Pharmacodynamic sodium channel blockers-induced seizure aggravation in patients with newly diagnosed focal epilepsy

Pharmacodynamic aggravation (PA) is an unpredictable increase in the frequency, the severity of existing seizures, and/or development of new seizure types despite rational (adequate for seizure type and epilepsy form) antiepileptic drug (AED) prescription. Many mechanisms and predictors of its development are still poorly understood.

Objective: to analyze PA of seizures in patients with newly diagnosed focal epilepsy receiving monotherapy with sodium channel blockers with epileptiform activity index (EAI) assessment.

Patients and methods. We enrolled 201 patients with newly diagnosed focal epilepsy aged 16—81 years. In twelve months, patients had five follow-up visits. At each visit, treatment tolerability and efficacy were assessed, taking into account changes in the type, severity, and frequency of seizures. Additionally, at each visit, video-electroencephalographic monitoring was performed with EAI assessment. PA of seizures occurred in patients on oxcarbazepine, carbamazepine, and lacosamide therapy.

Results and discussion. Five patients with PA of seizures had increased total EAI and EAI before sleep at the second follow-up visit after sodium channel blockers prescription. Electroencephalographic correlates of PA occurred earlier than clinical manifestations. In patients with PA, the absolute increase in EAI was minimal in patients receiving oxcarbazepine, and lacosamide therapy was associated with a minimal relative increase in EAI. At the end of the follow-up, total EAI decreased by 54—80% relative to its initial value in all five patients. The difference in the total index during the first and last visits was statistically significant.

Conclusion. Due to the low level of knowledge about PA of seizures, it seems necessary to consider its possibility in all cases of increased frequency, aggravation, or change in the type of seizures after the AED treatment initiation or an increase in its dose. It is also possible to use changes in total EAI and EAI before sleep as an early objective marker of PA in adults with focal epilepsy.

1. Karlov VA. Epilepsiya u detey i vzroslykh, zhenshchin i muzhchin. Rukovodstvo dlya vrachey [Epilepsy in children and adults, women and men. A guide for doctors]. 2nd ed. Moscow: BINOM; 2019. 896 p. (In Russ.).

2. Bartolini E, Sander JW. Dealing with the storm: An overview of seizure precipitants and spontaneous seizure worsening in drugresistant epilepsy. Epilepsy Behav.2019 Aug;97:212-8. doi: 10.1016/j.yebeh.2019.05.036. Epub 2019 Jun 26.

3. Murthy J. Seizure aggravation with antiepileptic drugs in idiopathic generalized epilepsies. Neurol India. Jan-Feb 2011;59(1):51-2. doi: 10.4103/0028-3886.76858

4. Arhan E, Serdaroglu A, Hirfanoglu T, Kurt G. Aggravation of seizures and status epilepticus after vagal nerve stimulation therapy: the first pediatric case and review of the literature. Childs Nerv Syst. 2018 Sep;34(9):1799-801. doi: 10.1007/s00381-018-3806-x. Epub 2018 Apr 22.

5. Brigo F, Trinka E. Drug-induced seizures. In: Shorvon S, Guerrini R, Schachter S, Trinka E, editors. The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children. Cambridge: Cambridge University Press; 2019. P. 840-2.

6. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):512-21. doi: 10.1111/epi.13709. Epub 2017 Mar 8.

7. Karlov VA, Kozhokaru AB, Vlasov PN, et al. Dynamics of epileptiform activity, efficacy and tolerability of valproic acid in adults and adolescents with newly-diagnosed epilepsy. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2020;120(7):35-43. doi: 10.17116/jnevro202012007135 (In Russ.).

8. Karlov VA, Ayvazyan SO. Epilepsiya v terminakh, vizual'nykh i EEG patternakh [Epilepsy in terms of visual and EEG patterns. Moscow: ANO Training Center «Nevromed-Clinic»; 2020. 72 p. (In Russ.).

9. Kane N, Acharya J, Benickzy S, et al. A revised glossary of terms most commonly used by clinical electroencephalographers and updated proposal for the report format of the EEG findings. Revision 2017. Clin Neurophysiol Pract. 2017 Aug 4;2:170-85. doi: 10.1016/j.cnp.2017.07.002. eCollection 2017.

10. Wallengren C, Li S, Morris MJ, et al. Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation. Clin Neuropharmacol. Mar-Apr 2005;28(2):60-5. doi: 10.1097/01.wnf.0000159955.87511.bc

11. Pires NM, Bonifacio MJ, Soares-da-Silva P. Carbamazepine aggravates absence seizures in two dedicated mouse models. Pharmacol Rep. 2015 Oct;67(5):986-95. doi: 10.1016/j.pharep.2015.03.007. Epub 2015 Mar 23.

12. Mukhin KYu, Pylaeva OA. The problem of aggravation of epileptic seizures during therapy with antiepileptic drugs. Russkiy zhurnal det-skoy nevrologii = Russian Journal of Child Neurology. 2014;9(2):30-1. doi: 10.17650/20738803-2014-9-2-30-31 (In Russ.).

13. Kaplan DI, Isom LL, Petrou S. Role of Sodium Channels in Epilepsy. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6):a022814. doi: 10.1101/cshperspect.a022814

14. Karlov VA. Epilepsiya u detey i vzroslykh, zhenshchin i muzhchin: Rukovodstvo dlya vrachey [Epilepsy in Children and Adults, Women and Men: A Guide for Physicians]. Moscow: Medicine; 2010. 717 p. (In Russ.).

15. Kotov AS. Antiepileptic drugs and seizure aggravation. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2014;114(11-2):32-6. doi: 10.17116/jnevro201411411232-36 (In Russ.).

16. Vendrame M, Khurana DS, Cruz M, et al. Aggravation of seizures and/or EEG features in children treated with oxcarbazepine monotherapy. Epilepsia. 2007 Nov;48(11):2116-20. doi: 10.1111/j.1528-1167.2007.01210.x. Epub 2007 Jul 21.

17. Kim TH, Reid CA, Petrou S. Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy. Epilepsia. 2015 Jan;56(1):e6-9. doi: 10.1111/epi.12866. Epub 2014 Dec 8.

18. Kholin AA, Fedonyuk ID, Kolpakchi LM, et al. Aggravation of epilepsy on levetiracetam therapy: 28 clinical observations, risk factors and possibility of prophylactic. Russkiy zhurnal detskoy nevrologii. 2014;9(1):5-22 (In Russ.).

19. Mironov MB, Mukhin KYu, Kakaulina VS. Aggravation of Epileptic Negative Myoclonus Against the Background of Use of Carbamazepine and Oxcarbazepine in Children. Farmateka. 2012;1(234):67-71 (In Russ.).

20. Ortiz de la Rosa JS, Ladino LD, Rodriguez PJ, et al. Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review. Seizure. 2018 Mar;56:34-40. doi: 10.1016/j.seizure.2018.01.014. Epub 2018 Feb 8.