Efficacy of botulinum toxin A for the treatment of hemiparesis in adults with chronic upper limb spasticity

Introduction this study aimed to evaluate the effectiveness of botulinum toxin A (BoNT-A) injection in hemiparetic patients with chronic spasticity in the upper limb resulting from stroke or traumatic brain injury. Methods we conducted a retrospective study including 45 patients seen, in our department of Physical Medicine and Rehabilitation, between January 2014 and December 2016. All patients received an injection of BoNT-A (Dysport, 100 U/ml). Affected upper-extremity muscles could be injected as per the investigator’s discretion to a maximum total dose of 1000 U. We evaluated muscle tone using Modified Ashworth Scale (MAS). Functional disability was assessed using Modified Frenchay Scale (MFS), Nine Hole Peg Test (NHPT) and Barthel Index (BI). Quality of life (QoL) was assessed using the 36-Item Short Form Health Survey (SF-36). The achievement of treatment goal was assessed by the Goal Attainment Scaling (GAS). Results patients decreased their MAS score over the first and the third months (p<0.05). MFS showed improvement at 1 month after injection with a median change from baseline of 8 (range: 1-16; p<0.001). The change from baseline ranged from 0 to 5 points for NHPT at 1 month after injection (p< 0.001). This functional improvement was maintained to 3 months. Improvements in Barthel Index was observed at 3 months with a median change from baseline of 5 points (range 0-15; p<0.001). The mean change from baseline of SF-36 score was 4.77 ± 3.39 (p<0.001). The mean GAS T-score was 47.04 ±7.78 (median 50, IQR 7.7), giving a mean (SD) change from baseline of 25.36 ± 8.46 (95% CI 22.82 to 27.90; p <0.001). Binary logistic regression was used to identify the independent factors predicting a favorable functional outcome of Bon-T treatment. It showed that neglect was independent predictive factor treatment failure (p=0.009, OR=3.2) while previous injection of BoNT-A was an independent predictive factors of treatment success (p=0.009, OR=0.3). Conclusion our study showed a good response to BoNT-A injection delivered in the management of chronic upper limb spasticity resulting from stroke or traumatic brain injury. It demonstrated its outcome in improving muscle tone, function and QoL. It also showed that the majority of patients achieved their goal as defined at the start of the treatment, mainly for patients who received previous injection of BoNT-A.


Introduction
Upper limb spasticity may cause deformity, pain and reduced function [1]. The treatments of this spasticity include oral antispastic drugs, botulinum toxin and surgical treatments as selective neurotomy and orthopedic surgery [1]. The botulinum toxin is increasingly used to treat spasticity due to stroke or traumatic brain injury (TBI). This treatment has been widely shown to reduce muscle tone [ This current study aimed to evaluate, with a person-centred measure of outcome, the effectiveness of BoNT-A injection, particularly in the active function, in hemiparetic patients with disabling spasticity in the upper limb resulting from chronic stroke or traumatic brain injury, and to identify baseline factors that predict favorable functional outcome of this treatment.

Methods
Study design and participants: we conducted a retrospective study including patients with hemiparesisthat were reviewed in our Physical Medicine and Rehabilitation Department, between January 2014 and December 2016. The main eligibility criteria for the inclusion of patients were adults ≥ 18 years with hemiparesis for at least 6 months after a stroke or traumatic brain injury (TBI), and whose a Modified Ashworth Scale (MAS) score in target muscle group was at least 2. Agreement on achievable goals set was also required. The exclusion criteria were any medical disorder increasing the risk of botulinum-toxin-A-related adverse events; severe muscle atrophy or infection in target sites, or current anticoagulant therapy with INR ≥ 3.5. Women were excluded if they were pregnant or planning to become pregnant during the course of the study. Patients were not excluded if they received previous BoNT-A injections. All patients signed approved informed consent prior to undergoing any studyspecific procedures. The study was approved by the regional ethics committee (Ref: CCP Sud: 0043/2017).
Study treatment: all patients received an injection of botulinum toxin type A (100 U/ml). Affected upper-extremity muscles, from the shoulder to fingers, could be injected as per the investigator's discretion, based on the participant's disability to a maximum total dose of 1000 U. The dosage of toxin for each muscle was based on muscle size and degree of increased tone in each specific muscle.
Injections employed a needle stimulation technique, with a monopolar injection electrode. Once the target muscle was identified, by obtaining an appropriate contraction with the lowest possible stimulus intensity, BoNT was injected into one to four sites, based on the size of the muscle. Immediately after injection, we prescribed a physiotherapy and occupational therapy program which included 3 sessions per week for 6 months. Patient's adherence to this program was recorded throughout the study. To carry out on days they were not attending therapy, participants were also given a home exercise program which included prolonged self-administered stretch postures and rapid alternating movements. Antispastic medication had to be maintained at a stable dose during the study. was assessed by the Goal Attainment Scaling (GAS). We used the simplified GAS approach described by Tuner-Strokes [11], which is based on the original method described by Kiresuk and Sherman [12] but designed to be timely and practical for use in a busy clinic setting. GAS results were expressed by two different ways: scoring each goal between -2 and +2, resulting in as many raw scores as there are scales [13] and giving a direct result for each goal, which is easily understood by the patient and easy to use in clinical practice: : ''+2'' is the initial pretreatment (baseline) level, "1" represents progression towards the goal without goal attainment, "0" is the expected level after treatment, (and therefore, the "most likely" level after treatment), ''+1'' represents a better outcome than expected, and "+2" is the best possible outcome that could have been expected for this goal; a T-score [11], which is supposed to enable GAS scores to be normalized and then analyzed with parametric statistics. Since all the goals have the same weight (difficulty and importance) , we used the simplified equation of T-score [14]: Where: Xi = the GAS score; C = a coefficient that depends on the patient's number of scales (and thus the number of scores). All assessments were done at baseline (screening visit) and at 1, 3 and 6 months (follow-up visits), except those of BI and GAS which were recorded at baseline and at 3 months and the SF-36 which was done at baseline and at the end-of-study visit (at 6 months).
Statistical analysis: all statistical analysis were conducted with SPSS.20 software package. Baseline characteristics were presented as descriptive statistics. Mean and SD were reported for data that fulfilled the criteria for normal distribution. Data following a non-normal distribution were described by median and range (minimum and maximum). Participants'' treatment response was calculated as the change in scale from baseline to follow-up. Comparison between mean scores before and after the treatment was analyzed using a parametric (paired t-test) or nonparametric (Wilcoxon signed ranks) test, depending on the type of data being analyzed. Scores of '1+' were entered as 1.5 in the calculation of MAS scores. Baseline scores of GAS were rated as -1='some function' and -2='no function' with respect to the goal. 'Responders' were those who achieved their goal (GAS score 0, 1 or 2: goal achieved). Relationships between scores were examined using Spearman's rank correlation coefficients. To identify the independent factors predicting a favorable functional outcome of BoN-T treatment, binary logistic regression test was performed using the variables showing statistically significant differences in the univariate analysis of the measured factors. A p value of 0.05 was used for statistical significance.

Results
Characteristics of participants: this study included 45 patients.
They were referred from the neurological service (68.9%), the intensive care unit (ICU) (15.6%), and the orthopedic service (15.6%). Only patients from ICU were sent for botulinum toxin injection. The other patients were sent only for rehabilitation care and the botulinum toxin injection was indicated by a consultant in rehabilitation medicine and then discussed in our neuro-orthopaedic staff. The mean age was 50.29±14.8 years and the mean time since onset of incident was 3.28 ± 3.01 years. Sixty-two per cent of the population was men; 75.55 % had stroke and 24.44 % had traumatic brain injury. Left and right hemisphere localization was approximately equal (55.6% and 44.4%, respectively). Baseline characteristics are detailed in Table 1. BoNT-A treatment: in this cohort, there was very wide variation in the total dose of BoNT-A. The most commonly injected muscles and doses are shown in Table 2. The most frequently injected muscles were the Flexor carpi (84.44%), followed by Flexor digitorum Superficialis (71.11%), Pronator teres (51.11%) and biceps (46.66%).
With the exception of the pectoralis major (which was injected in 13.3% of patients), the shoulder muscles were relatively rarely injected. Multiple injection points were most commonly used in the larger and more proximal muscles, such as the biceps (85%) and the pectoralis major (66.7%).
Concomitant treatments: in follow-up visit, over two-thirds (71.1%) of patients were adherent to physiotherapy prescribed at the start of the study. Only 57.8 % of participants received occupational therapy and 55.6% practiced home exercises. The proportion of patients on antispasmodic medication was 44.4%.

Evolution of outcome measure
Spasticity: patients decreased their MAS score for shoulder, elbow, wrist and fingers over the first month. The change from baseline was 0.66±0.41; 0.95±0.46; 1±0.65; and 1.03±0.59 points for pectoralis major, biceps brachii, flexor carpi ulnaris, and flexor digit superficialis respectively (p<.001). This tone reduction was maintained over the third month (p<.001) but not statistically significant 6 months after injection ( Table 3).

Range of motion:
there was a significant improvement in the passive and active ROM for shoulder, elbow, wrist and finger extension at 1, 3 and even 6 months after injection (p<.001).
Pain: there was a significant decrease in pain VAS score from baseline at 1 and 3 months after injection (p<.001). The change was not significant at 6 months. Correlations: there was a significant correlation between the baseline score and the change from baseline after BoNT-A injection for MFS (p <.001; rho = 0.524) and NHPT (p = .001; rho = 0.478).
GAS T-score correlated, moderately, with the change from baseline of VAS pain score (Spearman rho= 0.349; p=.01) and of BI score (Spearman rho 0.349; p=.01). It correlated more strongly, however, with the gain in total MFS score (Spearman rho 0.647; p<.001) and in NHPT score at follow-up (Spearman rho 0.424; p=.004).

Identification of factors predicting a favorable functional
outcome: in univariate analysis, previous injection of BoNT-A (p=.006) and occupational therapy (p=.02) were associated with favorable functional response to BoNT-A treatment, however spatial neglect (p=.01) and cognitive impairment (p=.04) were associated with treatment failure. Functional outcomes were not associated with sensory, osteoma and communicative impairment. In multivariate analysis, spatial neglect was an independent predictive factor of BoNT-A treatment failure (p=.005, OR=6.876) while previous injection of BoNT-A was an independent predictive factor of treatment success (p=.003, OR=0.29).

Discussion
This study showed a good response to BoNT-A injection delivered in the management of chronic upper limb spasticity in patients with hemiparesis for nearly 3 years after a stroke or TBI. It demonstrated its outcome in improving muscle tone, passive and active function and quality of life. It also showed that the majority of patients achieved their goal as defined at the start of the treatment, mainly for patients who received previous injection of BoNT-A and who practiced occupational therapy. BoNT-A reduced muscle tone and the level of reduction was similar to previous studies [15,16]. The peak efficiency was at 1 month after injection and the improvement was not sustained at 6 months. It is not surprising that antispastic effect wears off after 6 months. In fact, BoNT-A prevents the release of the neurotransmitter acetylcholine from axon endings and this blockage is slowly reversed as the toxin loses activity [17]. Besides, and like others reports, we found improvements occurred in the active and passive range of motion [18]. The improvement of active ROM suggests that the co-contraction was an important component of reduced upper limb ROM. Botulinum toxin type A was demonstrated to have a benefit in terms of pain reduction in which decreased pain VAS was seen at 1 and 3 months, but not at 6 months. The effect on reducing pain may be through a mechanism of spasticity reduction since muscle tone was not decreased at 6 months. Two previous trials had shown that botulinum toxin reduces upper limb pain up to 6 and even to 12 months [19,20] and explained this finding by the avoidance of complications of spasticity such as spasm and contracture or by a direct analgesic effect by blocking transmission of neurotransmitters involved in pain pathways. More important was the functional outcome which was significant in our study and consistent with previous reports [21][22][23][24][25]. Despite spasticity is believed to contribute to reduce active function, the precise relationship between spasticity and motor performance is debated [25,26]. Although there are those that advocate spasticity as an important component of reduced upper limb function, others believe the main problem is motor weakness [20]. Because this study demonstrated improved active function, it supported the argument that spasticity is of paramount importance. However detecting the functional effectiveness of BoNT-A treatment and comparing different studies is generally difficult due to the various outcome measures used by investigators [27]. In order to establish the best outcome measures, our study used the MFS which has six bimanual tasks among ten [28]. In fact, bimanual activities seem to be a good test for assessing progress in this type of population, they are more sensitive to change and therefore more relevant to assess functional improvement of spastic upper limb [27,29]. This score showed improvement at 1 and 3 months after injection and as described by Ferrapie and Slawek [27,29], there was a best impact of BoNT-A in bimanual activities. Concerning fine manual dexterity assessed by NHPT, we found significant improvement like others studies [24,25,30]. The change from baseline at 3 months after injection was larger than the change at 1 month, which may be due to muscle weakness at the time of maximum BoNT-A effect.
Additionally, there was a significant correlation between the baseline score and the change from baseline after BoNT-A injection for MFS and NHPT. This suggests that functional improvement was less likely to occur for patients with severe initial impairment. Over and above the attainment of each goal, the GAS T-score provides an overall assimilation of attainment goals regardless of the number of goals set. Some authors have cast doubt on the value of calculating a GAS T-score [34]. In this study, we put considerable efforts to ensure that GAS was applied rigorously, so it is worth reflecting on the What is known about this topic  Upper limb spasticity may cause deformity, pain and reduced function;  Botulinum toxin is increasingly used to treat spasticity due to stroke or traumatic brain injury;  Botulinum toxin has been widely shown to reduce muscle tone and improve basic upper limb activities such as hand hygiene and facilitation of dressing.

Competing interests
The authors declare no competing interests.

Authors' contributions
All the authors have read and agreed to the final manuscript.

Acknowledgments
Our gratitude goes to the National Coordinator and staff of the NTBLCP in their willingness to share the system data and participated as respondents for the questionnaires administered. Tables   Table 1: baseline clinical characteristics of the population