1,721,309 research outputs found
Monotherapy trials with the new antiepileptic drugs: Study designs, practical relevance and ethical implications
No full textTraditional randomized clinical trials for the monotherapy assessment of antiepileptic drugs (AED) involve allocation of newly diagnosed patients to long-term treatment with different AEDs in order to determine remission rates and side effect profile. Apart from being time-consuming, however, these trials are unlikely to show significant differences in seizure control between the various drugs, which may lead some regulatory agencies to argue that remission rates could be related to the natural history of the disease rather than to efficacy of the administered drugs. To circumvent this problem, a number of innovative designs for the monotherapy assessment of new AEDs have been developed in recent years. They all share the common feature of being aimed at demonstrating a difference in response rate over a short treatment period between a high dosage of a new AED and some form of suboptimal treatment (placebo or low-dose active control). Patients allocated to suboptimal treatment show unacceptable seizure control more rapidly than patients on high-dose active treatment and therefore they exit the trial at a faster rate: evidence of antiepileptic activity is therefore based on demonstration of differences in rate of deterioration rather than improvement. These trials are conducted with titration schedules, dosages and durations of treatment which are totally unrelated to optimal use of the same AEDs in routine clinical practice. No comparative data with an established reference agent are provided, and allocation of patients to suboptimal treatment raises serious ethical concerns. For these reasons, justification for the continued implementation of these trials is questionable. Randomized long-term comparative trials should be considered the gold-standard for the monotherapy assessment of new AEDs. A review of the literature, however, reveals that long-term trials with new AEDs completed to date had significant shortcomings in their design, including excessively rigid or inappropriate dosing schedules, enrollment of patients with heterogeneous seizure disorders, low statistical power and insufficient duration of follow-up. Because these studies are usually aimed at addressing regulatory requirements, the information obtained cannot be meaningfully applied to routine clinical practice. Large longer-term randomized comparative trials using more pragmatic approaches are highly needed to determine the real value of first-line therapy with new AEDs in patients with well defined seizure disorders.
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The pharmacological treatment of epilepsy in adults.
No full textTreatment decisions in epilepsy need to be individualised on the basis of careful analysis of the risk-benefit ratio of each available option. Key decision steps include the time at which antiepileptic drug treatment should be started, which drug should be chosen for first-line therapy, and which strategy is most appropriate for people who did not respond to the initially prescribed drug. With more than 20 antiepileptic drugs currently available to treat epilepsy in adults, opportunities to tailor drug therapy have never been greater, but optimum use of such a complex armamentarium is a challenge even for the epilepsy specialist. Antiepileptic drug choice is primarily based on evidence of efficacy and effectiveness for the individual's seizure type, but other patient-specific factors need to be considered, including age, sex, childbearing potential, comorbidities, and concomitant medications
Major birth defects after exposure to newer-generation antiepileptic drugs.
No full textnon disponibil
Navigating through signals towards foetal and maternal health: The challenge of treating epilepsy in pregnancy
No full textA rational approach to the treatment of women of childbearing potential with epilepsy has been hampered by the lack of conclusive data on the comparative teratogenic potential of different antiepileptic drugs (AEDs). Although, several cohort studies on birth defects associated with AED use during pregnancy have been published, these have generally failed to demonstrate differences in malformation rates between AEDs, probably mainly due to insufficient power. In particular, pregnancies with new generation AEDs have been too few. In recent years, pregnancy registries have been introduced to overcome this problem--EURAP (an international collaboration), the North American, and the U.K. AED and pregnancy registries are observational studies that prospectively assess pregnancy outcome after AED exposure using slightly different methods. Each has enlisted 3-5,000 pregnancies in women with epilepsy, and the North American and the U.K. have released preliminary observations. Thus the U.K. registry reported a higher malformation rate with valproate, 5.9% (4.3-8.2%; 95% CI), than with carbamazepine, 2.3% (1.4-3.7%), and lamotrigine, 2.1% (1.0-4.0%). Most of the more recent cohort studies have also identified a nonsignificant trend toward a higher teratogenicity with valproate. These signals need to be interpreted with some caution since none of the studies to date have fully assessed the impact of possible confounders, such as type of epilepsy, family history of birth defects, etc. However, with increasing number of pregnancies it should be possible in the near future for the pregnancy registries to take such confounding factors into account and thus make more reliable assessments of the causal relationship between exposure to specific AEDs and teratogenic risks. While awaiting more conclusive results, it appears reasonable to be cautious in prescribing valproate to women considering to become pregnant if other suitable treatment alternatives, and with less teratogenic potential, are available. Any attempt to change treatment should, however, be accomplished well before conception. The importance of maintained seizure control must also be kept in mind, and the woman who needs valproate to control her seizures should not be discouraged from pregnancy, provided that counseling at the best of available knowledge is given
Teratogenicity of antiepileptic drugs
No full textPurpose of review
We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure.
Recent findings
Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation.
Summary
The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception
Old versus new antiepileptic drugs: the SANAD study.
No full textComment on
The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. [Lancet. 2007]The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, et al.
Lancet. 2007 Mar 24; 369(9566):1016-26. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. [Lancet. 2007]The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, et al.
Lancet. 2007 Mar 24; 369(9566):1000-15
Increased risk of epilepsy in biopsy-verified celiac disease: a population-based cohort study.
No full textOBJECTIVES:
Celiac disease (CD) is associated with several neurologic disorders but it is unclear whether CD is associated with epilepsy. We therefore investigated whether biopsy-verified CD is associated with epilepsy.
METHODS:
Cohort study. Using biopsy report data from all Swedish pathology departments (n = 28), we identified individuals with CD who were diagnosed from 1969 to 2008 (Marsh 3: villous atrophy). Through Cox regression, we calculated hazard ratios (HRs) for epilepsy (defined as a diagnosis of epilepsy in the Swedish National Patient Register) in 28,885 individuals with CD and 143,166 controls matched for age, sex, calendar period, and county.
RESULTS:
Individuals with CD were at an increased risk of future epilepsy (HR = 1.42; 95% confidence interval [CI] = 1.24-1.62) (272 individuals with CD had a diagnosis of epilepsy vs an expected 192). The absolute risk of future epilepsy in patients with CD was 92/100,000 person-years (excess risk = 27/100,000 person-years). This risk increase was seen in all ages, including children with CD. The HR for having at least 2 interactions with health care due to epilepsy was 1.41 (95% CI = 1.19-1.66). When we restricted epilepsy to those with both a diagnosis of epilepsy and an independent record of antiepileptic drug prescriptions, CD was associated with a 1.43-fold increased risk of epilepsy (95% CI = 1.10-1.86).
CONCLUSION:
Individuals with CD seem to be at a moderately increased risk of epilepsy
Malformations in the offspring of pregnant women with epilepsy. Presentation of an international registry of antiepileptic drugs and pregnancy (EURAP)
No full textThe interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy
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