Effect of Early and Intensive Rehabilitation after Ischemic

Stroke on Functional Recovery of the Lower Limbs: A Pilot,

Randomized Trial

Wen-Xiu Wu, MD,* Cheng-Ye Zhou, MD,*,† Zhe-Wei Wang, MD,*

Guo-Qian Chen, MD,† Xiao-Li Chen, MD,† Hai-Min Jin, MD,* and
Dong-rui He, MD†

Objective: We aimed to develop an early and intense lower extremity training tech-
nique using a recumbent cycle ergometer system in patients with acute ischemic
stroke. Methods: This was a pilot, prospective, randomized, controlled study with 2
parallel groups followed for 3 months with blinded assessment of outcomes. Thirty-
one eligible patients were randomized to experimental and control groups. To
strengthen the motion of the lower extremities within 48 hours after stroke, the con-
trol and experimental groups received conventional treatment and additional inter-
ventions under a therapist’s guidance combined with conventional treatment,
respectively. The primary outcome measure was the change in lower extremity motor
control from admission to 4 weeks, assessed by the Fugl-Meyer Assessment. Second-
ary outcomes were the number of days to walking 50 m and the change in the Berg
Balance Scale score and Barthel index. The modified Rankin Score was used to assess
the overall function and prognosis at 3 months. Results: Fugl-Meyer Assessment and
Berg Balance Scale scores and Barthel index increased over time in the experimental
group, as did the Berg Balance Scale score and Barthel index in the control group
(P < .001). However, Fugl-Meyer Assessment scores in the control group were similar
over time (F = 2.303, P = 1.119). Fugl-Meyer Assessment scores in the experimental
group were higher than those in the control group after 2 and 4 weeks (P = .084 and
.037, respectively). Compared with the control group at 2 weeks or at discharge, the
percentage of patients who returned to unassisted walking in the experimental group
showed an increasing trend (56.3% versus 26.67%, P = .095), but there was no signifi-
cant difference between the 2 groups after 3 months (P = .598). The modified Rankin
Score at 3 months showed no significant difference between the 2 groups (P > .05).
Conclusions: Our early and intense lower extremity training technique involving a leg
cycle ergometer system contributes to the recovery of lower extremity function in
patients with acute ischemic stroke. This finding will provide a basis for future inves-
tigations on the applicability of the intervention in early lower extremity and walking
rehabilitation among individuals with neurological disorder.
Key Words: Ischemic stroke—disability—rehabilitation—functional recovery
© 2020 Elsevier Inc. All rights reserved.

From the *Department of Rehabilitation Medicine, The First Affiliated Hospital of Wenzhou Medical University, ZheJiang, China; and †Depart-
ment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, ZheJiang, China.
Received September 24, 2019; revision received November 25, 2019; accepted January 6, 2020.
Funding: This study was supported by a grant from Wenzhou Municipal Sci-Tech Bureau Program (Y20150028). The funding source had no fur-
ther role in study design, data collection and analysis, decision to publish, or preparation of the article.
Address correspondence to Wen-Xiu Wu, Department of Rehabilitation Medicine, The First Affiliated Hospital of Wenzhou Medical University,
No. 2, Fuxue Road, Lucheng District, Wenzhou, China. E-mail: [email protected].
1052-3057/$ - see front matter
© 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104649

Journal of Stroke and Cerebrovascular Diseases, Vol. 29, No. 5 (May), 2020: 104649 1
2 W.-X. WU ET AL.

Introduction Population
Stroke is the leading cause of serious, long-term disabil- Patients presenting less than 48 hours after acute ische-
ity among adults. Each year, approximately 2 million indi- mic stroke admitted to the neurology wards of First Affili-
viduals in China sustain a new or recurrent stroke, and ated Hospital of Wenzhou Medical University between
nearly 70%-80% survive with some level of neurological December 2015 and December 2016 were consecutively
impairment and disability.1 Walking disorders are com- screened for study entry. The inclusion criteria were: age
mon clinical dysfunctions following stroke. More than 18-80 years; admitted to the hospital within 48 hours of
one-half of those who survive the acute phase are not able onset, in line with the diagnostic criteria adopted by the
to walk and will require a period of rehabilitation to Fourth National Cerebrovascular Conference, and diagno-
achieve a functional level of ambulation.2 More rapid sis confirmed by CT or MRI; stable vital signs: systolic
improvement in walking function is thought to be one of blood pressure less than 220/120 mm Hg, heart rate
the most important rehabilitation goals for patients.3 40-100 beats/minutes, body temperature less than 38.5°,
Evidence suggests that very early mobilization (VEM) may and oxygen saturation greater than 92%;4 weakness in the
result in better motor recovery, with a significant positive lower limbs and a National Institutes of Health Stroke Scale
effect on recovery of walking; reduced mental, functional, (NIHSS) score17 of greater than or equal to 1 on item VI; no
and neurological disability; and improved quality of life.4-7 contraindications to mobilization within 48 hours of stroke
The recent European recommendations8 and those from the onset (based on the medical teams’ clinical judgment and
American Stroke Association9 promote VEM, although how exclusion criteria); the ability and willingness to provide
early and how much a patient should be mobilized remain informed consent. The exclusion criteria were as follows:
controversial. Some negative impacts of early (<24 hours) premorbid modified Rankin Scale (mRS) score18 greater
versus delayed (<48 hours) physical rehabilitation have been than 3 and/or lower limb fracture that prevented mobiliza-
reported, including the increased risk of death.10 The most tion within 3 months; intravenous thrombolysis or arterial
beneficial amount of exercise is also unclear. Regarding thrombectomy before admission; other progressive neuro-
VEM, a publication by the AVERT group found that too logical diseases such as dementia, Parkinson’s disease, epi-
much early mobilization is detrimental for prognosis.11 lepsy, tumor, or serious cardiovascular disease, pulmonary
Lower extremity strength correlates with gait speed in infection, uremia, or malignant tumor; severe cognitive
patients with stroke.12 Strengthening should be included impairment, aphasia, or visual or hearing impairment that
in the acute rehabilitation of patients with weakness after precluded performance of the evaluation.
stroke. This goal needs specific intensive training directed
at patients’ deficiencies, which is different from mobiliza- Procedure
tion. Such physical rehabilitation has been found to be
more effective for improvement in neural plasticity when When discussing informed consent, patients were told
provided at the subacute stage after stroke.13 The role of that they would be given 1 of 2 different types of rehabilita-
early intensive training or very early intensive rehabilita- tion. Computer generated, blocked randomization proce-
tion is still unknown. Few human studies have investi- dures and concealment with opaque envelopes were used
gated the role of intensive rehabilitation within the early to allocate patients to either the experimental group or the
time period after stroke, and conclusions are inconsis- control group. Randomization was stratified according to
tent.14-16 This study aimed to determine whether early stroke severity based on the NIHSS (mild = 0-7, moder-
and intensive lower extremity training involving the use ate = 8-16, and severe >16) to reduce the likelihood of
of a recumbent cycle ergometer system conducted within imbalance between groups.19
24-48 hours after ischemic stroke could promote the
recovery of lower limb function and walking ability. Intervention
After admission, the control group received standard care
Methods from ward therapists and nursing staff including position-
ing, range of motion exercises, bed mobilization, physiother-
Study Design
apy, and education of patients and family after 72 hours of
This was a pilot, prospective, randomized, controlled stroke onset. In accordance with the usual rules of the stroke
study, with 2 parallel groups followed up for 3 months unit, physiotherapy was performed for 20-30 minutes per
with blinded assessment of outcomes (ClinicalTrials.gov day, at least 5 days a week, to prevent immobility-related
NO. ChiCTR1900022872). Written informed consent was events. Patients randomized to the experimental group
obtained from all participants before randomization. began rehabilitation as soon as practical after randomiza-
Patients were assured of their right to refuse to participate tion, with the goal of first rehabilitation within 24-48 hours
or to withdraw from the trial at any time. The study was of stroke onset. The experimental group also received addi-
approved by our local ethics committee at the First Affili- tional interventions including intensive exercises under the
ated Hospital of Wenzhou Medical University. guidance of the therapist, with the aim to strengthen the
EFFECT OF EARLY AND INTENSIVE REHABILITATION 3

lower limbs. The recumbent cycle ergometer training in bed with poor outcome at 3 months’ follow-up, on the basis of
was used to strengthen the lower limbs, and the patient was the results from stroke unit studies with the best effect.1,24
assisted in practicing sitting and standing early, twice per However, due to slow recruitment, the inclusion of
day for 30 minutes. The recumbent cycle ergometer training patients was stopped before reaching the calculated sam-
was performed for 20 minutes, using active or passive ple size. Baseline data are presented as mean (standard
mode, with the resistance set based on patient-specific con- deviation) or median (interquartile range) or number (per-
ditions, combined with 10 minutes of sitting and standing centage). Categorical variables were compared using the
training, at least 5 days per week, lasting approximately x2 test or Fisher’s exact test, as appropriate. The t test was
2 weeks or until discharge. Occupational health and safety used to compare continuous variables that were approxi-
procedures for manual handling of patients were main- mately normally distributed, and the Wilcoxon Mann-
tained. Blood pressure, heart rate, oxygen saturation, and Whitney Rank-Sum test was used for continuous varia-
temperature were monitored before the first 3 mobilizations bles that were not normally distributed. Generalized esti-
in the experimental group. The treatment was interrupted if mating equation analyses were performed to compare
in the clinician’s judgement, the patient could not tolerate group by time interactions, using data from all functional
the mobilization (i.e., the patient became less responsive, tests including FMA, BBS, and Barthel Index from admis-
developed a headache, became nauseated or vomited, or sion to 4 weeks. The Bonferroni method was used to per-
became pale or clammy). Finally, the 2 groups of patients form pairwise comparisons of the repeatedly measured
were transferred to the rehabilitation ward to undergo func- data at different measurement times of each treated
tional recovery treatment until discharge. group. The t test or Mann-Whitney test were used to com-
pare pairwise data in different treated groups at each
Baseline Assessments measurement time. We performed an overall efficacy
analysis with the binary logistic regression model, with
Patient characteristics collected at baseline included treatment group as an independent variable and the
demographic data (age, sex, and body mass index), stroke 3 months’ mRS outcome (dichotomized into scores of 0-2
factors (type, side, and site of stroke; stroke severity as favorable outcome and scores of 3-6 as poor outcome)
according to NIHSS), and smoking status. Premorbid dis- as the dependent variable, including baseline stroke. Sta-
ability (as per mRS) and clinical comorbidities, including tistical significance was set at P less than .05 (2 sided), and
hypertension, diabetes mellitus, and cardiovascular dis- all analyses were conducted using SPSS for Windows ver-
eases, were documented. sion 17.0 (SPSS Inc., Chicago, IL).

Outcome Measures
Results
The outcomes assessments were conducted by a
Demographic and Clinical Characteristics
blinded evaluator physical therapist different from the
treating physical therapist. The primary outcome measure A total of 423 consecutively admitted patients with acute
was the change in lower extremity motor control from ischemic stroke were screened, and 46 met the entry crite-
admission to 4 weeks, assessed by the Fugl-Meyer Assess- ria. Figure 1 provides a study flow diagram and outlines
ment (FMA).20 Secondary outcomes were the number of reasons for patient exclusion. Thirty-one patients were
days to walking 50 m, the change in balance assessed by included in this study; 16 were randomized to the experi-
the Berg Balance Scale (BBS) score,21 and performance of mental group and 15 to the control group. Table 1 shows
activities of daily living assessed by the Barthel Index.22 the baseline characteristics of the 31 eligible patients (dem-
We defined walking as “walking unassisted by human ographics, smoking status, and clinical features). The mean
help (gait aid allowed) for a continuous distance of 50 m,” age of the patients was 61.84 § 10.13 years, and 31.3%
a distance used in the Functional Independence Measure23 were female. Notably, 61.3% of the patient population had
walking item and commonly marked out within hospital mild stroke, 38.7% had moderate stroke, and no patient
departments. Simultaneously, the mRS was used to assess had severe stroke. There were no significant differences
the overall function and prognosis of patients at 3 months between the groups in terms of age, sex, affected side, type
through face-to-face interview or telephone interview. We of stroke, NIHSS score, or mRS score on admission.
defined a favorable outcome as mRS scores of 0-2 (no or
minimum disability) and a poor outcome as scores of 3-6 Changes in FMA Score, BBS Score, and Barthel Index
(moderate or severe disability, or death).
There were no significant differences in FMA score, BBS
score, and Barthel index between the 2 groups before
Statistical Analysis
treatment (P > .05). From the repeated measurement anal-
The sample size was calculated to be 88 patients in each ysis of variance, there was no interaction between treat-
group (95% confidence interval , margin of error 5%) to ment and time in terms of the Barthel index and BBS
detect a difference of 20% in the proportions of patients score, and the main effect was analyzed. The BBS score
4 W.-X. WU ET AL.

groups. Simple effect analysis showed that the FMA

scores of the control group were similar over time
(F = 2.303, P = 1.119). The FMA scores of the experimental
group gradually increased over time, and this difference
was statistically significant (F = 29.964, P < .001). The
FMA of the experimental group was higher than that of
the control group after 2 weeks and 4 weeks; this differ-
ence was statistically significant (P = .084 and .037, respec-
tively), see Figure 2.

50 m Unassisted Walking
On admission, 93.5% (29 out of 31) of patients could not
walk or required hands-on assistance to walk short dis-
tances (13 in the control group, 16 in the experimental
group), and only 6.5% (2 out of 3) of the patients were
rated as able to walk with supervision (2 in the control
Figure 1. Patients flow chart. group). At 2 weeks or discharge, 56.3% (9 out of 16, 2
with the aid of cane) of patients in the experimental group
and the Barthel index were improved in both groups over had returned to unassisted walking compared with
time (F = 3.706, P = .054; F = 2.436, P = .096), but the differ- 26.67% (4 out of 15) of patients in the control group
ence between the 2 groups was not statistically significant (x2 = 2.783, P = .095). After 3 months, 77.4% (24 out of 31)
(F = .154, P = 0.698; F = .011, P = 9.919). There was an inter- of patients had returned to unassisted walking (11 in the
action effect between treatment and group on the FMA control group and 3 with the aid of cane, 13 in the experi-
score (F = 20.548, P < .001), that is, the recovery trend for mental group and 1 with the aid of cane), and 22.6%
lower extremity function was different between the 2 (7 out of 31) of patients still could not walk without

Table 1. Clinical and demographic characteristics of the samples under study

Variables Control group (n = 15) Experimental group (n = 16) t value or x2 value P value
Demographic characteristics
Age (y), means § SD 62.67 § 10.57 61.06 § 10.31 .428 .672
Sex (F/M) 5/11 4/12 /* 1.00
BMI (kg/m2), means § SD 22.46 § 2.89 22.99 § 1.95 .612 .546
Vascular risk factors
Current smoking 8 (53.33) 6 (37.50) .786 .376
History of hypertension 12 (80.00) 9 (56.25) 1.998 .157
History of diabetes 5 (33.33) 7 (43.75) .354 .552
Atrial fibrillation 0 (.00) 1 (6.25) /* 1.000
Clinical features
Side (left) 5 (33.33) 9 (56.25) 1.642 .200
Site of ischemic lesion 1.678 .437
TACI 6 (40) 4 (25)
PACI 5 (33.33) 9 (56.25)
POCI 4 (26.67) 3 (18.75)
NIHSS score, median(IQR) 7 (4-10) 7 (5-11) .975 .372
mild (<8) 10 (66.67) 9 (56.25) .354 .552
moderate (8-16) 5 (33.33) 7(43.75)
mRS score on admission, median(IQR) 4 (4-4) 4 (4-4) .594 .552
mRS score = 3 2 (13.33) 0 (.00) /* .501
mRS score = 4 10 (66.67) 13 (81.25)
mRS score = 5 3 (20.00) 3 (8.75)
Values are shown as number (percentage) except where noted.
Abbreviations: BMI, body mass index; M, median; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale;
PACI, partial anterior circulation infarcts; POCI, posterior circulation infarcts; QR, interquartile range; TACI, total anterior circulation
infarcts.
*The Fisher’s exact test was used.
EFFECT OF EARLY AND INTENSIVE REHABILITATION 5

Figure 2. Change in FMA score, BBB score, and Barthel index between enrolment and 4 weeks follow-up after treatment. (A) The mean values and standard of
Fugl-Meyer motor function score from enrolment to 4 weeks follow-up; (B) The mean values and standard of Berg Balance Scale score; (C) The mean values and
standard of Barthel index. Compared with the control group, the Fugl-Meyer score of the experimental group was higher in the 4 weeks after treatment
(*P < .05). Abbreviation: FMA, Fugl-Meyer Assessment.

human assistance. There was no significant difference patients with acute ischemic stroke. The results showed
between the groups (x2 = .278, P = .598). that intense lower limb training can promote improvement
in the lower limbs from the flexor spasm stage to the sepa-
Disability ration movement stage and increases the recovery of lower
limb function in the early period after stroke. These results
The mRS was 0-2 for 8 patients (3 in the control and 5 in
further reinforce the feasibility of implementing such a pro-
the experimental group) at 3 months; there was no signifi-
gram in an inpatient stroke setting. Due to an overall
cant difference in mRs scores between the 2 groups after
decline in brain plasticity over the course of symptom
treatment (x2 = 1.379, P = .470). Multivariable binary
onset, the optimal period for neuronal repair may be within
logistic regression results showed that the early intensive
a narrow window after stroke onset.25 Numerous studies
rehabilitation had no significant effect on the prognosis of
have shown that animals exposed to locomotor exercise
the patients after adjustment for the influence of the rele-
beginning 24-48 hours poststroke have better behavioral
vant factors at baseline, such as age, sex, and NIHSS
outcomes and smaller ischemic volumes than control ani-
(odds ratio (OR) = 1.643, 95% confidence interval .296-
mals who receive delayed or no exercise training.26,27 How-
9.119, P = .570), as shown in Table 2.
ever, several experiments have suggested that under
certain circumstances, especially in the first 24 hours post-
Discussion stroke,28,29 therapy may be detrimental. The importance of
Our randomized, controlled trial is the first to evaluate an intensive rehabilitation program for functional recovery
the use of early and intense lower extremity training in stroke patients based on neural plasticity has been sug-
involving the use of a recumbent cycle ergometer system in gested, but most previous studies were conducted with

Table 2. Multivariable binary logistic regressions, with independence in mRS of 0-2 at 3 months as the outcome variable

Variables B SE Exp (B) 95%CI P

Age .016 .051 1.017 .921-1.123 .745
Sex .865 1.183 .421 .041-4.278 .465
NHISS (mild versus moderate) 2.421 1.285 .089 .007-1.102 .059
Early intense rehabilitation .496 .875 1.643 .296-9.119 .570
6 W.-X. WU ET AL.

patients at the subacute stage, from 2 weeks to 3 months with cycle ergometry training.34,35 Repeated intensification
poststroke.13 Very few studies have investigated intensive exercises can increase the amount of separation movement
early training in humans, and drawing conclusions from training, improve the input of motor sensation in patients
animal studies is difficult because of the many differences with stroke, have a positive effect on the remodeling of ner-
between animal models and humans. vous system functions, and promote the recovery of walk-
Intensity is a relative concept, with increased exercise ing function.36 Therefore, recumbent cycle ergometry was
intensity considered to be more than that in the control selected as the training modality that could avoid the
group. The type of exercise applied differs among studies, impact of early and frequent out of bed activities on cerebral
with inconsistent findings. In an open study with positive perfusion. Comparable improvements were observed in
results, patients were provided 20 min/d of intensive both groups in terms of balance capacity and Barthel Index,
walking training with human or robotic assistance, added with no added effect of the exercise training. Of interest,
to 55 minutes of gait-oriented physical therapy.14 This can however, was the presence of a trend toward greater gains
be considered moderately intensive exercise. One large in paretic limb function and functional ambulation in the
retrospective pre- and/or post comparison study involv- experimental group. This may provide preliminary support
ing 1588 patients with stroke in a Japanese hospital for an additional early benefit of short-term recumbent
showed significant differences in functional outcome, cycle ergometry training in terms of improved lower limb
even though the difference in the average total rehabilita- dyscoordination.
tion time was only approximately 30 minutes.30 Con- This is valuable information for clinicians. While the
versely, the negative results from the VECTOR trial were improvements in limb function were not significantly dif-
attributable to very high intensity constraint-induced ferent between groups after 3 months, this may be due in
movement therapy (90% walking hours) and rehabilita- part to the short training duration.37 The benefits of treat-
tion (3 hours/day) as compared with 6 hours of con- ments delivered in the early stage might go undetected if
straint-induced movement therapy and 2 hours/day of the primary outcome is assessed greater than 3 months
rehabilitation.16 Another multicenter, randomized, con- after stroke, by which time the control group may have
trolled trial, Active Mobility Very Early After Stroke,31 caught up with the experimental group.37 As an addi-
compared 20 minutes per day of “soft” physical therapy tional benefit, considering feasibility in acute rehabilita-
(passive range-of-motion exercises aimed at preventing tion facilities, this training has the potential benefits of
immobility-related complications) with soft physical ther- lower demands on real-time clinical supervision; this is
apy plus 45 minutes of active intensive exercises, both very important for countries like China, where there is a
commencing within 72 hours of stroke. This trial found lack of human resources in hospitals.
no difference in motor impairment at 90 days, as mea- There are several limitations of this study. The main
sured by the Fugl-Meyer Motor Scale. One study investi- limitation is the relatively low number of patients. The
gated the efficacy of Weight Supported Balance Therapy estimated required population size was 200 participants.
in patients with acute stroke, with therapy initiated on Unfortunately, patient inclusion was difficult, and we had
average 13 days poststroke.32 Patients were randomized to stop recruitment before reaching the calculated sample
to Weight Supported Balance Therapy plus standard size. One reason for this may be that the sample was
physical therapy or standard physical therapy alone, and highly selected in order to obtain a homogeneous popula-
no significant differences were seen between the 2 groups tion, with more stringent criteria than those used in previ-
in any of the outcome measures. However, 2 questions ous studies performed in general stroke populations.5
should be considered carefully. One of the issues is Moreover, the Telestroke Emergency Care System was
whether early neural plasticity is not sufficient or whether not well established, and not being able to access patients
training can have any impact because of the severity of early within the trial setting made it challenging to mobi-
the deficiencies and general status of the patient. The sec- lize patients more rapidly. An additional limitation
ond issue is determination of the most appropriate includes the bluntness of the mRS as an outcome measure,
amount and type of intensive exercise. VEM is beneficial especially for a recovery trial in which the potential bene-
when provided from 24 or 48 hours after stroke, and the fit of the intervention is likely to be subtle. The last limita-
most appropriate amount seems to be 2-3 times per day; tion is that this population does not reflect the whole
this amount should not be increased.11 In this unstable population of stroke units. Our sample is characterized by
clinical phase, VER for patients with disability might also patients with mild stroke, at a relatively young age,
be applied within a neurosensorial approach, using vertic- receiving conservative treatment (no thrombolysis or arte-
alization by robotic devices and repetitive treatment with rial thrombectomy), and with a relatively low occurrence
a cycle ergometer in bed.33 of death. These higher functioning patients may be more
Previous studies that have implemented aerobic training likely to show spontaneous recovery.
in the subacute stroke phase have reported training related In conclusion, an earlier and more intensive rehabilita-
benefits including improvement in motor function of the tion program in the acute phase of stroke correlates with
lower extremities, walking ability, and balance performance good recovery of motor function of the lower extremity
EFFECT OF EARLY AND INTENSIVE REHABILITATION 7

and walking ability according to the concept that “time is a randomized controlled trial. Lancet 2015;386:46-55.
brain recovery.” The feasibility of VER involving the use https://doi.org/10.1016/S0140-6736(15)60690-0.
of a recumbent cycle ergometer system as a treatment 12. Bohannon RW, Walsh S. Nature, reliability, and predic-
tive value of muscle performance measures in patients
option for patients with ischemic stroke in the early time with hemiparesis following stroke. Arch Phys Med Reha-
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multiple clinical settings and countries specific to this 13. Pollock A, Baer G, Campbell P, et al. Physical rehabilitation
group are needed. approaches for the recovery of function and mobility follow-
ing stroke. Cochrane Database Syst Rev 2014;22:CD001920.
https://doi.org/10.1002/14651858.CD001920.pub3.
Conflicts of Interest 14. Peurala SH, Airaksinen O, Huuskonen P, et al. Effects of
intensive therapy using gait trainer or floor walking exer-
The authors declare no financial or other conflicts of cises early after stroke. J Rehabil Med 2009;41:166-173.
interest. https://doi.org/10.2340/16501977-0304.
15. Kwakkel G, Winters C, van Wegen EE, et al. Effects of uni-
Acknowledgments: The authors thank the staff and partici- lateral upper limb training in two distinct prognostic
groups early after stroke: the EXPLICIT stroke random-
pants of the study for their important contributions.
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816. https://doi.org/10.1177/1545968315624784.
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