The Pharmaceutical Journal Vol 262 No 7047 p470-473
April 03, 1999 Continuing education

Epilepsy

(3) New treatments

By Theodora Michael, BPharm, MRPharmS

Other articles in the series
Epilepsy - the disease (PJ, February 27, 1999, pp297-300)
Epilepsy treatment - the established drugs (PJ, March 27, 1999, pp432-5)

In the past 10 years there have been significant advances in the treatment of epilepsy. Improved formulations of the established antiepileptics have been developed and six new drugs have been licensed in the UK.
Between 25 and 30 per cent of patients with epilepsy are not well controlled on the established antiepileptic drugs¹ and these new drugs offer tools in the management of refractory epilepsy. The drugs are licensed as add-on therapy, usually for complex partial seizures, with or without secondary generalisation. Lamotrigine recently obtained a licence for monotherapy.
Until more experience is gathered in the use of these new drugs there is no evidence to show that one is more effective than another^2,3 and their place in the therapy of epilepsy is yet to be fully established.
Table 1 shows guidelines for drug selection in epilepsy, as recommended by the Royal College of Physicians.

Table1: SEIZURE TYPE AND DRUG SELECTION
Seizure type	First line drugs	Second line drugs
Partial (simple, complex, with or without secondary generalisation	Carbamazepine Sodium valproate	Clobazam Clonazepam Gabapentin Lamotrigine Phenytoin Tiagabine Topiramate Vigabatrin (Acetazolamide and phenobarbitone are possible alternatives)
Generalised absence	Sodium valproate	Clobazam Clonazepam Ethosuximide Lamotrigine
Generalised tonic-clonic	Sodium valproate	Carbamazepine Clobazam Gabapentin Lamotrigine Phenytoin Topiramate Vigabatrin (Acetazolamide, clonazepam and phenobarbitone are possible alternatives)
Myoclonic	Sodium valproate	Clobazam Clonazepam Ethosuximide Lamotrigine Piracetam

VIGABATRIN
Vigabatrin is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of the inhibitory neurotransmitter GABA. This leads to an ncreased amount of GABA in the brain.⁴
The drug is licensed as add-on therapy for partial seizures with or without secondary generalisation, and as monotherapy for infantile spasms. In some studies, seizure frequency was reduced by at least 50 per cent in over 50 per cent of patients.^1,2 Vigabatrin can worsen generalised absence and myoclonic seizures. The drug has been shown to be at least comparable in efficacy to carbamazepine in newly diagnosed patients with partial seizures but to be less effective than carbamazepine in patients with primary generalised seizures, most of whom did not respond.^5,6 The half life of vigabatrin is between five and eight hours; however, because of the specific irreversible inhibition of GABA-transaminase it takes up to six days to regain maximum enzyme activity when vigabatrin is stopped.^7,8
The manufacturer recommends a starting dose of 2g in adults, but lower doses of 500mg are usually used.^9,10 This allows tolerance to the drug's sedative effects to develop and also monitoring of behavioural changes. Most patients are controlled on 2g to 4g per day, given in one or two doses.
In infantile spasms, doses start at 40mg/kg per day, increased to the normal range of 80 to 150mg/kg per day.
The most common adverse effects are sedation and fatigue, which occur in 13 to 40 per cent of patients. Weight gain can occur in up to 40 per cent of patients, usually in the first three to six months of treatment.¹¹
The main serious adverse effects are depression, psychosis and visual field defects. Serious psychiatric symptoms occur in 7 per cent of patients.¹ Visual field defects recently reported with vigabatrin are of concern, and regular testing is required in patients who take the drug.¹²
Careful monitoring is, therefore, required in patients taking vigabatrin but serum drug level monitoring is of little value.
Vigabatrin has been reported to decrease phenytoin levels by 20 to 30 per cent.^8,10

PIRACETAM

Piracetam has been in use for many years as a "memory enhancer" although it was never licensed for this indication in the UK. After a number of case reports and trials confirming its efficacy in the treatment of myoclonic epilepsy, where it can have a dramatic effect, it was licensed as add-on therapy for use in myoclonus in the early 1990s. Piracetam increases blood flow at the capillary level and this is thought to contribute to its memory-enhancing action. However, the drug's antimyoclonic action is unclear.¹³
Starting doses are between 4.8g and 8g per day, with a usual maintenance dose of 18g to 24g per day, given in two or three doses.
The main adverse effects are gastrointestinal, such as nausea and diarrhoea. Others are dizziness, insomnia, weight gain, depression and hyperkinesia.
Piracetam is usually well tolerated but, because of the limited tablet strengths available, patients on high doses may need to take a large number of tablets.

LAMOTRIGINE

Lamotrigine acts by prolonging the inactivation of voltage sensitive sodium channels, thus inhibiting the release of the excitatory neurotransmitters glutamate and aspartate; although less important, it also acts on calcium channels.^4,5,15 It is licensed as add-on therapy and monotherapy (adults only) in the treatment of partial seizures and primary and secondarily generalised tonic clonic seizures. It can also be effective in generalised absences and myoclonic jerks.¹⁰ The drug has been shown to be as effective as carbamazepine in the treatment of newly diagnosed patients with partial seizures and primary tonic clonic seizures.¹⁴
When used as an add-on, studies have shown that 20 per cent of patients with severe epilepsy showed a decrease of 50 per cent or more in seizure frequency.¹¹
The half-life of lamotrigine is markedly sensitive to enzyme inducers and inhibitors and this is reflected in the different dosing regimes for monotherapy, therapy with inducers and therapy with sodium valproate. On monotherapy the half life is 25 hours, with enzyme inducers it is decreased to 15 hours and with sodium valproate it is increased to around 60 hours.^7,8 The recommended titration regimes must therefore be followed. Lamotrigine doses of between 200mg and 600mg per day may be needed with enzyme inducers in refractory epilepsy and doses as low as 100mg to 200mg per day may be needed with sodium valproate.¹⁰
There is no useful correlation between concentration and effect or toxicity with lamotrigine and blood level monitoring is rarely performed.^8,15 Lamotrigine is cleared by the liver and should be avoided in liver disease; caution is needed when used in renal impairment. Lamotrigine itself does not affect hepatic microsomal enzymes and does not affect the metabolism of other drugs. However, it can increase levels of an active metabolite of carbamazepine (carbamazepine epoxide) and if introduced in a patient taking carbamazepine it could precipitate carbamazepine toxicity.^8,10 There is also some evidence of autoinduction, whereby the drug induces its own metabolism.^7,13
Rashes occur in 5 to 10 per cent of patients, typically within the first six weeks of treatment, but only 0.1 per cent are severe.^15,16 They are more likely to occur in patients also taking sodium valproate and with starting regimes that are higher and faster than recommended.^10,17 Slow titration of dosage is essential because of the possibility of severe allergic reactions but these reactions, such as angioedema, Stevens- Johnson syndrome and toxic epidermal necrolysis, are rare.^3,14
The most common adverse effects are blurred vision, diplopia and headaches; less common are nausea, vomiting, dizziness and ataxia. Sedation and psychiatric reactions, such as agitation, confusion and depression, are rare. Tremor may be seen in high doses.
There have been rare reports of leucopenia and neutropenia.¹⁸ Patients should be counselled on the recognition of all idiosyncratic reactions.
The main advantage of lamotrigine is that it causes little cognitive impairment and is well tolerated.^13,14

GABAPENTIN

The antiepileptic action of gabapentin is unclear but is different from the other antiepileptic drugs. Although a derivative of the neurotransmitter GABA, the drug does not seem to interact with GABA, its receptors, its uptake or its degradation; it may bind to a specific site, possibly on calcium channels, on neuronal membranes.^4,8,19 Gabapentin is licensed as add-on therapy in partial seizures with or without secondary generalisation. It has been shown to be particularly effective in secondarily generalised partial seizures and complex partial seizures,19 being more effective in the former than the latter.^1,8
In gabapentin trials, the proportion of patients achieving at least a 50 per cent reduction in seizure frequency varied between 20 and 28 per cent.¹¹
Gabapentin has a half-life of six to seven hours and therefore multiple dosing is needed.⁷ Its absorption is saturable, resulting in a decrease in absorption with increasing dose;⁵ at doses of 1.2g per day absorption is 60 per cent but this can decrease to 35 per cent at doses of 4.8g per day.^5,7,8 Antacids reduce absorption further.¹⁹
The drug is not metabolised and is excreted unchanged by the kidneys. Dose reduction is therefore necessary in renal impairment. It is not protein bound and is not involved in any other drug interactions. There are no target serum concentrations and therapeutic drug monitoring is not indicated.
The average maintenance dose in adults is between 1.2g and 3.6g per day, given in three divided doses, with doses up to 4.8g in refractory cases.1,8 The manufacturer recommends a rapid dose escalation of 300mg daily increasing to 300mg three times daily by the third day and does not recommend doses above 2.4g per day. In clinical practice, dose escalation is much slower with intervals of three days or a week.^1,9
Adverse effects seem to be mild and infrequent. No serious idiosyncratic reactions have been specifically identified, apart from rare cases of Stevens-Johnson syndrome and pancreatitis. The most common adverse effects are somnolence, fatigue, dizziness, nausea, headache and ataxia. Weight gain, diplopia and tremor have also been reported.
Unlike other antiepileptic drugs, gabapentin does not show withdrawal seizures, even if the drug is rapidly tapered down.
The good tolerability of gabapentin makes it a useful drug in patients in whom other add-on drugs may cause problems with additive adverse effects or interactions.

TOPIRAMATE

Topiramate is a potent antiepileptic drug. It reduces repetitive neuronal firing by acting on sodium channels. It also potentiates the inhibitory effects of GABA at its receptor and the excitatory effects of glutamate on a subtype of its receptor, and has some carbonic anhydrase inhibitory activity.^4,13 These actions block the spread of seizures rather than increase the seizure threshold.⁵ Topiramate is licensed for use as add-on therapy in partial and secondarily generalised seizures and has been shown to be effective in idiopathic epilepsies.¹⁰ It has a similar antiepileptic activity to carbamazepine and phenytoin and appears to have synergistic properties when combined with these drugs.¹
In one multicentre European trial, 43 per cent of patients on topiramate doses as high as 800mg per day as add-on therapy showed a 50 per cent or more reduction in seizure frequency, with 35 per cent having a reduction of 75 to 100 per cent.²⁰ Doses up to 600mg per day have shown equally effective results, with 47 per cent of patients having a 50 per cent or more reduction in seizure frequency and half of those achieving a reduction of 75 per cent or more.²¹
Topiramate has a dose-dependent half-life of 18 to 23 hours, with low protein binding and weak enzyme induction; it is not extensively metabolised and unchanged topiramate and its metabolites are excreted by the kidneys.^1,7,8,13 Topiramate can increase phenytoin levels in some patients, while phenytoin and carbamazepine can significantly reduce its plasma concentrations, by 50 per cent and 35 per cent, respectively.⁸ It can also accelerate the metabolism of oestrogens. Therapeutic drug monitoring is not useful with topiramate.¹³
The doses have been recently revised to start at 50mg per day and increase at weekly intervals by 50mg to a maintenance dose of 200mg to 400mg per day in two divided doses; the maximum daily dose is 800mg. In practice, the drug may be introduced even more cautiously, with a starting dose of 25mg and weekly increments of 25mg.¹⁰ Patients on enzyme inducing drugs such as phenytoin and carbamazepine may need the maximum topiramate dose whereas those on sodium valproate may need doses as low as 100mg per day.¹⁰
The most common adverse effects, occuring in over a third of patients, are dizziness, fatigue, paraesthesia, ataxia and somnolence. Cognitive impairment (abnormal thinking and impaired concentration) is also common with high doses. The incidence of ataxia is higher in patients taking topiramate with two other antiepileptic drugs than those taking one other drug.²² Weight loss occurs typically in the first three months of therapy, peaking after 15 to 18 months and then tends to resolve with long- term treatment.²²
Paraesthesia and nephrolithiasis are thought to be attributed to the weak carbonic anhydrase inhibition of topiramate. Adequate hydration during therapy is advised to reduce the risk of nephrolithiasis.

TIAGABINE

Tiagabine is the most recently licensed drug for epilepsy and has a unique mode of action. It acts by selectively inhibiting GABA reuptake into presynaptic neurones and glial cells, thus prolonging its inhibitory effects.^4,5
The drug is licensed as add-on therapy for refractory partial seizures with or without secondary generalisation in adults. A meta-analysis of five trials showed that tiagabine reduced the seizure frequency (all types) by at least 50 per cent in 23 per cent of patients, compared with 9 per cent in the placebo group.²³
Tiagabine has a half-life that varies between five and nine hours and generally needs to be taken three times daily.^7,8,23 The half-life can be further reduced to two to four hours in some patients taking enzyme inducing drugs.^8,10,23
Although highly protein bound, no other significant drug interactions have been identified. The drug is extensively metabolised by the liver and should be used with caution in liver impairment and avoided in severe liver disease.^8,24 It is best taken with food; although food reduces the drug's absorption rate, it will avoid high peak concentrations which are associated with dizziness.^10,24 Therapeutic drug monitoring is not required.
Doses of 5mg twice daily are given for the first week, increasing with increments of 5mg or 10mg at weekly intervals to the required maintenance dose. In patients taking enzyme inducing drugs the maintenance dose is usually 30mg to 45mg per day. In other patients the maintenance dose is 15mg to 30mg. Doses can be given twice daily if below 30mg per day.²⁴
The main adverse effects reported in trials were dizziness, somnolence and headache. Others include ataxia, tremor, fatigue, gastrointestinal upset and depression. No idiosyncratic reactions or evidence of cognitive or memory impairment have been identified. On present evidence, tiagabine seems to be well tolerated but clinical experience is very limited.

OTHER DRUGS
Felbamate Felbamate is available on a named patient basis only in the UK. It is used to treat refractory partial seizures with or without secondary generalisation.¹
The drug is thought to act on sodium channels, to enhance the actions of GABA and to inhibit the actions of glutamate.^1,13
Although an effective antiepileptic drug felbamate was withdrawn from the market in the United States after reports of fatal aplastic anaemia and hepatotoxicity. It is now reserved for refractory cases.
The usual adult doses are between 1.2g and 3.6g per day, given in three divided doses. The main adverse effects are insomnia, irritability, anorexia, nausea and headaches.^1,5,8 Regular liver function tests and full blood counts are recommended. Felbamate can increase levels of phenytoin, sodium valproate and carbamazepine epoxide. It is hepatically cleared and its clearance is affected by enzyme inducers and inhibitors.¹

Oxcarbazepine Oxcarbazepine is functionally a pro-drug activated by liver metabolism. The active metabolite, unlike that of carbamazepine, is not an epoxide, which has been linked to many of carbamazepine's adverse effects.¹ It has similar efficacy to carbamazepine and and is mainly used on a named patient basis in patients who are allergic to carbamazepine when no other drugs have been effective. It is better tolerated than carbamazepine with less nausea, dizziness, and drowsiness.⁸
It is not a strong enzyme inducer but it may increase phenytoin and sodium valproate levels.^1,8

Remacemide This drug is undergoing trials in the treatment of complex partial seizures and secondarily generalised seizures.

Levetiracetam Levetiracetam (LO59) is an analogue of piracetam but has a broader spectrum of seizure activity.5 It is still undergoing trials and is available on a named patient basis.

CONCLUSION
New developments in the treatment of epilepsy have been long awaited and these new drugs offer alternatives although their place in therapy is still to be established. All are initially licensed as add-on therapy, and this may exacerbate the concerns about polypharmacy. As more experience in their use is gathered so a more rational approach to their use will develop.

ACKNOWLEDGMENTS I would like to thank Professor Simon Shorvon (professor in clinical neurology, Institute of Neurology, and consultant neurologist, National Hospital for Neurology and Neurosurgery) for his helpful comments.

Surgery in epilepsy Surgery is a consideration in those patients where drug therapy continually fails. Only a few patients are suitable. Seizures must be seen to arise from a localised area of the brain that can be safely removed without causing any danger to other areas. Over 70 per cent of patients who have surgery will become completely seizure free. A few patients have achieved a decrease in seizure frequency after vagus nerve stimulation. The vagus nerve is believed to be involved in seizures and stimulation via a small generator implant under the skin with a lead to the vagus nerve can intercept the signals. The generator is programmed with different frequencies of stimulation and can also be manually activated with a magnet in cases where a seizure is preceded by an aura.

Ms Michael is clinical pharmacist at the National Hospital for Neurology and Neurosurgery, Queen Square, London