Evaluation of the effects of antiepileptic drugs on complete blood count parameters

Abstract

Aim: The incidence of pediatric epilepsy ranges between 1-3%, and various anticonvulsant drugs are used in its treatment. Seizure type, effectiveness and side effects are important in drug selection. Various hematological side effects of anticonvulsants have been reported. This study aims to determine the hematological side effects of the anticonvulsants used in our clinic. Methods: A total of 87 epilepsy patients between the ages of 1 and 15 years, who were diagnosed and followed up in the Pediatric Neurology Outpatient Clinic of Health Sciences University, Okmeydanı Training and Research Hospital between January 2017-2018 and who received anticonvulsant medication for at least 3 months were included in this study. The blood values and hematological side effects of the anticonvulsants were noted from the patient files. The statistical analyses were performed with IBM SPSS Statistics v.22 (SPSS IBM, Turkey). Results: Among all, 44.8% of the patients were using Valproic acid (VPA), 28.7%, Levetiracetam (LEV), 12.6%, Oxcarbazepine (OXC), 8%, Phenobarbital (PB), and 4.6%, Carbamazepine (CBZ). Platelet values were below 150,000/ul in 7.6% of VPA users and 14.2% of PB users. The hemoglobin value fell below 10 g/dl in 2.5% of VPA users, 14.2% of PB users, and 8% of LEV users. Absolute neutrophil count fell below 1500/ul in 9% of the patients using OXC and 14.2% of those using PB. The decrease in platelet values before and after anticonvulsant use was statistically significant (P=0.039), while the decrease in hemoglobin and neutrophil values were not. Conclusion: In patients using antiepileptic drugs, complete blood count may be affected. Periodic monitoring of blood parameters is important in the close follow-up of patients. It is not known exactly how and how often the hematological side effects of antiepileptic drugs take place. Future studies on this subject are necessary.

Keywords

• antiepileptic drug
• child
• complete blood count

Antiepileptiklerin kan sayımı üzerine etkilerinin değerlendirilmesi

Öz

Amaç: Çocukluk çağında epilepsi görülme oranı %1-3 arasındadır. Epilepsi tedavisinde çeşitli antikonvülzan ilaçlar kullanılmaktadır. İlaç seçiminde nöbet tipi, ilacın etkinliği ve ilacın yan etkileri önemlidir. Antikonvülzan kullanımının çeşitli hematolojik yan etkileri bildirilmiştir. Bu çalışmanın amacı kliniğimizde kullanılan antikonvülzanlara bağlı hematolojik yan etkileri ve bu etkilerin sıklığını saptamaktır. Yöntemler: Ocak 2017 - Ocak 2018 tarihleri arasında Sağlık Bilimleri Üniversitesi Okmeydanı Eğitim ve Araştırma Hastanesi Çocuk Nöroloji polikliniğinde epilepsi tanısı almış ve en az 3 aydır antikonvülzan tedavi verilmiş, 1 - 15 yaş arasındaki 87 hastanın dosyalarından kan değerleri ve ilaçların hematolojik yan etkileri kaydedildi. Çalışmada elde edilen bulgular değerlendirilirken, istatistiksel analizler için IBM SPSS Statistics 22 (IBM SPSS, Türkiye) programı kullanıldı. Bulgular: Çalışmamızda hastaların %44,8'i Valproik asit (VPA), %28,7'si Levatiresetam (LEV), %12,6'sı Okskarbazepin (OXC), %8'i Fenobarbital (PB), %4,6'sı Karbamazepin (CBZ) kullanıyordu. VPA kullananların %7,6'sında, PB kullananların %14,2'sinde trombosit değerinin 150.000/ul altına düştüğü saptandı. VPA kullananların %2,5'inde, PB kullananların %14.2 'sinde, LEV kullananların %8'inde hemoglobin değerinin 10 g/dl altına düştüğü saptandı. OXC kullanan hastaların %9'unda, PB kullananların %14,2'sinde mutlak nötrofil sayısının 1500/ul altına düştüğü saptandı. İlaç öncesi ve sonrası değerler karşılaştırıldığında, hemoglobin ve nötrofil değerlerindeki düşüş anlamlı bulunmazken, trombosit değerlerindeki düşüş istatistiksel olarak anlamlı bulundu (P=0,039). Sonuç: Anti epileptik ilaç kullanan hastaların kan sayımı etkilenebilmektedir. Hastaların takibinde kan parametrelerinin periyodik olarak yakından izlenmesi önemlidir. Antiepileptik ilaçların hematolojik yan etkisinin nasıl ve ne sıklıkta olduğu tam olarak bilinmemektedir. Bu konuda yapılacak çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• Antiepileptik ilaç
• Çocuk
• Kan sayımı

Kaynakça

1. 1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14. PMID: 24730690.
2. 2. Fisher RS, Cross JH, D'Souza C, French JA, Haut SR, Higurashi N, et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017 Apr;58(4):531-42.
3. 3. Cormier J, Chu CJ, Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. Neuropsychiatr Dis Treat. 2013;9:295-306.
4. 4. Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Tomson T, et al. Fourteenth Eilat Conference on new antiepileptic drugs and devices (EILAT XIV). I. Drugs in preclinical and early clinical development. Epilepsia 2018;59:1811-41.
5. 5. Perry MS. New and Emerging Medications for Treatment of Pediatric Epilepsy. Pediatr Neurol 2020;107:24.
6. 6. Asadipooya AA, Sperling MR. Antiepileptic drugs and hematological disorders. Antiepileptic drugs: a clinician's manual. Oxford University Press, New York. 2009;165-170.
7. 7. Guerrini R, Zaccara G, la Marca G, Rosati A. Safety and tolerability of antiepileptic drug treatment in children with epilepsy. Drug Saf 2012;35(7):519-33.
8. 8. Weijenberg A, Brouwer OF, Callenbach PM. Levetiracetam Monotherapy in Children with Epilepsy: A Systematic Review. CNS Drugs 2015;29(5):371–82.

9. 9. Sankar R. Selecting appropriate pharmacotherapy for the child with epilepsy. Adv. Stud. Med 2005;5464–9.
10. 10. Füsun Ferda Erdoğan. New Antiepileptic Drugs. Epilepsi. 2014; 20(Ek-1):56-8.
11. 11. Sema saltık. Çocukluk Epilepsilerinde Tıbbi Tedavi. Epilepsi 2014;20(Ek 1):50-5.
12. 12. Verrotti A, Coppola G, Parisi P. Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg. 2010;112:1-10.
13. 13. Asadi-Pooya AA, Sperling MR. Mechanisms of actions and pharmacokinetic properties of antiepileptic drugs. Antiepi- leptic drugs: a clinician's manual. Oxford University Press, New York. 2009;69-148.
14. 14. El-Sayed S, Symonds RP Lorazepam induced pancyto- penia. Brit Med J. 1988;296:1332.
15. 15. Bautista-Quach MA, Liao YM, Hsueh CT Pancytopenia associated with clonazepam. J Hematology Oncology. 2010;3:24.
16. 16. Veall RM, Hogarth HC. Letter: Thrombocytopenia during treatment with clonazepam. Br Med J. 1975;4(5994):462.
17. 17. Bussien R. Acute granulocytopenia after simultaneous administration of gentamicin and diazepam. Nouv Presse Med 1974;3:1236.
18. 18. Baumes RM. Drug induced cytopenia: acute thrombopenic purpura and active antiplatelet antibodies in the presence of valium. Maroc Med. 1971;546:321-4.
19. 19. Handoko KB, Souverein PC, van Staa TP, Meyboom RH, Leufkens HG, Egberts TC, et al. Risk of aplastic anemia in patients using antiepileptic drugs. Epilepsia. 2006 Jul;47(7):1232-6.
20. 20. Andres E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol. 2008;15:15–21.
21. 21. Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia. 2007;48:1223–44.
22. 22. Blackburn SC, Oliart AD, Garcia Rodriguez LA, Pérez Gutthann S. Antiepileptics and blood dyscrasias: a cohort study. Pharmacotherapy. 1998;18:1277–83.
23. 23. Tichy E, Lam S, Militano U, Bessmertny O. A case of severe thrombocytopenia and antiepileptic hypersensitivity syndrome. J Pediatr Pharmacol Ther. 2003 Jan;8(1):29-33.
24. 24. Tohen M, Castillo J, Cole JO, Miller MG, Heros R, Farrer RJ. Thrombocytopenia associated with carbamazepine: A case series. J Clin Psychiatry 1991;52:496
25. 25. Abate MV, Stocco G, Devescovi R, Carrozzi M, Pierobon C, Valencic E, et al. Carbamazepine-induced thrombocytopenic purpura in a child: Insights from a genomic analysis. Blood Cells Mol Dis. 2016 Jul;59:97-9.
26. 26. Kumar R, Chivukula S, Katukuri GR, Chandrasekhar UK, Shivashankar KN. Carbamazepine Induced Thrombocytopenia. J Clin Diagn Res. 2017;11(9):OD12-3.
27. 27. Kimland E, Höjeberg B, von Euler M. Levetiracetam-induced thrombocytopenia. Epilepsia. 2004;45:877–8.
28. 28. Meschede A, Runge U, Sabolek M. Thrombocytopenia during levetiracetam therapy. Epilepsy. 2008;80:91–2.
29. 29. Oghlakian R, Nock C, Koubeissi M. A case of levetiracetam-induced thrombocytopenia. Epileptic Disord. 2010;12:335–7.
30. 30. Sahaya K, Goyal MK, Sarwal A, Singh NN. Levetiracetam-induced thrombocytopenia among inpatients: a retrospective study. Epilepsia. 2010;51(12):2492-5.
31. 31. Mahmud J, Mathews M, Verma S, Basil B. Oxcarbaze- pine-induced thrombocytopenia. Psychosomatics. 2006;47:73-4.
32. 32. Hsiao YT, Wei IH, Huang CC. Oxcarbazepine-related neutropenia: a case report. J Clin Psychopharmacol. 2010;30:94-5.
33. 33. Calamaras MR, Stowe ZN, Newport DJ. Pancytopenia associated with the introduction of oxcarbazepine. J Clin Psychopharmacol. 2007;27:217-8.
34. 34. Chaudhry MM, Abrar M, Mutahir K, Mendoza C. Oxcarbazepine-induced hemolytic anemia in a geriatric patient. Am J Ther. 2008;15:187-9.
35. 35. Suddock JT, Cain MD. Barbiturate Toxicity. 2020 Jul 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 29763050.
36. 36. Asadipooya AA, Sperling MR. Antiepileptic drugs and hematological disorders. Antiepileptic drugs: a clinician's manual. Oxford University Press, New York. 2009;165-70.
37. 37. Buoli M, Serati M, Botturi A, Altamura AC. The Risk of Thrombocytopenia During Valproic Acid Therapy: A Critical Summary of Available Clinical Data. Drugs R D. 2018;18(1):1-5.
38. 38. Gerstner T, Teich M, Bell N. Valproate-associated coagulopathies are frequent and variable in children. Epilepsia. 2006;47:1136-43.
39. 39. Teich M, Longin E, Dempfle CE, Konig S. Factor XIII deficiency associated with valproate treatment. Epilepsia. 2004;45:187-9.
40. 40. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr. 1990;117:495-9.
41. 41. Curnutte JT, Coates TD. Disorders of phagocyte function and number. Hematology: basic principles and practice, 3rd edn. Churchill Livingstone, New York. 2000;743-5.