This site is intended for health professionals only

Drug treatment of epilepsy: antiepileptic drugs

A Gaitatzis
MRCP
Clinical Research Fellow in Neurology

P Hosking
RGON MSc
Epilepsy Nurse Specialist

JW Sander

MD MRCP PhD
Professor of Neurology and Clinical Epilepsy

Department of Clinical and Experimental Epilepsy
University College London Institute of Neurology
National Hospital for Neurology and Neurosurgery
London
National Society for Epilepsy
Buckinghamshire

An epileptic seizure is produced by abnormal synchronised discharge of neurons in the cortex of the brain. It consists of sudden and transitory abnormal phenomena, which may include alterations of consciousness, as well as motor, sensory, autonomic or psychic events, perceived by the patient or an observer.
In the first part of this series,(3) we looked at the management of epilepsy in primary care. This second part looks specifically at antiepileptic drugs (AEDs).
AED treatment is initiated following a diagnosis of epilepsy, based on the occurrence of at least two unprovoked epileptic seizures. The aim of treatment is to control seizures with a single AED (monotherapy) that is well tolerated by the patient. A second drug can be introduced if the first one doesn't control seizures, either as a replacement or as an add-on (adjunctive).
All AEDs have associated side-effects, such as lethargy, dizziness, headache, nausea and tiredness. Each AED has its own profile of side-effects. These can be dose-related or toxic (such as tremor or ataxia associated with valproate), idiosyncratic/hypersensitive (such as the rash seen with lamotrigine) or long-term (osteoporosis associated with chronic use of phenytoin).
About 70% of patients are expected to be seizure-free with optimal AED treatment. The remaining 30% of patients develop refractory epilepsy, meaning that their seizures are not controlled with a combination of AEDs and/or they suffer from intolerable side-effects. This has profound consequences on patients' wellbeing. Over the last 12 years a number of new AEDs have been marketed  to complement treatment with the conventional "old" AEDs. The new AEDs currently licensed in the UK are lamotrigine, gabapentin, oxcarbazepine, tiagabine, topiramate, levetiracetam and vigabatrin,(4) although the latter is now given only in children with West's syndrome, because of the development of nonreversible visual field defect in more than 70% of patients on this treatment.
The initial choice of AED depends largely on the type of seizure. All new AEDs can be given as add-on treatments in patients with partial epilepsy, although their role has been expanding as more information and experience is accrued.
Firstline AEDs for partial seizures (most commonly of temporal lobe origin) are carbamazepine, oxcarbazepine, sodium valproate and lamotrigine. Secondline AEDs includes gabapentin, levetiracetam, topiramate and phenytoin. Simple (patient aware of the event), complex (impairment of consciousness) and secondarily generalised (becoming tonic-clonic) partial seizures are all treated in the same way.
Firstline AEDs for all types of generalised seizures are sodium valproate and lamotrigine. This extends to ethosuximide for absence seizures (previously called "petit-mal", these seizures last for seconds and may include minor automatisms), and clonazepam for myoclonic seizures (simple or multiple jerks, often upper limbs). Secondline drugs for generalised tonic-clonic seizures (previously called "grand-mal") include topiramate and levetiracetam.
The optimal use of AEDs also depends on the drug's metabolism, its potential for interaction with other drugs, the frequency of administration (compliance is improved with dosing once or twice daily), and side-effect frequency and profile. This is particularly important when treating special populations (see below).

AEDs and women
Contraception

Women on hepatic enzyme-inducing AEDs (phenytoin, carbamazepine, barbiturates) or topiramate wishing to take the combined oral contraceptive pill should:

  • Start with 50mg ethinyl oestradiol daily.
  • If breakthrough bleeding occurs, increase the dose to 75-100mg daily or consider taking three packs of the pill without a break ("tricycling").
  • Take additional birth control measures until the pattern of bleeding has been stable for at least three months.

Pregnancy
Women should take folic acid 5mg daily in the preconception period and throughout the pregnancy. The AED that provides the best seizure control in monotherapy should be chosen. Phenytoin, ­carbamazepine, ­phenobarbitone and sodium valproate have been associated with increased risk of major and minor malformations. New AEDs appear to be safer, especially gabapentin, tiagabine, lamotrigine and levetiracetam, although full information in humans is still lacking.
No predictions can be made regarding the effect of pregnancy in epilepsy. Women on hepatic enzyme-inducing AEDs should take vitamin K(1) 20mg daily in the last month of pregnancy (to prevent ­haemorrhagic disease of the newborn).

Breastfeeding
All women with epilepsy should be encouraged to breastfeed. Feeding difficulties, irritability and drowsiness can occur in breastfed babies, particularly in mothers taking barbiturates and benzodiazepines. In this case, alternate breast- and bottle feeding is advised.

Menopause
Long-term treatment with hepatic enzyme-inducing AEDs can cause osteomalacia and osteoporosis (because of increased metabolism of vitamin D). All postmenopausal women with epilepsy on enzyme-inducing AEDs should receive HRT provided there is no clinical contraindication. Vitamin D and calcium should be prescribed according to dietary needs and if there is ­evidence of reduced mineral density.

AEDs and adolescents
Compliance can be an important problem with adolescents. Also, alcohol, lack of sleep, and flickering lights (in the case of photosensitive epilepsy) can exacerbate or trigger seizures. Information needs to be provided on contraception, driving and minimising risk of injury during an attack. Sodium valproate can be used but is associated with weight gain, polycystic ovaries, hyperandrogenism and teratogenicity (spina bifida). In this context lamotrigine is a safer alternative.

AEDs and the elderly
Phenytoin is best avoided in newly diagnosed cases; it appears to be commonly used, but interactions with other drugs, and serum concentration-dependent neurotoxicity, can be a problem, even at low doses and during acute illness. Lamotrigine, carbamazepine/oxcarbazepine (beware of hyponatraemia), sodium valproate, gabapentin and levetiracetam appear to be safer.
Patients with partial seizures not responding to treatment with various combinations of AEDs may be considered for surgery, should certain conditions apply. This involves resection of the abnormal area of the brain that is responsible for the generation of seizures and can be curative if applied properly. Another option, although palliative, is vagal nerve stimulation. Only a small percentage of patients are candidates for these procedures, which require a rigorous selection process in specialised tertiary centre facilities with the appropriate expertise.

Further information
The standards of care for people with epilepsy have been assessed in a recent report produced by the Clinical Standards Advisory Group (CSAG).(5) It suggested that "there is [still] a lack of focus for services and lack of coordination between primary care, secondary care, specialist centres and the voluntary sector". Various recommendations to improve epilepsy services have been published over the last three years. With regards to primary care, it has been specified that all new patients should be referred to a specialist with an interest in epilepsy within four weeks,(6) and that primary care-based patient management should be closely integrated with epilepsy specialists in secondary care. It also recommends the appointment of clinical nurse specialists and increased liaison between primary, secondary and tertiary care.(7) It has been proposed that at least one GP within a group practice or PCG should take a lead role in epilepsy care, and take responsibility for implementing change at primary care level.(5) It is hoped that the above recommendations will form the basis of the epilepsy element of the newly developed National Service Framework, a set of standards of care for long-term health conditions with a particular focus on neurological conditions.

Conclusion
The management of epilepsy has advanced considerably over the past 10 years, aided by the addition of new AEDs, improved access to specialist, multidisciplinary services, specialised diagnostic investigations and the expanded role of epilepsy surgery for selected cases. In the UK, the provision of healthcare services is orchestrated at the primary care level. In this setting, improvement in the management of people with epilepsy should aim at improving shared care and communication between primary and secondary/tertiary care.

References

  1. Bell GS, Sander JW. The ­epidemiology of epilepsy: the size of the problem. Seizure 2001;10(4):306-16.
  2. Hopkins A, Shorvon S. Definitions and epidemiology of epilepsy. In: Hopkins A, Shorvon S, Cascino GD, editors. Epilepsy. London: Chapman & Hall Medical; 1995. p. 1-24.
  3. Gaitatzis A, Hosking P, Sander JW. Managing epilepsy in primary care. Nursing in Practice 2002;4:39-41.
  4. Sander JW. New drugs for epilepsy. Curr Opin Neurol 1998;11:141-8.
  5. Clinical Standards Advisory Group. Services for patients with epilepsy. London: Department of Health; 2000.
  6. Joint Epilepsy Council and Epilepsy Task Force. Service Development Kit. Leeds: Joint Epilepsy Council; 1998.
  7. British Epilepsy Association. Epilepsy care: making it happen. A tool kit for today. Leeds: British Epilepsy Association; 1999.

Resources
British Epilepsy Association (Epilepsy Action)
W:www.epilepsy.org.uk

Epilepsy Foundation (US)
W:www.epilepsyfoundation.org

National Society for Epilepsy
W:www.epilepsynse.org.uk

International Bureau of Epilepsy
W:www.ibe-epilepsy.org

American Epilepsy Society
W:www.aesnet.org

Scottish Intercollegiate Guidelines Network
W:www.sign.ac.uk

International League Against Epilepsy
W:www.ilae-epilepsy.org

Driving Regulations DVLA
W:www.dvla.gov.uk/at_a_glance/chl/neurological.htm