EPILEPSY

What is epilepsy?

Epilepsy is a chronic condition characterised by recurrent seizures caused by occasional, excessive and disorderly discharges from nerve cells which spread within the brain (Figure 1). Seizures vary from mild 'absences' through to full-scale convulsions. The seizures can be generalised or partial, affecting only part of the brain. In a few people, they are caused by brain lesions such as tumours or blood vessel abnormality, but in most there is no obvious organic cause.

Who does epilepsy affect and what does it cost?

One person in 20 will have an epileptic seizure at some time in their life. Epilepsy (the tendency to have recurrent seizures) is most often diagnosed in those under 20 years old and those over 60, although seizure frequency seems to decline with increasing age. It is estimated that 450,000 people are affected by epilepsy in the UK, with equal numbers of men and women. No recent figures are available for the costs associated with epilepsy and its treatment in the UK, but earlier surveys have shown that indirect costs (unemployment and raised death rates) account for about 70 per cent of the total.

Present treatments and shortcomings

Some people only have infrequent attacks and medication may not be appropriate, while in others attacks may be much more frequent and incapacitating. About 20-30 per cent of people with epilepsy have more than one seizure per month. A number of medicines have been available for over 25 years, including phenytoin, carbamazepine and sodium valproate, all of which are still in use. These older therapies can control seizures, but almost all cause some drowsiness and other side effects such as nausea, unsteadiness and other side effects. Seizures remain uncontrolled in about half of those being treated. Brain surgery has a role in people who do not respond to current medication, but only about 100 such operations are carried out each year in Britain.

Many new compounds have been introduced in the last decade. These are: vigabatrin (Sabril, Aventis), lamotrigine (Lamictal, GlaxoSmithKline), gabapentin (Neurontin, Pfizer), topiramate (Topamax, Janssen-Cilag), tiagabine (Gabitril, Cephalon), oxcarbazepine (Trileptal, Novartis), levetiracetam (Keppra, UCB), pregabalin (Lyrica, Pfizer) and zonisamide (Zonegran, Eisai). Lamotrigine, topiramate and oxcarbazepine can be used alone or with other medicines, while vigabatrin can be used alone in infantile spasms and in adults not well controlled on other medicines. All can be used in combination with other medicines.

Therapy usually begins with a single medicine, increasing its dose until the desired control of seizures is achieved. If side-effects become intolerable, another medicine is tried instead. Only when two or three such therapies have been tried and failed is it usual to add a second medicine. Many anti-epilepsy medications need to be taken at least twice a day and side-effects such as drowsiness, dizziness, headache and gastrointestinal symptoms such as nausea are common at first, even with the newer medicines. Only 30-40 per cent of people with epilepsy persist with the prescribed medication in the long term (more than five years) and seizures become intractable in 20-25 per cent.

What's in the development pipeline?

The brain chemistry of epilepsy is complex. The neurotransmitter gamma-amino butyric acid (GABA) damps down spontaneous nerve firing that might otherwise trigger an epileptic cascade, and several medicines act by affecting its level, including sodium valproate, vigabatrin and tiagabine. The newer pregabalin is both a GABA modulator and a calcium channel blocker, while Valeant is developing retigabine, which enhances GABA levels by increasing its production, but also acts as a potassium channel opener. Retigabine has reached Phase 3 trial.

A variety of other cellular processes are also targeted in the development of medicines for epilepsy. Several medicines (phenytoin, carbamazepine, lamotrigine, topiramate and zonisamide) act as sodium channel blockers and additional compounds of this type are in development. Eisai has developed rufinamide (Inovelon) for use in combination with other medicines and Newron Pharmaceuticals has a sodium channel inhibitor safinamide that has shown efficacy in Phase 2 trial. Meanwhile, GSK is developing an extended release form of lamotrigine, which is in Phase 3.

Levetiracetam is thought to act by preventing neurotransmitter release and also by lowering calcium levels between brain cells. UCB has two more compounds (brivaracetam and selectacetam) in Phase 2 trial that appear to act in a similar way, but appear to show much higher potency, which might lead to better tolerability.

Several companies are exploring the potential of modulators of the amino acid glutamate, in particular so-called AMPA receptor antagonists, in epilepsy. Eisai has the compound E-2007 in Phase 2 study and talampanel (Teva) and NS1209 (NeuroSearch) have reached the same stage. The latter compound is being explored for use in emergency treatment of life-threatening continuous tonic-clonic seizures.

Also in advanced clinical development is lacosamide (Schwarz Pharma). This compound is known not to show high affinity binding to receptors for the neurotransmitters adrenaline, histamine, glutamate, dopamine, acetylcholine (muscarinic), GABA, cannabinoids, or serotonin, or to block sodium, potassium or calcium channels. Nevertheless, it has been found in a Phase 3 trial to show efficacy as combination therapy and a further Phase 3 trial is in progress. Lastly, Johnson & Johnson has a compound (RWJ-333369) in Phase 2 trial for combination therapy of partial seizures.

FOR FURTHER INFORMATION CONTACT:

Epilepsy Action
New Anstey House, Gateway Drive
Yeadon
Leeds, LS19 7XY
Phone: 0808 800 5050 (Helpline)
Website: www.epilepsy.org.uk

The National Society for Epilepsy
Chesham Lane, Chalfont St Peter
Bucks, SL9 0RJ
Phone: 01494 601400 (Helpline)
Website: www.epilepsynse.org.uk