Lacosamide-induced second-degree atrioventricular block in a

patient with partial epilepsy*1Ahmad Nizam, *Krishna Mylavarapu, yDwithiya Thomas, *Klara Briskin, *Brenda Wu,

yDeepak Saluja, and *1Stephen Wong

*Department of Neurology, UMDNJ – Robert Wood Johnson Medical School, New Brunswick, New Jersey, U.S.A.; and yDivision of

Cardiology, Department of Medicine, UMDNJ – Robert Wood Johnson Medical School, New Brunswick, New Jersey, U.S.A.

SUMMARY

Dose-dependent PR interval prolongation has been

reported in preclinical studies of lacosamide (LCM), a

recently U.S. Food and Drug Administration (FDA)–

approved antiepileptic drug (AED). Here we report a case

of second-degree atrioventricular block (AV) block

caused by the addition of LCM to other AEDs known to

prolong the PR interval, resulting in hypotension and bra-

dycardia, with consequent seizure exacerbation. The

patient recovered completely after withdrawal of LCM.

This case demonstrates the need for caution and interval

cardiac testing when adding LCM to other AEDs known to

prolong the PR interval.

KEY WORDS: Lacosamide, Heart block, Arrhythmia.

Case Report

A 45-year-old man with frontal lobe epilepsy, seizure-free for 1 year, developed palpitations, dyspnea, and exer-cise intolerance 1 week prior to hospitalization for recurrentseizure. En route to the hospital, he was noted to have brady-cardia (44 bpm) with hypotension (83/64 mm Hg).

His medical history included craniopharyngioma at age6, treated with right frontal craniotomy, resection, radia-tion, and ventriculoatrial shunting. His course was compli-cated by right eye blindness and panhypopituitarism withdiabetes insipidus, hypothyroidism, and adrenal insuffi-ciency. At age 21, he developed acute lymphocytic leuke-mia, treated with chemotherapy. At age 23, he developedfrontal lobe epilepsy featuring generalized tonic–clonicseizures beginning with stereotyped right arm extension.There was no personal or family history of cardiacconduction disorders.

His medications included desmopressin, hydrocortisone,levothyroxine, somatropin, alfuzosin, risedronate, Carbatrol100 mg po qAM and 200 mg po qPM, oxcarbazepine600 mg po qAM, 600 mg po qPM, and 1200 mg po qHS,and LCM 200 mg nightly. His only medication change over

the last year was LCM replacing zonisamide (ZNS) forunclear reasons 3 months previously, reaching 200 mg2 months prior to presentation.

Initial laboratory evaluation with blood counts, electro-lytes, and hepatic enzymes was unremarkable; carbamaz-epine (CBZ) level was 3.8 lg/ml. Head computerizedtomography showed stable right frontal encephalomala-cia. Electrocardiography (ECG) showed second-degreeAV block (Mobitz I/Wenckebach) with frequent droppedbeats and bradycardia. A transvenous pacemaker wasplaced. After three further seizures, Carbatrol wasincreased to 200 mg twice daily, continuous intravenouslorazepam was added, and he was transferred to ourinstitution.

At our institution, physical examination revealed priorcraniotomy, depressed consciousness, and right afferentpupillary defect. Echocardiography, urinalysis, urine toxi-cology, and endocrine evaluation [including sodium,thyroxine, and morning cortisol] were unremarkable. Thy-roid-stimulating hormone was undetectable, as expected.His antiepileptic drugs (AEDs) were continued except forZNS replacing LCM. Initial cardiac monitoring showed amarkedly prolonged PR interval, frequent Mobitz I AVblock, and right bundle branch block. Continuous video–electroencephalography (EEG) showed frequent rightfrontal/frontopolar spikes without seizures. His second-degree AV block became intermittent and resolved 19 hafter LCM discontinuation, persisting at least 24 h afterresolution of seizure activity (6.5 h with EEG confirma-tion). His PR interval decreased progressively over thenext several days (Fig. 1). He made a complete recovery.

Accepted June 30, 2011; Early View publication July 29, 2011.Address correspondence to Stephen Wong, M.D., Department of

Neurology, UMDNJ – Robert Wood Johnson Medical School, ClinicalAcademic Building, 6th floor, New Brunswick, NJ 08901-1962, U.S.A.E-mail: wongst@umdnj.edu

1These authors contributed equally to this manuscript.

Wiley Periodicals, Inc.ª 2011 International League Against Epilepsy

Epilepsia, 52(10):e153–e155, 2011doi: 10.1111/j.1528-1167.2011.03212.x

BRIEF COMMUNICATION

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Discussion

Several adverse cardiac events have been reported withLCM. Mild events include dose-dependent PR interval pro-longation (Shaibani et al., 2009; Wymer et al., 2009;Krauss et al., 2010) and first-degree AV block (Ben-Mena-chem et al., 2007; Shaibani et al., 2009; Krauss et al.,2010). More serious events include atrial fibrillation/flutterat relatively high dosages of LCM at 600 mg/day (Shaibaniet al., 2009; Degiorgio, 2010). Single fatal cardiac arrestsreported in each of two clinical studies of LCM in patientswith diabetic neuropathy (Shaibani et al., 2009; Wymeret al., 2009) were thought to be due to coronary artery dis-ease. An instance of second-degree AV block observed inone study in a patient taking 600 mg/day of LCM (Shaibaniet al., 2009), but a clear causal relation could not be estab-lished as that observation was made 5 days after the lastdosage of LCM, with resolution on a subsequent visit.A case of transient third-degree AV block was recentlyreported in a patient with cardiac disease after high dosesof LCM were given intravenously for nonconvulsive statusepilepticus (Krause et al., 2011).

This report shows a causal relationship between LCMand second-degree AV block in a patient with partial sei-zures. Our patient’s baseline PR interval was 200 ms. Three

months after starting LCM, his PR interval had doubled,with concomitant second-degree AV block and symptom-atic hemodynamic compromise. We suspect that his hemo-dynamic changes triggered his seizure exacerbation. Hiscardiac findings resolved after discontinuing LCM. In con-trast to other major cardiac adverse events reported withLCM in the literature, our patient had no prior history of car-diac disease, and a reasonable dose of LCM was used.

We considered ictal mechanisms for our patient’s second-degree AV block, but ultimately felt that our case wasinconsistent with ictal AV block. A review of the literaturereveals that ictal AV block (1) is associated with temporallobe seizures and (2) recovers seconds to minutes afterthe ictus (Tigaran et al., 2002; Altenmuller et al., 2004;O’Regan & Brown, 2005; Surges et al., 2009). Our patient’sseizures were frontal in origin, and he had persistent sec-ond-degree AV block with at least 24 h of seizure-freedom,with 6.5 h confirmed by continuous EEG monitoring.Furthermore, his PR interval decreased progressively over5 days, consistent with a drug withdrawal time course.

CBZ is known to prolong the PR interval (Kasarskiset al., 1992). Our patient’s top-normal baseline PR intervalmay have been prolonged from CBZ, potentiating thedevelopment of second-degree AV block after LCM wasadded. Similar to the case of atrial fibrillation reported by

A

B

Figure 1.

Panel A: PR intervals versus time. The gray box indicates LCM therapy (start time approximate, 3 months prior to admission). The

period of second-degree AV block is split into a presumptive symptomatic period (dashed-line) of dyspnea and exercise intolerance

(start time approximate, 1 week prior to admission) and an ECG-verified period (solid line). PR intervals are plotted with circle

(white = cardiologist-verified from ECG rhythm strips, gray = outside 12-lead ECG, black = institutional 12-lead ECG). PR intervals

increase from 200 ms at baseline to >400 ms at maximum, and returned smoothly to baseline over 5–6 days after LCM discontinua-

tion. Vertical dashed lines (marked by numbers 1–4) indicate the times the ECG rhythm strips in Panel B were obtained. Panel B: ECG

rhythm strips from four time points in Panel A. Asterisks mark P-waves. Strip 1 is pre-LCM. Strips 2 and 3 show second-degree AV

block (Mobitz I/Wenckebach) immediately after discontinuation of LCM. Strip 4 shows recovery 3 days after LCM discontinuation.

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Epilepsia, 52(10):e153–e155, 2011doi: 10.1111/j.1528-1167.2011.03212.x

Degiorgio (2010), our patient was treated with LCM and atraditional sodium channel blocker. Because LCM’s mecha-nism of action involves a novel slow inactivation of sodiumchannels, there may be greater potential for synergistic PRinterval prolongation when combined with traditionalsodium channel blockers known to prolong the PR interval.

Clinical PR prolongation can result from AV nodal orinfra-Hisian conduction delay (Braunwald & Bonow,2012). Most cardiac tissues, including the His–Purkinje sys-tem, generate action potentials mainly through voltage-gated sodium channels. However, action potential genera-tion in the AV node is mediated through voltage-gated Ca2+

channels, with the sodium current playing a minimal role.LCM’s inhibition of sodium channels can possibly produceinfra-Hisian conduction delay; reported increases in QRSduration with LCM therapy are supportive of this hypothesis(Shaibani et al., 2009; Wymer et al., 2009; Degiorgio,2010). Alternatively, potential LCM effects on calcium cur-rents or autonomic tone may result in direct AV nodaleffects causing varying degrees of atrioventricular block.

In conclusion, we recommend caution when adding LCMto other AEDs known to prolong the PR interval. Electrocar-diographic testing before and during LCM therapy may helpto avoid cardiac arrhythmias.

Disclosure

None of the authors have any conflict of interest to disclose. We confirmthat we have read the Journal’s position on issues involved in ethical publi-cation and affirm that this report is consistent with those guidelines.

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