42399_2019_97_Article 1..5Drug-Induced Brugada Syndrome in a
Psychiatric Patient: a Case Report
C. Ottaviani1 & M. Luciani1 & E. Bentivegna1 & V.
Spuntarelli1 & S. Salemi1 & R. Di Rosa1 & P.
Martelletti1
Accepted: 6 June 2019 # Springer Nature Switzerland AG 2019
Introduction
Brugada syndrome is a hereditary arrhythmic disease characterized
by the presence of coved ST elevation (at least 2 mm), with a
negative T wave of the right precordial ECG leads (type 1 Brugada
pattern). It is related to at least one of the following criteria:
syncope or cardiac arrest, ventricular fibrillation or polymorphic
ventricular tachycardia (documented or inducible), fami- ly history
of type 1 Brugada pattern, sudden death be- fore 45 years old, or
nocturnal agonal respiration [1]. Moreover, signs of Brugada
syndrome have been found in asymptomatic patients exposed to
certain drugs [2].
In this report, we describe the case of a 44-year-old woman with
positive anamnesis for psychiatric drug use and recurrent syncopal
episodes. There was no surface ECG and 24-h holter ECG monitoring
and the ajmaline test were necessary to de- tect coved-type Brugada
pattern.
Case Summary
A 44-year-old Caucasian woman was accessed to emer- gency after
being rescued for syncope. In recent months, she had reported
multiple syncopal episodes that were sometimes followed by loss of
sphincter control and post-critical confusion without any
prodromes. The pa- tient’s medical history reported cerebral
aneurysms with
recurrent occipital headache and that she had suffered from major
depression in drug therapy. Reports of previ- ous self-performed
tests seemed to exclude syncope re- lated to a vaso-vagal or
epileptic nature. Hypothesizing a psychiatric genesis of syncopal
episodes, the patient be- gan topiramate 100 mg BID with a
transient reduction in the frequency of episodes.
The patient’s medical history detailed that she was taking
fluoxetine 25 mg, topiramate 100 mg BID, and alprazolam 0.25 mg. In
the past, levetiracetam had also been administered, but then
suspended. The patient demonstrated allergic reactions to
acetylsalicylic acid, metamizole, diclofenac, and paramagnetic
contrast agent (gadolinium). Four years prior, a middle cerebral
artery aneurysm was treated through an embolization.
Upon arrival at the hospital, general conditions were fair, Glasgow
Coma Scale was 15, and all objective examinations and vital signs
were normal. Blood tests were carried out; resting ECG (Fig. 1) and
chest x-rays were normal. A basal cerebral CT scan showed “outcomes
of embolization of in- tracranial aneurysm of the right middle
cerebral artery with no other encephalic alterations.” Neurological
counselling suggested the execution of an EEG that was negative for
epileptogenic foci. An ecocolordoppler test, as well as a
two-dimensional Doppler echocardiogram, showed arteries above the
aortic artery to be negative.
A resting electrocardiogram with precordial deriva- tions modified
for searching Brugada pattern showed negative T waves and minimum
ST elevation at right precordial derivations (Fig. 2). Type 1
Brugada pattern was induced with ajmaline test performed by
electro- physiologists (Fig. 3); a loop recorder system was placed.
The patient was informed about which drugs to avoid for this
clinical situation. According to the new diagnosis, a psychiatrist
specialist recommended ceasing the use of topiramate and
fluoxetine.
This article is part of the Topical Collection on Medicine
* V. Spuntarelli
[email protected]
1 Azienda Ospedaliera Sant’Andrea, Via di Grottarossa, 1035 Rome,
Italy
SN Comprehensive Clinical Medicine
https://doi.org/10.1007/s42399-019-00097-y
Discussion
Brugada syndrome (BS) is a familiar autosomal domi- nant
channelopathy characterized by an alteration of transmembrane ion
currents of cardiac cells. Mutations in the SCN5A gene have been
found in 10–30% of cases, and nearly 300 mutations of this gene
have been described [3]. Mutations in other genes, such as CACNA1C
and CACN2b, encoding for α1- and β2b- subunits of the L-type
calcium channel, have been pro- posed to be the cause of other
variants of BS [4].
This pathology is characterized by an incomplete pene- trance and a
high variability of expression: it is possible to have asymptomatic
individuals as well as sudden cardiac deaths during the first years
of life.
Arrhythmias usually arise during the fourth decade of life, and
sudden cardiac death often occurs during sleep [5, 6].
There are three types of repolarization patterns in the right
precordial leads. Type 1 ST segment elevation is diagnostic of BS
and is characterized by a coved ST segment elevation ≥ 2 mm (0.2
mV) followed by a neg- ative T wave. Type 2 ST segment elevation
has a saddleback appearance with a high takeoff ST segment
elevation of ≥ 2 mm, followed by a trough displaying ≥ 1-mm ST
elevation, followed by either a positive or bi- phasic T wave. Type
3 ST segment elevation has either a saddleback or coved appearance
with an ST segment el- evation of < 1 mm.
Several studies have reported that cases of sporadic Brugada
pattern without family history can be unmasked by class 1A and 1C
antiarrhythmic drugs with sodium channel blocking effects such as
ajmaline, procainamide, or flecainide [7–10]. It was hypothesized
that an external intervention causes a sufficient imbalance in
membrane currents in the right ventricular outflow tract inducing
surface ECG changes similar to those found in hereditary Brugada
syndrome.
Regarding the BS pathophysiology, several studies sug- gest that
rebalancing of currents active at the end of phase I, leading to an
accentuation of the action potential notch in the right ventricular
epicardium, is responsible for the accentu- ated J wave or ST
segment elevation associated with BS. It results from the
amplification of heterogeneities intrinsic to the early phases of
action potential among different transmural cell types. The
amplification is subordinate to a rebalancing of currents active
during phase I, including a reduction of INa or ICa or enhancement
of any one of a
Fig. 1 Normal resting EKG
SN Compr. Clin. Med.
number of outward currents. ST segment elevation occurs as a
consequence of the accentuation of the action potential notch,
leading to loss of the action potential dome in the right
ventricular epicardium, where transient outward current (Ito) is
most evident. That leads to a transmural as well as an epicardial
dispersion of repolarization. The transmural leak- age implies the
development of ST segment elevation and the creation of a
vulnerable window across the ventricular wall, whereas the
epicardial dispersion gives rise to phase II re-entry, which
provides the extrasystole that captures the vulnerable window, thus
precipitating tachyarrhythmias.
During the last few years, other class drugs have been reported to
induce Brugada ECG pattern, and an increas- ing number of reports
of drug-induced Brugada have been published [10]. Main
pharmacological agents indicted are tricyclic antidepressants,
fluoxetine, lithium, trifluoperazine, antihistamines, and cocaine
(Table 1) [11]. The scientific community has shown a growing
interest in these responsible drugs and on the possible mechanisms
underlying this phenomenon. However, it is still not clear whether
this syndrome is a latent one or if it requires genetic
predisposition. A possible
mechanism could be a latent disfunction of the mem- brane channels
due to an individual susceptibility similar to that in drug-induced
long QT syndrome [12]. However, further studies are needed to
support this hypothesis.
According to this case report, it is always important to pay
attention to the administration of these agents in psy- chiatric
patients. Physicians need to have a thorough un- derstanding of the
clinical history, and an ECG has to be performed at baseline and
after drug administration. Commonly administered antipsychotic and
antidepressant drugs should be used at the lowest possible dose,
and with great care in BS cases or when combined with agents known
to prolong QT intervals or predispose to acquired forms of BS.
Patients should be screened for relevant clinical risk factors to
minimize the cardiac risk. Major risk factors include structural
heart disease, congen- ital BS, family history of sudden death, and
previous ep- isode of drug-induced ECG alterations. Secondary risk
fac- tors include old age, kidney and renal failures,
dyselectrolytaemia, or concomitant use of other drugs in- ducing
the Brugada phenotype.
Fig. 2 Resting EKG performed with precordial derivations
“modified”: rSr′ pattern with inverted Twaves and minimum
STelevation in right precordial leads
SN Compr. Clin. Med.
Author Contribution All authors materially participated in the
research.
Dr. Ottaviani, Dr. Luciani, Dr. Bentivegna, and Dr. Spuntarelli
partic- ipated in data collection, in study design, and in article
preparation. Dr. Martelletti, Dr. Salemi, and Dr. Di Rosa
participated in acquisition of patient’s data.
All authors have approved the final article.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict
of interest.
Ethical Approval NA.
Consent Written informed consent was obtained from the patient for
publication of this case report and accompanying images.
Registration of Research Studies NA.
Guarantor Dr. Paolo Martelletti, MD.
Fig. 3 EKG during ajmaline test showing coved ST segment elevations
with T wave inversions in right precordial leads
Table 1 List of drugs Brugada induced
Drugs Brugada indicted
Psychotropic drugs Tricyclic antidepressant (clomipramine,
desipramine, nortriptyline, amitripryline) Antipsychotics
(loxapine, trifluoperazine) Lithium Anticonvulsants (clonazepam,
oxcarbazepine) Selective serotonin reuptake inhibitors (fluoxetine)
Phenothiazine
Antianginal drugs Calcium channel blockers (nifedipine, diltiazem)
Potassium channel opener (nicorandil)
Other drugs Cocaine Alcohol Anesthetics (propofol, bupivacaine)
Histaminic H1 receptor antagonists Acetylcholine, edrophonium
SN Compr. Clin. Med.
References
1. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R,
Corrado D, Gussak I., LeMarec H., Nademanee K., Perez Riera A.R.,
Shimizu W., Schulze-Bahr E., Tan H., Wilde A. Brugada syndrome:
report of the second consensus conference: endorsed by the Heart
Rhythm Society and the European Heart Rhythm Association,
Circulation , 2005, vol. 111 (pg. 659–670).
2. Akhtar M, Goldschlager NF. Brugada electrocardiographic pattern
due to tricyclic antidepressant overdose. J Electrocardiol.
2006;39:336–9.
3. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada
J, et al. An international compendium of mutations in the SCN5A-
encoded cardiac sodium channel in patients referred for Brugada
syndrome genetic testing. Heart Rhythm. 2010;7(1):33–46.
4. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti
MC, Aizawa Y, et al. Loss-of-function mutations in the cardiac
calcium channel underlie a new clinical entity characterized by
ST-segment elevation, short QT intervals, and sudden cardiac death.
Circulation. 2007;115(4):442–9.
5. Shimizu W, et al. Clinical impact of genetic studies in lethal
inherited cardiac arrhythmias. Circ J. 2008;72:1926–36.
6. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhyth-
mias. Nat Rev Cardiol. 2009;6:337–48.
7. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D,
Towbin JA, et al. Sodium channel blockers identify risk for sudden
death in patients with ST-segment elevation and right bundle branch
block but structurally normal hearts. Circulation.
2000;101:510–5.
8. Miyazaki T, Mitamura H,Miyoshi S, Soejima K, Aizawa Y, Ogawa S.
Autonomic and antiarrhythmic drug modulation of ST segment
elevation in patients with Brugada syndrome. J Am Coll Cardiol.
1996;27:1061–70.
9. Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H. ST
segment elevation in the right precordial leads induced with class
Ic antiarrhythmic drugs: insight into the mechanism of Brugada
syndrome. J Cardiovasc Electrophysiol. 1999;10:214–8.
10. Hermida JS, Jandaud S, Lemoine JL, Rodriguez-Lafrasse C,
Delonca J, Bertrand C, et al. Prevalence of drug-induced electro-
cardiographic pattern of the Brugada syndrome in a healthy popu-
lation. Am J Cardiol. 2004;94:230–3.
11. Minoura Y, Kobayashi Y, Antzelevitch C. Drug-induced Brugada
syndrome. Journal of Arrhythmia. 2013;29:88–95.
12. Yap YG, Behr ER, Camm AJ. Drug-induced Brugada syndrome.
Europace. 2009 Aug;11(8):989–94.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional
affiliations.
SN Compr. Clin. Med.
Drug-Induced Brugada Syndrome in a Psychiatric Patient: a Case
Report
Introduction