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Le Touquet – Paris-Plage, France

Brodie M.J.,Epilepsy Unit
Acta neurologica Scandinavica. Supplementum

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. Source

Brodie M.J.,Epilepsy Unit

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. Source

Duncan S.,Edinburgh and South East Scotland Epilepsy Service | Brodie M.J.,Epilepsy Unit
Epilepsy and Behavior

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. Source

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. Source

Brodie M.J.,Epilepsy Unit

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. Source

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