Therapy focus: Epilepsy

The diagnosis of epilepsy usually requires that seizures occur spontaneously, but certain types require particular triggers for seizures to take place, as is the case with photosensitive epilepsy, which results from flashing lights, and catamenial epilepsy, where seizures are linked to the menstrual cycle. Mutations in several genes have been linked to some types of epilepsy, while head trauma is believed to be a further cause, and brain lesions another.

It has been estimated that the six million people with epilepsy in Europe cost more than €20bn per year, with indirect costs caused by unemployment, underemployment and premature death. Different studies have revealed that in Europe unemployment is twice-to-three-times higher among people with epilepsy. Yet despite this, few European countries have national plans for managing the disorder.

The provision of epilepsy treatment and care was investigated in a survey by the Commission on European Affairs in 1997. It showed that, despite large national and regional variations, problems were similar across Europe, with countries lacking comprehensive care and epilepsy specialists. It found that most patients were seen by a neurologist and not an epileptologist. A typical family physician in Europe has 10-20 patients with epilepsy and, therefore, does not consider it a priority and as a result may not keep track of the latest developments.

The goal of treatment is for the patient to become seizure-free and have minimal side effects from antiepileptic drugs (AEDs), and the role of the physician is to help the patient find the best balance. A majority of patients can achieve this with monotherapy, but some patients require the use of two or more drugs.

Up to 70 per cent of patients may become seizure-free, about 60 per cent with the first drug and a further 10 per cent after further attempts. In 60 per cent of cases treatment can be withdrawn after about three years of seizure freedom. The success rates of newer and older drugs have been similar, though the newer drugs may have less side effects and lead to a better quality of life for patients.

However, a 1997 European study on quality of life revealed that 88 per cent of patients reported at least one side effect, such as mood changes, sleepiness or rashes. 

Further, there are safety issues surrounding the effects of medication on foetal development. In 1999 a prospective pregnancy register was set up to collect useful data in this area. More than 8,000 pregnancies had been registered by January 2007.

As well as the medication option, there are 200,000 epileptics that could benefit from surgery. However, the provision of such treatment varies widely between countries. In some cases the implantation of a stimulator of the vagus nerve or a ketogenic diet, which is high in fat and low in carbohydrates, have been found to be beneficial for patients. 

Historic Developments
The modern treatment of epilepsy began with potassium bromide in the mid-1800s, which is still used today. It was used along with digitalis, belladonna, cannabis, opium, borax and many other noxious substances. The next effective agent, phenobarbital, was not synthesised until 1911.  

The pharmacological age of AED therapy began with Alfred Hauptmann's discovery of the anticonvulsant properties of phenobarbital, which is still the most widely prescribed AED in the developing world and remains a popular choice in many industrialised countries because of its modest cost.

In the 1930s Tracy Putnam, based in Boston, set out to discover a less sedative AED, which led to the development of phenytoin. It is still the most widely used AED in the US. During the 1940s trioxidone became established for the treatment of petit mal, or absence seizures. The next major drug to be licensed was carbamazepine, which became commonly available in the mid-1960s, followed in 1963 by sodium valproate. 

Chronology of antiepileptic drugs introduction over the past 150 years (click image to enlarge)

The modern era of AED development began in 1975 when the National Institute of Neurological Disorders and Stroke in the US established the Anticonvulsant Drug Development Programme. Since its introduction, more than 28,000 new chemical entities have been screened, resulting in the licensing of an increasing list of AEDs.

In the past 20 years, 20 AEDs have been licensed. The potential choices of treatment as a monotherapy or in combination are so numerous that it is not possible for a doctor or his or her patient to try every permutation in a lifetime; there are almost 200 duotherapies or more than 1,000 combinations of three AEDs. Most people with refractory epilepsy take up to four drugs. To best use the range of available AEDs, the prescriber must have some understanding of what is known about how these drugs act in the brain. The knowledge base regarding their pharmacology is limited but slowly increasing.

Blockage of voltage-gated sodium channels is the most common mechanism of action among AEDs, but voltage-gated calcium channels represent another important target for several AEDs. A number of AEDs have their pharmacological action at GABA receptor.

The most successful two drug combinations in laboratory studies appear to be a single mechanism drug combined with an AED known to possess multiple mechanisms of action.

The Future
It is widely thought that convincing evidence to guide clinicians on when and how to combine AEDs is still lacking. Well-designed studies exploring the ever-expanding possibilities of AED combinations are needed to address these practical questions so that effective therapy could be offered to many more patients. In addition, the International League Against Epilepsy published a document on 'Appropriate Standards of Epilepsy Care Across Europe', which found that professionals treating people with epilepsy do not have sufficient specialist knowledge about the condition. In a number of European countries diagnostic facilities are lacking and inadequate.

Drugs licensed in the past 20 years have provided modest improvements. However, the problem still remains that it is not understood how seizures are generated in the brains of individual patients. There are few new AEDs in the pipeline and these have largely failed to make people with refractory epilepsy seizure-free in regulatory trials. In May 2011, GlaxoSmithKline launched its new epilepsy medicine Trobalt in the UK. It is the first anti-epileptic drug to target potassium channels involved in inhibitory mechanisms in the brain, which are thought to have a role in seizure control. However, only retigabine, perampel and brivaracetam are likely to reach the marketplace in the next five years.

The Author
Liz Wells is deputy editor of PME. She compiled this article from information provided by Prof Martin Brodie, director of the Epilepsy Unit at the Western Infirmary, Glasgow. He sits on the Scientific Advisory Boards of Eisai, GlaxoSmithKline, Metronic, Novartis, Pfizer, UCB and Valeant Pharmaceuticals.