Download Significance of syncope in patients with Alzheimer`s disease treated

Europace (2003) 5, 429–431
doi:10.1016/S1099-5129(03)00080-1
SHORT SERIES REPORT
Significance of syncope in patients with
Alzheimer’s disease treated with cholinesterase
inhibitors
P. Bordier1, S. Garrigue1, S. S. Barold2, N. Bressolles1,
S. Lanusse1 and J. Clémenty1
1
Hôpital Cardiologique du Haut-Le´veˆque, University of Bordeaux, Pessac, France; and
2
Florida Cardiovascular Institute and Tampa General Hospital, Tampa, FL, USA
We describe three cases of patients with Alzheimer’s disease
who presented with cardiac syncope soon after initiation of
a cholinesterase inhibitor therapy (donepezil). Bradyarrhythmia was documented in two patients, considered
probable in one, and was presumed related to the
cholinergic therapy. Pacemaker implantation seemed justified rather than donepezil cessation. More over, it permitted an increase in donepezil dosage.
(Europace 2003; 5: 429–431)
Ó 2003 The European Society of Cardiology. Published by
Elsevier Ltd. All rights reserved.
Introduction
instability, and syncope as sudden and complete loss of
consciousness. The diagnosis of Alzheimer’s disease was
established by a neurologist according to the Diagnostic
and Statistical Manual of Mental Disorders (Third
Edition, revised) criteria.
Alzheimer’s disease is a common worldwide public
health problem but few therapies delay its progression[1–4]. Cholinesterase inhibitors are used to treat
Alzheimer’s disease but their cholinergic side-effects may
result in discontinuation of therapy[5,6]. Symptomatic
cardiac conduction disorders are considered unusual
with cholinesterase inhibitors in therapeutic doses.
Bradycardia, dizziness, syncope and seizure are rarely
described and their relationship to therapy is
unclear[7–10]. We report our experience with three
patients with Alzheimer’s disease who presented with
cardiac syncope after starting donepezil. We defined
dizziness as a sensation of light-headedness or postural
Manuscript submitted 12 June 2002, and accepted after revision 14
June 2003.
Correspondence: Philippe Bordier, MD, Hôpital Cardiologique du
Haut-Lévêque, Avenue de Magellan, 33604 Pessac cedex, France.
Tel.: +33-5-56-76-57-82; Fax: +33-5-56-04-38-49.
E-mail: [email protected]
1099–5129/03/000429+03 $30.00/0
Key Words: Alzheimer’s disease, cholinesterase inhibitors,
bradycardia.
Case 1
An 80-year-old man with a 2-year history of Alzheimer’s
disease was hospitalized following two episodes of
syncope on the same day. There was no previous history
of syncope. He had been taking donepezil 5 mg dayÿ1
for 1 year and experienced dizziness since the onset of
therapy. His past history consisted of hypertension
treated with lisinopril and nicardipine, paroxysmal atrial
fibrillation treated with propafenone 600 mg dayÿ1 and
glaucoma treated with timolol eye drops. All these
medications had been taken for more than 10 years. The
physical findings and ECG are described in Table 1.
Carotid sinus massage was associated with no symptom
and no change in blood pressure. The results of other
investigations are shown in Table 2. The patient was
Ó 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
430 P. Bordier et al.
Table 1
Patient 1
Patient 2
Patient 3
Physical findings and baseline ECG with cholinesterase inhibitor. No ECG available before cholinergic therapy
BP (mmHg)
Orthostatic hypotension
Rhythm/HR (bpm)
PR interval (ms)
QRS complex
154/85
159/86
125/77
No
No
No
Sinus/56
Sinus/60
Sinus/51
220
200
180
Normal
Right BBB, duration 140 ms, axis ÿ80
Normal
BBB, bundle branch block; BP, blood pressure; HR, heart rate.
discharged without a diagnosis and the drug regimen
was continued. One week later, the patient was
readmitted with another episode of syncope. An
electrophysiological study revealed no inducible atrial
or ventricular tachycardia but the corrected sinus node
recovery time was 700 ms and the HV interval was 60
ms. Though these criteria were weak, a pacemaker was
finally implanted because of recurrent, unexplained
syncope despite extensive evaluation. A DDD pacemaker was implanted and all the medications were
continued. At 1 month and 23 months after pacemaker implantation no dizziness or syncope was reported by the patient or his wife. Donepezil was increased
to 10 mg dayÿ1 after 1 month without any symptom.
Case 2
An 83-year-old man with Alzheimer’s disease was
referred for evaluation of a first syncopal episode
resulting in severe facial trauma. There was no
significant past history. He was being treated with
trimetazidine 60 mg dayÿ1, domperidone 30 mg dayÿ1
and donepezil 5 mg dayÿ1. The latter was begun 2 weeks
before syncope. The clinical and ECG characteristics are
presented in Table 1.
Echocardiography and brain CT were performed on
the first day by the emergency team (Table 2), followed
by no further testing since we had clearly identified
the cause of syncope. In fact, on the second day, 2 : 1
atrioventricular (AV) block was recorded during continuous ECG monitoring, eventually progressing to
spontaneous complete AV block the next day. ECG
monitoring showed no ventricular escape rhythm, and
cardio-pulmonary resuscitation was performed for 20
min before the start of reliable percutaneous temporary cardiac pacing. A VDD pacemaker was implanted.
One month after discharge, the patient remained asympTable 2
Patient 1
Patient 2
Patient 3
tomatic and donepezil dose was increased to 10 mg
dayÿ1. The patient was still asymptomatic 28 months
after pacemaker implantation.
Case 3
An 87-year-old woman with Alzheimer’s disease was
admitted because of syncope and persistent sinus
bradycardia at 45 bpm. She had a past history of
hypertension and depression but no syncope. She had
been on propranolol 40 mg dayÿ1 for 4 years for
idiopathic tremor of the right arm, and clomipramine 10
mg dayÿ1, oxazepam 50 mg dayÿ1, and domperidone 30
mg dayÿ1. Donepezil (5 mg dayÿ1) had been started 19
days before syncope. Table 1 shows the results of physical
examination and ECG data. Light carotid sinus massage
caused sudden loss of consciousness 12 s after the onset
of sinus arrest without escape rhythm, followed by
convulsions. Since the effect of carotid sinus massage
was reproducible by a second manoeuver, we considered
that no other examination was warranted (Table 2).
After implantation of a DDD pacemaker the patient has
remained asymptomatic for 22 months, without any
change in her medications except for donepezil increased
to 10 mg dayÿ1 1 month after the implant.
Discussion
Peripheral cholinergic adverse effects of cholinesterase
inhibitors include nausea, vomiting, diarrhoea, dizziness, syncope and even seizure that may lead to
discontinuation of treatment[5,9,10–13]. Cholinergic-dependent side-effects on cardiac rhythm are related to
vagal tone stimulation[14]. Theoretically, sinus bradycardia, sino-atrial block, worsening of sinus node disease
and AV block can be induced[7,8,15]. These abnormalities
Complementary examinations
Routine
laboratory
studies
TSH
Holter
ECG 48 h
Echocardiography
Echo-Doppler
of supra-aortic
vessels
Head-up
tilt test
EEG
Brain CT
n
n
n
n
n
n
n
–
–
n
n
–
n
–
–
n
–
–
n
–
–
n
n
–
n, Normal; TSH, thyroid stimulating hormone; –, not performed.
Europace, Vol. 5, October 2003
Syncope significance in Alzheimer’s disease
resolve with atropine and stopping the medication[8].
The effect of cholinesterase inhibition on vagal tone has
been used with edrophonium as a provocative agent for
inducing syncope during tilt-table testing[16].
In patients 2 and 3, bradyarrhythmias observed
during hospitalization strongly suggested a relationship
with the episodes of syncope that had occurred out of
the hospital. The absence of recurrence of syncope after
pacemaker insertion during a follow-up of over 18
months in each patient may be further evidence of this
causal relationship. Circumstantial evidence strongly
implicates the role of donepezil in the development of
syncope in 2 patients and dizziness (and eventual
syncope) in another because the symptoms occurred
soon after the initiation of therapy.
Atropine (1 mg) was administered to patient 1 during
electrophysiological study without any significant
change in measured data. But at baseline these data
were slightly abnormal. For patient 2, the over-riding
factor was prolonged resuscitation. In the third case,
a second carotid massage after atropine was not performed for fear of possible further convulsions if
atropine was not effective.
Two patients had been treated with antiarrhythmic
drug therapy for a long time before donepezil was started
but they probably contributed little to the symptomatic
bradycardia induced by donepezil. In patient 1, the
symptoms were probably secondary to sick sinus
syndrome aggravated by donepezil, and the response to
pacing was dramatic in the relief of dizziness. In patient 2,
significant conduction system disease with right bundle
branch block and left anterior hemiblock associated with
the duration of the arrest suggested infra-His disease as
the primary problem rather than a drug effect which
would be expected at the AV nodal level. Nevertheless,
aggravation of conduction system disease by donepezil
was rather consistent. Patient 3 suffered from sick sinus
syndrome and marked carotid sinus hypersensitivity (not
an uncommon association with sick sinus syndrome)
unmasked by donepezil.
The documentation of severe bradycardia as a putative
adverse effect of an anticholinesterase led us to recommend the implantation of a pacemaker rather than
discontinuation of drug therapy. Though we recognized that permanent pacing to manage an adverse effect
from another therapy may be controversial, we made
this choice because cholinergic therapy is the only therapeutic option known to slow the progression of this disease, and considered that management of Alzheimer’s
disease was the priority. All patients received doses of
10 mg dayÿ1 of donepezil with no adverse effects during follow-up. This supported the appropriateness of
continuing drug therapy, while managing the secondary
bradyarrhythmias with permanent pacing.
In conclusion, dizziness and syncope are uncommon
features of Alzheimer’s disease even when treated with
donepezil and, although our findings only give an
inference as to the cause, these symptoms require investigation for a cardiac aetiology. If the aetiology is
431
shown to be cardiac and secondary to donepezil or
strongly suspected (an implantable loop recorder may
also be needed), pacemaker implantation may be
justified instead of drug cessation. Furthermore, a pacemaker permits an increase in donepezil dosage. A
prospective and large study is needed for screening
patients prior to commencement of cholinergic therapy
to determine whether risk factors may be identified for
severe bradycardia under this therapy.
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Europace, Vol. 5, October 2003