Standard And New Antiepileptic Drug Research Articles

Newer versus older antiseizure medications: further forward?

Since 1990, many new antiseizure medications have been launched. Many have been licensed on the basis of evidence from add-on therapy in resistant epilepsies; there have been few head-to-head comparative data in patients who are newly diagnosed. 1 Lattanzi S Zaccara G Giovannelli F et al. Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand. 2019; 139: 33-41 Crossref PubMed Scopus (46) Google Scholar Findings from Standard and New Antiepileptic Drugs (SANAD) I, the first SANAD trial, provided the first comprehensive data to address this question; lamotrigine was shown to be superior to carbamazepine, gabapentin, oxcarbazepine, and topiramate in time to treatment failure, 2 Marson AG Al-Kharusi AM Alwaidh M et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007; 369: 1000-1015 Summary Full Text Full Text PDF PubMed Scopus (677) Google Scholar and valproate was a clinically and cost-effective alternative to lamotrigine or topiramate. 3 Marson AG Al-Kharusi AM Alwaidh M et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007; 369: 1016-1026 Summary Full Text Full Text PDF PubMed Scopus (645) Google Scholar However, since these trials were done, other medications have been licensed for use, and levetiracetam has been increasingly considered a safe alternative in the treatment of both focal and generalised epilepsies, despite few head-to-head comparative data, 4 Shih JJ Whitlock JB Chimato N Vargas E Karceski SC Frank RD Epilepsy treatment in adults and adolescents: expert opinion, 2016. Epilepsy Behav. 2017; 69: 186-222 Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar specifically with the increasing concern about the effect of valproate in pregnancy on the unborn child. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trialThese findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Full-Text PDF Open AccessThe SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trialCompared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Full-Text PDF Open Access

Identification of patients who will not achieve seizure remission within 5 years on AEDs.

ObjectiveTo identify people with epilepsy who will not achieve a 12-month seizure remission within 5 years of starting treatment.MethodsThe Standard and New Antiepileptic Drug (SANAD) study is the largest prospective study in patients with epilepsy to date. We applied a recently developed multivariable approach to the SANAD dataset that takes into account not only baseline covariates describing a patient's history before diagnosis but also follow-up data as predictor variables.ResultsChanges in number of seizures and treatment history were the most informative time-dependent predictors and were associated with history of neurologic insult, epilepsy type, age at start of treatment, sex, and having a first-degree relative with epilepsy. Our model classified 95% of patients. Of those classified, 95% of patients observed not to achieve remission at 5 years were correctly classified (95% confidence interval [CI] 89.5%–100%), with 51% identified by 3 years and 90% within 4 years of follow-up. Ninety-seven percent (95% CI 93.3%–98.8%) of patients observed to achieve a remission within 5 years were correctly classified. Of those predicted not to achieve remission, 76% (95% CI 58.5%–88.2%) truly did not achieve remission (positive predictive value). The predictive model achieved similar accuracy levels via external validation in 2 independent United Kingdom–based datasets.ConclusionOur approach generates up-to-date predictions of the patient's risk of not achieving seizure remission whenever new clinical information becomes available that could influence patient counseling and management decisions.

Treatment outcome after failure of a first antiepileptic drug.

Objectives:We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes.Methods:SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes.Results:Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure.Conclusions:A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.

A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine

At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.

The reliability and validity of the Revised Liverpool Impact of Epilepsy Scale for use in people with new-onset epilepsy

The Impact of Epilepsy Scale was designed to assess the perceived impact of epilepsy on a number of different aspects of daily life. Following criticisms of the scale's content and focus, it was revised to incorporate an amended response continuum and additional items. A total of 1534 people with epilepsy completed the revised scale, along with other quality-of-life (QOL) measures, as part of the Standard and New Antiepileptic Drugs (SANAD) trial (Marson et al., 2007a,b) [9,10]. The revised scale had good reliability (internal consistency alpha coefficient of .83) and acceptable validity (concurrent and known-groups). Floor and ceiling effects were negligible. Therefore, the Revised Liverpool Impact of Epilepsy Scale is a reliable and valid instrument for assessing the perceived impact of epilepsy in people with new-onset epilepsy.

New and old: notable drug developments for clinical practice

Which drug to use and when for a particular condition is frequently a complex issue relating to individual patient characteristics and circumstance. However, it seems that it was only relatively recently that this quandary was a luxury more commonly associated with non-neurological diseases. However, the last 30 years has seen the exponential development of therapeutic interventions for neurological disease together with increasing and possibly excessive use of trial-related acronyms. Given current requirements for complex trial construction and meeting of regulatory demands, the development of a novel proven therapeutic intervention in area of need is no mean task and commonly followed by a prolonged period where indications are refined and then a more pragmatic analysis of treatment algorithms ensues. In Journal Club, this month we examine results for a new oral treatment for relapsing multiple sclerosis (MS) in the form of a placebo-controlled trial of laquinimod. It is perhaps a statement of advances made in MS treatments to date that this trial may finally herald the end of the placebo arm in controlled trials in relapsing MS. The results of this trial by contemporary standards, while demonstrating some limited effectiveness, might be considered disappointing. In turn, this then begs the question as to where the place of laquinimod might be in the expanding arsenal of treatments for relapsing disease. Secondly, we look at a head-to-head trial of intravenous alteplase and a potential alternative thrombolytic agent for acute ischaemic stroke. Finally, we review the latest output from the SANAD (Standard and New Antiepileptic Drug) trial, which examines prognostic factors for time to treatment failure across a wide range of standard antiepileptic drug interventions for focal epilepsy.

Antiepileptic Drug Comparison: More Details

In the Standard and New Antiepileptic Drug (SANAD) trial (JW Gen Med Apr 10 2007), 1721 patients with suspected focal epilepsy were randomized equally to carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate, to compare outcomes with the newer medications versus the older medication (carbamazepine). Now, researchers have conducted a post hoc analysis of the data to determine clinical factors that affect the probabilities of treatment failure and of achieving 12-month remission. Time to treatment failure was …

Levels of epilepsy stigma in an incident population and associated factors

We assess the psychometric properties of a revised stigma scale and report the levels of stigma in an incident population and the clinical, demographic, and quality-of-life factors associated with doing so. A total of 1566 people with new-onset epilepsy completed the revised stigma scale, as part of the Standard and New Antiepileptic Drugs (SANAD) trial. The revised scale had good internal consistency (0.85) and good concurrent validity. It also reduced the floor and ceiling effects associated with the original scale. Fifty-four percent of people reported feeling stigmatized (47.3% mild–moderate stigma, 6.1% high stigma). Reduced sense of mastery, younger age (< 50), side effects of medication, poorer cognitive function, feeling socially restricted, poor global quality of life, and more than four seizures at baseline were significant factors determining scores on this revised scale. These should be the focus of interventions to try and reduce feelings of stigma in those with new-onset epilepsy.

Self‐reported and parent‐reported quality of life of children and adolescents with new‐onset epilepsy

To investigate the self-reported quality of life (QOL) of children and adolescents with new-onset epilepsy and explore parent's perceptions of their child's QOL and the impact of epilepsy on the family. As part of the Standard and New Antiepileptic Drug (SANAD) trial, 248 children (aged 8-15 years) with new-onset epilepsy and their parents completed batteries of QOL measures. Children completed the KINDL and subscales of the QOLIE-AD-48. Parental questionnaires included the Rutter Parent Scales, Adverse Events Profile, and subscales of the Child Health Questionnaire. Compared with published norms, children with epilepsy had significantly poorer QOL across multiple domains compared with healthy children and children with asthma. Parents, particularly of younger children and those with other long-term health problems, were affected by their child's health or behavior, which affected their emotional well-being and time for their own needs. Children with new-onset epilepsy, particularly those with comorbid conditions, are at risk of reduced QOL at the time of diagnosis. It is important that children with epilepsy and their families are assessed for psychosocial problems so that early intervention can be undertaken.

Factors predictive of resilience and vulnerability in new-onset epilepsy

Epilepsy has been associated with reduced quality of life (QOL), but QOL outcomes are heterogeneous. Some people are able to maintain a good QOL despite poorly controlled epilepsy and others report poor QOL despite well-controlled epilepsy. Maintaining a good QOL in the face of adversity is embodied by the concept of resilience. We explored the factors associated with having a resilient outcome in people with epilepsy (PWE). Our definition of adversity included socioeconomic disadvantage as well as continuing seizures. We analyzed data collected as part of the Standard and New Antiepileptic Drugs (SANAD) trial. At the end of 4-year follow-up, patients were classified into four groups on the basis of seizure control (good/poor) and socioeconomic status (advantaged/disadvantaged). We identified individuals with resilient and vulnerable outcomes and the factors associated with having them. Seizure control was more important in determining QOL than material advantage, but socioeconomic status appeared to act as an additional protective or risk factor for QOL. Significant predictors of a resilient outcome were absence of depression and fewer adverse treatment effects at 4 years and good QOL at baseline. Significant predictors of a vulnerable outcome were fair/poor health perception, presence of depression, reduced sense of mastery, and more adverse treatment effects at follow-up. Reducing the adverse effects of treatment, along with psychosocial interventions to increase self-mastery, reduce health concerns, treat depression, and promote positive adjustment to a diagnosis will likely improve the QOL of PWE despite less favorable clinical and socioeconomic circumstances.

The Association Between Polymorphisms in RLIP76 and Drug Response in Epilepsy

Approximately 30% of patients with epilepsy are resistant to treatment with anti-epileptic drugs (AEDs). The ABC drug transporter proteins are hypothesized to mediate drug resistance in epilepsy. More recently, a non-ABC putative transporter, RLIP76, has also been proposed to be involved in the mechanism of pharmacoresistance. One previous association study of six polymorphisms in RLIP76 failed to find any association with drug resistance in a retrospective cohort of epilepsy patients. We aimed to look for an association with outcomes reflecting drug response in a larger prospective cohort, with gene-wide coverage. We investigated the role of common polymorphisms in RLIP76 in epilepsy pharmacoresistance by genotyping 23 common RLIP76 polymorphisms in a prospective cohort of 503 epilepsy patients, from the standard and new anti-epileptic drugs (SANAD) prospective study of new and old AEDs. A total of 13 of these were tested for association with four outcomes reflecting response to drugs: time to first seizure, time to 12-month remission, time to withdrawal due to inadequate seizure control, and time to withdrawal due to unacceptable adverse drug events. No significant associations, allowing for multiple testing, were found in the whole cohort. There was also no effect in a subgroup of patients on carbamazepine, which is thought to be a RLIP76 substrate, although two polymorphisms were associated with time to first seizure (p = 0.007). We failed to demonstrate any association between RLIP76 polymorphisms and four different measures of drug response in the larger cohort, but a subgroup analysis of patients receiving carbamazepine suggested an association that should be investigated further. Our data suggest that common variants in RLIP76 are unlikely to contribute to epilepsy drug response.

The influence of competing-risks setting on the choice of hypothesis test for treatment effect

There is considerable debate regarding the choice of test for treatment difference in a randomized clinical trial in the presence of competing risks. This question arose in the study of standard and new antiepileptic drugs (SANAD) trial comparing new and standard antiepileptic drugs. This paper provides simulation results for the log-rank test comparing cause-specific hazard rates and Gray's test comparing cause-specific cumulative incidence curves. To inform the analysis of the SANAD trial, competing-risks settings were considered where both events are of interest, events may be negatively correlated, and the degree of correlation may differ in the 2 treatment groups. In settings where there are effects in opposite directions for the 2 event types, a likely situation for the SANAD trial, Gray's test has greater power to detect treatment differences than log-rank analysis. For the epilepsy application, conclusions were qualitatively similar for both log-rank and Gray's tests.