drug-induced brugada syndrome in a psychiatric patient: a
TRANSCRIPT
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
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