Treatment Outcomes in Epilepsy
Submitting InstitutionUniversity of Liverpool
Unit of AssessmentPublic Health, Health Services and Primary Care
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences
Summary of the impact
The epilepsy research group at the University of Liverpool (UoL) has
undertaken a programme of work assessing treatment outcomes associated
with antiepileptic drug treatment in patients with epilepsy. This includes
two large pragmatic trials in patients with first seizures and newly
diagnosed epilepsy, and cohort studies assessing malformations and
cognitive development in children exposed to antiepileptic drugs in utero,
and the work of the Cochrane Epilepsy Group.
This work has influenced prescribing in the UK and worldwide through the
- Triggered NICE guidelines update (2012), underpinning guidance on
management of first seizures, new epilepsy, women with epilepsy
- Changes to drug labelling (SPC) for sodium valproate (2011)
- Informed guidance in other countries (e.g. German guidelines,
International League Against Epilepsy Guidelines; US Medicine
- Underpinned UK and EU policy on driving following first seizures and
antiepileptic drug withdrawal
The underpinning research was undertaken at the UoL between 1993 and 2013
and informs treatment decisions, guidelines and policy for people with
epilepsy through randomized controlled trials, cohort studies, systematic
review, prognostic modelling and statistical method development. It
addresses the key clinical questions: when to start treatment and which is
the appropriate treatment. These questions require assessment of both
benefit and harm.
Key researchers from the UoL are Profs A Marson, G Baker, P Williamson, A
Jacoby, D Chadwick (retired) and Dr C Tudur-Smith. The MRC Multicentre
Study of Early Epilepsy and Single Seizures (MESS 1993-2000) recruited
1,400 patients and compared the policies of immediate and deferred
treatment for patients presenting with single seizures and early epilepsy.
This trial provides the best evidence worldwide to inform decisions about
when to start treatment. Results showed that early treatment reduced the
risk of a recurrence but had no effect on longer term seizure outcome or
quality of life; and ends the long-standing debate that `seizures beget
seizures' in early epilepsy. Predictive modelling of data identified
patients at low, medium and high risk of recurrence, informing risk
prediction and thus clinical decisions. Data have also been modelled to
underpin driving policy in the UK and EU following a process to harmonise
legislation across the EU. Models identified time points at which it is
appropriate to allow patients to return to driving and identified patients
at higher risk.
The NIHR Health Technology Assessment Programme funded study of Standard
and New Antiepileptic Drugs (SANAD 1998-2006) compared clinical, quality
of life and cost effectiveness outcomes for standard and new antiepileptic
drugs for patients with newly diagnosed epilepsy. This trial provides the
best evidence worldwide to inform decisions about which is the drug of
choice for particular patients. This trial identified lamotrigine, a new
drug, as a first line treatment for newly diagnosed focal epilepsy, being
as effective as the standard treatment, carbamazepine, but better
tolerated, and cost effective. For generalised epilepsy patients,
valproate, the standard treatment, was identified as the most effective
treatment. This poses a significant challenge for the management of a
particular patient subgroup, women of child bearing potential, for whom
there is growing evidence that valproate is associated with a higher
This challenge is being addressed through the Liverpool group's
collaboration with colleagues in Manchester and the US in a series of
cohort studies assessing outcomes in children exposed to antiepileptic
drugs in utero. In their large prospective study the Liverpool Manchester
Neurodevelopment Group found a significant impact of sodium valproate
exposure on cognitive development, particularly verbal IQ, in children
assessed up to the age of 2 years. The NEAD study group (a UK/US NIH
funded collaboration) found that in utero exposure to sodium valproate had
a significant and negative impact on the IQ of children when assessed at
age 3 and 6 years in comparison to children exposed to other antiepileptic
drugs (carbamazepine, lamotrigine, and phenytoin). Further, the UoL UK
study demonstrated significant risks associated with in utero exposure to
Sodium Valproate in comparison with control children across key areas of
neuropsychological functioning, as well as an association with autism.
The Cochrane Epilepsy Group has its editorial base in Liverpool (NIHR
funded, Marson Coordinating Editor, Tudur Smith Statistical Editor) has
produced over 60 systematic reviews, focussing on drug treatments and
other interventions for epilepsy. These reviews also underpin guidance
provided by NICE in their 2012 epilepsy guidelines.
References to the research
1. Marson A, Jacoby A, Johnson A, Kim L, Gamble C,
and Chadwick D. Medical Research Council MESS Study Group.
Immediate versus deferred antiepileptic drug treatment for early epilepsy
and single seizures: a randomised controlled trial. Lancet 2005.
365(9476):2007-13 Citations: 155 Impact Factor: 39.060
2. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA,
et al. The SANAD study of effectiveness of carbamazepine, gabapentin,
lamotrigine, oxcarbazepine, or topiramate for treatment of partial
epilepsy: an unblinded randomised controlled trial. Lancet
2007;369:1000-1015. Citations: 266 Impact Factor: 39.060
3. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA,
et al. Valproate, lamotrigine or topiramate for generalized and
unclassifiable epilepsy: results from the SANAD trial. Lancet
2007;369:1016-1026. Citations: 285 Impact Factor: 39.060
4. Bonnet LJ, Tudur Smith C, Williamson PR, Marson
AG. Risk of recurrence after a first seizure and implications for
driving. Further analysis of the MESS study. BMJ 2010;341:c6477 Citations:
10 Impact Factor: 17.215
5. Meador K, Baker GA, et al. On behalf of the NEAD Study Group.
Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic
Drugs. New England Journal of Medicine (2009) 360 (16), 1597-1605
Citations: 258 Impact Factor: 51.658
Key Research Grants
1993-2002. MRC. Title, £1.3m, PIs Chadwick , Jacoby,
1998-2006. NIHR Health Technology Assessment Programme. Title,
£1.3m, PIs Chadwick, Jacoby, Donaldson
2007-2013. NIHR Programme Grant. Title, £515k, PIs Marson AG,
Jacoby A, Baker GA, Williamson PR, Tudur Smith
2003 to 2013. US NIH Grant. Neurodevelopmental study of children
exposed in utero £708,187. PI Baker GA
2009 to 2012 Epilepsy Research Foundation Cognitive consequences
of in utero exposure to second generation antiepileptic drugs £100,000.00
PI Baker GA
2009 to2013. Sanofi Sythelabo Educational Grant. Support for the
NEADS study: Antiepileptic Drugs exposure in utero £166,501.00 PI Baker
2011-2016. NIHR. Core support for the Cochrane Epilepsy Group.
£500k. A Marson.
Details of the impact
The SANAD Trial identified lamotrigine as first line treatment for
patients with focal epilepsy. This drug was demonstrated to be clinically
and cost effective to the NHS. SANAD also identified valproate as the most
effective treatment for patients with generalised epilepsy. A network
meta-analysis of similar antiepileptic drug trials provides the best
overview of currently available evidence. Prognostic modelling of these
data allow the identification of patients at differing risk of seizure
remission, allowing stratification for outcomes in patient consultations.
This work had the following impacts:
- SANAD triggered an update of the NICE epilepsy guideline which was
published in 2012 . This provides impact on the health and wellbeing
of over 32,000 people per year who are newly diagnosed with epilepsy as
well as over half of the 600,000 prevalent population that are treated
with antiepileptic drug monotherapy.
- Data from SANAD and the network meta-analysis underpins the 2012
guidance provided by NICE. Lamotrigine is recommended as a first line
treatment for focal epilepsy while gabapentin and topiramate are not.
Valproate is recommended as a first line treatment for generalised
epilepsy while topiramate is not. Identifying topiramate and gabapentin
as poor choices for monotherapy has resulted in significant savings for
- SANAD underpins guidance in other countries (e.g. German epilepsy
guidelines , International League Against Epilepsy (ILAE guidelines)
- SANAD allows better understanding of the impacts of taking
antiepileptic drugs, including: that there are few important differences
between drugs in quality of life outcomes; and that cognitive impairment
associated with epilepsy is more likely related to underlying pathology
than the drugs. This understanding will be important in devising future
The MESS trial compared antiepileptic drug treatment versus no treatment
following a first seizure and for early epilepsy and identified a subgroup
of patients likely to benefit from treatment. Further prognostic modelling
identifies patients at risk of recurrence to inform driving policy.
This work had the following impacts:
- MESS data underpin NICE guidance (2012) for patients with first
seizures . The guidance highlights the prognostic modelling to inform
risk stratification and decision making. This informs the management,
impacting on the health and wellbeing, of over 60,000 people who
experience a first unprovoked seizure per annum in the UK.
- Prognostic modelling of data from MESS informed UK and EU driving
policy (2012) [9,10]. Regulations changed for patients with a first
seizure who are allowed to drive once 6 months seizure free rather than
12 months, unless in a high risk group. Designation of `high risk' was
informed by prognostic modelling of MESS.
The aforementioned cohort studies assessing outcomes associated with in
utero exposure to antiepileptic drugs treatment inform treatment decisions
by providing reliable and valid information about the risks to the unborn
children. These studies have quantified risk to cognitive development
associated with a number of antiepileptic drugs and identify sodium
valproate as the drug with the greatest risk. Data allow better informed
decision making and have informed guidelines, and regulators.
This work has had the following impacts:
- Altered prescribing practices in the UK and US: There has been a
substantial reduction in the prescribing of valproate to women with
epilepsy of child bearing age and a subsequent increase in alternative
drugs including lamotrigine and levitaricatem [5,6,15].
- The recommendations of the Federal Drugs Administration  "The
U.S. Food and Drug Administration (FDA) is informing the public that
children born to mothers who take the anti-seizure medication
valproate sodium or related products (valproic acid and divalproex
sodium) during pregnancy have an increased risk of lower cognitive
test scores than children exposed to other anti-seizure medications
during pregnancy. This conclusion is based on the results of
epidemiologic studies that show that children born to mothers who took
valproate sodium or related products throughout their pregnancy tend
to score lower on cognitive tests (IQ and other tests) than children
born to mothers who took other anti-seizure medications during
- Updating of patient information leaflet for the drug Epilim (sodium
valproate), warning of the risks associated following feotal exposures
- The publication of guidelines for preconceptual counselling for WWE
both in the UK and US [12,13,14].
Beneficiaries of this work include
- People with new onset first seizures (60,000 per annum) and epilepsy
(32,000 per annum). The work has identified treatment options with the
best outcomes and has identified benefit harm trade-offs, leading to
better informed treatment choices and a focus on outcomes of importance
and relevance to them.
- The NHS and other health systems caring for people with epilepsy,
through providing effective and cost effective care. Topiramate and
gabapentin were found to be both less effective and more costly and are
rarely used a monotherapy in epilepsy.
- Guideline developers including NICE.
- DVLA and similar EU bodies currently harmonising regulations across EU
Sources to corroborate the impact
Each source listed below provides evidence for the corresponding numbered
claim made in section 4 (details of the impact).
- NICE Guidelines. The diagnosis and management of the epilepsies in
adults and children in primary and secondary care. Clinical Guideline 137,
- German guidelines. Elger CE, Beyenburg S, Dengg D et al. Erster
epileptischer Anfall und Epilepsien im Erwachsenenalter. In: Diener HC,
Putzki N (eds) Leitlinien für Diagnostik und Therapie im der Neurologie.
Stuttgart: Georg Thieme Verlag, 2008.
- ILAE Guidelines http://www.ilae.org/Visitors/Documents/Guidelines-epilepsia-12074-2013.pdf
- DVLA decision to adopt EU recommendations for single seizures. DfT
advisory panel minutes and at a glance guidance: http://webarchive.nationalarchives.gov.uk/20130411225420/http://dft.gov.uk/dvla/medical/medical_advisory_information/medicaladvisory_meetings/minutes/~/media/pdf/medical/mins_
- American Academy of Neurology and American Epilepsy Society
guidelines Management Issues for Women with Epilepsy Neurology 2009
- Royal Society of Medicine Primary Care Guidelines [Managing epilepsy
in women: new guidelines 2004, 2011].
- FDA alert June 2011, http://www.fda.gov/Drugs/DrugSafety/ucm261543.htm
- Updating of patient information leaflet for the drug Epilim [Sodium
Valproate], warning of the risks associated following feotal exposures. http://www.medicines.org.uk/emc/medicine/10913/PIL/Epilim+100mg+crushable+tablets/
- Ackers R, Besag FM, Wade A, Murray ML, Wong IC Changing
trends in antiepileptic drug prescribing
in girls of child-bearing potential. Arch Dis Child. 2009