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Poststroke Upper Limb Recovery Adelyn P. Tsu, DO1,2

Gary M. Abrams, MD, FAAN1,2

1 Department of Neurology/Rehabilitation Service, San Francisco VA

Medical Center, San Francisco, California 2 Department of Neurology, University of California, San Francisco, San Francisco, California 3 Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California

Nancy N. Byl, MPH, PhD, PT3 Address for correspondence Adelyn P. Tsu, DO, Department of Neurology/Rehabilitation Service, San Francisco VA Medical Center, San Francisco, CA 94121 (e-mail: [email protected]).

Abstract

Keywords

► stroke ► upper limb rehabilitation ► stroke management

Upper limb recovery after a stroke is suboptimal. Only a few individuals achieve full functional use of the hemiparetic arm. Complex primary and secondary impairments may affect recovery of upper limb function in stroke survivors. In addition, multiple personal, social, behavioral, economic, and environmental factors may interact to positively or negatively influence recovery during the different stages of rehabilitation. The current management of upper limb dysfunction poststroke has become more evidence based. In this article, we review the standard of care for upper limb poststroke rehabilitation, the evidence supporting the treatment modalities that currently exist and the exciting new developments in the therapeutic pipeline.

Stroke is a major health problem worldwide: Stroke occurs every 40 seconds.1 Rehabilitation can help individuals recover function after a stroke, but to date, intervention strategies have not been 100% effective. Although researchers and clinicians have made significant progress in the field of rehabilitation, recovery from upper limb hemiparesis has remained a therapeutic challenge. For example, 65% to 85% of individuals poststroke will regain walking ability,2,3 whereas only 5% of individuals will achieve full functional use of the arm.4 Nevertheless, recent evidence-based rehabilitation research and emerging technologies may lay the foundation toward improved restoration of upper limb function for stroke survivors.

Background The Problem At 6 months poststroke, 65% of stroke survivors are unable to incorporate the impaired upper extremity (UE) into daily activities.5 Upper limb sequelae and recovery of function poststroke are complex and multifactorial. Physical impairments of the affected UE range from extremity paresis/ paralysis, sensory loss, muscle activation abnormalities, abnormal tone, loss of dexterity, neglect, force dysregulation,

Issue Theme Neurologic Rehabilitation; Guest Editors, Karunesh Ganguly, MD, PhD, and Gary M. Abrams, MD, FAAN

edema, and shoulder subluxation to complex pain syndromes (e.g., joint, muscle and/or tendon pain, central pain, or complex regional pain). These impairments interact with other behavioral and environmental factors to enrich or inhibit maximum recovery of UE function. Once the patient is medically stable poststroke, independent ambulation is usually the primary concern of the patient and the family. To maximize the opportunity for patients to be discharged home posthospitalization, the rehabilitation team must concentrate on early mobility, safe transfers, and independent walking and self-care (especially toileting and dressing). During early, intensive mobility training, specific taskoriented training with the hemiparetic UE may not be prioritized,6,7 even though there is evidence for improved restoration of UE function by therapeutic intervention at all stages of recovery.8,9 Furthermore, from a practical point of view, selfcare activities often demand the patient to use the unaffected arm (e.g., using a cane, buttoning, brushing teeth, combing hair). If the hemiparetic arm is slow to recover and remains hypotonic, a sling may need to be applied to provide proximal stabilization and prevent shoulder subluxation and pain. Unfortunately, the sling can make it even harder for the patient to functionally use the arm. As time progresses,

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1396002. ISSN 0271-8235.

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hypertonicity develops, pulling the elbow, wrist, and fingers into a position of flexion. This flexed position compromises coordinated, voluntary prehensile movements as well as efficiency and effectiveness of muscle contractions. In frustration, the patient begins to use the unaffected UE even more to perform daily activities. Without requisite use of the hemiparetic arm (e.g., forced use), there is minimal demand for the brain to develop neuronal connections around the injury. Over time, all of these factors contribute to atrophy, “nonuse,” or repetitive maladaptive patterns of movement. Central neuropathic pain after a stroke, including tactile and thermal hyperesthesia or paresthesias, can impair motor function and hinder rehabilitation efforts.10 Sensory neglect is another important factor linked to reduced motor recovery, higher disability, and poor responses to rehabilitation. Compared with individuals without sensory neglect, stroke patients with sensory neglect not only have significantly more severe motor impairments at stroke onset, but also show a lesser degree of spontaneous recovery in early stages followed by diminished motor recovery in the later stages.11 Another factor potentially contributing to the low level of poststroke recovery of the upper limb may be related to the topography of the sensory and motor representations of the upper limb compared with the lower limb. The cortical areas of representation of the arm/hand are twice as large as the topographical representation of the leg/foot. Thus, to achieve functional use of the hand/arm, recovery of perilesional neuronal connections may need to be more extensive than is necessary for recovery of function (i.e., walking) of the lower limb. Environmental factors also interact with the recovery of function of the UE poststroke. For example, organized, comprehensive, acute, subacute, and chronic stroke rehabilitation programs are not universally available and accessible across all areas of the country. Coordinated outpatient rehabilitation services can become fragmented across different institutions even in the same community.12 Because many practitioners who care for stroke patients are not aware of the newest research evidence on stroke recovery, there is variability in the interpretation and application of the science of neural adaptation to clinical intervention strategies. There can also be significant limitations in insurance coverage for rehabilitation, particularly for patients in the subacute and chronic phases of recovery.

Stroke Sequelae and Course of Recovery Stroke causes UE impairments by ischemic damage to one or more cortical or subcortical regions of neuronal networks involved in arm and hand function. Improvements in function after a stroke can be understood in terms of restitution and substitution. When return of body functions or reduction in an impairment result in the ability to perform a function in a previously performed manner, it is considered restitution (repair or true neurological recovery) of motor function. Substitution (or compensation) takes place when different body segments or movement patterns are used to accomplish the same task.13 Within the first 10 weeks, almost all patients show a certain degree of spontaneous neurologic recovery or Seminars in Neurology

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restitution. This recovery follows a logarithmic pattern. More severely affected individuals tend to experience a slower rate of recovery compared with those with more mild impairments.14 Different mechanisms are believed to be involved in generating the nonlinear pattern of neurologic recovery after stroke. The mechanisms involved in restitution include salvation of tissue within and surrounding the infarcted area in the first days to weeks, resolution of diaschisis, and adaptive neuroplasticity (e.g., neurogenesis, new synaptic connections, recruitment of remaining healthy neurons). Using diffusion tensor imaging (DTI), it has been suggested that motor skill learning ability is associated with white matter microstructural status in patients poststroke.15 Additional improvement of motor function involves specific learningbased training or integration of compensatory strategies.13,16 Clearly, individuals affected by stroke retain motor learning capability17,18

Prognosis Understanding prognosis of arm paresis after a stroke, including its predictive factors, is important. It allows clinicians to customize and optimize treatment goals, as well as to properly inform and guide patients and caregivers. Half of stroke survivors remain chronically affected by hemiparesis. Between 30% to 66% of these individuals have primarily UE dysfunction. In general, the prognosis for UE recovery is poor. For example, among survivors of a first middle cerebral artery (MCA) stroke, 11.6% had complete functional recovery of the UE, 38% had some return of dexterity, and 62% failed to achieve any dexterity when measured at 6 months poststroke.4 Although individual recovery patterns and outcomes differ by lesion location, stroke severity and prestroke health status, prognostic studies report that UE function at 4 weeks and again at 3 months are both highly predictive of function at 6 months.4,13 For example, to reach maximal functional recovery poststroke, 95% of individuals with severe upper limb paresis were observed to require 11 weeks of acute and subacute rehabilitation compared with 6 weeks of rehabilitation for individuals with mild paresis.14 Most recovery of distal (reach–grasp) movements along with general motor recovery occurred within the first 13 weeks after a stroke.19 Additional spontaneous recovery is less likely after these periods,14 although functional gains may continue with intense task-oriented retraining, patient motivation, and adherence to specific, progressive behavioral protocols.9,20 The best predictive factors of UE outcomes after stroke (►Table 1) include the presence of motor-evoked potentials, lesion location as delineated by neuroimaging, and initial sensory and motor capabilities as measured by deep sensation, muscle tone, active range of motion, muscle strength, and performance-based measures.21 Subcortical areas of motor pathway involvement, such as the corona radiata and internal capsule, have a less-favorable prognosis than lesions confined to the cortex.22 Index and middle finger active extension against gravity at 3 weeks was strongly predictive of recovery of grasp at 13 weeks.19 Expectation

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Table 1 Best-evidence positive predictive factors for upper limb poststroke recovery Common assessments Presence of MEP

MEP, MEP amplitude, MEP latency measured (on average) day 1 to day 7 poststroke

Initial sensorimotor capability

FMA, tone, shoulder shrug, arm strength, hand dexterity, coordination, apraxia, neglect, deep sensation, index/middle finger active extension, measured (on average) between 1–45 days poststroke

Cortically confined lesion location

MRI Brain, CT Head performed (on average) 11 days or less poststroke

for a successful upper extremity rehabilitation outcome was not found to be significantly predictive of either the number of repetitions achieved during functional task training or actual functional recovery.23 Some evidence indicates that homotopic resting-state functional connectivity in chronic stroke may be associated with upper extremity control and real world use, but this needs to be further studied as a potential biomarker of motor recovery.24 Unfortunately, individuals with severe initial UE impairments who do not recover are difficult to distinguish from those with the same impairments who have notable recovery. More accurate prognostic methods, such as the recently described predicting recovery potential (PREP) algorithm, are needed to assess the extent of the impairment and the potential for recovery. This information is essential to assist in setting realistic goals, guiding the selection of customized evidence-based therapies, and allocating rehabilitation resources to optimize an individual’s potential for recovery.25

Clinical Case A 54-year-old right-handed man developed sudden slurred speech and left hemibody weakness. He was treated with intravenous (IV) tPA, with immediate improvement in his left leg. He was found to have an extensive right MCA acute infarction. On physical examination, he was initially drowsy, but responded appropriately. His speech and comprehension were intact. He had left hemifacial weakness and dysarthria. The weakness of the upper extremity (UE) was greater than the lower extremity (LE). He had mild left hemisensory loss, hemineglect self-correctable with cues, and intact coordination, but was unable to stand unsupported. It was noted that his previous functional level was full independence at home and in the community. The patient was evaluated by the occupational (OT), physical (PT), and speech therapy (SLP) teams, and was determined to be an excellent candidate for intense rehabilitation. Prior to his transfer to an acute inpatient rehabilitation facility, he received several sessions of OT and was able to achieve functional transfers with minimal assistance. The family was trained in passive and active range-of-motion (ROM) techniques for all joints of the left UE and LE. A left shoulder harness was placed to prevent glenohumeral subluxation. After completing 6 weeks of acute rehabilitation, he was discharged home and received community rehabilitation

services. During his initial outpatient OT reassessment, 2 months after his stroke, he had not regained functional use of his left UE. With weakness of finger and wrist extension but voluntary finger flexion, he was a good candidate for an adjustable wrist/hand dynamic extension splint. He was trained to use it as a part of a home exercise program (HEP). One short-term goal (i.e., achieve within 4 weeks) was to use his left hand to bring a cup to his mouth. A long-term goal was to use his left hand for self-feeding. He practiced grasp and release activities and was able to fully extend his fingers at the distal finger joints while wearing the splint. With further practice, he was able to grasp and release a cup and simulate drinking, pick up a ball from the floor and place it on a desk, and hold a handled spoon to simulate eating. He also made progress in his fine motor control and was able to grasp and release small pegs to complete a pegboard activity without wearing the splint. Most importantly, the patient reported increased functional use of the left UE at home, demonstrating functional tasks such as folding a towel using both upper limbs. Outpatient PT instructed him on resistive exercises for shoulder extension and abduction, finger extension, as well as stretches for his left hand. The short-term goal was to adhere to a strengthening and stretching HEP. Long-term goals included increasing active ROM of left finger extension, increasing strength of the left UE and improving integration of the UE in all activities. After 2 weeks, he reported good adherence to the HEP and had recovered the ability to perform arm pushups. Although his strength was improving, his movements continued to be limited by poor ROM. Manual therapy was initiated to decrease soft tissue restrictions and improve joint mobility. He was instructed on self soft tissue mobilization techniques (STM), along with a stretching regimen, stressing the importance of balancing stretching and STM with strengthening in order to improve range and function. This case illustrates the continuum of care for an individual with upper limb dysfunction after a stroke, from acute hospitalization to self–care strategies and community reintegration.

Current Methods of Management Consensus of Goals and the Development of a Treatment Plan Goal setting serves as the foundation for the treatment plan. Goals should be realistic, task-specific, and include a defined period to be accomplished. The goals and the treatment plan Seminars in Neurology

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Abbreviations: CT, computed tomography; FMA, Fugl-Meyer Assessment; MEP, motor evoked potential; MRI, magnetic resonance imaging,

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will depend on identified impairments, prognosis for functional recovery, available resources, and the development of realistic and functionally meaningful outcomes. Standardized measurement tools used to assess UE function can determine limitations at the body system/structure, activity, and participation levels, to help define and prioritize goals in the treatment plan. Examples of body system/structure-level measurements to quantify UE function after a stroke include assessment of strength, synergies, tone, sensation, cognition, and depression. Dynamometry and kinematic analysis can add further objectivity. The Fugl-Meyer Assessment of Sensorimotor Function after Stroke (FMA) is frequently used to document levels of synergistic and voluntary patterns of movement. Common activity-level tests include the Functional Independence Measure (FIM), Wolf Motor Function Test, and Jebsen Hand Function Test. Participation-level tests include the Stroke Impact Scale, Motor Activity Log, CAFÉ 40, and wearable accelerometers. Based on prognosis for some return of dexterity, goals can encompass task-oriented skill acquisition, capacity building, and motivational enhancement for the paretic arm.26 These techniques are considered appropriate for mild to moderately impaired stroke survivors. However, when spontaneous recovery is slow or poor, treatment may need to begin with mental practice, and visual and motor imagery. As voluntary function returns, treatment should shift to intense, behavioral task-oriented training, forced use paradigms matched to patient interests, and integration of assistive or robotic devices. At this point, a motivated individual with a supportive family is critical. The goals and treatment plan must be dynamic and appropriate to the individual’s current phase of recovery, changing physiological status and functional ability. Four poststroke treatment phases can be distinguished to help guide setting goals and appropriate rehabilitation (►Table 2).9

Hyperacute–Acute Phase (0–24 Hours) Within hours of a perfusion deficit, there may be loss of function that reverses or continues to evolve until an ischemic lesion is completed. At this stage, medical complications are stabilized, and reperfusion treatment may be administered to eligible patients within a narrow time window after careful decision making in the emergency room. Although improvements in general outcome measures have been demonstrated, a knowledge gap exists regarding the influence of acute reperfusion therapy on specific outcome domains such as upper limb motor recovery.26,27 From the current literature, the effects of early mobilization or initiation of physical exercise within 24 hours of the signs and symptoms of stroke,

although well-tolerated, remain unclear. Three randomized controlled trials found no significant difference in clinical outcome or complications whether individuals received early mobilization within 24 hours or 24 to 48 hours.28 Physical immobilization, quieting the nervous system, providing emotional support, calming the patient and the family, and delivering appropriate medications are the best strategies in this phase.

Early Rehabilitation Phase (24 Hours–3 Months) Weakness and flaccidity will initially predominate in this next stage. To prevent complications of immobilization and muscle flaccidity, slings help prevent shoulder subluxation and the consequent development of impingement and pain syndromes. Dependent edema may also develop. This can be managed with elevation, massage, and supportive garments. Screening for potential fractures secondary to the trauma experienced during the stroke should also take place. Deep venous thrombosis must be prevented. Evidence suggests initiating physical rehabilitation during the early rehabilitation phase, within 3 days rather than 7 days, may provide better functional outcomes and fewer complications. Unfortunately, at this time, it is not uncommon for patients to be tired, confused, and potentially unable to focus their attention to maximize their rehabilitation potential. Nevertheless, current best practice guidelines unanimously recommend stroke unit care for people poststroke, with early rehabilitation being the defining component.28 During early physical rehabilitation, spontaneous neurologic recovery ideally is facilitated. Maladaptive neuroplasticity and behaviors that potentially limit recovery of motor control are discouraged. Successful evidence-based therapies try to minimize “learned nonuse.” These therapies include task-oriented training, forced use of the impaired limb (Constraint Induced Movement Therapy), error-based feedback, movement science-based treatment (MSB), impairment oriented training (IOT), progressive task-specific repetitions spaced over time, learning-based activities using gaming principles, robotic-assisted movements, mental practice and imagery, virtual reality training, functional electrical stimulation, and skill acquisition training paired with impairment mitigation and motivational enhancement. A recent large randomized clinical trial (FLAME) suggests that administration of fluoxetine 20 mg within 5 to 10 days of an ischemic hemiparesis coupled with rehabilitation therapy improves arm motor outcomes, as well as global functional outcome.29 This benefit was demonstrated in patients without depression, although selective serotonin reuptake inhibitors (SSRIs) is additionally effective for treating poststroke depression when given in the early rehabilitation stage.30

Table 2 Four treatment phases

Late Rehabilitation Phase (3–6 Months) 0–24 h

Hyperacute–acute phase

24 h–3 mo

Early rehabilitation phase

3–6 mo

Late rehabilitation phase

 6 mo

Chronic rehabilitation phase

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At this point, most individuals will have returned to family, community participation, potentially outpatient rehabilitation, school, or work. Spontaneous healing and recovery are reaching a plateau and the potential long-term deficits that need to be addressed become clearer. In general, the

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(task-oriented; skill acquisition practice, such as reaching for different types of objects); (2) impairment training (e.g., correcting a problem in a specific body system, such as muscle strengthening; or sensory retraining); (3) augmented feedback training (use of variable, externally imposed controls or assistance, e.g., tactile, auditory, visual, kinesthetic) during the performance of a motor task)31; and (4) engagement of cognitive and psychological factors to enrich task-oriented training.

Evidence-Based Compensatory or Restorative Treatments Historically, patients with central nervous system (CNS) damage were re-educated using both compensatory and orthopedic approaches.16 In the mid- to late 20th century, knowledge regarding physiological mechanisms of recovery and neuroplasticity accumulated.20,31 Prominent master clinicians developed intervention strategies based on the contemporary understanding of neurologic recovery followed by formal testing of the efficacy of different clinical paradigms. A robust, evidence-based variety of upper limb interventions emerged, encompassing elements of task-oriented and task-specific training,34,35 learning principles (e.g., attention, motivation and compliance), high intensity repetition,36 with progressive practice,37 and patient/family engagement throughout the recovery process.9,20,38,39 A discussion of these treatment techniques (►Table 3) are presented below.

Chronic Phase (6 Months or Greater) As the final brain damage has been established, subsequent improvements are likely to be slower and involve a ’’relearning’’ of previous functions more than actual recovery. This process may unmask and strengthen existing neural pathways, shift connectivity and weighting across the involved neural networks, change the functionality of neural structures, and create new structural changes with dendritic arborization and sprouting.22 In this chronic phase, persistent functional losses in the realm of activities of daily living (ADLs) and community participation can be compensated with equipment and assistance from others. Continued risks of complications include deep venous thrombosis, contractures, hand–shoulder syndrome, and advanced stages of edema. Early treatment of spasticity using conservative measures and oral pharmaceuticals is key to preventing its disabling complications in the later phases of recovery.32 Chemodenervation with botulinum toxin, and phenol or ethyl alcohol can be considered for focal upper limb spasticity. Although evidence is not as well established, intrathecal baclofen for spasticity and tendon surgery for muscle/tendon shortening can be considered.33 Rehabilitation services may become less available as government and third-party payers limit the investment in resources for rehabilitation during the chronic stage of recovery.

Classifying Treatment Approaches Four main modes of therapy have been developed to address different ability levels: (1) functional training

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Neurodevelopmental Treatment One approach that developed as a result of advances in neuroscience and understanding of motor control—neurodevelopmental treatment (NDT)—was proposed by the Bobaths in England. In the Western world, NDT is one of the most common methods of treatment for neurologically impaired patients. Neurodevelopmental treatment includes a problem-solving approach to assessment and treatment of individuals with disturbances of function, movement, and postural control due to a lesion of the CNS. The aim of NDT is to identify, analyze, and treat movement dysfunction,

Table 3 Current evidence-based compensatory and restorative treatments for the upper limb poststroke Neurodevelopmental treatment (NDT) Constraint-induced movement therapy (CIMT) Impairment-oriented training (IOT) Movement science-based treatment Robotic rehabilitation Functional electrical stimulation Virtual reality Mirror therapy Mental practice with motor imagery

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magnitude of the improvement achieved to this point is predictive of functional outcomes. If progress is evident, it is important to continue to treat the primary upper limb impairments and strongly encourage the patient to use the arm. Assistive equipment may be needed to adapt to the patient’s changing condition. When there is delayed recovery and poor prognosis, to achieve independence, teaching the patient to manage existing deficits and employ compensatory strategies with the less-affected limb may be prudent.4 The focus on the affected limb may need to turn toward maintaining passive and active assistive motion and reducing tone to prevent pain, subluxations, soft tissue contractures, and hygiene problems. These activities paired with mental imagery and integration of the limb into limited functional activities can help minimize secondary impairments and maintain the foundation for potential future recovery. Impairments such as increased weakness, atrophy, short muscle and soft tissue length, capsular tightness, thrombophlebitis, traumatic fractures, pain (e.g., chronic reflex pain syndromes [CRPS] and other pain disorders), edema, orthopedic malalignment, joint subluxation, bone demineralization with immobility, and undesirable compensatory patterns of movement should be minimized.31 Over time, with little return of function and increasing muscle tone, negative expectations for improvement in the upper limb and depression can significantly interfere with recovery and should be addressed.

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structural impairments, independence in everyday life, and community participation.16 There is some evidence that interventions based on NDT can reduce shoulder pain as well as improve muscle tone. In some studies, NDT was equivalent to other approaches in improving muscle strength and motor control.40 Seventeen randomized controlled studies looked at upper limb sensorimotor rehabilitation after stroke. This review concluded alternative approaches were either as or more effective than NDT.16 Augmenting NDT or combining NDT with other therapies may have additive efficacy.9 Limited efficacy of NDT relative to upper limb motor recovery may be due to inadequate dosing parameters32,41,42 or inherent difficulty designing controlled studies due to the individualized, case-based, principle-guided, and provider-dependent variations in delivering NDT.16

Movement Science-Based Treatment Before the emergence of movement science-based treatment (MSB), spasticity was considered the major barrier to recovery following a stroke involving the pyramidal tract. Movement science-based treatment expanded the understanding of spasticity by taking into account the individual’s inability to activate muscles, fractionate movements, sustain contractions, and control force outputs. Besides biomechanics, MSB also emphasizes cognitive psychology of motor learning, and understanding of the neural and muscular physiological adaptive changes taking place as a result of variation in amount and type of motor activity.45 During the acute stage of stroke, MSB was associated with fewer days of hospitalization and greater improvement in motor function compared with NDT.46 A separate study suggested MSB may facilitate a more rapid recovery, but may not be superior to NDT in improving long-term motor outcomes.47

Constraint-Induced Movement Therapy Constraint-induced movement therapy (CIMT) is an approach that encourages the use of the paretic upper extremity in daily life by implementing “forced use” strategies, such as placing a mitt or a cast on the unaffected side to make it ineffective.9 Combined with repetitive training of the paretic UE on task-oriented activities, the approach of CIMT was designed to counter “learned nonuse.”43 This approach is usually demanding and intense. Different versions of CIMT have been developed. The original CIMT required a 2- to 3-week period of immobilization of the nonparetic arm for 90% of the waking hours, high repetition of selected task-oriented training for 6 or more hours a day, and behavioral strategies to improve adherence and transference of learned movements to home use.42,43 Derivatives of CIMT have been developed to improve the practicality of implementing CIMT, by incorporating shorter periods of training over a longer intervention period. There is class 1 evidence supporting the efficacy of the original form of CIMT for improving arm–hand activities, the amount of (self-reported) arm-hand use, and the integration of arm–hand movements in everyday life.9,43 All versions of CIMT significantly improve motor ability and functional use of the affected limb compared with no active therapy or with conventional or dose-matched physical rehabilitation.43

Impairment-Oriented Training Impairment-oriented training (IOT) focuses on the specific deficient body functions that limit activities and lead to restrictions of participation. The initial step in IOT is characterization of the nature of the various body dysfunctions and their consequences on functional activities. The second step is to develop training techniques that specifically address these body dysfunctions. Standardized “Arm BASIS” and “Arm Ability” upper extremity training programs were devised for severe and mild arm paresis, respectively. Compared with dose-matched conventional therapy, a preliminary study demonstrated better motor recovery after IOT. However, sustained effects were only documented for patients with mild arm paresis.44 Seminars in Neurology

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Robotic Rehabilitation Robotic technology can be classified as “service,” “assistive,” or “therapeutic.” Service-based devices are compensatory for patients who cannot provide sufficient voluntary movement to perform a task. Therapeutic devices provide task-specific training, whereas assistive devices provide variable amounts and types of assistance to help the patient complete a task. Rehabilitation robotic devices may also be described as endeffector type or exoskeleton type. End-effector-type devices apply mechanical forces to the distal segments of limbs, whereas exoskeleton-type devices are worn by the patient to provide unweighting or direct control of proximal and distal joints to enable functional movement.48 ►Figs. 1 and 2 illustrate different types of robotic devices for motor rehabilitation. Robotic rehabilitation has many advantages. It enables high-dosage, high-intensity repetitive training.49 Robotic devices can measure and analyze movement kinematics, remove the need for a therapist’s one-on-one attention, provide feedback, be programmed to provide fixed or variable amounts of assistance, correct abnormal synergies of movement and can be used at home. In addition, wireless technology allows some of these devices to gather information and give feedback to caregivers through telerehabilitation. There is evidence robot-assisted therapy of the UE alone, or in combination with usual rehabilitation, is at least as effective as usual rehabilitation alone.48,49 One randomized controlled study found that robot-assisted therapy delivered over 12 weeks for long-term moderate-to-severe UE impairment improved outcome assessed at 36 weeks over usual care, but not dose-matched intensive therapy.50 Studies of robots targeting shoulder and elbow motor function report improvement in range of motion, muscle strength, tone and pain in the paretic limb, but no improvement in distal function.9,51 Evidence for elbow and wrist robot-assisted therapy is more limited. However, one trial reported significant improvement in motor function, strength, ADL performance, and bimanual ability in a high-intensity robot training group.51 At this time, there is no difference in effectiveness

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Fig. 1 The MIT-MANUS robotic system (Interactive Motion Technologies, Watertown, MA) is an example of a set of robotic devices designed to unweight and assist movement using four modules: (A) the planar robot, a shoulder–elbow unit for horizontal movements; (B) the linear shoulder robot, an antigravity unit for vertical movements; (C) the wrist robot, a wrist unit for flexion–extension, abduction–adduction, and pronation– supination movements; and (D) a grasp-hand unit to facilitate closing and opening movements. (Adapted from Lo et al, 2010).

between bilateral (unaffected limb assists affected limb) versus unilateral robotic training of the paretic limb.49,52

Functional Electrical Stimulation Functional electrical stimulation (FES) refers to the use of neuromuscular electrical stimulation (NMES) to activate paralyzed muscles to directly assist in accomplishing functional tasks.53 Neuromuscular electrical stimulation stimulates intact lower motor neurons to activate muscles paralyzed or weakened as a consequence of a CNS lesion. Devices that apply NMES to the wrist and finger flexors and extensors have been shown to enhance motor recovery and

strength of the paretic arm, but not specific arm–hand activities. Neuromuscular electrical stimulation of the shoulder muscles showed a significant positive effect on shoulder subluxation, but it did not improve motor function of the paretic arm, range of motion, or pain. Neuromuscular electrical stimulation of specific muscle groups, such as the extensor muscles of the forearm, can be triggered by volitionally generated electromyographic signals obtained via surface electrodes that exceed a preset threshold. Electromyogramtriggered NMES for wrist and finger extension training has a significant positive effect on range of motion, motor function, and arm–hand activities of the paretic limb, but does not improve muscle strength or muscle tone.9

Virtual Reality Training of the arm and hand in a virtual environment using computer technology allows individuals to practice motor tasks in an engaging format and receive performance feedback. Evidence shows a significant positive effect on basic ADLs, but not on motor function of the paretic arm or arm– hand activities.9 According to one acute inpatient randomized control trial with ambulatory patients, virtual-reality exercises were associated with improved mobility. Future studies are needed in later poststroke stages, with nonambulatory patients, and those with primary impairments of the UE.54 Fig. 2 This wearable robotic orthosis (UL-EX07) is an example of an upper extremity exoskeleton-type robot that can be used unilaterally or bilaterally to assist movement in 7 degrees of freedom corresponding to human arm movement including shoulder abduction– adduction, flexion–extension, internal–external rotation; elbow flexion/extension; and wrist pronation/supination, flexion/extension, radial and ulnar deviation. (Adapted from Byl et al, 2013).

Mirror Therapy Originally designed to treat phantom limb pain, mirror therapy has been adapted to improve motor function in UE hemiparesis. A mirror reflecting the unaffected limb creates an illusion that the patient is observing normal movements of the weak arm/hand.9 Although the underlying mechanism is Seminars in Neurology

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unknown, the prevailing theory asserts that observing mirrored movements provides positive reinforcement and a positive image of successful movements to facilitate neural activity and cortical reorganization in motor areas in the injured hemisphere.55 Pooled evidence on mirror therapy in the late rehabilitation phase showed a nonsignificant effect on motor function of the paretic arm, muscle tone and pain, but a significant positive effect on arm–hand activities.9

Table 4 New developments for upper limb poststroke rehabilitation Accelerated Skill Acquisition Program (ASAP) Repetitive transcranial magnetic stimulation (rTMS) Transcranial direct current stimulation (tDCS) Deafferentation/de-efferentation of the affected limb Transcutaneous electrical nerve stimulation

Mental Practice with Motor Imagery

Regenerative medicine

Mental practice of motor tasks is used in UE rehabilitation training for the purpose of improving motor performance. If a patient has no active, voluntary function, mental practice with motor imagery (MI) must be considered a reasonable treatment option. In general, mental imagery of task performance can recruit approximately 25% of the neurons that would be activated if the task was physically performed.56 Research reveals similar functional neural connections during real and imagery conditions, suggesting common neural substrates are shared by both conditions.57 Although neural activation in the premotor cortex is usually studied during motor execution or direct stimulation, MI produces a better neural activation pattern than action observation. Finally, if passive movement is added, the neural activation pattern is even a little better.58 Older individuals as well as young subjects can do motor imagery. Interestingly, younger subjects are more likely to activate the posterior central gyrus and the supplementary cortex than older subjects. However, when older subjects do MI with the dominant hand, the putamen and lingual areas are more strongly activated than younger individuals.59 Poststroke, patients are still able to achieve neural activation with mental imagery; however, the amplitude of neuronal firing is generally smaller compared with healthy controls. In addition, there may also be some differences in lateralization characteristics after a stroke.60 An analysis of mental practice and motor imagery studies involving UE training of patients poststroke concluded, when combined with physical practice, mental practice with motor imagery has a significant positive effect on arm–hand activities, but nonsignificant effects for motor function, muscle strength, or basic ADLs.9

Acupuncture or electroacupuncture Brain–machine interface (BMI) technology

involved in reaching, grasping, and releasing objects, the potential to improve function is enhanced. There is currently a large randomized study of ASAP underway in the United States funded by the National Institutes of Health (Interdisciplinary Comprehensive Arm Rehabilitation Evaluation [ICARE]). A review of the evidence supporting this approach and a description of the intervention has been published.39 A small case series reported no adverse events and significant gains in movement time, deceleration time, reach velocity, as well as increased time with maximum aperture opening of the hand. This treatment approach appears promising.26

Repetitive Transcranial Magnetic Stimulation

►Table 4 lists new developments in upper limb poststroke rehabilitation. They are detailed in the following sections.

Repetitive transcranial magnetic stimulation (rTMS) is a painless, noninvasive technique that consists of a stimulator connected to a figure-eight magnetic coil that is positioned directly on the scalp to excite or inhibit neuronal firing in an underlying region of the brain. Increasing or decreasing cortical excitability of select regions of the brain may facilitate neuroplasticity associated with motor function recovery after a stroke.64 There is evidence that high-frequency rTMS of the lesioned hemisphere may improve the recovery of upper limb motor function. Conversely, low-frequency rTMS decreases cortical excitability in the unlesioned hemisphere to indirectly facilitate an increase in cortical excitability of the affected hemisphere.64,65 To confirm these preliminary findings, a multisite randomized clinical trial is being planned in the United States for patients in the subacute-phase poststroke. Repetitive transcranial magnetic stimulation has the potential to induce adverse effects such as headaches and seizures. Although rTMS is generally thought to be safe in patients with stroke, specific safety guidelines need to be followed.64

Accelerated Skill-Acquisition Program

Transcranial Direct Current Stimulation

Accelerated Skill-Acquisition Program (ASAP) integrates the essential principles of task-oriented, task-specific training20,38,61 and impairment mitigation during early outpatient recovery, with motivational enhancement.20,62,63 The program is designed for patients with mild to moderate impairments, 1 to 3 months poststroke. Each person performs selfselected reach-to-grasp coordination tasks, with a minimum intensity of 30 hours.39 With a focus on the complex skills

A transcranial direct current stimulation (tDCS) device consists of anodal and cathodal electrodes connected to a low intensity direct current stimulator. Transcranial direct current stimulation can be noninvasively and painlessly applied to modulate cortical excitability. Unlike TMS, tDCS does not directly cause neuronal firing. Anodal stimulation depolarizes the neuronal membranes and may lead to increased cortical excitability. Cathodal stimulation hyperpolarizes the

Interesting New Developments in the Therapeutic Pipeline

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Deafferentation/De-efferentation of the Affected Limb Sensory and motor maps may reorganize after partial deafferentation–de-efferentation of the upper limb by selective regional anesthesia of the upper nerve roots of the brachial plexus. When coupled with distal motor retraining, this technique may facilitate increase of distal upper limb representation of the hemiparetic hand. The clinical significance of this concept remains to be tested.8

Transcutaneous Electrical Nerve Stimulation Commonly used for the treatment of acute and chronic pain, transcutaneous electrical nerve stimulation (TENS) may also influence stroke recovery. Transcutaneous electrical nerve stimulation of the median, ulnar, and radial nerves using surface electrodes for 2 hours has been associated with short-term improved paretic hand function in stroke patients.8 Somatosensory electrical stimulation over hypersensitive muscles may also potentially reduce tone.67 More research is needed to confirm the effect of TENS alone or with usual care.

Acupuncture An ancient system using penetrating needles to stimulate points throughout the head and body, acupuncture has been used to treat poststroke hemiparesis. The impact of acupuncture on upper limb motor recovery is inconclusive. However, there is limited evidence that electroacupuncture may improve upper limb function in early stroke rehabilitation.8 More research is necessary to confirm the unique benefits of acupuncture with or without electrical stimulation.

cell-related events, deaths, or stroke recurrence have been reported after a 1-year follow-up study.70

Brain–Machine Interface Technology Another emerging technology is brain–machine interface (BMI) technology. Brain–machine interface technology permits the recording of neural signals from intact brain tissue and decodes the neural activity into outputs that can then be used to control an external device.71 Sensory feedback is incorporated to assist the user in generating and adjusting brain signals to optimize translation of desired performance.72 Preliminary and pilot studies in the stroke population have yielded limited, but promising evidence. Using BMI systems, individuals with paralysis caused by stroke have been able to control FES devices and upper limb robots. More research and development is required to address the current limitations of BCI technology and to better understand how to apply this technology to the stroke population.

Summary and Conclusions Stroke rehabilitation has become more evidence based. New approaches to retraining the UE poststroke may improve the effectiveness of functional outcomes. Comprehensive training of the upper limb based on the principles of recovery and neuroplasticity should be introduced early and continuously in the first 6 months poststroke. Although recovery is related to stroke severity, location, and general prestroke health status, functional restoration can be enhanced with early, specific, dynamic, task-oriented, and engaging activities relevant to patient ability. These activities should be spaced over time, adequately intensive, and progressively repetitious with elements of surprise and error feedback. Patients who expect to get better and invest time in sensory, perceptual motor ,and motor retraining have the greatest potential for recovery. After 6 months, recovery of function may slow, but can continue with regular engagement in learning-based activities and task-specific training by motivated patients. Regenerative medicine and innovative robotic and brain-interface technologies are on the horizon to modulate neuronal activity around injured areas, as well as enhance the effectiveness of UE rehabilitation interventions.

Regenerative Medicine Regenerative medicine is a new branch of medicine fusing neuroscience, tissue engineering, and molecular biology. It encompasses the study of therapeutic strategies for neural regeneration, repair, and replacement of damaged components of the nervous system. Its various neurorestorative approaches include transplantation of tissue and cells, biomaterials, and bioengineering.68 Currently, no definitive treatment exists to repair lost brain function. However, cell-based therapy is one promising approach perceived as a regenerative strategy for patients with fixed neurologic deficits after stroke.69 It may be too early to know whether this intervention can improve functional outcomes.70 Safety concerns include microembolism, risk of prion transmission, and stimulation of immunogenicity.69 To date, no adverse

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