Methods for a multisite randomized trial to investigate the effect of constraint-induced movement therapy in improving upper extremity function among adults recovering from a cerebrovascular stroke

This article describes the study design, methodological considerations, and demographic characteristics of a phase III RCT to determine if 1) constraint-induced therapy (CI therapy) can be applied with therapeutic success 3 to 9 months after stroke across different sites, 2) gains that might occur persist over 2 years, 3) initial level of motor ability determines responsiveness to CI therapy, and 4) the treatment effect differs between those treated before 9 months and after 1 year. Six sites will screen and recruit poststroke survivors stratified on initial level of motor ability and after randomization allocate participants to immediate or delayed intervention. Primary outcomes include a laboratory-based measure of function (Wolf Motor Function Test [WMFT]) and a real-world participant-centered functional use measure (Motor Activity Log [MAI]). Secondary outcomes concern function, behavior, and compliance. This is the first multisite, single-blind RCT of a formal training intervention for upper extremity rehabilitation in subacute stroke in the United States.     

Pediatric CI therapy for stroke-induced hemiparesis in young children

In this laboratory we have developed a set of techniques that randomized controlled studies and a multisite randomized controlled trial have shown can substantially reduce the motor deficit of adult patients with mild to severe chronic strokes. Equivalent results have been obtained with adult patients after traumatic brain injury and brain resection. The basic technique, termed Constraint-Induced Movement therapy or CI therapy was derived directly from basic research with monkeys with mature motor systems and with monkeys given surgical intervention either on their day of birth or prenatally by intrauterine surgical procedures. We report here the results of two randomized controlled trials of CI therapy with young children with asymmetric upper extremity motor deficits of varied etiologies from 8 months to 8 years of age in one study and with children with hemiparesis consequent to prenatal, perinatal, or early antenatal stroke from 2 to 6 years old in a second study. The procedures used with children are very similar to those used with adults and diverge simply to make the basic techniques age-appropriate. All forms of CI therapy for the upper extremity to date involve 3 main elements: (1) intensive training of the more affected extremity, (2) prolonged restraint of the less affected extremity, (3) a 'transfer package' of techniques to induce transfer of therapeutic gains achieved in the laboratory to the life situation. The results in children with cerebral palsy are considerably better than those obtained in adults. Marked changes were observed in the quality of movement in the laboratory scored by masked observers from videotape; actual amount of use of the more affected arm in the life situation; active range of motion; and emergence of new classes of behaviour never performed before, such as in individual cases, fine thumb-forefinger grasp, supination, and use of the more affected extremity in crawling with palmar placement and rhythmic alteration. In the second experiment, the control group, after receiving usual and customary care for 6 months, was crossed over to receive CI therapy and exhibited results that were as good as those for the children receiving CI therapy first. Retention of treatment gains was approximately 70% at 6 months after the end of treatment. For some children there was no decrement in retention while for others there was a marked drop-off. One of the important factors contributing to good retention was the compliance of parents with the recommended post-treatment regimen. When retention is poor, brush-up periods may be of value. In the first experiment children were treated for 6 hr/day for 21 consecutive days, while in the second experiment treatment occurred only on the weekdays of the 3-wk treatment period (15 days). The results were at least as good with 15 days of treatment as with 21 consecutive days, thereby allowing the protocol to be fit into the usual therapist work week and making it more practical and less expensive for clinical use. CI therapy does not make movement normal in children with cerebral palsy with asymmetric upper extremity motor disorders. However, as carried out in this laboratory, it can produce a substantial improvement in a majority of cases.     

Diffusion Tensor Imaging Study of the Response to Constraint-Induced Movement Therapy of Children With Hemiparetic Cerebral Palsy and Adults With Chronic Stroke

Objective

To investigate the relationship of white matter integrity and path of the corticospinal tract (CST) on arm function before and after constraint-induced (CI) movement therapy in children with hemiparetic cerebral palsy (CP) and adults with chronic stroke.

Design

Study 1 used a multiple-baseline pre-post design. Study 2 was a randomized controlled trial.

Setting

Outpatient rehabilitation laboratory.

Participants

Study 1 included children with hemiparetic CP (n=10; mean age ± SD, 3.2±1.7y). Study 2 included adults with chronic stroke (n=26; mean age ± SD, 65.4±13.6y) who received either CI therapy or a comparison therapy.

Interventions

Children in study 1 received CI therapy for 3.5h/d for 15 consecutive weekdays. Adults in study 2 received either CI therapy or a comparison therapy for 3.5h/d for 10 consecutive weekdays.

Main Outcome Measures

Diffusion tensor imaging was performed to quantify white matter integrity. Motor ability was assessed in children using the Pediatric Motor Activity Log–Revised and Pediatric Arm Function Test, and in adults with the Motor Activity Log and Wolf Motor Function Test.

Results

Participants in both studies improved in real-world arm function and motor capacity. Children and adults with disrupted/displaced CSTs and children with reduced fractional anisotropy values were worse on pretreatment tests of motor function than participants with unaltered CSTs. However, neither integrity (fractional anisotropy) nor distorted or disrupted path of the CST affected motor improvement after treatment.

Conclusions

Participants who had reduced integrity, displacement, or interruption of their CST performed worse on pretreatment motor testing. However, this had no effect on their ability to benefit from CI therapy. The results for children and adults are consistent with one another.     

Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax,bcl-xS) gene expression

Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2, IL-4, IL-7 and IL-15, which can all signal through the γ chain of the IL-2R (IL-2Rγ), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes (bcl-2 and bcl-x_L), but causes little change in expression of bax and bcl-x_S, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common γ chain cytokines can be dissociated. Thus, when proliferation is blocked, the common γ chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common γ chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common γ-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).     

A treatment for a chronic stroke patient with a plegic hand combining CI therapy with conventional rehabilitation procedures: case report

Constraint-Induced Movement therapy (CI therapy) is a recognized rehabilitation approach for persons having stroke with mild to moderately severe motor upper extremity deficits. To date, no rehabilitation treatment protocol has been proven effective that addresses both motor performance and spontaneous upper extremity use in the life situation for chronic stroke participants having severe upper extremity impairment with no active finger extension or thumb abduction. This case report describes treatment of a chronic stroke participant with a plegic hand using a CI therapy protocol that combines CI therapy with selected occupational and physical therapy techniques. Treatment consisted of six sessions of adaptive equipment and upper extremity orthotics training followed by a three-week, six-hour daily intervention of CI therapy plus neurodevelopmental treatment. Outcome measures included the Motor Activity Log for very low functioning patients (Grade 5 MAL), upper extremity portion of the Fugl-Meyer Motor Assessment, Graded Wolf Motor Function Test - for very low functioning patients (gWMFT- Grade 5), and Modified Ashworth Scale. The participant showed improvement on each outcome measure with the largest improvement on the Grade 5 MAL. In follow-up, the participant had good retention of his gains in motor performance and use of his more affected arm for real world activities after 3 months; after a one-week brush-up at 3 months, and at one year post-treatment.     

Constraint-Induced Movement therapy can improve hemiparetic progressive multiple sclerosis. Preliminary findings

OBJECTIVE: To evaluate whether Constraint-Induced Movement therapy (CI therapy) may benefit chronic upper extremity hemiparesis in progressive multiple sclerosis (MS). METHODS: Five patients with progressive MS, who had chronic upper extremity hemiparesis and evidence for learned non-use of the paretic limb in the life situation, underwent 30 hours of repetitive task training and shaping for the paretic limb over 2-10 consecutive weeks, along with physical restraint of the less-affected arm and a "transfer package" of behavioral techniques to reinforce treatment adherence. RESULTS: The patients showed significantly improved spontaneous, real-world limb use at post-treatment and 4 weeks post-treatment, along with improved fatigue ratings and maximal movement ability displayed in a laboratory motor test.Conclusions The findings suggest for the first time that slowly progressive MS may benefit from CI therapy. Further studies are needed to determine the retention of treatment responses.     

Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomised trial

BACKGROUND: The aim of constraint-induced movement therapy (CIMT) is to promote use of a limb that is functionally impaired after a stroke. In one form of CIMT to treat upper limb impairment, use of the less severely affected arm is restricted for many hours each weekday over 2 consecutive weeks. The EXCITE trial has previously shown the efficacy of this intervention for patients 3-9 months poststroke who were followed-up for the next 12 months. We assessed the retention of improvements 24 months after the intervention. METHODS: In the EXCITE trial, 106 of 222 participants who had mild to moderate poststroke impairments were randomly assigned to receive CIMT rather than usual and customary care. We assessed this group of patients every 4 months for the primary outcome measure of impaired upper limb function, as measured with the Wolf motor function test (WMFT) and the motor activity log (MAL). Health-related quality of life, measured with the stroke impact scale (SIS), was a secondary outcome measure. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00057018. FINDINGS: The effects at 24 months after treatment did not decline from those at 12 months for time taken to complete the WMFT (-0.32 s, 95% CI -3.70 to 3.06), for weight lifted in the WMFT (-1.39 kg, -2.74 to -0.04), for WMFT grip strength (-4.39 kg, -6.91 to -1.86), for amount of use in the MAL (-0.17, -0.38 to 0.04), or for how well the limb was used in the MAL (-0.14, -0.34 to 0.06). The additional changes were in the direction of increased therapeutic effect. For the strength components of the WMFT, p<0.0001. INTERPRETATION: Patients who have mild to moderate impairments 3-9 months poststroke have substantial improvement in functional use of the paretic upper limb and quality of life 2 years after a 2-week CIMT intervention. Thus, this intervention has persistent benefits.