Öz

Objective: This study aimed to evaluate the metabolic and hormonal effects of anti-seizure medications (ASMs) in children with epilepsy by comparing serum levels of vitamin D, calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), vitamin B12, folate, thyroid-stimulating hormone (TSH), and free thyroxine (fT4) between ASM-treated patients and healthy controls. A secondary aim was to investigate differences between patients treated with valproate (VPA) and those treated with levetiracetam (LEV).

Materials and Methods: A total of 106 pediatric epilepsy patients undergoing ASM therapy were included in the study, with 93 on monotherapy and 13 on polytherapy for at least six months. Additionally, 80 age- and sex-matched healthy controls were included. Serum biochemical parameters were analyzed retrospectively. Subgroup analyses compared patients on VPA and LEV monotherapy. Statistical comparisons and correlation analyses assessed relationships between drug exposure and biochemical values.

Results: Vitamin D levels were significantly lower in ASM-treated patients compared to controls (p<0.001). TSH levels were higher in the VPA group than in the LEV group (p<0.001), although there were no significant differences in thyroid hormone levels between ASM-treated patients and the healthy control group overall. No significant differences were observed in calcium, phosphorus, ALP, vitamin B12, or folate levels between the groups. The duration of ASM use was not correlated with any of the biochemical parameters.

Conclusion: Vitamin D deficiency and changes in thyroid function may occur in children treated with ASMs, especially VPA. However, vitamin B12 and folate levels tend to stay stable. Given the ongoing fluctuations in vitamin D and thyroid hormone levels, more frequent monitoring of these parameters may be warranted in pediatric epilepsy patients on ASM therapy. In contrast, less frequent assessment of vitamin B12 and folate may be enough unless there are clinical reasons to test further. More prospective studies are needed to determine the best monitoring approaches.

Anahtar Kelimeler: Antiepileptic drug, children, folate vitamin D, thyroid hormones

Kaynakça

  1. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-82. https://doi.org/10.1111/epi.12550
  2. Aaberg KM, Gunnes N, Bakken IJ, et al. Incidence and prevalence of childhood epilepsy: a nationwide cohort study. Pediatrics. 2017;139(5). https://doi.org/10.1542/peds.2016-3908
  3. Svalheim S, Sveberg L, Mochol M, Taubøll E. Interactions between antiepileptic drugs and hormones. Seizure. 2015;28:12-7. https://doi.org/10.1016/j.seizure.2015.02.022
  4. Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy research. 2000;40(1):7-15. https://doi.org/10.1016/S0920-1211(00)00101-7
  5. Nalivaeva NN, Belyaev ND, Turner AJ. Sodium valproate: an old drug with new roles. Trends in pharmacological sciences. 2009;30(10):509-14. https://doi.org/10.1016/j.tips.2009.07.002
  6. Yıldırım M, Bektaş Ö, Göktaş ÖA, Yüksel MF, Şahin S, Teber ST. Levetiracetam monotherapy in children with epilepsy: Experience from a tertiary pediatric neurology center. Epilepsy & Behavior. 2021;116:107745. https://doi.org/10.1016/j.yebeh.2020.107745
  7. Beniczky S, Tatum WO, Blumenfeld H, et al. Seizure semiology: ILAE glossary of terms and their significance. Epileptic Disorders. 2022(3):447-95. https://doi.org/10.1684/epd.2022.1430
  8. Linden MA, FREITAS RGBdON, Hessel G, Marmo DB, Bellomo-Brandão MÂ. Definition of vitamin D deficiency in schoolchildren: systematic review with meta-analysis. Arquivos de gastroenterologia. 2019;56:425-30. https://doi.org/10.1590/s0004-2803.201900000-64
  9. Benedetti MS, Whomsley R, Baltes E, Tonner F. Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronosyltransferase induction. European journal of clinical pharmacology. 2005;61:863-72. https://doi.org/10.1007/s00228-005-0056-0
  10. Rochtus AM, Herijgers D, Jansen K, Decallonne B. Antiseizure medications and thyroid hormone homeostasis: literature review and practical recommendations. Epilepsia. 2022;63(2):259-70. https://doi.org/10.1111/epi.17117
  11. Mattson RH, Cramer JA. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia. 1985;26:S40-S51. https://doi.org/10.1111/j.1528-1157.1985.tb05723.x
  12. Güngör O, Yüzbaşı BK, Özhan B, Orhan O, Şevik R, Güngör G. Effects of valproic acid, levetiracetam, carbamazepine, and oxcarbazepine on thyroid function tests in children. Revista da Associação Médica Brasileira. 2024;70(12):e20241177. https://doi.org/10.1590/1806-9282.20241177
  13. Sahu JK, Gulati S, Kabra M, et al. Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy. Journal of child neurology. 2012;27(5):594-7. https://doi.org/10.1177/0883073811421985
  14. Mikati M, Tarabay H, Khalil A. Risk factors for development of subclinical hypothyroidism during valproic acid therapy. The Journal of pediatrics. 2007;151(2):178-81. https://doi.org/10.1016/j.jpeds.2007.02.046
  15. Yılmaz Ü, Yılmaz TS, Akıncı G, Korkmaz HA, Tekgül H. The effect of antiepileptic drugs on thyroid function in children. Seizure. 2014;23(1):29-35. https://doi.org/10.1016/j.seizure.2013.09.006
  16. Isojärvi JI, Turkka J, Pakarinen AJ, Kotila M, Rättyä J, Myllylä VV. Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy. Epilepsia. 2001;42(7):930-4. https://doi.org/10.1046/j.1528-1157.2001.042007930.x
  17. Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. European journal of endocrinology. 2009;160(1):81-6. https://doi.org/10.1530/EJE-08-0325
  18. Güngör O, Özkaya AK, Temiz F. The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital. Acta Neurologica Belgica. 2020;120(3):615-9. https://doi.org/10.1007/s13760-018-0908-x
  19. Wood MD, Gillard M. Evidence for a differential interaction of brivaracetam and levetiracetam with SV2A: relevance to antiseizure activity. Epilepsia. 2017; 58(2):255-62. https://doi.org/10.1111/epi.13638
  20. Karatoprak E, Paksoy S. Thyroid functions in children on levetiracetam or valproic acid therapy. Journal of Pediatric Epilepsy. 2021;10(01):022-6. https://doi.org/10.1055/s-0040-1716916
  21. Shi K-l, Guo J-X, Zhao H-m, et al. The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: a prospective study. Epilepsy & Behavior. 2020;113:107555. https://doi.org/10.1016/j.yebeh.2020.107555
  22. Andersen NB, Jørgensen NR. Impaired bone health as a co-morbidity of epilepsy. Best Practice & Research Clinical Rheumatology. 2022;36(3):101755. https://doi.org/10.1016/j.berh.2022.101755
  23. Borusiak P, Langer T, Heruth M, Karenfort M, Bettendorf U, Jenke AC. Antiepileptic drugs and bone metabolism in children: data from 128 patients. Journal of child neurology. 2013;28(2):176-83. https://doi.org/10.1177/0883073812443005
  24. Xu Z, Jing X, Li G, et al. Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure. 2019;71:60-5. https://doi.org/10.1016/j.seizure.2019.06.009
  25. Li ZR, Wang CY, Zhu X, Jiao Z. Population Pharmacokinetics of Levetiracetam: A Systematic Review. Clin Pharmacokinet 2021;60(3):305-18. https://doi.org/10.1007/s40262-020-00963-2
  26. Nissen‐Meyer LSH, Svalheim S, Taubøll E, et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia. 2007;48(10):1850-60. https://doi.org/10.1111/j.1528-1167.2007.01176.x
  27. Fekete S, Simko J, Gradosova I, et al. The effect of levetiracetam on rat bone mass, structure and metabolism. Epilepsy research. 2013;107(1-2):56-60. https://doi.org/10.1016/j.eplepsyres.2013.08.012
  28. Vijayakumar M, Bk A, George B, Bhatia V. Vitamin D status in children on anticonvulsant therapy. Indian Journal of Pediatrics. 2022:1-5.
  29. Zhang Y, Zheng Y-x, Zhu J-m, Zhang J-m, Zheng Z. Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: a meta-analysis. Journal of Zhejiang University Science B. 2015;16(7):611. https://doi.org/10.1631/jzus.B1500021
  30. Yildiz EP, Poyrazoglu Ş, Bektas G, Kardelen AD, Aydinli N. Potential risk factors for vitamin D levels in medium-and long-term use of antiepileptic drugs in childhood. Acta Neurologica Belgica. 2017;117:447-53. https://doi.org/10.1007/s13760-017-0775-x
  31. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology & metabolism. 2011;96(7):1911-30. https://doi.org/10.1210/jc.2011-0385
  32. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. The Journal of Clinical Endocrinology & Metabolism. 2012;97(4):1153-8. https://doi.org/10.1210/jc.2011-2601
  33. Huang HL, Zhou H, Wang N, Yu CY. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients. Biomedical reports. 2016;5(4):413-6. https://doi.org/10.3892/br.2016.737
  34. Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlu S. Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12, and folic acid. Brain and Development. 2003;25(2):113-5. https://doi.org/10.1016/S0387-7604(02)00163-8
  35. Aslan K, Bozdemir H, Unsal C, Guvenc B. The effect of antiepileptic drugs on vitamin B12 metabolism. International Journal of Laboratory Hematology. 2008;30(1):26-35. https://doi.org/10.1111/j.1751-553X.2007.00910.x
  36. Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy research. 2000;41(3):253-7. https://doi.org/10.1016/S0920-1211(00)00150-9
  37. Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Annals of neurology. 2011;69(2):352-9. https://doi.org/10.1002/ana.22229
  38. Sharma TK, Vardey S, Sitaraman S. Evaluate the Effect of Valproate Monotherapy on the Serum Homocysteine, Folate and Vitamin B12 Levels in Epileptic Children. Clinical laboratory. 2015;61(8):933-40. https://doi.org/10.7754/Clin.Lab.2015.141230
  39. Geda G, Caksen H, Icagasioglu D. Serum lipids, vitamin B12 and folic acid levels in children receiving long-term valproate therapy. Acta neurologica belgica. 2002;102(3):122-6.
  40. Ozdemir O, Yakut A, Dinleyici EC, Aydogdu SD, Yarar C, Colak O. Serum asymmetric dimethylarginine (ADMA), homocysteine, vitamin B 12, folate levels, and lipid profiles in epileptic children treated with valproic acid. European journal of pediatrics. 2011;170:873-7. https://doi.org/10.1007/s00431-010-1366-5

Nasıl atıf yapılır

1.
Akıncı Göktaş Ö, Coşkun AN, Dünya B, Pınar A, Buluş AD. The hidden costs of seizure control: Metabolic and hormonal effects of anti-seizure medications in children. Turk J Pediatr Dis. 2026;Early View:1-7. https://doi.org/10.12956/TJPD.2025.1252