Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications

Traditional 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.     

Monotherapy trial design: conversion versus de novo.

It is difficult to design valid and well-controlled monotherapy trials that satisfy regulatory requirements and, at the same time, demonstrate the usefulness of a new drug in clinical practice. The conversion design is a drug-substitution trial in which patients with uncontrolled seizures are assigned to add-on treatment with an investigational drug and, usually, an appropriate control, after which pre-existing treatment is gradually discontinued. In the most utilised design, patients are randomised to receive a high dose versus low dose of the new drug, while concomitant medication is gradually discontinued. Exit criteria are predetermined to prevent excessive deterioration of seizures, and treatment retention time is used as the primary outcome variable to measure the effectiveness of the allocated treatments: the goal is to demonstrate higher retention rates in the high-dosage group. Conversion studies may help to fill some gaps in knowledge regarding efficacy and tolerability as monotherapy before larger-scale de-novo studies are started. In the de-novo design, newly diagnosed patients are randomised to receive the investigational drug or an active control. In equivalence (or non-inferiority) trials, the active control is usually an established antiepileptic drug (AED) such as carbamazepine or valproate, and outcome parameters may include proportion of patients achieving a predefined (for example, 6-month) seizure remission or the proportion of patients remaining in the trial (retention rate, a combined measure of efficacy and tolerability). In regulatory trials designed to show a difference, newly diagnosed patients are randomised to a high versus a low dose of the investigational drug, and exit criteria are again predetermined for patients whose seizures are not adequately controlled. In this case, outcome parameters may include time to first seizure in addition to retention in the trial. Comparative monotherapy trials in newly diagnosed patients are relevant to approximately 50% of the patients who develop epilepsy and can be satisfactorily managed with a single drug. These trials allow direct head-to-head comparisons and avoid the confounding effects of baseline drugs and co-medication withdrawal present in conversion studies. Long-term follow-up of patients who are receiving a drug in monotherapy at adequate doses gives the most clinically relevant answers regarding the usefulness of a new drug. It is concluded that the de-novo design is the gold standard when studying AEDs as monotherapy, but the conversion-to-monotherapy design can be used before starting the de-novo program in order to obtain estimates of efficacy and tolerability of the AED as monotherapy in a population of difficult-to-treat patients. With both designs, the use of suboptimal comparators incorporated into some of the regulatory trials is a cause of ethical concern.     

Epilepsy surgery,antiepileptic drug trials,and the role of evidence

Objective: We assessed whether recent randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) are informed by evidence about surgical effectiveness. We explored whether RCTs of AEDs consider the patients’ candidacy for surgery in their eligibility criteria, and whether the necessary investigations are requested in participating patients to determine their potential eligibility for surgery. Methods: We systematically analyzed RCTs published in the last 2 years investigating the efficacy of new AEDs in localization‐related epilepsy. Results from a surgical RCT and recommendations from an epilepsy surgery practice parameter were used to assess the degree to which surgical evidence informed the drug study design. Results: Eleven RCTs were analyzed. All were conducted in countries with access to epilepsy surgery. None of the studies required magnetic resonance imaging (MRI) with an epilepsy protocol or explicit statement of the epilepsy syndrome, which could lead to the identification of surgical candidates. Having temporal lobe epilepsy or being a potential surgical candidate were not exclusion criteria in any of the trials. The primary efficacy end point was the reduction in seizure frequency or responder rate. Seizure freedom was never the primary outcome, and it was reported in only seven studies. The pooled data analysis of these trials revealed that 1.9% of patients became seizure‐free on placebo and 4.4% on the study drug (p < 0.01). Conclusions: Important aspects of patient selection for new AED trials are not informed by the evidence about surgical effectiveness. Investigations that could lead to identification of patients for presurgical evaluation were not required in any of the studies.     

Monotherapy Clinical Trials of New Antiepileptie Drugs: Design, Indications, and Controversies

Summary: The focus in assessing new antiepileptie drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence-based clinical information, regulatory agencies look for efficacy and safety, and the health-care industry demands data on the risk-benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo-controlled, randomized clinical trials as add-on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.     

Characteristics of patients initiated on the new antiepileptic drugs: a PADS study

Whereas randomized controlled trials remain a standard for evaluating and comparing efficacy and safety of the new antiepileptic drugs (AEDs), postmarketing drug research offers a useful means of comparing efficacy and safety of new AEDs. However, differences in baseline characteristics of patients in different drug groups create the potential for bias in drug comparison studies. In this study, baseline demographic characteristics of 1,386 patients initiating lamotrigine (LTG), tiagabine (TGB), or topiramate (TPM) were compared to identify patient characteristics that may influence AED use in epilepsy patients. Data were collected at 14 epilepsy centers and included medications, seizure types and syndromes, and prior adverse events. There were 402 patients in the LTG group, 725 TPM, and 259 TGB. The groups differed both in their number of concurrent AEDs (p<0.001) and in their number of prior AEDs (p<0.01). There was no difference in proportion with partial versus generalized epilepsy syndromes. The groups differed in the proportions of patients with complex partial seizures (p=0.049), primary generalized tonic-clonic seizures (p=0.01), and myoclonic seizures (p=0.03). Baseline behavioral adverse event rate was lowest in patients initiating TPM (p<0.01); LTG patients had the lowest rate of prior AED-related rash (p=0.02). There was no relationship between AED assignment and patient age, age of epilepsy onset, epilepsy duration, institutionalization status, gender, or psychiatric history. Numerous epidemiological differences were identified among patients placed on the new AEDs, including current and prior AED profiles, seizure types, and prior adverse event history. Accounting for these differences is of crucial importance because they may bias conclusions of nonrandomized post-marketing trials comparing the drugs.     

Monotherapy trials: prerequisite data.

Is it possible for an antiepileptic drug (AED) to be effective as add-on therapy in refractory epilepsy but ineffective as monotherapy for the same seizure type(s)? If the answer is 'no', why not award a new AED a monotherapy licence once it has been shown to be effective as adjunctive treatment in placebo controlled, dose-ranging studies in patients with difficult-to-control epilepsy? The recent comparative study between carbamazepine and remacemide, however, suggests that subtle pharmacokinetic/pharmacodynamic interactions between established and new AEDs can indicate efficacy in add-on studies that does not necessarily transfer to monotherapy. There is some evidence that an AED whose primary mechanism of action does not involve blockade of voltage-dependent sodium channels may do less well than carbamazepine in terms of efficacy end-points in a double-blind, head-to-head comparison. These observations lead to the conclusion that monotherapy trials are, indeed, required. They should be undertaken after proof of efficacy has been obtained using a single short presurgical AED withdrawal study backed up by a substantive dose-ranging phase III efficacy trial. There is no reason to recommend earlier assessment since the clinical need for new AEDs is in refractory epilepsy. The subsequent monotherapy trial programme should contain elements utilising comparative and withdrawal designs. Sponsors should be able to seek a licence for their drug either as a first choice treatment in newly diagnosed epilepsy or as substitution monotherapy once treatment with at least one other AED has failed.     

Monotherapy in epilepsy: role of the newer antiepileptic drugs

BACKGROUND: Monotherapy is the goal for pharmacological treatment of epilepsy. Well-controlled trials have established the efficacy of some of the newer antiepileptic drugs (AEDs) as monotherapy. OBJECTIVE: To review clinical data and expert opinions pertinent to the evaluation of most of the newer AEDs as monotherapy for epilepsy. DATA SOURCES: The MEDLINE database was searched for clinical trials using newer AEDs. Reference sections of review articles were manually searched to identify relevant studies not retrieved in MEDLINE. STUDY SELECTION: The resulting list of references was manually reviewed to identify monotherapy studies. RESULTS: Lamotrigine and oxcarbazepine demonstrated efficacy in randomized active-control trials in patients with newly diagnosed epilepsy and in substitution trials in patients refractory to conventional AEDs. CONCLUSION: Lamotrigine and oxcarbazepine are as effective as conventional AEDs at controlling partial seizures and are better tolerated.     

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta‐analysis

Second and third generation AEDs have been directly compared to controlled‐release carbamazepine (CBZ‐CR) as initial monotherapy for new‐onset focal epilepsy. Conversely, no head‐to‐head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta‐analysis (NMA). Randomized, double‐blinded, parallel group, monotherapy studies comparing any AED to CBZ‐CR in adults with newly diagnosed untreated epilepsy with focal‐onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment‐emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ‐CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR‐CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6‐ and 12‐month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ‐CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ‐CR (OR 0.659, 95% CrI 0.428‐0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ‐CR     

Data from regulatory studies: what do they tell? What don't they tell?

Phase III studies of antiepileptic drugs (AEDs) are specifically designed to satisfy strict regulatory criteria. As they are conducted in protocol-restricted patient populations over short treatment periods and employ fixed study designs and dosing schedules, they are not fully representative of 'real-life' clinical practice. Therefore, in order to provide an overall assessment of clinical performance, regulatory studies must be backed up by post-marketing clinical experience. Phase IV studies provide information on a drug's performance in a setting more closely representing real clinical practice, with broader patient populations and a more flexible approach to individual treatment. Prospective long-term studies allow the determination of efficacy and safety (and cost-effectiveness) over extended treatment periods; these studies and audit data provide a means of assessing idiosyncratic side effects, unusual interactions and the effects of an AED in rare patient groups. By complementing regulatory evidence with real-life clinical experience, a comprehensive assessment of the risks and benefits of an AED can be made.     

Translating monotherapy trials into clinical practice: a look into the abyss

To be approved for monotherapy by regulatory authorities, new antiepileptic drugs (AEDs) must first be tested in well-controlled studies in refractory patients (conversion to monotherapy trials) or in patients with newly diagnosed epilepsy. However, the applicability of the information obtained in these trials to day-to-day clinical practice is limited. Clinical trials in newly diagnosed patients, particularly those allowing dose flexibility, offer more useful information, but a close scrutiny of methodological details is required to avoid misinterpretation of the findings. In many instances, the neurologist has a drug with a label, but lacks critical information on optimal titration rates, optimal target and maintenance dosages, response rates in populations with different epilepsy syndromes, different age ranges and comorbidities, and long-term safety data. Such information becomes available only through general clinical experience, well-designed phase IV studies, and postmarketing surveillance.     

Comparative bioethics in bipolar and epilepsy research.

RATIONALE: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed. METHOD: Comparative analysis and literature review of bipolar and epilepsy research designs. RESULTS: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs. CONCLUSIONS: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator.     

Innovative Designs of Controlled Clinical Trials in Epilepsy

Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.     

Interrater reliability of the international consensus definition of drug-resistant epilepsy: a pilot study

We evaluated the interrater reliability of the consensus definition of drug-resistant epilepsy proposed by the International League Against Epilepsy. According to the definition framework, outcome of each antiepileptic drug (AED) trial was categorized as "seizure freedom" or "treatment failure." This level 1 assessment was used to determine the level 2 classification, which defined drug-resistant epilepsy as the failure of adequate trials of two or more AED schedules to achieve sustained seizure freedom. Two raters classified treatment outcomes of 150 patients independently. The patients had received a total of 428 trials of AEDs. Categorization of level 1 outcome to individual AED trials by the raters was consistent in 413 (96.5%). For the level 2 classification of drug-resistant or drug-responsive epilepsy, there was absolute agreement between the raters in 141 patients (94%), with a κ index of 0.91 (P<0.001). The definition appeared to have a high degree of interrater reliability in this setting.     

Adults with Epilepsy: Is Monotherapy the Only Answer?

Summary: Monotherapy with antiepileptic drugs (AEDs) should be the aim in most patients with epilepsy and is achievable in most newly diagnosed cases. "Rational po-lytherapy" is a valuable new concept that can be usefully applied to a minority of patients. Assessment of new AEDs as monotherapy is a challenging problem, and appropriate clinical trial methodology is currently evolving. Although tiagabine (TGB) is established as an effective add-on agent in refractory partial epilepsy, its role in monotherapy is not yet clear. Preliminary studies suggest that TGB is effective and well tolerated as monotherapy. Ongoing large monotherapy studies should establish the comparative efficacy and tolerability of TGB vs. conventional AEDs.     

Levetiracetam is as effective as carbamazepine in newly diagnosed epilepsy

Evaluation of: Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 6, 402-408 (2007). Despite the emergence of multiple antiepileptic drugs (AEDs) in the past decade, the task of choosing the right drug for monotherapy in patients with newly diagnosed epilepsy remains a precarious task. This is especially true when trying to choose a new AED over a more traditional agent. Much of this uncertainty stems from the fact that there are only a handful of studies that are able to demonstrate efficacy of a new drug over an older AED. While the newer drugs appear more favorable because of better tolerability, safety profiles and simple pharmacokinetics, many do not have an indication for monotherapy. Of course, this is further contingent upon the stringent limitations placed by regulatory bodies, such as the US FDA, who govern approval of AEDs for monotherapy. The current randomized study attempts to evaluate the efficacy of levetiracetam in monotherapy compared with controlled-release carbamazepine, a gold standard in patients with newly diagnosed epilepsy.     

Topiramate in refractory epilepsy: a prospective observational study

PURPOSE: This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic. METHODS: One hundred seventy patients (82 men, 88 women, aged 18-75 years) with refractory localization-related (n = 134) or idiopathic generalized epilepsy (n = 36) were started on adjunctive TPM using a standard titration schedule. TPM was introduced after a 3-month prospective baseline, and doses were adjusted according to clinical response. End points were seizure freedom for 6 months, > or =50% seizure reduction for 6 months compared with baseline at the highest tolerated TPM dose (responder), or discontinuation of TPM because of side effects, lack of efficacy, or both. RESULTS: Thirty-nine (23%) patients were seizure-free, and 80 (47%) more patients had a useful therapeutic response. Thirteen seizure-free patients and 16 responders took 100 mg of TPM daily or less. TPM was discontinued in 51 (30%) patients. The most common side effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Concomitant antiepileptic drugs (AEDs) were stopped in 30 patients. Twelve were established on TPM monotherapy, eight of whom remained seizure-free. Final TPM doses and concentrations varied widely among the three outcome groups. CONCLUSIONS: TPM was efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use. A good response was obtained in many patients with TPM doses substantially lower than those studied in regulatory clinical trials. The wide variation in dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.     

Efficacy of New Antiepileptic Drugs

Regarding efficacy of new antiepileptic drugs (AEDs) for seizure control, there are three important clinical questions. How effective are new AEDs when corrected for the efficacy of placebo? And even more important: How do new AEDs fare in terms of seizure remission compared with established agents? And finally: Have patients seizure-free on new AEDs a better chance for lasting remission after withdrawal versus those withdrawing from older agents? The answers raise concerns. Although add-on therapy with marketed new AEDs is more effective than placebo, as expected, the treatment difference for becoming seizure-free is disappointingly small (6%; 95% CI: 4–8%; z = 6.47; p < 0.001). Although many, but not all, new AEDs have comparable efficacy to old standard drugs in well-controlled trials, none of the new AEDs is superior to old drugs in terms of seizure remission. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course. The sobering results suggest the need for novel experimental and clinical strategies for the development of more effective new AEDs that interrupt ictogenesis more effectively and prevent or abort epileptogenesis. Ideally, we need new drugs that block both ictogenesis and epileptogenesis, resulting in complete cure of epilepsy.Although a large number of new antiepileptic drugs (AEDs) that suppress or prevent seizures are now available, about 30 to 40 percent of the patients, children as well as adults, remain resistant to drug treatment (1). The situation is even worse for a range of severe epilepsy syndromes of infancy and adolescence. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course (2). The introduction of each new AED into the market raises valid expectations in patients and physicians for more effective treatment of epilepsy. Although safety, tolerability, and lack of interactions are important, better efficacy is a crucial feature for a new AED. This brief review is limited to a discussion of the efficacy of new versus old AEDs. In that respect, three questions are of particular clinical interest: How effective are new AEDs when corrected for the efficacy of placebo? And even more relevant: Are new AEDs more often leading to seizure remission compared with established agents? And finally: Can more patients maintain seizure remission after withdrawal of new AEDs compared with withdrawal of older agents? The following brief overview, which is not a comprehensive literature review, outlines the available evidence on the efficacy of modern AEDs based on randomized controlled trials of marketed modern AEDs.     

Seizure freedom with different therapeutic regimens in intellectually disabled epileptic patients.

BACKGROUND: Epilepsy is a frequent condition in persons with intellectual disability and is more often difficult to treat than in the average population. Seizure freedom is the primary therapeutic goal which has important implications for the patient's quality of life. The aim of this study was to find out which antiepileptic therapy regimens (monotherapy or combination therapy) are effective in achieving this goal in intellectually disabled epilepsy patients. We were especially interested in the impact of the new antiepileptic drugs (AEDs) which were introduced during the past decade. METHOD: We investigated retrospectively the antiepileptic regimens on which the resident patients of a large epilepsy centre (as a rule with additional intellectual disabilities of different degrees) were seizure free in 2002. Information on antiepileptic medication and seizure frequency was taken out of the individual case documentation. It was also determined whether seizure free patients had already been seizure free in 1992. RESULTS: Two hundred and forty out of 675 patients (35,6%) with epilepsy were seizure free. The proportion of seizure freedom was 43,7% in patients with borderline intelligence, 39,2% in mild, 33,2% in moderate, 31,9% in severe, and 21,9% in profound intellectual disability. One hundred and twenty-two (50,8%) seizure free patients were on monotherapy; 53 of them were on CBZ (PB: 34, VPA: 25, PHT: 7, LTG: 3). Ninety-three patients (38,7%) were on duotherapies, CBZ/PB (27 patients), PB/PHT (17), and LTG/VPA (14) being the commonest. Of 18 (7,5%) triple therapies, LTG/PB/VPA (4 patients) was the commonest. Taken together, the five most frequent therapeutic regimens were CBZ monotherapy, PB monotherapy, CBZ/PB, VPA monotherapy and PB/PHT (a clear preponderance of classic AEDs). A distinction was made between "old seizure free" (seizure free already in 1992) and "new seizure free" (in 1992 still seizures) patients. In the 132 old seizure free patients the classic AEDs prevailed again, monotherapies with CBZ, PB and VPA being the most frequent regimens. In comparison, in the 78 new seizure free patients the novel combination LTG/VPA was the third most frequent, after the classic regimens CBZ/PB and CBZ; PB monotherapies were rare. CONCLUSION:In a majority of intellectually disabled patients with epilepsy (including those who became seizure free since 1992), complete seizure control has been achieved by monotherapy or duotherapy with classic AEDs. Of the new AEDs LTG in combination with VPA appears to be an important innovation.     

The long term retention of levetiracetam in a large cohort of patients with epilepsy

Levetiracetam (Lev) is a new antiepileptic drug with a distinct mechanism of action, shown in regulatory trials to be effective. These controlled trials do not always predict how useful a drug will be in day to day clinical practice. Retention rates can provide a better indication of efficacy and tolerability in everyday use. Patients attending a tertiary referral centre for epilepsy and who received Lev in the first 2 years of its marketing were assessed (n = 811) to determine continuation rates of treatment with this drug. At the last follow up, 65% of patients were still taking Lev, and the estimated 3 year retention rate was 58%. In total, 11% attained seizure freedom of at least 6 months. Patients taking greater numbers of concurrent antiepileptic drugs (AEDs) were more likely to discontinue Lev, and those reaching higher maximum daily dosages were less likely to discontinue Lev. The retention rate for Lev compares favourably with that of other new AEDs.