Curr Atheroscler Rep (2013) 15:331

DOI 10.1007/s11883-013-0331-y

CARDIOVASCULAR DISEASE AND STROKE (D LEIFER AND JE SAFDIEH, SECTION EDITORS)

New Evidence for Therapies in Stroke Rehabilitation

Bruce H. Dobkin & Andrew Dorsch

# Springer Science+Business Media New York 2013

Abstract Neurologic rehabilitation aims to reduce impair- stroke inpatient stays have dropped to an average of less
ments and disabilities so that persons with serious stroke can than 16 days and as Medicare has capped the number of
return to participation in usual self-care and daily activities outpatient therapy sessions to 15/year [4•]. In effect, these
as independently as feasible. New strategies to enhance declines in service may limit rehabilitation gains and place
recovery draw from a growing understanding of how types greater burdens on caregivers. In contrast to these fiscally
of training, progressive task-related practice of skills, exer- driven realities, the science underlying stroke rehabilitation
cise for strengthening and fitness, neurostimulation, and offers new directions to improve outcomes.
drug and biological manipulations can induce adaptations Scientific advances based on animal models have sharp-
at multiple levels of the nervous system. Recent clinical ened our understanding of the genetic, molecular, physio-
trials provide evidence for a range of new interventions to logic, cellular, and behavioral adaptations that drive and
manage walking, reach and grasp, aphasia, visual field loss, may limit the recovery of function [5]. Novel types of
and hemi-inattention. therapies based on manipulating mechanisms of learning
and memory, neurogenesis and axonal regeneration, and
Keywords Stroke rehabilitation . Clinical trials . Robotics . neurotransmitters and growth factors can facilitate the re-
Neuroplasticity . Functional outcomes . Physical therapy covery process in models. In patients, non-invasive modal-
ities including functional and structural magnetic resonance
imaging (MRI) and neuronal excitatory and inhibitory stim-
Introduction ulation tools such as transcranial magnetic stimulation
(TMS) are characterizing changes in connectivity between
Stroke remains a leading cause of long-term disability in the brain regions after stroke [6]. Therapeutic strategies for
United States at a cost of $38 billion per year. About patients are also being drawn from engineering and comput-
650,000 persons survive a new stroke yearly and 7 million er science. Wireless health and communication technologies
Americans live with the complications of stroke [1]. Despite have produced wearable sensors to remotely record the
evidence that participation in formal rehabilitative therapies quality and quantity of walking practice, smartphone apps
lessens disability after stroke [2], less than a third receive to cue practice, and tele-rehabilitation programs to enable
inpatient or outpatient therapies [3]. Of those who do access treatment in the home or community [7].
therapies, the frequency of use varies by geographic location Evidence from adequately powered, randomized control
and socioeconomic status. For these patients, the amount of trials demonstrating the efficacy of new interventions when
rehabilitation available has progressively fallen as subacute compared to existing therapies has been far outpaced by the
number of novel strategies being developed. Trials can be
confounded by the patho-anatomic and functional heteroge-
This article is part of the Topical Collection on Cardiovascular Disease
and Stroke neity of patients, the complexity and cost of delivering an
intervention, and uncertainties regarding optimal therapy
B. H. Dobkin (*) : A. Dorsch
timing, dose, and duration [8]. Additionally, the outcome
Department of Neurology, Geffen School of Medicine, University
of California Los Angeles, Los Angeles, CA, USA measures used in trials are often relative surrogates for
e-mail: [email protected] patient performance rather than direct measures of the types,
A. Dorsch quantity, and quality of physical functioning [9]. When the
e-mail: [email protected] goal is to assess the use of the upper extremity, walking,
331, Page 2 of 9 Curr Atheroscler Rep (2013) 15:331

exercise, and participation in home and community activi- studies are identifying genetic and biochemical pathways
ties [10], existing measures may not fully capture clinically involved in the establishment of new anatomic connections
important changes in physical or cognitive impairments, and functional network reorganization (e.g., axonal sprouting,
disability, or health-related quality of life and participation dendrite proliferation, neurogenesis) [16•]. In patients, chang-
[11]. Despite these confounds, recent trials do provide use- ing patterns of brain activation appreciated by MRI and other
ful evidence about behavioral, pharmacologic, and non-invasive imaging techniques reflect regional plasticity of
neurostimulation treatments for stroke, as well as near future the neuronal ensembles that represent actions and thoughts.
hope for biological interventions for the most highly im- Such changes are time-dependent and associated with learning
paired patients. and practice, as well as behavioral compensation for the loss
of pre-stroke neural control. Thus, the brain of stroke patients,
like healthy persons, constantly undergoes anatomic and
Overview of Care in Rehabilitation physiologic changes induced by motor learning.
The second principle is that progressive, skilled motor
Patients are admitted for inpatient stroke rehabilitation usu- practice is essential for continued gains at any time after
ally because they are unable to walk without considerable stroke onset. Training must engage the attention, motiva-
human assistance and are dependent in other self-care tasks, tion, and learning networks of the brain to be effective.
yet have adequate memory, attention, and home support to Better gains also depend on greater sparing of the neural
be able to be discharged without the need for skilled nursing networks that represent the components of a behavior. Al-
placement [12]. In the U.S., Medicare requires that patients though observational studies suggest that maximal function-
can tolerate at least three hours of therapist-directed treat- al gains are made by 3 months after onset, these studies do
ment a day, usually begun within 5-10 days after onset of not account for other changes that can occur with regular
stroke. Internationally, the time from stroke onset to rehab practice, such as improved walking speed and distance or
admission is 1-6 weeks and the duration of inpatient care is greater coordination in the use of an affected hand [17].
3-8 weeks, but longer in Japan where a more comprehensive Large, randomized controlled trials in neurologic rehabilita-
post stroke care system is available [13]. tion have reported long-lasting functional improvements
The goals of inpatient therapy can include increased after 2-12 weeks of skilled motor practice in patients who
independence for self-care activities (e.g., feeding, were weeks to years past onset of hemiparesis [18, 19••,
grooming, bowel and bladder care); the ability to perform 20••]. Thus, starting at the time of initial rehabilitation,
safe toilet and wheelchair transfers; walking with or without physicians ought to instill in their patients a regimen of
assistive devices such as canes and orthoses that can brace daily repetitive skills practice that can be carried over into
the ankle and help control the knee; improved receptive and the outpatient setting and into daily activities.
expressive language skills; and better executive, visual-
perceptual, working memory, and other cognitive skills. In
the outpatient setting, patients work with therapists to refine Interventions for Mobility
and build upon these skills to increase their functional
independence in the home and community [14•]. Fitness and Muscle Strength
During rehabilitation, physical, occupational, and speech
therapists enable the practice of tasks of importance to Clinicians should emphasize ways for persons with stroke to
patients, set and update realistic goals within the limitations augment their general conditioning and muscle strength in
of residual reflexive and voluntary neural control, and instill both the affected and unaffected limbs. Pre-morbid
a regimen of daily skills practice of progressive intensity deconditioning due to sedentary behavior exacerbates the
and difficulty. Therapists may utilize neuromuscular facili- fall-off in activity resulting from new neurologic disability
tation techniques to begin to guide the re-acquisition of [21]. Indeed, patients disabled by stroke take half as many
motor skills, before building from simple to more complex steps, use their affected arm much less, and have longer daily
actions that comprise goal-directed behaviors [15]. sedentary periods compared to healthy age-matched persons
[22•, 23, 24]. It becomes very difficult for the hemiparetic
person to achieve an aerobic effect from exercise, due to a
Principles Underlying Rehabilitative Therapies combination of central weakness, inactivity, and muscle atro-
phy [25]. This is of concern because secondary stroke preven-
Two basic principles influence approaches to patient treat- tion recommendations include at least a half-hour of daily
ment. The first is that the adult central nervous system is exercise rigorous enough to have at least a mild aerobic effect
adaptive, or plastic, and has some capacity to re-organize itself [26]. Just as important, higher levels of physical activity are
to recover degraded cognitive and motor functions. Animal associated with greater neurogenesis, better performance on
Curr Atheroscler Rep (2013) 15:331 Page 3 of 9, 331

cognitive tasks, less age-related hippocampal atrophy, and a load a paretic leg. The treadmill induces rhythmic stepping,
reduced risk for vascular dementia.[27•, 28]. although the paretic leg and trunk often require physical
Standard rehabilitative therapies include selective assistance by therapists. The expectation, based on animal
muscle strengthening by isometric and isokinetic exer- studies, was that BWSTT would increase the amount of
cises to improve the power and endurance of affected practice while enabling more normalized sensory inputs to
and unaffected muscle groups. Sets of moderate resis- better drive motor output for stepping. The Locomotor Ex-
tance exercise with weights or elastic bands are feasible perience Applied Post Stroke (LEAPS) trial, however, failed
for most patients. Simply standing up and sitting down to identify an additional clinical benefit of BWSTT as com-
5-10 times during commercials on television can im- pared to a home exercise program of a similar intensity and
prove proximal leg strength. Aerobic exercise training, duration [20••]. Although initially a highly regarded poten-
whether by treadmill, over ground walking, or recum- tial intervention for poor walkers, BWSTT may not reflect
bent cycling, can produce a conditioning effect and the task-related environment of over-ground training for
increase walking speed and endurance [29]. The most motor learning [37•]. The cost in equipment and personnel
impressive results for aerobic exercise training have with the expertise to deliver BWSTT make it an intervention
been reported in chronic stroke patients who have re- to be tried only for patients who have at least modest motor
covered sufficient motor control to participate in control, but are not making progress with intensive over-
moderate-to-vigorous physical activity [30••]. Questions ground training.
remain about how best to provide and reinforce aerobic
exercise, such as through a support group [31], and how Robotic Gait Assist Devices
to maintain compliance with exercise [32]. Physicians
can encourage more frequent daily walks over longer Electromechanical-assistive devices, including robotic
distances and at faster speeds in addition to more formal steppers and exoskeletons, provide patients with either
exercise. full or partial guidance of the lower limbs during the
phases of the gait cycle [38]. As compared to BWSTT,
Over-ground Walking and Balance Training for example, these devices can provide automated gait
training on a treadmill or elliptical-like device and re-
Over-ground gait training is an integral component of quire no hands-on supervision by therapists. To date,
standard physical therapies to improve dynamic balance the devices have generally not led to greater overall
and ensure safe ambulation in the home. Patients first gains in over-ground walking parameters than the same
practice trunk and head control, sit-to-stand balance, and intensity of more conventional physical therapy [39].
then stepping in the controlled environment of the par- Robotic devices are being introduced that may better
allel bars. Over-ground training emphasizes clearance of enable motor learning by letting patients make kinemat-
the paretic foot to initiate leg swing, knee stability in ic errors during practice. Very recently, wearable, light-
stance, and stepping with a more rhythmic, safe gait weight, motorized exoskeletons have become available
pattern, using an assistive device or orthotic as needed. that assist with hip or knee flexion and weight bearing
A Cochrane review found positive correlations between while stepping over ground. Although rather expensive,
the amount of over-ground training and small improve- they may enable slow ambulation when otherwise not
ments in gait speed with no significant increase in the feasible; controlled studies will be needed to determine
number of adverse events such as falls [33]. Falls are a if their use can augment standard rehabilitation practice.
common outcome for patients recovering from stroke,
with an incidence of over 40 percent for more than one Functional Electrical Stimulation
fall in the first year [34]. The addition of a series of
balance and truncal exercises, either as a supplement to FES is a technique that takes advantage of peripheral nerves
inpatient therapies [35] or as part of an outpatient tele- and muscles left unaffected by damage to the central ner-
rehabilitation intervention, [36] may prove to be a cost- vous system. Electrical stimulation is applied to trigger
effective means by which to prevent further disability. contraction and relaxation of select muscle groups. In the
case of walking, excitation of the common peroneal nerve
Body Weight-supported Treadmill Training by an externally placed stimulator results in dorsiflexion at
the ankle to aid paretic foot clearance. Small, randomized
Body weight-supported treadmill training (BWSTT) enables studies of external [40] and implanted [41] electrodes
supervised, repetitive, task-related practice of walking. Pa- have reported improvements in gait lasting at least six
tients with limited motor control wear a chest harness months after the intervention. Though several commer-
connected to an overhead lift to reduce the need to fully cial devices are available in the United States, efforts
331, Page 4 of 9 Curr Atheroscler Rep (2013) 15:331

have only recently begun to demonstrate their potential too expensive for home use. These devices may prove
cost effectiveness [42]. more efficacious in combination with other rehabilitative
therapies such as non-invasive brain stimulation, [49]
but further research is needed.
Interventions for the Upper Extremity
Pharmacologic Therapies to Limit Spasticity
Constraint-induced Movement Therapy and Bimanual
Practice It is often not medically necessary to treat increased muscle
tone, unless spasms or flexor postures of the upper extremity
Therapy for the hemiparetic arm might begin with single- cause pain, skin breakdown or interfere with hygiene. Bac-
joint attempts at movement before proceeding gradually to lofen and tizanidine are frequently used as first-line agents
more complex, multi-joint actions, then task-specific prac- and dantolene’s effects on calcium action may also reduce
tice such as reaching to grasp a coffee cup, a process known hypertonicity. Botulinum toxin injected into selected muscle
as shaping. Facilitation of skilled motor practice for the groups will reduce flexor or extensor postures around a joint
upper extremity can take several forms, including shaping for about 3 months, but usually does not improve functional
plus constraint-induced movement therapy (CIMT). This use of a highly paretic hand [50, 51]. Shoulder pain is
technique includes 6 hours a day of progressive task- common after hemiplegic stroke, associated with subluxa-
related practice with restraint of the unaffected limb all tion and joint stresses [52]. Rapid management of pain with
day for 2 weeks. Increased use and faster skilled movements light exercise, range of motion, and anti-inflammatory med-
of the affected limb may result and persist for up to two ications can help prevent pain-induced spasticity in the arm
years [43•]. However, the intervention has shown efficacy and hand. Inversion and plantar flexion of the foot can also
only in patients who can partially extend the wrist and be lessened by medications and botulinum toxin to try to
fingers, meaning they have fair motor control and at least improve stepping. When a muscle is partially paralyzed by
modest corticospinal tract sparing. Extensive restraint may the toxin, daily stretching and ranging of the affected joint
not be as critical to gains as the high intensity of practice are necessary to maintain the improvement.
with a therapist; gains have been seen with just 2 hours of
daily practice and without restraining the unaffected hand all
day [44•, 45]. When the hand is chronically very weak, Interventions for Aphasia
commercially available forearm-hand orthotic devices with
embedded FES electrodes can enable a hand grasp or finger Melodic Intonation and Constraint-induced Therapies
pinch to assist functional use.
Bimanual practice with simultaneous arm movements A range of individual speech and language therapy
aims to activate the bilateral motor cortices and enhance techniques have been developed to address the wide
input to the affected upper extremity, thereby leading to variety of aphasic syndromes that occur after stroke
increased functional use of the paretic arm and hand. In [53]. Most patients need a multi-modal approach to
small trials, bimanual practice has resulted in a similar build on their strengths and to limit frustration in word
degree of functional recovery as CIMT [46•]. finding and fluency. Melodic intonation therapy was
developed for patients who have poor expression but
Mechanical Devices to Assist Arm Movements good comprehension. This technique uses simple melo-
dies and rhythmic tapping to engage networks that
Mechanical devices range from spring-loaded orthotics subserve prosody of language [54]. In a nod to the
to assist a specific movement, such as wrist extension, massed-practice paradigm of CIMT, constraint-induced
to fully automated, robotic limb prostheses for patient- aphasia therapy was developed as a means to improve
triggered assistance of shoulder, elbow and wrist move- verbal output [55]. Where comprehension is poor and
ments. Patients practice a series of specific joint move- output is perseverative, therapies have little effect. Re-
ments by guiding an object on a computer screen gardless of the treatment modality employed, regular
through a maze. As with the electromechanical- home-based practice with the family is imperative for
assistive devices designed for gait training, robotic arm the development of social communication.
devices may enable more practice with more normalized
limb kinematics. Used as a supplement to standard care, Digital Technologies
such devices may provide a benefit, [47, 48] but a
similar degree of function can usually be achieved using Advances in digital communication technology have led to
standard therapies at the same intensity [19••]. Most are treatments for aphasia that can be personalized and
Curr Atheroscler Rep (2013) 15:331 Page 5 of 9, 331

delivered in the home setting [56]. For example, a recent verbal output in aphasia [66], improve swallowing [67], and
study of speech entrainment that delivered an audiovisual increase walking speed [68] to give but a few examples.
intervention on an iPod screen reported a significant in- Generally modest gains in aspects of motor control have
crease in verbal output for chronic stroke patients with been reported when TMS is combined with other rehabili-
Broca’s aphasia [57]. Several helpful computer programs tative therapies [49, 69•, 70]. Similar equivocal results have
for home practice are also available. Treatment of speech been reported for tDCS protocols [71•]. A lack of consensus
and cognitive disorders is likely to be a growing application persists regarding appropriate patient selection, stimulation
of smartphone, tele-rehab, and other Internet-enabled practice protocol, location, and duration [72]. The Food and Drug
and cueing paradigms. Administration has not approved their use outside of re-
search, except for some types of depression. These tech-
niques seem to work best in patients who have some
Interventions for Visual Field Deficits and Inattention residual voluntary movement.
Modulation of sensorimotor cortex excitability can also
Visual field loss and visual hemi-inattention degrade long- be achieved through the stimulation of peripheral nerves,
term functional outcomes in patients with stroke [58]. While either in isolation [73] or in conjunction with cortical stim-
it is unlikely that rehabilitation will result in recovery from a ulation [74] [75]. Definitive evidence that peripheral ner-
hemianopia, computer-based compensatory therapy may as- vous system activation leads to improved functional
sist in directing visual search and attention into the area of outcomes is not yet available [76].
loss [59]. The direct dopamine agonist rotigotine modestly
lessened hemispatial neglect in sub-acute stroke patients
[60•]. For spatial hemi-neglect, a prism in eyeglasses will Mirror and Virtual Reality Therapies
shift the center of vision toward the abnormal field to
improve reading and some self-care tasks [61]. The connections between parietal cortex and pre-motor and
primary motor regions can be modulated by action observa-
tion and mirror therapy [77]. These techniques involve
Interventions for Locked-In Syndrome patients watching the movements of healthy individuals or,
via a mirror, the unaffected limb. The subject attempts to
Brain-machine interfaces utilize direct communication be- mimic the observed movements. In contrast to other reha-
tween the nervous system and devices outside of the body to bilitative techniques such as CIMT, action observation and
enable communication or the performance of goal-directed mirror therapy can be performed on patients with more
movements. The devices are most needed for people with severe limb paresis [78]. Clinical benefit has been reported
locked-in syndrome from brainstem stroke who are without in meta-analysis of small trials, but the magnitude of benefit
voluntary control of their limbs. Alterations in the amplitude depends upon the comparator therapy provided [79].
of the mu rhythm by thoughts about an action, are recorded Virtual reality (VR) therapies use technology to combine
with electroencephalography electrodes and interpreted by a action observation with repetitive skills practice. The hope
computer algorithm, allowing patients to select letters or is that this strategy will be especially engaging and reinforce
words on a computer screen for communication or to search practice paradigms. As simple as a commercially available
the Web [62]. More advanced systems can record directly video game that can be played at home or as complex as a
from implanted microelectrodes over a variety of cortical system that measures joint angles in the arm and provides
regions. An interface then controls directional movements visual corrective feedback, VR has generated much excite-
of a prosthetic limb [63•]. While some of these technologies ment in the rehabilitation community as a means to promote
are coming into routine use, many challenges about cost and and monitor skills practice [80]. Individual trials have
reliability remain. reported benefits [81], but given the diversity of interven-
tions and outcomes used, efficacy for a particular type or
degree of impairment has not yet been demonstrated [82•].
Non-invasive Brain Stimulation

In addition to being employed to study brain physiology and Pharmacologic Interventions

neuroplasticity [64], techniques including TMS and trans-
cranial direct current stimulation (tDCS) have been used to Attempts to augment stroke recovery by modulating the
modulate cerebral plasticity in combination with physical neurotransmitter pathways of the central nervous system
training. Most trials focus on the recovery of arm function, can also involve medications. Amphetamine showed prom-
[65] though the techniques are being exploited to increase ise in highly selected patients for motor gains, but no
331, Page 6 of 9 Curr Atheroscler Rep (2013) 15:331

adequately powered trial has been completed after twenty its use, and the science underlying its utilization in chronic
years of small studies [83]. Efforts to boost cerebral dopa- stroke is difficult to support. Etanercept, approved by the FDA
minergic action through the use of ropinirole proved inef- for use in psoriatic and rheumatoid arthritis, has been prof-
fective in patients with chronic stroke [84]. The NMDA fered as a treatment for chronic stroke in various clinics. The
receptor antagonist memantine was reported to improve manufacturer, Amgen, specifically points to a lack of evidence
spontaneous speech and naming skills in chronic stroke for its use in stroke and the few published reports by one
patients with aphasia [85]. While individuals seem to occa- dermatologist are highly biased and lack proper scientific
sionally improve in response to neurotransmitter-related theory, design, and interpretation of results [96].
drugs, no specific recommendations can be made.
The FLAME trial [86] tested fluoxetine in combination
with standard rehabilitative therapies and reported better Conclusions
Fugl-Meyer motor scores, which tests voluntary movements
against gravity, for those patients who received the drug. Most survivors of a stroke are left with chronic disability.
This work needs to be replicated [87]. The drug may also Rehabilitation efforts during the initial three to six months
provide benefits as an anti-depressant, as depression affects after stroke should aim to maximize patients’ physical,
at least 30 % of patients within one year after stroke. communicative, and cognitive functioning. Continued im-
provement in the chronic phase of stroke can occur with
regular, progressive skills practice of goal-directed tasks in
Cell-based and Biologic Therapies the home [12]. Many new rehabilitation strategies, built
upon attempts to leverage technological developments to
Embryonic and mesenchymal stem cells, cultivated precur- augment the effects of practice, are opening innovative
sors of neurons and oligodendrocytes, and other autologous avenues to amplify gains in performance at any time after
and commercialized cells are actively undergoing investiga- stroke. The future of stroke rehabilitation remains one of
tion as potential treatments for stroke. Cells could replace promise and challenge in treating residual disabilities, espe-
lost neurons or glial cells, remyelinate damaged axons, or cially for testing biological interventions for neural repair in
produce substances such as growth factors that could help the most profoundly affected individuals.
drive network function and plasticity [88]. Several reported
trials have not reported clinical efficacy, but others are being
planned [89, 90]. To be of value, cellular and biologic Conflicts of Interest Bruce H. Dobkin declares that he has no
interventions will have to be combined with applicable conflict of interest.
Andrew Dorsch declares that he has no conflict of interest.
rehabilitation strategies to optimize their incorporation and
action in neural networks.
Off-shore stem cell clinics are all too easy to find on the
Internet. These high-priced cellular interventions can have a
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