Alternative treatment for epileptic seizures in children

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EpilepsyThe anti-convulsant drug levetiracetam could be considered as a first-choice second-line treatment for the management of paediatricc onvulsive status epilepticus (CSE), found a three-year randomised clinical trial involving 30 UK emergency departments.

The study involved researchers from the University of Liverpool and Alder Hey Childrens Hospital Trust.

Every day in the UK, 87 people are diagnosed with epilepsy, affecting over 600,000 people. Many people with a new diagnosis of epilepsy will experience memory and other cognitive problems. The cause of these problems is unknown.

It has an annual incidence of 20 per 100,000 children, and is the second most common reason for unplanned admissions to paediatric intensive care units (PICUs) in the UK. Anti-epileptic drugs (AEDs), also known as anticonvulsants, are used to control seizures in people with epilepsy. Convulsive status epilepticus (CSE) is the situation when a tonic-clonic seizure doesn’t stop either on its own or with anticonvulsants. It is the most common life-threatening neurological emergency in children.

Currently, CSE is treated using an algorithm which incorporates 10 minute intervals between treatments. Second-line treatment is given when CSE persists either after two doses of the first-line treatment, which is an anticonvulsant called a benzodiazepine, or the child’s personalised emergency (rescue) treatment.

The anticonvulsant medication phenytoin has been used as the usual second-line treatment of CSE for several decades and is known to have rare but potentially dangerous side effects. However, some evidence suggests that another medication, levetiracetam could be an effective and safer alternative. To ascertain which treatment was safest and most effective the EcLiPSE Team, made up of doctors from Alder Hey and Bristol Childrens Hospitals together with research teams from the Universities of Liverpool and the West of England, conducted a trial to compare the efficacy and safety of both drugs for second-line management of CSE.

The EcLiPSE Team is led by Professor Richard Appleton, a Merseyside paediatric neurologist based at the University of Liverpool’s department of women’s and children’s health, and Alder Hey Children’s Hospital Trust.

Between 2014 and 2018 the team conducted a randomised clinical trial involving 30 UK emergency departments and almost 300 children.

The results did not show that levetiracetam was better than phenytoin, in stopping CSE. However, overall the results suggest levetiracetam may be considered as an alternative treatment to phenytoin.

Appleton, said: “The EcLiPSE trial has given doctors new and unique evidence for the choice of anticonvulsant and how to best treat this childhood neurological emergency. Our results suggest that levetiracetam could be considered as an alternative treatment to phenytoin for second-line management of paediatric CSE. Possible benefits of levetiracetam over phenytoin include its ease of preparation and administration, minimal interaction with anti-epilepsy and other drugs, and easy conversion to oral maintenance therapy. Further randomised clinical trial and meta-analysis data could help to confirm our results and might lead to levetiracetam being the preferred second-line anticonvulsant in children with benzodiazepine-resistant convulsive status epilepticus.

“The trial also highlights the importance of close and effective collaboration between two specialities in paediatrics, neurology and emergency medicine that will improve the care of children with epilepsy.”

The study was supported by PERUKI (Paediatric Emergency Research in the UK and Ireland) and funded by the National Institute for Health Research (NIHR) HTA (Health Technology Assessment) programme.

Abstract
Background: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.
Methods: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.
Findings: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]).
Interpretation: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus.

Authors
Mark D Lyttle, Naomi E A Rainford, Carrol Gamble, Shrouk Messahel, Amy Humphreys, Helen Hickey, Kerry Woolfall, Louise Roper, Joanne Noblet, Elizabeth D Lee, Sarah Potter, Paul Tate, Anand Iyer, Vicki Evans, Richard E Appleton, Matthew Pereira, Susie Hardwick, Shrouk Messahel, Joanne Noblet, Elizabeth D Lee, Rachel Greenwood-Bibby, Mark Buchanan, Lucy Lewis, Sharon Hughes, Stuart Hartshorn, Louise Rogers, Juliet Hopkins, Mark D Lyttle, Daphin Fernandez, Sarah Potter, Holly R Lavigne-Smith, Phoebe Moulsdale, Alice Smith, Tracey Bingham, James Ross, Natasha Ramsey, Jo Hacking, Niall Mullen, Paul P Corrigan, Sarah Prudhoe, Hani Faza, Gisela Robinson, Rachel C Sunley, Coral J Smith, Vanessa Unsworth, John Criddle, Martin Laque, Alyce B Sheedy, Mark Anderson, Kathryn Bell, Kirsty Devine, Alex Scott, Ramesh Kumar, Sonia Armstrong, Emer Sutherland, Fleur Cantle, Sinead Helyer, Paul Riozzi, Hannah Cotton, Alice J Downes, Helen Mollard, Damian Roland, Felix Hay, Christopher Gough, Sonya Finucane, Catherine Bevan, Rebecca Ramsay, Emily Walton, Julie-Ann Maney, Elizabeth Dalzell, Muriel Millar, Rachel J Howells, Andy Appelboam, Daisy Mackle, Jennie Small, Ashleigh Neil, Vince Choudhery, Stewart MacLeod, Jen Browning, Thomas O’Neill, Julia Grahamslaw, Ami Parikh, Imogen Skene, Rhys Thomas, Katherine Potier de la Morandiere, Jill L Wilson, Donna Danziger, Derek Burke, Shammi Ramlakhan, Jayne Evans, Julie Morcombe, Stuart Gormley, Jason M Barling, Katrina Cathie, Jane Bayreuther, Ruth Ensom, Yasser Iqbal, Sarah Rounding, Joanne Mulligan, Claire Bell, Shona McLellan, Shona Leighton, Tina Sajjanhar, Maggie Nyirenda, Laura Crome, Neil Williamson, Anastasia Alcock, Sara Edwards, Jeff Morgan, Colin VE Powell, Chaniyil A Ramesh, Solomon Kamal-Uddin, Mike Linney, Katia Vamvakiti, Sharon Floyd, Gill Hobden

University of Liverpool material
The Lancet abstract


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