Original Article

Atherosclerotic Effects of Long-Term Old and New Antiepileptic Drugs Monotherapy: A Cross-Sectional Comparative Study

Journal of Child Neurology 2015, Vol. 30(4) 451-457 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814551388 jcn.sagepub.com

Reham M. El-Farahaty, MD1, Ashraf El-Mitwalli, MD2, Hanan Azzam, MD1, Yasser Wasel, MD2, Mohamed M. Elrakhawy, MD3, and Bothina Mohammed Hasaneen, MD4

Abstract This work aimed to evaluate the metabolic and atherogenic effects of long-term antiepileptic drugs in a group of Egyptian epileptic patients. Sixty-nine epileptic patients on antiepileptic drug monotherapy for at least 2 years and 34 control subjects were recruited in this study. Patients were divided into 5 subgroups according to antiepileptic drugs used (valproate, carbamazepine, lamotrigine, topiramate, and levetiracetam). Fasting lipid profile (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), lipoprotein(a), homocysteine, free thyroxine, thyroid-stimulating hormone, and common carotid artery intima-media thickness were measured for all subjects. Significant higher mean values of low-density lipoprotein cholesterol, low-density lipoprotein / high-density lipoprotein ratio, lipoprotein(a), homocysteine, significantly lower mean value of high-density lipoprotein cholesterol, and significantly larger diameter of common carotid artery intima-media thickness were observed in each drug-treated group versus control group. Our study supports that long-term monotherapy treatment with valproate, carbamazepine, lamotrigine, and topiramate had altered markers of vascular risk that might enhance atherosclerosis, whereas levetiracetam exerted minimal effect. Keywords antiepileptic, atherosclerotic markers Received May 18, 2014. Received revised August 03, 2014. Accepted for publication August 21, 2014.

Epilepsy is a common chronic neurologic disorder that requires long-term or sometimes lifetime therapy.1Antiepileptic monotherapy has the advantages of having lower side effects, drug interactions, and ease of compliance.2 Epilepsy and prolonged use of antiepileptic drugs are critically implicated in pathophysiology and dysfunction of the vessel wall3 as well as hormonal abnormalities.4 The first-generation antiepileptic drugs, including carbamazepine and valproic acid, exert prominent effects on the hepatic enzyme system and may alter metabolic pathways that are related to increased vascular risks.4-6 Carbamazepine is a potent enzyme inducer whereas valproic acid is a wide-spectrum isoenzyme inhibitor.7 Enzyme inducer can enhance cytochrome p450 microsomal oxidative enzyme activity,2 which is involved in the synthesis of serum cholesterol and thereby shifts the lipid profile toward an atherogenic pathway.4 This may facilitate thrombotic events.8 It is not known if the new non–enzyme inducer antiepileptic drugs affect cardiovascular risk through mechanisms other than the cytochrome p450 system.9 Lamotrigine induces the uridine 50 -diphospho glucuronosyltransferases (UGTs).10 Topiramate

is a mild inducer of drug-metabolizing enzymes of the liver.11 Levetiracetam has no evident enzymatic activity.7 Serum lipoprotein(a) (Lp)(a) concentration in children is especially important because its level is much less affected by age, gender, weight, and diet than other classes of lipoproteins; further, hyperhomocysteinemia (hyper Hcy) is an independent risk factor in atherosclerosis,8 it has been also

1

Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt 2 Department of Neurology, Faculty of Medicine, Mansoura University, Mansoura, Egypt 3 Department of Radiodiagnosis, Faculty of Medicine, Mansoura University, Mansoura, Egypt 4 Department of Pediatric Neurology, Faculty of Medicine, Mansoura University, Mansoura, Egypt Corresponding Author: Bothina Mohammed Hasaneen, MD, Pediatrics/ Pediatric Neurology, Faculty of Medicine, Mansoura University, Mansoura University Children’s Hospital (MUCH), Mansoura, Egypt. Email: [email protected]

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suggested to contribute to the development of brain atrophy and seizure aggravation in epileptic patients.12 Antiepileptic drugs may affect thyroid function; many studies have reported the coexistence of thyroid hormone deficiency (particularly free thyroxin 4) and disturbed lipid metabolism among epileptic patients treated with antiepileptic drugs.13-15 Carotid artery intima-media thickness (CA-IMT) is a simple, rapid, noninvasive, and cost-effective surrogate method to detect atherosclerosis and it may provide information that can be used to identify young adults with premature atherosclerosis.16 Previous studies demonstrated that carotid artery intima-media thickness is elevated in drug-treated epilepsy patients,5,17 though there was no separation of individual drugs’ effects, except relatively recently by Chuang et al.6 The objective of this study is to reveal the long-term effects of antiepileptic drug monotherapy on the atherosclerotic risk markers (lipoprotein(a), Hyc), thyroid, and lipid profile and to assess their contribution to changes in carotid artery intima-media thickness in a group of Egyptian epileptic children and young adults in comparison to healthy group.

Case Summary A cross-sectional, comparative study was done from January 2012 to March 2014 on a total of 69 epileptic patients (44 male, 25 female) of whom 21 patients (30.4%) had generalized seizures and 48 patients (69.6) had partial seizures. They were recruited from attendants of pediatric and adult neurology outpatient clinics at Mansoura University hospitals. They were on antiepileptic drug monotherapy for at least 2 years at the time of testing. Their mean age was 16.1 + 5.4 years. A control group consists of 34 healthy sex, age, socioeconomic, and residential matched subjects were recruited from patient’s relatives. Patients with other chronic diseases (eg, kidney, liver, endocrine, metabolic), receiving more than 1 antiepileptic drug or on vitamin supply, folic acid antagonists or other medications that may affect lipid metabolism, family history of atherosclerosis and with uncontrolled seizure were excluded from our study. The study was approved by the Ethics Committee of the Mansoura University, and the patients or their parents gave informed consent to participate in this study. A detailed history, complete physical and neurologic examination, electroencephalography (EEG), and brain magnetic resonance imaging (to rule out the confounding high risk for atherosclerosis in participants with symptomatic epilepsy that arises from cerebrovascular diseases) were done for all patients. The patients were divided into 5 subgroups according to the antiepileptic drug monotherapy: group 1: n ¼ 20 patients who have been on valproic acid (20-40 mg/kg/d twice daily); group 2: n ¼ 14 patients on carbamazepine (10-17 mg/kg/ d); group 3: n ¼ 11 patients on lamotrigine (1-3 mg/kg/d); group 4: n ¼ 12 patients, on topiramate (1-3 mg/kg/d); and group 5: n ¼ 12 patients on levetiracetam (20-40 mg/kg/d).

Methods Automated enzyme-multiplied immunoassay technique was used to monitor therapeutic drug levels. Serum concentrations of valproic acid

and carbamazepine were maintained within the therapeutic range throughout the study (71.2, 10.2 mg/mL, respectively). Fasting morning venous blood sample was taken from all participants for estimation of serum fasting blood total cholesterol (TC), triglyceride (TG), and highdensity lipoprotein cholesterol (HDLC) by enzymatic colorimetric methods using a Hitachi 912 analyzer, Roche Diagnostics GmbH,18 whereas low-density lipoprotein cholesterol (LDL-C) was calculated by Friedewald equation.19 Optimal levels of lipid profile were quoted from the National Cholesterol Education Program guidelines20 for children and adolescents; total human lipoprotein(a) assay were performed by solid-phase capture sandwich enzyme-linked immunosorbent assay kit from Immunospec Corporation.21 A level of 30 mg/dL represents the atherogenic threshold of plasma lipoprotein(a).22 Serum thyroidstimulating hormone (TSH) and free thyroxin 4 levels were determined by sandwich and competitive enzyme-linked immunosorbent assay techniques, respectively (Human Diagnostic GmbH).18 Thyroid-stimulating hormone level >5 m IU/L was considered as an index of subclinical hypothyroidism23; homocysteinemia level was measured using an enzyme-linked immunosorbent assay kit (WKEA, New York)24; and hyper-homocysteinemia was defined as 9 in children younger than 10 years25 and >10.4 mmol/L for older children and adolescents.26 Carotid artery intima-media thickness was measured by highresolution real-time B-mode ultrasonography with high-frequency linear transducer (L12-3HD11XE Philips, Netherlands). Both left and right common carotid arteries were scanned, defined as the 1-cm vascular wall segment of the carotid artery immediately proximal to the dilation of the bifurcation plane. The intima-media thickness was defined as the distance between the leading edge of the luminal echo to the leading edge of the media/adventitia echo. The presence of carotid intima-media thickness > 0.9 mm was defined as thickened intima-media thickness.27 Measurements were carried out according to standardized protocol by an experienced ultrasound radiologist who was blinded to the clinical history of the studied participants.

Statistical Analysis Data were analyzed using SPSS (SPSS Inc, Chicago, IL) version 16. Qualitative variables were presented as number and percentage. Chi-square test or Monte Carlo exact test was used to compare between different groups as appropriate. Quantitative variables were presented as mean and standard deviation. Analysis of variance was used for comparison between groups with Bonferroni multiple comparison. Pearson’s correlation coefficient was used to calculate correlation between variables within the same group. Stepwise linear regression analysis was performed to detect the relative contribution of each predictor to mean carotid artery intima-media thickness. P  .05 was considered statistically significant.

Results There were no significant differences between patients receiving antiepileptic drugs and the control group regarding age and sex (P ¼ .16, .63, respectively), but there were significant differences in duration of antiepileptic drug treatment and type of epilepsy between different patients groups (P ¼ .001) (Table 1). Total cholesterol was significantly higher in patients treated with valproic acid and carbamazepine (P < .001); LDL-C and LDL / HDL lipoprotein were significantly higher in all antiepileptic drug–treated groups (P  .001, P ¼ .02 in the levetiracetam-treated group for LDL-C and TC / HDL-C was

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Table 1. Characteristics of the Patients for Each Antiepileptic Drug–treated Group and Controls.

Age (y) Male, n (%) Types of epilepsy, n (%) PS GS BMI (kg/m2) Duration (years)

Control group (n ¼ 34)

Valproate (n ¼ 20)

13.6 + 6.7 18 (52.9) NA 21.4 + 3.7 NA

Carbamazepine (n ¼ 14)

Lamotrigine (n ¼ 11)

Topiramate (n ¼ 12)

Levetiracetam (n ¼ 12)

15.6 + 7.3 12 (60%)

15.6 + 3.95 8 (57.1%)

17.0 + 4.4 7 (63.6%)

13.3 + 3.7 7 (58.3%)

11.6 + 1.9 10 (83.3)

19 1 23.8 5.5

12 (85.7) 2 (14.3) 24.2 + 2.2 8.5 + 4.2A, B

3 (27.3) 8 (72.7) 24.5 + 2.6A 4.68 + 1.8

2 (16.7) 10 (83.3) 21.2 + 2.2A 2.6 + 0.8A

12 (100%)

(95%) (5%) + 3.8 + 2.0

23.7 + 2.4 2.2 + 0.45 B

P .16 .63* .001** .003

Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study.

This work aimed to evaluate the metabolic and atherogenic effects of long-term antiepileptic drugs in a group of Egyptian epileptic patients. Sixty-ni...
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