Anticonvulsants used for Generalised Seizures

Authored by , Reviewed by Dr Colin Tidy | Last edited | Meets Patient’s editorial guidelines

This article is for Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Treatments for Epilepsy article more useful, or one of our other health articles.


Treatment of almost all medical conditions has been affected by the COVID-19 pandemic. NICE has issued rapid update guidelines in relation to many of these. This guidance is changing frequently. Please visit https://www.nice.org.uk/covid-19 to see if there is temporary guidance issued by NICE in relation to the management of this condition, which may vary from the information given below.

Other relevant separate articles include Status Epilepticus Management, Epilepsy in Adults, Epilepsy in Children and Young People and Epilepsy in Elderly People.

Generalised seizures are characterised by widespread involvement of bilateral cortical and subcortical regions at the outset and are usually accompanied by impairment of consciousness[1]:

  • The familiar tonic-clonic seizure (grand mal) is often preceded by a cry. The patient suddenly falls to the ground and exhibits typical convulsive movements, sometimes with tongue or mouth biting and urinary incontinence. Other subtypes of generalised seizures include absence, myoclonic, clonic, tonic and atonic seizures.
  • Absence seizures (previously known as petit mal), characterised by behavioural arrest, mainly affect children. Typical absence seizures usually last 5-10 seconds and commonly occur in clusters. They manifest as sudden onset of staring and impaired consciousness with or without eye blinking and lip-smacking. The electroencephalograph (EEG) typically shows generalised spike wave activity. There is a strong genetic component for the seizures as well as for the EEG abnormality. While absences will remit during adolescence in around 40% of patients, related tonic-clonic seizures may continue into adulthood.
  • Atypical absence seizures usually begin before 5 years of age in conjunction with other generalised seizure types and general learning disability. They last longer than typical absence seizures and are often associated with changes in muscle tone.
  • Myoclonic seizures consist of sudden, brief muscle contractions, either singly or in clusters, that can affect any muscle group. They arise as a result of abnormal excessive or synchronous neuronal activity and are associated with polyspikes on EEG.
  • Clonic seizures are characterised by rhythmic or semi-rhythmic muscle contractions, typically involving the upper extremities, neck and face.
  • Tonic seizures cause sudden stiffening of extensor muscles, often associated with impaired consciousness and falling to the ground.
  • Atonic seizures (drop attacks) produce sudden loss of muscle tone with instantaneous collapse, often resulting in facial or other injuries.

About two in three adults with new-onset epilepsy will achieve lasting seizure remission on or off antiepileptic drugs (AEDs), although around half will experience mild to moderately severe adverse effects[2].

General information about prescribing for epilepsy

  • MHRA safety advice on antiepileptic drugs in pregnancy should always be followed[4].
  • Treatment strategy should be individualised according to the seizure type, epilepsy syndrome, co-medication and comorbidity, the child, and young person or adult's lifestyle and preferences.
  • Unless the patient or their family does not consider it a concern, consistent supply of a particular manufacturer's AED preparation is recommended.
  • Treatment should be with monotherapy where possible. If this is unsuccessful, monotherapy with a different drug can be tried .
  • If seizures are not controlled with an AED (or if it is not tolerated) a second drug (alternative first-line or second-line) should be started and titrated up to an adequate or maximum tolerated dose. The first drug should then be tapered (with caution needed during the changeover period).
  • If the second drug does not control symptoms, either the first or second may be tapered before starting another drug.
  • Combination or add-on therapy should only be considered when monotherapy has not resulted in seizure freedom.
  • Carbamazepine, if used, should be offered in controlled-release preparations.
  • Topiramate can impair the effectiveness of hormonal contraceptives.
  • Carefully consider the risk:benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields.
  • Sodium valproate carries a risk of birth defect (including spina bifida; facial and skull malformations including cleft lip and palate; and malformations of the limbs, heart, kidney, urinary tract and sexual organs) in approximately 1 in 10 births among women who take it during pregnancy[5]and a 30-40% risk of developmental delay in children born. Consequently[6]:
    • In women or girls who are pregnant or planning pregnancy, valproate should never be prescribed unless no suitable/effective alternative exists.
    • It should never be used unless there is a pregnancy prevention programme (PPP) in place.
    • Girls and women must be advised that higher doses of sodium valproate (more than 800 mg/day) and polytherapy, particularly with sodium valproate, are associated with greater risk.
    • If used, valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged-release formulation divided into at least two single daily doses.
    • Valproate should only be initiated, and must be supervised, by a specialist.
    • Women or girls who plan to become pregnant should be referred urgently to the specialist managing their condition. They should not stop contraception or valproate until advised to by their specialist.
    • Women or girls with unplanned pregnancy should be urgently referred to a specialist and informed not to stop valproate before they are seen by the specialist.
    • If exposed to valproate during pregnancy, women should be referred for full evaluation to a specialist experienced in prenatal medicine.

Generalised tonic-clonic (GTC) seizures

  • First-line treatment: offer sodium valproate as first-line treatment to boys, men and women who are not of childbearing potential. Offer lamotrigine if sodium valproate is unsuitable. If the person has myoclonic seizures or is suspected of having juvenile myoclonic epilepsy (JME), be aware that lamotrigine may exacerbate myoclonic seizures. Consider carbamazepine and oxcarbazepine but be aware of the risk of exacerbating myoclonic or absence seizures.
  • Adjunctive treatment: offer clobazam, lamotrigine, levetiracetam or topiramate, if first-line treatments are ineffective or not tolerated, to women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years). Advise that topiramate can impair the effectiveness of hormonal contraceptives.
  • Offer clobazam, lamotrigine, levetiracetam, sodium valproate or topiramate as adjunctive treatment to boys, men and women who are not of childbearing potential.
  • If there are absence or myoclonic seizures, or if JME is suspected, do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Absence seizures

  • First-line treatment: for women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), offer ethosuximide.
  • First-line treatment: for boys, men and women who are not of childbearing potential, offer ethosuximide or sodium valproate. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable.
  • If ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated, offer lamotrigine.
  • Adjunctive treatment: if two first-line AEDs are ineffective, consider a combination of two of these three AEDs as adjunctive treatment: ethosuximide or lamotrigine (or sodium valproate for boys, men and women who are not of childbearing potential).
  • If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam, levetiracetam, topiramate or zonisamide.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Myoclonic seizures

  • First-line treatment: for boys, men and women who are not of childbearing potential, offer sodium valproate as first-line treatment, unless it is unsuitable.
  • First-line treatment: consider levetiracetam or topiramate if sodium valproate is unsuitable or not tolerated. Topiramate has a less favourable side-effect profile than levetiracetam and sodium valproate and can impair the effectiveness of hormonal contraceptives.
  • Adjunctive treatment: offer levetiracetam or topiramate if first-line treatments are ineffective or not tolerated. Sodium valproate can be offered to boys, men and women who are not, and will not in future be, of childbearing potential.
  • If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam, piracetam or zonisamide.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Tonic or atonic seizures

  • First-line treatment: for boys, men and women who are not of childbearing potential, offer sodium valproate as first-line treatment.
  • Adjunctive treatment: offer lamotrigine as adjunctive treatment if first-line treatment with sodium valproate is unsuitable, ineffective or not tolerated.
  • Discuss with a tertiary epilepsy specialist if adjunctive treatment is ineffective or not tolerated. Other AEDs that may be considered by the tertiary epilepsy specialist are rufinamide and topiramate.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine or vigabatrin.

Infantile spasms

See the separate West's Syndrome (Infantile Spasms) article.

  • First-line treatment: refer to a tertiary paediatric epilepsy specialist when an infant presents with infantile spasms. Offer a steroid (prednisolone or tetracosactide) or vigabatrin as first-line treatment of infantile spasms that are not due to tuberous sclerosis.
  • 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.

Dravet's syndrome (severe myoclonic epilepsy of infancy)[7]

  • First-line treatment: refer to a tertiary paediatric epilepsy specialist. Consider topiramate (or sodium valproate for boys, men and women who are not of childbearing potential) as first-line treatment in children with Dravet's syndrome.
  • Adjunctive treatment: discuss with a tertiary epilepsy specialist if first-line treatments are ineffective or not tolerated; consider clobazam or stiripentol as adjunctive treatment.
  • Do not offer carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Lennox-Gastaut syndrome

See also the separate Lennox-Gastaut Syndrome article.

  • First-line treatment: discuss with, or refer to, a tertiary paediatric epilepsy specialist. Offer sodium valproate as first-line treatment for for boys, men and women who are not of childbearing potential (including young girls who are likely to need treatment into their childbearing years).
  • Adjunctive treatment: offer lamotrigine as adjunctive treatment if first-line treatment with sodium valproate is unsuitable, ineffective or not tolerated.
  • Discuss with a tertiary epilepsy specialist if adjunctive treatment is ineffective or not tolerated. Other AEDs that may be considered by the tertiary epilepsy specialist are rufinamide and topiramate. Advise that topiramate can impair the effectiveness of hormonal contraceptives.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine or vigabatrin.
  • Felbamate should only be offered in centres providing tertiary epilepsy specialist care and when treatment with all AEDs above has proved ineffective or not tolerated.

Benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut-type)

  • First-line treatment: discuss with the child or young person and their family and/or carers whether AED treatment is indicated:
    • Offer lamotrigine to women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years).
    • Offer lamotrigine or carbamazepine to men and boys.
  • Consider levetiracetam or oxcarbazepine (or sodium valproate to boys, men and women who are not of childbearing potential) if carbamazepine and lamotrigine are unsuitable or not tolerated. If the first AED tried is ineffective, offer an alternative from these AEDs. Carbamazepine and oxcarbazepine may exacerbate or unmask continuous spike and wave during slow sleep, which may occur in some children with benign epilepsy with centrotemporal spikes.
  • Adjunctive treatment: offer carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine or topiramate (or sodium valproate if suitable) as adjunctive treatment if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist. Other AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide.
  • Carefully consider the risk:benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields.

Idiopathic generalised epilepsy (IGE)

  • First-line treatment: offer sodium valproate to boys, men and women who are not of childbearing potential as first-line treatment, particularly if there is a photo-paroxysmal response on EEG. Offer lamotrigine if sodium valproate is unsuitable or not tolerated. Lamotrigine can exacerbate myoclonic seizures. Consider topiramate but it has a less favourable side-effect profile than sodium valproate and lamotrigine.
  • Adjunctive treatment: offer lamotrigine, levetiracetam or topiramate (or sodium valproate with caveats above) as adjunctive if first-line treatments are ineffective or not tolerated.
  • If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam or zonisamide.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Juvenile myoclonic epilepsy (JME)

  • First-line treatment: offer sodium valproate as first-line treatment unless it is unsuitable (this includes women and girls of childbearing potential, as well as young girls who are likely to need treatment into their childbearing years).
  • Offer lamotrigine, levetiracetam or topiramate if sodium valproate is unsuitable or not tolerated. Topiramate has a less favourable side-effect profile than lamotrigine, levetiracetam and sodium valproate. Lamotrigine may exacerbate myoclonic seizures.
  • Adjunctive treatment: offer lamotrigine, levetiracetam, sodium valproate (only if suitable - see above) or topiramate as adjunctive if first-line treatments are ineffective or not tolerated.
  • If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam or zonisamide.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Epilepsy with generalised tonic-clonic (GTC) seizures only

  • First-line treatment: for men and boys, offer lamotrigine or sodium valproate as first-line treatment. If they have suspected myoclonic seizures, or are suspected of having JME, offer sodium valproate first, unless it is unsuitable. Consider carbamazepine and oxcarbazepine (see caveat below).
  • First-line treatment: for women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), offer lamotrigine.
  • Be aware of the risk of exacerbation of myoclonic or absence seizures with lamotrigine, carbamazepine and oxcarbazepine.
  • Adjunctive treatment: offer clobazam, lamotrigine, levetiracetam or topiramate as adjunctive treatment if first-line treatments are ineffective or not tolerated, or sodium valproate in suitable patients only.

Childhood absence epilepsy, juvenile absence epilepsy or other absence epilepsy syndromes

  • First-line treatment: offer ethosuximide as first-line treatment, or sodium valproate to boys, men and women who are not of childbearing potential. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable. Offer lamotrigine if ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated.
  • Adjunctive treatment: if two first-line AEDs are ineffective or not tolerated:
    • For boys, men and women who are not of childbearing potential, consider a combination of two of ethosuximide, lamotrigine or sodium valproate.
    • For women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), consider a combination of ethosuximide and lamotrigine
  • If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist and consider clobazam, clonazepam, levetiracetam, topiramate or zonisamide.
  • Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin.

Other epilepsy syndromes

Refer to a tertiary paediatric epilepsy specialist all children and young people with continuous spike and wave during slow sleep, Landau-Kleffner syndrome or myoclonic-astatic epilepsy.

  • Interactions between AEDs are complex and may enhance toxicity without a corresponding increase in anti-epileptic effect.
  • Interactions are usually caused by hepatic enzyme induction or hepatic enzyme inhibition; displacement from protein binding sites is not usually a problem.
  • These interactions are very variable and unpredictable.
  • AED therapy should only be started once the diagnosis of epilepsy is confirmed, except in exceptional circumstances. AED therapy should be initiated by a specialist.
  • Treatment with AED therapy is generally recommended after a second epileptic seizure. AED therapy should be considered and discussed after a first unprovoked seizure if:
    • There is a neurological deficit.
    • The EEG shows unequivocal epileptic activity.
    • The patient considers the risk of having a further seizure unacceptable.
    • Brain imaging shows a structural abnormality.
  • The dose of each medication should be titrated slowly to the maximally tolerated dose or the maximum level as recommended in the British National Formulary. The effect may be monitored by patient-recorded seizure frequency.
  • Formulations of AEDs are not interchangeable and generic substitution should not be routinely made. Routine switching between different manufacturers of AEDs should be avoided.
  • Maintain a high level of vigilance for adverse effects of treatment.
  • Be aware that treatment with AEDs is associated with a small risk of suicidal thoughts and behaviour, possibly as early as one week after starting treatment.
  • Continuing AED therapy should be planned by a specialist but part of an agreed treatment plan and the needs of the child, young person or adult and their family and/or carers as appropriate should be taken into account.
  • If management is straightforward, continuing AED therapy can be prescribed in primary care if local circumstances and/or licensing allow.
  • Adherence to treatment can be optimised with the following:
    • Educating children, young people and adults and their families and/or carers in the understanding of their condition and the rationale of treatment.
    • Reducing the stigma associated with the condition.
    • Using simple medication regimens.
    • Positive relationships between healthcare professionals, the child, young person or adult with epilepsy and their family and/or carers.
  • Regular blood test monitoring is not recommended as routine, and should be done only if clinically indicated. Indications for monitoring of AED blood levels are:
    • Detection of non-adherence to the prescribed medication.
    • Suspected toxicity.
    • Adjustment of phenytoin dose.
    • Management of pharmacokinetic interactions (eg, changes in bioavailability, changes in elimination, and co-medication with interacting drugs).
    • Specific clinical conditions - eg, status epilepticus, organ failure and certain situations in pregnancy.
  • Examples of blood tests include:
    • Before surgery - clotting studies in those on sodium valproate.
    • FBC, electrolytes, liver enzymes, vitamin D levels and other tests of bone metabolism (eg, serum calcium and alkaline phosphatase) every 2-5 years for adults taking enzyme-inducing drugs.
    • Asymptomatic minor abnormalities in test results are not necessarily an indication for changes in medication. 
  • Drug-resistant epilepsy has been defined as failure to achieve sustained seizure freedom after trials of two tolerated and appropriate AED schedules (as monotherapies or in combination). The majority of patients with newly diagnosed epilepsy respond well to AEDs. Failure to do so may be due to:
    • An incorrect diagnosis of epilepsy.
    • An inappropriate choice of AED for the epilepsy syndrome.
    • Failure to take the prescribed AED.
    • An underlying cerebral neoplasm, metabolic condition or immune process.
    • Concurrent drug or alcohol misuse.
  • Given a correct diagnosis of epilepsy, failure to control seizures completely with the first well-tolerated AED is a predictor of drug-resistant epilepsy. Once two AEDs have failed as monotherapy the chance of seizure freedom with further monotherapy is low.
  • Improvement in seizure control may be obtained by combining AEDs. A range of different AEDs appropriate to the epilepsy syndrome should be added as necessary in sequence, increasing the dose of each slowly to obtain the best response. It may be worthwhile trying the addition of a small dose of a third AED but it may be necessary to accept the persistence of some seizures.
  • For drug-resistant generalised or unclassified epilepsy: lamotrigine, levetiracetam, ethosuximide, sodium valproate and topiramate may be used in the adjunctive treatment of generalised epilepsy.
  • Failure to respond to appropriate AEDs should prompt a review of the diagnosis of epilepsy and adherence to medication.Combination therapy should be considered when treatment with two first-line AEDs has failed or when improved control occurs during the process of phased substitution.
  • The decision to continue or withdraw medication should be taken after a full discussion of the risks and benefits of continuing or withdrawing AED therapy. Withdrawal of AEDs must be managed by, or be under the guidance of, the specialist.
  • The risks and benefits of continuing or withdrawing AED therapy should be discussed when the person with epilepsy has been seizure-free for at least two years.
  • Withdrawal of AED treatment should be carried out slowly (at least 2-3 months) and one drug should be withdrawn at a time.
  • Particular care should be taken when withdrawing benzodiazepines and barbiturates (may take up to six months or longer) because of the possibility of drug-related withdrawal symptoms and/or seizure recurrence.
  • There should be an agreed plan that if seizures recur, the last dose reduction is reversed and medical advice is sought.

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Further reading and references

  1. Epilepsies: diagnosis and management; NICE Clinical Guideline (October 2019 - last updated May 2021)

  2. Schmidt D, Schachter SC; Drug treatment of epilepsy in adults. BMJ. 2014 Feb 28348:g254. doi: 10.1136/bmj.g254.

  3. Diagnosis and management of epilepsy in adults; Scottish Intercollegiate Guidelines Network - SIGN (2015 - updated 2018)

  4. Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review; GOV.UK - Medicines and Healthcare products Regulatory Agency (January 2021)

  5. Valproate use by women and girls; Department of Health, GOV.UK

  6. Safety and use guidance summary on valproate in children, young people and adult, including women or girls of childbearing potential and women or girls who are pregnant or planning pregnancy; NICE Clinical Guidance Summary (2020)

  7. Catarino CB, Liu JY, Liagkouras I, et al; Dravet syndrome as epileptic encephalopathy: evidence from long-term course and and neuropathology. Brain. 2011 Oct134(Pt 10):2982-3010. Epub 2011 Jun 29.

  8. British National Formulary (BNF); NICE Evidence Services (UK access only)

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