Main Article Content
Background Long-term anticonvulsant therapy, especially with enzyme inducers, has been associated with low 25-hydroxyvitamin D [25(OH)D] levels and high prevalence of vitamin D deficiency. However, there have been inconsistent results in studies on the effect of long-term, non-enzyme inducer anticonvulsant use on vitamin D levels.
Objective To compare 25(OH)D levels in epileptic children on long-term anticonvulsant therapy and non-epileptic children. We also assessed for factors potentially associated with vitamin D deficiency/insufficiency in epileptic children.
Methods This cross-sectional study was conducted at two pediatric neurology outpatient clinics in Jakarta, from March to June 2013. Subjects in the case group were epileptic children, aged 6-11 years who had used valproic acid, carbamazepine, phenobarbital, phenytoin, or oxcarbazepine, as a single or combination therapy, for at least 1 year. Control subjects were non-epileptic, had not consumed anticonvulsants, and were matched for age and gender to the case group. All subjects’ 25(OH)D levels were measured by enzyme immunoassay.
Results There were 31 epileptic children and 31 non-epileptic control children. Their mean age was 9.1 (SD 1.8) years. Most subjects in the case group were treated with valproic acid (25/31), administered as a monotherapy (21/31). The mean duration of anticonvulsant consumption was 41.9 (SD 20) months. The mean 25(OH)D level of the epileptic group was 41.1 (SD 16) ng/mL, lower than the control group with a mean difference of 9.7 (95%CI 1.6 to 17.9) ng/mL. No vitamin D deficiency was found in this study. The prevalence of vitamin D insufficiency in the epileptic group was higher than in the control group (12/31 vs. 4/31; P=0.020). No identified risk factors were associated with low 25(OH)D levels in epileptic children.
Conclusion Vitamin D levels in epileptic children with long-term anticonvulsant therapy are lower than that of non-epileptic children, but none had vitamin D deficiency.
Authors who publish with this journal agree to the following terms:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
2. Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav. 2004;5:S3-15.
3. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353-73.
4. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122:398-417.
5. Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepileptic drugs and bone metabolism. Nutr Metab. 2006;3:36-46.
6. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142-52.
7. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357: 266-81.
8. Zhu Z, Zhan J, Shao J, Chen W, Chen L, Li W, et al. High prevalence of vitamin D deficiency among children aged 1 month to 16 years in Hangzhou, China. BMC Public Health. 2012;12:126.
9. Saintonge S, Bang H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: the National Health and Nutrition Examination Survey III. Pediatrics. 2009;123:797-803.
10. Andiran N, Celik N, Akca H, Dogan G. Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol. 2012;4:25-9.
11. Khor GL, Chee WS, Shariff ZM, Poh BK, Arumugam M, Rahman JA, et al. High prevalence of vitamin D insufficiency and its association with BMI-for-age among primary school children in Kuala Lumpur, Malaysia. BMC Public Health. 2011;11:95.
12. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007;92:2130-5.
13. Petty SJ, O’Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos Int. 2007;18:129-42.
14. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia. 2004;45:1330-7.
15. Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology. 2004;63:S24-9.
16. Morijiri Y, Sato T. Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy. Arch Dis Child. 1981;56:446-9.
17. Guo CY, Ronen GM, Atkinson SA. Longterm valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia. 2001;42:1141-7.
18. Crosley CJ, Chee C, Berman PH. Rickets associated with long-term anticonvulsant therapy in a pediatric outpatient population. Pediatrics. 1975;56:52-7.
19. Cansu A, Yesilkaya E, Serdaroglu A, Hirfanoglu T, Camurdan O, Gulbahar O, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol. 2008;39:266-71.
20. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav. 2004;5:S41-7.
21. Dent CE, Richens A, Rowe DJF, Stamp TCB. Osteomalacia with long-term anticonvulsant therapy in epilepsy. Br Med J. 1970;4:69-72.
22. Hunter J, Maxwell JD, Stewart DA, Parsons V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. Br Med J. 1971;4:202-4.
23. Silver J, Davies TJ, Kupersmitt E, Orme M, Petrie A, Vajda F. Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs. Arch Dis Child. 1974;49:344-50.
24. Weisman Y, Fattal A, Eisenberg Z, Harel S, Spirer Z, Harell A. Decreased serum 24,25-dihydroxy vitamin D concentrations in children receiving chronic anticonvulsant therapy. Br MedJ. 1979;2:521-3.
25. Farhat G, Yamout B, Mikati AM. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002;58:1348-53.
26. Gough H, Bissesar A, Goggin T, Higgins D, Baker M, Crowley M, et al. Factors associated with the biochemical changes in vitamin D and calcium metabolism in institutionalized patients with epilepsy. Ir J Med Sci. 1986;155:181-9.
27. Menon B, Harinarayan CV. The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism--a longitudinal study. Seizure. 2010;19:153-8.
28. Misra A, Aggarwal A, Singh O, Sharma S. Effect of carbamazepine therapy on vitamin D and parathormone in epileptic children. Pediatr Neurol. 2010;43:320-4.
29. Nettekoven S, Ströhle A, Trunz B, Wolters M, Hoffmann S, Horn R, et al. Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy. Eur J Pediatr. 2008;167:1369-77.
30. Nicolaidou P, Georgouli H, Kotsalis H, Matsinos Y, Papadoupoulou A, Fretzayas A, et al. Effects of anticonvulsant therapy on vitamin D status in children: prospective monitoring study. J Child Neurol. 2006;21:205-9.
31. Pedrera JD, Canal ML, Carvajal J, Postigo S, Villa LF, Hernandez ER, et al. Influence of vitamin D administration on bone ultrasound measurements in patients on anticonvulsant therapy. Eur J Clin Invest. 2000;30:895-9.
32. Rieger-Wettengl G, Tutlewski B, Stabrey A, Rauch F, Herkenrath P, et al. Analysis of the musculoskeletal system in children and adolescents receiving anticonvulsant monotherapy with valproic acid or carbamazepine. Pediatrics. 2001;108:e107-11.
33. Baer MT, Kozlowski BW, Blyler EM, Trahms CM, Taylor ML, Hogan MP. Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status. Am J Clin Nutr. 1997;65:1042-51.
34. Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002;43:1488-92.
35. Williams C, Netzloff M, Folkerts L, Vargas A, Garnica A, Frias J. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J. 1984;77:834-42.
36. Rauchenzauner M, Griesmacher A, Tatarczyk T, Haberlandt E, Strasak A, Zimmerhackl LB, et al. Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children. Dev Med Child Neurol. 2010;52:283-8.
37. McCarty CA. Sunlight exposure assessment: can we accurately assess vitamin D exposure from sunlight questionnaires? Am J Clin Nutr. 2008;87:1097S-101S.
38. Borusiak P, Langer T, Heruth M, Karenfort M, Bettendorf U, Jenke AC. Antiepileptic drugs and bone metabolism in children: data from 128 patients. J Child Neurol. 2013;28:176-83.
39. Cetinkaya T, Kurtulmus YS, Tutkavul K, Tireli H. The effect of oxcarbazepine on bone metabolism. Acta Neurol Scand. 2009;120:170-5.
40. Krishnamoorthy G, Nair R, Sundar U, Kini, Shrivastava M. Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dosage: a prospective study. Neurol India. 2010;58:213-9.
41. Kulak CA, Borba VZ, Bilezikian JP, Silvado CE, Paola L, Boguszewski CL. Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs. Arq Neuropsiquiatr. 2004;62:940-8.
42. Institute of Medicine of the National Academies. Dietary reference intakes for calcium and vitamin D. Report Brief 2010; 1-4 [cited 2013 August 2]. Available from http://www.iom.edu/~/media/Files/Report%20Files/2010/DietaryReference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf.
43. Rajakumar K, Thomas SB. Reemerging nutritional rickets: a historical perspective. Arch Pediatr Adolesc Med. 2005;159:335-41.