Table 1

Study	Patients, (M, F), mean age; time after stroke	BTX type; dose, area, additional intervention	muscles	Spasticity scale	UL functional measures	Other measures	Spasticity reduction	Functional gain of UL	Description of results/adverse events
Simpson [37] RP, DB, PC, multicentre	37 pts (16 M, 21 F); 9 (75 MU), 9 (150 MU), 9 (300 MU), 10 ( placebo); mean age 59 ± 12 yrs; mean time from stroke onset 37 (9-133) months	BTX-A (Botox) 75, 150, 300 MU; elbow, wrist	BB, FCR, FCU by EMG guidance	AS ≥ 2 , Global Assessment of Spasticity Scale§1	FIM, Fugl-Meyer Scale, motor task/function rating scale	caregiver dependency scale, function and pain assessment, Rand 36-Item Health Survey	Significant reduction of spasticity for elbow and wrist in patients treated with 300 MU	negative	No improvement on the FIM, Fugl-Meyer, caregiver dependency, function and pain assessment, motor/function task rating scale, or the Rand 36-Item Health Survey. Significant improvement on physicians and patients global assessment in the high- and low-dose groups at 4 and 6 wks.
Hesse [38] RC, DB, PC single centre	24 pts (19 M, 5 F); 6 BTX, 6 BTX + ES, 6 ES + placebo, 6 placebo; mean age 52.3 yrs; mean post-stroke time interval was 7.45 months	BTX-A (Dysport) 1000 MU; elbow, wrist, finger flexors, electrical stimulation	BB, B, FCR, FCU, FDS, FDP by EMG guidance	MAS ≥ 3	Evaluation of 3 activities of daily living*¹	Global pain assessment	Significant reduction of spasticity in BTX + ES, particularly of the elbow and wrist joint. No difference in other groups	partial positive	Only activity in cleaning the palm of affected hand improved significantly in BTX + ES group
Bakheit [39] RC, DB, PC multicentre	82 pts (51 M, 31 F); 22 (500 MU), 22 (1000 MU, 19 (1500 MU), 19 Placebo; mean age 52.5 yrs; 3 months after stroke	BTX-A (Dysport) 500, 1000, 1500 MU; elbow, wrist, finger flexors	BB, FDP, FDS, FCR, FCU by anatomical landmark	MAS ≥ 2 Effective and safe dose (end-point)	RMA Scale (arm section), Bl, ADL, evaluation of 3 activities of daily living*¹	ROM, pain scale £	Significant decreases in MAS (any joint) at wk 4 with all BTX-A doses vs placebo. Decreased MAS score over 16 wks for elbow and wrist in all BTX groups and fingers in 1000 MU group.	positive	no significant differences between the groups in ROM, pain, RMA Scale, Bl for activities of daily living. Subjective caregiving scale not analyzed, but BTX-A treated patients showed improvement extending the elbow to put the affected arm into a garment sleeve or to open the hand for cleaning the palm or for cutting the fingernails.
Bhakta [40], RP, DB, PC single center	40 pts (23 M, 17 F); 20 (1000 MU) 20 placebo; mean age 60.2 yrs; mean time from stroke onset 3 yrs	BTX-A (Dysport) 1000 MU; elbow, wrist, finger flexors; physiotherapy	BB, B, FDP, FDS, FCU by anatomical landmark	MAS > 2	PDS*⁵ and CBS§³ (primary outcome)	MRC, MVG, ROM, pain	significant improvements in finger flexor spasticity with BTX-A vs placebo at wk 2, 6, and 12 (P = 0.001, P = 0.001, and P = 0.006); significant reduction of elbow spasticity at 2 wks. Decreased grip strength in BTX group compared with placebo at wk 6.	positive	Improvement of disability ( 8 of 17 patients in the BT-A group ) in cleaning the palm, putting the arm through sleeves, doing home physiotherapy exercises and cleaning armpit at 2 and 6 wks. Significant reductions in carer burden with BTX-A vs placebo at wk 2, 6, and 12 (P = 0.011, P =0.005, and P=0.027, respectively); no improvement in pain. Active ROM negative, passive shoulder and elbow ROM improved in BTX, but not significantly. Significant improvement in wrist ROM at 2 and 12 wks post-treatment
Bakheit [11] , RC, BD, PC multicenter	59 pts (26 M, 33 F); 27 BTX-A: mean age 64.1 ± 13.2; 32 placebo: mean age 67 ± 11.1; at least 3 months after stroke	BTX-A (Dysport) 1000 MU; elbow, wrist and finger flexors	BB, FDS, FDP, FCU, FCR by anatomical landmark	MAS ≥ 2 Effective and safe of single dose at 4 wks (end-point)	BI, GAS³, evaluation of 3 activities of daily living¹	ROM, pain score, GAB§⁴	Significant reduction in MAS at 4 wk in any joints ( (P= 0.004).	positive	No significant difference in BI score or the number of goals attained but significant improvement in GAB . Less difficult in extending the elbow to put the affected arm into a garment sleeve or to open the hand for cleaning the palm or for cutting the fingernails at 4 weeks after the BTX injections but statistical analysis was not performed. Improved passive range of movement at the elbow over 16 wk in BTX group compared with placebo. No significant difference in pain and active ROM
Brashear [41], RC, DB, PC multicenter	126 pts (63 M, 53F); 64 BTX-A, 62 placebo; mean age 60.5 yrs; 6 months elapsed from stroke	BTX-A (Botox) 221.3 ± 18.8 MU; wrist, finger flexors	FCR, FCU, FDS, FDP, FPL and thumb muscles; modality of injection not reported.	AS ≥ 2	DAS*² (primary outcome)	global assessment scale§²	Significant reduction of spasticity	positive	Improvements in DAS (pain, dressing, hygiene, cosmesis), physician and patient/caregiver global assessment. Eighty-three percent of BTX group had at least a one-point improvement in the score on the DAS in one or more of these areas, as compared with 53% of subjects who received placebo (P=0.007)
Childers [42] RC, DB, PC multicenter	91 pts; (60 M, 31 F); 21 BTX-A (90 MU), 23 BTX-A (180 MU, 21 BTX-A (360 MU), 26 (placebo); mean age 60 yrs; time from stroke onset 25.8 months (range 0.9 –226.9)	BTX-A (Botox) 90,180, 360 MU; wrist, elbow and finger flexors	BB, FCU, FCR, FDS, FDP by EMG guidance	MAS ≥ 2	FIM, 5-point assessment of functional disability	global assessments scale §², pain, SF-36,	Significant reduction spasticity in all BTX groups . High BTX pts showed more reduction of spastic wrist at all of the visits through week 12.	negative	No significant differences in functional disability, and composite FIM scores were detected between treatment groups. No significant differences in intensity of pain. The SF-36, detected significant improvement only in patients in the 90U BTX group at week 6 on the social functioning section.
Suputtitada et al. [43] RC, DB, PC single center	50 pts (26 M, 24 F); 15 BTX-A (350 MU), 15 BTX-A (500 MU), 5 (stopped) BTX-A (1000 MU), 15 placebo; mean age 55.2 ± 8.9 yrs in PC group, 46.5 ± 8.5, 53 ± 18.6, and 59.8 ± 9.1 yrs for BTX-A groups, mean time from stroke onset 8.5 months	BTX-A (Dysport) 350, 500, 1000 MU; elbow, wrist, and finger flexors; full program rehabilitation ^C therapy of the upper limb 3 days per week	BB, FCU, FCR, FDS, FDP by EMG guidance	MAS 4 End-point 1-The lowest effective dose of BTX, 2-onset and duration of BTX effect 3-hand function	ARAT*⁷, BI,	Pain (VAS)	Significant reduction of spasticity in 350 and 500 MU BTX-A group at 2 and 8 wks. Reduction of pain	positive effect for 350 and 500 MU BTX-A group (significant increase in ARAT at 8 and 24 wks)	Mean ARAT and BI increased during the first 8 weeks and then became rather stable throughout the 6-month study period in the 350 and 500 U group. Too much weakness in treated arm and reduced ARAT and BI for 1000 MU BTX-A subjects.
Jahangir et al. [44] RC, DB, PC single center	52 pts (33 M, 19 F); 27 BTX-A, 25 placebo; mean age 60.6 yrs; at least 1 year elapsed from stroke	BTX-A (Botox) 80 MU; wrist and finger flexors; regular physiotherapy session	FCR, FCU, FDS, FDP, modality of injection not reported.	MAS ≥ 2	BI^$	EQ-5D and EQ VAS	Decreased spasticity at wrist and fingers compared with placebo at 1 and 12 week	negative	Although there was an improvement in the measures of global function and quality of life in the BTX-A group compared to baseline, there was no significant improvement in between the two groups
Kanovský P [45] RC, DB, PC multicenter	148 pts (77 M, 71 F) 73 BTX-A, 75 placebo; mean age 55.6 (12.1) yrs; mean time from stroke onset 55 (48.7) months	BTX-A (Xeomin); mean dose 307 (80-435) MU; elbow, wrist, finger flexors; physical and occupational therapy ^C	BB, B, FCR, FRU, FDS, FDP, PQ, PT, thumb flexor. Pronators and thumb flexors were injected on the investigator’s clinical judgment by EMG or nerve stimulation	AS ≥ 2	DAS*²	GAB§⁴, CBS§³	Significant reduction of spasticity in wrist and finger flexors at 4 wks for BTX-A group	positive	Significant improvement in individual’s DAS domains for BTX-A group: hygiene (weeks 2, 4, and 8; P < 0.05), dressing (week 2; P = 0.003); limb position (weeks 2, 4, and 8; P < 0.009); and pain (weeks 2 and 4; P< 0.04). Significant improvement global assessment of efficacy and CBS
Meythaler JM [46] DB, CO, PC single center	21 pts (15 M, 6 F); 11 BTX-A plus physiotherapy; 10 PC plus physiotherapy; mean age 53.33 ± 14.8 yrs (range, 21–79); at least 6 months from stroke onset	BTX-A (Botox) 300-400 MU; elbow, wrist; occupational therapy ^A and a focused neuro-developmental therapy ^B	Elbow flexors, FRC, FRC by EMG guidance	AS≥ 3 (primary outcome)	The primary functional outcome measure was the MAL*⁶, Klein-Bell Activities of Daily Living Scale, BI	MOS-36 Item Short-Form Health Status Survey, ROM, motor and grip strength, pain	Significant reduction of spasticity in BTX-A group combined with therapy	positive	The use of BTX-A combined with therapy as compared with therapy only improved the functional status of the subjects on the MAL QOM subscale (P=0.018, t test) and showed a trend toward significance in the AOU subscale. In a crossover analysis for the randomized trial, there was a clear advantage of BTX-A combined with therapy over the placebo- controlled therapy (P=0.0605, ANOVA). No significant improvement in ROM, strength, pain, Klein-Bell Activities of daily living, BI and MOS-36
Mc Crory et al. [13] RC, DB, PC multicenter	96 pts (58 M, 38 F); 54 BTX, 42 placebo; mean age 59.5 yrs (58.4 ± 14.6 and 59.7 ± 12.2 in BTX-A and PC group, respectively); mean time elapsed from stroke 5.9 ± 10.5 yrs	BTX-A (Dysport) 750-1000 MU; wrist, elbow and finger flexors;	BB, B, BR, T, FCR, FCU, FDS, FDP, thumb flexors; EMG or nerve/muscle stimulation were all at the clinicians’ discretion.	MAS≥ 2 (primary end-point)	GAS³, PDS⁵, MMAS,	AQoL , (primary outcome), pain (100 point VAS), mood, GAB§⁴, CBS§³	Significant reduction of spasticity in BTX group at all visits	positive	Significant improvement in GAS score at week 20 for BTX-A (p< 0.01). No difference between groups in PDS, CBS, AQoL, pain, mood, MMAS. At wk 8, the chosen item from the patient disability rating scale (PFOM) was improved from baseline in 20/54 (37%) of the BTX-A group compared with only 6/38 (15%) of the placebo group (p = 0.02). A significantly higher proportion of both patients and investigators reported a benefit from treatment in the BTX-A group compared with the placebo group.
Tuner-Stokes [47]	secondary analysis of previous study (Mc Crory et al.)							positive	A significant treatment effect was observed with respect to GAS. Continued improvement in goal attainment between wks 8 and 20. Goal- scaling outcome T-scores were highly correlated with reduction in spasticity and global benefit. There were no significant associations with changes in pain, mood, or quality of life, nor with overall patient disability or carer burden.
Sun SF [48], RC, observer-blinded trial; single center	29 pts (24 M, 5 F), 15 BTX-A + mCIT, 14 pts BTX-A + conventional physiotherapy; mean age 58.7 ± 9.9 and 61.5 ± 9.4 yrs in experimental and control group, respectively; mean time from stroke onset 2.9 yrs	BTX-A (Dysport) 1000 MU; mCI and conventional physiotherapy& elbow, wrist and finger flexors	BB, FCR, FCU, FDP, FDS by anatomical landmarks	MAS≥3 (primary outcome)	MAL⁶, ARAT⁷ (secondary outcome)	Patients’ Global Satisfaction§6	significant improvement in spasticity for the combination group in elbow, wrist, and finger flexors at 6 months post-injection (P = 0 .019, P = 0.019, and P < 0.001, respectively)	positive	Both subscale scores of the MAL increased in the combination group at the 6-month follow-up. The combination group displayed greater improvements on the ARAT scores than the control group, with significant between-group differences at 3 months (P =0 .012) and 6 months (P < .001) post-injection. The combination group reported high subjective satisfaction at 3 months and 6 months post-injection.
Kaji [49], RC, DB, PC multicenter	109 pts (74M, 35F), 77 pts (51 BTX-A, 26 placebo), mean age 63.5 ± 9.3 and 63.6 ± 11 for BTX-A and PC in higher dose, respectively; 32 pts (21 BTX-A, 11 placebo), mean age 62.7 ± 9.7 and 62.9 ± 9.6 in lower dose; at least 6 months after stroke	BTX-A (Botox) Lower dose (120-150 MU), higher dose (200-240 MU); wrist and finger flexors	FCR, FCU, FDS, FDP by a nerve stimulator or EMG guidance	MAS > 2 (AUC score primary end-pont)	DAS*²	Clinical Global Impression §⁵	Significant improvement in wrist and fingers flexors spasticity with higher-dose BTX-A compared to placebo (AUC score) (p<0.001)	positive	A significant decrease in the DAS score for the principal therapeutic target was noted at every point in the higher and lower dose BTX-A groups compared to placebo groups. No significant differences between groups were noted at any time point in the scores for hygiene and pain. The CGI score by the investigator was significantly higher at every time point in the higher-dose BTX-A group compared to placebo group. No significant differences between lower-dose BTX-A and placebo groups were noted.
Shaw [50], RC, PC, observer-blinded trial; multicenter	332 pts (225 M, 107 F); 170 BTX-A plus standardized physiotherapy , 162 standardized physiotherapy; median age 66 and 67 yrs in BTX-A and control group; mean time from stroke onset 23.3 and 27 months for BTX-A and control group, respectively.	BTX-A (Dysport) 1000 MU; elbow, wrist, hand (finger flexors); standardized upper limb therapy&&	BB, BR, FCR, FCU, PQ, PT, FDS, FDP, thumb flexors using anatomical landmarks	MAS > 2	ARAT7 (primary end-point), NHPT, basic upper limb functional activity questions⁴, BI, Canadian Occupational Performance Measure	MI, grip strength , pain, Stroke Impact Scale, EQ-5 D and the Oxford Handicap Scale,	Significant reduction of elbow spasticity at 1 month. No difference in spasticity was seen at 3 or 12 months. Improvement in upper limb muscle strength (MI) at 3 months	positive	no significant difference in ARAT, BI, dexterity (NHPT), and pain. Significant improvement in some basic activities: dressing a sleeve, to clean the palm and opening the hand to cut fingernails in favor of the intervention group were seen at 1, 3, and 12 months
Wolf [51] RC, DB, PC; single center	25 pts (15 M, 10 F), 12 BTX-A plus physical therapy, 13 PC plus physical therapy; mean age 49.8 yrs; time from stroke 3 to 24 months	BTX-A (Botox) 300 MU; wrist, hand (finger flexors); standardized upper limb therapy&&&	FCR, FCU, FDS, FDP by EMG guidance	MAS (secondary end-point)	WMFT *⁸ (primary end-point)	Stroke Impact Scale (SIS), active ROM (secondary end-point)	Significant reduction of spasticity. MAS scores improved for the BTX-A group and worsened for the control group after injection (P=0.02)	negative	no mean WMFT differences were identified between the BTX-A and PC group. However significant improvements in proximal joint task times and inter-joint total limb coordinated activities were observed in BTX-A group compared to control group

Legend: PM = pectoralis major, BB = biceps brachii, B = brachioradialis, T = triceps, FDS = flexor digitorum superficialis, FDP = flexor digitorum profundus, FCU= flexor carpi ulnaris; FCR = flexor carpi radialis; PQ = pronator quatratus, PT = pronator teres; FLP = flexor longus pollicis; AS = Ashworth scale; MAS = modified Ashworth scale; AUC = area under the curve; MRC = Medical Research Council scale; MVG = maximum voluntary grip strength ; ROM = range of motion; MI = motricity Index; RMA = Rivermead Motor Assessment Scale; MMAS = Modified Motor Assessment Scale; GAS = Goal Attainment scale; MAL = Motor Activity Log; ARAT = Action Research Arm Test; FMS = Fugl-Meyer Scale; WMFT = Wolf Motor Function Test; NHPT = Nine-Hole Peg Test; DAS = Disability Assessment Scale; PDS = Patient Disability Scale; CBS = Carer Burden Scale; GAB = Global assessment of benefit; CGI = clinical global impression, BI = Barthel Index; ADL = Activity daily living; FIM = functional independence measure; VAS = visual analogue scale; SF-36 = Medical Outcomes Study 36-Item Short-Form Health Survey; AQoL = Quality of Life scale; EQ-5D = European Quality of Life-5 Dimensions; EQ VAS = visual analogue scale; MOS-36 Item Short-Form Health Status Survey; Rand 36-Item Health Survey; mCIT = modified constraint induced movement.
Upper Limb measurements*
Difficulties during three activities of daily living*¹: cleaning the palm, cutting fingernails and putting the affected arm through a sleeve, rated between 0 (no difficulties) and 4 (unable) [11,38,39].
DAS*²(Disability Assessment Scale): 0, no disability; 1, mild disability; 2, moderate disability; and 3, severe disability assessed on four functional domains (hygiene, dressing, pain, and limb position [41,45,49].
GAS*³ (Goal Attainment Scaling): a 5-point scale, where “0” denotes the expected level of achievement; “+1” and “+2” are respectively “a little” and “a lot” better than expected, whilst “–1” and “–2” are correspondingly a little and a lot less than the expected level. (Mc Crory13, in Bakheit11 was reported as very good, good, unchanged, worse and much worse).
Upper limb functional activity questions*⁴: ability to dress a sleeve, open the hand for cleaning the palm, open the hand for cutting the fingernails, ability to use cutlery, scored on a Likert scale from 1 (unable to perform activity) to 5 (no difficulty) [50].
PDS*⁵ (Patient Disability Scale): (8 items) identifies the patients’ ability to care for their affected limb (dressing, maintaining hygiene, etc.) and to use it actively, for example, for standing/walking balance [13,40].
MAL*⁶ (Motor Activity Log): valid and reliable scale of arm use and movement quality in real-world settings. It includes a 6-point amount of use (AOU) scale and a 6-point quality of movement (QOM) scale to rate how much and how well patients are using their affected arms for common daily tasks [46,48].
ARAT*⁷(Action Research Arm Test): functional assessment of upper extremity strength, dexterity, and coordination. It includes 19 items focusing on grasping objects of different shapes and sizes, and gross movement in the vertical and horizontal planes. The performance of each task is rated on a 4-point scale, ranging from 0 (no movement possible) to 3 (movement performed normally). The maximum sum score is 57 [43,48,49].
WMFT (Wolf Motor Function Test): It consists of 17 items: 2 strength measures and 15 timed performances on various tasks. The first half of the test involves simple limb movements; the second half involves more complex tasks involving coordinated motion.
Investigators, patients and caregivers assessment evaluation scales §
§1 Global Assessment of Spasticity Scale: physician’s and patient’s independent evaluation of response to treatment, graded from 0 = unchanged, to +4 = complete abolishment of symptom or to -4 = severe worsening [37].
§² Global Assessment Scale with a score of -4 indicating very marked worsening, 0 no change, and +4 very marked improvement [41,42].
§³ The Carer Burden scale: It identifies care tasks, such as dressing and maintaining hygiene, where these are performed by a carer. Items include cleaning the palm of the affected hand, cutting the fingernails of the affected hand, cleaning the armpit of the affected arm, and putting the affected arm through a sleeve. Each item is scored on a 5-point Likert scale rated from 0 = none to 4 = maximum disability or carer burden [13,45,40].
§⁴ Global Assessment of Benefit: The patient was asked “How would you rate the overall benefit you have received to your arm in the time since your last injection?”, and the response was categorized on a 5-point Likert scale [11,13,45].
§⁵ Clinical Global Impression8: The global impression of functional disability was assessed using the 11-point Numeric Rating Scale, with -5 indicating worst possible and 5 best possible, by the investigator, the patient, and the physical or occupational therapist [49].
§⁶ Patient’s global satisfaction resulting from the treatment on a 7-point categorical scale weighted from completely satisfied to completely dissatisfied [48] .
£ Pain scale: 0= no pain, 1 = mild pain, 2 = moderate pain, 3=severe pain
$ The items were weighted according to a scheme. The person received a score based on whether they had received help while doing the task. The scores for each of the items were summed to create a total score. The higher the score the more “independent” the person. Independence meant that the person needed no assistance at any part of the task. If a person did any of the task about 50% independently then the “middle” score would apply to that particular task [44].