Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

OBJECTIVE: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). METHODS: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. RESULTS: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). CONCLUSIONS: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Adverse effects of antiepileptic drugs

Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.     

Self-reported symptoms in patients on antiepileptic drugs in monotherapy

Wieshmann UC, Tan GM, Baker G. Self‐reported symptoms in patients on antiepileptic drugs in monotherapy.
Acta Neurol Scand: 2011: 124: 355–358.
© 2011 John Wiley & Sons A/S. Objective – To ascertain the frequency of self‐reported symptoms in patients taking antiepileptic drugs (AED). Methods – We included patients on carbamazepine (CBZ) n = 36, valproate (VPA) n = 21, levetiracetam (LEV) n = 12, phenytoin (PHT) n = 11, lamotrigine (LTG) n = 20, patients not taking anticonvulsive drugs n = 19, and healthy control subjects (CTRL) n = 41 to complete the Liverpool Adverse Event Profile (LAEP). Results – The mean LAEP scores were CBZ/PHT/LEV/VPA/LTG/noAED/CTRL = 44.97/42.00/41.00/40.33/32.42/42.00/30.80. LEV scored overall in the same range as the older AED but had a different adverse effect profile with self‐reported anger (33%) and shaky hands (42%) particularly frequent. Patients with depression or uncontrolled epilepsy had significantly higher LAEP scores than patients without depression or uncontrolled epilepsy. Conclusion – Our unblinded observational study of self‐reported symptoms suggested LTG was overall the drug with the least self‐reported symptoms. Larger studies are needed to determine whether this was a truly significant difference. LEV had a different side effect profile to older AED. Confounding factors were depression and uncontrolled epilepsy. This observation should be further tested with randomized studies.     

Prognosis of epilepsy withdrawn from antiepileptic drugs

Abstract Antiepileptic drugs (AED) were discontinued in 55 epileptics who had been free from seizures treated with AED, in accordance with the following criteria and procedures. (i) A reduction in AED commences when patients have been free from seizures for at least 2 years and epileptic discharges have also disappeared in repeated electroencephalogram (EEG) recordings during that period. (ii) AED are gradually reduced if no relapse is seen in clinical seizures and epileptic discharges in EEG. (iii) As a rule at least 2 years are required as the interval from the onset of a reduction to the withdrawal of AED. Forty-three patients were followed up by a questionnaire and/or by telephone and the follow-up period from the withdrawal of AED to the survey ranged from 0.9 to 8.8 years; in 38 patients (88.4%) the period was longer than 2 years. No relapse of seizures was found in any of the 43 patients. The severity of epilepsy judged by the total number and frequency of seizures, the presence of neuropsychiatric complications, the combination of different types of seizures, and the duration of epilepsy from the seizure onset to the last seizure appeared not to be risk factors for the recurrence of seizure. Normal EEG was, however, considered to be an important prerequisite for a good prognosis.     

Hepatotoxicity associated with antiepileptic drugs

BACKGROUND: Drug-induced liver injury associated with antiepileptic drugs (AED) is well recognized. The frequency of the most common AED is rare but the consequences can be very serious leading to death or liver transplantation due to acute liver failure induced by these drugs. CLINICAL FEATURES: Hypersensitivity features are found in more than 70% of patients with phenytoin-induced liver injury, whereas this is only observed in 30% of carbamazepine-associated hepatotoxicity and very rarely with valproate (VPA)-induced liver injury. PATHOPHYSIOLOGY: The underlying mechanisms behind hepatotoxicity induced by AED are not clear. Reactive metabolites from AED can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases this may lead to neoantigen formation inducing immunoallergic mechanisms. TREATMENT: No specific therapy is of proved value in severe hepatotoxicity due to AED. However, N-acetylcystein is an appropriate treatment in patients with clinically significant liver injury due to phenytoin and carbamazepine. In patients with VPA-associated liver injury, carnitine that is an important co-factor in the mitochondrial beta-oxidation of fatty acids is the recommended treatment. Early referral of patients with severe liver reactions and coagulopathy to liver transplant centers before encephalopathy can be the difference between liver transplantation and death.     

The ideal characteristics of antiepileptic therapy: an overview of old and new AEDs

New and improved anti-epileptic drugs (AEDs) have made the concept of choice, according to the individual prognosis and probable response to specific regimens, increasingly feasible. Inter-individual variability in syndrome severity and complexity make individualization necessary. We propose three categories of disorder control according to the individual objectives of the patient: (1) seizure control, (2) epilepsy control and ultimately, (3) "epilepsy cure"; the latter remaining a largely idealistic target today. An AED is likely to be successful if it exhibits "optimal" characteristics, such as drug efficacy, tolerability, pharmacokinetics, interactions and cost-effectiveness. This review discusses the "optimal" characteristics of add-on AEDs, which, in addition to seizure control, will contribute to the achievement of epilepsy control and therefore address the currently unmet clinical needs of epilepsy treatment.     

Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy

ObjectiveTo investigate pharmacokinetic changes in newer antiepileptic drugs (AEDs) and assess seizure frequencies and risk factors of increased seizures during pregnancy in women with epilepsy (WWE).MethodsA total of 56 pregnancies in 53 WWE who received newer antiepileptic drugs (AEDs) were enrolled. Data on seizure activity and types, daily dose, and AEDs blood levels were derived from routine clinical follow‐up. Changes in AEDs clearance were compared between each trimester and nonpregnant baseline. The ratio of AED levels of each trimester to their targets (nonpregnant baseline) concentrations (RTC) was compared between patients with and without an increased seizure. A binary logistic regression was used to investigate the risk factors contributing to seizure worsening during pregnancy.ResultsIncreased clearances of LTG, LEV, and OXC were observed in all trimesters versus nonpregnant baseline. The peak changes in the clearance of LTG (3.42‐fold baseline clearance) (p < 0.001) and LEV (2.78‐fold) (p < 0.001) occurred in the second trimester during pregnancy, followed by oxcarbazepine (2.11‐fold) in the third trimester (p < 0.03). Plasma concentrations of LTG and LEV during pregnancy were significantly decreased compared to baseline levels, except for OXC. However, no significant differences in RTC values were observed between patients with and without seizure worsening. Some risk factors as seizures for the prior nine months could significantly affect seizure frequency during pregnancy.ConclusionWe found substantial changes in the pharmacokinetics of multiple newer AEDs in WWE, reinforcing the need for therapeutic drug monitoring (TDM) during pregnancy. We would encourage at least one monitoring every trimester and probably more frequently for women with poorly seizure control before pregnancy, and AEDs dose adjustment should keep up with clearance changes. In addition, a well‐controlled seizure nine months before pregnancy could lower the risks of seizure during pregnancy, highlighting the importance of pre‐pregnancy counseling and seizure management before pregnancy.     

Epilepsy in children: the evidence for new antiepileptic drugs

Childhood epilepsy remains a challenge to treat. Despite the availability of antiepileptic drugs (AEDs), >25% of children with childhood epilepsy continue to have seizures. Conventional AEDs have been the mainstay of therapy for many years but are often poorly tolerated and have a tendency to interact with other drugs. Current American Academy of Neurology guidelines support the use of four of the newer AEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as adjunctive treatment of refractory partial seizures in children, based on class I evidence. This paper includes a summary of the results from a recent randomized, double-blind, placebo-controlled study, which shows that levetiracetam is also effective and well tolerated in this pediatric population, and provides evidence supporting its use in refractory partial seizures in children.     

New antiepileptic drugs in practice – how do they perform in the real world?

Most large-scale clinical trials of antiepileptic drugs (AEDs) are undertaken for regulatory purposes and generate basic data supporting the efficacy and safety of a new treatment. They do not, however, provide all the information required for physicians to know how well the drug will work in clinical practice. One valuable approach to generating more clinically meaningful information is to assess AED treatment retention rates, which reflect the combination of efficacy and tolerability in the real world, and have historically been low. Long-term retention rate data are available for levetiracetam (LEV), topiramate, gabapentin, and lamotrigine, and these data suggest that LEV is more likely to retain patients than other new AEDs. In a recent tertiary care study involving mainly refractory patients, 11% of participants became seizure-free on LEV and nearly two-thirds were retained on long-term treatment. High seizure freedom rates and good tolerability reported with LEV in clinical trials thus appear to translate into improved treatment retention rates in clinical practice.     

The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients

Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency.     

Epilepsy: fractures and the role of cumulative antiepileptic drug load

Beerhorst K, Schouwenaars FM, Tan IY, Aldenkamp AP. Epilepsy: fractures and the role of cumulative antiepileptic drug load.
Acta Neurol Scand: 2012: 125: 54–59.
© 2011 John Wiley & Sons A/S. Background– An association between antiepileptic drugs (AEDs), low bone mineral density (BMD), fractures, and abnormalities in bone metabolism has been suggested for a longer period, although conclusive evidence has not been reported. We aimed at studying patient characteristics in a high‐risk population. Methods – All adult patients from a residential unit of a tertiary epilepsy center who were diagnosed with osteoporosis and consequently treated with a bisphosphonate at that moment were included. Correlations between reported fractures and patient characteristics were explored. Results – Of the total population of 261 adult patients, 54 patients were included resulting in a high prevalence rate of 21% osteoporosis in this population. The number of fractures correlated significantly with ambulatory status (r = ?0.269, P = 0.05), drug load (r = 0.286, P = 0.04), and current number of AEDs (r = 0.283, P = 0.04). Correlations could not be provided for individual drugs in our population as only a minority was on monotherapy and even less patients had always been on monotherapy of the same antiepileptic drug. Linear regression analysis showed that cumulative drug load (defined by a surrogate parameter: the total duration of epilepsy multiplied by the number of AEDs) was the dominant factor explaining the occurrence of fractures. Conclusion – In this high‐risk population, we obtained a positive and strong correlation between the occurrence of fractures in a diagnosed population with osteoporosis and the cumulative drug load of AEDs. This effect seems general, independent of the type of AEDs that were used.     

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study

Objectives – We evaluated long‐term retention rates of newer antiepileptic drugs (AED) in adults with localization‐related epilepsy retrospectively. Methods – We estimated retention rates by Kaplan–Meier method in all 222 patients (age ≥ 16) with localization‐related epilepsy exposed to new AED at the Tampere University Hospital. Results – There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three‐year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. Conclusions – Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.     

Use of antiepileptic drugs in Estonia: an epidemiologic study of adult epilepsy

An evaluation of general antiepileptic treatment patterns and utilization of particular drugs was carried out based on the prevalence study of adult active epilepsy in a sample of the Estonian population. The antiepileptic drugs (AEDs) used, and their doses were recorded and compared with clinical characteristics. Nineteen per cent of the subjects did not take any AED on the prevalence day; 83% of those on medication were taking a single drug, 15% two, and 2% three AEDs. Localization-related symptomatic epilepsies were most frequently treated with AEDs and were also the largest group receiving polytherapy. The most common agent was carbamazepine (68%), followed by barbiturates. Valproate and phenytoin were used much less. The study design and its impact on the interpretation of results is discussed. The percentage of sodium-channel blockers is generally comparable with that reported from other European countries. The small share of valproate is probably a result of the extensive utilization of barbiturates, and is partially related to the age distribution in the study. The high figure of AED-free cases, and small percentage of polytherapy indicates a tendency for undertreatment. Some points for improvement in AED therapy are discussed.     

Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience

PURPOSE: We reviewed the impact of planned discontinuation of antiepileptic drugs (AEDs) in seizure-free patients on seizure recurrence and the seizure outcome of reinstituted treatment. METHODS: A literature review was performed yielding 14 clinical observations of seizure recurrence after discontinuation and its treatment outcome. RESULTS: Seizure recurrence rate after AED discontinuation ranged between 12 and 66% (mean 34%, 95%CI: 27-43) in the 13 reviewed studies (no data in one study). Reinstitution of AEDs after recurrence was efficacious between 64-91% (mean of 14 studies, 80%, 95%CI: 75-85%) at follow-up. Mean follow-up ranged from 1-9 years. Seizure outcome of resumed treatment was not different for series in children and adolescents (84%, mean of 4 studies, 95%CI: 75-93) or in adults only (80%, mean of 9 studies, 95%CI: 74-86). Although seizure control was regained within approximately one year in half of the cases becoming seizure free, it took some patients as many as 5-12 years. In addition, in 19% (mean of 14 studies, 95%CI: 15-24%), resuming medication did not control the epilepsy as before, and chronic drug-resistant epilepsy with many seizures over as many as five years was seen in up to 23% of patients with a recurrence. Factors associated with poor treatment outcome of treating recurrences were symptomatic etiology, partial epilepsy and cognitive deficits. CONCLUSIONS: These serious and substantial risks weigh against discontinuation of AEDs in seizure-free patients, except perhaps for selected patients with idiopathic epilepsy syndromes of childhood or patients with rare seizures.     

Antiepileptic drugs and mechanisms of epileptogenesis. A review

This paper analyzes the effect of conventional (phenobarbital, phenytoin, carbamazepine, ethosuximide, valproate) and some novel (vigabatrin, lamotrigine, felbamate) AEDs on some basic mechanisms involved in focal and/or generalized epileptogenesis (Na⁺ voltage-dependent channels and sustained repetitive firing, L-, N-, and T-type Ca²⁺ currents, GABA-mediated inhibition, Glu/Asp-mediated excitation, after-hyperpolarization). According to this analysis, AEDs can be divided into two main categories, those with only one specific action and those with multiple actions. A speculative correlation is proposed between AED effects on the mechanism of epileptogenesis and their known clinical effect on seizures.

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Sommario Vengono analizzate le azioni dei farmaci antiepilettici convenzionali (fenobarbital, fenitoina, carbamazepina, etosuccimide, valproato) e di quelli appartenenti alla nuova generazione (vigabatrin, lamotrigina, felbamato) sui meccanismi di base implicati nella genesi dell' epilessia focale e/o generalizzata. I meccanismi considerati sono: (1) canali Na⁺ voltaggio-dipendenti e scarica ripetitiva prolungata; (2) correnti Ca²⁺ dipendenti di tipo L, N e T; (3) inibizione GABA-mediata; (4) eccitazione Glu/Asp-mediata; (5) iperpolarizzazione postuma. Sulla base di queste variabili, i farmaci antiepilettici possono essere divisi in due principali categorie, quelli che presentano una sola azione specifica e quelli che agirebbero in più modi. Inoltre, si è cercato di correlare gli effetti che i farmaci antiepilettici hanno sui meccanismi di base dell' epilettogenesi con la loro azione clinica sulle crisi.

     

雄激素与癫痫

动物实验和临床研究均表明性激素与癫癎发作有关,比较肯定的结论认为雌激素水平升高时,可使癫癎发作的阈值降低,加剧癫癎发作;孕激素可使癫癎发作的阈值升高,减轻癫癎发作.但对雄激素与癫癎发作的关系了解甚少,关于雄激素与癫癎关系目前国内尚未见报道,国外报道它们之间的关系亦不一致.睾酮是最重要的雄激素,本文综述了睾酮的代谢和其与癫癎及抗癫癎药物之间的关系.