REVIEW
Neurorehabilitation of stroke
Sylvan J. Albert • Ju¨rg Kesselring
Received: 25 May 2011 / Revised: 4 September 2011 / Accepted: 8 September 2011 / Published online: 1 October 2011
Ó Springer-Verlag 2011
Abstract Despite ongoing improvements in the acute
treatment of cerebrovascular diseases and organization of
stroke services, many stroke survivors are in need of neurorehabilitation,
as more than two-thirds show persisting
neurologic deficits. While early elements of neurorehabilitation
are already taking place on the stroke unit, after the
acute treatment, the patient with relevant neurologic deficits
usually takes part in an organized inpatient multidisciplinary
rehabilitation program and eventually continues
with therapies in an ambulatory setting afterwards. A specialized
multidisciplinary neurorehabilitation team with
structured organization and processes provides a multimodal,
intense treatment program for stroke patients which
is adapted in detail to the individual goals of rehabilitation.
There are many parallels between postlesional neuroplasticity
(relearning) and learning in the development of
individuals as well as task learning of healthy persons. One
key principle of neurorehabilitation is the repetitive creation
of specific learning situations to promote mechanisms
of neural plasticity in stroke recovery. There is evidence of
achieving a better outcome of neurorehabilitation with
early initiation of treatment, high intensity, with specific
goals and active therapies, and the coordinated work and
multimodality of a specialized team. In this context,
interdisciplinary goal-setting and regular assessments of
the patient are important. Furthermore, several further
potential enhancers of neural plasticity, e.g., peripheral and
brain stimulation techniques, pharmacological augmentation,
and use of robotics, are under evaluation.
Keywords Stroke rehabilitation Á Neurorehabilitation Á
Motor learning Á Recovery Á Plasticity Á Cortical stimulation
Introduction
Stroke is the most common cause of long-term disability in
adults. Although progress in the acute treatment of stroke
(e.g., thrombolysis, the concept of stroke units, dysphagia
management) has occurred over recent years, neurorehabilitation
(mainly as organized inpatient multidisciplinary
rehabilitation) remains one of the cornerstones of stroke
treatment. The overall benefit of stroke units results not
only from thrombolysis—only a small proportion (about
10–15%) of all stroke patients are treated with this regimen—but
also more generally from the multidisciplinary
stroke unit management, including treatment optimization,
minimization of complications, and elements of early
neurorehabilitation [1]. After the acute treatment, stroke
patients with relevant neurological deficits should in general
be treated by a specialized neurorehabilitation clinic or
unit. The best timing for transferring a patient after initial
treatment (e.g., on a stroke unit) to a specialized neurorehabilitation
ward or clinic is dependent on many individual
factors, but early initiation of neurorehabilitation is mandatory
for outcome optimization.
A key point in successfully diminishing negative longterm
effects after stroke and achieving recovery is the work
of a specialized multidisciplinary team with structured
organization and processes which provides a multimodal,
intense treatment program for the stroke patient which is
adapted in detail to the individual goals of rehabilitation.
Neurorehabilitation nowadays is considered as a multidisciplinary
and multimodal concept to help neurological
patients to improve physiological functioning, activity, and
S. J. Albert (&) Á J. Kesselring
Department of Neurology and Neurorehabilitation,
Rehabilitation Center, 7317 Valens, Switzerland
e-mail: s.albert@klinik-valens.ch
123
J Neurol (2012) 259:817–832
DOI 10.1007/s00415-011-6247-y
participation by creating learning situations, inducing
several means of recovery. In this setting, early initiation of
treatment, the application of high intensity with specific
goals and active therapies, and the coordinated work and
multimodality of a specialized team play a major role [2].
Shared goal-setting and assessment is important. Implications
of the International Classification of Functioning,
Disability, and Health (ICF, WHO 2001) are now widely
accepted as a useful tool in goal-setting, making its way
into clinical practice. It adds a social perspective with
emphasis on participation.
In the following review, principles of neural plasticity
and their promotion by means of neurorehabilitation are
described, as well as specific techniques, e.g., brain stimulation
techniques and pharmacological augmentation
(although not all of them are yet part of routine clinical
practice).
Neural plasticity in stroke recovery
While for many decades of the last century it was believed
that, ‘‘once development is complete, the sources of growth
and regeneration of axons and dendrites are irretrievably
lost. In the adult brain the nerve paths are fixed and immutable:
everything can die, nothing can be regenerated’’ [3], a
paradigm shift has taken place. There have been several
reports on observations that therapeutic exercises influence
the course of spontaneous recovery of a brain affection [4].
It has been a long way, however, to what is widely accepted
now, first by measurement of the effects of rehabilitation:
the central nervous system of adult human beings has an
astounding potential for recovery and adaptability, which
can be selectively promoted [5]. The extent of recovery in
stroke is dependent on many factors, the initial size and
location of the cerebral lesion and the degree of success of
recanalization therapies being predominant factors. With a
varying individual relevance, the recovery curve flattens in
the course of time from the initial incidence.
Such recovery of the central nervous system over the
course of time after onset of stroke is possible due to
mechanisms described as neural plasticity or neuroplasticity,
which can be observed and investigated by different
approaches, e.g., from a clinical to a neurobiological and
neuropathological point of view. Hebb [6] first described
neuroplasticity with regard to the function of synapses, and
later this principle was also linked to the functioning of
neurons in the wider context of neuronal networks. The
term ‘‘neural plasticity’’ might refer to transiently achieved
functional changes in the context of learning and recovery,
as well as structural changes (overviewed by [7]) describing
the basis for neural plasticity as plastic changes in the
nervous system which are supposed to occur in four main
ways, including functional changes in synaptic efficacy,
modifying protein synthesis and proteinase activity in
nerve cells, creation of new anatomical connections or by
altering synapses morphologically, and by specific apoptosis.
The role of neurogenesis in human adult stroke
recovery still remains somewhat unclear.
In this context several overlapping and interacting
mechanisms of neural plasticity can be identified [8–13]:
– Plasticity of areas of cortical representation was
described in animal models in connection with the
variable size of cortical representation loco typico of
motor fields [11] and was also demonstrated in humans.
By using transcranial magnetic stimulation (TMS)
mapping in stroke patients, the area of cortical representation
of the abductor minimi muscle (ADM) transiently
increased even after a single training session [14].
These findings suggest a very modifiable functional
cortical representation. Using functional positron emission
tomography (PET) and functional magnetic resonance
tomography imaging (fMRI) different patterns of
activation during recovery have been described [12],
which partly overlap with the following mechanism:
– Vicariation (‘‘vice’’ = instead of) describes the hypothesis
that cortical functions of damaged areas can be
taken over by different regions of the brain. In clinical
practice this ability may vary widely and may be
insufficient for a large group of patients with remaining
difficulties after brain damage. With functional imaging,
however, it could be demonstrated that vicariation
takes place in cortical representation areas. In an
illustrative longitudinal study [15], a small group of
stroke patients with comparable circumscribed M1
lesions (similar to experimental lesions in animal
models) affecting the motor control of the contralateral
hand were assessed over several months. In the first
follow-up, ipsi- and contralateral activation patterns
were noted. After several months, activation was again
ipsilesional and closer to the former representation and
more dorsal for the function of finger extension as
compared with controls, reflecting functional reorganization
in the motor cortex adjacent to the lesion.
To summarize fMRI and PET studies after focal ischemic
brain lesions resulting in motor deficits with damage to
corticospinal tract, it is suggested that interruption of projections
from the primary motor cortex (M1) leads to
increased recruitment of secondary motor areas such as the
dorsolateral premotor cortex and supplementary motor
areas [13]. For this
• For the phase of early compensation in longitudinal
fMRI studies an initial upregulation in primary and
secondary motor regions (ipsi- and/or contralateral)
818 J Neurol (2012) 259:817–832
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but also activity of other nonprimary structures of the
sensorimotor network [13] could be observed, followed
by
• More precise activation patterns with more focused and
efficient brain activity in a later phase reflecting
recovery and accordingly reorganization [16], and
which are—in case of success—reminiscent of normal
activation patterns. A precondition to accomplish this
more successful course is the preservation of a sufficient
amount of specialized cortical and subcortical
brain tissue and especially the pyramid tract.
Persistent activation of many different areas may also
indicate less successful or failed reorganization in chronic
stroke patients: the greater the involvement of the ipsilesional
motor network, the better the recovery. In this
respect, interactions between lesional and contralesional
hemisphere may also play an important role [17–19].
However, many problems of imaging of stroke recovery
remain unsolved.
Basic underlying mechanisms of these findings include
both different functional use of existing networks and
synapses, but also structural changes. In the early course of
ischemic stroke, pathophysiological mechanisms in the
perilesional region are initiated, which include enhanced
expression of plasticity-related proteins, neurotrophic factors
(e.g., brain-derived neurotrophic factor, synapsin I),
and certain neurotransmitters, but also expression of
inhibitory factors occurs in the central nervous system
[20, 21]. These modifications probably lead to morphological
changes, e.g., synaptic plasticity and sprouting,
especially in the first weeks after stroke [22]:
– Synaptic plasticity refers to the altered synaptic function
when cells are communicating, leading to plastic
changes, stated as ‘‘cells that fire together, wire
together’’ by Hebb [6]. Changes in synaptic activity
can be measured by alterations in the number of, e.g.,
N-methyl-D-aspartate (NMDA) receptors and are morphologically
seen as ‘‘spines’’ between two neurons.
– Sprouting of axons and dendrites occurs in cortical
regions ipsi- and contralateral to the stroke lesion, as
demonstrated in animal model [23, 24]. Further results
from research in human recovery can be expected by the
use of MR diffusion-tensor tractography imaging (DTI),
which has been regarded as a useful method in showing
the relationship between structural corticospinal tract
damage and motor task-related cortical activity in
chronic hemiparetic stroke patients [25] as well as in
quantification of connectivity [26]. However, no longitudinal
studies of larger sample size in the course of
recovery are published. Sprouting of dendrites is more
common than sprouting of axons or neurogenesis.
Collateral sprouting can lead to a change of function in
neurons in a damaged network by receiving new synaptic
input from dendrites of nonlesioned sprouting neurons.
– Diaschisis is a term used by Von Monakow [27] to
describe the phenomenon that a focal lesion may also
lead to changes in brain functioning of areas located far
away. An example demonstrated by several recent
neuroimaging studies is enhanced contralesional cerebellar
activity after cortical infarction.
– Furthermore, enriched environment as a driver of
neuroplasticity has been demonstrated in animal models
[13]: rats with ischemic lesions due to middle
cerebral artery occlusion showed much better recovery
when held in an enriched environment with free access
to physical activity and social interactions [28].
Recent connectivity studies reviewed by [29] address
functional network interactions and changes in neural networks
after stroke, increasingly offering implications for
better understanding of neural plasticity and findings of
functional imaging during recovery as well as intervention
effects on connectivity. Especially primary M1, dorsal and
ventral premotor cortex, supplementary motor area, parietal
cortex, secondary somatosensory cortex, and prefrontal
cortex were considered in connectivity models. A major
finding is enhanced interhemispheric coupling between
homotopical areas as a common feature of reorganized resting-state
networks after stroke, which is, however, often paralleled
by a reduced network efficiency in these patients [29].
Inducing and promoting neural plasticity
There are many parallels between postlesional neuroplasticity
(relearning) and human learning as part of personal
development, education, or training leading to changes of
behavior and abilities or knowledge, e.g., by repetitive
interactions with the social environment. In clinical neurorehabilitation,
the main effect of the multidisciplinary
teamwork and applied therapies is to create repetitive
specified learning conditions and a stimulating learning
atmosphere in a defined way and considering interdisciplinary
treatment goals that match the patient’s individual
needs and deficits. This is achieved by therapeutic sessions
(see below) and methods as well as in everyday life on the
neurorehabilitation ward in interactions with physicians,
nursing team, therapists, and others, in which the patient is
guided to the highest meaningful degree of mental and
physical activity. A valuable didactical principle to force
the individual to learn is the use of constraint-induced
therapies (CIT), which, however, cannot be used in the
treatment of the majority of stroke patients (see below). In
addition, other stimulation techniques and enhancement by
use of medications are under evaluation, as overviewed in
the following section.
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Supporting neural plasticity by peripheral and noninvasive
electromagnetic brain stimulation techniques
Although not yet recommended for clinical routine, several
trials have been undertaken and are currently ongoing to
evaluate noninvasive cortical stimulation techniques with
the purpose of enhancing neuroplasticity and recovery,
using clinical outcome measures or fMRI. The main
techniques are repetitive transcranial magnetic stimulation
(rTMS) and transcranial direct current stimulation (TDCS),
which can be used for both cortical enhancement and
inhibition, depending on the setup parameters. Furthermore,
epidural electrical stimulation (EES) is an invasive
approach using a grid of electrodes implanted neurosurgically.
Therefore, its practical use in stroke patients is
limited.
Beside therapeutically modifying cortical activity in
certain cortex regions (e.g., motor or language-related
areas), which might be altered by damage or indirectly due
to mechanisms of neuroplasticity (see above), another
important theory behind influencing cortical activity is the
hypothesis of contralesional hemisphere overexcitability
[17–19]. To simplify, due to interhemispheric imbalance
after damage caused by overfunction of the nonlesioned
hemisphere, further negative functional effects with considerations
for recovery can occur. The main approaches to
brain stimulation are to increase the excitability of the
cortex in the ipsilesional hemisphere and/or suppression of
the contralesional hemisphere. This can be achieved noninvasively
in conscious humans using rTMS and TDCS.
In rTMS, an electric current is induced in the underlying
cortex by a magnetic field, which then activates the axons
of cortical neurons. Low-frequency rTMS around 1 Hz
results in decreased cortical excitability (which persists
after the application of rTMS) and is therefore used on the
contralesional hemisphere for downregulation. Higher
frequencies of more than 5 Hz increase cortical excitability
and can be applied to stimulate the cortex on the ipsilesional
hemisphere. Special patterns of rTMS (theta bursts)
have also been established and are reported to have longerlasting
modulatory capacity [30–33].
In TDCS, two electrodes (one active and one reference)
are placed on the skin, delivering weak polarizing electrical
current leading to different effects in the cortex, depending
on the polarity: anodal TDCS has an excitatory effect,
cathodal TDCS induces inhibition via presumed hyperpolarization.
Usually 10–20 min of TDCS at 1–2 mA is
regarded as safe and painless.
With the application of these newer treatment methods
in stroke patients, recent findings suggest a 10% functional
improvement in single sessions, and about 20% (up to
30%) in multiple sessions has been reported. Long-term
effects are widely unknown. As far as is known now,
cortical stimulation appears to be a safe and promising
intervention for stroke patients; however, more trials are
needed to assess the long-term benefit and to optimize
protocols [34, 35]. In a consensus paper [36], standards for
practical application in research and clinical practice for
diagnostic and therapeutic TMS are suggested. Main
potential (although rare overall) side-effects include seizure
induction, possible syncope, transient headache or
local pain, transient hearing changes, transient cognitive or
neuropsychological changes, burns from scalp electrodes,
and others. Also, a standard screening questionnaire for
rTMS candidates is provided, and ethical and regulatory
issues are discussed as well as protocols, with a supplementation
[37] according to a theta-bursts protocol.
However, many questions remain to be solved, including
patient selection, optimal stimulation parameters, and
localization, as well as the combination with other types of
interventions.
Furthermore, peripheral sensorimotor techniques to
improve voluntary movement control as well as functional
motor ability by indirectly influencing cortical activity
have been evaluated [38]. In a recent Cochrane review it is,
however, concluded that there is still insufficient robust
data to suggest clinical use of electrostimulation for neuromuscular
retraining [39] (Fig. 1).
Fig. 1 Stroke-related hemispheric imbalance (see text) is a target of
brain stimulation techniques. Repetitive transcranial magnetic stimulation
(rTMS) or transcranial direct current stimulation (TDCS) as
the main noninvasive brain stimulation techniques in stroke recovery
research can be used for cortical enhancement as well as inhibition,
depending on the setup parameters used:
Unaffected hemisphere
Decrease excitability
- cathodal TDCS
- inhibitory low-frequency rTMS (including
Affected hemisphere
Increase excitability
- anodal TDCS
- excitatory rTMS > 5Hz
theta burst protocols)
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Supporting neural plasticity by pharmacological
interventions
Pharmacological interventions can address several brain
neurotransmitter systems that have been identified to be
related to motor learning, e.g., glutamate, acetylcholine,
5-hydroxy-tryptophane, noradrenaline, and dopamine.
Drugs have been studied in animal models, healthy volunteers,
and stroke patients in single or multiple dosages,
with and without additional therapeutic tasks. No single
medication evaluated for its beneficial effect of modulating
plasticity in the human M1 in stroke patients has reached
class I evidence so far. Several studies using this approach
have been conducted for motor learning as well as aphasia
therapy, but the results of some studies are contradictory.
Especially levodopa, D-amphetamine, methylphenidate,
donepezil, reboxetine, and fluoxetine are found to be beneficial
in trials evaluating motor and/or aphasia recovery
after stroke, but in one study D-amphetamine was found to
have no effect [40–45]. In a recent study including 118
patients in a multicenter setting, fluoxetine was found to be
beneficial (initiated 5–10 days after onset of stroke) in
addition to standard inpatient rehabilitation in terms of
promoting motor recovery and independence, demonstrated
by significantly better scores using Fugl–Meyer and
Rankin scales than in the placebo group [46]. The noradrenergic
enhancement of reboxetine was found to be beneficial
in reduction of cortical hyperactivity, especially in
the ipsilesional ventral premotor cortex and supplementary
motor area, as well in improvements of pathological hypoconnectivity
of ipsilesional supplementary motor area
with the primary M1 [45], leading to functional improvements.
For further description of models of functional
network interactions and changes in neural networks after
stroke, refer to [29].
However, still larger controlled trials are needed, and
findings need to be replicated and patient selection criteria
reapproved before pharmacological augmentation can be
generally recommended; some trials are ongoing.
Meanwhile patients presenting reduced ability to take
part in therapies due to diminished alertness and drive
should be carefully evaluated for poststroke depression
first. If treatment with stimulating antidepressants is not
successful or not possible, use of levodopa or a central
stimulating agent may be an alternative treatment option,
considering regulative issues of ‘‘off-label’’ use. In a single-center
observational study with various drugs, pharmacological
augmentation was regarded as relatively safe
[48].
Negative effects on outcome were noted for benzodiazepines,
haloperidol, prazosine, and clonidine [47], leading
to the advice to rather avoid these drugs during
rehabilitation.
Structured multidisciplinary neurorehabilitation
Importance of multidisciplinary teamwork for stroke
recovery
According to a large meta-analysis (n = 1,437), the benefit
of postacute treatment in organized inpatient multidisciplinary
rehabilitation (as compared with treatment on a
general ward and other nonspecific rehabilitation clinics) is
associated with reduced odds for death, institutionalization,
and dependency. According to differences in place of stay
with respect to independence after poststroke rehabilitation,
of 100 patients treated by organized multidisciplinary
neurorehabilitation (as compared with general medical
treatment), an extra 5 returned home in an independent
state [49].
The amount of rehabilitation treatment in the acute
phase may vary widely, as a multicenter study examining
physical activity within the first 14 days of acute stroke unit
care has shown: in the daytime, patients spent more than
50% of the time resting in bed, 28% sitting out of bed, and
only 13% engaged in activities with the potential to prevent
complications and improve recovery of mobility. Furthermore
patients were alone for 60% of the time [50]. The best
timing for transferring a patient after initial treatment to a
specialized neurorehabilitation ward or clinic is still under
discussion, and concerns regarding optimal timing and
intensity might also contribute to the problem.
After acute stroke treatment, medically stable patients
with relevant neurological deficits should be treated in a
specialized neurorehabilitation clinic or stroke unit in an
in- or outpatient setting to take advantage of the impact of
the work of a specialized multidisciplinary team with
structured organization and processes: the patient takes part
in a multimodal, intensive treatment program which must
be adapted to the individual goals of rehabilitation with
regular interdisciplinary reevaluation.
A short and useful definition for organized inpatient
multidisciplinary rehabilitation includes [49]: (a) interdisciplinary
goal-setting; (b) input from a multidisciplinary
team of medical, nursing, and therapy staff with expertise
in stroke and rehabilitation whose work is coordinated
through regular weekly meetings; (c) involvement of
patients and family in the rehabilitation process; and (d) a
program of staff training (Fig. 2).
This approach should be centered on the individual
patient and family/caregivers, interacting closely with a
multidisciplinary team consisting mainly of physicians,
nursing experts, physical and occupational therapists,
kinesiotherapists, speech and language pathologists (SLP),
psychologists, recreational therapists, and social workers
[2]. The required equipment in a neurorehabilitation
department must be defined in detail to ensure structural
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quality. A description of medical and organizational processes
using a quality management system and ‘‘learning
from mistakes,’’ e.g., using a critical incidence reporting
system (CIRS), is also important for rehabilitation centers.
At the onset of the rehabilitation process, a multidisciplinary
assessment of deficits and resources is mandatory,
including clinical neurological examination, assessment of
functional performance, activities of daily living (ADL),
social and personal background, and coping strategies. To
achieve recovery of physical and psychological functions
and to reintegrate the patient into his/her social environment,
therapies and other interventions must be adopted to
the individual abilities and stroke-related deficits. In the
course of rehabilitation, the patient’s progress and abilities
are critically discussed and reevaluated in the multidisciplinary
team in at least weekly sessions, with adaptation
and reconsideration of treatment strategies and goals (see
below) if necessary [51].
Early mobilization, initiation, and intensity of therapies
In addition to thrombolysis, the multidisciplinary management
in a stroke unit or by a stroke team has been
shown to improve outcome significantly by reducing death
rates and dependency [number needed to treat (NNT) 7 for
thrombolysis versus NNT 9 for stroke unit treatment] [1].
The positive effect of stroke units is achieved by structural
organization and interdisciplinary management, but also by
early use of elements of neurorehabilitation. In a recent
study, early mobilization within 24 h after onset of stroke
of the medically stable patient led to better and faster
walking ability, and the group with later mobilization could
not catch up during study monitoring [52].
Clinical studies indicate that early start and high intensity
of therapies are decisive for favorable long-term outcome.
On the basis of pathophysiological data, the first
3 weeks after stroke are considered as a particularly
promising period: in animal models, active training leads to
better functional recovery and sprouting, whereas inactivity
results in additional loss of ability [10, 22, 24]. However,
some experimental studies in rats show that very early
(starting within 24 h) and intense forced activity could lead
to an enlargement of lesion areas. The occurrence of these
negative consequences is explained by cytotoxic effects of
glutamate, metabolic collapse of the penumbra region,
inhibition of upregulation of signal proteins, focal hyperthermia,
and other factors [53–55]. The transfer of some
results of animal studies to human stroke recovery seems
questionable, as some animals were forced to action during
their whole wake-time. Other recent animal studies, however,
support early initiation of appropriate activation.
Early motor activation after focal ischemia starting at day 5
had a superior outcome (functional measures and more
dendritic sprouting) as compared with a later beginning (at
days 14 and 30) [22] with similar results replicated in other
studies [56].
Clinical data are consistent with these findings. In
humans, however, other factors should be taken into
account: immobilization increases the rate of complications
after acute stroke, including thrombosis, infections,
Fig. 2 The patient-centered
model of multidisciplinary
specialized neurorehabilitation
includes assessment, individual
goal-setting, multimodal
therapies, and reevaluation. The
work of the multidisciplinary
team of medical, nursing, and
therapy staff with expertise in
stroke rehabilitation is
coordinated through regular
weekly meetings with
involvement of patients and
family in the rehabilitation
process
822 J Neurol (2012) 259:817–832
123
deconditioning, and ulcers. Early mobilization in the first
days and structured training at an early stage on a stroke
unit enhances the rate of discharges to the home with a
lower degree of disabilities, as compared with later activation
on a medical ward [57]. Better long-term outcome is
reported in stroke patients with early start of an organized
inpatient multidisciplinary rehabilitation within 7 days in a
multicenter study (n = 1,760) with reduction of disability
and better quality-of-life measures [58]. In another large
study (n = 969) specifically examining the impact of
timing of initiation of neurorehabilitation and functional
recovery, a highly significant correlation of early treatment
start and functional outcome was detected [59]. Not only
early initiation of treatment but also the intensity of rehabilitative
therapies is of significant importance, as shown in
a meta-analysis [60] with higher mobility, autonomy, and
improved executive functions when different therapeutic
modalities are performed with increased intensity. Therapy
intensity was also related to shorter lengths of stay and
to improvements in patients’ functional independence.
A higher intensity of therapies can also be achieved by
additional use of rehabilitation robotics in the multidisciplinary
approach, as established for arm functioning and
walking (see below).
To summarize:
– Standard immobilization after stroke for several days is
counterproductive (and should be reserved for specific
rare situations, e.g., in the case of unstable brain
perfusion due to arterial stenosis);
– An appropriate amount of activity should take place
very early after onset of stroke;
– This should include the initiation of specific and
intense, individually adapted neurorehabilitation of
the medically stable patient, ideally within the first
days after stroke, with clinical monitoring of the event
of mobilization;
– The course of treatment should include a high proportion
of multimodal therapies.
Goal-setting and assessment in stroke rehabilitation
Most widely accepted is the International Classification of
Functioning, Disability, and Health (ICF) proposed by the
World Health Organization (WHO) in 2001. In determining
treatment goals, the medical model is extended by adding a
social perspective and defining participation as an important
objective. Treatment goals measure the physical and psychological
status, examining the impact of deficits on social
aspects such as everyday life, social communication, or
ability to work. Even if some somatic functions cannot be
regained directly, higher social goals can be reached by
establishing compensatory strategies. Interdisciplinary
goal-setting is crucial for determining the exact treatment
schedule, for estimating the duration of neurorehabilitation,
and for evaluating rehabilitative potential (Fig. 3).
Assessment in stroke is crucial to demonstrate the course of
recovery and benefit of neurorehabilitation, and also to deliver
instruments for research purposes. It adds evaluation of
quality of life to activity as an outcome parameter. Activity
can be assessed by activity scales and scales of activities of
daily living. Activity scales evaluate abilities and have their
value in detailed measurement of aspects of specific therapies
Health condition - Stroke
Environmental factors Personal factors
ActivitiesBody functions
and -structures
Participation
Functions: muscle activity,
coordination, spasticity, ...
Structures: upper and lower limbs, ...
Inhibitors or Enhancers
Performing an activity or task
e.g. clothing, walking stairs,
communication, ... e.g. using public transportation,
working, living with the familye.g. hemiparesis, aphasia,
apraxia, ...
e.g. help from family,
easy accessability of domicile , ...
e.g. other comorbidities , physical fitness, ...
Location, size of lesion, timing, ...
Taking part in social and/or
family life
Fig. 3 The International
Classification of Functioning,
Disability, and Health (ICF)
proposed by the WHO
transforms ‘‘disability’’ of the
former WHO concept to
‘‘activity’’ and stresses the
interrelation of several
components (activity, body
functions, and structures), as
well as participation, with
interrelation to two context
factors: environmental and
personal factors, which might
have an enhancing or inhibiting
effect (figure adapted and
examples added from the
International Classification of
Functioning, Disability, and
Health, World Health
Organization, 2001)
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or in motor function research. For a description of the scales
refer to [61] or for a shorter overview to [62]. Stroke-specific
instruments include the Stroke Impact Scale (SIS) [63], which
is a self-report (patient and caregiver) health status measure to
assess multidimensional stroke outcomes.
Methods and subtopics
Concepts of physiotherapy
The predominant common concepts of physiotherapy, i.e.,
the Bobath, Brunnstrom, proprioceptive neuromuscular
facilitation (PNF), Vojta, and other methods, have in common
that they claim to have a neurophysiological basis in
which, e.g., facilitation and inhibition play a basic role.
From an evidence-based point of view there is no doubt
about the benefits of physiotherapy, but there are not sufficient
data available to identify one of these special concepts
as superior to another, as reviewed by [64]. Those authors
concluded that patients treated with physiotherapy benefit
from an intense training program with complex functional
tasks and early application after onset of stroke, but not from
programs that mainly focus on the impairment itself.
Motor rehabilitation
Motor impairment is the most common deficit in stroke,
often resulting in reduced independence and mobility.
Beside the concepts of physical, occupational, and other
therapies, the following methods are aimed especially at
motor recovery.
Treadmill training and gait machines
Walking is an important objective in stroke rehabilitation,
conventional gait training programs on the floor being
routine practice. With the aim of enhancing efficacy of gait
training and also of easing the burden on the therapists,
three groups of treadmill training concepts have been
developed and evaluated:
– Body-weight supported treadmill training (BWSTT):
partial body-weight support can be used to gain better
stepping kinematics in stroke patients unable to walk;
– Treadmill training without body-weight support;
– Robotic-assisted gait training (RAGT) using ‘‘gait
machines,’’ such as the Lokomat or Gait Trainer GTI,
in addition to BWSTT can provide a ‘‘gait pattern’’
even for seriously paretic limbs.
In rehabilitation practice these methods are used in
addition to conventional modalities, leaving no doubt about
the benefit in terms of easing the burden on therapists and
overall being regarded as useful for certain patients. In
addition, measurement of gait indicators such as velocity
and distance can be easily monitored. Several studies have
investigated the efficacy on different outcome parameters of
gait [65–69]. Some of the studies can be criticized for low
treatment contrast, since control groups also received
intense conventional training, and in addition different
outcome parameters and intensities make comparison of the
results harder. However, a meta-analysis [70] concludes
thatthere is weak evidence for overall effectiveness in
improvement of gait endurance. The authors recommend
that currently BWSTT should be reserved for patients whose
physical condition is too weak to tolerate intense training.
Gait training devices in stroke rehabilitation (their
benefit having already been shown in neurorehabilitation of
multiple sclerosis [71]) are currently being investigated
regarding the potential benefit for walking training as well
as for certain subgroups of stroke patients. It has been
assumed that there might be an additional benefit for
patients with neglect or pusher syndrome. In a recent study,
patients took part either in conventional training or in
robotic-assisted gait training, and the participants of the
conventional group had better benefits, e.g., in improving
their walking speed. The authors conclude that, for subacute
stroke participants with moderate to severe gait
impairments, the diversity of conventional gait training
interventions appears to be more effective than roboticassisted
gait training for facilitating returns to walking
ability [72]. However, benefits were found when integrating
treadmill training with structured speed dependence as
a complementary tool in gait rehabilitation of stroke
patients including physiotherapy, resulting in better gait
speed and cadence after a 2-week training program for
hemiparetic outpatients. These findings were recently
reproduced [73]: at the end of a 6-week trial including 67
patients in the first 3 months after subacute stroke, the
subgroup that received locomotor therapy with the use of
RAGT combined with regular physiotherapy showed
promising effects on functional and motor outcomes as
compared with regular physiotherapy alone, as expressed
by a greater functional ambulatory capacity score and in
their neurological status according to the National Institutes
of Health Stroke Scale (NIHSS). However, for the
primary outcome point (ability to walk independently)
there were nonsignificant differences between the groups.
It is therefore concluded [74] that patients who receive
robot-assisted training in combination with physiotherapy
after stroke are more likely to achieve better motor function
than patients trained without these devices, or only
with these devices. Further data need to be collected.
Gait training with rhythmical acoustical pacing was
found to be useful with or without further technical support.
Auditory stimulation was successfully combined with
824 J Neurol (2012) 259:817–832
123
treadmill training [75], resulting in gait symmetry improved
with acoustic pacing. Nonblinded studies illustrate the
positive effect of conventional gait training with rhythmic
cueing by a metronome or embedded in music, resulting in
better stride length and walking speed [76, 77] (Fig. 4).
Constraint-induced therapy (CIT)
The principles of constraint-induced therapy (CIT) or
constraint-induced movement therapy (CIMT) were
described by Taub in 1993 [78], who argued that, after
stroke patients try unsuccessfully to use the affected side,
discouragement due to initial failure leads to ‘‘learned
nonuse.’’ However, the relevance of CIT to practical neurorehabilitation
and experimental neuroscience came later
as three principles for this kind of therapy were formulated,
consisting of constraining the unaffected limb, forcing use
of the affected limb, and intensive practice. Using this
method for motor rehabilitation of the upper limb is possible,
if a selective function for the paretic wrist and fingers
is present before initiation of treatment with CIMT.
Therefore, its use as a general treatment method in stroke is
limited. A placebo-controlled study applying CIMT over a
2-week period in patients with stroke onset at 3–9 months
before therapies showed highly significantly greater
improvements than in the control group in motor and
functional improvement [79], still detectable at 2-year
follow-up [80]. In a recent review including further studies,
it was stated that the performed trials according to CIMT
delivered a large effect size and showed robust effects on
arm function, but not on hand function [81].
Repetitive training, aerobic exercises, and specific muscle
strength training
According to learning theories and knowledge derived
from studies of neuronal plasticity, repetition of tasks in
rehabilitation to achieve better functional outcome is
mandatory. A review of repetitive task training after stroke,
however, revealed modest improvement in lower limb
function only, not in upper limb function [82].
Stroke patients do not only suffer from neurological
deficits but also to varying extents from physical deconditioning
and sometimes also from cardiac comorbidity.
Several studies address the possible benefit of general
strengthening and aerobic exercises. In a retrospective
analysis, whole-body intensive rehabilitation was found to
be feasible and effective in chronic stroke survivors [83]. In
an observational study, aerobic capacity and walking
capacity were found to be decreased in hemiplegic stroke
patients but were directly correlated with each other [84].
Adding physical fitness programs, e.g., by water-based
exercise for cardiovascular fitness in stroke patients [85] or
task-related circuit training [86, 87], was found to be useful,
leading to better outcome not only in physical fitness
but also in various secondary measures such as walking
speed and endurance, muscle strength, and others.
One concern in specific muscle strength training is
increasing abnormal tone, leading to worsening of functional
recovery. However, current opinions based on
acquired data have changed; e.g., an observational study
[88] showed that targeted strength training significantly
increased muscle power in patients with muscle weakness
of central origin without any negative effects on spasticity.
Instead, it was beneficial for functional outcome, showing
that strength is related statistically to functional and
walking performance.
Robotics for upper limb rehabilitation with/without
elements of virtual reality
It has been stated that an estimated 30–60% of adult patients
after stroke do not achieve satisfactory motor recovery of the
upper limb despite intensive rehabilitation [89, 90]. Therefore,
robotics for upper limb rehabilitation and elements of
virtual reality (VR) have been combined in several technical
devices and used for therapy and studies. In a recent metaanalysis
of robot-assisted therapy of upper limb recovery
after stroke, only a subsequent sensitivity analysis showed a
significant improvement in upper limb motor function. No
significant improvements were found in ADL function [91].
It has been concluded that larger samples, adequately controlled
study design and follow-up, greater homogeneity in
selection criteria, and parameters measuring severity of
stroke, motor impairment, and recovery are necessary [89].
For an overview of different available robotics refer to [92].
Comparable to gait machines, some devices provide training
programs even for severely paretic limbs.
Virtual reality (VR) is a relatively recent approach that
(in combination with robotics or interfaces) may enable
Fig. 4 A stroke patient using a ‘‘gait machine’’ in robotic-assisted
gait training (RAGT) under supervision of a physiotherapist
J Neurol (2012) 259:817–832 825
123
simulated practice of functional tasks at a higher dosage
than traditional therapies and therefore enhance the effect
of repetitive task training as described above [93]. VR uses
computer technology to create environments that appear
similar to real-world objects and situations, and furthermore
VR technology has the capability of creating an
interactive, motivating environment in which practice
intensity and feedback can be manipulated to create individualized
treatments to retrain movement [89, 93].
Beside the development of robotics and VR devices for
rehabilitation purposes, there has been rising interest in
the use of available ‘‘off-the-shelf’’ gaming consoles, as
models with sensors are available that enable participants
to interact with games while performing wrist, arm, and
hand movements [94, 95], but more data need to be collected.
As there is a demand for cost-effective therapies
and augmentation of therapies, also having in mind the
worldwide burden of stroke in countries with lesser
capacities to spend money on medical devices, further
studies are regarded as valuable.
Mirror therapy
In mirror therapy a mirror is placed at 90° close to the
midline of the patient and the affected limb is positioned
behind the mirror. Using this arrangement, the patient is
instructed to watch the nonaffected limb in the mirror
with both eyes and perform exercises. Thereby, he
receives the visual impression that the limb in the
mirror—attributed as the affected limb—is now fully
functioning. The role of mirror therapy in motor rehabilitation
is not yet clear, but recently, after methodologically
weak publications, a promising randomized
controlled trial (n = 40) has been published for upper
limb rehabilitation of subacute stroke patients with severe
motor affection without aphasia or apraxia [96]: approximately
1 h of mirror therapy daily in addition to a conventional
rehabilitation program was more beneficial in
terms of motor recovery and hand-related functioning
than a similar treatment without mirroring. The beneficial
effect on hand functioning started posttreatment and
continued during the 6-month follow-up evaluation, as
rated by Functional Independence Measure subscales.
Several underlying mechanisms have been discussed, e.g.,
substitution of mirror illusions of normal movement of the
affected hand for decreased proprioceptive information,
thereby helping to activate the premotor cortex and promoting
rehabilitation by enhancing connections between
visual input and premotor areas [97]. Contralateral activation
of visual fields was also shown using fMRI [98],
with the result that healthy subjects view their hand as
their opposite hand by mirroring, activating the visual
cortex opposite to the seen hand. Mirror therapy could be
an additional option for rehabilitation of severely paretic
limbs, but more data need to be collected.
Mental practice
Several studies examined the additional use of mental
practice with motor imagery in stroke patients, especially
of the upper limb. While some studies reported promising
results with improvements of motor functions, e.g.,
[99–101], there have also been reports of no benefit [102].
Although the results of several publications suggest that
mental practice can be a promising addition in motor
rehabilitation of the severely affected limb, the role of
mental practice for clinical routine remains unclear by
now, and well-designed studies with sufficient numbers of
patients are needed [103]. There is also a lack of a current
meta-analysis of existing data, which is in preparation by
the Cochrane Collaboration.
Treatment of spasticity
Although spasticity as a consequence of stroke might also
have certain beneficial compensatory aspects, it can in many
cases also lead to increased disability, loss of function,
diminished voluntary movements in paretic limbs, pain, and
hindered care, and also carries the risk of secondary complications.
The treatment of spasticity requires mainly
physiotherapy, nursing care, occupational therapy, and in
many cases orthotic management. However, if physical
treatment reaches a limit, for generalized symptoms of
spasticity one might want to consider the option of oral
agents and intrathecal baclofen, although in most cases
orally given medication such as baclofen in cortical or
subcortical stroke has a disappointing effect versus sideeffect
ratio. In focal or sometimes multifocal spasticity,
botulinum toxin as part of a longer-term strategy is often a
successful treatment option, requiring patient assessment
and selection, with definition of the goals of treatment [104].
As several products of botulinum toxin A and B with different
rates of effectiveness per unit are available, documentation
of the product used is indispensable. In a recent
European consensus paper, it is stated that there is evidence
from about 20 randomized controlled trials that the treatment
leads to a decrease in muscle tone and improved passive
functions, including reduced impairment and improved
participation, and also growing evidence to show that
decreasing spasticity results in active functional improvements
[105]. In general, patient selection for this treatment is
very important, leading to cost-effectiveness of the treatment
of poststroke spasticity with botulinum toxin as part of
general management. If multimodal treatment of spasticity
(maybe also considering serial casting) fails, surgical therapy
in some cases may finally be a therapeutic option.
826 J Neurol (2012) 259:817–832
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Rehabilitation of speech disorders
Aphasia with its affection of different modalities, including
speech, comprehension, reading, and writing, is a common
consequence of stroke, mainly of the left hemisphere.
Because of its enormous impact on patients’ lives, rehabilitative
therapy is mandatory [106]. Even more than in
other therapeutic modalities, the importance of high treatment
intensity has been demonstrated: a meta-analysis
[107] shows that studies which demonstrated a significant
treatment effect of speech therapy on average provided
8.8 h of therapy per week for about 11 weeks. In contrast,
the negative studies only provided an average of 2 h per
week for about 23 weeks. Furthermore the total number of
hours of aphasia therapy applied were directly related to
outcome, as measured by the Token Test, for example.
In the acute stage, intense daily therapies are recommended.
While spontaneous recovery can also be expected
to some extent within the first year, only a minimal effect
size is reported after 1 year post onset [106]. Therefore,
there is a need for therapy in chronic aphasia and an appeal
for episodic concentration of therapies has been made, as
positive effects were found after intensive (3 h/day) shortterm
(10 consecutive days) intervention using communication
language games in a group-therapy setting [108].
For transfer of results from the therapeutic situation to the
patients’ environments, there is also an indication for
lower-frequency therapies of long duration. The effect of
aphasia therapy was also demonstrated using PET [109].
From functional imaging it is known that clinical aphasia
syndromes in practice are not strictly linked to anatomical
regions and furthermore, with these methods, the courses of
recovery and less successful progress can be revealed
[110, 111], showing that successful regeneration from
poststroke aphasia depends more on the integration of
available language-related brain regions than on recruiting
new brain regions. Using PET and rTMS interference,
restoration (for the right-handed patient) of the left hemisphere
network seems to be more effective, although in
some cases right hemisphere areas are integrated successfully.
As summarized by [112], responses due to tasks and
therapies in the right superior temporal gyrus especially in
Wernicke’s patients and in the inferior frontal gyrus are
seen, but restoration of language is usually achieved only if
left temporal areas are preserved and can be reintegrated
into the functional network. Furthermore, the existence of a
dual-pathway network for language and recovery with
different functions for repetition and comprehension has
been described, showing that the ‘‘classic’’ connection
between motor and sensory speech center, the arcuate
fascicle, is active during language repetition, even of
pseudowords [113], whereas the function of language
comprehension is linked to the integrity of the ventral
pathway through the extreme capsule, providing therefore a
different anatomical course (implicating a potentially different
location of damage) of these routes. These elaborated
findings of contemporary neuroscience can be linked
to already similar historical concepts of the scientists
Wernicke, Lichtheim, Freud, and Geschwind [114, 115].
Several studies examined the additional benefit from
brain stimulation techniques [116] and medication [42] on
recovery from aphasia with positive results. However, it is
premature to deduce a recommendation for clinical routine,
as for aphasic patients there is currently not enough evidence
that these task-specific improvements are persistent
or have any impact on real-life communication abilities
[117]. Dysarthria is an impairment of speech intelligibility,
which in about half of cases is due to lacunar syndromes,
and although severe persistence exists, this symptom is
supposed to have a rather good prognosis under standard
rehabilitation [118].
Dysphagia
Dysphagia is a potentially life-threatening complication, and
stroke is the most common cause of neurogenic swallowing
disorder. Dysphagia occurs in the acute state of stroke in
more than 50% of patients, probably leading to aspiration in
more than about 20% of them. In a meta-analysis of more
than 15 studies using techniques such as fiber-optic endoscopic
examination of swallowing (FEES), dysphagia rates
between 30% and 78% were found [119, 120].
The main dangers of dysphagia are (a) bolus, leading to
acute blockage of airways, (b) pneumonia due to aspiration,
and (c) malnutrition and/or dehydration.
On the other hand, swallowing and food intake are
important for quality of life and autonomy of patients and
will for many patients be considered an important goal of
rehabilitation. If a stroke patient presents with warning
signs and/or has failed a bedside test, at least three main
targets should be considered: (a) avoiding aspiration:
mandatorily discontinue oral food/fluid intake until a
detailed treatment plan is set up; (b) nutrition and hydration:
choose an alternative pathway, e.g., nasogastric tube
or in many cases percutaneous endoscopic gastrostomy;
and (c) quality of life, regaining autonomy: continuing
diagnosis and description of the swallowing problems
previous to individual therapy during the process of rehabilitation,
which in most cases will include technical
evaluation. For a further overview refer to [62] and for a
description of screening protocols to [121, 122].
Cognitive recovery of stroke
Besides defined neuropsychological syndromes, cognitive
impairment after a stroke is very common and may persist
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in the postacute and also the chronic phase. Individual
assessment includes evaluation of several aspects of attention,
intelligence, memory, executive functions, and personality
prior to devising an individual treatment schedule,
which can be neuropsychologically specific but should also
be interdisciplinary, as the impairment usually has an impact
on several aspects of the rehabilitation progress and the
ability to cope with the activities of daily living. Depending
on treatment goals, a more practical evaluation including
out-of-hospital observations can also be useful. For detailed
guidelines on cognitive rehabilitation refer to [123].
Spatial neglect
Spatial neglect is a common syndrome following stroke,
most frequently of the right hemisphere, predominantly but
not exclusively of the parietal lobe. It is a complex deficit
in attention and awareness which can affect extrapersonal
space and/or personal perception. Elements of spatial
neglect may be seen also with infarctions of the left
hemisphere; however, symptoms are clinically less consistent
than in right hemispheric neglect [124].
The therapeutic process is often prolonged. In multidisciplinary
neurorehabilitation, perception via the affected
side is enforced as much as possible, and additional alertness
training as well as visual, proprioceptive, and vestibular
stimulation techniques are used [125]. In addition to
focal disturbances, in this condition an interhemispheric
imbalance is supposed to be of clinical relevance. Therefore,
several pilot studies have been published to evaluate
the benefit of cortical stimulation techniques in neglect
therapy, addressing the contralesional hemisphere overexcitability
as a central pathophysiological mechanism in
hemispatial neglect. Using a special rTMS protocol with
theta burst, improvements were described in a pilot study
even after a single session [126]. For a review on available
data refer to [127].
Other neuropsychological syndromes
Hemianopia can be combined with neglect syndromes and
has in any event a large impact on daily activities that
appears in problems in reading, orientation, and safety in
traffic. Basic rehabilitative management includes stimulation
from the hemianopic side (e.g., positioning of the bed,
talking to the patient) and tasks with exploration to the
hemianopic side. While spontaneous recovery might occur
at least up to several months, treatment options such as
visual field training are discussed controversial. Using
compensatory visual field training, compared with a control
group no formal change of visual defect was reported by
[128], although the training improved detection of and
reaction to visual stimuli. Other groups recently reported
improvements of the visual field of up to 5% for ischemic
lesions and up to 10% benefit for stroke after hemorrhage,
using reaction perimetry treatment [129].
Space perception disorders can lead to spatial disorientation
(affecting a person’s topographical orientation),
well known in right hemisphere infarction. A misperception
of the body’s orientation in the coronal plane is seen in
stroke patients with a ‘‘pusher syndrome.’’ They experience
their body as oriented upright when it is in fact tilted to one
side, and therefore use the unaffected arm or leg to actively
push away from the unparalyzed side and typically try to
resist any attempt to passively correct their body posture.
The syndrome is a distinctive clinical disorder after unilateral
left or right brain lesions in the posterior thalamus or
in the insula and postcentral gyrus [130]. Recovery under
physical therapy, e.g., by trying to enhance sensorimotor
input from the contralateral side, is often prolonged.
Apraxia is a syndrome of left hemisphere infarction. It
often severely hinders ADL independence (apart from
contributing to speech disorders as speech apraxia), and
treatment of apraxia should definitely be part of the overall
neurorehabilitation program [123]. Although the literature
on recovery and treatment is limited, apraxia has been
shown to be improved by occupational therapy. For a
review of apraxia treatment and also on other aspects of
occupational therapy, refer to [131].
Outlook
As robust data clearly show, the overall effectiveness of
neurorehabilitation in stroke medicine, and the identification
of useful elements and methods to further enhance recovery,
lie at the center of research nowadays. Despite growing
evidence of the usefulness of the above-described emerging
methods, there is still a long way to go before, hopefully,
many of them can be integrated into routine clinical practice.
However, until now, for many methods there is a need
for further randomized controlled trials with assessment
of long-term benefits. The main problems are: (a) the
time window: many intervention studies take place in the
‘‘chronic phase’’ (even with promising results), although we
know from basic science that neuroplasticity is most likely
to occur in an early stage after stroke; (b) low intervention
contrast, as the ‘‘controls’’ also receive conventional therapies,
however, facing the dilemma that on the other hand it is
likely that (c) many of the emerging techniques can deliver
improvements only when combined with active learning;
(d) difficulties to identify the ‘‘dosage’’ of the interventions;
(e) heterogeneity of studies: different patient criteria as well
as heterogeneous types of stroke and outcome measures that
also make meta-analysis difficult; and (f) lack of funding for
nonpharmacological methods and therefore multicenter
828 J Neurol (2012) 259:817–832
123
organization. Further studies of interventions need careful
selection of patient groups which, for some methods, might
make a combination with imaging methods essential.
In spite of these obstacles to research, in many places,
neurorehabilitation of stroke continues to enhance its
benefit for stroke patients, because of improvements in the
organization of its application, proliferation of knowledge
of clinical practice, and closer interconnection to acute
stroke treatment.
Acknowledgments The authors would like to thank Dr. Serafin
Beer for helpful discussion and comments on the manuscript.
Conflict of interest None.
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