Hôpital-Camfrout, France
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Duncan S.,Western General Hospital | Brodie M.J.,Epilepsy Unit
Epilepsy and Behavior | Year: 2011

Sudden unexpected death in epilepsy (SUDEP) has an incidence ranging between 0.09 and 9 per 1000 patient-years depending on the patient population and the study methodology. It is the commonest cause of death directly attributable to epilepsy, and occurs at or around the time of a seizure. The principal risk factor for SUDEP is poorly controlled generalized tonic-clonic seizures. Other risk factors include polytherapy, male sex, early age at onset of epilepsy, symptomatic etiology, and, possibly, treatment with lamotrigine. The mechanisms underlying SUDEP are poorly understood, but autonomic dysfunction, central apnea, cerebral depression, and cardiac arrthymias have all been described in animal models of SUDEP and during human seizures. Prevention of this fatal event should be aimed at optimizing control of seizures, including prompt referral for consideration of epilepsy surgery. All patients should be told about the risks of SUDEP and informed that complete seizure control appears to be the one proven way of preventing the phenomenon. © 2011 Elsevier Inc.

Stephen L.J.,Epilepsy Unit | Brodie M.J.,Epilepsy Unit
CNS Drugs | Year: 2011

This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development.Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200600mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related.Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200mgday. Adverse effects include dizziness and somnolence.Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200mgday, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness.Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported.Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete.Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABAA receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients.The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy. © 2011 2011 Adis Data Information BV. All rights reserved.

Brodie M.J.,Epilepsy Unit
Seizure | Year: 2010

The story began on 11th May 1857 when Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of "hysterical" epilepsy in young women. The next development was the serendipitous discovery of the anticonvulsant properties of phenobarbital by Alfred Hauptmann in 1912. This predated by more than 20 years the screening of potential therapeutic agents against "electrical seizures" in cats by Houston Merritt and Tracy Putnam. The result was the launching of phenytoin in 1938. Next came primidone, ethosuximide, carbamazepine and valproic acid, all of which can be regarded as first generation antiepileptic drugs (AEDs). Shortly after their synthesis, the benzodiazepines were rapidly recognised as having anticonvulsant activity. The modern era focused on the systematic screening of many thousands of compounds against rodent seizure models under the Anticonvulsant Drug Development Program in the US. This resulted in the global licensing, in chronological order, of vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin and lacosamide. Rufinamide is available in the US and Europe for Lennox-Gastaut syndrome and stiripentol has been made available for Dravet syndrome under the European orphan drug scheme. Eslicarbazepine can be prescribed in Europe for partial seizures, but not in the US. Has all this activity improved the lives of people with epilepsy? The short answer is - probably yes, but not by very much! This paper will conclude with a précis of the views of a selected group of paediatric and adult epileptologists on the advances in pharmacological management achieved over the last 20 years. © 2010 British Epilepsy Association.

Chavez M.,French National Center for Scientific Research | Valencia M.,French National Center for Scientific Research | Navarro V.,Epilepsy Unit | Latora V.,University of Catania | Martinerie J.,French National Center for Scientific Research
Physical Review Letters | Year: 2010

We analyze the connectivity structure of weighted brain networks extracted from spontaneous magnetoencephalographic signals of healthy subjects and epileptic patients (suffering from absence seizures) recorded at rest. We find that, for the activities in the 5-14 Hz range, healthy brains exhibit a sparse connectivity, whereas the brain networks of patients display a rich connectivity with a clear modular structure. Our results suggest that modularity plays a key role in the functional organization of brain areas during normal and pathological neural activities at rest. © 2010 The American Physical Society.

Baulac M.,Epilepsy Unit | Brodie M.J.,Epilepsy Unit | Patten A.,Eisai Ltd | Segieth J.,Eisai Ltd | Giorgi L.,Eisai Ltd
The Lancet Neurology | Year: 2012

Background: Additional options are needed for monotherapy treatment of adults newly diagnosed with partial epilepsy. This trial compares the efficacy and tolerability of once-daily zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. Methods: In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18-75 years and newly diagnosed with partial epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26-78 weeks flexible-dosing period (200-500 mg/day vs 400-1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. Findings: 583 patients were randomly assigned to treatment groups (282 zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference -4·5%, 95% CI -12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. Interpretation: Zonisamide was non-inferior to controlled-release carbamazepine-according to International League Against Epilepsy guidelines-and could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy. Funding: Eisai Ltd. © 2012 Elsevier Ltd.

Brodie M.J.,Epilepsy Unit
Acta neurologica Scandinavica. Supplementum | Year: 2012

Zonisamide is a benzisoxazole derivative, chemically unrelated to other antiepileptic drugs, that appears to have multiple mechanisms of action, including inhibition of Na(+) channels and reduction of T-type Ca(2+) currents. It is currently licensed in Europe and the USA for adjunctive treatment of partial seizures in adults, and in Europe as monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy. Zonisamide displays predictable, dose-dependent pharmacokinetics and has a half-life of ~60 h, allowing once- or twice-daily administration. It has a low potential for interactions with other medications, including oral contraceptives. The clinical efficacy of adjunctive zonisamide therapy has been established in four pivotal, phase III, randomized, double-blind, placebo-controlled trials, which together included approximately 850 patients, aged 12-77 years, with refractory partial epilepsy. In all four trials, zonisamide 300-600 mg/day resulted in significant reductions in median total seizure rates vs placebo, and zonisamide was generally well tolerated; the most frequently reported adverse events being somnolence, dizziness and anorexia/weight loss. Subanalysis of the primary European trial indicated that zonisamide was effective when administered as first-line adjunctive treatment, and a long-term extension to the same trial demonstrated that the efficacy and safety/tolerability of adjunctive zonisamide was sustained for up to 36 months. Once-daily monotherapy with zonisamide (200-500 mg/day) has been shown to be non-inferior to, and as well tolerated as, twice-daily monotherapy with controlled-release carbamazepine (400-1200 mg/day) in adults with newly diagnosed partial epilepsy. Zonisamide has also been shown to have favourable long-term retention rates, an important indication of its overall effectiveness. © 2012 John Wiley & Sons A/S.

Brodie M.J.,Epilepsy Unit
Epilepsia | Year: 2012

This article reviews the current position of phenobarbital using articles published since 2000 and speculates on its likely future contribution to epilepsy care. Over the last decade there have been no major double-blind randomized placebo-controlled or comparative trials with phenobarbital. Previous studies have suggested that phenobarbital is as effective in monotherapy as phenytoin and carbamazepine. Several observational studies undertaken in developing countries over the last decade have confirmed its efficacy and safety for the common epilepsies. This was particularly so in the substantial demonstration project undertaken in rural China under the auspices of the World Health Organization in partnership with the International League Against Epilepsy and International Bureau for Epilepsy. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus. Recent data have confirmed in a prospective cohort of women taking phenobarbital as monotherapy that the drug can be associated with a range of congenital defects in exposed infants. Much effort has gone into exploring the apparent contradiction of higher withdrawal rates due to cognitive and behavioral side effects in studies undertaken in developed countries but not in those sited in the developing world. A raft of data over the last 10 years, including a systematic review, showed no important differences between the tolerability of phenobarbital compared to that with other antiepileptic drugs. Finally, cognitive test scores and mood ratings in 136 people with epilepsy receiving phenobarbital for a year were similar to those in 137 age-, sex-, and education-matched controls in a number of Chinese villages. Indeed, there were some cognitive gains in the patients possibly due to improved seizure control. Phenobarbital is still the most cost-effective pharmacologic treatment for epilepsy. All these data predict a healthy future for phenobarbital, particularly in helping to close the treatment gap in low- and middle-income countries during its second century of clinical use. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Stephen L.J.,Epilepsy Unit | Brodie M.J.,Epilepsy Unit
Current Opinion in Neurology | Year: 2012

Purpose of review Despite the availability of many new antiepileptic drugs (AEDs), only around 50% of people with epilepsy will become seizure free on their first drug. This article explores treatment options and issues influencing whether AEDs should be substituted or combined in the remainder of the patient population. Recent findings Prior to the introduction of novel AEDs, it was generally opined that combining traditional agents did not necessarily lead to an improvement in seizure control and might increase the propensity for side effects. Newer AEDs, many with different mechanisms of action, have increased the potential for polytherapy regimens, although robust data to support or refute this therapeutic strategy are sparse. It seems sensible to substitute rather than combine when the first AED produces an idiosyncratic reaction, is poorly tolerated at a low/moderate dose or shows no efficacy. Polytherapy may be preferred if the patient tolerates their first or second AED well, but with a suboptimal response, particularly when there is an identifiable anatomical substrate for the seizures. AED selection requires consideration of many factors some of which are discussed in this study. Summary There are no definitive answers on whether to combine or substitute AEDs. Different strategies are required for different scenarios in different patients. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.

This article lays the background for, and discusses the practical issues surrounding, the adjunctive use of the last four antiepileptic drugs (AEDs) to be licensed for the treatment of pharmacoresistant focal seizures in the UK and elsewhere. More than 30 % of adolescent and adult patients will not be fully controlled on the currently available therapeutic armamentarium. After not responding to their first three AED schedules, only a handful of patients attained seizure freedom on subsequent regimens. To optimise the response to any new AED in this setting, it is often necessary to reduce the existing drug burden. The pharmacology, tolerability and safety, and everyday use of lacosamide, eslicarbazepine acetate, retigabine (ezogabine) and perampanel will be reviewed and discussed. This will be accompanied by data from prospective audits with each drug undertaken at the Western Infirmary in Glasgow, Scotland, and a report of their successful introduction in an illustrative case. Overall, there is a large variation in the course of refractory epilepsy and the effect of AED therapy on this process seems minimal. Nevertheless, a number of patients will benefit from the introduction of each new AED, with some becoming seizure-free. © 2015 Springer International Publishing Switzerland.

Brodie M.J.,Epilepsy Unit
Epilepsia | Year: 2013

This short article reviews 30 years of prospective observations on outcomes relevant to an expanding cohort of adolescent and adult patients with newly diagnosed epilepsy, who received their first antiepileptic drug (AED) and subsequent long-term follow-up at the Epilepsy Unit at the Western Infirmary in Glasgow, United Kingdom. Despite the fact that the overall prognosis has slowly improved over this time, >30% of the patients remain uncontrolled despite the introduction of a range of new AEDs, some with unique mechanisms of action, over the last 20 years. Most patients followed a constant course (59% controlled, 25% refractory), which could usually be predicted early. The remaining 16% fluctuated between periods of remission and relapse. The likelihood of seizure freedom declined with successive drug regimens, most markedly from the first to the third. A number of factors predicting poorer outcomes have been identified, particularly high pretreatment seizure density and concomitant psychiatric comorbidities. Novel approaches to identifying and treating the processes underpinning the generation and propagation of seizures are required if the current rather disappointing scenario is to be substantially improved. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

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