COMMENTARIES

Vascular Risk Factors and Oxidative Stress as Independent Predictors of Asymptomatic Atherosclerosis in Adult Patients with Epilepsy

Sherifa A. Hamed1, Enas A. Hamed2, Ragaa Hamdy3, and Toshitaka Nabeshima4,
1Department of Neurology, Assiut University Hospital, Assiut, Egypt,
2Department of Physiology, Assiut University Hospital, Assiut, Egypt,
3Department of Biochemistry, Assiut University Hospital, Assiut, Egypt,
4Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

Please address correspondence to:
Sherifa Ahmed Hamed, MBBch., MSc., M.D.
Consultant Neurologist
Assistant Professor, Department of Neurology and Psychiatry, Assiut University Hospital, P.O.Box 71516
Assiut, Egypt
Tel: +2 088 2371820
Fax: +2 088 2333327, +2 088 2332278
E-mail: hamed_sherifa@yahoo.com

Introduction

Epilepsy is a frequent chronic medical problem [1]. In the last decade, several data are available about a number of vascular markers that are critically implicated in predisposition of atherosclerosis in patients with epilepsy [2]. However, there is still not enough information on the incidence of asymptomatic atherosclerosis among patients with epilepsy. We conducted our study in a relatively large number of adult epileptic patients (n = 225), untreated and treated with conventional antiepileptic drugs (AEDs), e.g. carbamazepine or CBZ, valproate or VPA, and combination therapy, with no manifest vascular disease or risk factors for atherosclerosis, to test the hypothesis that epileptic patients are at high risk for atherosclerosis. The central questions in our study are:

1)                  What is the prevalence of subclinical atherosclerosis and the possible vascular risk factors in patients with epilepsy with no previous history of vascular disease?

2)                  What is the effect of epilepsy and long-term conventional antiepileptic drug (AED) therapy on vascular risk factors, lipid peroxidation, and antioxidant biomarkers?

             We therefore undertook an integral approach at investigating patients comparing them with a matched control group, by measuring the carotid artery IMT (CA-IMT) using duplex ultrasound. We also investigated the influence of epilepsy and conventional AED treatment on blood levels of some potential vascular risk factors including total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c), total homocysteine (Hcy), von Willbrand factor (vWF), and fibrinogen. We evaluated the extent of oxidative damage through assessing the level of lipid peroxidation markers (oxidized LDL or Ox-LDL, malondialdehyde or MDA, and thiobarbituric acid reactive substance or TBARs) [3] and the magnitude of cell protection against oxidative stress through assessing the levels of total antioxidant capacity (TAC) [4]. Correlation between CA-IMT with all measured parameters was also evaluated.

 

Vascular Risk Factors in Epileptic Patients

We reported that some vascular risk factors get worse and the majority of patients (80%) have multiple vascular risk factors (≥ 3). Increased levels of TC, LDL-c, and TG were identified particularly among enzyme inducers AEDs or EI-AEDs (e.g. CBZ) [5,6]. We reported elevated levels of Ox-LDL in 75% of patients. It is positively correlated with CA-IMT thickness, MDA, Hcy, and vWF (vonWillbrand factor) negatively correlated with HDL-c and TAC. EI-AEDs compete with cholesterol in the utilization of hepatic microsomal enzymes (P-450 system) which leads to reduction in the transformation of cholesterol in bile acids with increased serum cholesterol level [7]. Hypercholesterolemia is known to result in increased endothelial permeability, retention of lipoproteins within the arterial intima, inflammatory cell recruitment, and foam cell formation filled with Ox-LDLs [8]. Low levels of HDL-c were identified in the majority of epileptic patients (59.5%), treated and untreated and independent on TC, LDL, and TG levels. HDL is a well-known antiatherogenic factor and a powerful protective factor against coronary heart disease. A low level of HDL is known to decrease the reverse transportation of cholesterol from the peripheral tissues to the liver [9], increase lipid peroxidation [10], induce vasoconstriction, and enhance muscle wall proliferation and thrombotic properties [11].

We identified hyperhomocysteinemia in more than 2/3 of epileptic patients, particularly with EI-AEDs (e.g. CBZ). EI-AEDs can reduce folic acid levels, thereby raising Hcy levels and increasing the risk of vascular disease [12]. Homocysteine (Hcy) is recognized as an important risk factors for arteriosclerosis and atherothrombosis, independent of the long-recognized identified common risks [13]. High levels of Hcy induce arterial endothelial damage and enhance inflammatory responses [14]. The endothelial damaging effect of Hcy has been found to be, in part, through its autoxidation and this promotes production of hydroxyl radicals, thiolactone, and known lipid peroxidation initiators with creation of a prothrombotic environment [15,16].

Increased levels of fibrinogen and von Willbrand factor were identified in 26% and 85% of patients, respectively.

 
Oxidative Stress/Antioxidant Homeostatic Alteration in Epilepsy

We reported high levels of lipid peroxidation markers (malondialdehyde or MDA and thiobarbitric acid reactive substance or TBARs) and the low levels of total antioxidant capacity (TAC) in 33.5%, 29%, and 60% of patients, respectively. MDA has a high ability to interact with lipoproteins while TBARs can induce oxidative damage via NMDA (N-methyl-D-aspartate) receptors, activation of nitric oxide synthase (NOS), and associated free radicals formation [8]. Many controlled in vivo and in vitro studies demonstrated that the biological effects of free radicals has been shown to be controlled by a wide range of antioxidants such as vitamin E, vitamin C, vitamin A, uric acid, glutathione, and antioxidant enzymes including glutathione reductase (GSH.R), glutathione peroxidase (GSH.Px), and superoxide dismutase (SOD) which can be collectively assessed by measuring the TAC [4].

 
Carotid Artery Intima-Media Thickness (CA-IMT) in Epileptic Patients

Thickened intima-media thickness (IMT) of the common carotid, area of bifurcation, and internal carotid arteries was reported in 51%, 73%, and 44% of patients, respectively. Increased arterial IMT may pre-date the clinical manifestations of atherosclerosis by many years in subjects at risk of atherosclerosis [17].

We suggest that the unbalanced oxidative stress/antioxidant disequilibrium caused, in part, by various vascular risk factors may contribute to endothelial dysfunction and vessel wall damage among patients with epilepsy. The disturbance of oxidative stress/antioxidant balance may result in modification of lipoproteins by oxidation which has shown to be taken up by macrophages and transformed into foam cells through degradation of the Ox-LDL via the scavenger receptors in the arterial wall [18]. This contributes to early atherosclerotic streak formation and the development and progression of atherogenesis [19].

The increased CA-IMT in various group of epileptic patients (treated and untreated) suggests that either chronic epilepsy and/or its antiepileptic medications are the cause [20]. Our study may offer the basis for discussion about the possible prevention of endothelial dysfunction and development of atherosclerosis among patients with epilepsy.

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