Anticonvulsant drug treatment in epilepsy

Anticonvulsant drugs (AEDs) are the mainstay of antiepileptic drug therapy (1).

NICE (1) state that:

• an epilepsy specialist should:
  • recommend initiation of appropriate AED treatment
  • plan continuation of treatment
  • manage, or provide guidance, for withdrawal
• antiepileptic drug (AED) therapy
  • should only be started once the diagnosis of epilepsy is confirmed, except in exceptional circumstances that require discussion and agreement between the prescriber, the specialist and the individual and their family and/or carers as appropriate
  • is generally recommended after a second epileptic seizure
  • should be considered and discussed with individuals and their family and/or carers as appropriate after a first unprovoked seizure if:
    • the individual has a neurological deficit
    • the EEG shows unequivocal epileptic activity
    • the individual and/or their family and/or carers consider the risk of having a further seizure unacceptable
    • brain imaging shows a structural abnormality.
  • should be individualised according to the seizure type, epilepsy syndrome, co-medication and co-morbidity, the child, young person or adult’s lifestyle, and the preferences of the person and their family and/or carers as appropriate (1)

Note:

• a recent large multicentre trial (the SANAD trial) evaluating newer drugs in newly diagnosed epilepsy (accepting some limitations) suggested that sodium valproate should be the drug of choice in generalised and unclassifiable epilepsies, and lamotrigine in focal epilepsies
• antiepileptic treatment is associated with a small increased risk of suicidal thoughts and behaviour. Patients and caregivers should be alert to signs of suicidal thoughts or behaviour throughout treatment (2)

anticonvulsant drug treatment guidelines in epilepsy

Some broad treatment guidelines in epilepsy are as follows:

It is recommended that individuals should be treated with a single antiepileptic drug (monotherapy) wherever possible. If the initial treatment is unsuccessful, then monotherapy using another drug can be tried (1)

Tonic clonic or generalized seizures:

Pharmacological treatment of newly diagnosed generalised tonic-clonic (GTC) seizures

First-line treatment in children, young people and adults with newly diagnosed GTC seizures

• sodium valproate should be offered as first-line treatment to children, young people and adults with newly diagnosed GTC seizures. Follow the MHRA safety advice on sodium valproate
• if sodium valproate is unsuitable then offer lamotrigine
  • if the person hasmyoclonic seizures or is suspected of having juvenile myoclonic epilepsy (JME), be aware that lamotrigine may exacerbate myoclonic seizures. Follow the MHRA safety advice on sodium valproate
  • consider carbamazepine and oxcarbazepine but be aware of the risk of exacerbating myoclonic or absence seizures

Adjunctive treatment in children, young people and adults with GTC seizures

• clobazam, lamotrigine, levetiracetam, sodium valproate or topiramate should be offered as adjunctive treatment to children, young people and adults with GTC seizures if first-line treatments (see are ineffective or not tolerated. Follow the MHRA safety advice on sodium valproate
• if there are absence or myoclonic seizures, or if JME is suspected, do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin

Focal seizures:

Pharmacological treatment of focal seizures

First-line treatment in children, young people and adults with newly diagnosed focal seizures

• carbamazepine or lamotrigine should be offered as first-line treatment to children, young people and adults with newly diagnosed focal seizures
• offer levetiracetam, oxcarbazepine or sodium valproate if carbamazepine and lamotrigine are unsuitable or not tolerated
  • if the first AED tried is ineffective, offer an alternative from these five AEDs. Follow the MHRA safety advice on sodium valproate

Adjunctive treatment in children, young people and adults with refractory focal seizures

• carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate should be offered as adjunctive treatment to children, young people and adults with focal seizures if first-line tretments are ineffective or not tolerated. Follow the MHRA safety advice on sodium valproate

Absence seizures:

First-line treatment in children, young people and adults with absence seizures

• ethosuximide or sodium valproate should be offered as first-line treatment to children, young people and adults with absence seizures. If there is a high risk of generalised tonic-clonic (GTC) seizures, then offer sodium valproate first, unless it is unsuitable. Follow the MHRA safety advice on sodium valproate
• offer lamotrigine if ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated. Follow the MHRA safety advice on sodium valproate

Myoclonic seizures:

First-line treatment in children, young people and adults with myoclonic seizures

• sodium valproate should be offered as first-line treatment to children, young people and adults with newly diagnosed myoclonic seizures, unless it is unsuitable. Follow the MHRA safety advice on sodium valproate
• levetiracetam or topiramate should be considered if sodium valproate is unsuitable or not tolerated. Be aware that topiramate has a less favourable side-effect profile than levetiracetam and sodium valproate. Follow the MHRA safety advice on sodium valproate
  
  

Notes:

• over- or underdosage may cause an increase in frequency of epileptic attacks. Blood drug levels are indicated if there is doubt about compliance or concern about toxicity. They are not required in routine management. Initial doses and therapeutic ranges (these may vary between laboratories)
  • carbamazepine e.g. 100mg od; therapeutic range 20-50 Umol/l
  • phenytoin e.g. 100mg bd; therapeutic range 40-80 Umol/l
  • ethosuximide e.g. 250mg bd; therapeutic range 300-700 Umol/l
  • valproate e.g. 300mg bd limited value
  • vigabatrin, lamotrigine and gabapentin are more recent and useful anticonvulsants.Initial doses with existing anti-epileptic medication:
    • vigabatrin 1g od
    • lamotrigine 50mg bd (with enzyme inducing drugs)
    • gabapentin 300mg increasing to 900mg daily
      
      
• gabapentin add-on treatment for drug-resistant focal epilepsy (3)
  • a systematic review concluded that:
    • Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy, and seems to be fairly well-tolerated.
      However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a
      three-month period

The respective SPC must be consulted before prescribing any of the drugs listed.

Reference:

• (1) National Clinical Guideline Centre (NCGC) 2018. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care.
• (2) Medicines and Healthcare products Regulatory Agency (MHRA). Antiepileptics: risk of suicidal thoughts and behaviour. Drug Safety Update 2008;2(1), 2.
• (3) Panebiancol M et al. Gabapentin add-on treatment for drug-resistant focal epilepsy. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.: CD001415. DOI: 10.1002/14651858.CD001415.pub4.