The pharmacological treatment of epilepsy in adults

doi:10.1016/S1474-4422(11)70047-3

The Lancet Neurology

Volume 10, Issue 5, May 2011, Pages 446-456

https://doi.org/10.1016/S1474-4422(11)70047-3 Get rights and content

Summary

Treatment 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.

Introduction

10% of people will have at least one seizure in their lifetime, and about a third of them will go on to develop epilepsy.1, 2 In terms of both prevalence and cumulative incidence, epilepsy is one of the most common serious neurological disorders, with the same burden of disease as lung cancer in men or breast cancer in women.³ It has been estimated that, in Europe alone, the costs attributable to active epilepsy exceed €20 billion per year.⁴ In addition to psychosocial disability and seizure-related injuries, epilepsy is associated with other comorbidities, including depression and increased mortality.⁵ In a population-based cohort⁶ that was followed up for 40 years since childhood, overall mortality in people with epilepsy was 24%—three-times the rate expected in the general population—and more than half the deaths were related to epilepsy itself, including sudden unexpected death (SUDEP) in a third of all fatalities.

Because of the seriousness of the disorder and its epidemiological dimension, it is of concern that epilepsy is often suboptimally diagnosed and managed, even in the European region.⁷ Conceptual and practical considerations for the medical management of epilepsies in children were reviewed in this journal in 2008.⁸ However, most people with epilepsy are adults, with features that are specific to their age group. Studies in recent years have provided new grounds for rational management of these patients. Here, we focus on the pharmacological treatment of this disorder in adults by addressing a number of key questions, including indications for starting treatment, initial drug selection, strategies when treatment fails, and risks and benefits of withdrawal of treatment in seizure-free patients.

Section snippets

When should treatment be started?

Antiepileptic drugs (AEDs) are the mainstay of the treatment of epilepsy, and although their number has expanded exponentially, current principles governing drug therapy are in many ways similar to those established a century ago.⁹ Because AED therapy is typically maintained for several years and often for life, particularly in adults, a decision to initiate treatment has far-reaching consequences and needs to be based on careful risk-benefit analyses.¹⁰

The predicted efficacy of AEDs has to be

Which AED should be chosen for initial treatment?

The ultimate goal of epilepsy treatment is lasting freedom from seizures without adverse effects. Therefore, selection of the first AED should be guided primarily by evidence of efficacy for the patient's seizure type or epilepsy syndrome and by tolerability considerations, preferably on the basis of data from well designed randomised controlled trials. The proportion of patients who remain on the allocated AED for a period of time, often referred to as effectiveness, provides a combined

Which formulation?

Some AEDs are available as sustained-release formulations. At least for carbamazepine, sustained-release tablets offer superior tolerability to immediate-release formulations when a twice daily schedule is used.⁶⁶ The same evidence is not available for most other AEDs, and the introduction of modified-release formulations is often motivated by marketing considerations rather than demonstration of any clinical advantage.

For many AEDs, there is also a choice between trade names and generics. A

Which dosage?

Correct dosage is as important as choice of the most appropriate drug. For most AEDs, a gradual dose titration can improve CNS tolerability, reduce the risk of idiosyncratic adverse reactions, or both.⁶⁴ Therefore, unless an immediate anti-seizure effect is required, treatment is generally started with a low dose, which is then increased with time. The optimal duration of the titration period varies with type of AED, selected target maintenance dose, and individual response (table 4).

Ideally,

What is the next course of action when initial monotherapy fails?

About 50% of a typical adult population will achieve sustained seizure freedom without intolerable side-effects on the initially prescribed AED.⁷¹ If the initial monotherapy fails, subsequent management should take into account a number of factors. If the first AED had to be discontinued because of an idiosyncratic reaction, an alternative AED should be tried. Care should be taken to avoid, if possible, drugs that are likely to show crossreactivity for the same reaction. For example, if an

How should drug-refractory patients be managed?

Patients who do not achieve sustained seizure freedom after adequate trials of at least two appropriate AEDs, given alone or in combination, meet ILAE criteria for pharmacoresistance as defined in a 2010 position paper.⁷⁹ The rationale for this definition is that the probability of seizure freedom on another AED decreases in proportion to the number of drugs tried unsuccessfully in the past, and is probably no greater than 20% after failure of two such drugs.71, 75, 76 The main objective of the

Should AEDs be discontinued in seizure-free patients?

Discontinuation of AED treatment might be considered after at least 2–4 years of seizure freedom, but only after careful discussion with the patient about associated risks and potential benefits. Consideration should be given not only to prognostic factors, but also to the presence of adverse effects from ongoing medication, the individual's lifestyle, and the patient's attitude towards both continuation of treatment and the possibility of relapse.26, 99

In general, the risks of seizure

Conclusions

The key to optimum epilepsy management is to adapt treatment decisions to the characteristics of the individual. In general, AED monotherapy is indicated after two seizures, but in high-risk patients initiation of treatment after one seizure might be justifiable. AED choice is determined by seizure type, adverse-effect profile, and patient-specific features, including age, sex (with special reference to childbearing potential), and comorbidities. Dose titration and dosing regimens also need to

Search strategy and selection criteria

References for this Review were identified through searches of PubMed until Feb 28, 2011, with the search terms “epilepsy”, “treatment”, “antiepileptic drugs”, “efficacy”, “effectiveness”, “adverse effects”, and “humans”. References were also identified from relevant review articles and through searches of the authors' files. Only articles published in English were reviewed. The final reference list was based on relevance to the topics covered in the Review.

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Cited by (247)

Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials
2024, eClinicalMedicine
Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area.
We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130).
A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400 mg/d was top-ranked, followed by RTG 1200 mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d. Regarding tolerability, LCM 600 mg/d had the lowest ranking, followed by CNB 400 mg/d. For the safety outcome of AEs, ESL 1200 mg/d was ranked lowest, followed by CNB 400 mg/d. Regarding SAEs, LCM 400 mg/d was ranked lowest, followed by RTG 1200 mg/d.
ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS.
None.
Structural insights of novel mutational frames in Bromodomain Containing-2 gene (BRD2) in juvenile myoclonic epilepsy: bed, bench, and laptop profiles
2023, Epilepsy and Behavior
Juvenile myoclonic epilepsy (JME) is an adolescent onset type of idiopathic generalized epilepsies. Bromodomain containing protein-2 gene (BRD2), a transcriptional regulatory protein, has a susceptible role in the expression of JME. Considering the polymorphic variations observed in exon 3 of the BRD2 gene, we evaluated the molecular interactions with anti-seizure medication in individuals diagnosed with JME.
The genomic DNA was extracted from 5 mL of peripheral venous blood of JME participants (n = 55) and healthy control subjects (n = 55). Detailed anti-seizure medication and outcomes were noted during the study period. Identified novel mutations at nucleotide and protein sequences, compared by multiple sequence alignment. Wild-type (WT) and mutated-type (MT) structures were investigated for molecular docking and interactions with anti-seizure drugs.
A common variant at c.1707G>A was found among 23 participants, while a single variant at c.1663ins C was found in one participant. The deletion positions were observed at c.1890delA, c.1892A>T, c.1895A>T, c.1896G>T, c.1897T>C, c.1898T>C, c.1899C>T, c.1900G>T, c.1901C>T and c.1902A>T exhibiting stop codon after p.111Pro>stop; these variants resulted in a truncated protein. In silico analysis was conducted to validate changes; docking analysis showed that novel variant has a significant role in the interactions with anti-seizure drugs.
Besides clinical and genetic outcomes, ∼5.45% unique genetical variations were observed in the participants. Significant mimicked at the binding site position (92–111) of human BRD2 ranges ∼8.2%, ∼16.4%, and ∼10.6%. Further, research is needed to identify the importance of polymorphism alterations at the binding site and their molecular interactions with anti-seizure drugs, which might be confirmed in a diverse population with JME.
No short-term mortality from benzodiazepine use post-acute ischemic stroke after accounting for bias
2023, Journal of Clinical Epidemiology
Older adults receive benzodiazepines for agitation, anxiety, and insomnia after acute ischemic stroke (AIS). No trials have been conducted to determine if benzodiazepine use affects poststroke mortality in the elderly.
We examined the association between initiating benzodiazepines within 1 week after AIS and 30-day mortality. We included patients ≥65 years, admitted for new nonsevere AIS (NIH-Stroke-Severity[NIHSS]≤ 20), 2014–2020, with no recorded benzodiazepine use in the previous 3 months and no contraindication for use. We linked a stroke registry to electronic health records, used inverse-probability weighting to address confounding, and estimated the risk difference (RD). A process of cloning, weighting, and censoring was used to avoid immortal time bias.
Among 2,584 patients, 389 received benzodiazepines. The crude 30-day mortality risk from treatment initiation was 212/1,000 among patients who received benzodiazepines, while the 30-day mortality was 34/1,000 among those who did not. When follow-up was aligned on day of AIS admission and immortal time was assigned to the two groups, the estimated risks were 27/1,000 and 22/1,000, respectively. Upon further adjustment for confounders, the RD was 5 (−12 to 19) deaths/1,000 patients.
The observed higher 30-day mortality associated with benzodiazepine initiation within 7 days was largely due to bias.
Anti-seizure medications and quality of life in person with epilepsy
2022, Heliyon
The goal of this study was to determine the effects of mono-, bi-, and polytherapy anti-seizure medications (ASMs) in terms of seizure reduction and quality of life (QOL) in persons with epilepsy (PWE).
A cross-sectional observational study was conducted. All PWE with age <75 years were recruited and further classified into two groups: responders and non-responders, based on the response of the ASMs to the treatments for reduced seizure frequency since the last one year. Other demographic and clinical data such as seizure frequency, type of seizures, age at onset of seizures, and information about ASMs with their daily doses were assessed for the descriptive analysis. The quality of life was assessed in randomly selected PWE (n = 100) using the quality of life in epilepsy inventory-31 (QOLIE-31) in adults.
With a total of 486 PWE, the median age (years) was comparable in both groups. Out of these the non-responders group was found to be significantly higher (77.8%) than the responders group (22.2%). In the responders group, the percentage of PWE who were on monotherapy was significantly higher (51.85 %) than those who were on polytherapy (17.59%), whereas in the non-responders group, 21.16% of PWE were on monotherapy and 44.86% were on polytherapy. The duration of epilepsy was similar in both groups, but the average seizure frequency was significantly higher in the non-responders. In QOL assessments, 43% of PWE were observed in the responders group, whereas 57% of PWE were found in the non-responders group. The overall comparative QOL scores were also significantly higher (p < 0.0001) in the responders group as compared to the non-responders group.
Our findings revealed that those PWE who were on monotherapy showed better reduction in seizure frequency and improved QOL in responder groups as compared to non-responder groups.
Association between anti-seizure medication and the risk of lower urinary tract infection in patients with epilepsy
2022, Epilepsy and Behavior
The aim of this retrospective study was to analyze the incidence of lower urinary tract infections (LUTI) and antibiotic prescriptions within 12 months after initial prescription of anti-seizure medication (ASM) between January and December 2020 (index date) and to investigate the association between a broad spectrum of ASMs and the risk of LUTI in patients with epilepsy.
This retrospective cohort study included a total of 9186 adult patients (≥18 years) with an initial diagnosis of epilepsy and a prescription of an ASM treated in 1284 general practices in Germany between January 2010 and December 2020 (index date). Six frequently prescribed ASMs with at least 1000 available patients were analyzed. Patients treated with one of six ASMs were matched to each other by propensity scores based on sex, age, and secondary diagnoses. Cox regression models were used to analyze the association between the use of ASM and LUTI risk.
The cumulative LUTI incidence 12 months after the start of therapy was highest in patients treated with pregabalin (16.7%), followed by valproate (11.6%) and gabapentin (10.2%). A similar trend was observed for LUTI with antibiotic prescription (9.2% pregabalin, 6.8% valproate, 6.8% gabapentin). Conditional regression analyses revealed that pregabalin therapy was significantly positively associated with LUTI (HR: 1.76; 95% CI 1.29–2.39) and LUTI-based antibiotic prescription (HR: 2.16; 95% CI 1.43–3.27). Carbamazepine was associated with a significantly lower incidence of LUTI in women (HR: 0.47; 95% CI: 0.30–0.75), but not in men. No significant associations were observed for other ASMs.
The present study identifies a significant positive association between ASM and LUTI incidence and antibiotic prescriptions in patients with epilepsy treated with pregabalin, whereas a protective effect was found for carbamazepine in women only. No significant associations were observed for the four remaining ASMs.
Neurologists’ knowledge of and attitudes toward physical exercise for people with epilepsy in Latin America
2022, Epilepsy and Behavior
Despite the favorable effects of exercise in people with epilepsy (PWE), the lower participation in physical/sports activities may be partly due to inadequate knowledge and attitudes of health professional about their benefits. In this regard, in 2016, the International League Against Epilepsy (ILAE) through its Task Force on Sports and Epilepsy published a consensus paper that provided general guidance concerning participation in exercise/sport activities for PWE. We investigated views and attitudes toward physical exercise practice among neurologists in Latin America.
A 22-item cross-sectional online questionnaire-based study among neurologists included the following: (1) profile of participating neurologists, (2) doctors’ attitudes and perceptions about physical/sport activities for PWE, and (3) neurologist experience concerning patient’s report about their involvement in physical/sport activities.
In total, 215 of 519 neurologists from 16 different countries returned the questionnaire. Although about one-third of neurologists had no information about the effect of exercise on epilepsy, and 60% of them did not know the published recommendations of the ILAE Task Force on Sports and Epilepsy, the majority (92.5%) advised the practice of exercise, were aware of sport activities for their patients and agreed that exercise can reduce comorbidities associated with epilepsy (X² = 249.34; p < 0.001). Most of the neurologists did not believe that exercise is a seizure-inducing factor, but more than half would restrict their patients with uncontrolled seizures for exercise practice (X² = 250.77; p < 0.001). Most barriers considered by PWE in the past, currently are not viewed by neurologists and their patients (X² = 249.34; p < 0.001).
While this study reveals that neurologists have some knowledge gaps in attitudes toward physical exercise for PWE, encouraging attitudes were observed by neurologists. Considering that physicians can impact on patient confidence and decision, a better communication between neurologists and their patients concerning the benefits of exercise can increase PWE participation in physical/sports activities. To improve this scenario, more efforts should be made to increase the neurologists’ knowledge and perceptions on this issue.

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ReviewThe pharmacological treatment of epilepsy in adults

Summary

Introduction

Section snippets

When should treatment be started?

Which AED should be chosen for initial treatment?

Which formulation?

Which dosage?

What is the next course of action when initial monotherapy fails?

How should drug-refractory patients be managed?

Should AEDs be discontinued in seizure-free patients?

Conclusions

Search strategy and selection criteria

Epilepsy Res

Lancet Neurol

Epilepsy Res

Lancet Neurol

Lancet

Lancet Neurol

Epilepsy Res

Lancet

Lancet

Lancet

Epilepsy Res

Epilepsy Res

Epilepsy Behav

Lancet Neurol

Epilepsy Res

Lancet Neurol

Lancet Neurol

Neurol Clin

Seizure

Epilepsy Res

Lancet Neurol

Epilepsy Res

Epilepsy Behav

Epilepsy and seizure statistics

Estimating risk for developing epilepsy. A population-based study in Rochester, Minnesota

Neurology

Bringing epilepsy out of the shadows

BMJ

Epilepsy in the WHO European region (2010)

Long-term mortality in childhood-onset epilepsy

N Engl J Med

Epilepsy must become a higher priority in Europe

Lancet Neurol

Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909–1958

Epilepsia

The risk of seizure recurrence following a first unprovoked seizure: a quantitative review

Neurology

Risk of recurrent seizures after two unprovoked seizures

N Engl J Med

Epileptic seizure and epilepsy: definitions proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)

Epilepsia

Guidelines for epidemiological studies on epilepsy

Epilepsia

Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic clonic seizure

Neurology

Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy

Neurology

Treatment of the first tonic-clonic seizure does not affect long-term remission of epilepsy

Neurology

Quality of life outcomes of immediate or delayed treatment of early epilepsy and single seizures

Neurology

When to start antiepileptic drug treatment and with what evidence?

Epilepsia

ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

Epilepsia

Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Epilepsia

Clinical guideline 20 the epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care

Diagnosis and management of epilepsy in adults. A national clinical guideline. updated Oct 20, 2005

Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy

Neurology

Introduction to the choice of antiepileptic drugs

Epilepsia

Antiepileptic drug use of women with epilepsy and congenital malformations in offspring

Neurology

The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies

Aust N Z J Obstet Gynecol

Review
The pharmacological treatment of epilepsy in adults