|Ahead of print
Metabolic effects of long-term antiepileptic drug therapy in South Indian children
Kingini Bhadran1, Nisha Bhavani1, Kollencheri Puthenveettil Vinayan2, Praveen V Pavithran1
1 Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Cochin, Kerala, India
2 Department of Pediatric Neurology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Cochin, Kerala, India
|Date of Submission||03-Sep-2020|
|Date of Decision||24-Dec-2020|
|Date of Acceptance||29-Dec-2020|
|Date of Web Publication||12-Jul-2021|
Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Cochin 682041, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Objectives: The adverse metabolic effects of long-term antiepileptic drug (AED) therapy are well known. But there is limited data on the same in children from India. This study was designed to look into the effect of long-term AEDs on anthropometry, glycemic parameters, insulin resistance, lipid profile, and hepatic steatosis in a cohort of South Indian children compared to healthy controls. This cross-sectional study was done in a pediatric epilepsy clinic of a tertiary care university teaching hospital. Materials and Methods: Ambulant children aged 5 to 15 years with epilepsy on AEDs for at least one year were identified. This cohort was divided into monotherapy and polytherapy groups. Age- and sex-matched controls were selected from healthy children in the community. All the cases and controls underwent a detailed general physical examination and investigations, including fasting blood glucose, fasting insulin, fasting lipid profile, and liver transaminases along with ultrasonogram of abdomen. Statistical Analysis Used: Student’s t-test, chi-square test, ANOVA/Kruskall–Walli test with Bonferroni adjustment. Results: Fifty children on long-term AED therapy (25 on monotherapy and 25 on polytherapy) and 22 controls were included in the study. Children on AED had significantly higher LDL-cholesterol, fasting blood glucose, and insulin resistance compared to controls. Four children on multiple AEDs had non-alcoholic fatty liver disease (NAFLD). Children taking oxcarbazepine regimen were found to have an adverse metabolic profile compared to those on other drugs. Conclusion: This cohort of South Indian children with epilepsy on long-term AED therapy had an adverse metabolic profile compared to matched healthy controls. Further larger community-based studies are needed to further characterize the association and develop successful intervention strategies. Emphasis on a healthy life style should be part of comprehensive epilepsy care program.
Keywords: Antiepileptic drugs, insulin resistance, levetiracetam, non-alcoholic fatty liver disease, oxcarbazepine, sodium valproate
| Introduction|| |
An abnormal metabolic profile has been described in many patients with epilepsy on chronic antiepileptic drug (AED) therapy. A relatively inactive lifestyle that many of these patients follow might be responsible for this. However, the ability of the AEDs to alter the enzymes of the Cytochrome P450 (Cyp 450) system also seems to play a major role. Most of the first generation AEDs such as phenytoin sodium, phenobarbital, primidone, and carbamazepine (CBZ) are enzyme inducers while Sodium Valproate (VPA) is an enzyme inhibitor. Classically, VPA, CBZ, pregabalin, vigabatrin, and gabapentin have been associated with weight gain, lamotrigine, levetiracetam, and phenytoin are weight neutral whereas felbamate, topiramate, and zonisamide are associated with weight loss., However, studies have not been uniform in this regard and phenytoin has also been shown to be associated with weight gain and insulin resistance. Other studies have shown gender differences in the metabolic effects of AEDs. The effect of the AEDs on lipids has also been conflicting. Most studies have shown that phenytoin and CBZ increase lipid levels, VPA decreases lipid levels and lamotrigine and levetiracetam are lipid neutral., A few studies have shown that switching from phenytoin and CBZ to lamotrigine or levetiracetam lead to an improvement in the lipid profile. However, some recent studies have shown that levetiracetam increases LDL-cholesterol. Phenytoin, CBZ, and VPA have been shown to increase Lipoprotein (a) levels in children. Hyperinsulinemia and insulin resistance (IR) were demonstrated in those receiving VPA and phenytoin. Other metabolic abnormalities demonstrated in epileptic patients on long-term AEDs are abnormalities in markers of inflammation and oxidative stress like C reactive protein, homocysteine, uric acid, and matrix metalloproteinase 9., Non-alcoholic liver disease (NAFLD) which is considered the hepatic manifestation of metabolic syndrome was demonstrated in adults receiving VPA, CBZ, and lamotrigine monotherapy.,, Long-term treatment with VPA has also been shown to cause NAFLD in obese adolescents.,
Epilepsy has also been associated with higher cardiovascular morbidity and mortality., Although direct causation of atherosclerosis has not been fully proven, all the adverse metabolic abnormalities seen in patients with epilepsy on AEDs may predispose to atherosclerotic cardiovascular disease. Carotid intima-media thickness, a marker of atherosclerosis has been shown to be increased in men on carbamazepine, phenytoin, and valproic acid but not on lamotrigine monotherapy.
Most of the above-mentioned studies have been done in adults and there are only very few studies in children on long-term AED therapy demonstrating adverse metabolic changes. There is even more limited literature from India., The metabolic side effects of AEDs are most often overlooked as these children might have many other pressing issues like learning problems, behavioral abnormalities, personality changes, and hyperactivity. Indians and South East Asians are ethnically more prone to premature cardiovascular disease. There is a growing epidemic of obesity and metabolic syndrome in Indian children with an estimated prevalence of 20%. The prevalence of epilepsy in India is also high at 5.5 to 10 per thousand. Hence it is assumed that there is a potential risk that metabolic adverse effects in children with epilepsy on long-term AEDs may become a significant health problem for this population. This hospital-based cross-sectional study was planned to look into the prevalence of components of metabolic syndrome-obesity, dyslipidemia, hypertension, insulin resistance, and NAFLD in a cohort of South Indian children with epilepsy on long-term AED therapy and to compare the findings with normal age- and sex-matched healthy children from the same community.
| Subjects and Methods|| |
The study was conducted in the pediatric epilepsy clinic of a tertiary referral university teaching hospital in South India. Ambulant children diagnosed with epilepsy as per International League Against Epilepsy definition aged between 5 and 15 years on monotherapy (single AED) or polytherapy (more than one AED) for at least one year prior to enrolment were included in the study. Children who were on drugs which might alter the lipid profile or blood glucose such as steroids, insulin, and statins, those having thyroid disorders or other endocrine diseases, chronic liver, heart or renal disease, progressive neurological or psychiatric illness, and children with severe neurodevelopmental disabilities were excluded from the study. Age, sex, and socioeconomic status matched children with no history of epilepsy or other medical, neurodevelopmental or psychiatric disorders were selected from the community and served as controls. Informed consent was obtained from the parents of both cases and controls. The study was approved by the institutional ethics committee.
All the children initially underwent a detailed medical history followed by clinical and anthropometric evaluation (including height, weight, body mass index [BMI], and waist circumference). Blood samples were analyzed for blood glucose, lipid profile, insulin, and liver function tests (LFT) after overnight fasting. Weight was measured using a standard digital weighing scale and height using a Harpenden stadiometer. BMI was calculated using the Quetelet index (weight in kilograms/height in square metre) and plotted in IAP BMI charts. Overweight was defined as a BMI between the 85th and 95th centile and obesity as >95th centile for age and gender. Systolic and diastolic blood pressures were obtained by sphygmomanometer using appropriate cuff sizes as per age. Blood pressure was classified as normal, pre-hypertension and stage 1 hypertension as per the fourth report on diagnosis, evaluation, and treatment of high blood pressure in children and adolescents according to age and height centiles. Insulin resistance was assessed by the homeostatic model assessment for insulin resistance (HOMA-IR) according to the formula: Insulin × glucose/22.5. An Ultrasonogram (USG) of the abdomen was done by a single radiologist on all these subjects to look for NAFLD. Fasting blood glucose more than 100 mg/dl was taken as impaired fasting glucose (IFG). Acceptable, borderline, and high lipids was defined as total cholesterol less than 170, 171–199 and more than 200 mg/dl and low density lipoprotein (LDL) cholesterol less than 110, 110–129 and more than 130 mg/dl respectively. Metabolic syndrome per se was not characterized in this study as the definition of metabolic syndrome in children according to the International Diabetes Federation (IDF) was applicable only to those above 10 years of age.
Statistical analysis was done using IBM SPSS Statistics 20 Windows (SPSS Inc, Chicago USA). Categorical variables are expressed as frequency and percentage and continuous variables are expressed as mean and standard deviation or median with range. For comparison of means, independent sample t-test was applied in the case of normality and the Mann-Whitney test in the case of non-normality. To test the statistical significance of fatty liver in cases and controls, chi-square test was used. To compare the polytherapy, monotherapy and control group with each other analysis of variance (ANOVA) was used. Kruskall Walli test was used when data was not normally distributed. Multiple comparison test (Bonferroni adjustment) was used to find the significant pairs. A P value of <0.05 was considered statistically significant. All tests of statistical significance were two-tailed.
As the study was designed as a proof of concept one, the sample size was calculated based on the study by Luefetal, and with 95% confidence interval and 90% power, a minimum sample size of 15 cases in each of the two groups was required.
| Results|| |
Seventy-two children were included in the study. 25 children on single AED and 25 on multiple AEDs served as cases and 22 healthy children from the community who were not on any AEDs served as controls. Male to female ratio was 23:27 among cases and 12:10 among controls. 39 children (78%) had a diagnosis of epilepsy due to unknown cause and the rest had postencephalitis sequelae (6), cerebral palsy (2), and febrile illness-related epilepsy syndrome(3). The AEDs used were Sodium Valproate in 17, Oxcarbezepine in 16, Levetiracetam in 16, Clobazam in 14, Carbamazepine in 6, Phenytoin in 4, and Phenobarbitone in 3 children. Among the 25 children on polytherapy, 19 were on 2 drugs, and 2 each were on 3, 4, and 5 AEDs respectively.
Family history of diabetes and hypertension was present in 24 and 9 out of the 50 cases respectively whereas it was present only in 9 of the controls. 18 children on AEDs had normal BMI, 22 were overweight and 10 were obese compared to 12 normal and 10 overweight children in controls. Seven children on AEDs had IFG and none had hypertension. 13 children on AEDs had high total and/or LDL-cholesterol, and 17 had borderline values whereas 15 controls had normal lipid profile.
Comparison of anthropometric indices, blood glucose levels, insulin levels, HOMA-IR (measure of insulin resistance), and lipid profile in cases and controls and between polytherapy and monotherapy groups are given in [Table 1]. Fasting blood glucose, insulin resistance, and LDL-cholesterol were significantly higher in children on AEDs compared to controls in spite of comparable anthropometric indices. Children on polytherapy had higher insulin resistance compared to monotherapy. Blood glucose and LDL cholesterol were significantly higher in monotherapy vs controls (P 0.013 and 0.03) whereas insulin resistance was significantly higher in the polytherapy group vs controls (P 0.03); other differences were not statistically significant.
|Table 1: Comparison of children on AEDs vs controls and monotherapy vs polytherapy|
Click here to view
Among the 50 children on AEDs, four had NAFLD whereas none of the controls had the same. All four of them were on polytherapy of which three were on oxcarbazepine-based regimens and one was on valproate-based regimen. Two children were on AED therapy for almost 12 years, however, the other two were on a relatively short duration of two years only. All four were females, with a median age of 14 years, and had clinical signs of insulin resistance like acanthosis. All of them were overweight and two were frankly obese. Impaired fasting glucose was seen in two of these children.
The effects of VPA, oxcarbazepine, and levetiracetam on anthropometric indices and metabolic parameters were analyzed. Patients on VPA did not show any statistically significant difference in their anthropometric parameters, fasting blood glucose, fasting insulin, insulin resistance levels, total cholesterol and HDL levels but the VPA group had significantly lower LDL-cholesterol levels compared to the non-valparin group (P = 0.013). Patients on levetiracetam group did not show any statistically significant difference in any of the parameters when compared to patients on other treatment/controls. Patients taking oxcarbazepine had a higher mean weight and BMI (P value = 0.028 and 0.013, respectively), higher fasting blood glucose, serum insulin, and insulin resistance (P = 0.016, 0.006, and 0.003, respectively) compared to patients on other AEDs. Compared to controls, the patients who were on oxcarbazepine had significantly higher weight (P = 0.017), BMI (P = 0.003), fasting blood glucose (0.001), fasting insulin, insulin resistance, and LDL-cholesterol (P = <0.001). The details are given in [Table 2].
| Discussion|| |
This study on a cohort of 72 South Indian children reveals that children on AEDs have a worse metabolic profile compared to age- and sex-matched controls with 64% those on AEDs being overweight or obese and 14% having IFG. The LDL-cholesterol, fasting blood glucose, serum insulin, and IR were significantly higher in children on AEDs compared to controls. Among the individual drugs, oxcarbazepine had a worse metabolic profile compared to levetiracetam or VPA.
The adverse metabolic profile of children on AEDs compared to controls is seen despite a comparable anthropometric profile which indicates that it is probably not mediated through weight gain and adiposity alone. The mechanisms of adverse metabolic profile of AEDs in children with epilepsy are not fully understood but may be related to enzyme alterations due to AEDs, increased appetite, and probably mediated by leptin, ghrelin, and insulin resistance. The neurohypothalamic alterations of the underlying etiology and frequent seizures might also contribute to altered metabolic regulation by the brain.,,,,
NAFLD was seen in four children (16%) in the treatment groups, all of whom were adolescent females, had clinical insulin resistance, and were on polytherapy regimens containing oxcarbazepine and/or VPA. Given the fact that the ultrasound scan of the liver detects NAFLD only when intrahepatic fat accumulation increases above 33%, the actual presence of mild NAFLD might be even higher. None of the patients had any deranged liver function tests. In a study by Luef et al. who also used ultrasound, NAFLD was demonstrable in 60.9% of VPA, in 22.7% of CBZ, in 8.7% of Lamotrigine treated adult patients, and in 12.5% of the healthy controls, with the highest level of steatosis seen in VPA treated patients., The exact pathophysiologic mechanism behind AED induced NAFLD remains unclear to date though insulin resistance may be playing a role.
Although classically VPA is described as the AED associated with maximum metabolic abnormalities, this study showed that children on VPA did not show any difference in obesity, insulin resistance, blood glucose or total cholesterol levels but only a lower LDL-cholesterol level. Mechanisms implicated in VPA associated metabolic abnormalities are hypothalamic dysregulation, its effect on adipocytokines, hyperinsulinemia, insulin resistance, and genetic susceptibility. VPA therapy has been shown to associated with increased expression of leptin, resistin, and fasting-induced adipose factor., Previous Indian studies from North India had shown that VPA therapy may be associated with higher triglycerides and cholesterol levels in children and altered body composition in adults.,
The striking feature of this study is the finding that children on oxcarbazepine had the highest risk of obesity, insulin resistance, higher blood glucose values, and higher total cholesterol compared to other drugs. Oxcarbazepine is an antiepileptic drug structurally related to carbamazepine with activity mostly due to its monohydroxy derivative metabolite but the difference is that its metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs like phenytoin. Literature on the metabolic effects of oxcarbezepine is conflicting. Some studies have shown that oxcarbezepine therapy may cause significant and persistent alterations in lipid and thyroid profiles whereas others have shown that it neither causes weight change nor alterations in serum glucose, insulin, cortisol, leptin, NPY, galanin, and ghrelin levels or carotid intima-media thickness in children with epilepsy.,,, Replacing CBZ with oxcarbazepine has been shown to normalize the Cyp 450 activity and decrease total cholesterol but increase LDL-cholesterol levels. Eslicarbazepine acetate the newer derivative of oxcarbazepine has been shown to better than conventional carboxamides in its effect on lipid metabolism.
This cross-sectional study clearly proves the hypothesis that South Indian Children with epilepsy on long-term AEDs have an adverse metabolic profile compared to their age- and sex-matched peers from the same community. It also shows a trend regarding the adverse effects of certain drugs compared to others. Strength of the study is that to the best of our knowledge this is the only study from South India looking into the adverse metabolic profile of children on long-term AEDs and comparing them to normal healthy children from the community. Limitation is the smaller sample size and the overlap of patients on various drugs. Hence larger community-based studies are needed to find out the effects of varying dosage of the individual drugs and the different combinations on the adverse metabolic parameters and the mechanisms underlying them. Till then monitoring for metabolic complications and emphasis on following a healthy lifestyle to maintain an ideal BMI may be made part of any comprehensive epilepsy care in children.
| Conclusion|| |
Children on long-term AEDs have higher incidence of obesity, higher mean fasting blood glucose levels, insulin resistance, and LDL-cholesterol compared to age- and sex-matched healthy children. The incidence of NAFLD was higher in children on multiple AEDs. Among the AEDs, oxcarbazepine-based regimens were found to have significantly worse metabolic profile with higher blood glucose levels, insulin resistance, and total cholesterol.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Strolin Benedetti M, Ruty B, Baltes E. Induction of endogenous pathways by antiepileptics and clinical implications. Fundam Clin Pharmacol 2005;19:511-29.
Ben-Menachem E. Weight issues for people with epilepsy–a review. Epilepsia 2007;48(Suppl 9):42-5.
Hamed SA. Antiepileptic drugs influences on body weight in people with epilepsy. Exp Rev Clin Pharmacol 2015;8:103-14.
Zeng K, Wang X, Xi Z, Yan Y. Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients. Clin Neurol Neurosurg 2010;112:291-5.
Jee Young Kim, HyangWoon Lee. Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy. Epilepsia 2007;48;1366-70.
Najafi MR, Bazooyar B, Zare M, Aghaghazvini MR, Ansari B, Rajaei A, et al
. The investigation of insulin resistance in two groups of epileptic patients treated with sodium valproate and carbamazepine. Adv Biomed Res2017;6:25.
Keenan N, Sadlier LG, Wiltshire E. Vascular function and risk factors in children with epilepsy: associations with sodium valproate and carbamazepine. Epilepsy Research2014;108:1087-94.
Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, et al
. Effects of antiepileptic drugs on lipids, homocysteine and C-reactive protein. Ann Neurol 2009;65:448-56.
Verrotti A, Manco R, Agostinelli S, Coppola G, Chiarelli F. The metabolic syndrome in overweight epileptic patients treated with valproic acid. Epilepsia 2010;51:268-73.
Katsiki N, Mikhailidis DP, Nair DR. The effects of antiepileptic drugs on vascular risk factors: a narrative review. Seizure2014;23:677-84.
Svalheim S, Luef G, Rauchenzauner M, Morkrid L, Gjerstad L, Tauboll E. Cardiovascular risk factors in epilepsy patients taking levetiracetam, carbamazepine or lamotrigine. Acta Neurol Scand 2010;190:30-3.
Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol 2010;12:300-8.
Kim DW, Lee SY, Shon YM, Kim JH. Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy. Epilepsia 2013;54:e146-9.
Luef GJ, Waldmann M, Sturm W, Naser A, Trinka I, Unterberger I, et al
. Valproate therapy and non-alcoholic fatty liver disease. Ann Neurol2004;55:729-32.
Luef G, Rauchenzauner M, Waldmann M, Sturm W, Sandhofer A, Seppi K, et al
. Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res 2009;86:42-7.
Verrotti , Agostinelli S, Parisi P, Chiarelli F, Coppola G. Nonalcoholic fatty liver disease in adolescents receiving valproic acid. Epilepsy Behav 2011;20:382-5.
Ladino LD, Tellez-Zenteno JF. Epilepsy and obesity: a complex interaction. In Mula M, editor. The comorbidities of epilepsy. London: Elsevier Inc, Academic Press; 2019. pp. 131-58.
Neligan A, Bell GS, Johnson AL, Goodridge DM, Shorvon SD, Sander JW. The long-term risk of premature mortality in people with epilepsy. Brain 2011;134:388-95.
Janszky , Hallqvist J, Tomson T, Ahlhom A, Mukamal KJ, Ahnve S. Increased risk and worse prognosis of myocardial infarction in patients with prior hospitalization for epilepsy – the Stockholm Heart Epidemiology Program. Brain 2009;132:2798-804.
Dhir A, Sharma S, Jain P, Bhakhri BK, Aneja S. Parameters of metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy. J Pediatr Neurosci 2015;10:222-6.
] [Full text]
Sarangi SC, Tripathi M, Kakkar AK, Gupta YK. Comparison of body composition in persons with epilepsy on conventional & new antiepileptic drugs. Indian J Med Res 2016;143:323-30.
] [Full text]
Ranjani H, Mehreen TS, Pradeepa R, Anjana RM, Garg R, Anand K, et al
. Epidemiology of childhood overweight & obesity in India: a systematic review. Indian J Med Res 2016;143:160-74.
] [Full text]
Santhosh NS, Sinha S, Satishchandra P. Epilepsy: Indian perspective. Ann Indian Acad Neurol 2014;17:S3-11.
Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al
. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745-50.
Pylvänen V, Pakarinen A, Knip M, Isojärvi J. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav 2006;8:643-8.
Belcastro V, D'Egidio C, Striano P, Verrotti A. Metabolic and endocrine effects of valproic acid chronic treatment. Epilepsy Res 2013;107:1-8.
Garoufi A, Vartzelis G, Tsentidis C, Attilakos A, Koemtzidou E, Kossiva L, et al
. Weight gain in children on oxcarbazepine monotherapy. Epilepsy Res 2016;122:110-3.
Garoufi A, Koemtzidou E, Katsarou E, Dinopoulos A, Kalimeraki I, Fotinou A, et al
. Lipid profile and thyroid hormone concentrations in children with epilepsy treated with oxcarbazepine monotherapy: a prospective long-term study. Eur J Neurol 2014;21:118-23.
Cansu A, Serdaroglu A, Cinaz P. Serum insulin, cortisol, leptin, neuropeptide Y, galanin and ghrelin levels in epileptic children receiving oxcarbazepine. Eur J Paediatr Neurol 2011;15:527-31.
Yiş U, Doğan M. Effects of oxcarbazepine treatment on serum lipids and carotid intima media thickness in children. Brain Dev 2012;34:185-8.
Isojärvi JI, Pakarinen AJ, Rautio A, Pelkonen O, Myllylä VV. Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxcarbazepine. Epilepsia 1994;35:1217-20.
Pulitano P, Franco V, Mecarelli O, Brienza M, Davassi C, Russo E. Effects of eslicarbazepine acetate on lipid profile and sodium levels in patients with epilepsy. Seizure 2017;53:1-3.
[Table 1], [Table 2]