Pediatric Neurology 53 (2015) 88e90
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Effect of Carbamazepine and Valproate Monotherapy on Cardiovascular Risks in Epileptic Children Deepika Harit MD a, *, Anju Aggarwal MD a, Swati Kalra MD a, Neelam Chhillar MD b a b
Department of Pediatrics, University College of Medical Sciences and GTB Hospital, Delhi, India Department of Neurochemistry, Institute of Human Behavior and Allied Sciences, Delhi, India
abstract OBJECTIVE: We determined the effects of carbamazepine and valproic acid on the serum lipids and apolipoprotein A and B in epileptic children on long-term monotherapy and 3 months after drug discontinuation. METHOD: Thirty-
three epileptic children (17 boys, 16 girls, mean age 9.79 2.5 years) were evaluated for serum lipids and lipoprotein results at the initiation of antiepileptic drug tapering and 3 months after cessation of antiepileptic therapy. RESULTS: In the carbamazepine group (n ¼ 13), there was no significant difference in the lipid profile at the end of therapy or at 3 months after the discontinuation, whereas in the valproate group (n ¼ 20), triglycerides and apoprotein B and high-density lipoprotein cholesterol increased significantly 3 months after discontinuation. The ratios of total cholesterol:high-density lipoprotein improved but low-density lipoprotein:high-density lipoprotein and apolipoprotein:apolipoprotein remained unchanged. CONCLUSION: Because these ratios are better predictor of atherosclerosis risk than the absolute values, the overall risk is not increased by the long-term use of carbamazepine and valproate. Keywords: antiepileptic drugs, pediatric epilepsy, valproate, carbamazepine, lipid profile
Pediatr Neurol 2015; 53: 88-90 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Cardiovascular disease is a major global health problem. Various studies have indicated that atherosclerosis process begins early in childhood1-3 and serum cholesterol levels in childhood correlates to atherosclerosis risk in adults. Valproate and carbamazepine are first-line drugs frequently used in the treatment of pediatric epilepsy. There is growing evidence that long-term antiepileptic drug therapy has a significant effect on the lipid profile.4-6 Long-term therapy with these two drugs alters the lipid profile, but various studies
Funding: none. Competing interest: none. Details of Contribution of each author: DH and AA conceived and designed the study. SK and NC collected the data. AA, DH and NC interpreted the data, DH, SK drafted the article. All authors revised the manuscript critically and approved the final version to be published. DH acts as guarantor of the study.
Article History: Received December 18, 2014; Accepted in final form February 21, 2015 * Communications should be addressed to: Dr. Harit; 27/63; Street no #8; Vishwas Nagar; Delhi 110032, India. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.018
have shown conflicting results.4-7 Whether these alterations in the lipid profile persist is yet not well-studied. In this prospective study, we investigated the lipid profile of epileptic children during and after completion of long term anticonvulsant monotherapy with valproate and carbamazepine. Methods The study was conducted at a tertiary care hospital from May 2011 to April 2012. We recruited developmentally normal children of 3 years of age, who had received at least 2 years of monotherapy with either valproate or carbamazepine and were seizure-free for at least 2 years. Patients were divided into two groups: group 1 comprised patients on carbamazepine therapy and group 2 consisted of those on valproate therapy. The protocol of the study was fully explained to the parents/ guardians and an informed consent was obtained from the parents. The study was approved by our institution’s ethical research oversight committee. Exclusion criteria were as follows: 1. Children receiving more than one antiepileptic drug anytime during the treatment. 2. Children with preexisting thyroid dysfunction, liver disease, familial hypercholesteremia, cerebral palsy, dysmorphism, neurodegenerative disease, mental retardation or endocrinal disorders.
D. Harit et al. / Pediatric Neurology 53 (2015) 88e90
Statistical analysis
TABLE 1. Group Characteristics
Weight (kg) Height (m) Body mass index (kg/m2) Duration of therapy (mo)
89
Group 1
Group 2
Carbamazepine (n ¼ 13)
Valproate (n ¼ 20)
Mean Standard Deviation
Mean Standard Deviation
27.15 10.5 1.3 0.16 15.55 3.2
27.20 10.8 1.3 0.13 15.4 3.7
24.8 1.0
25.6 1.9
Based on a study by Castro Gago et al.,8 sample size of 15 was calculated keeping a level of 0.05 and power of 90% to detect a mean difference in fall of 18 mg/dL of total cholesterol and standard deviation of 30 mg/dL in patients receiving long-term anticonvulsants 3 months after the end of therapy as compared to their total cholesterol before starting drug tapering using one sided t-test. Difference in the lipid profile of the two groups was determined using paired t-test. Assuming a loss to follow up of 20%, total of 36 patients (18 in each group) were required to complete the study. Statistical analysis was done by windows based SPSS, version 17. Paired and unpaired t-test was applied to find the difference in means of various parameters in the two groups.
Results 3. Children with a family history of cardiovascular disease or hypercholesterolemia. First blood sample was taken before the tapering of the antiepileptic drug. The drug was tapered off over next 6-8 weeks and then stopped. Patients were followed up 3 months after stopping the drug and, the second blood sample was taken for lipid profile if there has been no seizure in those 3 months. Five milliliters of blood sample in plain vial was collected for lipid profile and apoprotein estimation after overnight fasting of 8-12 hours and before taking the first dose of the day. Serum was separated and stored at 20 C. Serum was analyzed for lipid profile by autoanalyzer using colorimetric method for triglycerides and total cholesterol (ENZOKIT RANBAXY). High-density lipoprotein cholesterol (HDL-C) was determined using AutoZyme HDL-cholesterol Precipitating Reagent (ACCUREX BIOMEDICAL). Low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoproteins cholesterol (VLDL-C) were calculated using formulae. 1. LDL-C ¼ Total cholesterol (HDL-C þ VLDL-C) 2. VLDL-C ¼ Triglycerides/5. Apolipoprotein A1 and apolipoprotein B were analyzed in serum using immunoturbidimetry (Fortress Diagnostics, UK).
A total of 45 patients were recruited and 33 completed the study (seven had repeat seizure during tapering and five were lost to follow-up). There were 17 boys and 16 girls. Of these 33 patients, 13 were taking carbamazepine (group 1) and 20 were taking valproate (group 2). Clinical characteristics are shown in Table 1. Mean weight, height, and body mass index were comparable between the two groups. The individual groups mean serum levels of lipids and lipoproteins at the end of therapy and 3 months after the discontinuation are presented in Table 2. None of the studied parameters showed any significant difference in the group taking carbamazepine. However, in the patients receiving valproate HDL-C increased significantly from 17.5 to 26.8 mg/dL. Triglycerides also increased significantly from 59.9 to 84.4 mg/dL. Apoprotein B also increased from 50.4 to 64.2 mg/dL. The ratio of total cholesterol: HDL-C showed significant fall from 9.6 during therapy to 5.9 after 3 months of stopping valproate. Despite these changes, the ratios of LDL:HDL and apolipoprotein A1 to apolipoprotein B did not show any significant difference in either group.
TABLE 2. Mean Serum Lipid Levels and Ratios of the Two Groups Before and After Discontinuation of Drug
Group 1
Group2
Carbamazepine (n ¼ 13)
Valproate (n ¼ 20)
Mean SD
Mean SD
At the End of Therapy Total cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) VLDL (mg/dL) TG (mg/dL) ApoA (mg/dL) ApoB (mg/dL) LDL:HDL Total cholesterol: HDL ApoA:ApoB Abbreviations: ApoA ¼ Apolipoprotein A ApoB ¼ Apolipoprotein B HDL ¼ High-density lipoprotein LDL ¼ Low-density lipoprotein TG ¼ triglycerides VLDL ¼ Very low-density lipoprotein * P < 0.05.
110.69 53.08 29.92 21.23 60.15 92.77 52.0 2.51 5.29 1.77
31.8 21.8 17.0 22.9 30.9 52.8 25.4 1.67 3.39 0.65
3 Months After Discontinuation 112.0 45.00 25.92 33.77 93.15 91.92 61.54 2.42 5.0 1.62
35.5 20.3 16.6 32.2 55.4 41.4 24.7 1.94 2.89 0.67
P Value
At the End of Therapy
0.904 0.339 0.467 0.187 0.076 0.957 0.362 0.76 0.17 0.060
109.8 46.6 17.5 21.5 59.9 89.5 50.4 3.32 9.66 1.76
40.9 28.2 14.2 21.1 21.9 44.9 20.1 2.41 8.06 0.59
3 Months After Discontinuation 112.2 52.5 26.8 32.5 84.45 94.70 64.20 3.09 5.96 1.61
34.5 20.2 15.4 32.8 41.1 42.1 28.5 3.75 4.58 0.77
P Value 0.864 0.383 0.012* 0.260 0.033* 0.672 0.042* 0.58 0.03* 0.83
90
D. Harit et al. / Pediatric Neurology 53 (2015) 88e90
Discussion
Pediatric epilepsy often requires lifelong treatment. There is growing evidence that long-term antiepileptic treatment is associated with changes in various vascular risk markers (carotid intima thickness, total cholesterol, lipoprotein a, C-reactive protein, homocysteine).9 Both carbamazepine and valproate are known to alter the lipid profile significantly,4-6 but the literature is sparse on the persistence of these effects after the discontinuation of therapy. Our study reveals that in the carbamazepine group there was no significant difference in the lipid profile at the end of therapy and 3 months after the discontinuation, whereas in the valproate group, HDL-C improved significantly 3 months after discontinuation. Moreover, the triglycerides and apolipoprotein B also increased significantly. This influence is similar to that demonstrated by Castro-Gago et al.8 who found a significant increase in triglycerides, total cholesterol, LDL-C, and VLDL cholesterol. In the present study, despite an increase in HDL-C, triglycerides, and apolipoprotein-B in the valproate group, there was no alteration in the atherogenic ratios of LDL:HDL and apolipoprotein A:apolipoprotein B. The ratio of total cholesterol:HDL showed a significant improvement after the discontinuation of valproate. Because these ratios are more important than the absolute values of lipid components in predicting the atherosclerosis risk, the overall risk is not increased by the long term use of carbamazepine and valproate. However, long-term follow-up is required to demonstrate the permanence or
reversibility of the effect of these drugs and their effect on cardiovascular risks.
References 1. Juhola J, Magnussen CG, Viikari JS, Kahonen M, Hutri-Kahonen N, Jula A. Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study. J Pediatr. 2011;159:584-590. 2. Berenson GS, Bogalusa Heart Study Investigators. Bogalusa Heart Study: a long-term community study of a rural biracial (black/white) population. Am J Med Sci. 2001;322:293-300. 3. Raitakari OT, Juonala M, Kähönen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003;290: 2277-2283. 4. Aynaci FM, Orhan F, Orem A, Yildirmis S, Gedik Y. Effect of antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood. J Child Neurol. 2001;16:367-369. 5. Sonmez FM, Demir E, Orem A, et al. Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes. J Child Neurol. 2006; 21:70-74. 6. Aggarwal A, Singh V, Batra S, Faridi MM, Sharma S. Effect of carbamazepine therapy on serum lipids in children with partial epilepsy. Pediatr Neurol. 2009;40:94-97. 7. Bramswig S, Sudhop T, Luers C, von Bergmann K, Berthold HK. Lipoprotein (a) concentration increases during treatment with carbamazepine. Epilepsia. 2003;44:457-460. 8. Castro GM, Novo RMI, Blanco BMO, et al. Evolution of serum lipids and lipoprotein (a) levels in epileptic children treated with carbamazepine, valproic acid, and phenobarbital. J Child Neurol. 2006;21: 48-53. 9. Cheng LS, Prasad AN, Rieder MJ. Relationship between antiepileptic drugs and biological markers affecting long-term cardiovascular function in children and adolescents. Can J Clin Pharmacol. 2010; 17:e5-e46. Available at: http://www.jptcp.com/pubmed.php? articleId¼230. Accessed February15, 2015.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Effect of Carbamazepine and Valproate Monotherapy on Cardiovascular Risks in Epileptic Children Deepika Harit MD a, *, Anju Aggarwal MD a, Swati Kalra MD a, Neelam Chhillar MD b a b
Department of Pediatrics, University College of Medical Sciences and GTB Hospital, Delhi, India Department of Neurochemistry, Institute of Human Behavior and Allied Sciences, Delhi, India
abstract OBJECTIVE: We determined the effects of carbamazepine and valproic acid on the serum lipids and apolipoprotein A and B in epileptic children on long-term monotherapy and 3 months after drug discontinuation. METHOD: Thirty-
three epileptic children (17 boys, 16 girls, mean age 9.79 2.5 years) were evaluated for serum lipids and lipoprotein results at the initiation of antiepileptic drug tapering and 3 months after cessation of antiepileptic therapy. RESULTS: In the carbamazepine group (n ¼ 13), there was no significant difference in the lipid profile at the end of therapy or at 3 months after the discontinuation, whereas in the valproate group (n ¼ 20), triglycerides and apoprotein B and high-density lipoprotein cholesterol increased significantly 3 months after discontinuation. The ratios of total cholesterol:high-density lipoprotein improved but low-density lipoprotein:high-density lipoprotein and apolipoprotein:apolipoprotein remained unchanged. CONCLUSION: Because these ratios are better predictor of atherosclerosis risk than the absolute values, the overall risk is not increased by the long-term use of carbamazepine and valproate. Keywords: antiepileptic drugs, pediatric epilepsy, valproate, carbamazepine, lipid profile
Pediatr Neurol 2015; 53: 88-90 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Cardiovascular disease is a major global health problem. Various studies have indicated that atherosclerosis process begins early in childhood1-3 and serum cholesterol levels in childhood correlates to atherosclerosis risk in adults. Valproate and carbamazepine are first-line drugs frequently used in the treatment of pediatric epilepsy. There is growing evidence that long-term antiepileptic drug therapy has a significant effect on the lipid profile.4-6 Long-term therapy with these two drugs alters the lipid profile, but various studies
Funding: none. Competing interest: none. Details of Contribution of each author: DH and AA conceived and designed the study. SK and NC collected the data. AA, DH and NC interpreted the data, DH, SK drafted the article. All authors revised the manuscript critically and approved the final version to be published. DH acts as guarantor of the study.
Article History: Received December 18, 2014; Accepted in final form February 21, 2015 * Communications should be addressed to: Dr. Harit; 27/63; Street no #8; Vishwas Nagar; Delhi 110032, India. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.018
have shown conflicting results.4-7 Whether these alterations in the lipid profile persist is yet not well-studied. In this prospective study, we investigated the lipid profile of epileptic children during and after completion of long term anticonvulsant monotherapy with valproate and carbamazepine. Methods The study was conducted at a tertiary care hospital from May 2011 to April 2012. We recruited developmentally normal children of 3 years of age, who had received at least 2 years of monotherapy with either valproate or carbamazepine and were seizure-free for at least 2 years. Patients were divided into two groups: group 1 comprised patients on carbamazepine therapy and group 2 consisted of those on valproate therapy. The protocol of the study was fully explained to the parents/ guardians and an informed consent was obtained from the parents. The study was approved by our institution’s ethical research oversight committee. Exclusion criteria were as follows: 1. Children receiving more than one antiepileptic drug anytime during the treatment. 2. Children with preexisting thyroid dysfunction, liver disease, familial hypercholesteremia, cerebral palsy, dysmorphism, neurodegenerative disease, mental retardation or endocrinal disorders.
D. Harit et al. / Pediatric Neurology 53 (2015) 88e90
Statistical analysis
TABLE 1. Group Characteristics
Weight (kg) Height (m) Body mass index (kg/m2) Duration of therapy (mo)
89
Group 1
Group 2
Carbamazepine (n ¼ 13)
Valproate (n ¼ 20)
Mean Standard Deviation
Mean Standard Deviation
27.15 10.5 1.3 0.16 15.55 3.2
27.20 10.8 1.3 0.13 15.4 3.7
24.8 1.0
25.6 1.9
Based on a study by Castro Gago et al.,8 sample size of 15 was calculated keeping a level of 0.05 and power of 90% to detect a mean difference in fall of 18 mg/dL of total cholesterol and standard deviation of 30 mg/dL in patients receiving long-term anticonvulsants 3 months after the end of therapy as compared to their total cholesterol before starting drug tapering using one sided t-test. Difference in the lipid profile of the two groups was determined using paired t-test. Assuming a loss to follow up of 20%, total of 36 patients (18 in each group) were required to complete the study. Statistical analysis was done by windows based SPSS, version 17. Paired and unpaired t-test was applied to find the difference in means of various parameters in the two groups.
Results 3. Children with a family history of cardiovascular disease or hypercholesterolemia. First blood sample was taken before the tapering of the antiepileptic drug. The drug was tapered off over next 6-8 weeks and then stopped. Patients were followed up 3 months after stopping the drug and, the second blood sample was taken for lipid profile if there has been no seizure in those 3 months. Five milliliters of blood sample in plain vial was collected for lipid profile and apoprotein estimation after overnight fasting of 8-12 hours and before taking the first dose of the day. Serum was separated and stored at 20 C. Serum was analyzed for lipid profile by autoanalyzer using colorimetric method for triglycerides and total cholesterol (ENZOKIT RANBAXY). High-density lipoprotein cholesterol (HDL-C) was determined using AutoZyme HDL-cholesterol Precipitating Reagent (ACCUREX BIOMEDICAL). Low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoproteins cholesterol (VLDL-C) were calculated using formulae. 1. LDL-C ¼ Total cholesterol (HDL-C þ VLDL-C) 2. VLDL-C ¼ Triglycerides/5. Apolipoprotein A1 and apolipoprotein B were analyzed in serum using immunoturbidimetry (Fortress Diagnostics, UK).
A total of 45 patients were recruited and 33 completed the study (seven had repeat seizure during tapering and five were lost to follow-up). There were 17 boys and 16 girls. Of these 33 patients, 13 were taking carbamazepine (group 1) and 20 were taking valproate (group 2). Clinical characteristics are shown in Table 1. Mean weight, height, and body mass index were comparable between the two groups. The individual groups mean serum levels of lipids and lipoproteins at the end of therapy and 3 months after the discontinuation are presented in Table 2. None of the studied parameters showed any significant difference in the group taking carbamazepine. However, in the patients receiving valproate HDL-C increased significantly from 17.5 to 26.8 mg/dL. Triglycerides also increased significantly from 59.9 to 84.4 mg/dL. Apoprotein B also increased from 50.4 to 64.2 mg/dL. The ratio of total cholesterol: HDL-C showed significant fall from 9.6 during therapy to 5.9 after 3 months of stopping valproate. Despite these changes, the ratios of LDL:HDL and apolipoprotein A1 to apolipoprotein B did not show any significant difference in either group.
TABLE 2. Mean Serum Lipid Levels and Ratios of the Two Groups Before and After Discontinuation of Drug
Group 1
Group2
Carbamazepine (n ¼ 13)
Valproate (n ¼ 20)
Mean SD
Mean SD
At the End of Therapy Total cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) VLDL (mg/dL) TG (mg/dL) ApoA (mg/dL) ApoB (mg/dL) LDL:HDL Total cholesterol: HDL ApoA:ApoB Abbreviations: ApoA ¼ Apolipoprotein A ApoB ¼ Apolipoprotein B HDL ¼ High-density lipoprotein LDL ¼ Low-density lipoprotein TG ¼ triglycerides VLDL ¼ Very low-density lipoprotein * P < 0.05.
110.69 53.08 29.92 21.23 60.15 92.77 52.0 2.51 5.29 1.77
31.8 21.8 17.0 22.9 30.9 52.8 25.4 1.67 3.39 0.65
3 Months After Discontinuation 112.0 45.00 25.92 33.77 93.15 91.92 61.54 2.42 5.0 1.62
35.5 20.3 16.6 32.2 55.4 41.4 24.7 1.94 2.89 0.67
P Value
At the End of Therapy
0.904 0.339 0.467 0.187 0.076 0.957 0.362 0.76 0.17 0.060
109.8 46.6 17.5 21.5 59.9 89.5 50.4 3.32 9.66 1.76
40.9 28.2 14.2 21.1 21.9 44.9 20.1 2.41 8.06 0.59
3 Months After Discontinuation 112.2 52.5 26.8 32.5 84.45 94.70 64.20 3.09 5.96 1.61
34.5 20.2 15.4 32.8 41.1 42.1 28.5 3.75 4.58 0.77
P Value 0.864 0.383 0.012* 0.260 0.033* 0.672 0.042* 0.58 0.03* 0.83
90
D. Harit et al. / Pediatric Neurology 53 (2015) 88e90
Discussion
Pediatric epilepsy often requires lifelong treatment. There is growing evidence that long-term antiepileptic treatment is associated with changes in various vascular risk markers (carotid intima thickness, total cholesterol, lipoprotein a, C-reactive protein, homocysteine).9 Both carbamazepine and valproate are known to alter the lipid profile significantly,4-6 but the literature is sparse on the persistence of these effects after the discontinuation of therapy. Our study reveals that in the carbamazepine group there was no significant difference in the lipid profile at the end of therapy and 3 months after the discontinuation, whereas in the valproate group, HDL-C improved significantly 3 months after discontinuation. Moreover, the triglycerides and apolipoprotein B also increased significantly. This influence is similar to that demonstrated by Castro-Gago et al.8 who found a significant increase in triglycerides, total cholesterol, LDL-C, and VLDL cholesterol. In the present study, despite an increase in HDL-C, triglycerides, and apolipoprotein-B in the valproate group, there was no alteration in the atherogenic ratios of LDL:HDL and apolipoprotein A:apolipoprotein B. The ratio of total cholesterol:HDL showed a significant improvement after the discontinuation of valproate. Because these ratios are more important than the absolute values of lipid components in predicting the atherosclerosis risk, the overall risk is not increased by the long term use of carbamazepine and valproate. However, long-term follow-up is required to demonstrate the permanence or
reversibility of the effect of these drugs and their effect on cardiovascular risks.
References 1. Juhola J, Magnussen CG, Viikari JS, Kahonen M, Hutri-Kahonen N, Jula A. Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study. J Pediatr. 2011;159:584-590. 2. Berenson GS, Bogalusa Heart Study Investigators. Bogalusa Heart Study: a long-term community study of a rural biracial (black/white) population. Am J Med Sci. 2001;322:293-300. 3. Raitakari OT, Juonala M, Kähönen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003;290: 2277-2283. 4. Aynaci FM, Orhan F, Orem A, Yildirmis S, Gedik Y. Effect of antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood. J Child Neurol. 2001;16:367-369. 5. Sonmez FM, Demir E, Orem A, et al. Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes. J Child Neurol. 2006; 21:70-74. 6. Aggarwal A, Singh V, Batra S, Faridi MM, Sharma S. Effect of carbamazepine therapy on serum lipids in children with partial epilepsy. Pediatr Neurol. 2009;40:94-97. 7. Bramswig S, Sudhop T, Luers C, von Bergmann K, Berthold HK. Lipoprotein (a) concentration increases during treatment with carbamazepine. Epilepsia. 2003;44:457-460. 8. Castro GM, Novo RMI, Blanco BMO, et al. Evolution of serum lipids and lipoprotein (a) levels in epileptic children treated with carbamazepine, valproic acid, and phenobarbital. J Child Neurol. 2006;21: 48-53. 9. Cheng LS, Prasad AN, Rieder MJ. Relationship between antiepileptic drugs and biological markers affecting long-term cardiovascular function in children and adolescents. Can J Clin Pharmacol. 2010; 17:e5-e46. Available at: http://www.jptcp.com/pubmed.php? articleId¼230. Accessed February15, 2015.
