Metabolic and Inflammatory Effects of Antiepileptic Treatment in Children with Epilepsy

Abstract

Aim: The objective of this study was to evaluate the effects of long-term antiepileptic drug (AED) use on metabolic, hematological, endocrine, and inflammatory parameters in children with epilepsy and to compare these markers with healthy controls. Materials and Methods: This cross-sectional retrospective study included 85 children with idiopathic epilepsy followed at Düzce University Faculty of Medicine who had been receiving AED monotherapy (valproic acid, carbamazepine, or levetiracetam) for at least six months. A control group of 85 healthy children was established using frequency matching for age and sex. Laboratory data, including hemogram parameters, lipid profiles, vitamin B12, folate, vitamin D, TSH, fT4, and CRP levels, were analyzed. Inflammatory indices, such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI), were calculated. Results: Total cholesterol, LDL, HDL, vitamin D, and TSH levels were significantly lower in the epilepsy group compared to the healthy controls (p < 0.05). Conversely, inflammatory markers, including NLR, SII, SIRI, and CRP levels, were significantly higher in children with epilepsy (p < 0.05). No significant differences were observed between the groups regarding other metabolic and hematological parameters. Conclusion: Long-term AED therapy is associated with significant metabolic, endocrine, and inflammatory alterations. These findings suggest the presence of a mild but persistent inflammatory state in children receiving epilepsy treatment. Routine monitoring of inflammatory markers and vitamin D levels may be clinically vital in the follow-up of pediatric patients. Future prospective studies are needed to confirm these results and assist in individualizing AED selection.

Keywords

• Epilepsy
• child
• adolescent
• anticonvulsants
• biomarkers
• vitamin D

Epilepsili Çocuklarda Antiepileptik Tedavinin Metabolik ve İnflamatuvar Etkileri

Abstract

Amaç: Çocukluk çağı epilepsisinde uzun süreli antiepileptik ilaç (AEİ) kullanımının metabolik, hematolojik, endokrin ve İnflamatuvar parametreler üzerindeki etkilerini değerlendirmek ve sağlıklı kontrol grubuyla karşılaştırmaktır. Gereç ve Yöntemler: Bu kesitsel retrospektif çalışma, Düzce Üniversitesi Tıp Fakültesi'nde en az altı aydır antiepileptik ilaç(AEİ) monoterapisi (valproik asit veya karbamazepin veya levetirasetam) alan 85 idiyopatik epilepsili çocuk ve yaş-cinsiyet uyumlu 85 sağlıklı çocuk ile yürütülmüştür. Hastaların hemogram, lipid profili, vitamin B12, folat, D vitamini, TSH, serbest tiroksin(fT4) ve CRP düzeyleri incelenmiştir. Ayrıca nötrofil-lenfosit oranı (NLR), sistemik immün-inflamasyon indeksi (SII) ve sistemik İnflamatuvar yanıt indeksi (SIRI) gibi İnflamatuvar belirteçler hesaplanmıştır. Bulgular: Epilepsi grubunda toplam kolesterol, LDL, HDL, vitamin D ve TSH seviyeleri sağlıklı kontrol grubuna göre anlamlı derecede düşük bulunmuştur (p <0,05). Buna karşın, inflamasyon göstergeleri olan NLR, SII, SIRI ve CRP seviyeleri epilepsili çocuklarda anlamlı derecede yüksek saptanmıştır (p <0,05). Diğer metabolik ve hematolojik parametrelerde gruplar arası anlamlı bir fark gözlenmemiştir. Sonuç: Uzun süreli AEİ tedavisi; metabolik, endokrin ve İnflamatuvar değişikliklerle ilişkilidir. Bulgular, çocukluk çağı epilepsisinde tedavi sürecinde hafif ancak kalıcı bir İnflamatuvar durumun varlığına işaret etmektedir. AEİ tedavisi alan çocukların takibinde İnflamatuvar belirteçlerin ve vitamin D düzeylerinin rutin kontrolü klinik açıdan büyük önem taşımaktadır. Tedavi seçiminin kişiselleştirilmesi için daha kapsamlı prospektif çalışmalara ihtiyaç duyulmaktadır.

Keywords

• Epilepsi
• çocuk
• ergen
• antikonvülzanlar
• biyobelirteçler
• D vitamini

References

1. 1. Tan TY, Lu CH, Chuang HY, Lin TK, Liou CW, Chang WN, et al. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia. 2009;50(6):1579–86. doi:10.1111/j.1528-1167.2009.02024.x.
2. 2. Chuang YC, Chuang HY, Lin TK, Chang CC, Lu CH, Chang WN, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53:120–8. doi:10.1111/j.1528-1167.2011.03316.x.
3. 3. Demircioğlu S, Soylu A, Dirik E. Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. Pediatr Neurol. 2000;23(2):142–6. doi:10.1016/s0887-8994(00)00175-2.
4. 4. Castro-Gago M, Novo-Rodríguez MI, Blanco-Barca MO, Urisarri-Ruíz de Cortázar A, Rodríguez-García J, Rodríguez-Segade S, et al. Evolution of serum lipids and lipoprotein(a) levels in epileptic children treated with carbamazepine or valproic acid, and phenobarbital. J Child Neurol. 2006;21(1):48–53. doi:10.1177/08830738060210011601.
5. 5. Sreedharan M, Devadathan K, Mohammed Kunju PA, Sasidharan B, Pillai JP, Vasumathy Amma MA, et al. Vitamin D deficiency in ambulant children on carbamazepine or sodium valproate monotherapy. Indian Pediatr. 2018;55(4):307–10.
6. 6. Xu Z, Jing X, Li G, Sun J, Guo H, Hu Y, et al. Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure. 2019;71:60-5. doi:10.1016/j.seizure.2019.06.009.
7. 7. Misra A, Aggarwal A, Singh O, Sharma S. Effect of carbamazepine therapy on vitamin D and parathormone in epileptic children. Pediatr Neurol. 2010;43(5):320–4. doi:10.1016/j.pediatrneurol.2010.05.013.
8. 8. Dwajani S, Ravi L, Bindu CM, Prema R. Effect of antiepileptic drugs on serum vitamin B12 and folic acid among children with epilepsy in Bangalore. Biomed Pharmacol J. 2024;17(1):263–9. doi:10.13005/bpj/2854.

9. 9. Sharma TK, Vardey SK, Sitaraman S. Serum homocysteine, folate, and vitamin B12 levels in carbamazepine-treated epileptic children. Clin Lab. 2016;62(7):1217–24. doi:10.7754/Clin.Lab.2015.150911.
10. 10. Ray K. Epilepsy: antiepileptic drugs reduce vitamin B12 and folate levels. Nat Rev Neurol. 2011;7(3):125. doi:10.1038/nrneurol.2011.9.
11. 11. Sanz P, Rubio T, Garcia-Gimeno MA. Neuroinflammation and epilepsy: from pathophysiology to therapies based on repurposing drugs. Int J Mol Sci. 2024 Apr 9;25(8):4161. doi:10.3390/ijms25084161.
12. 12. Foiadelli T, Santangelo A, Costagliola G, Costa E, Scacciati M, Riva A, et al. Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay. Front Pediatr. 2023;11:1251914. doi:10.3389/fped.2023.1251914.
13. 13. Dingledine R, Varvel NH, Ravizza T, Vezzani A. Neuroinflammation in epilepsy: cellular and molecular mechanism. In: Noebels JL, Avoli M, Rogawski MA, Vezzani A, Delgado-Escueta AV. editors. Jasper's basic mechanisms of the epilepsies [Internet]. 5th ed. New York: Oxford University Press; 2024 [cited 2026 Jan 20]. p. 611-632. doi:10.1093/med/9780197549469.003.0030.
14. 14. Huang Q, Zhang Z, Fan R, Liu S, Zheng W, Xiao F, et al. Association of blood count-derived immunoinflammatory markers and risk of epilepsy: a prospective cohort of 497,291 participants. Seizure. 2024;123:9–16. doi:10.1016/j.seizure.2024.10.006.
15. 15. Aygun D, Uzun H. Association of comorbidity and inflammatory and nutritional markers with epilepsy and seizure frequency. Nutrients. 2025;17(11):1847. doi:10.3390/nu17111847.
16. 16. Hu YM, Huang H, Chen YT, Wang WJ, Zhang BH. Correlation between systemic inflammatory response index and post-stroke epilepsy based on multiple logistic regression analysis. Front Neurol. 2025;16:1640796. doi:10.3389/fneur.2025.1640796.
17. 17. Li W, Wu J, Zeng Y, Zheng W. Neuroinflammation in epileptogenesis: from pathophysiology to therapeutic strategies. Front Immunol. 2023;14:1269241. doi:10.3389/fimmu.2023.1269241.
18. 18. Yılmazbaş P, Şenbil N. Hematological side effects of valproate used for the treatment of epilepsy. Nam Kem Med J. 2021;9(1):39–42. doi:10.4274/nkmj.galenos.2020.800497.
19. 19. Acharya S, Pradhan S. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22(1):62–5. doi:10.1097/00043426-200001000-00012.
20. 20. Dilber B, Yıldız N, Yaman H, Kamasak T, Esenülkü G, Özkan P, et al. Evaluation of long-term effects of levetiracetam monotherapy on hematological and liver function parameters in children with idiopathic epilepsy. Turk J Pediatr Dis. 2022;16(2):144–149. doi:10.12956/tchd.975416.
21. 21. Kaczorowska-Hac B, Matheisel A, Maciejka-Kapuscinska L, Wisniewski J, Alska A, Adamkiewicz-Drozynska E, et al. Anemia secondary to valproic acid therapy in a 13-year-old boy: a case report. J Med Case Rep. 2012;6:239. doi:10.1186/1752-1947-6-239.
22. 22. Sözüer DT, Atakil D, Dogu O, Baybas S, Arpaci B. Serum lipids in epileptic children treated with carbamazepine and valproate. Eur J Pediatr. 1997;156(7):565-7. doi:10.1007/s004310050664.
23. 23. Junges C, Machado TD, Nunes Filho PR, Riesgo R, Mello ED. Vitamin D deficiency in pediatric patients using antiepileptic drugs: systematic review with meta-analysis. J Pediatr (Rio J). 2020;96(5):559-568. doi:10.1016/j.jped.2020.01.004.
24. 24. Yuluğ B, Özşimşek A, Özdemir Öktem E. Investigation of the antiepileptics on levels of vitamin D and calcium. Acta Med Alanya. 2022;6(2):167–72. doi:10.30565/medalanya.1116431.
25. 25. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81. doi: 10.1056/NEJMra070553.
26. 26. Chen S, Zhang Y, Chen L, et al. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J Neuroinflammation. 2018;15(1):150. doi:10.1186/s12974-018-1193-6.
27. 27. Guo A, Li J, Luo L, Chen C, Lu Q, Ke J, et al. Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response. Int Immunopharmacol. 2021;92:107332. doi:10.1016/j.intimp.2020.107332.
28. 28. Kim T, Song S, Park Y, Kang S, Seo H. HDAC Inhibition by valproic acid induces neuroprotection and improvement of PD-like behaviors in LRRK2 R1441G transgenic mice. Exp Neurobiol. 2019;28(4):504-15.