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Medscape

BACKGROUND: More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures. METHODS: We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year. RESULTS: Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent). CONCLUSIONS: Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.

Early Identification of Refractory Epilepsy

Summary Assessment of long-term outcomes is essential in brain surgery for epilepsy, which is an irreversible intervention for a chronic condition. Excellent short-term results of resective epilepsy surgery have been established, but less is known about long-term outcomes. We performed a systematic review and meta-analysis of the evidence on this topic. To provide evidence-based estimates of longterm results of various types of epilepsy surgery and to identify sources of variation in results of published studies, we searched Medline, Index Medicus, the Cochrane database, bibliographies of reviews, original articles and book chapters to identify articles published since 1991 that contained >20 patients of any age, undergoing resective or non-resective epilepsy surgery, and followed for a mean/median of >5 years. Two reviewers independently assessed study eligibility and extracted data, resolving disagreements through discussion. Seventy-six articles fulfilled our eligibility criteria, of which 71 reported on resective surgery (93%) and five (7%) on non-resective surgery. There were no randomized trials and only six studies had a control group. Some articles contributed more than one study, yielding 83 studies of which 78 dealt with resective surgery and five with non-resective surgery. Forty studies (51%) of resective surgery referred to temporal lobe surgery, 25 (32%) to grouped temporal and extratemporal surgery, seven (9%) to frontal surgery, two (3%) to grouped extratemporal surgery, two (3%) to hemispherectomy, and one (1%) each to parietal and occipital surgery. In the non-resective category, three studies reported outcomes after callosotomy and two after multiple subpial transections. The median proportion of long-term seizure-free patients was 66% with temporal lobe resections, 46% with occipital and parietal resections, and 27% with frontal lobe resections. In the long term, only 35% of patients with callosotomy were free of most disabling seizures, and 16% with multiple subpial transections remained free of all seizures. The year of operation, duration of follow-up and outcome classification system were most strongly associated with outcomes. Almost all long-term outcome studies describe patient cohorts without controls. Although there is substantial variation in outcome definition and methodology among the studies, consistent patterns of results emerge for various surgical interventions after adjusting for sources of heterogeneity. The long-term (>5 years) seizure free rate following temporal lobe resective surgery was similar to that reported in short-term controlled studies. On the other hand, long-term seizure freedom was consistently lower after extratemporal surgery and palliative procedures.

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Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

/pdf/antiepileptic-drugs-best-practice-guidelines-for-therapeutic-2fvwrwdstw.pdf

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

Nearly a quarter of patients with seizures have drug-resistant epilepsy. This review examines how this diagnosis should be established and how to recognize pseudoresistance. It explains possible mechanisms of drug-resistant epilepsy and presents treatment strategies.

/pdf/drug-resistant-epilepsy-4fqrkkd7mq.pdf

Drug-Resistant Epilepsy

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.

New avenues for anti-epileptic drug discovery and development

Despite the development of various new antiepileptic drugs (AEDs) since the early 1990s, the available evidence indicates that the efficacy and tolerability of drug treatment of epilepsy has not substantially improved. What are the reasons for this apparent failure of modern AED development to discover drugs with higher efficacy? One reason is certainly the fact that, with few exceptions, all AEDs have been discovered by the same conventional animal models, particularly the maximal electroshock seizure test (MES) in rodents, which served as a critical gatekeeper. These tests have led to useful new AEDs, but obviously did not help developing AEDs with higher efficacy in as yet AED-resistant patients. This concern is not new but, surprisingly, has largely been unappreciated for several decades. A second-admittedly speculative-reason is that progress in pharmacologic treatment of drug-resistant epilepsy will not be made unless and until we develop drugs that specifically target the underlying disease. Although better preclinical approaches will not be able to circumvent regulatory requirements, more efficacious drugs may allow us to abandon clinically questionable trials with intentionally less efficacious controls and noninferiority designs, and require evidence for comparative effectiveness. The failure of AED development has led to increasing disappointment among clinicians, basic scientists, and industry and may halt any further improvement in the treatment of epilepsy unless we find ways out of this dilemma. Therefore, we need new concepts and fresh thinking about how to radically change and improve AED discovery and development. In this respect, the authors of this critical review will discuss several new ideas that may hopefully lead to more efficacious drug treatment of epilepsy in the future.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2011.03024.x

Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.

Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2005.54904.x

Drug resistance in epilepsy : Putative neurobiologic and clinical mechanisms

It is not well known how often drug resistance, a major clinical problem, occurs early or late in the course of epilepsy and how often epilepsy follows a continuous, remitting or relapsing-remitting pattern. To provide evidence if, in fact, different patterns of evolution of drug resistance and remission exist, a prospective, long-term population-based study of 144 patients followed on the average for 37.0 years (SD 7.1, median 40.0, range 11-42) since their first seizure before the age of 16 years was performed. At the end of follow-up, 67% of 144 patients were in terminal remission, on or off antiepileptic drugs. Early remission, starting within the first year of treatment, was seen in 45 patients (31%). In 23 (16%) of them, first remission continued, uninterrupted by relapse, to terminal remission. Late remission with a mean delay of 9 years was achieved by a further 72 patients (50%), including 46 (32%) patients who achieved terminal remission without any relapse and suggested, together with 23 patients, a remitting course. Following a relapse after early or late remission, 28 (19%) patients achieved terminal remission, suggesting a remitting-relapsing pattern. Altogether 20 patients (14%) did not re-enter remission, indicating a worsening course of epilepsy. Twenty-seven (19%) patients were drug-resistant from the start to the end of follow-up. In conclusion, half the patients with childhood-onset epilepsy will eventually enter terminal remission without relapse and a fifth after relapse. One-third will have a poor long-term outcome in terms of persistent seizures after remission or without any remission ever.

Dieter Schmidt

Papers

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

New avenues for anti-epileptic drug discovery and development

Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.

Drug resistance in epilepsy : Putative neurobiologic and clinical mechanisms

Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study