort specific second-level-categories should be used.Our findings suggest that rehabilitation may better reflect lived experience if it focuses on Body Function (Chapters 1, 2, 4, 7), Activity and Participation (Chapters 1-9), and Environment (Chapters 1, 2, 3, 5) because Body Structure was rarely mentioned in this or previous post-stroke ICF mapping research.

[Impact of integrated upper limb spasticity management including repeat botulinum toxin type A (BoNT-A) injections on patient-centred goal attainment in real-life practice: results from the prospective, observational Upper Limb International Spasticity cohort study (ULIS-III) in a Russian subpopulation]. / Vliyanie kompleksnogo lecheniya spastichnosti verkhnei konechnosti, vklyuchayushchego povtornye in"ektsii botulinicheskogo toksina tipa A, na dostizhenie tselei, orientirovannykh na nuzhdy patsienta, v real'noi klinicheskoi praktike: rezul'taty mezhdunarodnogo prospektivnogo, nablyudatel'nogo issledovaniya spastichnosti verkhnei konechnosti ULIS-III v rossiiskoi podgruppe patsientov.

OBJECTIVE: To assess the longitudinal attainment of patient-centred and function related goals after integrated spasticity management including repeated cycles of botulinum toxin A type A (BoNT-A) injections in real life settings over a period of 2 years. The article presents analysis of the results within the subpopulation of patients from Russia. MATERIAL AND METHODS: This international, multicentre, observational, prospective, longitudinal cohort study (registered at clinicaltrials.gov as NCT02454803) included patients ≥18 years old with upper-limb spasticity of any aetiology in whom a decision had already been made to inject any BoNT-A formulation commercially available in the Russi. The treatment outcomes were evaluated using the Upper Limb Spasticity Index, which combines the patient-centred Goal Attainment Scaling (GAS) with a set of targeted standardised measures to assess the neurological impairment. The extent of functional impairment was assessed using the DAS. RESULTS: 168 Russian patients from 7 sites with a mean age of 49.8 years participated in the study. The Russian subpopulation had some differences from the overall study population in baseline characteristics of patients and injection practices of BoNT-A treatment. During the study period, the majority of Russian patients received AboBoNT-A (Dysport) injections - 142 (85%) patients at cycle 1, while OnaBoNT-A (Botox) was used in 14 (8%) patients, and IncoBoNT-A (Xeomin) - in 12 (7%) patients. Higher doses of AboBoNT-A were observed compared to the overall population, mean doses of AboBoNT-A between cycles 1 and 4 were 909-934 U in the Russian patients and 814-859 U in the overall population. In general, patients of the Russian subpopulation successfully achieved their treatment goals. The mean cumulated GAS T-score over the study was 51.1±3.0, marginally exceeding the same parameter in the overall population (49.5±5.9). Across the 6 goal domains, cumulated GAS T-scores in Russian subpopulation were highest for the goals related to passive function and pain relief, with mean scores of 51.8±4.2 and 51.6±4.8, respectively. In the overall population cumulated GAS T-scores were highest for involuntary movements (mean 50.5±5.6) and pain relief (mean 50.4±6.2). The lowest GAS T-scores were for the treatment goals related to active function in both Russian subpopulation and overall population, the mean scores were 48.3±5.5 and 46.6±7.4 respectively. The study results also showed significant improvement in in terms of reduction of muscle tone according to MAS (Modified Ashworth Scale) and the extent of functional impairment according to DAS (Disability Assessment Scale). CONCLUSIONS: The results of this subgroup analysis on patients from Russia showed high effectiveness of repeated cycles of BoNT-A injections as part of the integrated upper limb spasticity management conducted in real life settings, both in terms of reduction of muscle tone and correction of functional impairment, which contributes to the successful achievement of the treatment goals. The right choice of individual patient-centred treatment goals and methods for assessing their achievement are important components of the treatment and rehabilitation process for patients with spastic paresis of the upper limb.

Comparative efficacy, safety, and cost-effectiveness of abobotulinumtoxinA and onabotulinumtoxinA in children with upper limb spasticity: a systematic literature review, indirect treatment comparison, and economic evaluation.

OBJECTIVE: The objective of this study was to compare clinical- and cost-effectiveness of type A botulinum toxin (BoNT-A) therapies for management of pediatric upper limb spasticity, including AbobotulinumtoxinA (aboBoNT-A) and Onabotulinumtoxin A (onaBoNT-A). METHODS: Systematic literature review and indirect treatment comparisons were conducted of randomized controlled trials reporting efficacy and safety outcomes. Efficacy was characterized by Modified Ashworth Scale (MAS) and Ashworth Scale (AS) up to 16-weeks post-injection. Results were used to inform a cost-effectiveness model with a 1-year time horizon, linking response rates with health-related quality-of-life (HRQoL) outcomes and costs from a UK perspective. Other data sources included in the cost-effectiveness model were drug unit costs, health care resource utilization based on UK physician survey, and HRQoL impacts of adverse events associated with oral anti-spasticity therapies. Results were characterized as cost per quality-adjusted life year and cost per responder. RESULTS: Six studies were included in evidence syntheses. There was a trend towards greater response rate for aboBoNT-A which resulted in improved HRQoL and lower annual costs compared with onaBoNT-A. Safety outcomes were similar across BoNT-A therapies. In cost-effectiveness analysis, aboBoNT-A was an economically dominant therapy with respect to cost per quality-adjusted life year. The cost per responder at 1 year was estimated to be £39,056 for aboBoNT-A vs. £54,831 for onaBoNT-A. LIMITATIONS AND CONCLUSIONS: Based on observed safety and efficacy data, aboBoNT-A is estimated to result in higher treatment response and consequently increased quality-of-life and reduced costs, vs. onaBoNT-A in children with upper limb spasticity. Limitations to the study include study heterogeneity limited details available for onaBoNT-A studies (e.g. use of physical therapy), and limited availability of responder data. Where assumptions were required, they were made to be conservative towards aboBoN-A.

Predictors of Clinically Important Improvements in Motor Function and Daily Use of Affected Arm after a Botulinum Toxin A Injection in Patients with Chronic Stroke.

Identifying patients who can gain minimal clinically important difference (MCID) in active motor function in the affected upper extremity (UE) after a botulinum toxin A (BoNT-A) injection for post-stroke spasticity is important. Eighty-eight participants received a BoNT-A injection in the affected UE. Two outcome measures, Fugl-Meyer Assessment Upper Extremity (FMA-UE) and Motor Activity Log (MAL), were assessed at pre-injection and after 24 rehabilitation sessions. We defined favorable response as an FMA-UE change score ≥5 or MAL change score ≥0.5.Statistical analysis revealed that the time since stroke less than 36 months (odds ratio (OR) = 4.902 (1.219-13.732); p = 0.023) was a significant predictor of gaining MCID in the FMA-UE. Medical Research Council scale -proximal UE (OR = 1.930 (1.004-3.710); p = 0.049) and post-injection duration (OR = 1.039 (1.006-1.074); p =0.021) were two significant predictors of MAL amount of use. The time since stroke less than 36 months (OR = 3.759 (1.149-12.292); p = 0.028), naivety to BoNT-A (OR = 3.322 (1.091-10.118); p = 0.035), and education years (OR = 1.282 (1.050-1.565); p = 0.015) were significant predictors of MAL quality of movement. The findings of our study can help optimize BoNT-A treatment planning.

[Yin-yang balance penetrating acupuncture combined with rehabilitation training on upper limb spasticity in stroke hemiplegia].

OBJECTIVE: To compare the therapeutic effect of yin-yang balance penetrating acupuncture combined with rehabilitation training and single rehabilitation training on upper limb spasticity in patients with stroke hemiplegia. METHODS: A total of 60 patients with upper limb spasticity of stroke hemiplegia were randomized into an observation group and a control group, 30 cases in each one. On the basis of conventional western medication, rehabilitation training was adopted in the control group. On the basis of treatment in the control group, yin-yang balance penetrating acupuncture was applied from Jianyu (LI 15) to Binao (LI 14), Quchi (LI 11) to Shaohai (HT 3), Yanglingquan (GB 34) to Yinlingquan (SP 9), Xuanzhong (GB 39) to Sanyinjiao (SP 6), etc. of the affected side in the observation group. The treatment was given once a day, 5 days were as one course, with a 2-day interval between two courses, 4 courses were required in both groups. The classification of modified Ashworth spasticity scale (MAS), surface integrated electromyogram (iEMG) of affected upper limb and the scores of National Institute of Health stroke scale (NIHSS), Fugl-Meyer assessment (FMA) of upper limb and modified Barthel index (MBI) before and after treatment were observed, the therapeutic effect was evaluated in both groups. RESULTS: ①After treatment, the MAS classification reduced in both groups (P<0.05), the cases of grade 0 to Ⅰ+ in the observation group were more than those in the control group (P<0.05); iEMG values of the maximum isometric voluntary contraction of affected usculus biceps brachii, musculus triceps brachii, musculus flexor carpi, musculus extensor carpi, extensor digitorum, aductor pollicis brevis were increased in both groups (P<0.05), and the variations of iEMG of above muscles on the affected side in the observation group were larger than those in the control group (P<0.05). ②After treatment, the scores of NIHSS were decreased (P<0.05), the scores of FMA, MBI were increased in both groups (P<0.05), and the variations of NIHSS, FMA and MBI scores were larger than those in the control group (P<0.05). ③The total effective rate was 93.3% (28/30) in the observation group, which was superior to 70.0% (21/30) in the control group (P<0.05). CONCLUSION: Yin-yang balance penetrating acupuncture combined with rehabilitation training can improve upper limb spasticity, heighten the motor function of upper limb and daily self care in patients with stroke hemiplegia, its therapeutic effect is superior to single rehabilitation training.

Efficacy and Safety of OnabotulinumtoxinA 400 Units in Patients with Post-Stroke Upper Limb Spasticity: Final Report of a Randomized, Double-Blind, Placebo-Controlled Trial with an Open-Label Extension Phase.

In many countries, 400 units (U) is the maximum dose of onabotulinumtoxinA available to treat upper limb spasticity, but few studies have demonstrated the optimal use of this dose. In the double-blind phase of this randomized, controlled trial, we compared the efficacy and safety of 400 vs. 240 U onabotulinumtoxinA in patients with post-stroke upper limb spasticity. Both groups received 240 U onabotulinumtoxinA injected in the forearm. An additional 160 U onabotulinumtoxinA (400 U group) or placebo (240 U group) was injected in the elbow flexors. Both groups showed similar muscle tone reduction in the wrist, fingers, and thumb; muscle tone reduction in the elbow flexors was greater in the group treated with onabotulinumtoxinA (400 U group) compared to placebo (240 U group). Functional disabilities improved in both groups. No substantial difference was found in safety profiles. In the subsequent open-label phase, all participants received repeat injections of 400 U onabotulinumtoxinA (target muscles and doses per muscle determined by the physician). Similar efficacy and safety outcomes, as with the 400 U group in the double-blind phase, were confirmed. This final report demonstrates that injection of onabotulinumtoxinA 400 U relieves muscle tone in a wide range of areas and improves functional disabilities; generally, it was well-tolerated, and no new safety concerns were identified. The dosing data in the open-label phase will inform optimal use of onabotulinumtoxinA in clinical practice (ClinicalTrials.gov: NCT03261167).

Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system.

Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.

Duration of Treatment Effect Using IncobotulinumtoxinA for Upper-limb Spasticity: A Post-hoc Analysis.

The efficacy and safety of incobotulinumtoxinA ≤400 U was demonstrated in subjects with post-stroke upper-limb spasticity in a randomized, double-blind Phase 3 study with an open-label extension (OLEX; EudraCT number 2005-003951-11, NCT00432666). We report a post-hoc analysis of the duration of the treatment effect. Subjects completing the placebo-controlled main period (single injection cycle with 12-20-week observation) entered the OLEX and received a maximum of five further treatments (maximum duration 69 weeks) with incobotulinumtoxinA ≤400 U at flexible intervals with a minimum duration of 12 weeks, based on clinical need. Intervals between two consecutive incobotulinumtoxinA injections, excluding treatment intervals prior to the end-of-study visit, were evaluated. Of 437 incobotulinumtoxinA treatment intervals, 415 received by 136 subjects were included in the post-hoc analysis. More than half (52.3%; 217/415) of all incobotulinumtoxinA reinjections were administered at Week ≥14, 31.1% (129/415) at Week ≥16, 19.0% (79/415) at Week ≥18, and 11.6% (48/415) at Week ≥20. The duration of effect may vary and can exceed 20 weeks or more, which was observed in at least one injection cycle in 29.4% (40/136) subjects over the course of their treatment. Data show that incobotulinumtoxinA retreatment for upper-limb spasticity may not be required at 12-week intervals and provides evidence for flexible treatment intervals beyond this time frame.

- balance penetrating acupuncture combined with rehabilitation training on upper limb spasticity in stroke hemiplegia / 中国针灸

OBJECTIVE@#To compare the therapeutic effect of - balance penetrating acupuncture combined with rehabilitation training and single rehabilitation training on upper limb spasticity in patients with stroke hemiplegia.@*METHODS@#A total of 60 patients with upper limb spasticity of stroke hemiplegia were randomized into an observation group and a control group, 30 cases in each one. On the basis of conventional western medication, rehabilitation training was adopted in the control group. On the basis of treatment in the control group, - balance penetrating acupuncture was applied from Jianyu (LI 15) to Binao (LI 14), Quchi (LI 11) to Shaohai (HT 3), Yanglingquan (GB 34) to Yinlingquan (SP 9), Xuanzhong (GB 39) to Sanyinjiao (SP 6), etc. of the affected side in the observation group. The treatment was given once a day, 5 days were as one course, with a 2-day interval between two courses, 4 courses were required in both groups. The classification of modified Ashworth spasticity scale (MAS), surface integrated electromyogram (iEMG) of affected upper limb and the scores of National Institute of Health stroke scale (NIHSS), Fugl-Meyer assessment (FMA) of upper limb and modified Barthel index (MBI) before and after treatment were observed, the therapeutic effect was evaluated in both groups.@*RESULTS@#①After treatment, the MAS classification reduced in both groups (<0.05), the cases of grade 0 to Ⅰ in the observation group were more than those in the control group (<0.05); iEMG values of the maximum isometric voluntary contraction of affected usculus biceps brachii, musculus triceps brachii, musculus flexor carpi, musculus extensor carpi, extensor digitorum, aductor pollicis brevis were increased in both groups (<0.05), and the variations of iEMG of above muscles on the affected side in the observation group were larger than those in the control group (<0.05). ②After treatment, the scores of NIHSS were decreased (<0.05), the scores of FMA, MBI were increased in both groups (<0.05), and the variations of NIHSS, FMA and MBI scores were larger than those in the control group (<0.05). ③The total effective rate was 93.3% (28/30) in the observation group, which was superior to 70.0% (21/30) in the control group (<0.05).@*CONCLUSION@#- balance penetrating acupuncture combined with rehabilitation training can improve upper limb spasticity, heighten the motor function of upper limb and daily self care in patients with stroke hemiplegia, its therapeutic effect is superior to single rehabilitation training.

Cost-Utility Analysis of Incobotulinumtoxin-A Compared With Conventional Therapy in the Management of Post-Stroke Spasticity in Romania.

Objectives: In Romania, the strokes' incidence is of 61,500 per year and improving upper limb function is the essence in rehabilitation after a stroke to maximize the patient quality of life and reduce disability. In this study, it is compared the cost-effectiveness of the treatment of post-stroke upper limb spasticity with incobotulinumtoxin-A (INCO), with or without electromyographic control, against the conventional therapy programme alone (CON). Methods: A Markov state transition model was developed to effectuate a cost-utility analysis (CUA). Measurements of health-related quality of life were derived from relevant clinical trials. Utility values for quality of life by response status were derived from the Short-Form-12 (SF-12) Health Survey data from a published study. The incremental cost-effectiveness ratio (ICER) of INCO (fixed, every 12 weeks) against CON was calculated in Ron per quality-adjusted life-year (QALY) gained for both therapies. Costs and outcomes were discounted using different scenarios at 3% and 5% per year with a time horizon of 3 and 5 years because Romanian legislative norms don't specify the discount rates and time horizon for pharmacoeconomic analysis. Probabilistic sensitivity analyses (PSA) were managed on the base case with distributions attributed to the frequency of repeat dosing and utility valuation of the responder and the non-responder for health utilities derived from both mental and physical health state. Results: Compared with CON, in all 4 scenarios, therapy with INCO had an incremental cost-effectiveness ratio (ICER) of less than 950 Euro per QALY gained (1 Euro = 4.7 Ron). INCO proved to be more favorable treatment option than CON in the treatment of upper limb spasticity in Romania. Despite costs being higher for patients treated with INCO, this treatment has more advantageous Incremental Cost-Effectiveness Ratio. Conclusions: This therapy should be taken into account when considering rehabilitation options because it is highly cost-effective at < EURO 1,000/QALY gained, a very low WTP (Willingness To Pay) threshold. INCO proved to be a disruptive innovation because it is a new and more effective treatment, and, in the end, much higher in quality of life for patients with post-stroke upper limb spasticity.

[Treatment goals in patients with post-stroke upper limb spasticity following injection of botulinum toxin A : Results of the German-Austrian subgroup of the ULIS-II study]. / Therapieziele bei Patienten mit Armspastik nach Schlaganfall nach Injektion mit Botulinumtoxin A : Ergebnisse der deutsch-österreichischen Subgruppe der ULIS-II-Studie.

BACKGROUND: The ULIS-II was an international cohort study (NCT01020500) evaluating current treatment of upper limb spasticity in post-stroke adult patients with botulinum toxin A (BoNT-A) in real-life practice. OBJECTIVE: Post hoc analysis to compare current management of post-stroke adult patients regarding goal setting and attainment with BoNT-A in Germany (D) and Austria (A) with the full cohort of ULIS-II. MATERIAL AND METHODS: The ULIS-II was a global, open-label, prospective, multicenter observational study with 2 visits conducted in 84 centers worldwide. A total of 468 patients aged ≥18 years with post-stroke upper limb spasticity were included. The primary outcome measure was the responder rate defined as achievement of a goal attainment scale (GAS) score of 0, 1 or 2 after 1 cycle of BoNT-A. RESULTS: A total of 57 patients from D/A were included in the efficacy analysis. The number of patients in D/A and the full cohort achieving the primary (78.9% vs. 79.6%) and secondary treatment goal (76.8% vs. 75.6%), respectively, was comparable. Deviating from the full cohort, the most common primary treatment goal in D/A was related to impairment (33.3%). Compared to baseline there was a marked reduction in concomitant therapies at the follow-up visit after 3-5 months in the D/A group: patients receiving oral anti-spastic medication 61.4% vs. 40.4%, positioning 50.9% vs. 36.8% and splinting 43.9% vs. 31.6%. Injection control techniques were less frequently used in the D/A group compared to the global study cohort (electrical stimulation: 26.3% vs. 45.8% and electromyography: 12.3% vs. 29.2%). No adverse events were documented in the D/A cohort. CONCLUSION: A single injection of BoNT-A in adult patients with post-stroke spasticity of the arm led to a high response rate of approximately 80% in both cohorts. The BoNT-A injections in post-stroke adult patients contributed to an improvement in the daily life of patients and their carers beyond simple reduction of muscle tone or spasticity.

Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.

Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in SAMHD1, a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific SAMHD1 variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.

Early AbobotulinumtoxinA (Dysport®) in Post-Stroke Adult Upper Limb Spasticity: ONTIME Pilot Study.

The ONTIME study investigated whether early post-stroke abobotulinumtoxinA injection delays appearance or progression of upper limb spasticity (ULS) symptoms. ONTIME (NCT02321436) was a 28-week, exploratory, double-blind, randomized, placebo-controlled study of abobotulinumtoxinA 500U in patients with ULS (Modified Ashworth Scale [MAS] score ≥ 2) 2⁻12 weeks post-stroke. Patients were either symptomatic or asymptomatic (only increased MAS) at baseline. Primary efficacy outcome measure: time between injection and visit at which re-injection criteria were met (MAS ≥ 2 and ≥1, sign of symptomatic spasticity: pain, involuntary movements, impaired active or passive function). Forty-two patients were randomized (abobotulinumtoxinA 500U: n = 28; placebo: n = 14) with median 5.86 weeks since stroke. Median time to reach re-injection criteria was significantly longer for abobotulinumtoxinA (156 days) than placebo (32 days; log-rank: p = 0.0176; Wilcoxon: p = 0.0480). Eleven (39.3%) patients receiving abobotulinumtoxinA did not require re-injection for ≥28 weeks versus two (14.3%) in placebo group. In this exploratory study, early abobotulinumtoxinA treatment significantly delayed time to reach re-injection criteria compared with placebo in patients with post-stroke ULS. These findings suggest an optimal time for post-stroke spasticity management and help determine the design and sample sizes for larger confirmatory studies.

Post-stroke Upper Limb Spasticity Incidence for Different Cerebral Infarction Site.

OBJECTIVE: The purpose of this study was to evaluate the incidence rate of post-stroke upper limb spasticity and its correlation with cerebral infarction site. METHODS: A total of 498 inpatient and outpatient cases are included in the present study. The post-stroke upper limb spasticity rate of different cerebral infarction site was calculated. RESULTS: A total of 498 patients with cerebral infarction are enrolled in this study. Of these patients, 91 have dropped out and 407 have completed the study. Of the completed cases, 172 are in the spasm group and 235 are in the non-spasm group. The total incidence of upper limb spasticity is 34.5%. The incidences of upper extremity spasms are 12.5%, 20%, 22.5%, 35%, 40%, and 42.5% in 2 weeks, 1 month, 2 months, 3 months, 6 months, and 12 months, respectively. The incidence of upper extremity spasms increases with time. The incidences of upper limb spasticity are 12.1%, 63.3%, 58.5%, 9.4% and 8.3% when cerebral infarction occurs in the cortical and subcortical mixed areas, basal ganglia and internal capsule, cerebralcortex, brainstem and cerebellum respectively. The incidence of upper limb spasticity varies in different infarction sites (P < 0.05). CONCLUSION: The post-stroke upper limb spasticity rates were different according to the different cerebral infarction site. Patients with the ganglia and internal capsule infarctions had the highest risk of developing post-stroke upper limb spasticity.