Analysis of the effects of the upper limb improvement programme in patients after ischemic stroke treated with botulinum toxin

Introduction: Stroke is not only a medical problem, but also – due to the permanent disability of the injured person – a signifi cant social problem. A signifi cant number of patients after a neurological event develop increased muscle tone. Upper motoneuron damage syndrome promotes pain, stiffness, muscle contracture and weakness, which can potentially delay or prevent success in the rehabilitation process. In the upper limb, the spastic pattern is most often expressed through adduction and internal rotation of the glenohumeral joint, combined with fl exion in the elbow, radiocarpal joint and interphalangeal joints. The specifi city of spasticity-type increased tension makes rehabilitation of patients suffering from this disorder one of the most diffi cult tasks of neurological rehabilitation. Aim: The aim of the study was to assess muscle tone and range of motion of the inferior limb in patients after ischemic stroke subjected to 4 cycles of intramuscular injections of a botulinum toxin preparation and subjected to motor rehabilitation. Research Project: Pilot experimental study. Methodology: The study was carried out in the Neurological Unit with Stroke Sub-unit and Sub-Department of Neurological Rehabilitation at John Paul II Specialist Hospital in Krakow in the period from September 2014 to November 2015. The study group consisted of 20 patients after ischemic stroke (13 men, 7 women), age 30 to 72. All patients completed a 4-cycle study, which included injections of the botulinum toxin preparation, combined with a 15-day cycle of individual rehabilitation exercises. Each training session lasted 90 minutes. In order to verify the therapeutic process, active and passive mobility was measured according to the SFTR method and the assessment of muscle tone level was done using the Modifi ed Ashworth Scale. Results: The taken therapeutic actions caused a positive increase in mobility, mostly passive, in the glenohumeral-scapular, elbow and forearm as well as the radiocarpal joints. There was also a slight increase in active mobility of the upper limb joints. In the course of obtaining results, it was shown that the use of botulinum toxin, combined with the rehabilitation exercise programme, signifi cantly reduced pathological muscle tone both within the elbow, radiocarpal joint, and the interphalangeal joints of the hands. Conclusions: The presented results showed that the use of the botulinum toxin combined with medical rehabilitation allows local treatment of spasticity without exposing patients to adverse systemic reactions associated with oral medication. In addition, it has a positive effect on the increase in passive and – to a lesser extent – active range of motion in the joints of the inferior limb. The individual division of this paper was as follows: a – research work project; B – data collection; C – statistical analysis; D – data interpretation; E – manuscript compilation; F – publication search Article received: 30 Dec. 2016; Accepted: 01 Aug. 2017 Please cite as: Mirek E., Opoka K., Kozioł K., Filip M., Pasiut S., Szymura J., Legwant A., Wasielewska A., Michalski M., Tomaszewski T. Analysis of the effects of the upper limb improvement programme in patients after ischemic stroke treated with botulinum toxin. Med Rehabil 2017; 21 (3): 14-22. DOI: 10.5604/01.3001.0010.5008 Internet version (original): www.rehmed.pl


Does botulinum toxin treatment
combined with motor rehabilitation infl uence the range of active and passive mobility in the upper limb joints in patients after ischemic stroke? 2. Do intramuscular injections of botulinum toxin type A reduce the muscle tone in patients after ischemic stroke?

MATERIAL AND METHODS
The study was carried out at the Neurological Department with Stroke Sub-unit and the Neurological Rehabilitation Sub-unit at John Paul II Specialist Hospital in Krakow in the period from September 2014 to November 2015. The permission of the bioethical commission with the signature 99/KBL/OIL/2016 was obtained for conducting this experiment.

Material
From the group of 200 patients participating in the recruitment process, 140 people met the treatment pro-frequently within the elbow (79%), wrist (66%) and ankle joint (66%). In the upper limbs, the spastic pattern is most often expressed through adduction and internal rotation of the glenohumeral joint, combined with fl exion in the elbow joint, the radiocarpal joint and the interphalangeal joints of the hands. The shoulder complex is lowered, its mobility is also limited 3,4 . The specifi city of increased spasticitytype tension makes rehabilitation of patients suffering from this disorder one of the most diffi cult tasks of neurological rehabilitation. Numerous unfavourable symptoms and complications associated with spasticity affect the signifi cant reduction of quality of life in patients 5,6 .

STUDY AIM
The aim of the study was to evaluate the benefi ts of treatment of stroke patients with type A botulinum toxin and motor rehabilitation. The presented clinical experiment sought answers to the following questions:
therapists. Treatment included multifactorial procedures described below as "combination therapy". Combination therapy consisted of the following interactions: 1. Injection of botulinum toxin type A; 2. Movement therapy.
Patients were injected with BOTOX (Botulinum Toxin Type A) using sterile 25, 27 or 30 G 10 needles in the superfi cial and long muscles in the deep muscles. In controlled clinical trials, doses of 100 units of BOTOX A were administered to patients. They were divided between occupied muscle groups and administered during one procedure under the control of an ultrasound machine. The patients were given the following muscle injections: The patients qualifi ed for the research programme were subjected to 4 cycles of intramuscular injections of the botulinum toxin. Subsequent applications of Botox were performed every 12 weeks. Each time, 3 weeks after the injection, the patients took part in a 3-week programme of individual therapeutic exercises. Participants were subjected to clinical evaluation at the time they were qualifi ed for each of the 4 stages of the study programme, as well as upon completion of each study programme. During the improvement training, they were required to go to therapy 5 days a week. Each session lasted 90 minutes. During the programme, specialized exercises were carried out to improve functioning of the upper limb and improve the overall fi tness of the patients.
Patients participated in individual rehabilitation sessions at a gym. Each time, motor training was preceded by 30-minute muscle elongation with increased tension using a pneumatic cuff (Photos 1 and 2). Then, they took part in the 60-minute improvement programme which consisted of a warm-up lasting 10 minutes, including mobilization of joint, nerve, -with hypersensitivity to the neurotoxin complex or any of botulinum type A (BOTOX A) components that have severe side effects after drug administration, -having a baclofen pump, -resistant to the drug.

Research methods
The measurements conducted in the experiment included the evaluation of active and passive mobility of the occupied and indirectly occupied upper limb in the glenohumeral-scapular, elbow, antebrachial and the radiocarpal joint in accordance with the SFTR method using a goniometer. Patient positioning and alignment of the goniometer axis were made in accordance with the applicable standards 7 . The measurement of the range of motion in the joints of the indirectly occupied upper limb did not deviate from the norm. The goniometric examination included analysis of passive and active mobility successively in the joints of the limb affected by paresis: 1. The glenohumeral-scapular joint -movements in the sagittal, transverse, frontal and rotational planes. 2. The elbow joint -movements in the sagittal plane. 3. The antebrachial joint -movement in the rotational plane, 4. The carpal joint -movements in the sagittal and frontal plane. Another measurement was conducted to assess the spasticity level of muscle groups in the upper limb using The Modifi ed Ashworth Scale -MAS. The research considered muscles including the elbow joint, the radiocarpal joint and the interphalangeal joints of the hands. The measurements were made in accordance with the applicable standards by a qualifi ed physician and physiotherapist 8,9 . The therapists conducting rehabilitation exercises were excluded from the process of clinical evaluation of patients.

Treatment procedure
The treatment procedure was conducted by a multidisciplinary team consisting of physicians and physio-gramme criteria for inclusion in the study. In this group, 20 people were appointed who underwent a fourfold therapy programme including administration of Botox A and motor improvement. The experimental group consisted of patients after ischemic stroke (13 men, 7 women), age 30 to 72. The average age was 56.35 (Table 1). Due to ethical reasons, no control group was created. Qualifi cation for testing was done by neurology specialist. The basic criterion for inclusion of patients in the research programme was a history of ischemic stroke. Other criteria for participation in the program were: -age of at least 18 years, -documented hospitalization for ischemic stroke, -post-stroke spasticity of the upper limb (MAS≥2) in at least one muscle group, -established date of medical rehabilitation no later than 3 weeks after administration of the drug. The study program excluded patients: -with severe swallowing or breathing disturbances, -pregnant or breastfeeding, -with myasthenic syndrome, -taking drugs that inhibit neuromuscular transmission (e.g. aminoglycosides), -with symptoms of general infection, -with the presence of infl ammation within the planned injection site, -with dementia (MMSE test <=18 points) -not applicable to patients with aphasia, alexia or agraphy who take acenocoumarol or warfarin and on the day of drug administration, had INR value exceeding 2.5, -with persisting upper limb contraction or muscle atrophy in the affected limb, muscular and fascial structures, and education of how to shift body weight to the directly occupied side (Photos 3 and 4). The introductory part was followed by the 40-minute main part,, which included activities, i.e. active muscle exercises of the indirectly occupied limb with simultaneous support on the paretic limb injected with Botox A, active and supported exercises of the inferior limb muscles in closed kinematic chains, shaping a correct movement pattern and inhibition of associated reactions, exercises to effectively and effi ciently interact with a changing environment using utensils (i.e. water bottles, cup, towel, clothes), manipulative exercises of the paretic upper limb (Photos 5, 6 and 7). The therapy was completed with 10--minute calming exercises.

Methods of statistical analysis
The obtained results were subjected to statistical analysis using the Statistica 9.1 programme. A signifi cance level of 0.05 was assumed for all tests. For the analysis of changes in active and passive mobility of the upper limb joints in patients after ischemic stroke, after four cycles of botulinum toxin type A injection, the Student's t-test for dependent samples was used. To determine the effect of type A botulinum toxin on the muscular tone of patients after ischemic stroke, after four cycles of botulinum toxin injection type A the Student's t-test for dependent samples was used.

RESULTS
The data obtained during the measurements of active and passive mobility of the upper limb in the glenohumeral-scapular, elbow and antebrachial and radial-carpal joints revealed signifi cant statistical improvement in passive mobility: in the glenohumeral-scapular, the passive extension movement increased on average by 23.25° (p = 0.000) ( Preparation of the limb for exercise using a pneumatic cuff -front view 0.0001) ( Table 2) and adduction -on average by 3.4° (p = 0.0398) ( Table 2); in the ulnar and antebrachial joints, there was an increase in the range of passive fl exion -on average by 11.5° (p = 0.0161) ( Table 3) and supination -on average by 21.25° (p = 0.0028) ( Table 3). During the analyses, a signifi cant increase in the active extension in the glenohumeral joint was demonstrated -on average by 13.5° (p = 0.008) ( Table 2) and radial defl ection in the carpal-radial joint, by an average 2.5° (p = 0.0289) ( Table  4). The remaining measurements did not reveal the occurrence of statisti-cal signifi cance, however, there was a growing trend in the range of active mobility in all upper limb joints. In the group of 20 patients qualifi ed for the botulinum toxin type A programme, a statistically signifi cant pathological decrease was noted in increased spastic muscle tone. The biggest difference from the initial tension was noted in the muscle group within the carpal joint, successively in the muscle group including the interphalangeal joints and the ulnar joint. Following rehabilitation, the muscle tension within the elbow was reduced by an average of 1.58 MAS ment was obtained using 1,000 units of the preparation (Dysport). At the higher dose of 1,500 units, excessive weakness of the injected muscles was observed 12 . The lack of changes in the active mobility of the limb injected with the botulinum toxin may result from the inhomogeneous clinical condition presented by people qualifi ed to participate in the study, which infl uenced the differentiation of rehabilitation activities. Not without signifi cance were also some perceptual impairments that patients had to deal with as a result of a neurological event or in the course of dementia syndrome. The reasons for the lack of improvement in terms of active mobility and functioning of the upper limb may be a consequence of too low sensitivity of the clinical trials 13,14,15 .
Also, statistical scales used to assess the effects of Botox A may also be too sensitive to detect changes. Based on my own observations, as well as other authors, it should be assumed that an unfavourable role in the analysed research programme could also be played by the time factor from the onset of ischemic stroke to the time of qualifying patients for the study. In my own research, it was on average 33 months. In the research by Simpson et al. 17 , it was 37 months, Bakheit et al. 18 , also 37, and Brashear -52 months 19 . The analysis of my research also shows that ther-xin type A. They analysed 10 experiments, and their assessment showed a signifi cant reduction in pathological muscle tone and an increase in passive motion in the upper limbs in all the analysed works. The results of their observations proved that in the majority of patients, there was no increase in the range of active mobility or it was insignifi cant. Both the amount of improvement and the time of maintaining the effects of therapy were only partially dependent on the dose and place of administration of the drug 11 . Sławek and Bogucki 13 evaluated the results of work on the use of type A botulinum toxin in the treatment of post-stroke spasticity occurring over the years. The authors analysed a number of studies confi rming the effectiveness of therapy with the use of toxins in reducing muscle tone, increasing the range of motion to relieve pain and improve self-care activities related to personal hygiene and dressing. However, they noted a lack of studies with control or placebo groups, clearly confi rming the effectiveness of the botulinum toxin preparation in increasing the active mobility of the inferior limb. In these observations, they emphasize the importance of choosing the proper dose of the drug allowing to reduce the tension while maintaining muscle function. The authors cite the results of research in which the most important functional improve-(p = 0.000) ( Table 5). There was also a signifi cant difference in muscle tone of the carpal joint before and after rehabilitation. The therapy signifi cantly reduces tension, and the average difference was 1.8 MAS (p = 0.000) ( Table 5). There was also a signifi cant difference in muscle tone in the interphalangeal joints before and after rehabilitation. Following physical therapy, signifi cantly lower tension was recorded, and the average difference was 1.92 MAS (p = 0.000) ( Table 5).

DISCUSSION
All patients participating in the experiment reported an increase in the passive range of motion, but it was not possible to prove that the therapy with the use of botulinum toxin injections combined with motor rehabilitation, cause a statistically signifi cant increase in active mobility of most joints within the inferior upper limb. However, there was a growing tendency for the range of active movement along with subsequent stages of therapy.
The results of the conducted studies are in line with the results presented by the team of the II Neurological Clinic at the Institute of Psychiatry and Neurology in Warsaw. These authors conducted a joint review of clinical trials on the treatment of post--stroke spasticity using botulinum to-    27,28 .

Photo 5, 6 i 7 Active and supported exercises of the inferior limb muscles in closed and open kinematic chains -front and side view
In this context, a reasonable recommendation seems to be that future experimental protocols should be conducted using a variety of different interactions (combination therapy). An important factor that increases the effectiveness of therapy in patients after ischemic stroke may also be the prolongation of treatment time. In addition, in order to obtain reliable results showing improvement in active mobility of the upper limb, it may be necessary to exclude patients from participation in the experiment with upper limb affected paralysis and those in which cognitive defi cits prevent full, active involvement in the therapy carried out in a functional way. More importantly, planned therapeutic interventions should be precisely designed and in accordance with current training protocols based on reliable physiological premises, their aim should be to determine the most effective way of treatment for patients after ischemic stroke. Summing up the results of the conducted study, it can be assumed that the treatment of patients after ischemic stroke with the use of botulinum toxin combined with motor improvement, effectively leads to increased passive mobility of the upper limb, as well as re-education in pathological muscle tone. Most of the patients did not manage to achieve an increase in active mobility in the joints of the upper limb.
Today, we know with certainty that the use of botulinum toxin should not be the only method of therapeutic treatment in patients after ischemic stroke, and the best results can be obtained using pharmacotherapy ing the MAS scale compared to the control group, where placebos 19,20,21 were used. Kwolek and Myjkowska 22 , among others, undertook the same subject of research 22 . In the conducted experiment, they assessed a group of 44 patients injected with the toxin and subjected to rehabilitation. These authors showed a reduction in spasticity within the area of the upper limb and hand, where the mean value for the entire limb was reduced by 0.9 points on the MAS scale, while for the hand by 1 point on the same scale. After further analysis, they obtained results approximate to those presented in my work, namely 12 weeks after the fi rst test, the mean spastic tension reduction for the upper limb was only 0.8 points, and for the hand 0.9 points on the MAS scale. Characteristic fl uctuations in the tension level before consecutive cycles of application can result from the temporary therapeutic effect of botulinum toxin, which after about 12 weeks is gradually removed from the body. It can be concluded that the positive changes in muscle tone and the longer duration of the drug's action on the muscles are not only the result of the botulinum preparation, but also the systematically conducted, purposeful, rehabilitation combined with re-education of muscle tone.
Maintaining proper patient behaviours at their home environment and during daily activities is needed to extend the duration of positive results of therapy in the fi eld of muscle tone 22,23,24 . However, there was no signifi cant improvement in the functioning of the upper limb as measured by clinical tests 25,26 . This allows to conclude that the reduction of pathological muscle tone does apy with the use of botulinum toxin signifi cantly infl uenced the increase in the range of passive motion in the joints of the inferior upper limb, and to a lesser extent also affected the improvement of the range of active mobility. The basic level of spasticity and functioning of the limb presented by patients at the time of qualifying for the experiment was of great importance in increasing the scope of active mobility. In those who were diagnosed with slight active mobility in the limb joints prior to the project, there was signifi cant improvement in its scope. An important aspect of the therapy was the joint implementation of individually selected therapeutic goals. Based on numerous publications referring to this issue, it can be assumed that pathologically increased tension is not always the primary problem deciding on the lack of active mobility of the limb occupied by the disease process. Thus, therapy based only on its reduction may prove ineffective. It should also be concluded that the lack of improvement in the functional activity of the limb is related to pathophysiology of spasticity, weakness of the inferior limb and other adverse symptoms associated with damage to the central motor neuron 12,19 . Many authors suggest that combating only muscle hyperactivity does not directly translate into improvement of their active work 26 .
Many experimental studies, including the results obtained in my own studies, confi rm the effectiveness of botulinum toxin therapy to reduce abnormal muscle tone. In numerous clinical trials with different doses and toxin preparations, there was a signifi cant reduction in the level of spasticity measured us-  30,31 . The use of botulinum toxin allows the treatment of local spasticity without exposing patients to unwanted systemic reactions associated with oral medication. In addition, the preparation is selectively injected within the affected muscles, without affecting the muscles in their surroundings 29,30,31 . Due to the large size of this group of patients, it is necessary to conduct further clinical observations, including the assessment of the effectiveness of combination therapy with the participation of, inter alia, surgeons, neurologists, pharmacologists as well as physiotherapists.

CONCLUSIONS
The obtained results allowed to formulate the following conclusions: Application of botulinum toxin type A in patients after ischemic stroke combined with individualized motor rehabilitation increases the range of active and passive mobility of the upper limbs, thus favourably affecting their functional effi ciency.
The local application of botulinum toxin type A in patients after ischemic stroke results in the reduction of muscle tone.