Effects of the Removal of Phenytoin, Carbamazepine, and Valproate on the Electroencephalogram

We report the EEG changes that occurred on discontinuance of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in patients with active epilepsy. Discontinuation of CBZ was associated with an increase in mean frequency of dominant rhythm and reduction in amount of slow activity. Patients who had a marked increase in seizures on discontinuation of an antiepileptic drug had a slower mean dominant rhythm at baseline than did patients who did not have an increase in seizures. Subsequent EEGs, during and at the end of drug reduction, showed an increase in bursts of interictal epileptiform activity (IEA) and in slow activity in patients who had a marked increase in seizures. The amount of slow activity and IEA did not alter in patients who did not have an increase in seizures. No patients developed photosensitivity.     

Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.     

Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.     

Absence Seizures and Carbamazepine in Adults

Summary: Carbamazepine (CBZ) therapy was associated with development of absence seizures in 4 adults with generalized epilepsy. Two patients had new appearance of absence seizures and 2 patients had recrudesence of remote absence seizures. The seizures abated after discontinuation of CBZ therapy or addition of ethosuximide (ESM) in 1 patient intolerant of valproate (VPA).     

Effects of Discontinuation of Phenytoin, Carbamazepine, and Valproate on Concomitant Antiepileptic Medication

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.     

Drug Interaction Profile of Topiramate

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy-tochrome P450 isoforms show an effect of TPM only on the CYP2C_meph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.     

Clinical Side Effects of Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate During Monotherapy in Children

The rate of onset of side effects was examined in 392 pediatric outpatients who received long-term monotherapy with phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), or valproate (VPA) for epilepsy or febrile convulsions. The severity of side effects (based on need to alter treatment), the nature of each drug's most common side effects, and the doses and plasma levels of occurrence were recorded. Our results show that usually accepted therapeutic ranges are well tolerated. Indeed, although some form of side effect occurred in 50% of patients, treatment had to be changed in only 18% and the drug had to be stopped in only 7%. In decreasing order, the rates for side effects were PHT (71%) greater than PB (64%) greater than CBZ (43%) greater than VPA (43%) greater than PRM (29%). Serious side effects requiring withdrawal of treatment occurred at the following rates: PHT (10%) greater than VPA (8%) greater than PRM (8%) greater than PB (4%) greater than CBZ (3%). Among our patients, the best tolerated antiepileptic drug (AED) was CBZ, and the least tolerated was PHT. Behavioral disorders were most common with PB, neurologic disorders with PHT, digestive tract disorders with VPA, and gingival hyperplasia and hirsutism with PHT. Behavioral disorders involving excitement seen with PB and PRM occurred most commonly at low plasma levels. Behavioral disorders involving depression seen with PB and VPA, those involving excitement seen with PHT and VPA, and digestive disorders seen with VPA occurred particularly when plasma levels were high.     

Infertility secondary to valproate

Valproic acid (VPA) is generally thought to be more benign in terms of fertility effects in patients with epilepsy than carbamazepine (CBZ) or phenytoin (PHT) due to its lack of liver-enzyme-inducing properties. We report a patient treated with VPA for partial seizures, previously fertile on CBZ. When conception failed while taking VPA, semen analysis revealed a decreased number of sperm, reduced motility, and altered morphology. Endocrinologic studies and evaluation of the patient's wife were all normal. Successful pregnancy was achieved and abnormal sperm indices reverted to normal when VPA was discontinued and CBZ reinstituted. It is probable that a direct gonadal or sperm membrane effect of VPA is the responsible mechanism for this rare phenomenon.     

Oxcarbazepine in Focal Epilepsy and Hepatic Porphyria: A Case Report

PURPOSE: Despite the development of new antiepileptic agents (AEDs), the therapy of epilepsies along with hepatic porphyrias remains difficult. Most AEDs such as carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) may precipitate clinically latent porphyria by inducing hepatic metabolism and increasing hepatic heme synthesis. Actually, only gabapentin (GBP), an AED without any hepatic metabolism, is known as a potential therapy for partial seizures in patients having hepatic forms of porphyria. METHODS: We present the case of a 28-year-old man with porphyria cutanea tarda (PCT) who has had pharmacoresistant epilepsy with complex partial and secondarily generalized seizures since early childhood. Despite having undergone several AED therapies over the years, no seizure-free interval had been observed. Only CBZ could cause a seizure reduction, but this treatment had to be discontinued as an elevation of the transaminases as well as pruritus and erythema were noted. The patient was then started on oxcarbazepine (OCBZ), a ketoanalogue of CBZ similar in its pharmacologic mechanism as well as its clinical use, but which, in contrast to CBZ, has only a low hepatic induction of microsomal enzymes. A final maintenance dose four times higher than that of CBZ was prescribed. RESULTS: In the follow-up, the patient stopped having seizures, and his liver functions became normal. CONCLUSIONS: It can be concluded that OCBZ can successfully be administered to patients with hepatic porphyria and focal epilepsy who did not respond to treatment with GBP.     

Seizure freedom with different therapeutic regimens in intellectually disabled epileptic patients.

BACKGROUND: Epilepsy is a frequent condition in persons with intellectual disability and is more often difficult to treat than in the average population. Seizure freedom is the primary therapeutic goal which has important implications for the patient's quality of life. The aim of this study was to find out which antiepileptic therapy regimens (monotherapy or combination therapy) are effective in achieving this goal in intellectually disabled epilepsy patients. We were especially interested in the impact of the new antiepileptic drugs (AEDs) which were introduced during the past decade. METHOD: We investigated retrospectively the antiepileptic regimens on which the resident patients of a large epilepsy centre (as a rule with additional intellectual disabilities of different degrees) were seizure free in 2002. Information on antiepileptic medication and seizure frequency was taken out of the individual case documentation. It was also determined whether seizure free patients had already been seizure free in 1992. RESULTS: Two hundred and forty out of 675 patients (35,6%) with epilepsy were seizure free. The proportion of seizure freedom was 43,7% in patients with borderline intelligence, 39,2% in mild, 33,2% in moderate, 31,9% in severe, and 21,9% in profound intellectual disability. One hundred and twenty-two (50,8%) seizure free patients were on monotherapy; 53 of them were on CBZ (PB: 34, VPA: 25, PHT: 7, LTG: 3). Ninety-three patients (38,7%) were on duotherapies, CBZ/PB (27 patients), PB/PHT (17), and LTG/VPA (14) being the commonest. Of 18 (7,5%) triple therapies, LTG/PB/VPA (4 patients) was the commonest. Taken together, the five most frequent therapeutic regimens were CBZ monotherapy, PB monotherapy, CBZ/PB, VPA monotherapy and PB/PHT (a clear preponderance of classic AEDs). A distinction was made between "old seizure free" (seizure free already in 1992) and "new seizure free" (in 1992 still seizures) patients. In the 132 old seizure free patients the classic AEDs prevailed again, monotherapies with CBZ, PB and VPA being the most frequent regimens. In comparison, in the 78 new seizure free patients the novel combination LTG/VPA was the third most frequent, after the classic regimens CBZ/PB and CBZ; PB monotherapies were rare. CONCLUSION:In a majority of intellectually disabled patients with epilepsy (including those who became seizure free since 1992), complete seizure control has been achieved by monotherapy or duotherapy with classic AEDs. Of the new AEDs LTG in combination with VPA appears to be an important innovation.     

Outpatient sleep recording during antiepileptic drug monotherapy

The effects of sleep and sleep deprivation on epilepsy are well known, but the effects of seizures and antiepileptic drugs (AEDs) on sleep have been less well studied. We recorded nocturnal sleep in 17 patients receiving antiepileptic monotherapy with ambulatory cassette EEG devices. Twelve patients had complex partial seizures and five had tonic-clonic convulsions. Two patients' seizures were largely nocturnal, and no seizures occurred during sleep recording. Five patients each were taking phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), and two were taking clonazepam (CZP), all with therapeutic serum levels and no toxic symptoms. Total sleep time was reduced, wakefulness increased, and sleep latency prolonged in partial seizures as compared with generalized epilepsy. REM sleep was reduced and its latency decreased in partial seizure patients. Both groups had decreased slow wave sleep; that of partial seizure patients was decreased more markedly. PHT increased sleep latency and decreased sleep time, and CBZ increased awakening and diminished slow wave and REM sleep. Patients taking VPA had slight reduction in slow wave sleep; those taking CPZ had decreased sleep and REM latencies. Epilepsy may affect nocturnal sleep, and the effects of partial and generalized seizure disorders may be different. AEDs may also have differential effects on nighttime sleep. These may prove important in the long-term management of epileptic patients.     

Effectiveness and tolerance of adjunctive treatment of lamotrigine and conversion to monotherapy in pediatric patients with epilepsy. Preliminary studies

The examination concerned patients with intractable epilepsy aged 9-19 years with partial seizures simple or complex, developing into generalized ones years, treated with VPA (valproate) or CBZ (carbamazepine). They received VPA or CBZ for at least 4 weeks and even with the therapeutic concentration of these drugs in blood serum in the month preceding the examination they demonstrated seizures at least twice. For a period of 8 weeks lamotrigine (LTG) was progressively added to the therapy. Both drugs were administered for at least 8 weeks in a full dose. In case of achieving a good therapeutic effect assessed on the basis of at least 50% seizure reduction the use of VPA or CBZ was gradually discontinued. In the period of 12-week observation an application of LTG monotherapy 2/3 of patients achieved 50-100% reduction of seizures. These patients improved reasoning dynamics and memorizing ability. After LTG administration EEG showed normalization of background activity and reduction of number and time of epileptic discharges.     

Treatment guidelines for adult epilepsy]

We reviewed the treatment strategies and choices of drugs for adult patients with epilepsy. As evidence from controlled studies for the older drugs is scarcely available from the literature, we added a clinical study performed in our hospital and an expert consensus study. Published randomized clinical studies revealed carbamazepine (CBZ) to be the treatment of choice, but provided little evidence for the differences in efficacy between phenytoin (PHT), valproate (VPA), phenobarbital (PB) and zonisamide (ZNS). The clinical study in our patients with intractable localization-related epilepsy indicated the superior efficacy of CBZ and PHT over VPA or ZNS. Sixty-nine experts converged on the opinion that monotherapy should be started with VPA for seizures of both idiopathic and symptomatic generalized epilepsy, and with CBZ for seizures of localization-related epilepsy. When the trials with 2-3 monotherapy failed, surgery should be considered for localization-related epilepsy. We proposed practical guidelines for treatment of patients with adult epilepsy, including rehabilitation and care for improvement of quality of life.     

The importance of drug interactions in epilepsy therapy

Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.     

Clobazam Has Equivalent Efficacy to Carbamazepine and Phenytoin as Monotherapy for Childhood Epilepsy

Summary: Purpose: To compare the effectiveness of mono-therapy clobazam (CLB) to carbamazepine (CBZ) and phenytoin (PHT) in children with epilepsy.
Methods: Children aged 2–16 years with newly diagnosed epilepsy or previous failure of one drug (for poor efficacy or side effects) were assigned to one of two study arms and then randomized–CLB versus CBZ or CLB versus PHT. Eligible children had partial epilepsies or only generalized tonic-clonic seizures. After a drug initiation protocol, monotherapy treatment mimicked the usual routines used by Canadian child neurologists. Blinding used a "double dummy" technique with blinded medication serum levels (6–point scale). Intention to treat analysis using survival curves assessed the primary end-point–length of retention on the initial medication during the year after randomization.
Results: Fifteen centers entered 235 patients: 159 randomized to CLB versus CBZ and 76 to CLB versus PHT. Altogether, in all study arms, 119 received CLB, 78 CBZ, and 38 PHT. Overall, 56% continued to receive the original medication for l year with no difference between CLB and standard therapy (CBZ and PHT). Seizure control was equivalent for all three medications, as were side effects. PHT and CBZ induced more biologic side effects, such as rash, while CLB induced slightly more behavioral effects. Tolerance developed in 7.5% of patients receiving CLB, 4.2% with CBZ and 6.7% with PHT.
Conclusions: CLB should be considered as "first line" monotherapy along with CBZ and PHT for all partial and selected generalized childhood epilepsies.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

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.