Drugs Aging 2005; 22 (8): 687-694

ORIGINAL RESEARCH ARTICLE 1170-229X/05/0008-0687/$34.95/0

 2005 Adis Data Information BV. All rights reserved.

Causes of Syncope in Patients with

Alzheimer’s Disease Treated
with Donepezil
Philippe Bordier, Stephane Lanusse, Stephane Garrigue, Charlotte Reynard,
Frederic Robert, Laurent Gencel and Alexia Lafitte
Cardiovascular Hospital of Haut-Leveque, Bordeaux-Pessac, France

Abstract Introduction: Treatment of Alzheimer’s disease (AD) with cholinesterase inhibi-

tors carries a theoretical risk of precipitating bradycardia. Though syncope occurs
in patients with AD, its aetiology is unclear. The aim of this study was to
determine the causes of syncope in patients with AD who were treated with
donepezil and hospitalised for evaluation of syncope.
Methods: We studied 16 consecutive patients (12 women, 4 men) with AD aged
80 ± 4 years who were hospitalised for evaluation of syncope. All patients
underwent staged evaluation, ranging from physical examination to electrophysi-
ological testing.
Results: The mean dose of donepezil administered was 7.8 mg/day, and the mean
duration of donepezil treatment at the time of syncope was 12 ± 8 months. A cause
of syncope was identified in 69% of patients. Carotid sinus syndrome was
observed in three patients, complete atrioventricular block in two patients, sinus
node dysfunction in two patients, severe orthostatic hypotension in two patients
and paroxysmal atrial fibrillation in one patient. A brain tumour was discovered in
one patient. No cause of syncope was found in 31% of patients despite compre-
hensive investigation. Repetition of the investigations after discontinuation of
donepezil was noncontributory.
Conclusion: In patients with AD treated with donepezil, a noninvasive evaluation
identified a probable cause of syncope in over two-thirds of patients. Cardiovascu-
lar abnormalities were predominant. Noninvasive evaluation is recommended
before discontinuing treatment with cholinesterase inhibitors in patients with AD
and unexplained syncope.

Cholinesterase inhibitors are currently the main
treatment for delaying the progression of
Alzheimer’s disease (AD).[1-4] While these agents
exert their therapeutic activity at the level of the
central nervous system (CNS), cholinesterase inhib-
itors also produce vagally mediated peripheral ad-
verse effects which are the main reason for discon-
tinuation of these drugs.[5,6] Treatment with cholin-
esterase inhibitors may be complicated by
bradycardia, although this adverse effect has been
reported only when these drugs are administered in
excessive doses.[7,8] Furthermore, cholinesterase in-
hibition with rivastigmine in a large population of
patients with AD revealed no electrocardiogram
688
(ECG) changes compared with placebo.[9] On the
other hand, lightheadedness, syncope and seizures
have been described in patients with AD, although
their link to treatment with cholinesterase inhibitors
remains unclear.[10,11] In light of results from a re-
cent study[12] that suggested a relationship between
severe bradycardia and syncope and initiation of
cholinesterase inhibitors for AD, we conducted a
range of neurocardiovascular investigations to de-
termine the causes of syncope in patients with AD
treated with donepezil and hospitalised for evalua-
tion and management of syncope.
Patient Recruitment and Methods
Between July 2000 and July 2004, 16 consecu-
tive patients with AD were referred to our service
after ≥1 recent syncopal episode. Syncope was de-
fined as a sudden, complete and transient loss of
consciousness and postural tone, with spontaneous
recovery. Patients who had a history of syncope or
orthostatic hypotension before initiation of cholines-
terase inhibitors were excluded from the study.
The diagnosis of AD had been confirmed by a
neurologist or a geriatrician, according to the criteria
listed in the Diagnostic and Statistical Manual of
Mental Disorders and recommendations from The
National Institute of Neurological and Communica-
tive Disorders and Stroke – Alzheimer’s Disease
and Related Disorders Association.[13,14] The pa-
tients were in an early to moderately advanced stage
of the disease, and all were being treated with
donepezil. Patients suspected by experts to have
dementia associated with Lewy bodies or Parkin-
son’s disease were not included in the study.
Clinical Investigations
Patients were initially assessed by detailed histo-
ry-taking, physical examination and measurement
of systemic blood pressure at rest in the supine
position. Then, a standard 12-lead ECG was ob-
tained using an automatic Mac 1 8 recorder (Mar-
quette Electronics Inc., Milwaukee, WI, USA).
Screening laboratory tests, including thyroid stimu-
1 The use of trade names is for product identification purposes only and does not imply endorsement.
 2005 Adis Data Information BV. All rights reserved.
Bordier et al.
lating hormone assay, were conducted while treat-
ment with donepezil was continued.[15] The follow-
ing manoeuvres and investigations were then con-
ducted until a probable cause of syncope was
identified: (i) postural blood pressure measurements
in search of orthostatic hypotension;[16,17] (ii) 48-
hour cardiac rhythm monitoring with an automated
HP Viridia arrhythmia analyser (Hewlett-Packard
Company, Andover, MA, USA);[18] (iii) carotid si-
nus massage;[19-21] (iv) head-up tilt test (HUTT);[19]
and (v) echocardiogram and echography of the
supra-aortic vessels.[22] If the cause of syncope still
remained unclear, a neurological consultation was
requested, along with an electroencephalogram
(EEG) and computerised tomography (CT) of the
brain. The evaluation was completed, if necessary,
by a cardiac electrophysiological study with the
consent of the patients and their relatives. Some
patients underwent brain CT scan earlier in the
sequence of tests if requested to do so by the emer-
gency team who evaluated patients before their ad-
mission to the cardiology department.
Interpretation of Tests
Blood pressure was automatically recorded using
an Accutorr Plus vital signs monitor (Datascope,
Paramus, NJ, USA). Recordings were taken minute-
by-minute, over a 5-minute period, to detect ortho-
static hypotension, with the lowest value being re-
tained. Orthostatic hypotension was diagnosed in
the presence of a ≥20mm Hg decrease in systolic
blood pressure, or a ≥10mm Hg decrease in diastolic
blood pressure, or both, in association with syncope
or presyncope within 3 minutes of assuming an
upright posture. After a ≥15-minute period of rest in
the supine position, right-sided carotid sinus mas-
sage was performed for 5–10 seconds at the anterior
margin of the sternocleidomastoid muscle, at the
level of the cricoid cartilage, during ECG and blood
pressure monitoring. In the absence of response, a
second massage was applied to the opposite side 1
minute later. No massage was performed in the
upright position. Carotid sinus massage was consid-
Drugs Aging 2005; 22 (8)
Syncope in Donepezil-Treated Patients with Alzheimer’s Disease 689

Table I. Clinical and electrocardiogram observations during treatment with donepezil after syncopal episodes in the 16 study patients.
Unless otherwise indicated, all patients had a narrow QRS and normal QRS axis
Patient Sex/age (y) AAD SBP/DBP (mm Hg) HR (bpm) PR interval CSM OH
(ms)
1a M/85 None 159/86 60 200 NP –
2 M/82 Propafenone + timolol 154/85 56 220 – –
ophthalmic drops
3 F/89 None 125/77 51 180 + –
4 F/83 Verapamil 152/66 52 184 – –
5 F/80 None 122/76 35 171 + –
6 F/82 None 132/88 65 146 – –
7 F/76 Acebutolol 163/91 58 151 – +
8 F/80 None 110/52 67 168 – –
9 F/76 None 150/76 71 151 + –
10b M/79 None 189/88 50 234 – –
11 F/74 None 186/107 64 170 – –
12 F/82 Atenolol 154/72 61 188 – +
13 M/81 None 182/85 42 272 NP –
14 F/74 None 151/80 77 160 NP –
15 F/83 None 144/78 75 160 NP –
16 F/77 None 142/73 66 160 – –
Means ± SD 150 ± 22/80 ± 12 59 ± 11 183 ± 33
a Right bundle branch block (BBB) + –80° QRS axis deviation.
b Left BBB + –57° QRS axis deviation.
AAD = treatment with negatively dromotropic antiarrhythmic drug; bpm = beats per minute; CSM = carotid sinus massage; DBP = diastolic
blood pressure; F = female; HR = heart rate; M = male; ms = millisecond; NP = not performed; OH = orthostatic hypotension; SBP = systolic
blood pressure; – indicates negative; + indicates positive.

ered positive if it caused a ≥3-second ventricular
pause, a ≥50mm Hg decrease in systolic blood pres-
sure, or both, in association with syncope or pre-
syncope. HUTT was performed to detect neurally
mediated syncope.[19]
After identification of a probable cause of synco-
pe, the abnormal diagnostic test was repeated no
sooner than 5 days after discontinuation of treatment
with donepezil.
Grouped results are presented as means ± SD.
Results
The mean age of the 12 women and four men
included in this study was 80 ± 4 years. At the time
of presentation, they had been treated with
donepezil 5, 7.5 or 10 mg/day (mean = 7.8mg) for a
mean of 12 ± 8 months. The first three patients
(number 1, 2, 3 in table I, table II and table III)
experienced syncopal episodes early after initiation
of donepezil. These patients had received donepezil
5 mg/day for 15, 8 and 19 days, respectively, at the
time of syncope. The other patients were treated
with donepezil for >6 months. All patients were in
sinus rhythm at the time of investigation. The QRS
complex was narrow and its axis was normal in all
but two patients (table I). Other important individual
clinical characteristics, ECG observations and the
results of carotid sinus massage and orthostatic test-
ing are presented in table I.
Clinical Investigations
The results of routine screening laboratory tests
were normal in all patients. The outcomes of com-
plementary investigations are shown in table II, and
the main laboratory or clinical observations pointing
to the cause of syncope identified in individual
patients are presented in table III.
During 48-hour cardiac rhythm monitoring, sev-
eral diurnal episodes of sinoatrial block with >5
second ventricular standstill, as well as frequent

 2005 Adis Data Information BV. All rights reserved. Drugs Aging 2005; 22 (8)
690 Bordier et al.

Table II. Results of complementary investigations after syncopal events in the 16 study patients
Patient 48-h ECG HUTT Echo Doppler echo Neuro/EEG Brain CT EPS
1 Complete AVB NP n NP NP n NP
2 n – n n n n CSNRT = 700msa
3 NP NP NP NP NP NP NP
4 n – n n n n n
5 NP NP NP n NP n NP
6 n – n n n n n
7 n NP n n n n n
8 n – n n n n NP
9 NP NP Mild aortic NP NP n NP
stenosis
10 n – n n NP Brain tumour NP
11 Paroxysmal AF – n n n n n
12 n NP n n n n n
13 Complete AVB NP n NP NP NP NP
14 n – n n n n n
15 Sinus exit block NP NP n n n NP
16 n – n n n n n
a Also had a His-ventricular interval = 60ms.
48-h ECG = 48-hour cardiac rhythm monitoring; AF = atrial fibrillation; AVB = atrioventricular block; CSNRT = corrected sinus node
recovery time; CT = computed tomography; Doppler echo = Doppler echography of supra-aortic vessels; Echo = echocardiogram; EPS =
electrophysiological study during treatment with donepezil; HUTT = head-up tilt test; n = normal; Neuro/EEG = neurological examination +
electroencephalogram; NP = not performed; – indicates negative.

episodes of sinus bradycardia at 20 beats per minute,
were associated with marked lightheadedness in one
(number 15) of five patients who had sinus node
dysfunction. Prolonged sinus arrest with >10 second
ventricular asystole and syncope were induced by
carotid sinus massage in three patients (numbers 3,
5, 9), two of whom had associated convulsions. One
patient (number 2) had sinus node dysfunction iden-
tified during electrophysiological study, with a cor-
rected sinus node recovery time of 700ms, and a
His-ventricular interval of 60ms, with no significant
changes after the administration of intravenous atro-
pine 1mg. Seven patients (numbers 1, 2, 3, 5, 9, 13,
15) underwent implantations of pacing systems, but
cholinesterase inhibitor therapy was continued be-
cause donepezil had no apparent effect on the ECG,
as explained in the next section. One of these pa-
tients (number 2) was treated with antiarrhythmic
drugs and cholinesterase inhibitor concomitantly.
He received a pacemaker despite the nonspecificity
of the abnormality observed during electrophysio-
logical study because he continued to experience
recurrent and unexplained syncopal episodes despite
complete evaluation. In three other patients (num-

Table III. Main results of evaluation and causes of syncope identified in each study patient
Patients Investigation findings Diagnostic method
1, 13 Complete atrioventricular block Cardiac rhythm monitoring
15 Sinus exit block resulting in ventricular standstill Cardiac rhythm monitoring
3, 5, 9 Sinus arrest or exit block resulting in ventricular standstill Carotid sinus massage
2 Prolonged corrected sinus node recovery time Electrophysiological study
11 Paroxysmal atrial fibrillation Cardiac rhythm monitoring
7, 12 Severe orthostatic hypotension Orthostatic testing
10 Brain tumour Brain computerised tomography
4, 6, 8, 14, 16 None Complete evaluation

 2005 Adis Data Information BV. All rights reserved. Drugs Aging 2005; 22 (8)
Syncope in Donepezil-Treated Patients with Alzheimer’s Disease
bers 4, 7, 12), no abnormality of impulse formation
or conduction was uncovered during the investiga-
tions, despite the administration of drugs which may
interfere with sinus or atrioventricular node func-
tion. In patient number 11, paroxysmal atrial fibril-
lation was the only abnormal finding, and this was
asymptomatic. In two patients (numbers 7, 12) who
had severe, symptomatic orthostatic hypotension,
HUTT was not needed to confirm the diagnosis.
Both patients were successfully treated by modify-
ing their antihypertensive drug regimens. Patient
number 10, whose CT scan revealed the presence of
a brain tumour, was retrospectively considered to
have probably experienced seizures rather than the
syncope suspected initially. After the tumour was
detected, further diagnostic tests, such as an elec-
trophysiological study, were abandoned. However,
the presence of left bundle branch block on the ECG
meant that a diagnosis of paroxysmal atrioventricu-
lar block remained a possibility. No abnormality
was found in five patients (31%) despite extensive
investigations. It is noteworthy that none of our
patients developed syncope while experiencing gas-
trointestinal adverse effects of donepezil.
Follow-Up Testing After Discontinuation
of Donepezil
In five patients with sinus node disease, the same
abnormalities were observed on 48-hour ECG moni-
toring, carotid sinus massage and electrophysiologi-
cal studies irrespective of whether or not the patient
was taking donepezil. The two patients with ortho-
static hypotension also had no change in their disor-
der after washout of the drug, in contrast to the
marked improvement observed after modification of
their antihypertensive drug regimens. Repetition of
investigations in the absence of donepezil was con-
sidered futile in the two patients with spontaneous
complete atrioventricular block, as well as in the
remainder of the study population, in whom no
cardiovascular cause of syncope was identified.
Long-Term Outcomes
All patients except the patient with a brain tu-
mour remained on a regimen of donepezil. None
 2005 Adis Data Information BV. All rights reserved.
691
experienced recurrence of syncope within a mean
follow-up of 25 ± 12 months (range 4–48).
Discussion
Clinicians are frequently reminded of the need to
be vigilant for the risk of bradycardia in patients
taking cholinesterase inhibitors. However few data
are available,[5,7,8,23] and one study reported an ab-
sence of ECG changes in a large population of
patients with AD treated with a cholinesterase inhib-
itor.[9] Furthermore, both the risk of syncope without
distinct aetiology,[10,11] and a suspected role played
by bradycardia early after initiation of cholinester-
ase inhibitor therapy,[12] have been reported. In theo-
ry, cholinesterase inhibitors may cause sinus brady-
cardia, sinoatrial block, aggravation of pre-existing
sinus node disease and atrioventricular block, all as
a result of cholinergic adverse effects.[24] These ef-
fects are can be reversed with atropine and resolve
after discontinuation of the medication.[8] The ef-
fects of cholinesterase blockade on vagal activity
have been demonstrated with edrophonium, a pro-
vocative agent for inducing syncope during
HUTT.[25] The adverse effects of donepezil on car-
diovascular autonomic control are also manifested
by a significant decrease in heart rate variability.[26]
Therefore, involvement of cholinesterase inhibitors
may be legitimately suspected in the presence of
syncope. Up to one-third of patients with AD may
be taking cardiovascular medications,[9] which may
increase the risk of bradycardia in the presence of
antiarrhythmic therapy. In our study, over 50% of
patients had a cardiovascular history, consisting
mainly of systemic hypertension or paroxysmal atri-
al fibrillation, and approximately one-third were
being treated with cardioactive medications. Thus,
several patients with known systemic hypertension
were not being treated, a choice made by their
primary physician. Among the cardioactive drugs
used, those which slow cardiac impulse formation or
conduction may contribute to bradycardia when
combined with a cholinesterase inhibitor. However,
the four patients in our study who were treated with
both donepezil and antiarrhythmic drugs did not
have a greater propensity for bradycardia than the
Drugs Aging 2005; 22 (8)
692
remainder of the population. Of these four patients,
one had sinus node disease, two had severe ortho-
static hypotension, and no cause of syncope was
identified in the fourth patient. These patients had
already been treated with antiarrhythmic drugs for
several years when donepezil was introduced.
We found that observation of heart rate and blood
pressure during simple manoeuvres such as postural
changes and carotid sinus massage allowed the iden-
tification of mechanisms of syncope in 50% of our
patients. Our observations confirm that, in the pres-
ence of normal left ventricular function, most epi-
sodes of syncope result from bradycardia. Atrial
fibrillation per se is rarely a cause of syncope,
whereas the pause that follows the termination of an
episode of tachyarrhythmia, prior to the resumption
of sinus rhythm, can be a cause of syncope in
patients with paroxysmal atrial fibrillation.[27]
HUTT was, as usual,[28-30] unhelpful in this elderly
population, since vagal tone declines with advanc-
ing age, even in patients treated with medications
that increase cholinergic activity, such as cholines-
terase inhibitors. As is usually the case,[19,22,31]
neurological investigations were also of no value in
identifying the causes of syncope. Of 37 neurologi-
cal tests performed, including echography of the
supra-aortic vessels, EEG and brain CT scan, only
one test yielded a positive result. Therefore, we
recommend that patients be evaluated by a cardiolo-
gist after experiencing a syncopal event.
The prevalence of cardiovascular causes of syn-
cope is similar in patients with or without AD.[32]
Although we did not have a control population to
compare with our study patients, the causes of syn-
cope that we identified were consistent with those
described in general populations of patients without
AD.[20,33-37] Few studies of the mechanisms of syn-
cope in the elderly have been published.[22,31,33] In
nearly one-third of our patients, no distinct aetiology
of syncope was identified, compared with 20–40%
rates reported in general, elderly popula-
tions.[22,33,34,36,37] In a general US population, the
prevalence of syncope was 6.2 per 1000 person-
years. The most frequently identified causes were
vasovagal, followed by cardiac and orthostatic dis-
 2005 Adis Data Information BV. All rights reserved.
Bordier et al.
orders, with the cause remaining undetermined in
more than one-third of patients.[34]
The absence of recurrences of syncope after
pacemaker implantation during long-term follow-up
may be further evidence in favour of a causal rela-
tionship between the bradyarrhythmias observed
during our investigations and the episodes which
occurred before hospitalisation of the patients.
Therefore, since cholinesterase inhibitor therapy re-
mains the most effective treatment of AD,[1-4] im-
plantation of a pacemaker in the presence of severe
bradycardia seems justified, just as it would be
indicated in patients without AD. When a relation-
ship between a documented bradycardia and the
occurrence of syncope is strongly suspected,[12] per-
manent cardiac pacing may be preferable to discon-
tinuation of the cholinesterase inhibitor. The issue of
pacemaker implantation in AD should be addressed
in the early-to-moderately advanced stage of the
disease. All patients in our study tolerated donepezil
10 mg/day without developing long-term adverse
effects. Furthermore, the cost of care for AD is
lower when patients are treated with cholinesterase
inhibitors than when they are left untreated.[2,38-41]
Without treatment, progression of the disease forces
the early placement of patients in extended care
facilities, which are considerably more expensive
than living at home.
Although our study population of patients with
AD and syncope was small, it is, to our knowledge,
the largest reported series thus far. However, our
observational study made no attempts to compare
the causes of syncope in our patients with those of
an age-matched, control population. In addition, we
did not examine whether use of cholinesterase inhib-
itors was more prevalent in AD patients with syn-
cope compared with those without syncope. No
epidemiological data are available that provide an
estimate of the proportion of demented persons in
the general elderly population in our region, or the
proportion of patients with AD treated with cholin-
esterase inhibitors. In addition, in our study, treat-
ment with donepezil was initiated by several physi-
cians specialised in the management of dementia
from various institutions, and our service was not
Drugs Aging 2005; 22 (8)
Syncope in Donepezil-Treated Patients with Alzheimer’s Disease
the only one that admitted patients for the manage-
ment of syncope. Therefore, we were unable to
determine the percentage of the population in our
area treated for AD that was represented by our 16
patients. Furthermore, all patients did not undergo
all tests, since investigations were usually discontin-
ued when a likely diagnosis was made. Finally, no
ECG was recorded prior to the initiation of cholines-
terase inhibitor therapy in any patient, and thus no
comparisons between ‘on’ and ‘off’ therapy were
possible.
Conclusions
Since syncope is uncommon in AD, including
those patients treated with cholinesterase inhibitors,
its occurrence warrants investigation. A meticulous,
noninvasive evaluation was sufficient to confirm
predominantly cardiovascular causes of syncope in
over two-thirds of our patients. The causes of synco-
pe in our population were similar to those encoun-
tered in a general population of elderly individuals,
confirming that most episodes of syncope are cardi-
ac in origin and, in the absence of left ventricular
dysfunction, usually a result of bradyarrhythmias.
Neurological investigations are futile when search-
ing for causes of syncope. If profound bradycardia is
documented, it may be a manifestation of pre-exist-
ing disturbance of impulse formation or conduction
abnormalities, in which case continuation of treat-
ment with donepezil might be considered in con-
junction with implantation of a pacemaker. There-
fore, although the cause of syncope may be mul-
tifactorial, particularly in the elderly, the importance
of referring patients with AD to a cardiologist after a
syncopal episode must be highlighted.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this study. The authors have no conflicts of interest
that are directly relevant to the content of this study.
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Correspondence and offprints: Dr Philippe Bordier, Hopital
Cardiologique du Haut-Leveque, avenue de Magellan,
33604 Pessac cedex, France.
E-mail: Phibordier@aol.com
Drugs Aging 2005; 22 (8)