Efficacy of botulinum toxin combined with rehabilitation treatments in the treatment of post-stroke spasticity: A systematic review and network meta-analysis

Abstract

Background

There is growing interest in the combination of botulinum toxin (BoNT) and rehabilitation techniques for the treatment of post-stroke spasticity. Nevertheless, systematic evaluations of this approach are scarce.

Objective

To systematically evaluate the efficacy of BoNT combined with rehabilitation techniques for post-stroke spasticity.

Methods

The PubMed, Embase, Cochrane Library, and Web of Science databases were systematically searched from their inception to May 2024 for randomized controlled trials of BoNT combined with rehabilitation treatments for post-stroke spasticity. Reductions in the Modified Ashworth Scale (MAS) score at short-term and medium-term weeks after treatment were calculated.

Results

Eighteen studies were analyzed. Regarding the short-term effect of BoNT combined with rehabilitation treatments on post-stroke spasticity, the top one ranked combination treatments were BoNT plus conventional therapy (CT) and splinting. The results showed that two evidence networks regarding the medium-term efficacy of BoNT combined with rehabilitation treatments for post-stroke spasticity. The top one ranked combination treatments for Network A were BoNT plus CT and electrical stimulation, and for Network B, BoNT plus casting.

Conclusions

The limited quantity of literature included in these studies did not permit the ordering of probabilities. Consequently, these results must be interpreted with caution and further validated using high-quality studies.

Keywords

botulinum toxin rehabilitation spasticity network meta-analysis

Introduction

Stroke is the second-leading cause of death and the third-leading cause of disability (GBD 2019 Stroke Collaborators, 2021). From 1990 to 2019, the absolute numbers of stroke morbidity and mortality increased by 70% and 43%, respectively (GBD 2019 Stroke Collaborators, 2021; Krishnamurthi et al., 2020; Martin et al., 2024). Spasticity is the most common complication of stroke, with a prevalence ranging from 30% to 80% among stroke survivors (Shi et al., 2019). Spasticity can lead to dysfunction of the patient's muscle movement, causing pain and postural abnormalities, which greatly diminishes their quality of life and places added strain on their caregivers (O'Dell, 2023; Santamato et al., 2019). When the patient's lower limbs are in spasm, the knee joints are involuntarily straightened, the ankle joints are turned inward when the soles of the feet touch the ground, and the supportive phases of the lower limbs on the affected side are shortened, resulting in the hemiplegic gait of “walking in a circle” (Santamato et al., 2019). A prolonged state of spasticity can lead to contracture of the Achilles tendon, and constant abnormal pressure during walking can cause pressure sores (Li & Francisco, 2021). Continued activation of spastic calf muscles during weight-bearing has been linked to the development of foot drop (Li & Francisco, 2021). Increased upper extremity flexor tone can lead to flexion of the elbow, wrist, and finger joints. Spasticity affecting the hands and wrists is a particularly problematic form of spasticity, as it can significantly impair activities of daily living, including dressing and personal hygiene (Lee et al., 2024; Ye et al., 2023). Therefore, it is imperative to identify effective methods for alleviating the challenges posed by spasticity after stroke.

Spasticity is a movement disorder that is defined by a velocity-dependent increase in the stretch reflex and the presence of abnormal tendon reflexes (Sheean, 2002). Current treatment options for poststroke spasticity include exercise, oral spasticity medications, physical therapy, botulinum toxin (BoNT) injections, and surgery (Thibaut et al., 2013). Among these, BoNT-A is the treatment of choice for focal spasticity affecting the upper and lower extremities (Wissel et al., 2009). BoNT-A is a metalloproteinase that provides transient chemical innervation to injected muscles by inhibiting the presynaptic release of acetylcholine at the neuromuscular junctions (Brin et al., 1987). BoNT-A injections exert various effects on spastic muscles, including neural and non-neural components associated with elevated tone, muscle strength, and motor performance (Chen et al., 2022). Several studies have demonstrated that BoNT-A injections can reduce muscle tone, address muscle imbalance, and enhance muscle function (Sun et al., 2019).

Nevertheless, there is evidence that in some patients, the response to BoNT-A therapy may diminish over time (Pitcher et al., 2015). To enhance the effects of BoNT-A, researchers have proposed various techniques to improve clinical outcomes. These include stretching (Allart et al., 2022), intensive rehabilitation (Hara et al., 2018), casting (Farag et al., 2020), repetitive transcranial magnetic stimulation (Shao et al., 2022), robotic assistance (RA) (Cotinat et al., 2024), electrical stimulation (ES) (Baricich et al., 2019), extracorporeal shock wave (ESWT) (Du et al., 2024), constraint-induced movement therapy (Nasb et al., 2021), isokinetic training (Cinone et al., 2019), and repetitive facilitative exercise (Hokazono et al., 2022). The link between BoNT-A and rehabilitation is widely accepted. However, there is no consensus regarding which combination therapy is most effective. Consequently, there is growing interest in the combination of BoNT-A and rehabilitation techniques for the treatment of post-stroke spasticity. Nevertheless, there is a dearth of systematic evaluations of this therapeutic approach. In light of these considerations, the objective of this study was to conduct a network meta-analysis of the existing literature on post-stroke spasticity. The objective of this study was to compare the efficacy of BoNT-A with different rehabilitative therapies and to provide evidence-based medical recommendations for optimizing the outcome of combined therapy for patients with post-stroke spasticity.

Materials and methods

This systematic review adheres to the PRISMA Guideline and strictly follows the Cochrane System Review Manual (Cumpston et al., 2022; Hutton et al., 2015). This review has been registered with PROSPERO under the registration number CRD 42024533485.

Inclusion criteria

The inclusion criteria were defined in accordance with the PICOS principles, which included the following: (1) Subjects: patients with post-stroke spasticity; (2) Intervention Measures: BoNT combined with rehabilitation; (3) Outcome Indicator: the Modified Ashworth Scale (MAS) was used to measure spasticity (Asimakidou & Sidiropoulos, 2023); and (4) Study Type: prospective randomized controlled trials including at least two treatment groups (Hsu et al., 2022).

Exclusion criteria

The following exclusion criteria were applied: (1) patients with other serious diseases, (2) use of monotherapy, (3) use of scales other than the MAS for spasticity evaluation, and (4) animal studies.

Search strategy

A computerized search was conducted in the PubMed, Embase, Cochrane Library, and Web of Science databases from their inception to May 2024, with no language restrictions. The search terms included (“stroke” OR “cerebrovascular apoplexy”) AND (“spasticity” OR “spasticism”) AND (“toxin, botulinum” OR “toxins, clostridium botulinum”). The search strategy is outlined in Table S1.

Literature screening and data extraction

The literature was independently screened and recorded by two researchers using Endnote 20. Data were subsequently extracted, coded, and crosschecked using Excel. In case of disagreement, a third researcher assessed the data and harmonized them through discussion. The following information was extracted from the literature: author(s), year, number of patients, sex, age, stroke type, post-stroke follow-up, intervention arm, intervention details, guidance, evaluation of joints/muscles, outcome measurements, and follow-up. Data were extracted based on baseline and endpoints (short- and medium-term) of the trial report. The short and medium terms were defined as the periods before or at the 6th week post-treatment and between the 7th and 12th weeks post-treatment, respectively (Hsu et al., 2022). However, if there were multiple measurements within the same timeframe (short- or medium-term), the outcome recorded at the last follow-up visit was selected (Hsu et al., 2022).

Risk of bias evaluation

The quality of the included studies was evaluated using the risk-of-bias assessment tool recommended in the Cochrane 5.1 manual. This tool assesses seven aspects: random allocation, allocation concealment, blinding of subjects and investigators, blinding of outcome assessments, completeness of outcome data, selective reporting, and other biases (Higgins et al., 2011). Each item is rated on three levels: low risk, uncertainty, and high risk. The risk of each entry was assessed, and the results were presented in a visual format using Review Manager 5.4.1 software. Two reviewers engaged in a comparative analysis of their respective ratings, with any discrepancies being addressed through group discussion by the research team.

Statistical analysis

The generation of evidence networks and probability rankings was achieved through the use of the network meta-package in R Studio 4.2.1, facilitating direct and indirect comparisons of diverse interventions (Shim et al., 2019). As part of the analysis, network meta-analysis and heterogeneity testing were conducted. An I² value of 50% was identified as the critical threshold for selecting an appropriate effects model (Shim et al., 2019). Given that I² ≤ 50% indicates minimal heterogeneity, a fixed effects model was employed (Zhou et al., 2024). Otherwise, a random-effects model was used. The consistency between direct and indirect evidence was evaluated using nodal analysis. Continuous variables were expressed as mean difference. The lower SUCRA was employed to rank each intervention. The SUCRA values ranged from 0 to 1 (Salanti et al., 2011). A value approaching zero indicates a low probability of the event in question, whereas a value approaching one indicates a high probability.

Results

Basic information on the included studies

Figure 1 illustrates the process of literature screening. Based on the set search strategy, 3286 documents were initially examined. Among these, 1020 duplicates from different databases and 2135 documents were excluded after reading the titles and abstracts. This process excluded irrelevant documents, including meeting abstracts, reviews, animal experiments, and similar materials. After reading the full texts of the 131 papers on outcome indicators, monotherapy, and related topics, 18 were included in the analysis. Detailed information provided in Tables 1 and 2 includes the demographics of the study participants, type of stroke, intervention arm, intervention details, joint/muscle evaluation, outcome measurements, and follow-up period. A total of 385 and 240 patients were included in the experimental and control groups, respectively. The patients received 17 different combination therapies, including BoNT plus modified constraint-induced movement therapy (mCIMT), BoNT plus active control treatment (AC) and conventional therapy (CT), BoNT plus mirror therapy (MT) and CT, BoNT plus taping, BoNT plus taping and CT, BoNT plus casting and CT, BoNT plus casting, BoNT plus stretching and splinting, BoNT plus splinting and CT, BoNT plus stretching and CT, BoNT plus stretching, BoNT plus ES, BoNT plus ES and CT, BoNT plus ESWT, BoNT plus RA, BoNT plus RA and CT, and BoNT plus dry needling and CT.

Figure 1.

Selection of studies for inclusion.

Table 1.

Characteristics of included studies.

Author, year	Number of patients			Gender (male/female)			Age (years) (mean ± SD)			Stroke Type (ischemic/hemorrhagic)			Post-stroke follow-up (mean ± SD)
Group	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3
Pennati et al., 2015	7	8	/	/	/	/	/	/	/	/	/	/	/	/	/
Hesse et al., 1998	6	6	/	/	/	/	50.39 ± 10.92	53.38 ± 16.00	/	/	/	/	/	/	/
Gandolfi et al., 2019	16	16	/	12/4	10/6	/	59.31 ± 14.40	59.13 ± 14.97	/	/	/	/	6.00 ± 3.10(Y)	5.10 ± 2.20(Y)	/
Erbil et al., 2018	29	14	/	16/13	11/3	/	50.10 ± 11.80	48.70 ± 10.40	/	19/10	9/5	/	39.00 ± 34.30(M)	25.90 ± 24.60(M)	/
Kosem et al., 2022	15	15	/	9/6	11/4	/	60.21 ± 14.37	60.20 ± 9.49	/	4/11	3/12	/	43.99 ± 45.42(M)	48.19 ± 35.93(M)	/
Ding et al., 2017	41	39	/	21/20	20/19	/	61.23 ± 6.20	62.52 ± 7.10	/	29/12	28/11	/	127.6 ± 27.6(D)	125.5 ± 31.3(D)	/
Picelli et al., 2016	11	11	/	7/4	9/2	/	62.40 ± 9.50	65.10 ± 3.40	/	/	/	/	6.20 ± 4.20(Y)	6.10 ± 3.80(Y)	/
Baricich et al., 2008	8	8	7	5/3	3/5	5/2	64.75 ± 7.36	60.30 ± 12.75	61.29 ± 5.74	/	/	/	17.12 ± 6.49(M)	20.75 ± 13.68(M)	18/55.28 ± 8.85(M)
Lai et al., 2009	15	15	/	7/8	10/5	/	49.10 ± 4.00	55.60 ± 5.00	/	/	/	/	/	/	/
Hung et al., 2022	13	12	12	10/3	7/5	7/5	47.68 ± 12.79	44.34 ± 10.05	49.71 ± 10.86	8/5	6/6	7/5	33.38 ± 22.71(M)	33.08 ± 16.98(M)	38.17 ± 25.02(M)
Karadag-Saygi et al., 2010	10	10	/	3/7	5/5	/	63.80 ± 9.00	57.30 ± 12.00	/	/	/	/	35.20 ± 29.00(M)	39.40 ± 30.00(M)	/
Sun et al., 2010	15	14	/	12/3	12/2	/	58.70 ± 9.90	61.50 ± 9.40	/	12/3	11/3	/	2.90 ± 1.50(Y)	2.90 ± 1.30(Y)	/
Carda et al., 2011	23	26	18	13/11	12/15	10/8	62.20 ± 11.70	64.50 ± 12.5	59.60 ± 14.3	19/5	20/7	16/2	46.90 ± 41.30(M)	52.30 ± 43.80(M)	43.90 ± 39.60(M)
Nasb et al., 2019	27	27	/	/	/	/	/	/	/	/	/	/	/	/	/
Santamato et al., 2013	16	16	/	6/10	7/9	/	63.10 ± 7.03	64.40 ± 6.09	/	/	/	/	9.30 ± 3.97(M)	10.50 ± 2.12(M)	/
Santamato et al., 2015	35	35	/	18/17	20/15	/	55.90 ± 7.70	57.90 ± 8.40	/	17/18	22/13	/	12.60 ± 3.80(M)	12.20 ± 3.20(M)	/
Farina et al., 2008	6	7	/	4/2	3/4	/	62.00 ± 11.83	65.60 ± 5.20	/	/	/	/	16.83 ± 5.34(M)	15.29 ± 5.77(M)	/
Lee et al., 2024	9	7	/	7/2	4/3	/	52.12 ± 22.30	52.00 ± 18.37	/	4/5	4/3	/	60.00 ± 68.66(M)	15.73 ± 18.37(M)	/

Remark Column：If there are two groups, 1 group is the experimental group and 2 group is the control group. If there were 3 groups, 1, 2, and 3 groups were all experimental groups. M: month; Y: year; D: day.

Table 2.

Summary of intervention details.

	intervention arm	Intervention detail	Guidance	Evaluating joint/muscle	Outcome measurement	Follow-up
Pennati et al., 2015	BoNT RA	BoNT-A (Dysport) RA :10 sessions lasting 60 min each, 2 or 3 days a week	EMG	UL (Shoulder, elbow, wrist)	FMA, Box & Block Test FIM, MAS, Euro-Qol，and muscular recruitment pattern	4-5 weeks
	control	RA :10 sessions lasting 60 min each, 2 or 3 days a week	N/A	UL (Shoulder, elbow, wrist)		4-5 weeks
Hesse et al., 1998	BoNTES	BoNT-A (Dysport®): biceps brachii 250U, brachialis 250U, FCU 125U, FCR 125U, FDP 125U .+CTES: arm (biceps and triceps) and forearm (wrist and finger flexors and extensors) muscles for half an hour 3 times per day for 3 days.	EMG	UL (elbow, wrist, fingers and metacarpophalangeal joints)	MAS, Limb position at rest, and Daily Living	2, 6 and 12 weeks
	control	ES: arm (biceps and triceps) and forearm (wrist and finger flexors and extensors) muscles for half an hour 3 times per day for 3 days. + CT	N/A	UL (elbow, wrist, fingers and metacarpophalangeal joints)	MAS, Limb position at rest, and Daily Living	2, 6 and 12 weeks
Gandolfi et al., 2019	BoNTRA	BoNT (Onabotulinumtoxin A, Abobotulinumtoxin A, and Incobotulinumtoxin A)RA: 45 min/session, two sessions/week	ultrasound	UL (Shoulder, elbow, wrist)	MAS, FMA, and MRC	4 weeks
	control	BoNT (Onabotulinumtoxin A, Abobotulinumtoxin A, and Incobotulinumtoxin A) + physiotherapy	ultrasound	UL (Shoulder, elbow, wrist)	MAS, FMA, and MRC	4 weeks
Erbil et al., 2018	BoNTRA	BoNT-A + RA + CT	ES	LL (plantar flexor muscle、ankle)	MAS, Tardieu Scale, Berg Balance Scale,Timed Up and Go test, and Rivermead Visual Gait Assessment	6 and 12 weeks
	control	BoNT-A + CT	ES	LL (plantar flexor muscle、ankle)		6 and 12 weeks
Kosem et al., 2022	BoNT dry needling	BTX-A (Dysport): biceps brachii 500Udry needling: immediate, the 3rd, 6th and 9th days after the BTX-A injection. + CT	ultrasound	UL	MAS, Modified Tardieu scale, and FMA	Immediate, 3 days, 2 weeks, and 3 months
	control	BTX-A (Dysport): biceps brachii 500U. + CT	ultrasound	UL	MAS, Modified Tardieu scale, and FMA	Immediate, 3 days, 2 weeks, and 3 months
Ding et al., 2017	BoNTES	BTX-A350U: gastrocnemius muscle-medial head 100U, gastrocnemius muscle-lateral head 100U, soleus 100U, tibialis posterior 50UES (spasmodic muscle therapeutic instrument): one treatment course was 10 days, with a total of three treatment courses + CT	ultrasound	LL (tibialis posterior, gastrocnemius muscle and soleus)	MAS, FMA, MBI, ADL, Step Size, and walking speed	1, 4, 8 and 12 weeks
	control	BTX-A 350U: gastrocnemius muscle-medial head 100U, gastrocnemius muscle-lateral head 100U, soleus 100U, tibialis posterior 50U + CT	ultrasound	LL (tibialis posterior, gastrocnemius muscle and soleus)	MAS, FMA, MBI, ADL, Step Size, and walking speed	1, 4, 8 and 12 weeks
	intervention arm	Intervention detail	Guidance	Evaluating joint/muscle	Outcome measurement	Follow-up
Picelli et al., 2016	BoNTRA	BTX-A: gastrocnemius medialis 250U, gastrocnemius lateralis 250U, soleus 250URA :30 min a day for five consecutive days	ultrasound	LL (ankle)	MAS, Tardieu scale ，and the 6-min walking test	Immediate, and 1month
	Control	BTX-A: gastrocnemius medialis 250U, gastrocnemius lateralis 250U, soleus 250U	ultrasound	LL (ankle)	MAS, Tardieu scale ，and the 6-min walking test	Immediate, and 1month
Baricich et al., 2008	BoNTTaping	BoNT-A (Dysport®)500IU: lateral and medial head of the gastrocnemiusTaping: maintained for 5 days	EMG	LL (ankle)	MAS, PROM, MAP, and kinematic evaluation	10, 20 and 90 days
	BoNTESStretching	BoNT-A (Dysport®)500IU: lateral and medial head of the gastrocnemiusES: 5 Hz, 5 days, 30 min twice a dayStretching: each electrical stimulation session was followed by stretching of the calf muscles for 20 min
	BoNTStretching	BoNT-X (Dysport®)500IU: lateral and medial head of the gastrocnemiusStretching: 30 min stretching of the calf muscles twice a day for 7 days
Lai et al., 2009	BoNTSplinting	BTX-A: biceps 150U, brachialis 75U, and brachioradialis 75U + CTSplinting (Elbow Extension Dynasplint®): 6 to 8 h of continual wear while sleeping	NR	UL (elbow)	MAS, and AROM	1and 14 weeks
	Control	BTX-A: biceps 150U, brachialis 75U, and brachioradialis 75U + CT	NR	UL (elbow)	MAS, and AROM	1and 14 weeks
Hung et al., 2022	BoNTRA	BTX-A (Allergan) + CTRA: 75 min (RT 45 min + 30 min functional activities), 3 times weekly, for 8 weeks	ultrasound	UL(elbow flexor, forearm pronator, wrist flexor, PIP)	FMA, MAS, MAL, AOU,QOM, and arm activity level	Immediate, 3 months
	BoNTMT	BTX-A (Allergan) + CTMT: 75 min (MT 45 min + 30 min functional activities), 3 times weekly, for 8 weeks
	BoNTAC	BTX-A (Allergan) + CTAC: 75 min (AC 45 min + 30 min functional activities), 3 times weekly, for 8 weeks
Karadag-Saygi et al., 2010	BoNTTaping	BTX-A (Botox®: medial head of the gastrocnemius 75 – 100IU, lateral head of the gastrocnemius 75—100IU + CTTaping	ES	LL(ankle)	MAS, PROM, gait velocity, and step length	2 weeks and 1, 3, and 6 months
	Control	BTX-A (Botox®): medial head of the gastrocnemius 75—100IU, lateral head of the gastrocnemius 75—100IU + CTSham Taping	ES	LL(ankle)	MAS, PROM, gait velocity, and step length	2 weeks and 1, 3, and 6 months
Sun et al., 2010	BoNTmCIMT	BTX-A (Dysport)1000U: biceps brachii 400U, FDS 150U, FDP 150U, FCU 150U, FCR 150UmCIMT: massed practice (affected upper extremity for 2 h/d, 3 d/week + restraining the nonaffected upper extremity with soft mitt for atleast 5 h/d of their waking hours for 3 months), shaping, a behavioral contractand a daily treatment diary	EMG	UL(elbow, wrist, fingers)	MAS, motor activity log, action research arm test, and patients’ global satisfaction	4 weeks and 3，6 months
	Control	BTX-A (Dysport)1000U: biceps brachii 400U, FDS 150U, FDP 150U, FCU 150U, FCR 150U + CT	EMG	UL(elbow, wrist, fingers)		4 weeks and 3，6 months
	intervention arm	Intervention detail	Guidance	Evaluating joint/muscle	Outcome measurement	Follow-up
Carda et al., 2011	BoNTCasting	BTX-A (Xeomin)100IU: lateral and medial heads of the gastrocnemius, soleus + CTCasting: changed twice a week. Time required to apply the cast was approximately 30 min	ES	LL(ankle)	MAS, PROM six-min walking test, 10-metre walking test, functional ambulation categories, and ankle dorsiflexor strength	Immediate, 20 days and 90 days
	BoNTTaping	BTX-A (Xeomin)100IU: lateral and medial heads of the gastrocnemius, soleus + CTTaping ：time required to apply the taping was approximately 45 min the first day, then 10 min each day for rearrangement
	BoNTStretching	BTX-A (Xeomin)100IU: lateral and medial heads of the gastrocnemius, soleus + CTStretching :30 min’ stretching of the calf muscles twice a day for a week
Nasb et al., 2019	BoNTmCIMT	BoNT (BOTOX®): biceps brachii 400U, FCR 150U, FCU 150U, FDP 150U, FDS 150UmCIMT：wearing a padded mitten (glove) on the healthy UL for restraint and to use it for approximately 3 h daily + massed practice (1 h per day, 6 times per week, for 4 weeks)	ultrasound	UL(elbow, wrist, fingers)	MAS, FMA, and BI	4 weeks
	Control	BoNT (BOTOX®): biceps brachii 400U, FCR 150U, FCU 150U, FDP 150U, FDS 150U + CT	ultrasound	UL(elbow, wrist, fingers)	MAS, FMA, and BI	4 weeks
Santamato et al., 2013	BoNTESWT	BTX-A (BOTOX®)：FDSESWT: the belly of the flexor digitorum superficialis (1000 impulses) + the proximal muscle-tendon junction of flexor digitorum superficialis (1000 impulses), 4 Hz, 0.030 mJ/mm2, once a day for 5 days	ultrasound	UL	MAS, VAS, and SFS	15, 30 and 90 days
	BoNTES	BTX-A (BOTOX®)：FDSES: 30 min twice a day for 5 days	ultrasound	UL	MAS, VAS, and SFS	15, 30 and 90 days
Santamato et al., 2015	BoNTTaping	BTX-A (Xeomin®): FCR or FCU 50- 100 UI, finger flexor muscles 50–200UI Taping: put in place for 10 days	ultrasound	UL(wrist, fingers)	MAS, Disability Assessment Scale, and fingers position at rest	10 days
	BoNTStretchingSplinting	BTX-A (Xeomin®): FCR or FCU 50- 100 UI, finger flexor muscles 50–200 UIStretching + Splinting：total daily time 60 min, 10 consecutive days with manual muscle stretching about 30 min + splinting	ultrasound	UL(wrist, fingers)		10 days
Farina et al., 2008	BoNTCasting	BTX-A (BOTOX®): 190-320U (tibialis posterior, gastrocnemius lateralis, gastrocnemius medialis, soleus)Casting: rigid night-time made-to-measure ankle foot orthoses for four consecutive months	EMG	LL	static and dynamic baropodometric tests, MAS, and the 10 meter walking test	2 and 4 months
	Control	BTX-A (BOTOX®): 190-320U (tibialis posterior, gastrocnemius lateralis, gastrocnemius medialis, soleus)	EMG	LL		2 and 4 months
Lee et al., 2024	BoNTESWT	BoNT (Nabota®): biceps brachii, brachioradialis, pronator teres, FCR, FCU, FDP, FDSFocused ESWT: 1000 shots, 4 HZ, energy flux density 0.030 mJ/mm2, once a day for 5 day	ES	UL(elbow, wrist, fingers)	MAS, and modified Tardieu scale	3 weeks and 3 months
	Control	BoNT (Nabota®): biceps brachii, brachioradialis, pronator teres, FCR, FCU, FDP, FDS	ES	UL(elbow, wrist, fingers)	MAS, and modified Tardieu scale	3 weeks and 3 months

Abbreviations: BoNT, botulinum toxin; RA, robot assisted; N/A, not applicable; BoNT-A, botulinum toxin type A; EMG, electromyography; UL, upper limb; FMA, Fugl–Meyer Assessment; FIM, Functional Indipendence Measure; MAS, modiﬁed ashworth scale; Euro-Qol, the Quality of Life ;RFE, repetitive facilitative exercise; ARAT, Action Research Arm Test; aROM, active range of motion; ES, electrical stimulation; FCU, flexor carpi ulnaris; CT, conventional therapy; FCR, flexor carpi radialis; FDP, flexor digitorum profundus; IJS, Institute J. Stefan, Ljubljana, Slovenia; MRC: Research Council Scale; LL, lower limb; MBI, modified Barthel index; ADL, activity of daily living; MAP, motor action potential; AROM, active range of motion; NR, not recorded; MT, mirror therapy; AC, active control treatment; MAL, Motor Activity Log; AOU, amount of use; QOM, quality of movement; PIP, proximal interphalangeal joint; mCIMT, modified constraint-induced movement therapy; FDS, flexor digitorum superficialis; BI, Barthel index; ESWT, extracorporeal shock wave therapy; VAS, visual analogue scale; SFS, spasm frequency scale.

Quality assessment of the included studies

Plots A and B in Figure 2 illustrate the results of the risk of bias assessment. With regard to the methodology of random assignment, 13 studies provided detailed information on the specific random assignment methods employed, dominated by computerized random sequence assignment, which was assessed as a low-risk item (Baricich et al., 2008; Carda et al., 2011; Farina et al., 2008; Gandolfi et al., 2019; Hung et al., 2022; Kosem et al., 2022; Lai et al., 2009; Lee & Yang, 2024; Pennati et al., 2015; Picelli et al., 2016; Santamato et al., 2013, 2015; Sun et al., 2010); the remaining five studies, which reported only randomized allocation but no specific methodological description, were assessed as uncertain-risk items (Ding et al., 2017; Erbil et al., 2018; Hesse et al., 1998; Karadag-Saygi et al., 2010; Nasb et al., 2019). The area with the most failures was the blinding of participants and staff, as most studies employed a single-blind design. Eight studies explicitly described allocation concealment as low risk. For reporting bias, all 18 articles were assessed as low risk. All studies were assessed as having a low risk of other biases, as no other factors that could contribute to the risk of bias were mentioned in the included literature.

Figure 2.

Risk of bias. A Risk of bias summary. B Risk of bias graph.

MAS before or at the 6th week after intervention

Evidence network

As illustrated in Figure 3, the evidence network is constituted by a graph where each node represents an intervention. The thickness of the connecting lines between the nodes was positively correlated with the number of studies. The network included 17 BoNT combination rehabilitation therapies from 17 studies with a total of 612 patients.

Figure 3.

Network plots of enrolled treatments in terms of the MAS reduction (before or at the 6th week after intervention). MAS reduction (before or at the 6th week after intervention). Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; RA, robot assisted; MT, mirror therapy; AC, active control treatment; mCIMT, modified constraint-induced movement therapy; ESWT, extracorporeal shock wave therapy.

Heterogeneity test and network meta-analysis

Figure 4 depicts the results of the heterogeneity test, which demonstrated that there was minimal heterogeneity between studies for the same intervention (I²< 50%), thereby justifying the use of a fixed-effects model for the analysis. A network meta-analysis was performed on the included studies (Figure 5). The network meta-analysis showed that for the short-term efficacy of BoNT combined with rehabilitation on post-stroke spasticity, BoNT plus CT and splinting was superior to BoNT plus CT and stretching and BoNT plus CT and casting.

Figure 4.

Forest plots of network comparisons in terms of MAS reduction before or at the 6th week after intervention. Abbreviations: CrI: credible interval; BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; mCIMT, modified constraint-induced movement therapy.

Figure 5.

Network meta-analysis for the efficacy of botulinum toxin combined with rehabilitation therapy for post-stroke spasticity before or at the 6th week after intervention. Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; RA, robot assisted; MT, mirror therapy; AC, active control treatment; mCIMT, modified constraint-induced movement therapy; ESWT, extracorporeal shock wave therapy.

Probability ranking

Table 3 shows the surface of the cumulative ranking curve (SUCRA) value rankings for the short-term MAS evaluation results. The closer the SUCRA ranking value is to 0, the lower the probability of suggesting a higher score and the higher the ranking. The results demonstrated that, in terms of the short-term efficacy of BoNT in combination with rehabilitation for post-stroke spasticity, the top three ranked combinations were BoNT plus CT and splinting, BoNT plus CT and ES, and BoNT plus ESWT.

Table 3.

Probability ranking of the short-term efficacy of botulinum toxin combined with rehabilitation for post-stroke spasticity.

MAS reduction before or at the 6th week after intervention
Intervention	SUCRA	Rank
BoNT + CT + Splinting	0.23	1
BoNT + CT + ES	0.24	2
BoNT + ESWT	0.25	3
BoNT + CT + RA	0.30	4
BoNT + RA	0.36	5
BoNT + ES	0.40	6
BoNT + CT + MT	0.43	7
BoNT + CT + AC	0.44	8
BoNT + CT + Taping	0.45	9
BoNT + Taping	0.51	10
BoNT + mCIMT	0.55	11
BoNT + Stretching + Splinting	0.69	12
BoNT + CT + Dry Needling	0.79	13
BoNT + Stretching	0.80	14
BoNT + CT + Casting	0.87	15
BoNT + CT + Stretching	0.91	16

Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; RA, robot assisted; MT, mirror therapy; AC, active control treatment; mCIMT, modified constraint-induced movement therapy; ESWT, extracorporeal shock wave therapy.

MAS between the 7th and 12th weeks

Evidence network

The evidence networks are depicted in Figure 6, where each node represents an intervention. The thickness of the connecting lines between the nodes was positively correlated with the number of studies. Two evidence networks were constructed based on the results of the medium-term MAS evaluation. Network A included eight BTX-combined rehabilitation treatments involving seven studies with a total of 288 patients. Network B included five BTX-combined rehabilitation treatments in four studies, with a total of 82 patients.

Figure 6.

Network plots of enrolled treatments in terms of the MAS reduction (between the 7th and 12th weeks). A MAS reduction (between the 7th and 12th weeks). B MAS reduction (between the 7th and 12th weeks). Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; RA, robot assisted; MT, mirror therapy; AC, active control treatment; mCIMT, modified constraint-induced movement therapy.

Heterogeneity test and network meta-analysis

Figure 7 shows the results of the heterogeneity test, indicating no significant heterogeneity between studies for the same intervention, with an I2 value <50%. Consequently, a fixed-effects model was selected for the analysis. A Network A meta-analysis was performed on the included studies. Two evidence networks were identified for the medium-term MAS evaluation results (Figure 8). It showed that for the medium-term efficacy of BoNT combined with rehabilitation on post-stroke spasticity, BoNT plus CT and ES was superior to BoNT plus CT, BoNT plus CT and RA, BoNT plus CT and taping, BoNT plus CT and casting, and BoNT plus CT and stretching. Network B showed that for the medium-term efficacy of BoNT combined with rehabilitation for post-stroke spasticity, BoNT plus casting was superior to BoNT plus stretching.

Figure 7.

Forest plots of network comparisons in terms of MAS reduction between the 7th and 12th weeks after intervention. Abbreviations: CrI: credible interval; BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation.

Figure 8.

Network meta-analysis for the efficacy of botulinum toxin combined with rehabilitation therapy for post-stroke spasticity between the 7th and 12th weeks after intervention. A MAS reduction between the 7th and 12th weeks after intervention. B MAS reduction between the 7th and 12th weeks after intervention. Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; RA, robot assisted; MT, mirror therapy; AC, active control treatment; mCIMT, modified constraint-induced movement therapy.

Probability ranking

Table 4 illustrates the rankings of SUCRA values for the medium-term MAS evaluation results. The closer the SUCRA ranking value is to 0, the lower the probability of indicating a higher score and the higher the ranking. The results demonstrated that, in terms of the medium-term efficacy of BoNT in combination with rehabilitation for post-stroke spasticity, the top three ranked combinations were BoNT plus CT and ES, BoNT plus CT and MT, and BoNT plus CT and RA for Network A and BoNT plus casting, BoNT plus ESWT, and BoNT plus ES for Network B.

Table 4.

Probability ranking of the medium-term efficacy of botulinum toxin combined with rehabilitation for post-stroke spasticity.

A MAS reduction between the 7th and 12th weeks after intervention
Intervention	SUCRA	Rank
BoNT + CT + ES	0.03	1
BoNT + CT + MT	0.32	2
BoNT + CT + RA	0.33	3
BoNT + mCIMT	0.35	4
BoNT + CT + AC	0.38	5
BoNT + CT + Taping	0.61	6
BoNT + CT + Casting	0.87	7
BoNT + CT + Stretching	1.00	8
B MAS reduction between the 7th and 12th weeks after intervention
Intervention	SUCRA	Rank
BoNT + Casting	0.17	1
BoNT + ESWT	0.23	2
BoNT + ES	0.55	3
BoNT + Taping	0.71	4
BoNT + Stretching	0.99	5

Abbreviations: BoNT, botulinum toxin; CT, conventional therapy; ES, electrical stimulation; MT, mirror therapy; RA, robot assisted; mCIMT, modified constraint-induced movement therapy; AC, active control treatment.

Discussion

This meta-analysis explored the efficacy of BoNT combined with rehabilitation treatments for post-stroke spasticity deriving from randomized controlled trials. Previous studies extensively researched the efficacy of BoNT in the treatment of post-stroke spasticity (Asimakidou & Sidiropoulos, 2023). Furthermore, the injection protocols employed in these studies differed in terms of the type of BoNT used, the muscle group targeted, and the dose of BoNT administered. Differences in injection protocols may have led to bias when comparing the treatment effects of BoNT combined with rehabilitation. Among the articles, abobotulinum toxin A was the most commonly used formulation, which was consistent with previous findings (Hsu et al., 2022). We observed differences in the dose of BoNT used when injected into large muscle groups (e.g., bicipital muscle, 250–400 U; brachialis muscle, 75–250 U; gastrocnemius muscle, 200–500 U and 150–200 IU; and soleus, 100–250 U). Nevertheless, the range of injections into small muscle groups remained relatively consistent (e.g., flexor carpi ulnaris, flexor carpi radialis, and flexor digitorum profundus). Furthermore, the guidance tools used for BoNT injections exhibited heterogeneity across the studies. These tools include ultrasonography, electromyography, and electrical stimulation. However, a few studies did not employ guidance tools. It is imperative to ensure utmost precision when administering BoNT injections, as this is essential for achieving optimal results in the targeted muscles. (Asimakidou & Sidiropoulos, 2023) provided the first quantitative evidence that guided BoNT injections were superior to non-guided injections. However, the distinction between ultrasound and electrical stimulation was insignificant (Asimakidou & Sidiropoulos, 2023). Furthermore, previous studies have demonstrated no differences in the efficacy of ultrasound- or electrical stimulation-guided BoNT injections in triceps surae spasticity after stroke (Hauret et al., 2023). Consequently, future research on guided BoNT injections should be conducted in a manner that minimizes the influence of confounding factors other than those directly related to the research objectives.

This meta-analysis revealed that BoNT therapy in conjunction with electrical stimulation had a significant impact on the clinical outcome of post-stroke spasticity, particularly in terms of short- and medium-term efficacy. These findings are consistent with those of other relevant studies (Picelli et al., 2021). A series of studies conducted on rat diaphragm preparations in the 1960s demonstrated a reduction in the latency of BoNT-A paralytic effect onset after electrical stimulation of motor nerve endings (Hughes & Whaler, 1962). Electrical stimulation can be employed as an additional treatment along with BoNT-A to enhance its efficacy. Several studies have combined different types of electrical stimulation. Wang et al. demonstrated that the combination of BoNT-A and electromyographic biofeedback therapy significantly alleviates lower limb muscle spasms and enhances lower limb motor function and daily living abilities in post-stroke patients (Wang et al., 2022). Another study demonstrated that the combination of a spasmodic muscle therapeutic instrument with BoNT-A prolonged the duration of action of BoNT-A on spastic muscles (Ding et al., 2017). Therefore, the combined therapy provided better management of spasticity. Nevertheless, recent clinical practice guidelines indicate that functional electrical stimulation is not an appropriate intervention to reduce plantar flexor spasms (Johnston et al., 2021). In a subsequent study, Baricich et al. divided patients with post-stroke spastic clubfoot who received BoNT-A injections into two groups. They found that electrical stimulation of antagonistic muscles did not improve the clinical outcomes in these patients (Baricich et al., 2019). Consequently, further research is required to ascertain which form of electrical stimulation is more efficacious when combined with BoNT-A and how electrical stimulation can be employed more optimally.

Furthermore, the combination of BoNT and ESWT demonstrated a significant impact on the clinical outcome of post-stroke spasticity, with notable efficacy in both the short and medium terms. A recent systematic review and meta-analysis indicated that ESWT has a favorable therapeutic effect on spasticity in patients with upper motor neuron injury (Mihai et al., 2022; Opara et al., 2021). One study compared the efficacies of BoNT and ESWT for post-stroke spasticity. These results demonstrated that ESWT is as effective as BoNT injections (Hsu et al., 2022). The potential mechanisms by which ESWT may improve spasticity include induction of nitric oxide synthesis, reduction in motor neuron excitability, dysfunction of neuromuscular transmission, and development of fibrosis in chronically hypertonic muscles (Leng et al., 2020; Xiang et al., 2018). ESWT is a mechanical wave with acoustic, optical, and mechanical properties (Martínez et al., 2020). The two primary types of ESWT include focused extracorporeal shock wave therapy (fESWT) and radial extracorporeal shock wave therapy (rESWT). A systematic review indicated that rESWT may offer certain advantages over fESWT in the treatment of spastic muscles (Dymarek et al., 2020). Some studies have demonstrated that rESWT influences the viability of human skeletal cells and regulates muscle cell proteins at the gene expression level. This finding suggests that this may be a more suitable treatment for spasticity (Mattyasovszky et al., 2018). However, a comparative study of the effects of fESWT and rESWT on spastic equinus in post-stroke patients revealed no significant differences between the two groups (Wu et al., 2018). This indicates that further investigation is required to ascertain the clinical differences between radial and focused shockwaves. A systematic review yielded substantial evidence indicating that adjunctive therapies enhance outcomes following BoNT injections, with ESWT exhibiting the most pronounced efficacy (Mills et al., 2016). It is hypothesized that the neurological effects of BoNT-A on reducing the spasticity grade are integrated with the rheological effects of ESWT on spastic muscles, having a synergic effect on muscle contracture (Martínez et al., 2020). Nevertheless, only one article in the literature explicitly used fESWT. Therefore, future studies should clearly specify the type of shockwave used and adopt a standard shockwave type.

The findings of this study indicate that in the short term, the combined use of BoNT injections and splinting is associated with a significant improvement in the clinical outcome of spasticity following stroke. However, evidence for the use of static and dynamic splinting to reduce upper limb spasticity is limited (Kerr et al., 2020). Findings suggest that adhesive patching of the wrist and finger flexors may be more effective than daily manual muscle stretching combined with passive joint loosening and palmar splinting in enhancing the efficacy of BoNT-A treatment (Santamato et al., 2015). This discrepancy may be attributed to the inclusion of a single article on the use of BoNT in conjunction with splinting for the treatment of post-stroke spasticity. The limited sample size may have introduced a degree of bias into the results. Further studies are required in the future.

Regarding medium-term outcomes, there is evidence that the use of adjunctive casting immobilization for post-stroke spasticity improves outcomes subsequent to BoNT injections. A review of relevant studies indicates that sustained postural maintenance through taping and casting immobilization produces superior and more enduring effects on spasticity, range of motion, and gait function than stretching alone (Lee & Yang, 2024). Nevertheless, casting protocols vary widely in the literature, and priority needs to be given to future studies to determine the protocol that yields the best results (Farag et al., 2020). Wortley et al. presented a standardized protocol for the application of upper-extremity casting as a continuous treatment for elbow spasms (Wortley et al., 2024). Subsequent studies should employ a uniform, standardized protocol to control for variables other than the study factors. Both splinting and casting are forms of prolonged muscle stretching that can result in soft tissue changes. Furthermore, prolonged immobilization in the extended position may increase the length and number of serial muscle segments (Stoeckmann, 2001). The objective of stretching is to enhance the viscoelastic properties of the muscle-tendon unit, thereby facilitating greater extension (Lee & Yang, 2024). The study found that a stretching program for more than 20 min per day for six weeks (16 h in total) was more likely to result in permanent contracture reduction (Harvey et al., 2002). The evidence indicates that maintaining a sustained position (through the use of taping or casting, even if for a brief period) following injections is an effective method for reducing spasticity. This approach is endorsed by experts and is regarded as a Grade A recommendation (Allart et al., 2022). Further investigation is required to elucidate the potential benefits of this combination.

This study had some limitations. First, the MAS, a subjective assessment tool, was used as the primary outcome. However, few trials in the relevant literature have employed non-MAS assessment for spasticity. Consequently, this may have had a negligible effect on the results. Therefore, future studies should employ a greater use of more objective assessment methods. Second, long-term outcomes were not included in our study. Accordingly, additional research is required to ascertain the long-term efficacy of BoNT in conjunction with diverse rehabilitation techniques. Lastly, owing to the limited quantity of literature included in the study, the probability ranking does not fully account for clinical efficacy. Therefore, it is imperative that these results be interpreted with caution and that further high-quality research be conducted in order to validate them.

Conclusions

This study is the first effort to assess the efficacy of BoNT combined with various rehabilitation treatments for post-stroke spasticity using a network meta-analysis. These findings suggest that the combined treatment may be judiciously employed for the management of post-stroke spasticity. Nevertheless, the insufficient quantity of included literature and the relatively modest sample size limited a comprehensive depiction of clinical efficacy through probability ranking. In light of these considerations, the results must be interpreted with caution and validated by further high-quality studies.

Supplemental Material

sj-docx-1-nre-10.1177_10538135241290110 - Supplemental material for Efficacy of Botulinum Toxin Combined With Rehabilitation Treatments In The Treatment of Post-Stroke Spasticity: A Systematic Review and Network Meta-Analysis

Supplemental material, sj-docx-1-nre-10.1177_10538135241290110 for Efficacy of Botulinum Toxin Combined With Rehabilitation Treatments In The Treatment of Post-Stroke Spasticity: A Systematic Review and Network Meta-Analysis by Meihua Ke, Dongxia Li, Peike Zhou, Hongli Geng, Qingfang Zhang, Liang Zhi, Yaqing Hong, Yulong Wang and Jianjun Long in NeuroRehabilitation

Footnotes

Acknowledgments

We would like to thank all the researchers and participants involved in this study. Furthermore, we express our gratitude to Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital for giving advice on the paper.

ORCID iDs

Peike Zhou

Yulong Wang

Jianjun Long

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research was funded by Sanming Project of Medicine in Shenzhen, grant number No.SZSM202111010.

Supplemental material

Supplemental material for this article is available online.

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