Proarrhythmogenic effects of lamotrigine during ajmaline testing for Brugada syndrome

Leong, Kevin; Seligman, Henry; Varnava, Amanda

doi:10.1016/j.hrcr.2016.11.006

Cited by 8 publications

(3 citation statements)

References 10 publications

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“…29 This is illustrated by a case report in which a 60-year-old woman using lamotrigine and levetiracetam was undergoing an ajmaline sodium channel blockade test as part of the diagnostic procedure for Brugada syndrome. 30 During ST elevation testing, QRS broadening and the development of bigeminy were observed. The ECG normalized after the ajmaline testing was stopped, and a repeat test off lamotrigine showed a type 1 Brugada pattern with no QRS broadening or electrical alternans.…”

Section: Discussionmentioning

confidence: 99%

Sudden Death and Cardiac Arrythmia With Lamotrigine

et al. 2022

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Objective:A recent FDA warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurological community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or electrocardiogram abnormalities.Methods:We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies, studies of people with or without epilepsy, with one of the following outcome measures: SUDEP and sudden cardiac death, as well as the development or worsening of electrocardiogram abnormalities. All titles and abstracts were independently screened, and the full texts of relevant studies were obtained. We re-evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence.Results:We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and three studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on electrocardiogram parameters, there was no statistically significant increased risk among lamotrigine users except for two studies. These two studies reported either “slight increases” in PR interval or an increased PQ interval that the primary study authors felt to be more related to structural cardiac differences rather than an effect of lamotrigine. One study was rated class II while all others were class III or IV. We had “very low confidence” in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with pre-existing cardiac conditions.Conclusion:There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes, in people with or without epilepsy as compared to ASM or placebo. This is due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

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Section: Discussionmentioning

confidence: 99%

Sudden Death and Cardiac Arrythmia With Lamotrigine

et al. 2022

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“…This hypothesis is further supported by patients with gastrointestinal disease harboring the SCN5A mutation expressing variable symptoms within each age group (34). Furthermore, Leong et al highlight a case of a patient harboring an SCN5A mutation with temporal lobe epilepsy and BrS (16). Animal studies in rats demonstrate the expression of SCN5A genes within the limbic system, suggesting that it can alter neuronal action potential propagation (35).…”

Section: Discussionmentioning

confidence: 96%

Unmasking of Brugada syndrome by lamotrigine in a patient with pre-existing epilepsy: A case report with review of the literature

Omer

Omer²,

Alyousef³

et al. 2022

Front. Cardiovasc. Med.

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Brugada syndrome is an inherited cardiac channelopathy arising from mutations in voltage-gated cardiac sodium channels. Idiopathic epilepsy portrays a coalescent underlying pathophysiological mechanism pertaining to the premature excitation of neuronal voltage-gated ion channels resulting in the disruption of presynaptic neurons and the unregulated release of excitatory neurotransmitters. The coexistence of epilepsy and Brugada syndrome may be explained by mutations in voltage-gated ion channels, which are coexpressed in cardiac and neural tissue. Moreover, the incidence of sudden unexpected death in epilepsy has been associated with malignant cardiac arrhythmias in the presence of mutations in voltage-gated ion channels. Lamotrigine is an antiepileptic drug that inhibits neuronal voltage-gated sodium channels, thus stabilizing neural impulse propagation and controlling seizure activity in the brain. However, lamotrigine has been shown to inhibit cardiac voltage-gated sodium channels resulting in a potential arrhythmogenic effect and the ability to unmask Brugada syndrome in genetically susceptible individuals. We are reporting a case of a 27-year-old male patient with a background of presumed idiopathic epilepsy who was initiated on lamotrigine therapy resulting in the unmasking of Brugada syndrome and the onset of syncopal episodes. This case provides further evidence for the arrhythmogenic capacity of lamotrigine and highlights the relationship between epilepsy and Brugada syndrome. In this report, we aim to review the current literature regarding the associations between epilepsy and Brugada syndrome and the impact of lamotrigine therapy on such patients.

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“…Whether LTG also blocks the cardiac sodium current (I Na ) at therapeutic doses (100–500 mg/day) yielding an effective plasma concentration between 2–16 µg/mL (7.8–62.5 µmol/L) [ 8 , 9 , 10 ], is unknown. However, clinical observations of Brugada syndrome (BrS) phenotype [ 11 , 12 , 13 , 14 ] and QRS prolongation [ 15 ] on the electrocardiograms (ECG) of epileptic patients treated with LTG are consistent with conduction disturbances and I Na block. Those observations, coupled with a series of case reports on LTG cardiotoxicity [ 16 , 17 , 18 ], prompted the FDA to restrict the use of LTG in 2021 and to add a warning label stating that “ Lamictal exhibits class 1B antiarrhythmic activity at therapeutically relevant concentrations.…”

Section: Introductionmentioning

confidence: 99%

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current INa by Lamotrigine; A Potential for Acquired Arrythmias

et al. 2022

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Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (INa) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks INa in the heart. We found that Lamotrigine inhibited 60% of INa peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of INaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for INa may in part explain the clinical phenotypes observed in epileptic patients.

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Proarrhythmogenic effects of lamotrigine during ajmaline testing for Brugada syndrome

Cited by 8 publications

References 10 publications

Sudden Death and Cardiac Arrythmia With Lamotrigine

Sudden Death and Cardiac Arrythmia With Lamotrigine

Unmasking of Brugada syndrome by lamotrigine in a patient with pre-existing epilepsy: A case report with review of the literature

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current INa by Lamotrigine; A Potential for Acquired Arrythmias

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