Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study Saravanan Chandrasekaran, 1 Sooraj Patil, 1 Renu Suthar, 2 Savita Verma Attri, 1 Jitendra Kumar Sahu, 2 Naveen Sankhyan, 2 Mini Tageja, 1 Pratibha Singhi 3 1 Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India 2 Unit of Pediatric Neurology and Neurodevelopment, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India 3 Chief unit of Pediatric Neurology and Neurodevelopment, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India Correspondence to Dr Savita Verma Attri, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India; attrisavi@yahoo.co.in Received 15 June 2016 Revised 11 October 2016 Accepted 13 October 2016 To cite: Chandrasekaran S, Patil S, Suthar R, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/ archdischild-2016-311436 ABSTRACT Objective Long-term therapy with phenytoin and carbamazepine is known to cause hyperhomo- cysteinaemia. We evaluated the prevalence of hyperhomocysteinaemia in North Indian children receiving phenytoin or carbamazepine monotherapy for >6 months duration and the effect of folic acid supplementation on plasma homocysteine. Methods In this cross-sectional observational study we enrolled consecutive children aged 2–12 years with epilepsy who had received phenytoin or carbamazepine monotherapy for >6 months. Plasma total homocysteine, folic acid, vitamin B12 and antiepileptic drug concentrations were measured. Healthy age- and sex- matched controls were recruited. Children with homocysteine >10.4 mmol/L received folic acid supplementation for 1 month and homocysteine and folic acid concentrations were measured after 1 month follow-up. Results A total of 112 children receiving antiepileptic monotherapy for >6 months were enrolled. Hyperhomocysteinaemia was present in 54 children (90%) receiving phenytoin, 45 children (90%) receiving carbamazepine therapy and 17 (34%) controls (p<0.05). Mean plasma homocysteine concentrations were significantly higher (18.9±10.2 vs 9.1±3 mmol/L) and serum folic acid concentrations (10.04±8.5 ng/ml vs 12.6±4.8 p<0.001) and vitamin B12 concentrations (365±155 pg/mL vs 474±332 pg/mL, p=0.02) were significantly lower in the study group compared with the control group. Duration of antiepileptic drug therapy correlated significantly with elevated homocysteine and reduced folic acid concentrations (p<0.05). Supplementation with folic acid for 1 month led to a reduction in plasma homocysteine concentrations in the study group (from 20.9±10.3 mmol/L to 14.2 ±8.2 mmol/L, p<0.05). Conclusions Phenytoin or carbamazepine monotherapy for >6 months duration is associated with hyperhomocysteinaemia in 90% of North Indian children. Elevated homocysteine concentrations were normalised in these children with folic acid supplementation. INTRODUCTION Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism. Hcy concentrations are maintained dynamically by trans- sulfuration and remethylation pathways ( figure 1). 1 Children with epilepsy tend to have hyperhomocys- teinaemia more frequently than the general popula- tion (10–40% vs 5%). 2–7 The pathogenesis is multifactorial and includes deficiencies of various cofactors such as folic acid, vitamin B12, pyridoxal phosphate, reduced activity of certain enzymes and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. 8–12 Depletion of various cofactors due to hepatic enzyme induction by older antiepileptic drugs (AEDs) is a possible mechanism for elevated Hcy in children with epi- lepsy. 13 Hyperhomocysteinaemia is a known risk factor for atherosclerosis, cerebrovascular diseases, dementia and brain atrophy. 14 15 Since children with epilepsy receive AEDs for years, these complications might be of significant concern. Elevated Hcy itself is reported to be epi- leptogenic and suspected to cause brain atrophy. 15 Phenytoin, carbamazepine and phenobarbitone among first-generation AEDs and topiramate and oxcarbazepine among the newer AEDs have been reported to cause hyperhomocysteinaemia in about 15–60% cases. 16 17 In view of the fact that older generation AEDs constantly deplete various cofactors intricately involved in Hcy metabolism, folic acid supplementation has been advocated to provide long-term benefit in preventing adverse cardiovascular events secondary to elevated Hcy concentrations. 18 What is already known on this topic? ▸ Long-term therapy with phenytoin or carbamazepine is known to cause hyperhomocysteinaemia. ▸ Hyperhomocysteinaemia is associated with cerebrovascular disease and brain atrophy and has a proconvulsive effect. What this study adds? ▸ 90% of children on phenytoin or carbamazepine therapy had hyperhomocysteinaemia. ▸ Vitamin B12 and folic acid concentrations were low in children with hyperhomocysteinaemia. ▸ Duration of antiepileptic drug therapy significantly correlated with homocysteine concentration. ▸ Elevated homocysteine concentration was normalised with folic acid supplementation. Chandrasekaran S, et al. Arch Dis Child 2016;0:1–6. doi:10.1136/archdischild-2016-311436 1 Original article ADC Online First, published on November 7, 2016 as 10.1136/archdischild-2016-311436 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.