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The Effects of Antiepileptic Drugs on Complete Blood Cell Counts in Children with Epilepsy

Year 2019, Volume: 13 Issue: 6, 429 - 434, 23.12.2019
https://doi.org/10.12956/tjpd.2018.387

Abstract

Objective: Since antiepileptic drug use is long-term, it may be important to know their effects on blood cell counts during the management of these patients. However, these effects have not been adequately evaluated in epileptic children. In our study, the effects of valproate, levetiracetam and carbamazepine on complete blood counts were assessed in children. 

Material

and

Methods:
Material and methods: Consecutive epilepsy patients under monotherapy were reviewed retrospectively. Eighty patients, whose data were available before the treatment and at 2-6 months and 9-16 months after treatment initiation were included in the study. The ages at the start of the treatment were taken into consideration. Hemoglobin, hematocrit, erythrocyte, platelet and leucocyte counts, leukocyte subset percentages and the mean volume and distribution width of the erythrocytes and thrombocytes were recorded.

Results:
There were no statistically significant differences between the levels at pre-treatment and at 2-6 and 9-16 months after treatment initiation in the patients treated with levetiracetam (n=25) and carbamazepine (n=20). In the valproate group (n=35), there was an increase in mean corpuscular volume and monocyte percentage, and a decrease in platelet counts, in the first six months (p=0.015, p=0.001, p=0.005, respectively). At 9-16 months, the lymphocyte percentage increased while the neutrophil and eosinophil percentages decreased (p=0.016, p=0.014, p=0.01, respectively) in this group.






Conclusion: In our study, valproate caused an increase in the percentage of lympho-monocytes and mean corpuscular volume, and a decrease in the platelet count, neutrophil and eosinophil percentages. These effects seem to be related to the fact that valproate is a histone deacetylase inhibitor.

References

  • 1. Verrotti A, Scaparrotta A, Grosso S, Chiarelli F, Coppola G. Anticonvulsant drugs and hematological disease. Neurol Sci 2014;35:983–93.
  • 2. Bartels M, van Solinge WW, den Breeijen HJ, Bierings MB, Coffer PJ, Egberts TCG. Valproic acid treatment is associated with altered leukocyte subset development. J Clin Psychopharmacol 2012;32:832–4.
  • 3. Guenther S, Bauer S, Hagge M, Knake S, Olmes DG, Tackenberg B, et al. Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans. Seizure 2014;23:666–9.
  • 4. Kurahashi H, Takami A, Murotani K, Numoto S, Okumura A. Decreased platelet count in children with epilepsy treated with valproate and its relationship to the immature platelet fraction. Int J Hematol 2018;107:105-11.
  • 5. Dinopoulos A, Attilakos A, Paschalidou M, sirouda M, Garoufi A, Moustaki M, et al. Short-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: A prospective study. Epilepsy Res 2014;108:820–3.
  • 6. Bartels M, Geest CR, Bierings M, Buitenhuis M, Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Haematologica 2010;95:1052–60.
  • 7. Kose D, Koksal Y. The activity of valproic Acid in the treatment of refractory hyperleukocytosis in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2013;30:583–5.
  • 8. Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: A prospective monotherapy study. Epilepsia 2008;49:438–45. 9. Barr RD, Copeland SA, Stockwell ML, Morris N, Kelton JC. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982;57:681–4.
  • 10. Hauser E, Seidl R, Freilinger M, Male C, Herkner K. Hematologic manifestations and impaired liver synthetic function during valproate monotherapy. Brain Dev 1996;18:105–9.
  • 11. Vasudev K, Keown P, Gibb I, McAllister-Williams RH. Hematological effects of valproate in psychiatric patients. J Clin Psychopharmacol 2010;30:282–5.
  • 12. Chateauvieux S, Eifes S, Morceau F, Grigorakaki C, Schnekenburger M, Henry E, et al. Valproic acid perturbs hematopoietic homeostasis by inhibition of erythroid differentiation and activation of the myelo-monocytic pathway. Biochem Pharmacol 2011;81:498–509.
  • 13. Kieslich M, Schwabe D, Cinatl J Jr, Hernaiz Driever P. Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol 2003;20:15–22.
  • 14. Cho GW, Kang BY, Kim K-S, Kim SH. Effects of valproic acid on the expression of trophic factors in human bone marrow mesenchymal stromal cells. Neurosci Lett 2012;526:100–5.
  • 15. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience 2012;221:140–50.
  • 16. Arbez J, Lamarthée B, Gaugler B, Saas P. Histone deacetylase inhibitor valproic acid affects plasmacytoid dendritic cells phenotype and function. Immunobiology 2014;219:637–43.
  • 17. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2009;31:27–36.
  • 18. Heers H, Stanislaw J, Harrelson J, Lee MW. Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer. Eur J Pharmacol 2018;835:61–74.
  • 19 Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci 2002;99:2995–3000.
  • 20. Ji Y, Ke Y, Gao S. Intermittent activation of notch signaling promotes bone formation 2017;9:2933–44.

Epilepsili Çocuklarda Antiepileptik İlaçların Tam Kan Sayımı Üzerine Etkileri

Year 2019, Volume: 13 Issue: 6, 429 - 434, 23.12.2019
https://doi.org/10.12956/tjpd.2018.387

Abstract

Amaç: Antiepileptik ilaçların kan hücreleri üzerine etkilerinin bilinmesi, uzun süreli kullanımları nedeniyle hastaların izleminde önemlidir. Bu etkiler, epilepsili çocuklarda yeterince değerlendirilmemiştir. Çalışmamızda; valproat, levetirasetam ve karbamazepin tedavisi alan epilepsili çocukların tam kan sayım üzerine, tedavinin etkileri incelenmiştir. 


Gereç

ve

Yöntemler:
Çocuk Nörolojisi polikliniğine ardışık olarak başvuran, idiopatik epilepsi nedeniyle tekli antiepileptik ilaç kullanan hastalar, geriye dönük olarak incelendi. Tedavi öncesi, tedaviden sonraki 2-6 ay ve 9-16 aydaki tam kan sayımı verileri olan 80 hasta çalışmaya alındı. Hastaların tedavi başlangıcındaki yaşları dikkate alındı. Hemoglobin, hematokrit, eritrosit, trombosit, lökosit sayıları, lökosit alt tip (lenfosit, nötrofil, monosit, eozinofil) oranları, eritrosit ve trombositlerin ortalama hacmi ve dağılım genişliği kaydedildi. 


Bulgular: Levetirasetam (25 hasta) ve karbamazepin (20 hasta) grubundaki hastaların, tedaviden 2-6 ay ve 9-16 ay sonrası değerleri ile tedavi öncesi değerleri arasında istatistiksel fark saptanmadı (p>0.05). Valproat (35 hasta) grubunda ise ilk 6 ayda, ortalama eritrosit hacmi ve monosit yüzdesinde artış, trombosit sayısında azalma saptandı (sırasıyla, p=0.015, p=0.001 ve p=0.005). Tedavinin 9-16 aylık döneminde, ek olarak, lenfosit oranında artış, nötrofil ve eozinofil oranında azalma vardı (sırasıyla, p=0.016, p=0.014 ve p=0.01).


Sonuç:
Çalışmamızda, valproat tedavisinin, lenfomonositer hücre oranı ve ortalama eritrosit hacminde artışa; trombosit sayısı, nötrofil ve eozinofil oranında azalmaya neden olduğu saptanmıştır. Valproat tedavisiyle ortaya çıkan bu etkiler, histon deasetilaz inhibitörü olmasıyla ilişkili görünmektedir.

References

  • 1. Verrotti A, Scaparrotta A, Grosso S, Chiarelli F, Coppola G. Anticonvulsant drugs and hematological disease. Neurol Sci 2014;35:983–93.
  • 2. Bartels M, van Solinge WW, den Breeijen HJ, Bierings MB, Coffer PJ, Egberts TCG. Valproic acid treatment is associated with altered leukocyte subset development. J Clin Psychopharmacol 2012;32:832–4.
  • 3. Guenther S, Bauer S, Hagge M, Knake S, Olmes DG, Tackenberg B, et al. Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans. Seizure 2014;23:666–9.
  • 4. Kurahashi H, Takami A, Murotani K, Numoto S, Okumura A. Decreased platelet count in children with epilepsy treated with valproate and its relationship to the immature platelet fraction. Int J Hematol 2018;107:105-11.
  • 5. Dinopoulos A, Attilakos A, Paschalidou M, sirouda M, Garoufi A, Moustaki M, et al. Short-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: A prospective study. Epilepsy Res 2014;108:820–3.
  • 6. Bartels M, Geest CR, Bierings M, Buitenhuis M, Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Haematologica 2010;95:1052–60.
  • 7. Kose D, Koksal Y. The activity of valproic Acid in the treatment of refractory hyperleukocytosis in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2013;30:583–5.
  • 8. Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: A prospective monotherapy study. Epilepsia 2008;49:438–45. 9. Barr RD, Copeland SA, Stockwell ML, Morris N, Kelton JC. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982;57:681–4.
  • 10. Hauser E, Seidl R, Freilinger M, Male C, Herkner K. Hematologic manifestations and impaired liver synthetic function during valproate monotherapy. Brain Dev 1996;18:105–9.
  • 11. Vasudev K, Keown P, Gibb I, McAllister-Williams RH. Hematological effects of valproate in psychiatric patients. J Clin Psychopharmacol 2010;30:282–5.
  • 12. Chateauvieux S, Eifes S, Morceau F, Grigorakaki C, Schnekenburger M, Henry E, et al. Valproic acid perturbs hematopoietic homeostasis by inhibition of erythroid differentiation and activation of the myelo-monocytic pathway. Biochem Pharmacol 2011;81:498–509.
  • 13. Kieslich M, Schwabe D, Cinatl J Jr, Hernaiz Driever P. Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol 2003;20:15–22.
  • 14. Cho GW, Kang BY, Kim K-S, Kim SH. Effects of valproic acid on the expression of trophic factors in human bone marrow mesenchymal stromal cells. Neurosci Lett 2012;526:100–5.
  • 15. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience 2012;221:140–50.
  • 16. Arbez J, Lamarthée B, Gaugler B, Saas P. Histone deacetylase inhibitor valproic acid affects plasmacytoid dendritic cells phenotype and function. Immunobiology 2014;219:637–43.
  • 17. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2009;31:27–36.
  • 18. Heers H, Stanislaw J, Harrelson J, Lee MW. Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer. Eur J Pharmacol 2018;835:61–74.
  • 19 Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci 2002;99:2995–3000.
  • 20. Ji Y, Ke Y, Gao S. Intermittent activation of notch signaling promotes bone formation 2017;9:2933–44.
There are 19 citations in total.

Details

Primary Language Turkish
Subjects ​Internal Diseases
Journal Section ORIGINAL ARTICLES
Authors

Sevim Şahin This is me

Publication Date December 23, 2019
Submission Date May 16, 2018
Published in Issue Year 2019 Volume: 13 Issue: 6

Cite

Vancouver Şahin S. Epilepsili Çocuklarda Antiepileptik İlaçların Tam Kan Sayımı Üzerine Etkileri. Türkiye Çocuk Hast Derg. 2019;13(6):429-34.


The publication language of Turkish Journal of Pediatric Disease is English.


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