The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (update). NICE 2012;CG137
Epilepsy is the most common serious neurological condition seen in primary care. It has been estimated that around 70% of those with active epilepsy could be seizure free with effective management. But it is widely recognised that the level of care is far from ideal and specific problems identified include misdiagnosis, suboptimal treatment, sudden unexpected death that might have been prevented and the management of epilepsy during pregnancy.
NICE updated its 2004 epilepsy guidance in January this year, primarily to review the role of anti-epileptic drugs (AEDs) in the light of new data.1
This article will outline the main changes in the 2012 guidance, focusing on the treatment of focal seizures and generalised tonic-clonic seizures, the management of epilepsy in women of childbearing age and on the role of a ketogenic diet. It will omit new recommendations on the management of patients who have been admitted to hospital with a seizure and those who are likely to be managed totally in a secondary or tertiary setting with GPs having little role in their ongoing care – such as with infantile spasms or Dravet syndrome.
More pragmatic approach to drug therapy
The 2004 guideline recommended that AED therapy should only be started once the diagnosis of epilepsy is confirmed, except in ‘exceptional circumstances’ – but the update is more pragmatic. It states that – if possible – the AED should be chosen on the basis of the epilepsy syndrome, for example idiopathic generalised epilepsy. But if this is not clear at presentation the decision should be made on the seizure type – for example, generalised tonic-clonic.
Another new recommendation concerns the prescribing of carbamazepine. Controlled-release formulations have been available for a long time but the evidence about their benefit was conflicting. As recently as 2011, a Cochrane review said there was some evidence to suggest fewer adverse events in newly diagnosed patients prescribed the controlled-release form but no evidence it had any impact on seizure rates.2
However, the NICE guideline development group, based on their clinical experience and opinion, have recommended controlled-release formulations be prescribed to avoid peak concentrations of the drug.
New first-time role for lamotrigine in focal seizures
The new advice on focal seizures is arguably the most important of the changes to recommended treatments and is based largely on the conclusions of the influential Standard and New Anti-epileptic Drugs (SANAD) trial.
In 2004, the place of the newer AEDs like lamotrigine and topiramate was still very uncertain. SANAD – published in the Lancet in 2007 – was an NHS-funded, pragmatic, randomised, unblinded trial comparing new AEDs with what was considered standard therapy at that time: carbamazepine for focal seizures (arm A) and sodium valproate for generalised seizures (arm B).
The results from arm A suggested that lamotrigine is both a clinically and cost-effective alternative to carbamazepine as a first-line treatment3 and this is reflected in the new guidance.
If the first-line treatment is not effective, patients should be offered one of the following as adjunctive treatment: carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproate or topiramate.
Patients whose seizures are still not adequately controlled should then be seen in tertiary care for consideration of other AEDs. One of these is vigabatrin, which used to be a recommended adjunctive treatment, but concern over a risk of irreversible visual field damage has led to a more cautious approach.
Valproate first choice for generalised tonic-clonic seizures
The 2004 guidance recommended four AEDs as options for patients newly diagnosed with generalised tonic-clonic seizures, but the new guidance cites valproate first line. This is partly based on SANAD data again – in arm B it was seen to be better tolerated than topiramate and more efficacious than lamotrigine.4
But there is also evidence that the other options may exacerbate seizure rates in some patients. So lamotrigine is now recommended as a first-line treatment if valproate is unsuitable, but it may exacerbate seizures in patients with myoclonic seizures and those with juvenile myoclonic epilepsy. Similarly, carbamazepine and oxcarbazepine may exacerbate myoclonic seizures.
Recommended adjunctive treatments are now clobazam, lamotrigine, levetiracetam, valproate or topiramate.
Warning over suicide risk
In 2008, the MHRA told AED manufacturers to reword their labels after a European review of data on anti-epileptic treatments found that approximately two in every 1,000 patients experienced suicidal thoughts or behaviour. These findings were then confirmed in a similar US study.5
So the new NICE guideline recommends prescribers maintain a high level of vigilance for the emergence of neuropsychiatric problems and that the small risk of suicidal thoughts and behaviour applies to all AEDs and may occur as early as a week after starting treatment.
Wider role for ketogenic diet
A ketogenic diet is a diet high in fat and low in carbohydrate and protein, designed to mimic the biochemical response of the body to starvation when ketone bodies become the main fuel for the brain’s energy demands.
Although the diet has been recommended for the treatment of epilepsy in children for almost a century, the guideline development group now recommends it for children and young people whose seizures have not responded to AEDs.
In fact, it states a successful and sustained response to the ketogenic diet can allow for the successful withdrawal of some or all AEDs in some patients. However, there is no data on the use of the diet in adults.
New data on women and epilepsy
Data from the UK Epilepsy and Pregnancy Register and similar registers across the world mean that a lot more is known about the risks of AEDs during pregnancy than was the case in 2004. So the new recommendation is much more detailed than the one included previously, citing specific concerns over the use of valproate in pregnancy – although we still know less about the newer drugs.
The 2012 recommendation states that the risk of AEDs causing malformations and possible neurodevelopmental impairments in an unborn child should be discussed with women of childbearing age. But it also stresses those discussions need to take place with young girls who will probably need to take AEDs into their childbearing years, and their parents if appropriate.
The continued use of valproate is of particular concern, especially with higher doses – over 800mg a day – which are associated with greater risk. Multi-drug combinations are also of concern – especially if they include valproate.
There is also a new recommendation about the interaction between lamotrigine and oestrogen-based contraceptives, which can result in a significant reduction in lamotrigine levels.
The key changes at a glance
- Carbamazepine should be prescribed as a controlled-release formulation.
- A first anti-epilepsy drug (AED) should be chosen on a diagnosis of seizure syndrome when possible,
- but seizure type if not.
- Lamotrigine and carbamazepine are first-line options for newly diagnosed focal seizures.
- Valproate is now the preferred first-line option for newly diagnosed generalised tonic-clonic seizures – lamotrigine if valproate is unsuitable.
- All AEDs appear to be associated with a small increased risk of suicidal thoughts and behaviour – possibly within a week of starting treatment.
- Children who have not responded to AEDs should be referred for a ketogenic diet.
- The risks of AEDs to the unborn child should be discussed with women and young girls – doses of valproate higher than 800mg a day and multi-drug combinations, especially if they contain valproate, are of particular concern.
Dr Jane Williamson is a GP in Birmingham and an associate specialist in epilepsy
1 NICE. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (update). 2012;CG137
2 Powell G, Saunders M and Marson A. Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy. Cochrane Database Syst Rev 2010;1:CD007124
3 Marson A, Al-Kharusi A, Alwaidh M et al, on behalf of the SANAD study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000-15
4 Marson A, Al-Kharusi A, Alwaidh M et al, on behalf of the SANAD study group. The SANAD study of effectiveness of valproate, lamotrigine or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1016-26
5 Bagary M. Epilepsy, anti-epileptic drugs and suicidality. Curr Opin Neurol 2011;24:177-82
Go to pulse-learning.co.uk for a case-based learning module on epilepsy worth a suggested 2 CPD hours. Hot topics in epilepsy uses four primary care case histories to update you on the new NICE guidance, but also includes the new QOF indicators, guidance on contraception and epilepsy, and the latest research on sudden death in epilepsy.