Epilepsy treatment in Rett syndrome

Rett syndrome is a neurodevelopmental disorder predominately affecting females. The majority of patients have epilepsy in the early stages of the disease. This study evaluates the clinical course of epilepsy and the effect of antiepileptic drug treatment in Rett syndrome using retrospective data analysis. Epilepsy was present in 16 of 19 (84%) patients with Rett syndrome in this series. The mean age of seizure onset was 4 years. Remission of seizures was achieved after the first monotherapy in 56% and after the second monotherapy in 18.5% of patients. Valproate, lamotrigine, and carbamazepine were the drugs used most frequently as monotherapy. Valproate monotherapy was highly effective as 75% of treated patients achieved seizure remission. Monotherapy with lamotrigine or carbamazepine was effective in half of the treated patients. There was a clear tendency toward seizure remission after the age of 15 years.     

Monotherapy trials in antiepileptic drugs: are modified "presurgical studies" a way out of the dilemma?

Monotherapy trials in epilepsy are confronted with a dilemma: either they are in conflict with ethical requirements, or they are scientifically not meaningful. Monotherapy trials, which are performed as controlled studies randomizing patients to ineffective (pseudo)placebo treatment, are incompatible with the Helsinki Declaration. On the other hand, equivalence or noninferiority studies using an active-control design do not permit valid conclusions on the efficacy of the test drug. Therefore, they do not fulfill scientific requirements for trials on new drugs. As an alternative approach, a monotherapy trial design for epilepsy patients undergoing presurgical evaluation was outlined. During presurgical evaluation, antiepileptic drugs are routinely tapered down for seizure recording. This situation is used for a placebo-controlled short-term monotherapy trial. Four trials according to this design have been completed so far. Recently, several points of concern have been raised against this design, especially for matters of ethics and external validity. In the present article, these objections are outlined and discussed. In the proposed modification the randomization and the titration of the test drug or control begins prior to the presurgical investigations. The advantages are: the test drug does not have to be titrated quickly, pure monotherapy conditions are achieved, and the subjects do not have to experience more seizures than are required for the presurgical evaluation.     

Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study

PURPOSE: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure. METHODS: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months. RESULTS: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences. CONCLUSIONS: No differences were found in overall neurotoxicity between monotherapy and polytherapy.     

Challenging epilepsy with antiepileptic pharmacotherapy in a tertiary teaching hospital in Sri Lanka

The goal of antiepileptic drug (AED) therapy is to achieve a seizure-free state and eliminate the medical and psychosocial risks of recurrent seizures. Burden of epilepsy on the economy of a country may be largely due to the expenditure on AEDs. The adverse effects may influence the compliance to AEDs and effective control of epilepsy. We determined the pattern of AED use, the degree of epileptic control achieved and the adverse effects experienced by the epileptics in a Tertiary Teaching Hospital in Sri Lanka. Carbamazepine was found to be the most frequently used AED. Monotherapy was used on 70.8% of subjects. 86.27% of the study sample had achieved effective control of epilepsy with a 50% or more reduction in seizure frequency. Of them 72.64% were on monotherapy and they were either on carbamazepine, sodium valproate, phenytoin sodium or phenobarbitone. None of the new AEDs were prescribed to these patients. 50.9% on monotherapy and 51.5% on polytherapy reported adverse effects. Somnolence followed by headache was found to be the most frequently reported adverse effects by those on monotherapy and polytherapy both. This study shows that most epileptics can be effectively managed with the conventional AEDs with clinical monitoring.     

Rational polytherapy

Monotherapy has been considered the gold standard for drug treatment of epilepsy. However, there is renewed interest in polytherapy because of the advent of new drugs with fewer drug interactions and novel mechanisms of action, and the realization that most patients with refractory epilepsy are eventually treated with drug combinations. Careful consideration must be given to drug additions and conversions; it may be less risky to add a drug than to convert from one monotherapy to another in patients with frequent or severe seizures. Rational choice of drug combinations is, at present, based more on avoidance of pharmacodynamic or pharmacokinetic side effects than on evidence for supra-additive efficacy. There are indications that combinations of two sodium-channel blocking agents are less effective than combinations of drugs with different primary mechanisms of action, and some human studies suggest that lamotrigine and valproate may be synergistic for efficacy. However, more animal and human research is needed, with attention to the effects of various combinations on both toxicity and seizure control.     

Factors That Preclude the Successful Use of Monopharmacy in the Medical Treatment of Patients with Epilepsy

Abstract: A neurologist conducted research efforts for more than 12 years as a step toward the establishment of monotherapy for epilepsy. Of 406 patients with epilepsy, seizures could be controlled for more than one year in 72% and for more than 3 years in 54%. Monotherapy was given to 57% of all the patients with a success rate of 54%. Factors that were found likely to interfere with a reduction in antiepileptic drug therapy to one drug modality included: symptomatic etiology, prolonged duration of illness, low age at onset and secondary generalized epilepsy with a large number of seizures in combination, for generalized epilepsies; symptomatic etiology, prolonged duration of illness, low age at onset, other than occipital lobe origin, complex partial seizure with secondary generalization, temporal lobe epilepsy with associated automatisms, elementary sensorimotor seizure and high frequency of seizures, for partial epilepsies. In addition to these factors relevant to the nature of epilepsies, other factors apparently unrelated to the disease process, e.g., liability of polypharmacy to produce side effects precluding dosage elevation, patient's rejection to reduce drug and the inability of a physician to treat the patient properly for want of information, were also recognized to exist.     

Factors that preclude the successful use of monopharmacy in the medical treatment of patients with epilepsy

A neurologist conducted research efforts for more than 12 years as a step toward the establishment of monotherapy for epilepsy. Of 406 patients with epilepsy, seizures could be controlled for more than one year in 72% and for more than 3 years in 54%. Monotherapy was given to 57% of all the patients with a success rate of 54%. Factors that were found likely to interfere with a reduction in antiepileptic drug therapy to one drug modality included: symptomatic etiology, prolonged duration of illness, low age at onset and secondary generalized epilepsy with a large number of seizures in combination, for generalized epilepsies; symptomatic etiology, prolonged duration of illness, low age at onset, other than occipital lobe origin, complex partial seizure with secondary generalization, temporal lobe epilepsy with associated automatisms, elementary sensorimotor seizure and high frequency of seizures, for partial epilepsies. In addition to these factors relevant to the nature of epilepsies, other factors apparently unrelated to the disease process, e.g., liability of polypharmacy to produce side effects precluding dosage elevation, patient's rejection to reduce drug and the inability of a physician to treat the patient properly for want of information, were also recognized to exist.     

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     

Historical control monotherapy design in the treatment of epilepsy

Purpose: Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled “withdrawal to monotherapy” in treatment‐resistant patients, which employs a so‐called “pseudo‐placebo” as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo‐placebo. Such an approach reduces patient risk that would result from exposure to pseudo‐placebo. In this article, we present the data submitted to the FDA to justify a historical control. Methods: We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan‐Meier estimates of the percent exiting were calculated at 112 days. Results: The percent meeting exit criteria were uniformly high, ranging from 74.9–95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed‐effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval. Conclusion: There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo‐placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment‐resistant patients.     

Zonisamide monotherapy for epilepsy in children and young adults

Several of the newer antiepilepsy drugs have not been tested as monotherapy in controlled trials. Zonisamide is a broad-spectrum antiepilepsy drug indicated for the adjunctive treatment of partial seizures in adults. However, several small, open-label studies have indicated that it may be safe and effective as monotherapy. The present chart review study was conducted to evaluate the safety and effectiveness of zonisamide monotherapy in a pediatric and young adult patient group. Patient records at the Blue Bird Circle Clinic for Pediatric Neurology were reviewed to identify patients receiving zonisamide monotherapy. Efficacy was assessed from seizure diaries and patients' subjective evaluations. Safety and tolerability were evaluated by analysis of adverse events and change in body weight. The study included 131 patients aged 1 to 21.8 years with a broad spectrum of seizure types and epilepsy syndromes. A total of 101 patients (77.1%) achieved a 50% or greater decrease in seizure frequency, including 39 patients who achieved seizure freedom. Zonisamide monotherapy was well tolerated, with three patients (2.3%) discontinuing for adverse events. These results support open-label studies from Japan reporting that zonisamide monotherapy is safe and effective in pediatric and young adult patients.     

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.     

Trial duration and follow-up.

The chronic nature of most seizure disorders requires that antiepileptic drugs (AEDs) be administered for many years. Therefore, new drugs should be evaluated over a period sufficient to assess potential development of tolerance as well as long-term safety. While patients and prescribers desire extensive long-term data prior to registration, too stringent requirements would discourage industry's investment into new treatments, and a compromise between these stakes should be sought. In add-on studies, it is recommended that patients completing double-blind assessment be offered indefinite open-label treatment, and that safety data be collected prospectively. Monotherapy trials in refractory patients include presurgical and conversion to monotherapy studies. Duration of assessment in these studies rarely exceeds few weeks, and endpoints relate to seizure deterioration rather than improvement; this surrogate measure of efficacy is not necessarily predictive of clinical usefulness and, in view of ethical concerns, the rationale for these studies should be questioned. There may be scope, however, for alternative study designs whereby refractory patients are converted to monotherapy and followed up for several months. Active-control long-term monotherapy trials in newly diagnosed patients represent the mainstay for evaluating efficacy and safety. In patients with partial or generalized tonic-clonic seizures, most trials conducted to date had a duration of 6-12 months, but this period may be insufficient to assess seizure freedom rates at optimized dosages, and at least one 2-year trial would be desirable. With respect to open-label follow-up, many protocols require that the randomization code not be broken until the database has been sealed. Patients completing blind assessment are often forced through unblinding procedures which involve tapering of trial medication and institution of an open-label therapy which may differ, in dosage or type of medication, from that taken previously. In view of ethical concerns, the rationale for this practice should also be questioned.     

Long-term treatment with gabapentin for partial epilepsy.

Gabapentin was studied as an open-label 'add-on' antiepileptic drug in 35 patients with partial seizures. Follow-up at 6 months, 12 months, 18 months, and 24 months is reported. There was a trend toward improvement in simple (SPS) and complex partial seizures with it reaching significance for SPS at 12 and 24 months and for the weighted combination of seizures at 3 months. Five of nine patients were subsequently successfully converted to gabapentin monotherapy. Of those five, one is now seizure free and three are significantly improved since baseline. One remains with unchanged seizure frequency compared to baseline, but is experiencing less toxicity than at that time. This long-term observation suggests that the short-term effect demonstrated in blinded studies continues and that indeed some patients with refractory epilepsy can be maintained on gabapentin alone. Based on these findings, double-blind monotherapy trials of this drug are presently being conducted.     

Adjunctive Therapy in Resistant Epilepsy

Summary: : It is now established that the overall prognosis for epilepsy is good and that remission will occur in at least 75% of patients following adequate treatment with monotherapy. Patients who fail to respond to monotherapy, who are not suitable for surgery, and who continue to have frequent seizures may have to be considered for an alternative drug regimen. A review of the literature indicates that complete seizure control with adjunctive treatment is rare, but improved seizure control can be obtained in up to 40% of patients. In a study of clobazam as adjunctive treatment, 60% (N = 20) of our patients responded to treatment initially and 33% maintained an improvement over an 18-month period. In 31 patients who failed to respond to carbamazepine as monotherapy, primidone (N = 16) or valproate (N = 15) were prescribed as adjunctive treatment. One patient obtained complete freedom from seizures and 14 (45%) had a > 50% reduction in seizure frequency. Suggested indications for the use of additive treatment in epilepsy are discussed.     

Topiramate Monotherapy for Partial Onset Seizures

Summary: Purpose: Evaluation of topiramate (TPM) as monotherapy in patients with uncontrolled partial onset seizures.
Methods: A total of 48 patients were evaluated in a doubleblind, parallel-group trial. During a 56-day baseline period, patients had at least eight partial onset seizures while being treated with one or two standard antiepileptic drugs (AEDs). After 1–2 weeks of open-label treatment with TPM 100 mg/day, patients were randomly assigned, in equal proportions, to receive double-blind therapy with TPM 100 or 1,000 mg/day in a 5-week conversion and an 11-week monotherapy period. The study endpoint was completion of 112 study days (success) or fulfillment of one or more exit criteria: doubling of average 28- day or highest 2-day baseline seizure rate, a generalized tonic-clonic seizure (GTCS) if none had occurred at baseline, or significant prolongation of generalized seizure duration.
Results: Time until exit was longer (p = 0.002) and success frequency was higher (p = 0.005) with TPM 1,000 as compared with 100 mg/day. Seizure-rate reductions of 50, 75, or 100% were achieved by 46, 25, and 13% of the 1,000-mg/day group, respectively, as compared with 13, 8, and 0% of the 100-mg/day group, respectively. Most adverse events (AE) were mild or moderate in severity.
Conclusions: Monotherapy with TPM 1,000 mg/day for partial onset seizures with or without secondarily generalized seizures was effective, with a favorable safety profile.     

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.     

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

OBJECTIVE: This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. METHODS: This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician's choice). Patients were converted during an 相似文献   

Zonisamide monotherapy in a multi-group clinic.

OBJECTIVE: Reports on zonisamide monotherapy are limited despite favourable preliminary data, and typically restricted to tertiary referral centres. The goal of this study is to report clinical experience with zonisamide monotherapy in a large, multi-group clinic setting. METHODS: We reviewed the charts of patients treated with zonisamide monotherapy in the Neurology Department of the Kelsey-Seybold Clinic (Houston, Texas) during an 18-month period. We analysed subgroups of patients who were naive to antiepileptic drug (AED) therapy (Group 1) and those who had previous exposure to AEDs (Group 2). RESULTS: The study included 54 paediatric and adult patients with a variety of seizure types: 15 patients in Group 1 and 39 patients in Group 2. Mean maintenance zonisamide dosages in the two groups were similar (193 mg/day in Group 1 vs. 218 mg/day in Group 2). Thirty-eight patients (70.4%) continued zonisamide monotherapy, with 7 patients (13.0%) adding a second AED and 9 patients (16.7%) switching to a different drug. Of the 24 patients who became seizure free on zonisamide monotherapy, 11 were on the 100-mg initial dosage. Zonisamide monotherapy was well tolerated. CONCLUSIONS: Zonisamide monotherapy is safe and effective for a variety of seizure types and may be appropriate as first-line therapy in some cases.     

Long-term treatment with oxcarbazepine in clinical practice

Oxcarbazepine (up to 1800 mg daily orally) was given for 12 months to 61 adult epileptic patients in clinical practice, as monotherapy (n=52) or adjunctive therapy (n=9). Patients on monotherapy became seizure-free (76.9%) or experienced > or = 75% seizure rate reduction, with two exceptions. In the adjunctive therapy group, one patient became seizure-free and two experienced a 50-75% seizure rate reduction. These seizure-free rates are higher than those reported in the literature. The drug was well tolerated; only two patients withdrew because of intolerance (3.3%). Long-term data is essential when evaluating a drug for lifelong treatment. This study contributes to the growing body of 12-month evidence on oxcarbazepine.     

Valproate in children with newly diagnosed idiopathic generalized epilepsy

Holland KD, Monahan S, Morita D, Vartzelis G, Glauser TA. Valproate in children with newly diagnosed idiopathic generalized epilepsy.
Acta Neurol Scand: 2010: 121: 149–153.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Sparse information on dose–response characteristics for initial antiepileptic drug monotherapy in children with idiopathic generalized epilepsy (IGE) is available. The aim of this study is to characterize the therapeutic dose of valproate in children with newly diagnosed IGE. Materials and methods – Effect of initial valproate monotherapy and doses associated with seizure freedom were examined in consecutive children with IGE identified from a New Onset Seizure Clinic. Results – Of 84 patients identified, 48 (57%) became seizure‐free on valproate monotherapy and another 10 patients became seizure‐free but discontinued VPA because of adverse effects. The mean dose in seizure‐free children was 15.7 mg/kg/day and over 95% of IGE patients will respond below 25 mg/kg/day. Conclusions – Half of children became seizure‐free on valproate monotherapy and did so at modest doses.