Skip to content
2000
image of Levetiracetam Monotherapy and its Combination with Phenytoin: Exploring Novel Biomarkers in Pediatric Epilepsy

Abstract

Introduction

Epilepsy is a neurological disorder characterized by recurrent seizures that can cause long-standing disturbance of normal brain function. It may adversely affect academic performance, behavior, emotional adjustment, social adaptability, and overall development in children. Neurotrophic factors and inflammatory markers are believed to play key roles in the pathogenesis of epilepsy. This study evaluated the effect of levetiracetam monotherapy and its combination with phenytoin on serum brain-derived neurotrophic factor (BDNF) levels, Interleukin-2 (IL-2) levels, and social adaptability/development in children with epilepsy.

Methods

Children with epilepsy, aged 1 to 12 years, were given levetiracetam monotherapy (=30) and combination therapy of levetiracetam and phenytoin (=30) for 20 weeks. Healthy controls (=30) were also included. Serum BDNF and IL-2 levels were assessed at baseline and 20 weeks, along with social adaptability and development, using the Vineland Social Maturity Scale (VSMS) and Developmental Screening Test (DST) scores, respectively.

Results

Pretreatment, serum BDNF and IL-2 levels were significantly ( <0.001) lower and higher respectively, in both treatment groups compared to controls. After 20 weeks, BDNF and IL-2 levels were significantly ( <0.001) increased and decreased, respectively, in the monotherapy group and combination therapy group. VSMS and DST scores improved significantly ( <0.001).

Discussion

The findings suggest that levetiracetam and its combination with phenytoin modulate neurotrophic and inflammatory pathways in pediatric epilepsy, with parallel improvements in social and developmental outcomes.

Conclusion

Levetiracetam monotherapy and its combination therapy with phenytoin increased serum BDNF levels, decreased IL-2 levels, and improved VSMS and DST scores in pediatric epilepsy patients, suggesting that these treatments influence epileptogenesis.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnr/10.2174/0115672026402551251003065428
2025-10-10
2025-10-30

  • From This Site

    /content/journals/cnr/10.2174/0115672026402551251003065428
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Fisher R.S. Boas W.E. Blume W. Epileptic seizures and epilepsy: Definitions proposed by the international league against epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005 46 4 470 472 10.1111/j.0013‑9580.2005.66104.x 15816939
    [Google Scholar]
  2. Gururaj G. Amudhan S. Satishchandra P. Epilepsy in India I: Epidemiology and public health. Ann. Indian Acad. Neurol. 2015 18 3 263 277 10.4103/0972‑2327.160093 26425001
    [Google Scholar]
  3. Camfield P. Camfield C. Incidence, prevalence and aetiology of seizures and epilepsy in children. Epileptic Disord. 2015 17 2 117 123 10.1684/epd.2015.0736 25895502
    [Google Scholar]
  4. Surguchov A. Surgucheva I. Sharma M. Sharma R. Singh V. Pore-forming proteins as mediators of novel epigenetic mechanism of epilepsy. Front. Neurol. 2017 8 3 10.3389/fneur.2017.00003 28149289
    [Google Scholar]
  5. Clossen B.L. Reddy D.S. Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. Biochim. Biophys. Acta Mol. Basis Dis. 2017 1863 6 1519 1538 10.1016/j.bbadis.2017.02.003 28179120
    [Google Scholar]
  6. van Dijkman S.C. Voskuyl R.A. de Lange E.C. Biomarkers in epilepsy: A modelling perspective. Eur. J. Pharm. Sci. 2017 109 S47 S52 10.1016/j.ejps.2017.05.035 28528284
    [Google Scholar]
  7. Alvim M.K.M. Morita-Sherman M.E. Yasuda C.L. Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology. Epilepsia 2021 62 10 2385 2394 10.1111/epi.17023 34331458
    [Google Scholar]
  8. Nowroozi A. Salehi M.A. Mohammadi S. Brain-derived neurotrophic factor in patients with epilepsy: A systematic review and meta-analysis. Epilepsy Res. 2021 178 106794 10.1016/j.eplepsyres.2021.106794 34773766
    [Google Scholar]
  9. Heinrich C. Lähteinen S. Suzuki F. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol. Dis. 2011 42 1 35 47 10.1016/j.nbd.2011.01.001 21220014
    [Google Scholar]
  10. Falcicchia C. Paolone G. Emerich D.F. Seizure-suppressant and neuroprotective effects of encapsulated BDNF-producing cells in a rat model of temporal lobe epilepsy. Mol. Ther. Methods Clin. Dev. 2018 9 211 224 10.1016/j.omtm.2018.03.001 29766029
    [Google Scholar]
  11. Chen N.C. Chuang Y.C. Huang C.W. Interictal serum brain-derived neurotrophic factor level reflects white matter integrity, epilepsy severity, and cognitive dysfunction in chronic temporal lobe epilepsy. Epilepsy Behav. 2016 59 147 154 10.1016/j.yebeh.2016.02.029 27152461
    [Google Scholar]
  12. Demir M. Akarsu E.O. Dede H.O. Investigation of the roles of new antiepileptic drugs and serum BDNF levels in efficacy and safety monitoring and quality of life: A clinical research. Curr. Clin. Pharmacol. 2020 15 1 49 63 10.2174/1574884714666190312145409 30864528
    [Google Scholar]
  13. Zhang D. Qiu L. Zhang Y. Sang Y. Zheng N. Liu X. Efficacy and safety of sodium valproate plus lamotrigine in children with refractory epilepsy. Exp. Ther. Med. 2020 20 3 2698 2704 10.3892/etm.2020.8984 32765764
    [Google Scholar]
  14. Sinha S. Patil S.A. Jayalekshmy V. Satishchandra P. Do cytokines have any role in epilepsy? Epilepsy Res. 2008 82 2-3 171 176 10.1016/j.eplepsyres.2008.07.018 18783922
    [Google Scholar]
  15. Matsuo T. Komori R. Nakatani M. Levetiracetam suppresses the infiltration of neutrophils and monocytes and downregulates many inflammatory cytokines during epileptogenesis in pilocarpine-induced status epilepticus mice. Int. J. Mol. Sci. 2022 23 14 7671 10.3390/ijms23147671 35887020
    [Google Scholar]
  16. Himmerich H. Bartsch S. Hamer H. Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro. J. Psychiatr. Res. 2013 47 11 1751 1759 10.1016/j.jpsychires.2013.07.026 23978396
    [Google Scholar]
  17. Steinborn B. Żarowski M. Winczewska-Wiktor A. Wójcicka M. Młodzikowska-Albrecht J. Losy J. Concentration of Il-1β, Il-2, Il-6, TNFα in the blood serum in children with generalized epilepsy treated by valproate. Pharmacol. Rep. 2014 66 6 972 975 10.1016/j.pharep.2014.06.005 25443723
    [Google Scholar]
  18. Zubareva O.E. Sinyak D.S. Kalita A.D. Antiepileptogenic effects of anakinra, lamotrigine and their combination in a lithium–pilocarpine model of temporal lobe epilepsy in rats. Int. J. Mol. Sci. 2023 24 20 15400 10.3390/ijms242015400 37895080
    [Google Scholar]
  19. Sarangi S.C. Kumar S. Tripathi M. Kaleekal T. Singh S. Gupta Y.K. Antiepileptic-drug tapering and seizure recurrence. Indian J. Pharmacol. 2022 54 1 24 32 10.4103/ijp.ijp_253_21 35343204
    [Google Scholar]
  20. Zhou H. Wang N. Xu L. Huang H. Yu C. The efficacy of gastrodin in combination with folate and vitamin B12 on patients with epilepsy after stroke and its effect on HMGB-1, IL-2 and IL-6 serum levels. Exp. Ther. Med. 2017 14 5 4801 4806 10.3892/etm.2017.5116 29201182
    [Google Scholar]
  21. Labh R. Gupta R. Narang M. Halder S. Kar R. Effect of valproate and add-on levetiracetam on inflammatory biomarkers in children with epilepsy. Epilepsy Behav. 2021 125 108358 10.1016/j.yebeh.2021.108358 34717170
    [Google Scholar]
  22. Callaghan B. Schlesinger M. Rodemer W. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia 2011 52 3 619 626 10.1111/j.1528‑1167.2010.02929.x 21269287
    [Google Scholar]
  23. Connolly A. Quirke M. Crowley S. The efficacy and tolerability of levetiracetam as a first line monotherapy in childhood epilepsy. Ir. Med. J. 2020 113 2 18 32401003
    [Google Scholar]
  24. Elberry A.A. Felemban R.K. Hareeri R.H. Kurdi S.M. Efficacy and safety of levetiracetam in pediatric epilepsy. Saudi Pharm. J. 2012 20 1 81 84 10.1016/j.jsps.2011.06.001 23960780
    [Google Scholar]
  25. Lynch B.A. Lambeng N. Nocka K. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. USA 2004 101 26 9861 9866 10.1073/pnas.0308208101 15210974
    [Google Scholar]
  26. Yaari Y. Selzer M.E. Pincus J.H. Phenytoin: Mechanisms of its anticonvulsant action. Ann. Neurol. 1986 20 2 171 184 10.1002/ana.410200202 2428283
    [Google Scholar]
  27. Çelen Yoldaş T. Günbey C. Değerliyurt A. Erol N. Özmert E. Yalnızoğlu D. Behavioral problems of preschool children with new-onset epilepsy and one-year follow-up — A prospective study. Epilepsy Behav. 2019 92 171 175 10.1016/j.yebeh.2018.12.025 30660968
    [Google Scholar]
  28. Rantanen K. Timonen S. Hagström K. Hämäläinen P. Eriksson K. Nieminen P. Social competence of preschool children with epilepsy. Epilepsy Behav. 2009 14 2 338 343 10.1016/j.yebeh.2008.10.022 19027086
    [Google Scholar]
  29. Srivastava M. Gupta A. Talukdar U. Kalra B.P. Lahan V. Effect of parental training in managing the behavioral problems of early childhood. Indian J. Pediatr. 2011 78 8 973 978 10.1007/s12098‑011‑0401‑5 21394590
    [Google Scholar]
  30. Fisher R.S. Cross J.H. French J.A. Operational classification of seizure types by the International League Against Epilepsy: Position paper of the ILAE commission for classification and terminology. Epilepsia 2017 58 4 522 530 10.1111/epi.13670 28276060
    [Google Scholar]
  31. Naumenko V.S. Kulikov A.V. Kondaurova E.M. Effect of actual long-term spaceflight on BDNF, TrkB, p75, BAX and BCL-XL genes expression in mouse brain regions. Neuroscience 2015 284 730 736 10.1016/j.neuroscience.2014.10.045 25451288
    [Google Scholar]
  32. Pan D. Li X. Jiang J. Luo L. Effect of levetiracetam in combination with topiramate on immune function, cognitive function, and neuronal nutritional status of children with intractable epilepsy. Am. J. Transl. Res. 2021 13 9 10459 10468 34650715
    [Google Scholar]
  33. Shorvon S.D. Löwenthal A. Janz D. Bielen E. Loiseau P. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000 41 9 1179 1186 10.1111/j.1528‑1157.2000.tb00323.x 10999557
    [Google Scholar]
  34. Ben-Menachem E. Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: A multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000 41 10 1276 1283 10.1111/j.1528‑1157.2000.tb04605.x 11051122
    [Google Scholar]
  35. Glauser T.A. Pellock J.M. Bebin E.M. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002 43 5 518 524 10.1046/j.1528‑1157.2002.13101.x 12027913
    [Google Scholar]
  36. Sirsi D. Safdieh J.E. The safety of levetiracetam. Expert Opin. Drug Saf. 2007 6 3 241 250 10.1517/14740338.6.3.241 17480174
    [Google Scholar]
  37. Kasperavičiūtė D. Sisodiya S.M. Epilepsy pharmacogenetics. Pharmacogenomics 2009 10 5 817 836 10.2217/pgs.09.34 19450130
    [Google Scholar]
  38. Kesavan R. Kukreti R. Adithan C. Genetic polymorphism of drug refractory epilepsy. Indian J. Med. Res. 2011 134 3 253 255 21985806
    [Google Scholar]
  39. İpek R. Makharoblidze K. Polat B.G. Developmental evaluation in children experiencing febrile convulsions. Turk. J. Pediatr. 2021 63 4 602 611 10.24953/turkjped.2021.04.007 34449142
    [Google Scholar]
  40. Rangarajan A. Mundlamuri R.C. Kenchaiah R. Efficacy of pulse intravenous methylprednisolone in epileptic encephalopathy: A randomised controlled trial. J. Neurol. Neurosurg. Psychiatry 2022 93 12 jnnp-2022-329027 10.1136/jnnp‑2022‑329027 36376023
    [Google Scholar]
  41. Browne T.R. Szabo G.K. Leppik I.E. Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique. J. Clin. Pharmacol. 2000 40 6 590 595 10.1002/j.1552‑4604.2000.tb05984.x 10868309
    [Google Scholar]
  42. Johannessen S.I. Landmark C.J. Antiepileptic drug interactions - principles and clinical implications. Curr. Neuropharmacol. 2010 8 3 254 267 10.2174/157015910792246254 21358975
    [Google Scholar]
  43. Patsalos P.N. Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: Pharmacokinetic and pharmacodynamic interactions between AEDs. Clin. Pharmacokinet. 2013 52 11 927 966 10.1007/s40262‑013‑0087‑0 23784470
    [Google Scholar]
/content/journals/cnr/10.2174/0115672026402551251003065428
Loading
Levetiracetam Monotherapy and its Combination with Phenytoin: Exploring Novel Biomarkers in Pediatric Epilepsy
Bentham Science Publishers ; https://doi.org/10.2174/0115672026402551251003065428
/content/journals/cnr/10.2174/0115672026402551251003065428
/content/journals/cnr/10.2174/0115672026402551251003065428
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: pediatric ; neurology ; epilepsy ; interleukin-2 ; brain-derived neurotrophic factor ; biomarkers ; Levetiracetam ; phenytoin

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test