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• W2012125567 abstract "We report the case of a 24-year old female with a seizure disorder and previously undiagnosed long QT syndrome whose QT interval increased and developed into torsades de pointes after her levetiracetam dose was increased. The patient had been having seizures since age 10. The episodes typically occurred in the early morning and witnesses describe shaking of her entire body, incontinence, and while the patient was not aware of the events at the time when they occurred, she did get tired and confused after the events. She had been started on carbamazepine as a child, with escalating doses as she aged. She presented to the NorthShore epilepsy clinic for the first time after a generalized seizure, and was started on levetiracetam 250 mg twice a day with the plan of increasing the dose over weeks then weaning her carbamazepine (initial random carbamazepine level was 10.1 μg/ml). A brain MRI showed minimal T2 hyperintensities in white matter which were interpreted as non-specific. Her EEG showed intermittent right temporal sharp waves with an electrophysiological maximum at T4 and occasional right temporal polymorphic theta-range slowing suggestive of mild focal cerebral dysfunction. While seizures have not been captured on EEG, the combination of her clinical presentation and focal abnormalities on EEG suggests she has an epileptic disorder. At one-month follow up her serum levetiracetam level was 8.1 μg/ml, and an ECG showed a QTc of 520 ms (Fig. 1A). She was referred to cardiology for evaluation of her prolonged QT interval. Eleven days later she presented to an outside hospital after a generalized seizure; 3 days before presentation her twice daily levetiracetam had been increased to 500 mg. At that visit to the ED her levetiracetam dose was increased to 1000 mg twice a day and she was discharged home. The following day she presented to the NorthShore ED with complaints of “difficulty breathing.” Initial ECG showed normal sinus rhythm with a QTc of 771 ms (Fig. 1B). Her levetiracetam level was 34 μg/ml and carbamazepine level was 8.1 μg/ml. While in the ED her mental status deteriorated and her heart rhythm changed into polymorphic ventricular tachycardia/torsades de pointes. She was treated with a lidocaine drip which had almost no effect, and intravenous magnesium sulfate was more effective at terminating the rhythm, but the rhythm recurred, requiring multiple cardioversions. The patient also developed sustained monomorphic ventricular tachycardia of varying morphologies that appeared to initiate with PVCs suggestive of early after depolarizations (Fig. 1C). Because of concerns of recurrent hemodynamic collapse she was intubated and sedated; a continuous infusion of magnesium sulfate was used to control her ventricular arrhythmias and her anti-epileptics were discontinued. The day after presentation her QTc decreased to 670 ms with a levetiracetam level of 2.7 μg/ml and carbamazepine level of 4.9 μg/ml; on subsequent days her levetiracetam level became undetectable (carbamazepine was 2.1 μg/ml the following day, then became undetectable) with lower QT intervals (Fig. 2). Her hospitalization was complicated by pneumonia and diabetes insipidus but she was successfully extubated and the following week a dual-chamber defibrillator device was implanted. She recovered to her baseline, and in the 2-year follow up period her seizures have been well controlled on clobazam with no further episodes of ventricular tachyarrhythmia. As part of the patient's work up for long QT interval, a point mutation was identified in the KCNH2 potassium channel (Met645Ile). KCNH2 is a delayed rectifier channel involved in cardiac repolarization, and mutations in KCHN2 are associated with the LQT2 syndrome that can present with both long QT intervals and seizures [[1]Anderson J.H. Bos J.M. Cascino G.D. Ackerman M.J. Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome.Heart Rhythm. 2014; 11: 53-57Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. The prolongation of QT interval after increasing the levetiracetam dose was unexpected since levetiracetam has been one of the AEDs thought to have a minimal effect on QT intervals. Siniscalchi and coworkers reported an increase of only about 25 ms in QTc in post-stroke patients treated with levetiracetam [[2]Siniscalchi A. Scaglione F. Sanzaro E. Iemolo F. Albertini G. Quirino G. et al.Effects of phenobarbital and levetiracetam on PR and QTc intervals in patients with post-stroke seizure.Clin Drug Investig. 2014; 34: 879-886Crossref PubMed Scopus (14) Google Scholar]. These patients had adult-acquired seizure disorders and are presumed to have had wild-type ion channels. Levetiracetam has multiple proposed mechanisms of action, among them is inhibition of Kv3.1 that like KCNH2 is a delayed-rectifier potassium channel. Unlike KCNH2, however, Kv3.1 is widely expressed in brain tissue, is not thought to play a significant role in cardiac conduction, and has different gating kinetics than KCNH2 [[3]Huang C.W. Tsai J.J. Huang C.C. Wu S.N. Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (KV3.1): contribution to the firing of action potentials.J Physiol Pharmacol. 2009; 60: 37-47PubMed Google Scholar]. As a result, it is unknown if levetiracetam would affect either wild-type or mutant KCNH2 channels. Other AEDs do inhibit KCNH2, with phenytoin, phenobarbital, and lamotrigine having the most significant effect [[4]Danielsson B.R. Lansdell K. Patmore L. Tomson T. Phenytoin and phenobarbital inhibit human HERG potassium channels.Epilepsy Res. 2003; 55: 147-157Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Carbamazepine, which this patient was also taking, has been shown to inhibit KCNH2, but with a high IC50/unbound therapeutic concentration making it unlikely to be clinically relevant [[4]Danielsson B.R. Lansdell K. Patmore L. Tomson T. Phenytoin and phenobarbital inhibit human HERG potassium channels.Epilepsy Res. 2003; 55: 147-157Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], and the dose of carbamazepine had not been changed in the preceding year. This case raises the possibility that levetiracetam has an unanticipated effect on cardiac conduction in patients with KCNH2 mutations, especially when used in combination with other AEDs. Author N.P.I. is a shareholder in the for-profit ventures Medical Resource Group, LLC and MomMD, LLC which receive advertising revenue from medically related industries including pharmaceutical companies. Authors J.T.N. and W.G.F. have no conflict of interest disclosures." @default.
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• W2012125567 date "2015-07-01" @default.
• W2012125567 modified "2023-10-15" @default.
• W2012125567 title "QT interval prolongation in a patient with LQT2 on levetiracetam" @default.
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• W2012125567 doi "https://doi.org/10.1016/j.seizure.2015.04.006" @default.
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