Stroke Rehabilitation: Strategies to Enhance Motor Recovery

ANRV367-ME60-05 ARI 4 December 2008 13:56

Michael W. O’Dell, Chi-Chang David Lin, and Victoria Harrison

Department of Rehabilitation Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York 10021; email: [email protected]

Annu. Rev. Med. 2009. 60:55–68 Key Words The Annual Review of Medicine is online at technology, disability med.annualreviews.org

This article’s doi: Abstract 10.1146/annurev.med.60.042707.104248 Recent evidence indicates that the brain can remodel after stroke, pri- Copyright c 2009 by Annual Reviews. marily through synaptogenesis. Task-speciﬁcand repetitive exercise ap- All rights reserved pear to be key factors in promoting synaptogenesis and are central el- 0066-4219/09/0218-0055$20.00 ements in rehabilitation of motor weakness following stroke. Expert by Boston University on 10/28/10. For personal use only. medical management ensures a patient is well enough to participate in rehabilitation with minimal distractions due to pain or depression.

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org Contraint-induced motor therapy and body-weight-supported ambulation are forms of exercise that “force use” of an impaired upper extremity. Technologies now in common use include robotics, functional electrical stimulation, and, to a lesser degree, transcranial magnetic stimulation and virtual reality. The data on pharmacological interventions are mixed but encouraging; it is hoped such treatments will directly stimulate brain tissue to recovery. Mitigation of factors preventing movement, such as spasticity, might also play a role. Research evaluating these motor recovery strategies ﬁnds them generally good at the movement level but somewhat less robust when looking at functional performance. It remains unclear whether inconsistent evidence for functional improvement is a matter of poor treatment efﬁcacy or insensitive outcome measures.

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INTRODUCTION tive devices and bracing, environmental mod- ification at home and work, and prevention of Stroke is defined as a sudden, focal neurologi- further disability (3). Motor recovery: cal deficit due to a cerebrovascular abnormality It is essential to distinguish motor recov- improvement in the and is the third leading cause of death in the ery from functional recovery following stroke. strength, speed, or United States, behind heart disease and cancer. accuracy of arm and Motor recovery refers to improvements in the There are about 600,000 new and 180,000 re- leg movements strength, speed, or accuracy of arm and leg current strokes each year in the United States; (“getting better”) movements. These improvements occur as a 1.1 million adults reported some degree of func- Functional recovery: result of both natural recovery and rehabilita- tional limitation due to stroke in 1999 (1). improvement in tion interventions. Functional recovery refers performance, e.g., self About 50%–70% of persons with stroke even- to improvement in performance, such as self care or walking tually regain independence, but 15%–30% are care or walking. Although complex, functional (“doing better”) left with a permanent disability. At six months recovery is determined by the type, severity, and poststroke, 30% of survivors require assistance resolution of motor deficits, the ability of the for walking and one quarter need help to per- patient to learn and implement new strategies form activities of daily living (ADL) (1). Given including compensation with the intact extrem- the risk of age for stroke and the rapidly aging ities, and the characteristics of rehabilitation population of the United States, successful re- therapy provided (its type, timing, quantity, fre- habilitation will have enormous public health quency, etc.) (2). One can think of motor recov- implications over the next few decades. ery as “getting better” and functional recovery The specific deficits seen after stroke de- as “doing better.” There is considerable debate pend on the area of the brain affected. Apha- over how much rehabilitation should empha- sia, dysarthria, dysphagia, neglect, pain, cog- size compensation versus recovery (2, 4, 5). nitive deficits, sensory loss, and depression are common and can be extremely limiting. Mo- tor weakness may be the deficit most obvious to both patient and outside observer and is the Mechanisms of Motor Recovery primary focus of this review. Hemiparesis, the Following Stroke simultaneous weakness of an arm and leg on Motor recovery is also a multifaceted pro- one side, is the most common pattern of weak- cess. In the hours to weeks following a stroke, ness, seen in ∼60% of cases (1). The severity natural recovery depends on decreasing local of motor weakness is a strong predictor of the edema, reperfusion of the ischemic penumbra,

by Boston University on 10/28/10. For personal use only. severity of functional deﬁcits (2). and resolution of diaschisis or areas of metaboli- Rehabilitation medicine is the medical spe- cally depressed brain distant from the infarction cialty that addresses and manages function, (2, 4). Natural recovery is passive, requiring nei- Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org best thought of as “performance.” Neurol- ther effort nor learning by the patient. [Intra- ogy and neurosurgery diagnose and treat acute venous and intraarterial thrombolysis aimed at stroke, but rehabilitation professionals man- reducing infarction and restoring the viability age the residual deﬁcits in communication, self of the ischemic penumbra also contribute sub- care, and ambulation performance, i.e., func- stantially to recovery and have been recently re- tion. Stroke rehabilitation is managed by health viewed in this journal (6).] Motor recovery can care teams that include physiatrists, sometimes also be due to actual reorganization of brain tis- neurologists, nurses, physical and occupational sue in and around areas of damage. This is an therapists, speech-language pathologists, social active process and requires considerably more workers, and others. The rehabilitation team time. The underlying mechanisms for late brain uses a variety of techniques to improve perfor- reorganization are likely related to increases mance following stroke, such as strengthening in the absolute numbers and concentration of of both weak and intact extremities, use of assis- synapses on dendrites (7) and unmasking of

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latent neural networks (5, 7). Sparing of the MEDICAL AND PSYCHOLOGICAL secondary motor cortex may be particularly im- MANAGEMENT TO MAXIMIZE portant in longer-term motor recovery (2). This PARTICIPATION “rewiring” allows the motor cortex to shift the If remodeling motor cortex following stroke relative control of a given body part. It also ap- requires active, specific, and repetitive exer- pears to occur only as a result of the patient’s cise, then a patient must be able to partici- experience. Defining the optimal nature, char- pate. The management of medical complica- acteristics, intensity, and timing of this experi- tions, pain, and depression may help explain ence constitutes the fundamental challenge in why care in organized stroke units reduces mor- stroke rehabilitation. tality and complications and improves recovery (4, 11). Langhorne & Duncan (12) recently es- The Patient’s Experience of timated that “for every 100 patients receiving Rehabilitation Following Stroke organized, inpatient multidisciplinary rehabilitation, an extra 5 will be returned home in an In recent years, two factors have emerged independent state.” A recent Cochrane review as important for cortical reorganization and of 31 trials and 6936 patients concluded that plasticity: task-specific activity and repetition persons with stroke who received inpatient care (4, 8). For example, to improve walking, a pain a stroke unit were more likely to be inde- tient must exercise the muscles used in walking pendent and living at home one year poststroke and exercise them multiple times. In addition, (13). several authors have pointed out the impor- tance of integrating motor learning principles into the rehabilitation experience (9, 10). Other factors that may be critical to motor recovery Medical Issues include the emotional impact of the activity (is In a study of 663 patients with acute is- it important and enjoyable?), the concomitant chemic strokes, the most frequent infections use of tactile and visual stimuli, varying the were pneumonia in 10% and urinary tract in- task within and between exercise sessions, and fection in 13% of patients (14). Risk factors the role of sleep in consolidating new motor for developing pneumonia include atrial fibril- skills. lation, greater age, and congestive heart fail- Specificity and repetition of exercise under- ure, all of which were independently associated lie many rehabilitation interventions following with higher inpatient mortality and decreased by Boston University on 10/28/10. For personal use only. stroke, including several of the technological ambulatory status on discharge. Swallowing is and novel treatment approaches discussed here. compromised in at least 40% of stroke patients,

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org The most effective strategy to maximize long- increasing the risks for pneumonia and dehy- term motor recovery is likely a combination dration. Most dysphagia is transient, with <2% of acute interventions to salvage viable brain of stroke survivors still dysphagic one month tissue and effective rehabilitation to remodel poststroke. Although limited by small samples what viable tissue remains (4). This brief review and use of historical controls, a recent review highlights some established and emerging re- concluded that poststroke dysphagia programs habilitation strategies to enhance motor recov- are accompanied by a reduction in pneumonia ery following stroke. The discussion is grouped rates (15). Initial management of severe dyspha- into four categories: (a) medical and psycho- gia includes diagnostic testing, such as modified logical management to maximize participation, barium swallow testing and fiberoptic visualiza- (b) novel approaches to exercise, (c) technology, tion; nasogastric and percutaneous gastrostomy and (d) pharmacological strategies. We con- feedings; modified-texture oral diets; and swal- clude with promising trends that may shape the lowing exercises and maneuvers such the “chin future of stroke rehabilitation. tuck.”

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In the Post-Stroke Rehabilitation Outcomes as shoulder-hand syndrome. The etiology of Project (PSROP) database, 5.6% of 1161 reha- CRPS is not entirely clear but may involve bilitation patients developed a deep vein throm- exaggerated inflammatory and abnormal sym- bosis (DVT) (16). Early mobilization, use of pathetic responses (21). Pain at the shoulder blood-thinning agents, and hydration may help or hand, or both, occurs 2–4 months from prevent DVT. Use of heparin reduces the inci- stroke onset and is usually described as burn- dence of DVT and pulmonary embolism, and ing, continuous, and exacerbated by movement. one indirect comparison of unfractionated and Physical examination is remarkable for hand low-molecular-weight heparin (LMWH) sug- edema, changes in skin blood flow, allodynia, gests that low-dose LMWH is more effective and hyperalgesia, and the elbow is typically in decreasing DVT and pulmonary embolism spared. Other than physical interventions to without a clear increase in hemorrhage (17). reduce hand edema, oral steroids are proba- Although mechanical compression devices are bly the treatment of choice (21), followed by widely used, there is limited evidence for their nonsteroidal anti-inflammatory drugs and an- effectiveness in stroke. ticonvulsants such as gabapentin. Nonpharma- Seizures occur in just over 3% of strokes at cological treatments include psychotherapy and onset and are associated with a higher mortal- transcutaneous electrical nerve stimulation. ity at 30 days. A higher incidence is seen among The flaccid hemiplegic shoulder is partic- hemorrhagic strokes and younger patients (18). ularly susceptible to glenohumeral subluxa- Ongoing antiepileptic treatment is required in tion. The relationship between subluxation and only 3% of cases within 7 years of the event (19). shoulder pain is not clear, however. Expert con- Age, intracerebral hemorrhage, lesion size, in- sensus recommends the use of lapboards or pil- creasing stroke severity, and early seizures are lows to support the weak arm and minimize independent predictors of poststroke epilepsy subluxation (22). The use of slings to reduce (i.e., recurrent seizures). Seizure prophylaxis is subluxation is controversial; slings should prob- not routinely initiated following stroke, with ably be used only during ambulation. Shoul- the possible exception of large hemorrhagic der taping, electrical stimulation, intraarticular strokes. Cognitive impairment and sedation as- steroids, and botulinum toxin have all been de- sociated with antiepileptic agents are a signifi- scribed as effective treatments (22, 23). cant concern for rehabilitation participation.

Poststroke Depression by Boston University on 10/28/10. For personal use only. Pain Management Depression is seen in up to 50% of persons dur- A number of pain syndromes are seen after ing the 12 months following stroke (24). Post-

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org stroke, and effective management can greatly stroke depression is likely underrecognized and facilitate participation. Central poststroke pain undertreated, partly owing to its subtle pre- (CPSP), formerly known as thalamic pain syn- sentation, “minor depression with dysthymia” drome of Dejerine´ and Roussy, is a central neu- in 80% of cases. Several studies have iden- ropathic pain occurring in patients with subcor- tified a clear association between depression tical strokes. The incidence of CPSP is at least and both mortality and poor rehabilitation out- 8% during the first year following stroke, with comes (24). Depression often thwarts rehabil- >60% experiencing onset of the pain within itation participation through poor motivation one month (20). Treatment is notoriously diffi- or secondary attention and memory deficits cult and includes amitriptyline and lamotrigine that limit the learning of new skills. The pro- as first-line and mexeletine, fluvoxamine, and phylactic use of antidepressant medications has gabapentin as second-line treatments. been recently reviewed and may hold promise Complex regional pain syndrome (CRPS) of (25). Once recognized, poststroke depression the hemiparetic arm after stroke is also known can be effectively and safely treated with either

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selective serotonin reuptake inhibitors or tri- functional tasks and on a subjective measure of cyclic antidepressants (23). hand function. The two-year follow-up docu- mented no decline from one year, and there were even trends toward continued improve- APPROACHES TO EXERCISE ment (30). Recent kinematic data have also con- There are several philosophies of exercise to firmed improvements in quality of movement as promote motor recovery following stroke. Un- a result of CIMT (31). til recently, there was little evidence favoring CIMT is personnel-intense and costly, and any one approach over another (8). The science there currently are no mechanisms for re- behind exercise in neurological disease is not imbursement (28). Several groups are explor- outstanding but does support a “weak, but sig- ing modifications of CIMT (less intense over nificant dosage effect with conventional ther- longer time periods) that might increase its apy” (26). Persons with stroke tend to avoid practicality (28). CIMT requires a remarkable using an impaired extremity. This “learned degree of patient motivation, since the inabil- nonuse,” originally described by Taub and col- ity to compensate with the intact arm can be leagues (27, 28), may result from decreased terribly frustrating. In the EXCITE trial (28), cortical representation due to the stroke itself or gains in speed and subjective patient assess- “low spontaneous use” of the limb due to frus- ment of arm use were more robust than gains tration or overemphasis of compensation using in objective observations of arm ability or mo- the intact extremities (28). Physical and occupa- tor strength. The control group received only tional therapists look for opportunities to “force “usual and customary care,” which is a cen- use” of a weak extremity to break this pattern tral point of criticism of the study because the and facilitate cortical activation (2). CIMT group received a greater “dose” of exercise. Despite the study’s methodological weak- nesses, maintaining gains two years after two Constraint-Induced Movement weeks of exercise is rather remarkable. Therapy (CIMT) CIMT magnifies the concept of forced use by requiring a patient to perform functionally ori- Body-Weight-Supported Gait Training ented activities using only the paretic arm while the unimpaired arm is physically restrained with Body-weight-supported (BWS) gait training is a sling or mitt. In addition, therapists provide a novel approach to the enhancement of walk- by Boston University on 10/28/10. For personal use only. hand-over-hand skilled guidance (“shaping”) to ing after stroke by means of forced use, speci- assist the weaker arm in repetitive functional ficity, and repetition (32). While suspended in

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org tasks (28). a parachute-like harness hanging from a frame The Extremity Constraint Induced Therapy (see Figure 1), a patient is able to simulate and Evaluation (EXCITE) Trial was a multicenter practice complex gait cycles. Some authors feel single-blind randomized controlled trial (RCT) that even in stroke, spinal cord mechanisms may comparing CIMT to customary care in 222 per- play a role in improving walking patterns (33). sons within 3–9 months of a ﬁrst stroke (29). The effect of body-weight support is somewhat Some degree of voluntary ﬁnger extension was analogous to the buoyancy of walking in a swim- required to qualify for the study. CIMT was ming pool. Hesse (34) has estimated that BWS provided over two weeks, during which shap- training can increase the number of steps in a ing was provided by a therapist 6 h per day, treatment session from 50 to >1000. The ther- 5 days per week, and a mitt was worn on the apy allows the patient to practice more nearly unaffected hand 90% of waking hours, includ- normal gait patterns and to avoid developing ing weekends. At one year, the CIMT group “bad walking habits” (35). BWS training can performed better on a series of timed, semi- occur over ground, on a traditional treadmill,

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in walking independence and functional status among the BWS/Gait Trainer group than in the traditional-therapy group in a single- blind RCT with equal treatment times between groups. Results are encouraging, but a better understanding is needed concerning the use of a handrail, the magnitude of body support, the intensity and length of training, and the speed of the treadmill (35).

TECHNOLOGY The use of new technological strategies to improve motor recovery after central neurological disease, including stroke, has exploded over the past two decades. This technological revolution is in its infancy, but already there are questions about effectiveness versus cost.

Robotics Robotics have been used widely to assist exercise and quantify movements in stroke rehabilitation over the past 15 years (38–40). Both upper (UE) and lower extremity (LE) units are commercially available, but published research is mostly on the UE devices. These focus on either proximal (shoulder, elbow) or distal (wrist, finger) muscles (see Figure 2a,b). Potential ad- vantages over conventional therapy include increased intensity, more repetitions, better pa- Figure 1 tient engagement, enhanced motor learning via In this example of body-weight-supported training, a subject is suspended from additional visual stimuli, outstanding standard- by Boston University on 10/28/10. For personal use only. a steel frame over a standard treadmill. The partial body-weight support allows ization of movements within and between ses- the subject to activate lower extremity muscles and to simulate a more normal sions, and the ability to track patient response walking pattern than would be possible without support. Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org longitudinally over time (38–40). The most so- phisticated units are haptic, i.e., they interface or on a “mechanical gait trainer” (34). Despite with the user via the sense of touch, and possess its reasonable underlying rationale, the liter- the ability to quantify patient performance and ature on BWS training reports mixed results adjust future treatment parameters (38). There (35, 36). is evidence that distorting a patient’s move- Published studies are quite variable in the ment, such as pushing the arm off course dur- time from stroke, initial walking ability, in- ing a reaching activity, may actually increase tensity of treatments, and approach to con- effectiveness (38). One very small study (41) trol groups (33, 36). The best data are from demonstrated that bimanual therapy may be Europe and examine BWS training using an less effective than unimanual, but this requires “electromechanical Gait Trainer,” a device sim- confirmation. ilar to the elliptical trainer seen in many health The efficacy of UE robotics for motor clubs. Pohl et al. (37) reported greater gains recovery is reasonably well established (38–40).

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a c

b by Boston University on 10/28/10. For personal use only. Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org Figure 2 Stroke rehabilitation robotics. (a) The MIT-MANUS wrist unit focuses on ﬂexion/extension and supination/pronation of the weak wrist after stroke. (b) The MIT-MANUS proximal arm unit provides or assists movement to the shoulder and elbow while the subject moves the cursor on the computer screen. (c) The Lokomat combines partial body-weight-supported treadmill training with active robotic control at the hip and knee and passive control at the ankle.

The most extensive work has used the MIT- LE device is the Lokomat (see Figure 2c) (40). MANUS and the MIME units. A recent meta- Like the Gait Trainer, the Lokomat uses body- analysis of 218 patients (39) concluded UE weight support, but it is larger, more complex, robotic treatment results in improved UE mo- and more expensive. Initially used in spinal cord tor recovery compared to traditional rehabilita- injury, the Lokomat provides active control tion therapy, but no differences were found for at the hip and knee and passive control at the performance-based measures. The best-studied ankle. A recent, small RCT of Lokomat versus

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conventional therapy in persons with stroke reported improvement in gait patterns and anthropometric measures among the treatment a group, but no improvement in gait-assistance category or speed (42). A second, smaller, nine-week crossover study found Lokomat training superior to conventional therapy for gait and distance achieved on a six-minute walk (43).

Functional Electrical Stimulation Functional electrical stimulation (FES) provides short, coordinated bursts of electricity to weak muscles to facilitate functional movement b (44). FES can also be used to strengthen muscle, improve range of motion, and reduce spasticity. FES is not useful in the presence of lower motor neuron disease (i.e., peripheral neuropathy, radiculopathy) and probably has greater functional utility for the lower extremities. There are two surface, peroneal nerve stim- ulators available in the United States and a third in Great Britain. LE FES stimulates the common peroneal nerve during the swing phase of gait, producing ankle dorsiﬂexion and eversion (see Figure 3a). This offsets the ankle equino- c varus typically seen after stroke and results in easier clearance of the leg. A recent Cochrane review (44) concluded LE FES was beneﬁcial compared to no treatment for gait and motor recovery, although the quality of research was by Boston University on 10/28/10. For personal use only. generally poor. Not included in that review is a recent nonrandomized unblinded study report-

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org ing a 34% increase in walking speed and improved gait symmetry in 24 patients with stroke after 8 weeks of LE FES treatment (45). An- other recent small study found a trend toward increased walking speed and improved perfor- Figure 3 mance on a functional mobility test with LE Functional electrical stimulation. (a) Components of the Bioness L300 unit include the heel switch (not FES compared to a conventional plastic ankle- shown), the wireless transmitter on the inside of the foot orthosis (46). shoe, and the proximal leg cuff providing Several UE FES units are available, and de- stimulation to the peroneal nerve during the swing spite mixed quality, the research in stroke sup- phase of gait. Other panels show the Bioness H200 ports a positive impact on motor recovery at stimulating full ﬁnger ﬂexion (b) and extension (c), which can be used to simulate a functional the hand (see Figure 3b,c). Several studies re- grasp. port better outcomes among subjects having at least some degree of active movement of the

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hand and fingers. In one of the better pub- tual environment. Simpler, nonimmersive sys- lished studies, Powell et al. (47) randomized 60 tems use a computer screen to simulate an ex- subjects (mean time poststroke = 22 days) to perience, but the degree of immersion appears 30 min FES for 8 weeks versus standard reha- to be a factor in treatment success (50). The bilitation treatment. At 32 weeks, better motor enjoyment of training encourages repetition, recovery was reported in the FES group. The which promotes motor recovery. Systems are commercial availability of FES will undoubt- also available to facilitate walking activities (51). edly increase its use, but further research is re- A recent review concluded that although effec- quired to substantiate functional gains given the tiveness data are limited, VR training may lead cost of the technology. to improvements in motor strength and walking. As with many of the technologies discussed, further and better-designed research is needed Transcranial Magnetic Stimulation to evaluate VR. Transcranial magnetic stimulation (TMS) is a newer technological addition to stroke rehabilitation. TMS uses a magnetic pulse to nonin- Phamacological Interventions vasively and reversibly disrupt electrical trans- The idea of combining catechoaminergic med- missions in the brain. It has been suggested that ications and rehabilitation to improve motor TMS produces “virtual lesions” of the brain. function after acquired brain injury has been Thus, it can be used to map cortical changes in popular since Feeney’s classic animal studies motor control resulting from an intervention in the early 1980s (52). The two medica- such as CIMT (48). Repetitive TMS (rTMS) tions most studied in stroke are d-amphetamine is used to achieve a longer-lasting effect, up to and levodopa. Animal studies have demon- 15 min depending on the frequency of the pulse. strated that amphetamines increase noradren- At higher frequencies (10 Hz), TMS increases ergic and activity-dependent neurotransmis- cortical excitability for a few minutes. TMS ap- sion and neosynaptic growth in peri-infarction pears to be safe and very well-tolerated by sub- and contralateral brain tissue. Most authorities jects with stroke. In addition to brain mapping, feel that medications should be temporally cou- Takeuchi and colleagues (49) recently reported pled with task-specific rehabilitation (53). improvements in motor movement when us- Human studies are mixed. Some find that ing TMS to stimulate the opposite hemispheric 10 mg of dextroamphetamine before physi- primary motor cortex—suggesting an inhibitory cal therapy facilitates motor recovery (54, 55) by Boston University on 10/28/10. For personal use only. role for the contralateral motor areas. No side whereas others find no effect (56, 57). A recent effects were noted. study was better-powered with 71 subjects and

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org still failed to find an effect of 10 physical therapy sessions coupled with 10 mg amphetamine Virtual Reality (versus 10 sessions with placebo) (58). Virtual reality (VR) uses computer technol- Side effects have generally been quite mild. ogy to provide real-time input to multiple Overall, a 2007 Cochrane review concluded systems—sight, sound, and touch. These inter- that the data “suggested benefits on motor func- actions are designed to be novel, fun, and spe- tion” from amphetamines after stroke (59). A cific to an individual patient’s needs, in accord double-blind RCT (60) showed that a single dose with motor learning theory (9, 50). Some VR of levodopa in patients with chronic stroke en- allows a patient to don a computerized glove hanced motor learning compared with placebo. that provides sensorimotor biofeedback to the Another randomized study of 53 stroke patients paretic hand (i.e., CyberGlove and Rutgers showed that a single 100-mg dose of levodopa Master II-ND). Other systems use goggles or plus three weeks of physical therapy resulted special glasses to “immerse” the user in a vir- in better motor recovery than placebo and the

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same exercise protocol (61). Larger trials with muscle tone is an appealing, although debated more aggressive dose escalations are warranted, (5), outcome. given the minimal side-effect profile and trends A variety of medications are available. toward better motor recovery. Baclofen and tizanadine are commonly used for mild to moderate generalized spasticity but sedation is a relatively frequent limiting side ef- SPASTICITY fect (62). Opinions differ on the effectiveness of The identification and treatment of function- oral agents in reducing tone, and data regarding ally significant spasticity in persons with stroke the impact on functional motor parameters are is an area of increasing interest among reha- rather limited (62). Intrathecal baclofen (ITB) bilitation professionals. The definition of spas- delivered through a surgically implanted pump ticity as “velocity-dependent tone” on passive is a more recent treatment for moderate to se- ranging of a joint is a clinically and scien- vere generalized spasticity. The therapeutic ef- tifically inadequate description but is widely fect of ITB is more prominent in the legs than used nonetheless. From the patient’s stand- in the arms. It is unclear if ITB alters long- point, spasticity is an involuntary “muscle stiff- term motor recovery after stroke, but the ther- ness” that may or may not be accompanied by apy clearly reduces spasticity (63). Data are less muscle weakness. There are many endpoints clear on the impact of ITB on gait speed and for treatment of spasticity, including decreased other gait parameters (63), but quality of life pain, improved range of motion, and enhanced was significantly enhanced in a recent open- hygiene of the palm and perineum. Enhanc- label trial (64). Importantly, ITB does not seem ing underlying motor movement limited by to have a detrimental impact on strength in the unaffected leg (63). When moderate to severe focal spasticity limits function, botulinum toxin (BT) can be BION3 injected into the affected muscle. BT is partic- ABC ularly helpful for the smaller muscles control- ling the hand and foot. Like ITB, BT clearly BION1 BION1 reduces spasticity and improves subjective dis- AMI AMF ability. Recent data suggest a significant improvement of quality of life with several injec- tions over a year (65, 66). by Boston University on 10/28/10. For personal use only. Orthopedic and neurosurgical procedures are also used if more conservative measures fail

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org to alter joint biomechanics and improve range of motion and motor control (67). For all spasticity treatments, functional outcome needs to be more closely examined.

16 mm long 2.0 mm dia. FUTURE TRENDS IN 16.5 mm long MOTOR RECOVERY 2.5 mm dia. FOLLOWING STROKE 27 mm long The revolutions of stem cell transplantation 3.3 mm dia. and human genetics may hold promise for Figure 4 motor recovery following stroke. Manipula- BION devices, in various types and sizes, have self-contained power sources and tion of growth factors, stem cells, migration of are implanted under the skin to stimulate either muscles or peripheral nerves. neuroblasts, and targeted cell differentiation in

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the brain could play a significant role in enhanc- sively (71) or noninvasively (72, 73) to a com- ing neurogenesis after stroke and other neu- puter network. In the next generation of FES, rological disorders (68). Genetic testing might already in limited use, surface electrodes are differentiate which patients respond best to re- abandoned in favor of tiny, self-contained intra- habilitation intervention (69, 70). Future ad- muscular or perineural implants called BIONs vances in neuroimaging will undoubtedly pro- (see Figure 4) (74). Wireless activation of a se- vide new insights, including a better delineation ries of BIONs could simulate functional move- of mechanisms of motor recovery and quan- ment of a hand or foot without using an external tification of physiological changes serving as device. With very few exceptions, the strategies a “biomarker” for treatment effect (69, 70). discussed in this review have been implemented Technology will play an ever-expanding role and studied in isolation. The ultimate ques- in stroke rehabilitation. Among the most ex- tion may be how to combine simultaneous and citing developments are brain-computer inter- sequential interventions at specific times post- faces that allow a subject to think about moving stroke to achieve the best motor and functional a robotic or other device while connected inva- recovery (9).

DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.

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by Boston University on 10/28/10. For personal use only. 6. Suwanwela N, Koroshetz WJ. 2007. Acute ischemic stroke: overview of recent therapeutic developments. Annu. Rev. Med. 58:89–106 7. Turkstra LS, Holland AL, Bays GA. 2003. The neuroscience of recovery and rehabilitation: What have

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40. Hidler J, Nichols D, Pelliccio M, et al. 2005. Advances in the understanding and treatments of stroke impairment using robotics devices. Top. Stroke Rehabil. 12:22–35 41. Lum PS, Burgar CG, VanderLoos M, et al. 2006. MIME robotics device for upper-limb neurorehabilitation in subacute stroke subjects: a follow-up study. J. Rehabil. Res. Dev. 43:631–42 42. Husemann B, Muller F, Krewer C, et al. 2007. Effects of locomotion training with assistance of a robot- driven gait orthosis in hemiparetic patients after stroke: a randomized, controlled pilot study. Stroke 38:349–54 43. Mayr A, Koﬂer M, Quirbach E, et al. 2007. Prospective, blinded, randomized crossover study of gait rehabilitation in stroke using the Lokomat gait orthosis. Neurorehabil. Neural. Repair 21:307–14 44. Pomeroy VM, Pollack A, Baily-Hallam A, et al. 2006. Electrostimulation for promoting recovery of movement or functional ability after stroke (review). Cochrane Sys. Rev. CD003241 45. Hausdorff JM, Ring H. 2008. Effects of a radio-frequency controlled neuroprosthesis on gait symmetry and rhythmicity in patients with chronic hemiparesis. Am. J. Phys. Med. Rehabil. 87:4–13 46. Shefﬂer LR, Hennessey MT, Naples GG, et al. 2006. Peroneal nerve stimulation versus an ankle foot orthosis for correction of footdrop in stroke: impact on functional ambulation. Neurorehabil. Neural. Repair 20:355–60 47. Powell J, Pandyan AD, Granat M, et al. 1999. Electrical stimulation of wrist extensors in poststroke hemiplegia. Stroke 30:1384–89 48. O’Malley MK, Ro T, Levin HS. 2006. Assessing and inducing neuroplasticity with transcranial magnetic stimulation and robotics for motor function. Arch. Phys. Med. Rehabil. 87(Suppl. 2):S59–66 49. TakeuchiN, Chuma T, Matsuo Y, et al. 2005. Repetitive transcranial magnetic stimulation of contralateral primary motor cortex improves hand function after stroke. Stroke 36:2681–86 50. Henderson A, Korner-Bitensky N, Levin M. 2007. Virtual reality in stroke rehabilitation: a systematic review of its effectiveness for upper limb motor recovery. Top. Stroke Rehabil. 14(6):52–61 51. Deutsch JE, Mirelman A. 2007. Virtual reality-based approaches to enable walking for people poststroke. Top. Stroke Rehabil. 14(2):45–53 52. Feeney DM, Gonzalez A, Law WA. 1982. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 27(4562):855–57 53. Goldstein LB. 1999. Amphetamine-facilitated poststroke recovery. Stroke 30:696–98 54. Crisostomo EA, Duncan PW, Propst M, et al. 1988. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann. Neurol. 23:94–97 55. Walker-Batson D, Smith P, Curtis S, et al. 1995. Amphetamine paired with physical therapy accelerates motor recovery after stroke: further evidence. Stroke 26:2254–59 56. Platz T, Kim IH, Engel, et al. 2005. Amphetamine fails to facilitate motor performance and to enhance

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Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org after stroke: a randomized, placebo-controlled study. Clin. Rehabil. 17:590–99 58. Gladstone DJ, Danells CJ, Armesto A, et al. 2006. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo controlled trial. Stroke 37:179– 85 59. Martinsson L, Hardemark H, Eksborg S. 2007. Amphetamines for improving recovery after stroke (review). Cochrane Database Syst. Rev. CD002090 60. Floel A, Hummel F, Breitenstein C, et al. 2005. Dopaminergic effects on encoding of a motor memory in chronic stroke. Neurology 65:472–74 61. Scheidtmann K, Fries W, Muller¨ F, et al. 2001. Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 358(9284):787–90 62. Montane E, Vallano A, Laporte JR. 2004. Oral antispastic drugs in nonprogressive neurologic disease: a systemic review. Neurology 63:1357–63 63. Francisco GE, Yablon SA, Schiess MC, et al. 2006. Consensus panel guidelines for the use of intrathecal baclofen therapy in poststroke spastic hypertonia. Top. Stroke Rehabil. 13:74–85

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64. Ivanhoe CB, Francisco GE, McGuire JR, et al. 2006. Intrathecal baclofen management of poststroke spastic hypertonia: implications for function and quality of life. Arch. Phys. Med. Rehabil. 87:1509–15 65. Ozcakir S, Sivrioglu K. 2007. Botulinum toxin in poststroke spasticity. Clin. Med. Res. 5:132–38 66. Elovic E, Brashear A, Kaelin D, et al. 2008. Repeated treatments with botulinum toxin type A produce sustained decreases in the limitations associated with focal upper-limb poststroke spasticity for caregivers and patients. Arch. Phys. Med. Rehabil. 89:799–806 67. Smyth MD, Peacock WJ. 2000. The surgical treatment of spasticity. Muscle Nerve 23:153–63 68. Kalluri HSG, Dempsey RJ. 2008. Growth factors, stem cells and stroke. Neurosurg. Focus 24:E13 69. Cramer SC, Riley JD. 2008. Neuroplasticity and brain repair after stroke. Curr. Opin. Neurol. 21:76–82 70. Kalra L, Ratan RR. 2007. Advances in stroke regenerative medicine 2007. Stroke 39:273–275 71. Alonso-Alonso M, Fregni F, Pascual-Leone A. 2007. Brain stimulation in poststroke rehabilitation. Cerebrovasc. Dis. 24(Suppl. 1):157–66 72. Fregni F, Pascual-Leone A. 2007. Technology insight: noninvasive brain stimulation in neurology per- spectives on the therapeutic potential of rTMS and tDCS. Nat. Clin. Pract. Neurol. 3:383–93 73. Buch E, Weber C, Cohen LG, et al. 2008. Think to move: a neuromagnetic brain-computer interface (BCI) for chronic stroke. Stroke 39:910–17 74. Loeb GE, Richmond FJR, Baler LL. 2006. The BION devices: injectable interfaces with peripheral nerves and muscles. Neurosurg. Focus 20:E2 by Boston University on 10/28/10. For personal use only. Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org

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Annual Review of Medicine Contents Volume 60, 2009

Transcatheter Valve Repair and Replacement Susheel Kodali and Allan Schwartz ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1 Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension Steven H. Abman ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp13 Oral Iron Chelators Maria Domenica Cappellini and Paolo Pattoneri pppppppppppppppppppppppppppppppppppppppppppp25 The Treatment of Hyperhomocysteinemia Bradley A. Maron and Joseph Loscalzo ppppppppppppppppppppppppppppppppppppppppppppppppppppppp39 Stroke Rehabilitation: Strategies to Enhance Motor Recovery Michael W. O’Dell, Chi-Chang David Lin, and Victoria Harrison pppppppppppppppppppppppp55 Cardiomyopathic and Channelopathic Causes of Sudden Unexplained Death in Infants and Children David J. Tester and Michael J. Ackerman ppppppppppppppppppppppppppppppppppppppppppppppppppp69 Bisphosphonate-Related Osteonecrosis of the Jaw: Diagnosis, Prevention, and Management

by Boston University on 10/28/10. For personal use only. Salvatore L. Ruggiero and Bhoomi Mehrotra ppppppppppppppppppppppppppppppppppppppppppppppp85 IL-23 and Autoimmunity: New Insights into the Pathogenesis

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org of Inﬂammatory Bowel Disease Clara Abraham and Judy H. Cho pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp97 Necrotizing Enterocolitis Marion C.W. Henry and R. Lawrence Moss ppppppppppppppppppppppppppppppppppppppppppppppp111 Cancer Screening: The Clash of Science and Intuition Barnett S. Kramer and Jennifer Miller Croswell ppppppppppppppppppppppppppppppppppppppppp125 Biomarkers for Prostate Cancer Danil V. Makarov, Stacy Loeb, Robert H. Getzenberg, and Alan W. Partin pppppppppppp139 Management of Breast Cancer in the Genome Era Phuong Khanh H. Morrow and Gabriel N. Hortobagyi pppppppppppppppppppppppppppppppppp153

v AR367-FM ARI 15 December 2008 18:20

MicroRNAs in Cancer Ramiro Garzon, George A. Calin, and Carlo M. Croce pppppppppppppppppppppppppppppppppp167 Erythropoietin in Cancer Patients John A. Glaspy ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp181 Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia David J. Kuter ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp193 Evolving Treatment of Advanced Colon Cancer Neil H. Segal and Leonard B. Saltz pppppppppppppppppppppppppppppppppppppppppppppppppppppppp207 Barrett’s Esophagus and Esophageal Adenocarcinoma Robert S. Bresalier ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp221 Primary Myeloﬁbrosis: Update on Deﬁnition, Pathogenesis, and Treatment Omar I. Abdel-Wahab and Ross L. Levine ppppppppppppppppppppppppppppppppppppppppppppppppp233 Nicotine Dependence: Biology, Behavior, and Treatment Riju Ray, Robert A. Schnoll, and Caryn Lerman pppppppppppppppppppppppppppppppppppppppppp247 Food Allergy: Recent Advances in Pathophysiology and Treatment Scott H. Sicherer and Hugh A. Sampson pppppppppppppppppppppppppppppppppppppppppppppppppp261 Immunomodulation of Allergic Disease David H. Broide ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp279 Hypereosinophilic Syndrome: Current Approach to Diagnosis and Treatment Amy Klion pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp293 Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen by Boston University on 10/28/10. For personal use only. Sheela Shenoi and Gerald Friedland ppppppppppppppppppppppppppppppppppppppppppppppppppppppp307

Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org Polycystic Kidney Disease Peter C. Harris and Vicente E. Torres pppppppppppppppppppppppppppppppppppppppppppppppppppppp321 The Kidney and Ear: Emerging Parallel Functions Elena Torban and Paul Goodyer pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp339 The Expanded Biology of Serotonin Miles Berger, John A. Gray, and Bryan L. Roth pppppppppppppppppppppppppppppppppppppppppp355 Advances in Autism Daniel H. Geschwind pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp367 Chronic Consciousness Disorders James L. Bernat ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp381

vi Contents AR367-FM ARI 15 December 2008 18:20

Goals of Inpatient Treatment for Psychiatric Disorders Steven S. Sharfstein ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp393 Understanding and Reducing Variation in Surgical Mortality John D. Birkmeyer and Justin B. Dimick ppppppppppppppppppppppppppppppppppppppppppppppppp405 MRI-Guided Focused Ultrasound Surgery Ferenc A. Jolesz pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp417 Genetic Testing in Clinical Practice Steven W.J. Lamberts and André G. Uitterlinden pppppppppppppppppppppppppppppppppppppppp431 The HapMap and Genome-Wide Association Studies in Diagnosis and Therapy Teri A. Manolio and Francis S. Collins pppppppppppppppppppppppppppppppppppppppppppppppppppp443 Prospects for Life Span Extension Felipe Sierra, Evan Hadley, Richard Suzman, and Richard Hodes pppppppppppppppppppppp457 Emerging Concepts in the Immunopathogenesis of AIDS Daniel C. Douek, Mario Roederer, and Richard A. Koup ppppppppppppppppppppppppppppppppp471 Lessons Learned from the Natural Hosts of HIV-Related Viruses Mirko Paiardini, Ivona Pandrea, Cristian Apetrei, and Guido Silvestri pppppppppppppppp485

Indexes

Cumulative Index of Contributing Authors, Volumes 56–60 ppppppppppppppppppppppppppp497 Cumulative Index of Chapter Titles, Volumes 56–60 pppppppppppppppppppppppppppppppppppp501

Errata by Boston University on 10/28/10. For personal use only. An online log of corrections to Annual Review of Medicine articles may be found at http://med.annualreviews.org/errata.shtml Annu. Rev. Med. 2009.60:55-68. Downloaded from www.annualreviews.org

Contents vii