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Published on 1 March 2002

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Epilepsy: management and pharmacotherapy

A Gaitatzis
MD MRCP
Clinical Research Fellow in Neurology

JW Sander
MD MRCP PhD
Professor of Neurology and Clinical Epilepsy
Department of Clinical and Experimental Epilepsy
UCL Institute of Neurology

Epilepsy is a condition characterised by recurrent epileptic seizures, unprovoked by any immediately identified cause.(2) Seizures are classified into partial and generalised, according to their origin and manifestation.(3) A separate classification exists for the various types of epilepsy and epilepsy syndromes that is based on seizure type, age of onset, electroencephalogram (EEG) and imaging findings.(4) Depending on its severity and response to treatment, epilepsy may have deleterious effects on a person’s quality of life. This is because epilepsy and its treatment may affect cognitive, psychological and social development, pose lifestyle restrictions, is complicated by other co-occurring disorders and ­treatment side-effects, and is associated with increased mortality and risk of death.(1,5)

Management of epilepsy
The management of patients with epilepsy is based on an accurate diagnosis of epilepsy and the identification –
if possible – of the epileptic syndrome responsible. A misdiagnosis may lead to iatrogenic complications and can have devastating implications on employment and quality of life. Patients presenting with a first seizure should be referred immediately to a hospital specialist with an interest in epilepsy, who should undertake further investigations, such as EEG and magnetic resonance imaging (MRI), to identify the type and cause of epilepsy.

Family and emergency care doctors are often the first to see a patient presenting with a seizure. Their role is to take the history from the patient and a witness, make an initial diagnosis, provide information to the patient, make the initial referral, and initiate treatment if required (ie, if there is a long delay before assessment by the specialist). Continuing care needs to be established and a review plan agreed between patient, specialist and family doctor. Involved doctors should address patient and their carers’ concerns, review seizure control and medication (prescribing, effectiveness, compliance and side-effects), and provide information and advice. Patients should be re-referred to the specialist for issues such as inadequate seizure control, drug withdrawal (usually after a 3–5-year remission) and for preconception counselling.

An emergency referral should be made in the case of seizure clustering or status epilepticus, in patients with prolonged confusional state postictally (consider absence or complex partial status epilepticus), and in patients with a progressive or new brain lesion (suggested by a change in seizure type and/or neurologic deficit).(6)

Pharmacological treatment
The cornerstone of epilepsy treatment is the use of 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.

AED therapy should be started at low doses and titrated up to a low maintenance dose. If seizures continue, the dose should be titrated upwards to a higher maintenance dose level until seizures are controlled or side-effects develop. The frequency of administration is often determined by plasma half-life, and should be kept as low as possible to encourage patient compliance. Most AEDs can be given twice daily when used in average dosage. Some AEDs (such as tiagabine, gabapentin, felbamate and conventional carbamazepine) may require daily administration in three divided doses using large doses to avoid adverse effects associated with high peak plasma concentrations. A second drug can be added if the first one does not control seizures, either as a replacement for the original drug or as an add-on (adjunctive) if seizures are not fully controlled by the added drug. The changeover from one AED regimen to another should be made cautiously, withdrawing the first only when the effectiveness of the new regimen has been established. Before alternative medication is considered, AED dose, patient compliance and diagnosis need to be reviewed.(7)

Interactions between AEDs are complex and may enhance toxicity without a corresponding increase in antiepileptic effect. Hepatic enzyme inducers such as carbamazepine, phenytoin and the barbiturates accelerate the metabolism of other lipid-soluble AEDs, such as tiagabine, lamotrigine, topiramate and felbamate (levels may drop by 50%). Gabapentin, vigabatrin and ­levetiracetam are practically free of pharmacokinetic interactions. Sodium valproate inhibits the metabolism of lamotrigine, extending its half-life to approximately 60 hours (30 hours as monotherapy, 15 hours with enzyme-inducing AEDs). A pharmacodynamic interaction between carbamazepine/oxcarbazepine and lamotrigine will often produce neurotoxicity (headache, dizziness, tiredness, diplopia and ataxia).

Routine serum level monitoring of AEDs is usually employed for phenytoin, carbamazepine and sodium valproate. Ideally, it should be indicated only for: adjustment of phenytoin dose; assessment of compliance in patients with ­apparently refractory seizures; assessment of possible toxic effects (measurement at time of peak levels); assessment during physiological or pathological conditions known to be associated with altered or changing pharmacokinetics (eg, hepatic/kidney ­disease, pregnancy); and assessment of changes in bioavailability caused by changes in drug formulation.

This is because the so-quoted “therapeutic” range of AED concentrations is only a rough guide for determining the appropriate dose. Measurement of levels for the new AEDs is not generally useful and, to date, values have not been clearly established for levetiracetam, oxcarbazepine, topiramate, gabapentin and lamotrigine. Remember to treat the patient and not the drug concentration. Common errors include: increasing drug dosage in patients fully controlled because the concentration is below the quoted range; lowering drug dosage in patients without side-effects because the serum level is above the quoted range; and ignoring adverse effects because the levels are within the quoted range.(7)

About 70% of patients are expected to be seizure-free with optimal AED treatment. The remaining 30% develop refractory (or intractable) epilepsy, meaning that their seizures are not controlled with a combination of AEDs and/or they suffer from intolerable side-effects.(1,5) All AEDs are associated with side-effects, such as lethargy, dizziness, headache, nausea and tiredness, although each AED has its own profile of side-effects. These can be dose-related (toxic: eg, tremor or ataxia associated with valproate), idiosyncratic /hypersensitivity (eg, rash with carbamazepine) or long-term (eg, ­osteomalacia with chronic use of phenytoin). Toxic effects can be managed by reducing the dose by 25–50% and waiting for 1–2 weeks for tolerance to develop. If an idiosyncratic reaction is suspected the drug should be stopped immediately and replaced by a suitable alternative.

Over the last 12 years a number of new AEDs have been marketed in order to complement treatment with the conventional, “old” AEDs. The new AEDs currently licensed in most European countries are lamotrigine, felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, levetiracetam and vigabatrin.(8) The latter is now only given to children with West’s syndrome, because of the development of nonreversible visual field defects over time in more than 70% of patients on chronic treatment. The initial choice of AED depends on the type of seizure. All new AEDs can be given as add-on treatment to 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 include gabapentin, levetiracetam, tiagabine, topiramate and phenytoin. Simple, complex and secondarily generalised partial seizures are all treated the same. Firstline AEDs for all types of generalised seizures are sodium valproate and lamotrigine. Ethosuximide is a firstline option for generalised absence on its own. Secondline drugs for generalised tonic–clonic seizures include topiramate and levetiracetam. It should be noted that phenytoin, carbamazepine and gabapentin are ineffective against, and may even aggravate, absence seizures and myoclonus. Clobazam, a frequently underestimated AED with a broad spectrum of action, can be used as ­adjunctive treatment and is particularly useful for intermittent ­therapy (eg, catamenial epilepsy), one-off prophylaxis  (eg, on days of travel or examinations) and nonconvulsive status epilepticus.(7) The optimal use of AEDs depends on the drug’s metabolism, its potential for interactions with other drugs, frequency of administration (compliance improved with dosing once or twice daily), and side-effect frequency and profile. This is particularly important when treating special populations (see Tables 1–3).

[[HPE03_table1_66]]

[[HPE03_table2_67]]

[[HPE03_table3_67]]

Patients not responding to treatment with various combinations of AEDs may be considered for surgery if certain conditions apply. The goal of therapy in people with intractable seizures, who are not eligible for surgery, is to achieve the best balance between inadequate seizure control and drug-induced side-effects, although the end result is judged by the individual.

Conclusion
Epilepsy management has advanced considerably over the past 10 years, aided by the addition of new AEDs. As the field continues to expand, knowledge of developments in diagnosis and management is essential for healthcare professionals who care for patients with epilepsy. However, apart from the technicalities of epilepsy pharmacotherapy, the patients’ wishes should be respected when formulating a successful therapeutic scheme.

References

  1. Bell GS, Sander JW. The ­epidemiology of epilepsy: the size of the problem. Seizure 2001;10:306-16.
  2. Hopkins A, Shorvon S. Definitions and epidemiology of epilepsy. In: Hopkins A, Shorvon S, Cascino GD, editors. Epilepsy.Lomdon: Chapman & Hall Medical; 1995. p. 1-24.
  3. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.
  4. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99.
  5. Devinsky O. Patients with refractory seizures. N Engl J Med 1999; 340:1565-70.
  6. Browne TR, Holmes GL. Primary care: epilepsy. N Engl J Med2001;344:1145-51.
  7. Shorvon S. Handbook of epilepsy ­treatment. Oxford: Blackwell Science; 2000.
  8. Sander JW. New drugs for epilepsy. Curr Opin Neurol 1998;11(2):141-8.
  9. Crawford P, et al. Best practice guidelines for the management of women with epilepsy. Seizure 1999;8:201-17.
  10. Tallis RC. Epilepsy and seizure in geriatric practice. In: Duncan JS, Sisodiya SM, Smalls JE, editors. Epilepsy 2001: from science to patient. Oxford: International League Against Epilepsy; 2001. p. 369-74.

Epilepsy Associations
Austria
Epilepsie Selbsthilfegruppen
E:m.alexa@kba.at
Czech Republic
Spolecnost ‘E’
W:www.ecn.cz/epilepsie
Denmark
Dansk Epilepsiforening
W:www.epilepsiforeningen.dk
Finland
Epilepsialiitto
W:www.epilepsia.fi
France
AISPACE
W:www.fraternet.org/aispace
Germany
Deutsche Epilepsie Vereinigung
W:www.epilepsie.sh
Greece
Greek National Association against Epilepsy
E:graaepil@otenet.gr
Hungary
Hungarian Association of People Living with Epilepsy (HALE)
E:mesz@drotposta.hu
Iceland
LAUF
W:www.lauf.is
Ireland
Brainwave
W:www.epilepsy.ie
Italy
Associazone Italiano contro l’Epilessia
E:aice_naz@freemail.it
Norway
Norsk Epilepsiforbund
W:www.epilepsi.no
Poland
Polish Epilepsy Association
W:www.padaczka.bialystok.org.pl
Portugal
Portuguese League against Epilepsy
W:www.lpce.pt
Scotland
Epilepsy Action Scotland
W:www.epilepsyscotland.org.uk
Spain
Asociacion Espanola de Ayuda al Epileptico
E:mcdo@anit.es
Sweden
Swedish Epilepsy Association
W:www.epilepsi.se
Switzerland
Schweizerische Liga gegen Epilepsie
W:www.epi.ch
UK
British Epilepsy Association
W:www.epilepsy.org.uk
Yugoslavia
Jugoslovensko Drustvo za Epilepsiju
E:Yusepi@ztp.co.yu



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