Induction of epileptic negative myoclonus by addition of lacosamide to carbamazepine

Induction of epileptic negative myoclonus by addition of lacosamide to carbamazepine

Epilepsy & Behavior 20 (2011) 589–590 Contents lists available at ScienceDirect Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev ...

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Epilepsy & Behavior 20 (2011) 589–590

Contents lists available at ScienceDirect

Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

Letter to the Editor Induction of epileptic negative myoclonus by addition of lacosamide to carbamazepine

To the Editor: Lacosamide, a novel compound with an anticonvulsant effect, has the ability, unique among older and newer antiepileptic drugs (AEDs), to interact with sodium channel slow inactivation without affecting fast inactivation [1]. In clinical studies, lacosamide has shown no influence on plasma levels of concomitantly administered AEDs, including carbamazepine, levetiracetam, lamotrigine, topiramate, valproate, and phenytoin [2]. We describe a patient who de novo developed almost continuous epileptic negative myoclonus (ENM), triggered by the addition of lacosamide to carbamazepine, that promptly reverted after carbamazepine dosage reduction. A 27-year-old woman was referred to our attention because she experienced a brief loss of the muscular tone of the arms, clearly predominating in the left upper limb. She was born spontaneously after an uneventful pregnancy at term, and family history for epilepsy was negative. At age 6, she experienced several nocturnal tonic–clonic seizures. The EEG revealed frontal right-sided slow waves, and an MRI study of the brain showed right frontal cortical dysplasia. The patient was started on carbamazepine, and at a dosage of 25 mg/kg body wt, no further seizures occurred. The epilepsy was well controlled (less than one nocturnal tonic-clonic seizure for year) until age 27 when she experienced two nocturnal tonic–clonic seizures; the EEG revealed frontal right-sided slow waves and an MRI study confirmed right frontal cortical dysplasia. On carbamazepine retard (1200 mg/daily, 10.8 μg/mL), lacosamide was started 50 mg twice daily with a view toward increasing the dose to 300 mg daily over 3 weeks. After addition of lacosamide, no further seizures occurred. Noteworthy, on lacosamide 300 mg/daily, she complained of episodes characterized by drops of her left upper limb, which caused the patient to let objects fall. Polygraphic EEG recordings, including the EMG tracing of the left deltoid muscle and wrist extensor muscle, showed an abrupt and brief period of electrical silence when the patient was asked to extend the arms and dorsiflex the hands in a sustained posture. Moreover, the interruption of tonic muscle activity occurred in conjunction with epileptiform EEG abnormalities, consistent with ENM (Fig. 1). To exclude the possibility that carbamazepine intoxication might have caused the symptom, serum levels was obtained; however, serum levels of carbamazepine did not show any significant change (i.e., 10.5 μg/mL). As seizure frequency had decreased significantly after the introduction of lacosamide 300 mg daily, carbamazepine was abruptly reduced to 600 mg daily resulting, after 2 days, in remission of ENM. The patient has been followed for 2 months on lacosamide 300 mg daily and carbamazepine 600 mg daily (5.5 μg/mL) and she has not experienced ENM or aggravation of seizures. At the latest follow-up, as noted before the occurrence of ENM, the EEG revealed frontal right-sided slow waves. Epileptic negative myoclonus is a well-known side effect of some anticonvulsant drugs such as carbamazepine, valproic acid, phenytoin, 1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.01.022

lamotrigine, and oxcarbazepine [3]. Lacosamide is generally well tolerated, with mostly dose-dependent central nervous system side effects (dizziness, diplopia, blurred vision, somnolence, headache) [2]. In an attempted suicide, even after ingestion of 12 g lacosamide, a patient was found comatose; however, complete physical recovery occurred after supportive treatment and the patient has experienced neither ENM nor seizure aggravation [4]. To our knowledge, this is the first report of ENM induced by lacosamide as add-on medication. Noteworthy, our patient had never experienced such a condition or any other ictal manifestation apart from nocturnal tonic–clonic seizures. Based on the hypothesis that the slow-wave component reflects enhanced inhibitory events [3], the blockage of voltage-gated sodium channels (VGSCs) induced by carbamazepine and lacosamide could play a role in the enhanced cortical inhibitory activity underlying the slow-wave component of the spike–wave complex and, in turn, ENM. In our patient, unfortunately, lacosamide blood levels were not assessed. Thus, we cannot comment on a possible correlation between ENM and serum lacosamide concentrations; however, we did not find any significant changes in concentrations of carbamazepine. In our patient we observed prompt remission of the symptoms after carbamazepine load reduction, which may suggest a pharmacodynamic interaction. On the other hand, the possibility of a pharmacodynamic interaction with other VGSC-blocking AEDs has been postulated in people with epilepsy who experienced significant side effects during the introduction of lacosamide as add-on medication [5]. Although our patient developed ENM when lacosamide was added to her preexisting carbamazepine treatment, there is no evidence here that the drug alone induces this seizure type, as ENM resolved after carbamazepine reduction without any change in lacosamide. However, because lacosamide as add-on therapy is a recently introduced practice that will most likely increase among physicians, it is important to increase physicians’ awareness that lacosamide may induce ENM, especially when the drug is administered in association with other VGSC-blocking AEDs.

Conflict of interest statement V.B. has received travel and research grants from UCB Pharma.

References [1] Curia G, Biagini G, Perucca E, Avoli M. Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs 2009;23:555–68. [2] Doty P, Rudd GD, Stoehr T, Thomas D. Lacosamide. Neurotherapeutics 2007;4: 145–8. [3] Rubboli G, Tassinari CA. Negative myoclonus: an overview of its clinical features, pathophysiological mechanisms, and management. Neurophysiol Clin 2006;36: 337–43. [4] Bauer S, Rudd GD, Mylius V, Hamer HM, Rosenow F. Lacosamide intoxication in attempted suicide. Epilepsy Behav 2010;17:549–51. [5] Novy J, Patsalos PN, Sander JW, Sisodiya SM. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction? Epilepsy Behav 2011;20:20–3.

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Letter to the Editor

Fig. 1. Simultaneous electromyographic silent periods of left deltoid muscle (EMG) and wrist extensor muscle (EMG 1). The silent EMG period occurred in conjunction with epileptic EEG abnormalities. Note: The vertical bars represent 1 second.

Vincenzo Belcastro⁎ Marco Arnaboldi Unitá Operativa di Neurologia, Dipartimento di Neuroscienze, Ospedale Sant'Anna, Como, Italy ⁎Corresponding author at: Unitá Operativa di Neurologia, Dipartimento di Neuroscienze, Azienda Ospedaliera Sant'Anna, via Ravona, 22100 Como, Italy. Fax: +39 0315859553. E-mail address: [email protected] (V. Belcastro).

Paolo Prontera CRR Genetica Medica, Università di Perugia, Perugia, Italy

Angelo Taborelli Dipartimento di Neuroscienze, Ospedale S.Anna-Como, Italy

1 January 2011