- Top of page
Purpose: Long-term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long-term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process.
Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme-inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme-inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C-reactive protein (hs-CRP), or thiobarbituric acid reactive substances (TBARS).
Key Findings: Long-term monotherapy with older-generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme-inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs-CRP. On the other hand, patients on enzyme-inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long-term LTG monotherapy.
Significance: Patients with epilepsy who were receiving long-term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long-term AED therapy, particularly in aged and high-risk individuals.
Although the prognosis for a majority of patients with epilepsy is good, >30% of patients do not have remission despite appropriate antiepileptic drug (AED) therapy (Kwan & Brodie, 2000). Long-term or lifelong AED therapy is usually required for those patients with refractory epilepsy. Of note is that prolonged AED therapy is often associated with a wide range of chronic adverse effects, including metabolic and endocrine disturbances, behavioral or psychiatric problems, idiosyncratic reactions, negative cognitive effects, and drug interactions (Greenwood, 2000; Aldenkamp & Bodde, 2005; Mintzer, 2010). In particular, growing evidence suggests that the older-generation AEDs that are commonly used for treatment of epilepsy, including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and valproic acid (VPA), exert prominent effects on the hepatic enzyme system and may alter metabolic pathways that are related to increased vascular risks (Hamed et al., 2007; Mintzer & Mattson, 2009; Tan et al., 2009a; Lopinto-Khoury & Mintzer, 2010).
Heightened atherosclerotic risks may account for the higher mortality and morbidity arising from cerebrovascular disease or atherosclerosis-related heart disease in patients with epilepsy who received prolonged AED therapy (Cockerell et al., 1994; Mohanraj et al., 2006). We and others have identified a number of circulatory biomarkers that are related to risks of cerebrovascular and cardiovascular diseases, including lipid profiles, lipoproteins, C-reactive protein (CRP), total homocysteine (tHcy), and uric acid from patients with epilepsy who are receiving AED therapy (Nikolaos et al., 2004; Sener et al., 2006; Hamed et al., 2007; Mintzer et al., 2009; Tan et al., 2009a; Belcastro et al., 2010; Svalheim et al., 2010; Yuen et al., 2010). In addition, based on measurement of common carotid artery (CCA) intima-media thickness (IMT), a well-established surrogate marker for both stroke and myocardial infarction (Bots et al., 1997), we further demonstrated that age, gender, and duration of AED therapy are important independent factors of CCA IMT (Tan et al., 2009a). Our results implied that cumulative effects of long-term exposure to AEDs play a pivotal role in the pathogenesis of atherosclerosis.
Another important issue is that individual AEDs may have differential effects on the markers of vascular risk. Recent studies (Mintzer et al., 2009; Belcastro et al., 2010) indicated that PHT and CBZ are potent inducers of the cytochrome P450 (CYP450) system, which exerts strong effects on serum lipid profiles, CRP, and tHcy. It follows that those enzyme-inducing drugs may substantially increase the risk of atherosclerosis. However, studies that evaluated the relationship between metabolic consequences and atherosclerotic changes in patients with epilepsy who are under long-term AED monotherapy are wanting, as are different effects of individual classes of AEDs. In our previous study (Tan et al., 2009a), we have shown that CCA IMT in patient with epilepsy appears to be positively correlated with the duration of AED therapy. The present study extended those experiences (Tan et al., 2009a) to evaluate the long-term drug-specific effects of AED monotherapy, including nonenzyme inducers (lamotrigine, LTG), enzyme inducers (CBZ or PHT), or enzyme inhibitors (VPA) on serologic biomarkers and quantified CCA IMT in patients with epilepsy.
- Top of page
The present study provided evaluations on vascular risk factors in patients with epilepsy who are under AED monotherapy. We also validated the advantage of direct quantification of atherosclerotic changes in vessel wall by B-mode ultrasound system in those patients. Based on CCA IMT measurements, we demonstrated that the duration of monotherapy with CBZ, PHT, or VPA is significantly associated with acceleration of atherosclerosis in patients with epilepsy, albeit via different underlying mechanisms.
Dyslipidemia has long been known to be an important risk factor for atherosclerosis (Kullo & Ballantyne, 2005). LDL-C plays an important role in the atherosclerotic process by increasing endothelial permeability, retention of lipoproteins within the intima of blood vessels, recruitment of inflammatory cells, and formation of foam cells (Stocker & Keaney, 2004; Kullo & Ballantyne, 2005). Emerging evidence further showed that treatment with enzyme-inducing AEDs, such as CBZ and PHT, is significantly associated with increased blood levels of total cholesterol, atherogenic (non-HDL) cholesterol, triglycerides, and tHcy (Mintzer et al., 2009; Belcastro et al., 2010; Svalheim et al., 2010). It is, therefore, of interest that our present results showed that the increase in thickness of CCA IMT in monotherapy with PHT or CBZ may be related to total cholesterol and LDL-C.
The effects of VPA on changes in lipid profiles and lipoproteins remains controversial (Eirís et al., 1995; Geda et al., 2002; Pylvänen et al., 2006; Lopinto-Khoury & Mintzer, 2010). Other studies (Mintzer et al., 2009; Svalheim et al., 2010) showed that newer AEDs, including LTG, do not affect blood lipid profiles. In addition, switching patients from enzyme-inducing (CBZ or PHT) to noninducing (LTG) AEDs resulted in amelioration of serologic markers of vascular risk, including lipids, tHcy, and CRP (Mintzer et al., 2009). By demonstrating that changes in the levels of total cholesterol and LDL-C were insignificant in the VPA and LTG monotherapy groups, the present study revealed that VPA and LTG exert minimal effects on blood lipids in patients with epilepsy who are on chronic therapy.
Another vascular marker of interest is tHcy, a nonessential amino acid with prothrombotic properties. High serum level of tHcy was found to be associated with increased mortality from ischemic stroke, coronary heart disease, and other cardiovascular disease (Cui et al., 2008). An increase in tHcy concentration may promote overproduction of reactive oxygen species, enhancement of platelet aggregation, inhibition of protein C, activation of nuclear factor-κB, and increase in the release of inflammatory mediators, all of which further create a prothrombotic environment (Temple et al., 2000; Kullo & Ballantyne, 2005). Chronic AED therapy may lead to hyperhomocysteinemia and lowered level of folate (Tamura et al., 2000; Verrotti et al., 2000; Tan et al., 2009a). Recent studies (Mintzer et al., 2009; Belcastro et al., 2010) showed significantly increased tHcy levels in patients who received enzyme-inducing AEDs, although tHcy level remained stable in those who received the enzyme-inhibiting VPA (Belcastro et al., 2010). In partial agreement with those findings, we observed that monotherapy with PHT, CBZ, and VPA significantly increased tHcy level and decreased folate level in our patients, whereas LTG was devoid of both effects. One possible explanation for the disruption of tHcy and folate metabolism in the VPA group may be related to its long-term use (13.3 ± 8.9 years) in our patients. Folate is a cofactor in methylation of tHcy, the primary means for regulating tHcy concentration (Temple et al., 2000). The deficiency in folate in patients under long-term VPA may also contribute to hyperhomocysteinemia. Whereas further studies are needed to substantiate this explanation, we noted that reports on the association between VPA and disruption of tHcy metabolism are conflicting (Gidal et al., 2005; Attilakos et al., 2006a; Belcastro et al., 2010).
Hyperuricemia has been reported to be related to cardiovascular and cerebrovascular morbidity and mortality (Bos et al., 2006; Chen et al., 2009). Higher levels of serum uric acid may be associated with the development of atherosclerosis that is independent of other atherosclerotic risk factors (Chen et al., 2009). Uric acid is the major end-product of purine metabolism (Rao et al., 1991). Hyperuricemia may increase superoxide production, stimulate vascular smooth cell proliferation, and upregulate the expression of platelet-derived growth factor or monocyte chemoattractant protein-1, leading to damages of endothelial cells that cause atherosclerosis (Rao et al., 1991; Bos et al., 2006). Although the effect of AEDs on serum uric acid concentrations is controversial (Ring et al., 1991; Attilakos et al., 2006b; Aycicek & Iscan, 2007), our results showed that uric acid level was significantly higher in patients with VPA monotherapy. On the other hand, PHT, CBZ, or LTG did not elicit significant effect on the metabolism of uric acid. As such, long-term therapy with VPA in patients with epilepsy may increase the levels of uric acid that may contribute to atherosclerotic risk.
Long-term AED therapy may result in low-grade systemic inflammation and increase in oxidative stress, as manifested by higher concentrations of hs-CRP and TBARS (Mintzer et al., 2009; Tan et al., 2009a). Chronic production of reactive oxygen species may exceed the capacity of cellular antioxidants, resulting in oxidative modification of LDL-C, promotion of proinflammatory responses, recruitment of macrophage, and development of atherosclerotic lesion (Stocker & Keaney, 2004). Moreover, hs-CRP has been found to induce the expression of cytokines and cell adhesion molecules, which are recognized as activators of the extrinsic pathway of the coagulation system (Ridker, 1998; Kullo & Ballantyne, 2005). Whereas the hs-CRP level was significantly increased in the PHT or CBZ treatment group in our study, the plasma concentration of TBARS remained relatively stable. VPA induced opposite effects, with a significant increase in TBARS and insignificant change in hs-CRP level. Otherwise, long-term monotherapy with LTG has no effects on hs-CRP and TBARS. Therefore, the risk of atherosclerosis in CBZ and PHT groups may be related to inflammatory mechanisms and the VPA group may be associated with oxidative mechanisms.
Prospective and retrospective incidence cohort studies have established that patients with epilepsy carry a significantly higher mortality rate than the general population (Lhatoo et al., 2001; Jallon, 2004; Mohanraj et al., 2006). Whereas cardiovascular disease is not considered a contributing factor (Lhatoo et al., 2001; Mohanraj et al., 2006), a number of studies reported an elevated standardized mortality ratio for patients with epilepsy to die of cerebrovascular diseases that are related to atherosclerosis (Cockerell et al., 1994; Jallon, 2004; Mohanraj et al., 2006). However, few data exist regarding the long-term effects of specific AEDs on vascular events. Our previous study revealed that the IMT of CCA was significantly increased in patients with long-term AED therapy (Tan et al., 2009a). An important observation in the present study is the long-term effect of AED monotherapy on the degree of increment in CCA IMT. Based on multiple linear regression analysis, we also revealed that long-term treatment with PHT, VPA, and CBZ had detrimental effects on average CCA IMT thickness, which was not shown for the LTG monotherapy group. In addition, the more detrimental effect on increment of CCA IMT was noted in the PHT monotherapy group.
The duration of AED therapy is significantly associated with the acceleration of atherosclerosis in patients with epilepsy, alongside independent contributions of age and gender to the atherosclerotic process (Tan et al., 2009a). In the present study, our linear regression models on mean CCA IMT after adjustment for age and gender also revealed positive correlation with AED duration in the PHT, CBZ, and VPA treatment groups, whereas the LTG group was not significant. Therefore, it is reasonable to suggest that the duration of monotherapy with the older-generation AEDs—including CBZ, PHT, and VPA—is at least one of the important and contributing risk factors to the atherosclerotic process. We are aware that the duration of evaluation for our LTG group was shorter than that for the other groups because LTG is a newer AED. As such, it is plausible that the shorter duration of LTG monotherapy may be a contributing factor for its lack of effect on CCA IMT. Although we are unable to rule out this factor, we reason that because this group of patients did not manifest significant changes in the markers for vascular risk, the possibility that LTG contributes to atherosclerosis by damaging vascular endothelial cells is deemed minimal. However, further studies are needed to evaluate more long-term effects of the newer-generation AEDs, including LTG on CCA IMT.
The present study provided insights into AED monotherapy by showing that prolonged use of CBZ, PHT, or VPA significantly changed serologic biomarkers of vascular risk that are associated with accelerated progression of atherosclerosis in patients with epilepsy. However, our results demonstrated that the mechanisms that underlie the progression of atherosclerosis in patients under long-term monotherapy with different AEDs might be different. The augmented CCA IMT observed in patients under long-term therapy with the CYP450 enzyme inducers, CBZ and PHT may be related to disturbances of cholesterol, tHcy, and folate metabolism, alongside increased inflammation. However, an elevation in the levels of uric acid and tHcy, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. On the other hand, patients under long-term monotherapy with the nonenzyme-inducer, LTG did not manifest significant changes in markers for vascular risk or augmented CCA IMT. Our results also suggest that long-term use of older-generation AEDs with prominent effects on the enzyme system, including CBZ, PHT, and VPA, may contribute to the progression of atherosclerosis in patients with epilepsy. To minimize metabolic disturbances and vascular risks and to reduce atherosclerosis-related diseases caused by long-term AED therapy, newer-generation AEDs such as LTG that exert no or weak effect on the enzyme system might be the most favorable choice. This information offers a guide for the choice of drug for patients with epilepsy who require long-term AED therapy, particularly in aged and high-risk individuals.