Research progress of vagus nerve stimulation in the treatment of epilepsy

The International League Against Epilepsy (ILAE) defined drug‐resistant epilepsy (DRE) that epilepsy seizure symptoms cannot be controlled with two well‐tolerated and appropriately chosen antiepileptic drugs, whether they are given as monotherapy or in combination. According to the WHO reports, there is about 30%‐40% of epilepsy patients belong to DRE. These patients need some treatments other than drugs, such as epilepsy surgery, and neuromodulation treatment. Traditional surgical approaches may be limited by the patient's clinical status, pathological tissue location, or overall prognosis. Thus, neuromodulation is an alternative choice to control their symptoms. Vagus nerve stimulation (VNS) is one of the neuromodulation methods clinically, which have been approved by the Food and Drug Administration (FDA). In this review, we systematically describe the clinical application, clinical effects, possible antiepileptic mechanisms, and future research directions of VNS for epilepsy.     

Severe new seizures after initiation of vagus nerve stimulation therapy

Vagus nerve stimulation is considered to be a safe and effective adjunctive therapy for patients with drug-resistant epilepsy. Contrary to some antiepileptic drugs, vagus nerve stimulation is not known to precipitate or aggravate new or preexisting seizures. We describe the emergence of a new type of disabling, recurrent partial seizure immediately after initiation of vagus nerve stimulation in a 51-year-old man with a known history of refractory partial epilepsy. Discontinuation of vagus nerve stimulation therapy and multiple antiepileptic drug interventions were required to abort these unexpected new seizures. We conclude that vagus nerve stimulation may induce paradoxical seizures, similarly to some antiepileptic drugs.     

Place of antiepileptic drug combinations

Over almost 3 millennia, epilepsy was often treated with combinations of agents that were believed at the time of their use to have antiepileptic properties. Bromide, the first really effective remedy for epilepsy, became available in the latter half of the 19th century. After that time, even if some of the previously available agents were employed simultaneously with bromide, there was what amounted to de facto drug monotherapy until other efficacious antiepileptic drugs began to appear from 1912 onwards. Thereafter, antiepileptic drug combinations were widely used until 20 years ago, when pharmacokinetic principles and plasma drug concentration monitoring began to be applied to the treatment of epilepsy. It then soon became clear that skilfully optimized antiepileptic drug monotherapy usually provided satisfactory control of epileptic seizures. Unfortunately, some antiepileptic drug monotherapy failures still occurred. Consequently, with growing knowledge of the molecular mechanisms underlying antiepileptic drug action, and recognition of the apparent success of antiepileptic drug combinations during the clinical trial testing of new antiepileptic agents in monotherapy-resistant patients, the possibilities of rationally-based antiepileptic drug combinations have begun to be considered again. The effectiveness of such combinations and their optimal pattern of use in clinical practice remain to be established.     

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.     

Opinion of Belgian neurologists on antiepileptic drug treatment in 2006: Belgian study on epilepsy treatment (BESET‐2)

Objectives – (i) To describe the medical treatment of epilepsy in Belgium in 2006, (ii) to detect the presence or absence of consensus in epilepsy treatment and (iii) to analyze the evolution of the neurologists’ opinion between 2003 and 2006. Materials and methods – In December 2006, 100 neurologists were interviewed with a structured questionnaire, based on ordinal four‐point scales. The questionnaire contained questions on treatment choices in adult patients with epilepsy. The results of this survey were compared with results of a previous one done in 2003. Results – Initial monotherapy was the preferred treatment strategy. Valproate was first choice in idiopathic generalized epilepsy. Carbamazepine and oxcarbazepine were first choice in focal epilepsy with partial seizures. Valproate was also first choice in focal epilepsy with secondarily generalized seizures. New antiepileptic drugs were recommended in second line. However, in special treatment situations, they were considered first‐line, e.g. lamotrigine in case of women in childbearing age. In comparison with 2003, there was a trend of using earlier the new antiepileptic drugs. Conclusions – In end 2006, carbamazepine, valproate and oxcarbazepine were considered to be first choice drugs, whereas other newer drugs, like lamotrigine, levetiracetam and topiramate were predominantly prescribed in second line.     

Lacosamide use in refractory idiopathic primary generalized epilepsy

Treatment of refractory idiopathic primary generalized epilepsy can be very challenging, with limited drug options, especially in young women of childbearing age. Here we describe the cases of two young women with refractory idiopathic primary generalized epilepsy refractory to multiple antiepileptic drugs in monotherapy or combination before achieving a long-term remission with adjunctive lacosamide (LCS) treatment. Larger, randomized prospective studies are necessary to establish the effectiveness of lacosamide in these patients.     

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   

Polytherapy, Monotherapy, and Carbamazepine

Summary: Despite the widespread and traditional use of polytherapy in the treatment of epilepsy, there is little evidence of its advantages over monotherapy. Among other undesirable effects, it can produce subtle cognitive and behavioral changes and sometimes even exacerbate the epilepsy. Recent studies provide evidence that in many patients seizures can be controlled by carefully monitored monotherapy: Approximately 75% of newly diagnosed, previously untreated epileptic patients will enter a 2-year remission with this form of treatment. The theory has even been advanced that early control of seizures may help prevent the evolution of drug-resistant, chronic epilepsy. In some patients with chronic epilepsy, multiple-drug therapy can be reduced to single-drug treatment, usually with an improvement in cognitive function and without increase in seizures. Trials conducted to date have shown no evidence of superiority of any one major antiepileptic drug over another in control of a particular seizure type. The choice of antiepileptic drug for monotherapy may therefore be influenced by differences in toxic effects associated with individual agents. On the basis of clinical and psychometric evidence, carbamazepine has been shown to cause fewer adverse effects than other antiepileptic drugs on cognitive function, mood, and behavior.     

The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies

OBJECTIVE: To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined. METHODS: All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates. RESULTS: 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%). CONCLUSIONS: Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.     

Comparison of levetiracetam and oxcarbazepine monotherapy among Korean patients with newly diagnosed focal epilepsy: A long‐term,randomized, open‐label trial

This open‐label, multicenter, randomized phase IV trial (NCT01498822) of noninferiority design compared the long‐term effectiveness, safety, and tolerability of levetiracetam (LEV) monotherapy with those of oxcarbazepine (OXC) monotherapy in adults with newly diagnosed focal epilepsy. Korean patients (16–80 years), with ≥2 unprovoked focal seizures in the year preceding the trial, who had not taken any antiepileptic drugs (AEDs) in the last 6 months, were randomized to receive LEV or OXC (1:1). Effectiveness, safety, and tolerability were assessed over a 50‐week period. Treatment failure rates (per protocol set) were 15/118 (12.7%) in the LEV‐treated group and 30/128 (23.4%) in the OXC‐treated group, an absolute difference of ?10.7% (95% confidence interval [CI] ?20.2, ?1.2). Because the upper 95% CI limit was less than the pre‐specified noninferiority margin of 15%, LEV was considered noninferior to OXC. Twenty‐four‐week and 48‐week seizure freedom rates were 53.8% and 34.7% for LEV vs. 58.5% and 40.9% for OXC. Both LEV and OXC were well tolerated, with 8.7% and 8.6% of patients reporting serious treatment‐emergent adverse events, respectively. By comparing LEV with OXC, another newer AED, LEV can be considered a useful option as initial monotherapy for patients with newly diagnosed focal epilepsy.     

Zonisamide for the treatment of epilepsy

The availability of new antiepileptic drugs with different mechanisms of action has widened our therapeutic choice, allowing better tailoring of treatment regimens to address specific needs. Zonisamide is the latest addition to the pharmacological management of epilepsy in Europe, following extensive clinical experience in Japan and the USA. This article reviews the structure, mechanism of action, pharmacokinetics and drug interactions of zonisamide. The four double-blind, placebo-controlled trials in patients with drug-resistant focal seizures are also presented. They complement pre- and postmarketing studies conducted in Japan and provide clear-cut evidence that the drug has efficacy as an add-on treatment in this indication. Reports on zonisamide monotherapy and on the use of the drug for the control of several types of seizures (typical and atypical absences, tonic and myoclonic) and syndromes in children and adults are also commented on. These were all open-label studies, as is often the case with other antiepileptic drugs, dealing with treatment of epilepsy in children. The Japanese, US and European data provide a large database of safety information suggesting that the drug is well tolerated with mild-to-moderate adverse events (e.g., somnolence and dizziness). Nephrolithiasis appears to have a very low incidence and cutaneous reactions are rare. The available data provide an excellent foundation on which clinicians can build their knowledge on this drug, although the broad-spectrum efficacy of zonisamide needs to be confirmed through randomized trials.     

The use of recently approved antiepileptic drugs: use with caution, use in refractory patients or use as first-line indications?

Approximately 50% of patients with newly diagnosed epilepsy achieve immediate remission, and up to 50% enter terminal remission with first-generation antiepileptic drugs. However, 20-30% of cases are still refractory to current treatments. This population is the target of newer antiepileptic drugs and other compounds in development. The licensing of newer antiepileptic drugs represents an advance in the development of more manageable products and the control of several disturbing adverse drug reactions of the older compounds. However, despite the development of several new antiepileptic drugs, the efficacy and tolerability of drug treatment of epilepsy has not substantially improved in terms of effectiveness and risk-benefit and cost-benefit profiles. Newer antiepileptic drugs are, at best, equivalent in efficacy to their predecessors, but some of them are more manageable and better tolerated. However, the use of a first-generation compound at low doses in newly diagnosed patients is still preferable because the disease can be as well-controlled and the incidence of intolerable side effects is minimized. Newer generation compounds should be used as alternative treatments in patients who are nonresponding to first-generation drugs and in those for whom these drugs are contraindicated or poorly tolerated. As an exception, some new-generation drugs are a valuable option in the presence of comorbidities known to respond to these products or in patients with selected epilepsy syndromes. In light of the heterogeneity and the complexity of the mechanisms underlying epileptic seizures, the future of drug development will be the discovery of drugs efficacious for the treatment of selected epilepsy syndromes or, more specifically, targeting genetic defects leading to molecular abnormalities.     

Treatment options and paradigms in childhood temporal lobe epilepsy

Temporal lobe epilepsy in adults is a relatively homogenous syndrome with hippocampal sclerosis being its most common pathologic substrate. In the pediatric age group, low-grade neoplasms and cortical dysplasia are much more common than hippocampal sclerosis. Pediatric temporal lobe epilepsy has distinct semiologic, electrophysiologic and imaging characteristics as compared with its adult counterpart. The various treatment options for pediatric temporal lobe epilepsy include antiepileptic drugs, resective surgery, vagal nerve stimulation and the ketogenic diet. In spite of the multiple antiepileptic drugs currently available, 5-10% of all newly diagnosed cases will remain intractable to medical therapy and should be referred for presurgical evaluation. Resective surgery offers the best chance of seizure freedom in carefully selected patients. Future areas of research include new drug development, better imaging and localization techniques, and brain stimulation.     

Monotherapy Trials of New Antiepileptic Drugs

Summary: A number of clinical trials that test the efficacy and safety of the newer antiepileptic drugs (AEDs) have recently been concluded. Two dose-response trials in inpatients with refractory partial seizures and outpatients with newly diagnosed partial epilepsy established the efficacy of gabapentin as monotherapy. Lamotrigine was found to have efficacy similar to that of phenytoin and carbamazepine (CBZ) and to be better tolerated than CBZ in patients with newly diagnosed epilepsy. It was also shown to have efficacy as monotherapy in partial seizures, based on the results of an active controlled trial, and in the treatment of absence seizures, based on the results of a responder-enriched study. Topiramate as monotherapy was found to be efficacious for treatment of partial-onset seizures, based on the results of a single-center dose-response trial. A dose-response trial that tested the efficacy of tiagabine monotherapy in patients with refractory partial epilepsy was uninformative. Oxcarbazepine was found to be safe and efficacious in four comparative trials in patients with newly diagnosed epilepsy as well as in one placebo-controlled inpatient trial in patients with refractory partial seizures.     

Overtreatment in adults with epilepsy

Overtreatment of epilepsy patients is traditionally associated with the use of polytherapy, i.e. use of more than one antiepileptic drug (AED). Although monotherapy is now being used in 70% of patients with epilepsy, these patients are also at risk at being overtreated. Ten to 20% of patients withdraw from their first drug because of adverse effects. This is partly related to high starting dosages and fast titration rates. The conventional AEDs are still first choice monotherapy drugs, although they potentially have more adverse effects, especially in the elderly. Other problems are the random selection of second or third choice drugs and the uncertainty about when to switch to polytherapy. Several authors have suggested that patients with progressive forms of epilepsy, such as patients with mesiotemporal sclerosis, should be treated adequately as soon as possible and that epilepsy surgery should be considered for them in a much earlier stage. Overtreatment in polytherapy is still a large threat, due to several reasons: drug loads are much higher, and thus more adverse effects are likely to develop; drug combinations are selected randomly, as evidence about effective combinations has been scarce; the constant choice between continuing the existing treatment (which is suboptimal) and trying new drugs (which may disturb a patient's equilibrium); the long-term use of benzodiazepines.     

Zonisamide: Review of Recent Clinical Evidence for Treatment of Epilepsy

Zonisamide is an orally administered antiepileptic drug that was first approved for clinical use in Japan in 1989. Since then, it has been licensed in Korea for a broad spectrum of epilepsies in adults and children, and in the USA for adjunctive therapy of adults with partial seizures, and in Europe for monotherapy of adults with newly diagnosed partial seizures and adjunctive therapy of adults and adolescents and children aged ≥6 years with partial seizures with or without secondary generalization. Zonisamide is a benzisoxazole derivative with a unique chemical structure, predictable dose‐dependent pharmacokinetics, and multiple complementary mechanisms of action. Treatment with zonisamide is well tolerated and is not known to be associated with clinically significant drug–drug interactions, including with oral contraceptives or other antiepileptic drugs. There have been >2 million patient‐years of experience with zonisamide for treatment of epilepsy, and this drug has International League Against Epilepsy level A evidence for efficacy/effectiveness as initial monotherapy for adults with partial‐onset seizures. This review presents the evidence for zonisamide across the spectrum of epilepsy, with emphasis on real‐world clinical practice and special populations of patients (children, elderly patients, and women of childbearing age) who are likely to be treated in daily clinical practice.     

Rapid versus slow withdrawal of antiepileptic monotherapy in 2-year seizure-free adult patients with epilepsy (RASLOW) study: a pragmatic multicentre,prospective, randomized,controlled study

Antiepileptic drug withdrawal may be an option for patients who have been seizure free for some years. The best withdrawal rate is questionable; in particular, it is unknown whether “rapid” withdrawal is associated with a higher risk of relapse as compared to “slow” withdrawal. We aim to establish if a slow or a rapid withdrawal schedule of antiepileptic monotherapy influences relapse rate in adult patients with focal or generalized epilepsy who have been seizure free for at least 2 years. This multicentre, prospective, randomized controlled study will enroll adult patients with focal or generalized epilepsy, who are seizure free on monotherapy. Patients will be randomized to a slow (160 days) or a rapid (60 days) schedule. Follow-up will last 1 year after randomization. The primary endpoint is the time to seizure relapse; secondary endpoints are compliance to the assigned schedule, occurrence of status epilepticus, of seizure-related injuries and mortality. A sample size of 350 patients has been planned. Univariate and multivariate analysis by Kaplan–Meier curves and Cox regression (primary endpoint) and by logistic regression (secondary endpoint) will be performed. The present study should contribute to better define the best withdrawal period for AED treatment in adult patients with epilepsy.     

Dietary therapy is not the best option for refractory nonsurgical epilepsy

The ketogenic diet (KD) is currently a well‐established treatment for patients with medically refractory, nonsurgical epilepsy. However, despite its efficacy, the KD is highly restrictive and constitutes a treatment with serious potential adverse effects, and often with difficulties in its implementation and compliance. Patients on the KD require strict follow‐up and constant supervision by a medical team highly experienced in its management in order to prevent complications. Other alternative treatments for patients with refractory epilepsy include vagus nerve stimulation (VNS), new‐generation antiepileptic drugs (AEDs), corpus callosotomy (CC), and responsive focal cortical stimulation (RNS). In this review, we explain not only the difficulties of the KD as a therapeutic option for refractory epilepsy but also the benefits of other therapeutic strategies, which, in many cases, have proven to have better efficacy than the KD itself.     

Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines

BACKGROUND: Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20-30% of patients are refractory to these drugs. RECENT DEVELOPMENTS: The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential. WHERE NEXT: The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.