Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing.

OBJECTIVES: The dose of carbamazepine required to achieve optimal seizure control varies widely from patient to patient. We investigated polymorphic variants in various genes involved in the pharmacokinetics and pharmacodynamics of carbamazepine in an effort to identify predictors of maintenance dose. METHODS: : A total of 70 patients with epilepsy (49% were males; median age, 34 years; range, 14-72 years) who had benefited (>50% reduction in seizure frequency for at least 12 months) from treatment with carbamazepine monotherapy were included in the analysis. Known variants in drug-metabolizing enzyme genes, including those encoding cytochrome P450s, uridine 5'-diphosphate-glycosyltransferase, and microsomal epoxide hydrolase, together with a sodium channel polymorphism in SCN2A, were screened using polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. Associations between demographic and genetic variables and carbamazepine dose were identified by univariate and multivariate regression analyses. RESULTS: All genotype frequencies were consistent with Hardy-Weinberg equilibrium (P > 0.05). No single demographic or genetic variable was of sufficient strength to independently influence carbamazepine dosing requirements. However, a multivariate model, incorporating patient age and specific genotypes (c.337T>C, c.416A>G) of the EPHX1 gene encoding microsomal epoxide hydrolase, revealed a significant association with the maintenance dose of carbamazepine (r(2) = 0.362, P= 0.002). CONCLUSIONS: This proof-of-principle study suggests that genetic variants in EPHX1 can be used to predict maintenance doses of carbamazepine. A large-scale prospective investigation of genetic influences on drug dosing strategies in epilepsy, with specific focus on whole gene variability for those proteins involved in the pharmacokinetics and pharmacodynamics of antiepileptic agents, is warranted.

Multidrug-resistant genotype (ABCB1) and seizure recurrence in newly treated epilepsy: data from international pharmacogenetic cohorts.

PURPOSE: The association between a specific polymorphism (3435C>T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy. METHODS: Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures. RESULTS: Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C>T genotype and the rate of recurrence of unprovoked seizures in the three cohorts individually or combined; however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence. CONCLUSIONS: The ABCB1 3435C>T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field.

Predictors of pharmacoresistant epilepsy.

Outcome data were analysed from 780 patients newly diagnosed with epilepsy and followed up at a single centre over a 20-year period to investigate which clinical factors predicted pharmacoresistance. Patients were divided at the time of analysis into those whose seizures had been controlled for at least the last 12 months of follow up (n=462) and those whose epilepsy remained refractory (n=318). Numbers of pre-treatment seizures were greater in uncontrolled patients. Those reporting more than 10 seizures prior to initiation of therapy were more than twice as likely to develop refractory epilepsy. Univariate and multivariate logistic regression analyses demonstrated that pharmacoresistance was also associated with family history of epilepsy, previous febrile seizures, traumatic brain injury as the cause of the epilepsy, intermittent recreational drug use, and prior or current psychiatric comorbidity, particularly depression. Factors not predicting poorer outcome included gender, neurological deficit and mental retardation. The most interesting new finding was the correlation between psychiatric comorbidity and lack of response to antiepileptic drug therapy. The deleterious neurobiological processes that underpin depression, anxiety and psychosis may interact with those producing seizures to increase the extent of brain dysfunction and thereby the likelihood of developing pharmacoresistant epilepsy.

Sodium valproate versus lamotrigine: a randomised comparison of efficacy, tolerability and effects on circulating androgenic hormones in newly diagnosed epilepsy.

We have performed a randomised, prospective study to compare the efficacy and tolerability of sodium valproate (VPA) and lamotrigine (LTG) monotherapy, and their effects on circulating androgenic hormones, in newly diagnosed epilepsy. A total of 225 patients (116 male; median age 35 years, range 13-80 years) were followed-up at 6-weekly intervals until they reached an end-point (12 months' seizure freedom; withdrawal due to intolerable side-effects; lack of efficacy despite adequate dosing). Twelve month seizure-free rates were identical (47%) in the VPA (n=111) and LTG (n=114) treatment arms. More patients taking VPA withdrew from the study due to adverse events (26 VPA versus 15 LTG; p=0.046). Eight patients, all taking VPA, dropped out during the first 6 months due to weight gain. There were no changes in mean serum concentrations of testosterone, sex-hormone binding globulin and androstenedione or in the free androgen index after 6 or 12 months' treatment with either drug in 112 patients who fulfilled the criteria for hormone analysis. No difference in efficacy was found between VPA and LTG in our patients with newly diagnosed epilepsy. LTG appeared to be better tolerated. Neither drug appeared to alter the circulating levels of androgenic hormones.

Mortality in epilepsy.

All studies report an increased mortality risk for people with epilepsy compared with the general population. Population-based studies have demonstrated that the increased mortality is often related to the cause of the epilepsy. Common etiologies include neoplasia, cerebrovascular disease, and pneumonia. Deaths in selected cohorts, such as sudden unexpected death in epilepsy (SUDEP), status epilepticus (SE), suicides, and accidents are more frequently epilepsy-related. SUDEP is a particular cause for concern in younger people, and whether and when SUDEP should be discussed with patients with epilepsy remain problematic issues. Risk factors for SUDEP include generalized tonic-clonic seizures, increased seizure frequency, concomitant learning disability, and antiepileptic drug polypharmacy. The overall incidence of SE may be increasing, although case fatality rates remain constant. Mortality is frequently secondary to acute symptomatic disorders. Poor compliance with treatment in patients with epilepsy accounts for a small proportion of deaths from SE. The incidence of suicide is increased, particularly for individuals with epilepsy and comorbid psychiatric conditions. Late mortality figures in patients undergoing epilepsy surgery vary and are likely to reflect differences in case selection. Future studies of mortality should be prospective and follow agreed guidelines to better quantify risk and causation in individual populations.

Sudden unexpected death in epilepsy: a search for risk factors.

Sudden unexpected death in epilepsy (SUDEP) is the commonest cause of seizure-related mortality in people with refractory epilepsy. Of the 6140 patients registered with the Epilepsy Unit at the Western Infirmary in Glasgow between 1982 and 2005, 529 had died, 62 (11.7%) of whom succumbed to SUDEP. All but 2 deaths occurred at home; 3 were witnessed. Two living controls were matched with each SUDEP case for year of birth, gender, and syndromic classification. Mean duration of epilepsy was significantly longer in cases compared with controls (P=0.001). More people succumbing to SUDEP had had a seizure within the previous year (P=0.007). There were no significant associations between SUDEP and a history of generalized tonic-clonic seizures, drug polytherapy, and current use of carbamazepine. There is an urgent need for a large-scale, prospective, international, community-based study of SUDEP to explore more closely the risk factors to plan preventive strategies.

Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study.

BACKGROUND: People with epilepsy are at increased risk of premature death compared with the general population. Many clinicians are unsure whether and when this issue should be broached with their patients. We analysed mortality in patients with newly diagnosed and chronic epilepsy over a 20-year period. METHODS: Patients who attended the epilepsy service at the Western Infirmary in Glasgow, UK between 1981 and 2001, with newly diagnosed epilepsy (n=890) or referred after receiving unsuccessful treatment elsewhere (n=2689) were included in the study. Mortality data were obtained from the General Registrar Office for Scotland. Causes of death were ascertained from death certificates and primary care and health authority records. The two patient cohorts were compared with age-matched and sex-matched Scottish comparison groups. Standardised mortality ratios (SMR) were calculated for each epilepsy type, 10-year age band, and cause of death category. FINDINGS: Newly diagnosed patients had a 42% increase in mortality (SMR 1.42, 95% CI 1.16-1.72) compared with the comparison group. Increased mortality was recorded in those who had not responded to treatment, with no increase in risk observed in patients who were seizure free. In the chronic epilepsy cohort, there was more than double the expected number of deaths (2.05, 1.83-2.26). The incidence of sudden unexpected death in epilepsy was 1.08 and 2.46 per 1000 patient-years in patients with newly diagnosed and chronic epilepsy, respectively. The greatest excess in mortality was reported in patients younger than 30 years. INTERPRETATION: Mortality risks and preventive strategies should be discussed with patients with epilepsy when treatment fails or is refused despite recurrent seizures.

Modern antiepileptic drugs: guidelines and beyond.

PURPOSE OF REVIEW: Ten antiepileptic drugs have been licensed since 1990. Their usage will be briefly reviewed focusing on new data and inclusion in guidelines. The hypotheses exploring the underlying basis of pharmacoresistance will be presented. RECENT FINDINGS: Lamotrigine, gabapentin, topiramate, and oxcarbazepine are available for use as monotherapy in many countries following comparative studies with older antiepileptic drugs. Zonisamide and pregabalin have recently obtained licences as adjuvant therapy in the US and Europe for partial epilepsy with or without secondary generalization. The UK National Institute for Clinical Excellence guideline has advised, largely based on cost, against the routine use of modern antiepileptic drugs, except when older drugs have failed or are contraindicated. This contrasts with the US guidelines which are less conservative. Surgically resected specimens from patients with refractory epilepsy have led to the development of two hypotheses to explain pharmacoresistant epilepsy. SUMMARY: The introduction of 10 new antiepileptic drugs has provided greater choice for patients and doctors, although evidence in support of their superiority over the older drugs is sparse. This has led to conflicting advice in guidelines. Recent developments in the understanding of pharmacoresistance may explain the relatively high incidence of refractory epilepsy.

Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: five case reports.

Sexual dysfunction has been reported in both men and women with epilepsy. Associated factors are diverse but include, among others, antiepileptic drugs. We present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy.

Evidence-based treatment of idiopathic generalized epilepsies with older antiepileptic drugs.

Older antiepileptic drugs continue to play a major role in the treatment of the idiopathic generalized epilepsies. Comparative studies of ethosuximide and valproate have demonstrated equivalence in the treatment of childhood absence epilepsy. Valproate can be regarded as the recommended first-line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic-clonic seizures have not separated out idiopathic from secondary generalized events. Treatment for the other idiopathic generalized epilepsy syndromes lacks evidence other than a few case reports and diverse expert opinion. Further randomized controlled trials of older antiepileptic drugs are recommended to solidify the evidence-based treatment of the idiopathic generalized epilepsies.