3 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

3.1 Newly diagnosed seizures (focal and generalised) – monotherapy

How do the newer AEDs compare in efficacy to the standard AEDs in the treatment of newly diagnosed epilepsy?

  • Focal seizures: carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, pregabalin[26] and zonisamide.

  • Generalised seizures: lamotrigine, levetiracetam, sodium valproate and zonisamide.

Why this is important

Levetiracetam and other AEDs licensed for the treatment of focal and generalised seizures since publication of the original NICE guideline on epilepsy in 2004 have not been evaluated as first-line monotherapy.

The research should include:

  • a prospective randomised controlled trial

  • all age groups

  • subgroup analyses on seizure types and syndromes

  • primary outcome of seizure freedom

  • secondary outcomes, including seizure reduction, quality of life and cognitive outcome

  • an attempt to obtain data on pharmaco-resistance.

3.2 Epilepsy syndromes

What are the initial and add-on AEDs of choice in the treatment of the epilepsy syndromes with onset in childhood, for example, myoclonic-astatic epilepsy and Dravet syndrome?

Why this is important

Despite the need to diagnose individual epilepsy syndromes, there is little evidence on the most appropriate initial or add-on AEDs in the treatment of the rarer epilepsies.

The research should include:

  • multicentre randomised controlled comparative trials with centralised national data collection

  • the ketogenic diet as one of the randomised treatments

  • primary outcome of seizure freedom

  • secondary outcomes, including seizure reduction, quality of life and cognitive outcome

  • an attempt to obtain data on pharmaco-resistance

  • the possibility of including all children with specific epilepsy syndromes for consideration in the trial.

3.3 Infantile spasms

Does treatment response relate to cause in infantile spasms? Does early treatment success in seizure control and resolution of the hypsarrhythmic EEG influence the long-term developmental and cognitive outcomes more than the underlying cause of the spasms?

Why this is important

The UK Infantile Spasms Study (UKISS)[27] demonstrated 14-day outcome efficacy of steroids over vigabatrin, although this excluded children with tuberous sclerosis. This study provided no specific subgroup analysis based on the cause of the spasms. There was also no analysis on the effect of treatment lag (delay) on the study findings. Further data are available on behavioural outcomes with different treatments at 14 months and 4 years but with no analysis based on cause or treatment lag. Further developmental and cognitive outcomes would be useful, including response by specific cause and by treatment lag.

The research should include:

  • prospective randomised design, including subgroup analyses based on both cause and treatment lag; this would require large numbers of patients and would need to be multicentre, possibly involving Western Europe

  • EEG outcomes

  • developmental status at presentation, and at follow-up

  • an attempt to obtain data on pharmaco-resistance.

3.4 Treatment of convulsive status epilepticus (that is, not just refractory)

What is the most effective and safest AED to treat:

  • established (usually lasting longer than 30 minutes) convulsive status epilepticus

  • refractory convulsive status epilepticus?

Why this is important

Convulsive status epilepticus (CSE) should be treated as an emergency. The most important aspect of treatment is to try to stop the seizure. Prompt, successful treatment of CSE avoids the need for admission to an intensive care unit (ICU). The most commonly used medication is phenytoin. This should be used with care and close monitoring because of the risk of hypotension and cardiac arrhythmia. Sodium valproate and levetiracetam are potentially as effective and safer alternatives but there are very limited comparative data.

CSE that is refractory to first-line treatment (RCSE) is rare and often complicated by irreversible neurological and intellectual sequelae, including death. Reasons for these complications include the underlying cause of RCSE, its duration and management. The majority, if not all patients with RCSE are managed in an ICU. There are no agreed drugs or treatment protocols for treating RCSE. The three most commonly used anticonvulsants are thiopental sodium, midazolam and propofol (propofol is rarely used in children). Data on treatment in children, young people and adults are limited and anecdotal. A recently completed 2-year audit of everyone younger than 16 years with RCSE treated in an ICU in England, Wales and Scotland will provide unique epidemiological data on paediatric RCSE, its causes and current management. These data could be used to design a randomised controlled trial (RCT) of specific drug treatments and protocols.

The research should include:

  • a multicentre randomised comparative trial of intravenous levetiracetam, sodium valproate and phenytoin in initial treatment of status epilepticus

  • a multicentre RCT of treatment of refractory status epilepticus in ICUs, including midazolam and thiopental sodium (and propofol in adults)

  • primary outcome of cessation of CSE

  • secondary outcomes including recurrence within a designated period (probably 12 hours), mortality and morbidity

  • cost data including treatment costs and days in intensive care.

3.5 AEDs and pregnancy

What is the malformation rate and longer term neurodevelopmental outcome of children born to mothers who have taken AEDs during pregnancy?

Why this is important

Pregnancy registers are increasing the data that are available on established AEDs; however, these registers may give malformation rates but do not provide controlled long-term data on neurodevelopmental outcome.

The research should include:

  • measures of maternal outcome, including seizure frequency and quality of life

  • major and minor rates of congenital malformations

  • prospective neurodevelopmental (including cognitive) and behavioural outcomes in children born to women and girls with epilepsy (these should be undertaken on a long-term basis and ideally using a cohort study, followed from birth until adult life).

[26] As of 1 April 2019, gabapentin and pregabalin are Class C controlled substances (under the Misuse of Drugs Act 1971) and scheduled under the Misuse of Drugs Regulations 2001 as Schedule 3. Evaluate patients carefully for a history of drug abuse before prescribing and observe patients for development of signs of abuse and dependence (MHRA, Drug Safety Update April 2019).

[27] Lux AL, Edwards SW, Hancock E et al. (2004) The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 364: 1773–8.

  • National Institute for Health and Care Excellence (NICE)