Abstract
Background and Purpose Spasticity, an aspect of upper motor neuron syndrome, is a widespread problem in patients with stroke. To date, no study has reported the long-term (up to 1 year) outcomes of botulinum toxin (BTX) injection in combination with constraint-induced movement therapy in patients with chronic stroke. In this case report, the long-term (1 year) effects of the combination of BTX type A injection and constraint-induced movement therapy on spasticity and arm function in a patient with chronic stroke and arm paresis are described.
Case Description The patient was a 66-year-old man who had had an infarction in the right posterior limb of the internal capsule 4 years before the intervention. At screening, the patient was not able to voluntarily extend his interphalangeal or metacarpophalangeal joints beyond the 10 degrees required for constraint-induced movement therapy. From 12 days after BTX type A injection, the patient received 5 hours of constraint-induced movement therapy for 10 weekdays.
Outcomes All outcome measures (Modified Ashworth Scale, Fugl-Meyer Assessment, Action Research Arm Test, and amount of use scale of the Motor Activity Log) improved substantially over the 1-year period (before intervention to 1 year after intervention). Repeat BTX type A injections were not necessary because muscle tone and arm function did not worsen during the observation period.
Discussion The improved arm function may have reflected improvements in volitional movements and coordination or speed of movements in the paretic arm as a result of a reduction in spasticity, a reduction of learned nonuse behaviors, or use-dependent plasticity after the combination of BTX type A injection and constraint-induced movement therapy. In addition, the possibility of an influence of the passage of time or the Hawthorne effect cannot be ruled out. If this approach proves useful in future controlled studies, it may reduce the rising medical costs of the treatment of stroke.
Spasticity, which has been defined as a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks resulting in hyperexcitability of the stretch reflex, is a component of upper motor neuron syndrome.1 In a systematically identified cohort of patients who were admitted to a hospital with stroke, the prevalence of spasticity at 12 months after stroke was 38%.2 Botulinum toxin (BTX) is the most widely used treatment for focal spasticity.3 The duration of efficacy of BTX is 3 to 5 months4; as a result, a large proportion of patients with chronic spasticity after stroke receive repeated BTX treatments. Therefore, rehabilitation after BTX injection has focused on increasing BTX efficacy in patients with spastic hemiparesis after stroke. Recently, Sun et al5 reported the short-term effect (up to 6 months) of BTX injection in combination with intensive task training in constraint-induced movement therapy. To date, however, no study has reported the long-term improvements (up to 1 year) in functional outcomes after BTX injection in combination with constraint-induced movement therapy in patients with chronic stroke. Moreover, BTX is perceived as an expensive treatment.6 The requirement for repeated BTX treatments increases the cost of treating patients with stroke.
The use of BTX is appropriate for focal spasticity in the arm. In addition, evidence from multiple randomized controlled trials has indicated that constraint-induced movement therapy is efficacious for rehabilitating arm function in adults who have chronic stoke and cannot use the paretic arm.7 Therefore, our goal was to determine whether the combined application of BTX type A injection and constraint-induced movement therapy is a viable therapeutic option. In this case report, the long-term (1 year) improvements in spasticity and arm function after treatment with the combination of BTX type A injection and constraint-induced movement therapy in a patient with chronic stroke and arm spasticity are described. We also considered the cost of the treatment.
Case Description
The patient was a 66-year-old man who had had an infarction in the right posterior limb of the internal capsule 4 years before the intervention, with resultant hemiparesis in his nondominant (left) hand and arm. Immediately after the stroke, the patient received 2 hours of standard inpatient rehabilitation every day for 6 months. After being discharged from the hospital, he received 1 hour of standard outpatient rehabilitation per week in a clinic. This rehabilitation continued until the day before the intervention. The patient was identified for the intervention after independently responding to a website recruitment for an ongoing stroke research project on constraint-induced movement therapy at The Hospital of Hyogo College of Medicine, Hyogo, Japan. We confirmed that the patient had not received any prolonged therapy in the past.
At screening, the patient showed difficulty with mass extension of the fingers, which made many activities of daily living (ADL) difficult. Moreover, he exhibited arm spasticity and was unable to voluntarily extend the metacarpophalangeal or interphalangeal joints of the fingers beyond 10 degrees. Screening also revealed that few attempts were being made to use the affected arm for ADL. No cognitive deficits were noted. The goals set by the patient were to hold a bowl with the affected arm while eating rice with chopsticks, to push and pull a lever in his car with the affected arm, and to use a golf club with both arms.
Clinical Impression #1
The patient had no obvious differential diagnosis. The primary problems were arm spasticity and inability to voluntarily extend the fingers beyond the 10 degrees required for constraint-induced movement therapy.8 The patient was able to extend the wrist to 20 degrees, and the only limitation for constraint-induced movement therapy was insufficient finger extension. The patient appeared to be motivated and excited about the intervention and had not received BTX or any oral medication for spasticity in the past. An attending physician informed the patient that he would not be able to receive BTX or any oral medication for spasticity for 1 year after the intervention unless he received specific permission from the team providing the intervention, and the patient agreed to these terms.
Examination
The primary outcome measure was the Modified Ashworth Scale (MAS),9 which was used to evaluate muscular tone. Secondary outcome measures were the Fugl-Meyer Assessment (FMA),10 for evaluating arm impairment; the Action Research Arm Test (ARAT),10 for evaluating paretic arm performance; and the amount of use scale of the Motor Activity Log (MAL),11 for evaluating the amount of paretic arm use. Cognitive function was assessed with the Mini-Mental State Examination (MMSE).12 All assessments were made by trained occupational therapists.
The MAS assesses muscular tone (muscle spasms) during passive joint movements. The MAS is reliable for the assessment of arm spasticity13 and has adequate convergent validity (Spearman rho of .51).14 The degree of resistance to passive muscle stretch is graded by the examiner and scored on a 6-point ordinal scale ranging from 0 (no increase in muscle tone) to 4 (the paretic part is rigid in both flexion and extension). A 1-point decrease in the MAS score has been defined as clinically meaningful.15
The FMA assesses the movement, sensation, and balance functions of the extremities and trunk. In this case, we used the arm motor component of the FMA, which has very high interrater and test-retest reliability (intraclass correlation coefficients and rho of >.95)10 and construct validity16 in patients with stroke. The arm motor component of the FMA consists of 30 items that evaluate basic arm function (movements and reflexes of the shoulder, elbow, forearm, wrist, and hand) and 3 items that evaluate coordination and speed. Each item is scored on a 3-point ordinal scale, and the total score for the assessment ranges from 0 to 66 points. A 6.6-point increase in the FMA score17 has been defined as clinically meaningful.
The ARAT primarily assesses the ability of the patient to handle small and large objects. This assessment is achieved with a variety of qualitatively rated items and, therefore, can be considered an arm-specific measure of activity limitation.10 The ARAT is an observational test that consists of 19 items, which are subdivided into 4 categories: grasp, grip, pinch, and gross movement. Each item is graded on a 4-point ordinal scale ranging from 0 to 3, and the total score for the test ranges from 0 to 57. The ARAT has high intrarater (r=.99) and test-retest (r=.98) reliability and validity.18 A 5.7-point increase in the ARAT score14 has been defined as clinically meaningful.
The amount of use scale of the MAL is a structured questionnaire in which 14 specific ADL tasks are each rated on a 6-point scale ranging from 0 to 5. The MAL has acceptable validity and reliability.11,19 The questionnaire gathers information on how well and how often ADL tasks are performed with the affected arm in the home environment. A 0.5-point increase in the score on the amount of use scale of the MAL has been defined as clinically meaningful.20
The MMSE is a brief cognitive screening tool. The total MMSE score can range from 0 to 30. We used the MMSE to detect any gross cognitive disorder that may have occurred during the intervention.
The patient's initial rating on the MAS was 1+ for elbow, 2 for wrist, and 3 for fingers. The initial FMA score was 44 (of 66), and the initial ARAT score was 31 (of 57). The average score on the amount of use scale of the MAL was 1.83. The MMSE score was 27 (of 30), suggesting that the patient had no gross cognitive disorder before the intervention.
Clinical Impression #2
On the day when the initial evaluation began and before the intervention was undertaken, the MAS score confirmed that the patient had a high resistance to passive muscle stretch at the wrist and finger joints and, therefore, did not meet the criteria for constraint-induced movement therapy,8 which requires a patient to be able to voluntarily extend the fingers at least 10 degrees.
The planned intervention was a combination of BTX type A injection and constraint-induced movement therapy. Stretching the finger and wrist flexor muscles resulted in temporary improvement of active wrist and finger extension. Therefore, we believed that the combined application of BTX type A injection and constraint-induced movement therapy was a viable therapeutic option. According to Sun et al,5 the treatment of patients with stroke and strong spasticity is within the scope of a combined application of BTX injection and constraint-induced movement therapy.
Intervention
Informed consent was obtained from the patient.
Forty units of BTX type A were injected to allow the patient to actively extend his elbow, wrist, and fingers. BTX type A (Botox, Glaxo Smith Kline K.K., Tokyo, Japan) supplied as a vacuum-dried powder in a 100-U vial was reconstituted with 2.0 mL of sterile saline (0.9%) to obtain a concentration of 50 U/mL. The muscle belly of the biceps brachii muscle was injected with 20 U. The flexor digitorum superficialis and flexor digitorum profundus muscles were each injected with 10 U. The injections were done by a trained physician and were placed in the motor endplate zone. Wrist flexor muscles, such as the flexor carpi radialis and flexor carpi ulnaris, were not injected with BTX type A because spasticity was not detected upon palpation of these muscles. We assumed that the wrist spasticity was derived from spasticity of the flexor digitorum superficialis and flexor digitorum profundus muscles, which also act as wrist flexor muscles. This assumption was supported by the observation that stretching the finger flexor muscles decreased the resistance to passive wrist flexion for a short time.
From 12 days after BTX type A injection, the patient received 5 hours of constraint-induced movement therapy for 10 consecutive weekdays. The constraint-induced movement therapy protocol involved 3 main elements: (1) repetitive, task-oriented training of the affected arm, which was approached in small steps of progressively increasing difficulty to suit the arm function and physical condition of the patient; (2) the transfer package, which was designed to facilitate the transfer of therapeutic gains made in the clinical setting to the patient's real-world activities; and (3) restraining of the unaffected arm to enforce use of the affected arm.21 The patient was restrained by verbal instruction for safety purposes.
We modified a conventional 6-hour training protocol to fit into a 5-hour time frame to conform to the usual clinical schedule of The Hospital of Hyogo College of Medicine. This 5-hour training protocol would be considered typical rehabilitation for patients with chronic stroke and would be covered by the Japanese medical insurance system. Additionally, we modified the transfer package to fit the hospital's clinical setting. The efficacy and validity of the modified transfer package were previously reported.22 The transfer package had 3 components: (1) a behavioral contract between therapist and patient on intensive use of the affected arm for specific ADL tasks in real-life situations; (2) completion of a home diary or statements describing the use of the affected arm for ADL in detail; and (3) problem-solving mentoring, which involved introducing assistive devices, building orthotic devices, and motion modification to facilitate the use of the affected arm for ADL. In this case, a short opponent splint was temporarily used to facilitate the use of the affected arm for ADL. The training was provided by 4 experienced occupational therapists.
Outcome
The intervention (training and follow-up) was conducted from October 2012 to October 2013 at The Hospital of Hyogo College of Medicine. Outcome measures were assessed the day before BTX type A injection and the day before and 1 day, 6 months, and 1 year after constraint-induced movement therapy. All outcome measures improved substantially over the 1-year period (before intervention to 1 year after intervention) (Table). Active extension of the wrist and finger joints improved after BTX type A injection, as indicated by the increase in the scores on the arm motor component of the FMA and the ARAT. The MAS, FMA, ARAT, and MAL (amount of use scale) scores at each time point (the day before BTX type A injection and the day before and 1 day, 6 months, and 1 year after constraint-induced movement therapy) are shown in the Table. After the intervention, the patient was able to hold (pinch) and release objects using the affected fingers. After the 10-day constraint-induced movement therapy intervention, the patient was asked to answer “yes” or “no” to questions about whether he thought he had accomplished all the goals that he set before the intervention, and he answered “yes” for each goal. During the intervention, the patient did not receive ambulatory rehabilitation from any other clinics or hospitals.
Outcome Measures for the Paretic Arm
Discussion
This case report describes the long-term follow-up of a patient with chronic stroke and arm spasticity after the combined application of BTX type A injection and constraint-induced movement therapy. Our goals were to determine whether spasticity and arm function improved after 10 weekdays of constraint-induced movement therapy delivered after BTX type A injection and whether any improvements were maintained at 1 year after the intervention. Our clinical results indicated that spasticity and arm function improved over the 1-year period (before intervention to 1 year after intervention). Repeated BTX type A injections were not necessary because the muscle tone and arm function of the patient did not worsen during the observation period.
We expected that the gains achieved during the intervention would be maintained for more than 3 months if spasticity did not return during this time. This assumption was based on the guidelines for the use of BTX in the management of spasticity in adults, which state that, “If the muscle can be stretched or active function regained during this window, continued physical management may then be sufficient to manage spasticity, so the benefits can be long-lasting.”23(p2) In addition, there have been some reports of long-term effects of constraint-induced movement therapy.24,25 Therefore, we anticipated that the benefits would be long-lasting if appropriate management was applied.
In the reported case, our intervention improved spasticity (MAS score), function (FMA and ARAT scores), and the use of the affected arm for ADLs (MAL amount of use scale score). More than one therapist evaluated the patient over the course of the intervention, but all tests had very high interrater reliability.10,11,13,18,19 The improvements in the MAS, FMA, ARAT, and MAL (amount of use scale) scores in this case were greater than the thresholds for clinically meaningful change15,17,18; therefore, the treatment can be considered clinically effective. It is noteworthy that the patient continued to show improvements at 1 year after constraint-induced movement therapy, even though he received no further rehabilitation or medication after the completion of the intervention.
The observed changes in outcome measures may be attributed to several factors. They may have reflected improvements in volitional movements and coordination or speed of movements in the paretic arm as a result of a reduction in spasticity, a reduction of learned nonuse behaviors, or use-dependent plasticity of the motor cortex after the combination of BTX type A injection and constraint-induced movement therapy. It is possible that either BTX type A injection or constraint-induced movement therapy alone was the critical factor underlying the observed improvements. In addition, we cannot ignore the possibility of an influence of the passage of time or the Hawthorne effect. The Hawthorne effect has long been known as a possible explanation for positive results in intervention studies.
We believe that the long-term effects of the combined treatment have the potential to reduce the rising medical costs of stroke rehabilitation. Because of the high cost of medical care for patients with stroke in many countries, several governments have tried to control medical spending. There has been a marked increase in the number of publications on the economic aspects of stroke.26 As an inevitable consequence, clinicians are being required to reduce medical costs in hospitals or clinics. The combined treatment of BTX type A injection and 10 weekdays of constraint-induced movement therapy cost about US $2,551 (¥261,830). In Japan, the cost of repeated BTX treatments over a 1-year period is US $2,937 to $3,916 (¥301,440–¥401,920). This calculation is based on the assumption that BTX treatments are repeated 3 or 4 times over the course of the year. Therefore, the combined treatment is less expensive than repeated BTX treatments. Moreover, Sahrmann and Norton concluded that weakness after stroke occurs because of insufficient agonist muscle drive/recruitment in addition to increased stretch reflex of the antagonist muscle27; therefore, BTX treatment alone is not guaranteed to result in functional gains. These observations suggest the possibility of superior performance at a lower cost with the combination of BTX injection and constraint-induced movement therapy than with BTX injection alone.
Our patient did not need any repeated BTX treatments over the 1-year observation period, despite the limited duration of the efficacy of BTX type A. This observation suggests that a suitable intensive training program may have a stabilizing influence on BTX-induced improvements in spasticity. Considering the growth in medical spending, this promising observation may be useful for reducing medical costs. Our observations support the suggestion that a combination of BTX type A injection and constraint-induced movement therapy may reduce the cost of treatment for patients with stroke, who can temporarily achieve more active extension in wrist and finger joints by stretching.
This case report has some limitations. First, we were unable to prove the efficacy of the combined treatment on the basis of only a single case. Single- or multicenter studies with large samples and a long follow-up period are needed to confirm our observations.
Second, because this case report was prospective, there was no control group. This design was not sufficient for proving the long-term efficacy of the combination of BTX type A and constraint-induced movement therapy. Future studies should use a more rigorous design, such as a randomized controlled trial.
Third, the evaluators in this case were aware of the treatment that the patient received. To fully elucidate the efficacy of the combined approach, future studies with masking of evaluators are needed.
Fourth, the calculated potential reduction in the cost of treatment was valid only for Japan. Future studies should evaluate the reduction in medical costs across multiple nations.
Fifth, we were not able to calculate the proper amount of BTX type A required for the patient because of the lack of data on the optimal amount of BTX type A for Japanese patients with poststroke spastic hemiparesis; therefore, we used a low dose of BTX type A. More study on the optimal amount of BTX type A for Japanese adults is needed.
Sixth, the lack of more frequent follow-up assessments and the lack of patient-reported outcomes during the follow-up period may mean that other possible relevant factors were overlooked. In addition, more frequent evaluations in the days after BTX injection would be useful for deciding when to begin constraint-induced movement therapy. To address these issues, large-scale studies with frequent follow-up assessments and patient-reported outcomes are needed.
Seventh, the setting in this case was an outpatient rehabilitation setting, and the influence of treatment environment (ie, the influence of different practice settings) on the observed effects was not addressed. Some recent reports highlighted the importance of the treatment environment for improving body function.28,29 Further studies are needed to determine the influence of treatment environment on the effects of constraint-induced movement therapy in combination with BTX injection on arm function in adult patients with hemiparesis after stroke (chronic stroke).
Eighth, the patient in this case was treated with the intervention 4 years after stroke. In the Japanese medical insurance system, patients sometimes receive regular therapy a few years after stroke. However, this practice is not common in other developed countries, and additional studies with more limited criteria are needed to increase the generalizability of the observations.
Considering the promising outcomes seen in this case report, we believe that the combined approach offers promise for effectively improving spasticity and arm function in patients with stroke and spastic hemiparesis. In conclusion, BTX type A injection in combination with constraint-induced movement therapy is a relevant approach to the management of arm spasticity after stroke.
Footnotes
Mr Amano, Mr Takebayashi, and Mr Umeji provided concept/idea/project design. Mr Amano, Mr Takebayashi, and Dr Furukawa provided writing. Mr Hanada, Mr Umeji, and Dr Marumoto provided data collection. Mr Amano and Mr Takebayashi provided data analysis. Mr Amano, Mr Takebayashi, Mr Hanada, Dr Marumoto, and Dr Domen provided project management. Dr Domen provided fund procurement, facilities/equipment, and institutional liaisons. Mr Hanada and Mr Umeji provided administrative support. Mr Amano, Mr Takebayashi, Mr Hanada, Mr Umeji, Dr Furukawa, and Dr Domen provided consultation (including review of manuscript before submission). The authors express their appreciation to all therapists at the hospital for their commitment to excellence during the intervention.
The Ethics Committee of Hyogo College of Medicine approved the treatment protocol.
This work was partly supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (KAKENHI [26282158]).
- Received August 4, 2014.
- Accepted January 5, 2015.
- © 2015 American Physical Therapy Association
References
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