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Abstract
The epilepsies of childhood are a heterogeneous group of disorders with different causes, treatments and outcomes. The choice of anti-epileptic drug is largely determined by its effectiveness in a specific epilepsy syndrome, or seizure type(s) if a syndrome cannot be readily identified, and the drug's safety profile. There are minimal randomised controlled trial data to help inform this decision. In January 2012, the National Institute for Health and Clinical Excellence (NICE) published its partially revised and updated clinical guideline on the pharmacological treatment of the epilepsies in children and adults. This partial update provides additional data and also specific recommendations that improve the evidence base for the use of specific anti-epileptic drugs in treating the epilepsies of childhood.
- Therapeutics
- Epilepsy
- Anti-epileptic drugs
- NICE
- Recommendations
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Background
The specific epilepsy syndrome or seizure type(s), effectiveness and safety profile largely determine the choice of anti-epileptic drug (AED). Therefore, it is important to update prescribers when any new data from randomised controlled trials (RCTs) become available; unfortunately, there is a lack of good RCTs of AEDs in children. However, January 2012 saw the publication of the revised and partially updated clinical guideline from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis and management of the epilepsies in adults and children.1 The guideline updates and replaces the pharmacological recommendations in NICE's 2004 version (CG20) as there was uncertainty over whether the newer AEDs provided additional clinical benefits vis-a-vis their cost for seizure control. Previously, the available evidence from NICE technology appraisals (TA)2 ,3 and the full guideline published in 20044 showed no difference in effectiveness between the newer and older AEDs as monotherapy for seizure control. However, following publication of the results of the large national SANAD trial5 ,6 and other limited new randomised data on AEDs, NICE and its stakeholders felt that this new evidence should be reviewed and a partial update of the clinical guideline provided. The NICE Guidelines Manual indicates that review for update is considered 3 years after publication. Exceptionally, if further evidence becomes available that might impact on current recommendations, this review process may be conducted sooner.
Updating the guidelines took almost 3 years, and was undertaken by the specifically recruited and independent Guideline Development Group (GDG); the authors were the three paediatric members of this group. The GDG was comprised of a psychiatrist (who chaired the GDG), two patient representatives (who described the patient experience with the third sector (the national voluntary support organisations), two paediatric neurologists (one of whom (JHC) was appointed as clinical advisor), two adult neurologists, a general practitioner, a general paediatrician, a clinical pharmacologist and two epilepsy specialist nurses. The GDG was supported by an excellent project team from the National Clinical Guideline Centre, Royal College of Physicians (London).
Scope
NICE's process for developing or updating its clinical guidelines initially involves a public consultation with registered stakeholders on a draft scoping document; this outlines what the update should and should not cover, based on clinical need and available evidence. After consultation, the final suggestion was that NICE's epilepsy update should provide advice on first-line and adjunctive pharmacological treatments for all seizure types, including refractory focal, generalised tonic-clonic (GTC) and newly diagnosed focal seizures, and absences, in addition to treatment by epilepsy syndrome. The proposal included all AEDs from CG20 and NICE's technology appraisals2 ,3 and five additional drugs (pregabalin, rufinamide, zonisamide, stiripentol and eslicarbazepine) and corticosteroids. Following stakeholder consultation, the proposal was extended to include the ketogenic diet.
NICE considered that it was not necessary to produce separate clinical guidelines for children and adults. Instead separate recommendations are provided throughout the guideline where there is evidence relevant only to children; otherwise, combined recommendations are provided across all ages.
The full guideline, a summary containing all the recommendations, and electronic flowcharts that show how the recommendations relate to other NICE guidance (ie, the NICE Pathway) can be found at www.nice.org.uk/CG137. Simultaneously with the full revised guideline, NICE also published a document specifically addressed to the users of epilepsy services. A shortened and very useful overview was published in the BMJ.7
Methodology
The GRADE methodology (Grade of Recommendations, Assessment, Development and Evaluation; http://www.gradeworkinggroup.org/) was used to assess the different studies which informed the update rather than the traditional and commonly used levels of evidence (I, II and III) and strength of recommendation (A, B, C). The GRADE methodology is used across all NICE clinical guidelines and refers to the quality of available evidence for pre-defined important outcomes for patients rather than the quality of the clinical study (traditionally assessed using levels of evidence). GRADE-based outcomes assessed include:
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proportion of seizure-free patients
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proportion of study participants having at least a 50% reduction in seizure frequency
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proportion of participants having their treatment withdrawn
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the time to the end of the study or to the withdrawal of allocated treatment
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the time to the first seizure
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the time to 12-month remission
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the incidence of adverse events
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any outcomes relating to cognitive effects
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any outcomes relating to quality of life.
GRADE uses four levels of quality of evidence (‘high’, ‘moderate’, ‘low’ and ‘very low’) and two levels of recommendation (‘strong’ and ‘weak’). Predictably, GRADE provides a very rigorous scientific assessment of studies. Consequently, based on the levels of quality of evidence, most studies evaluated in the updated guideline were categorised as being ‘moderate’, ‘low’ or ‘very low’ and only a few as ‘high’. This resulted in a very active and protracted debate among members of the GDG and stakeholders before consensus was achieved.
Health economics and cost-effectiveness are important aspects of all NICE clinical guidelines. Economic models were developed to compare the cost-effectiveness of seven different AEDs for adults with newly diagnosed focal seizures. Of these, lamotrigine was the most cost-effective and carbamazepine was a reasonable alternative. There was substantial uncertainty over levetiracetam, in part because this drug had only just come off patent and a generic tariff had not been established at the time the guideline was published. The same economic model was applied to children but because of extremely limited evidence, conclusions were subject to considerable uncertainty. Another economic model was used to compare the cost-effectiveness of 11 different AEDs licensed for the treatment of adults with refractory focal seizures. Lamotrigine and oxcarbazepine were found to be the most cost-effective; results for children were broadly similar. There was considerable debate on the pragmatism of these cost-effective models and how their results might relate to ‘real life’.
Finally the expertise, experience and opinions of the GDG members and stakeholders, the latter obtained during the consultation process, informed many recommendations. This was important because it reflected everyday clinical practice rather than the rather artificial nature and short duration of various clinical trials, some of which were funded by the pharmaceutical industry. This approach also compensated for lack of data in those areas where there was limited evidence.
Definitions
A few of the GDG definitions as outlined in the updated clinical guideline are explained below.
Age groups: A ‘child’ is a child aged from 1 month to 11 years, while ‘young person’ is used to describe those between the ages of 12 and 17 years and ‘adult’ those aged 18 and over.
‘Specialist’: For a child and young person, the specialist should be a doctor who treats and cares for children (a paediatrician) and who has had special training in diagnosing and treating epilepsy (the term ‘special training’ has not yet been clearly and formally defined but is being currently discussed with the Royal College of Paediatrics and Child Health and the British Paediatric Neurology Association).
‘Tertiary centre’ or ‘tertiary service’: This defines a ‘team’ more than an individual. This team should be “experienced in assessing children with epilepsy that is hard to treat or complicated for other reasons. It should include specialist nurses and doctors who have trained and specialised in treating conditions involving the brain with medication (a neurologist) and with surgery (a neurosurgeon)”. A specific recommendation made in the NICE guideline is that: “It is very important that children who are suspected of having developed epilepsy in the first few years of life (particularly those under 2 years of age) are referred to a specialist centre as soon as possible so that they can be diagnosed and, if necessary, treated to prevent seizures from affecting their development”.
Results
Some of the key recommendations in the updated guideline are given below; the full guideline can be obtained at www.nice.org.uk/CG137. It is also recommended that the reader consults the BMJ article published in January 2012.7 With all AED recommendations, it is important to be aware of their specific paediatric licences applicable when the update was published.
Diagnosis
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All children and young people with a recent onset suspected seizure should be seen urgently by a specialist (the GDG considered that ‘urgently’ meant being seen within 2 weeks). This is to ensure precise and early diagnosis and initiation of therapy as appropriate to their needs.
Investigations
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Children and young people needing an EEG should have the test performed soon (within 4 weeks) after it has been requested.
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In children and young people, consider a 12-lead ECG in cases of diagnostic uncertainty.
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MRI should be the imaging investigation of choice in everyone with epilepsy. MRI is particularly important in those patients who develop epilepsy before the age of 2 years, who have any suggestion of any focal onset on history, examination or electroencephalography (unless there is clear evidence of benign focal epilepsy) and in whom seizures continue despite first-line medication.
Management
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All children and young people should have a comprehensive care plan that is agreed between the person, their family and/or carers as appropriate and primary and secondary care providers.
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It may not be possible to make a definite diagnosis of epilepsy. If the diagnosis cannot be clearly established, further investigations and/or referral to a tertiary epilepsy specialist should be considered. Follow-up should always be arranged.
Starting drug treatment
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When possible, choose which AED to offer on the basis of the presenting epilepsy syndrome. If the epilepsy syndrome is not clear at presentation, base the decision on the presenting seizure type(s) (a new recommendation from 2012 and based on the experience and opinion of the GDG).
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If using carbamazepine, offer controlled release preparations.
Consistency of supply (of anti-epileptic medication)
There has been long-standing concern over the consistency of the preparation of AEDs and specifically changing between their often many generic and usually only single branded preparations.8 ,9 The guideline includes a specific recommendation on this issue.
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Consistent supply to the child, young person or adult with epilepsy of a particular manufacturer's AED preparation is recommended, unless the prescriber, in consultation with the child, young person or adult, considers that this is not a concern. In the case of a child or young person this discussion may involve the parent or carer as well. Different preparations of some AEDs may vary in bioavailability or pharmacokinetic profiles and care needs to be taken to avoid reduced effect or excessive side effects. The prescriber is advised to consult the summary of product characteristics and the British National Formulary (available at www.bnf.org) on the bioavailability and pharmacokinetic profiles of individual AEDs, but note that these do not give information on comparing the bioavailability of different generic preparations (new recommendation).
First-line treatment for newly diagnosed focal seizures
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Offer carbamazepine or lamotrigine as first-line treatment to children and young people with newly diagnosed focal seizures (new recommendation).
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Consider adjunctive treatment if a second, well-tolerated AED is ineffective (new recommendation).
First-line treatment for newly diagnosed GTC seizures
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Offer sodium valproate as first-line treatment to children and young people with newly diagnosed GTC seizures. When prescribing sodium valproate to women and girls of present and future childbearing potential, discuss the possible risk of malformation and neurodevelopmental impairments in a young child, particularly with high doses of this AED or when using as part of polytherapy (new recommendation).
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Offer lamotrigine if sodium valproate is unsuitable. If the person has myoclonic seizures or is suspected of having juvenile myoclonic epilepsy, be aware that lamotrigine may exacerbate myoclonic seizures.
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Consider carbamazepine and oxcarbazepine, but be aware of the risk of exacerbating myoclonic or absence seizures (new recommendation).
First-line treatment for absence seizures
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Offer ethosuximide or sodium valproate to children and young people with absence seizures. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable. Be aware of teratogenic risks of sodium valproate (new recommendation).
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Offer lamotrigine if ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated (new recommendation).
First-line treatment in infants with infantile spasms
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Discuss with, or refer to, a tertiary paediatric epilepsy specialist when an infant presents with infantile spasms.
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Offer a steroid (prednisolone or tetracosactide) or vigabatrin as first-line treatment to infants with infantile spasms that are not due to tuberous sclerosis. Carefully consider the risk–benefit ratio when using vigabatrin or steroids (new recommendation).
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Offer vigabatrin as first-line treatment to infants with infantile spasms due to tuberous sclerosis. If vigabatrin is ineffective, offer a steroid (prednisolone or tetracosactide). Carefully consider the risk–benefit ratio when using vigabatrin or steroids (new recommendation).
Prolonged or repeated seizures and convulsive status epilepticus
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Only prescribe buccal midazolam or rectal diazepam for use in the community for children and young people who have had a previous episode of prolonged or serial convulsive seizures (new recommendation).
Ketogenic diet
There was also a specific recommendation on the use of the ketogenic diet in treating epilepsies in childhood.
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Refer children and young children with epilepsy whose seizures have not responded to appropriate AEDs to a tertiary paediatric epilepsy specialist for consideration of the use of a ketogenic diet (new recommendation).
Advice for women and girls with epilepsy
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Discuss with women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), and their parents and/or carers if appropriate, the risk of AEDs causing malformations and possible neurodevelopmental impairments in an unborn child. Assess the risks and benefits of treatment with individual drugs. There are limited data on risks to the unborn child associated with newer drugs. Specifically discuss the risk of continued use of sodium valproate to the unborn child, being aware that higher doses of sodium valproate (>800 mg a day) and polytherapy, particularly with sodium valproate, are associated with greater risk (new recommendation).
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Discuss with women and girls who are taking lamotrigine that the simultaneous use of any oestrogen-based contraceptive can result in a significant reduction in lamotrigine levels and loss of seizure control. When a woman or girl starts or stops taking these contraceptives, the dose of lamotrigine may need to be adjusted.
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Do not routinely monitor AED levels during pregnancy. If seizures increase or are likely to increase, monitoring AED levels (particularly levels of lamotrigine and phenytoin, which may be particularly affected in pregnancy) may be useful when making dose adjustments (new recommendation based on the experiences and opinion of the GDG).
People with learning difficulties (a new recommendations based on the experience and opinion of the GDG)
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Ensure adequate time for consultation to achieve effective management of epilepsy in children and young people with learning disabilities.
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Do not discriminate against children and young people with learning disabilities and offer the same services, investigations and therapies as for the general population.
Finally, the updated clinical guideline1 included a recommendation on possible future research in the epilepsies and cited five specific topics: an evaluation of the efficacy of the newer AEDs in the treatment of newly diagnosed focal and generalised epilepsies; the initial and add-on AEDs of choice in the treatment of the epilepsy syndromes with an onset in childhood (including Dravet syndrome); the most effective and safest anticonvulsant in the treatment of established and refractory convulsive status epilepticus; the malformation rate and longer term neurodevelopmental outcome of children born to mothers who have taken AEDs in pregnancy; and the effectiveness of the ketogenic diet in adults with epilepsy.
Conclusions
The specific pharmacological updates and their recommendations will have implications for both adults and children with epilepsy and their medical practitioners. In children, this reflects appropriate focus on specific epilepsy syndromes, most of which have an onset in childhood, and on the fact that the vast majority of new prescriptions for AEDs will be initiated in secondary or tertiary and not primary care. In part this reflects the unease experienced by most primary care physicians (general practitioners) when asked to prescribe unlicensed or off-label AEDs in children.10 ,11
The updated clinical guideline on epilepsy is likely to have positive national consequences. However, the guideline means, and will mean, nothing and may have little impact without the commitment of and implementation by the entire NHS. If the guideline is not universally adopted, practice is likely to continue to vary depending on the patient's postcode, the attitude of the local primary care trust (or its equivalent replacement), other commissioners and the championing of the various recommendations by the specialist and tertiary epilepsy team. The hope is that everyone, regardless of their postcode or primary care trust, will have access to the care recommended in this guideline.
Acknowledgments
The authors are very grateful to the following project team members from the National Clinical Guideline Centre, London, for their advice, guidance and comments on this review: Vanessa Delgado Nunes, MSc, Guideline Lead and Senior Research Fellow; Laura Sawyer, MSc, Senior Health Economics Consultant, Symmetron Limited (previously of the National Clinical Guideline Centre); Julie Neilson, MSc, Senior Research Fellow; Dr Grammati Sarri, Senior Research Fellow; and Susan Latchem, Operations Director.
Footnotes
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Contributors REA conceived of the article, fully supported by AF and JHC. REA prepared and wrote the first draft; AF and JHC contributed equally to all revisions and all subsequent drafts.
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Competing interests Professor J Helen Cross was clinical adviser to the project team of the National Clinical Guideline Centre. The other two authors have no competing interests.
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Provenance and peer review Not commissioned; externally peer reviewed.