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Corresponding author at: Serviço de Neurologia, Departamento de Neurociências e Saúde Mental, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.
Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, PortugalFaculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Faculdade de Medicina, Universidade de Lisboa, Lisbon, PortugalCardiology, Heart and Vascular Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, PortugalFaculdade de Medicina, Universidade de Lisboa, Lisbon, PortugalEEG/Sleep Laboratory, Hospital de Santa Maria, Centro Hospital Universitário Lisboa Note, Lisbon, PortugalReference Centre for Refractory Epilepsy of Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal (Full Member of ERN EpiCARE)
Neurology, Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, PortugalFaculdade de Medicina, Universidade de Lisboa, Lisbon, PortugalReference Centre for Refractory Epilepsy of Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal (Full Member of ERN EpiCARE)
Brugada syndrome is a rare inherited channelopathy predisposing to ventricular arrhythmias and leading to an increased risk of sudden cardiac death, despite a structurally normal heart. The most common mutation is a loss-of-function mutation in SCN5A gene, rsesponsible for encoding the α-subunit of the sodium channel. Diagnosis is based on a specific electrocardiogram (ECG) pattern, observed either spontaneously or during a sodium channel blocker test. Considering the two different Brugada pattern types, type 1 is the most frequently associated with the SCN5A gene mutation [
Lamotrigine is a widely used antiepileptic drug which blocks voltage-gated sodium channels, thereby acting on cardiac as well as in the cerebral cortex, with very few reported cardiac events.
2. Clinical case
A 64-year-old man, with a medical history significant for major depression, was admitted to the emergency department due to a nocturnal generalized tonic-clonic seizure during sleep lasted for three minutes. His-family described monthly nocturnal episodes of repeated chewing movements and bi-manual automatisms, lasting three to five minutes, since his twenties. There was no history of any identifiable precipitants. On examination he presented a lateral tongue bite. Neurological examination was normal. Blood tests and neuroimaging were unremarkable. He was diagnosed with focal epilepsy of unknown etiology and started on sodium valproate 500 mg twice daily. Sleep electroencephalography revealed bilateral focal slow temporal activity and right temporal epileptic activity (Fig. 1). Brain-MRI disclosed a slightly ectasia of the cortical sulci in the high right parietal convexity. During follow-up, the patient maintained nocturnal episodes and lamotrigine 100 mg/daily was added. Shortly thereafter, he started to have frequent episodes of loss of consciousness lasting for seconds and with immediately recovery, suggestive of syncope.
Fig. 1EEG showing bilateral focal slow waves on the temporal regions and right temporal epileptic activity (longitudinal bipolar montage).
A 24 h Holter showed a rSr’ pattern with a coved type 2 mm ST-segment elevation followed by a negative and symmetric T-wave in the right precordial lead V1, suggestive of type 1 Brugada pattern (Fig. 2). Previous patient's ECGs were carefully revised and Brugada pattern was not present before lamotrigine treatment. Therefore, lamotrigine was stopped and switched to levetiracetam 500 mg twice daily. The flecainide provocative drug test two weeks after lamotrigine discontinuation was negative. The 12 right-sided leads ECG showed normal sinus-rhythm with no signs of Brugada pattern. Transthoracic echocardiogram was unrevealing and genetic testing for SNC5A mutations was negative. Given the exclusion of other causes and the temporal relation with the introduction and suspension of the drug, a lamotrigine-induced Brugada syndrome was assumed.
Fig. 212 lead ECG reconstruction using three orthogonal leads (from 24 h Holter monitoring): rSr’ pattern with ST-segment elevation followed by a negative T-wave in the right precordial lead V1.
The association of several psychotropic drugs with malignant arrhythmias in Brugada syndrome is known. An increasing number of drugs prescribed in routine clinical practice have been reported to induce or unmask the characteristic type 1 Brugada Syndrome. The mechanisms by which these drugs can induce a Brugada pattern and proarrhythmic effects are not completely understood. Most of them are thought to act through sodium channels blockage, promoting a decrease in calcium channels or an increase in transient outward currents.
Lamotrigine is a voltage-gated sodium channels blocker, and it is thought that it acts on the central nervous system to stabilize the pre-synaptic membrane and therefore prevent excitatory glutamate cell release. We hypothesized that the non-selective blockade of sodium channels at the systemic level (especially cardiac) by lamotrigine was the possible mechanism of inducing the Brugada syndrome. This effect could also be augmented by the co-administration of sodium valproate. There are only three previous cases in the literature reporting Brugada syndrome induced by lamotrigine [
] the proposed mechanism was the interaction of a predisposed genetic background (a new SCN9A mutation) and the lamotrigine intake. This highlights that there is significant heterogeneity in Brugada syndromes, even though SCN5A mutations are the most common. The blood levels of lamotrigine in a toxic range were also mentioned in other clinical report [
]. In the presented case, we were not able to measure blood levels of lamotrigine as it was not available in our hospital.
Drug-induced Brugada syndrome represents a challenge for the prescribing clinicians as well as for pharmaceuticals and drug regulatory entities. Regarding cardiac rhythm and conduction abnormalities and lamotrigine, the US Food and Drug Administration (FDA) recently updated prescribing information warning and precautions of lamotrigine [
]. At therapeutically relevant concentrations, lamotrigine exhibits class IB antiarrhythmic activity that could slow ventricular conduction and induce arrhythmia, including sudden death, in people with structural heart disease or myocardial ischemia. Therefore, it is recommended to avoid its use in people with underlying cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome or other sodium channelopathies). Moreover, concomitant use of other sodium channel blockers may increase the risk of arrhythmia. FDA also states that in people over 60 years, as the probability of undiagnosed cardiac conduction abnormalities increases, an ECG may be considered prior lamotrigine treatment. Besides, ECG should also be considered in people younger than 60 with known cardiac disease or significant risk factors. When in doubt if lamotrigine initiation is safe, a cardiological evaluation and consultation before initiating lamotrigine should be performed. Moreover, we also advocate that clinician may consider measuring the blood levels of lamotrigine at least when the maximum dosage is reached. In summary, this clinical report highlights the need for awareness to recognize these rare adverse events in patients treated with lamotrigine.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
Li K.H.C.
et al.
Brugada syndrome: a comprehensive review of pathophysiological mechanisms and risk stratification strategies.
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