Authors:
Marcelo L. Berthier, MD
Jesús Pujol, MD
Alexandre Gironell, MD
Jaime Kulisevsky, MD
Joan Deus, PhD
Julían Hinojosa, PhD
Carles Soriano-Mas, PhD

Stroke

Case Report

Affiliations:
From the Department of Medicine,
University of Malaga School of
Medicine, Malaga, Spain (MLB); the
Magnetic Resonance Center of
Pedralbes, CETIR, Barcelona, Spain
(JP, JD, CSM); the Movement
Disorder Section, Department of
Neurology, Sant Pau Hospital and
Autonomous University of Barcelona,
Barcelona, Spain (AG, JK); and the
Marine Hospital of Torremolinos,
Malaga, Spain (JH).

Correspondence:
Address requests for reprints to
Marcelo L. Berthier, MD,
Departamento de Medicina Facultad
de Medicina, Universidad de Málaga,
Campus Universitario Teatinos,
29.071, Málaga, España.
0894-9115/03/8209-0725/0
American Journal of Physical
Medicine & Rehabilitation
Copyright © 2003 by Lippincott
Williams & Wilkins
DOI: 10.1097/01.PHM.0000083668.48396.84

Beneficial Effect of Donepezil on
Sensorimotor Function After Stroke
ABSTRACT
Berthier ML, Pujol J, Gironell A, Kulisevsky J, Deus J, Hinojosa J,
Soriano-Mas C: Beneficial effect of donepezil on sensorimotor function
after stroke. Am J Phys Med Rehabil 2003;82:725–729.
Pharmacotherapy of poststroke sensorimotor deficits is currently used
alone or combined with physiotherapy to promote recovery of mobility
problems. This case study examined the effectiveness of donepezil
hydrochloride (HCl) administered to a stroke patient with chronic,
dense, left sensorimotor deficit. The patient received donepezil HCl (5
mg daily for 4 wk, followed by 10 mg daily for 12 wk) but no physiotherapy. Baseline and posttreatment evaluations were performed with
the Fugl-Meyer scale and the Rivermead Mobility Index. One month
after starting donepezil HCl (10 mg/day), sensorimotor function improved dramatically in the hemiplegic lower limb and shoulder. It was
concluded that donepezil HCl may be an effective treatment for improving sensorimotor function in chronic stroke patients. Randomized controlled trials are required to support these preliminary findings.
Key Words: Sensorimotor Deficits, Stroke, Donepezil Hydrochloride,
Functional Magnetic Resonance Imaging, Transcranial Magnetic
Stimulation, Bereitschaftspotentials

L

arge hemispheric infarcts impede the functional recovery of contralateral
sensorimotor deficits by reducing the capacity of surviving peri-infarct tissue for
reorganization.1 Although some recovery of motor function occurs in the weeks to
months after the stroke, the effectiveness of conventional physiotherapy in cases
showing little or no spontaneous functional recovery is limited, particularly when
mobility problems remain for ⬎1 yr.2 However, a new physiotherapeutic technique
for the densely hemiplegic upper limb (constraint-induced movement therapy)
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Donepezil in Poststroke Sensorimotor Deficits

725

produces prolonged functional improvement,3 and psychostimulant
treatments in combination with physiotherapy improve functional motor
recovery.4,5
Pharmacologic treatments in
stroke patients are directed to restore
neurotransmitter system deficiencies, and agents that restore or augment norepinephrine, dopamine, and
serotonin activity have been used to
promote recovery of hemiplegia, neglect, and aphasia.4 – 6 Recent studies
in animal models and in humans indicate that central cholinergic neurotransmission is involved in motor
function.7–9 A positron emission tomography study in monkeys found
that activation of the somatosensory
cortex induced by contralateral somatosensory stimulation is abolished
by scopolamine and reversed by physostigmine and tacrine.7 Transcranial
magnetic stimulation (TMS) studies
in healthy volunteers found that antagonists of muscarinic receptors (atropine, scopolamine) modify the excitability of the motor cortex8 and
substantially attenuate the magnitude of use-dependent plasticity.9
Donepezil hydrochloride (HCl) is a
reversible acetylcholinesterase inhibitor with a selective central action.10
It is safe and widely prescribed to
improve cognition and memory in
patients with Alzheimer’s disease and
other neurologic conditions (i.e.,
head trauma).10,11 To evaluate the efficacy of cholinergic therapy in improving sensorimotor deficits associated with stroke, we used donepezil
HCl to treat a stroke patient and examined its effects on cortical reorganization using functional magnetic
resonance imaging (fMRI) and neurophysiologic techniques.

CASE REPORTS
The patient was a 64-yr-old,
strongly right-handed woman who,
at age 59, suffered a large right-hemisphere ischemic infarction, which
left her with a dense left hemiplegia,

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Berthier et al.

left hemisensory loss, and “crossed”
conduction aphasia. After the stroke,
she received two sessions of traditional physiotherapy daily for 2 yr.
Because she was unable to recover
voluntary movements, physiotherapy
was stopped, and she had not received
physiotherapy since then. By that
time, an MRI disclosed a large infarct
in the vascular territory of the right
middle cerebral artery involving the
temporoparietal cortex and extending
deeply into the posterior insula, putamen, corona radiata, and internal
capsule. There was a severe shrinkage
of the right cerebral peduncle. The
inferior frontal, primary sensorimotor, dorsolateral prefrontal, and mesial frontoparietal cortices and the
thalamus and a small portion of the
posterior limb of the internal capsule
were spared. Regional cerebral blood
flow, measured with single photon
emission computed tomography and
99m TC-HMPAO (Ceretec, Exametazime, Amersham Madrid, Spain), was
significantly decreased (regions of interest, ⬍0.70 [values in normal controls, ⱖ0.93])12 in the whole right
hemisphere, even in those regions
that did not show structural damage
on MRI (thalamus, primary sensorimotor cortex—lateral and mesial).
On the baseline neurologic evaluation, carried out 5 yr after stroke
onset, she had a dense left spastic
hemiplegia for proximal and distal
motor function with sensory loss.
She did not show signs of neglect.
Her score on the Fugl-Meyer scale13
was 10 (motor component for upper
limb, 4 [range, 0 – 66]; motor component for lower limb, 6 [range, 0 –34];
sensation, 0 [range, 0 –24]), and her
Rivermead Mobility Index14 score was
6 (range, 0 –15). A repeat tridimensional MRI confirmed the precise location of the infarct.
After signing an informed consent
agreement, the patient received 5 mg
of donepezil HCl daily for 1 mo, followed by 10 mg daily for 3 mo, and
thereafter, a 4-wk washout period. Adverse events were monitored during

therapy. Two weeks after receiving
donepezil HCl (5 mg/day), the patient
developed touch- and warmth-evoked
allodynia in the left foot, calf, and forearm. Allodynia lasted 2 wk, and its disappearance coincided with the recovery
of sensation for touch, temperature,
and joint-position sense in the left leg
and arm. Four weeks after starting 10
mg of donepezil HCl, she began to recover voluntary movements of the left
leg and shoulder, but the left hand remained totally plegic. Eight weeks
later, her Fugl-Meyer scale score increased to 34 (motor component for
upper limb, 7; motor component for
lower limb, 18’ sensation, 9) and her
Rivermead Mobility Index score to 13.
Recovery of motor function in the left
foot was associated with the development of mirror movements, yet passive
flexion-extension exercises of the left
foot did not elicit visible movements in
the unaffected right foot. Donepezil
HCl did not induce adverse effects.
Withdrawal evaluation 4 wk later revealed the maintenance of gains in sensorimotor function obtained during
treatment (Fugl-Meyer scale score, 34;
Rivermead Mobility Index score, 13).

ANCILLARY STUDIES
Twelve weeks after starting donepezil HCl treatment (10 mg/day), the
functional correlates of recovery were
examined with fMRI and neurophysiologic techniques (Bereitschaftspotential and TMS).
Functional MRI. The patient was
scanned 12 wk after initiation of
donepezil HCl treatment (10 mg/day)
on a 1.5-T magnetic resonance scanner (Signa, GE Medical Systems, Milwaukee, WI) equipped with echospeed gradients and single-shot
echoplanar imaging software.15,16
Eight interleaved slices, parallel to
the anteroposterior commissure line,
were obtained for each functional sequence to cover the cortical motor
system (four slices).16,17 The functional time series consisted of 60 con-

Am. J. Phys. Med. Rehabil. ● Vol. 82, No. 9

secutive images obtained in 3 min, in
which 30-sec periods of rest and activation were alternated. The patient
was instructed to perform active, selfinitiated movements of the left foot.
In addition, passive flexion-extension
movements were performed by the
examiner to assess the proprioceptive
sensory input of the motor-sensory
loop.6 Foot exercises were selected
because recovery of motor function
during donepezil HCl treatment
mainly took place in the distal left leg
and because active shoulder movements of the plegic arm induced head
movements.
Bereitschaftspotential. The Bereitschaftspotential (BP) recordings
were obtained with an analogic amplifier (Grass 8-pluss electroencephalogram) and further processed using
an analog/digital converter Neuroscan 3.0 (Herdnon, VA). Brisk voluntary unilateral extensions of the left
deltoid muscle (recorded by surface
electromyography) were repeated at a
self-paced rate of every 4 –5 sec. The
electroencephalographic segments
from 2 sec before to 1 sec after the
trigger movement were digitized and
stored at a sampling rate of 400 Hz.
The stored electroencephalographic
segments were average-time locked
to the precise onset of the rectified
electromyograph, which was determined through off-line inspection of
each trial. During this procedure, trials with apparently significant artifacts were excluded. The amplitude of
the early BP component (650 msec
before electromyographic onset) and
the late BP component (negative
slope, maximal BP negativity peak
minus BP negativity peak at 650
msec before electromyographic onset) were identified by visual
inspection.18
TMS. TMS was delivered using a
90-mm outer diameter circular coil,
which was applied centered at the
vertex with a posterior-to-anterior–
September 2003

induced current for the stimulated
hemisphere (Magstim Rapid, Carmarthenshire, UK). Motor-evoked potential (MEP) was recorded at the
right abductor pollicis brevis muscle
and at right and left deltoid muscles.
Motor threshold was assessed by application of single stimuli for activation of the right abductor pollicis
brevis muscle. After cortical stimulation at 20% over motor threshold,
latency and amplitude of the MEPs
recorded at deltoid muscles were
measured during maximal voluntary
contraction. Two to four repetitions
were performed, and the latency was
measured to the highest amplitude
reasonable MEP. Cervical root (neck)
stimulation was also performed at
100% of stimulator output to calculate the central conduction time.

RESULTS
Functional MRI. Active flexion-extension movements of the paretic left
foot basically induced activation of
the contralateral right mesial sensorimotor cortex, together with functional activity in the supplementary
motor area (Fig. 1). The activation
pattern was accurately replicated in a
second fMRI trial with the active task,
and similar results were obtained after passive flexion-extension movements of the left foot (Fig. 1).
Bereitschaftspotential. The voluntary
contraction of the left deltoid muscle
was preceded by a BP of higher amplitude in the ipsilateral electroencephalographic leads, especially in the late
part or negative slope. Ipsilateral leads,
early/late parts: F3, 7.7/11.8 ␮V; C3,

Figure 1: Functional magnetic resonance imaging. The activation pattern
observed in our patient during left foot flexion-extension movements is shown in
three consecutive slices at the brain’s vertex region. There is a relevant activation of contralateral sensorimotor cortices, with minor ipsilateral contribution.
Supplementary motor area was activated bilaterally. Similar patterns were
observed in both active and passive situations, although the extension of the
changes was greater in the former. Activation images are displayed in pseudo
color, scaled according to significance, and superimposed on corresponding
anatomic images.
Donepezil in Poststroke Sensorimotor Deficits

727

Figure 2: Neurophysiologic studies. A, movement-related cortical potentials
obtained as the patient performed a left deltoid contraction movement. Note
the higher amplitude of the potential obtained at the ipsilateral leads, especially
for the second part of the potential (negative slope). Horizontal calibration, 250
msec; vertical calibration, 5 ␮V. B, motor-evoked potentials obtained at the
deltoid muscles (contralateral, upper trace; ipsilateral, lower trace) after transcranial magnetic stimulation of the left motor cortex. Note the latency delay of
the response induced in the ipsilateral muscle. Two consecutive trials are
superimposed in each trace to show consistency of the responses. Horizontal
calibration, 5 msec; vertical calibration, 20 ␮V. EMG, electromyography.
6.4/7.3 ␮V; P3, 3.1/4.6 ␮V. Contralateral leads: F4, 4.5/1.9 ␮V; C4, 3.3/0.7
␮V; P4, 3.1/1.9 ␮V (Fig. 2).
TMS. Motor threshold for the right
abductor pollicis brevis muscle and
central conduction time elicited with
TMS were within normal limits (62%
and 9.0 msec, respectively). The MEP
latency at the right abductor pollicis
brevis muscle was 22.8 msec and 11.8
msec at the right deltoid muscle. Interestingly, a MEP was also recorded at
the ipsilateral deltoid muscle with a
latency of 24.1 msec (Fig. 2). When
stimulation was applied over the right
motor cortex, no MEPs were recorded
at the abductor pollicis brevis or at the
deltoid muscles, even at the maximal
stimulator output intensity.

DISCUSSION
In the present case, recovery of
chronic sensorimotor deficits followed donepezil HCl treatment, ad-

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Berthier et al.

ministered 5 yr after onset. Such a
late response in a stroke patient in
the absence of a concomitant physiotherapy treatment that can by itself
explain the patient’s recovery, coupled with allodynia preceding sensory
recovery and the improvement of left
foot and shoulder movements, suggest that donepezil HCl enhanced
neural activity in surviving brain systems. To the best of our knowledge,
this is the first study that examines
the efficacy of donepezil HCL on
poststroke sensorimotor deficits. The
cortical activation pattern correlating
with recovered foot functions was
documented with fMRI as an almost
identical pattern of activation of the
contralateral mesial somatosensory
cortex and the supplementary motor
area during active and passive left
foot movements. Neurophysiologic
techniques (BP and TMS) showed an
enhancement of ipsilateral motor
representations during active movements of the left shoulder, suggesting

recruitment of ipsilateral motor
pathways.19
Structural MRI disclosed a large
right cortical infarct with subcortical
extension and major involvement of
the corticospinal motor and sensory
pathways, except for a small part of
the posterior limb of the internal capsulae and the “leg representation
zone” in mesial somatosensory cortex
(Brodmann’s areas 4, 312, and 5).
Moreover, these structurally intact
peri-infarct regions still showed a
marked hypoperfusion on a brain single photon emission computed tomography performed 2 yr after stroke
onset. Thus, it is possible that these
islets of spared parenchyma did not
promote functional recovery of the
hemiplegic lower limb under physical
therapy because they remained disconnected for a long period after the
stroke as a result of enduring central
input alterations.20
The earliest clinical changes during donepezil HCl (5 mg/day) treatment involved improvement of deficits in left foot sensation, perhaps
through a short-lived maladaptive reorganization resulting in touch- and
warmth-evoked allodynia, followed
by left leg motor recovery and proximal left arm improvement. Recent
evidence in humans shows that reduced input to a cortical sensory region leads to reduced excitability of
adjacent motor cortex20 and that somatosensory stimulation increases
hand muscle strength of stroke patients.21 It is therefore possible that
donepezil HCl contributes in reversing the deprivation of sensory input
by activating sensory processing and
ultimately promoting motor function
recovery. Maladaptive plastic changes
also occurred for motor function because functional recovery in the left
foot was associated with the development of mirror movements.
Reorganization of the motor system was probably not confined to the
contralateral somatosensory cortex.
Less dramatic, though clinically evident, left shoulder recovery was also

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observed. Because of the virtually
massive damage to the internal capsule, the recovered motor function in
this bodily region was presumably
controlled by ipsilateral structures, as
suggested by BP and TMS, that may
also be receptive to the beneficial action of donepezil HCl. Although our
findings suggest that donepezil HCl
is a potentially viable treatment option for patients with chronic poststroke sensorimotor deficits, randomized, controlled clinical trials are
necessary to support these preliminary findings.

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