Approach

The goal of treatment for any epilepsy syndrome is complete freedom from seizures. Evidence on efficacy of treatments is limited; adverse effects and patient characteristics need to be taken into account when deciding on management strategies.[43]​​​​ Monotherapy is preferred, but an adjunctive drug to first-line therapy may be required. Evidence suggests that earlier age of onset and male sex may increase the need for a second agent for seizure control.[44]

Treatment for epilepsy with myoclonic absence and eyelid myoclonia is not covered in this topic; see Generalised seizures in children.

Typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy [CAE])

Ethosuximide is recommended as the first-line treatment for patients with CAE with typical absence seizures only.[45][46][47]​

Valproic acid or lamotrigine are alternative options for these patients if treatment with ethosuximide fails; however, the adverse-effect profile of valproic acid is not as favourable as that of ethosuximide, and lamotrigine is less effective.[10]​​[43][45]​​[46][47]

If seizures persist despite maximal dose of monotherapy, addition of a second anticonvulsant may be considered.[10][46]​​​​ The choice of the additional anticonvulsant should be made in consultation with a consultant.

The following anticonvulsants may exacerbate absence seizures and so are usually avoided: carbamazepine, gabapentin, oxcarbazepine, phenobarbital, phenytoin, pregabalin, tiagabine, and vigabatrin.[47][48]​​

For further details of treatment for CAE, see Generalised seizures in children.

Typical absence seizures with a history of generalised tonic-clonic seizures (CAE, JAE, JME)

If there is any history of generalised tonic-clonic seizures, ethosuximide is not appropriate.

Valproic acid is the preferred first-line agent with lamotrigine or levetiracetam as alternative options, particularly for patients for whom valproic acid may not be appropriate.[45][49]​​[50]​ A combination of valproic acid and lamotrigine may be used in resistant cases.[49]

Other treatment options include topiramate or zonisamide. Typically, these agents are added as adjunct therapy to first-line therapy, but they may also be used as alternative monotherapy with the first-line drug being weaned when seizures are under control.[46]

The following anticonvulsants may exacerbate absence seizures and so are usually avoided: carbamazepine, gabapentin, oxcarbazepine, phenobarbital, phenytoin, pregabalin, tiagabine, and vigabatrin.[47][48]​​

For further details of treatment for CAE, JAE, and JME see Generalised seizures in children.

Atypical absence seizures

Valproic acid, lamotrigine, and topiramate are all indicated for first-line treatment of atypical absence seizures, syndromes with generalised epilepsies, or multiple seizure types. Typically, zonisamide and levetiracetam are second-line agents that are added as adjunct therapy to first-line therapy. However, second-line therapy can be substituted for the first-line therapy, with the first-line drug being weaned.

For details of treatment for Lennox-Gastaut syndrome and epilepsy with myoclonic absence see Generalised seizures in children.

Failure of therapy

Multiple other therapies can be considered if initial therapies have been insufficiently effective (i.e., lack of seizure freedom), such as clobazam, amantadine, acetazolamide, felbamate, ketogenic diet, and vagus nerve stimulation. These are beyond the scope of this review and would be initiated by an epileptologist. GLUT1 testing should be considered before initiating a ketogenic diet.

For further details see Generalised seizures in children.

Considerations for patients of childbearing potential

Patients with the potential to become pregnant should be provided with information from early adolescence about the risk of unplanned pregnancy, contraceptive options, and potential adverse pregnancy outcomes. Anticonvulsants with enzyme-inducing properties can lower contraceptive efficacy and lead to an increased failure rate.[51]​ 

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. A specialist should be consulted for guidance on the use of specific drugs in pregnancy.

Valproic acid and its derivatives

Valproic acid and its derivatives may cause major congenital malformations, including neurodevelopmental disorders and neural tube defects, after in utero exposure.[52]​ These drugs are contraindicated during pregnancy; however, if it is not possible to stop them, treatment may be continued with appropriate consultant care.

  • These agents must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention programme in place, and certain conditions are met.

  • Precautionary measures may also be required in male patients owing to a potential risk that use in the 3 months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children.

  • Regulations and precautionary measures for female and male patients may vary between countries, with some countries taking a more heightened precautionary stance, and you should consult your local guidance for more information.

If the patient is taking the drug to prevent major seizures and is planning to become pregnant, the decision of continuing valproic acid versus changing to an alternate agent should be made on an individual basis.

Topiramate

One large cohort study reported an association between antenatal exposure to topiramate and increased risk of child neurodevelopmental disorders.[53] Topiramate exposure in pregnancy is associated with cleft lip and being small for gestational age.[52]

  • In some countries, topiramate is contraindicated in pregnancy and in women of childbearing age unless the conditions of a pregnancy prevention programme are fulfilled to ensure that women of childbearing potential: are using highly effective contraception; have a pregnancy test to exclude pregnancy before starting topiramate; and are aware of the risks associated with use of the drug.[54][55] 

Safety of other anticonvulsants in pregnancy

The American Academy of Neurology recommends that clinicians consider using lamotrigine or levetiracetam in women of childbearing potential to minimise the risk of major congenital malformations, when appropriate considering the woman’s epilepsy syndrome, comorbidities, and likelihood of achieving seizure control.[52]​ A review of the safety of anticonvulsants (other than valproic acid) in pregnancy by the UK Medicines and Healthcare products Regulatory Agency (MHRA) concluded that lamotrigine and levetiracetam, at maintenance doses, are not associated with an increased risk of major congenital malformations. Studies included in the review did not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to lamotrigine or levetiracetam, but data were more limited.[56] Data from EURAP (International Registry of Antiepileptic Drugs and Pregnancy) also suggest that lamotrigine and levetiracetam are associated with a lower risk of major congenital malformations in exposed offspring.[57]​ Another study has suggested an association between antenatal exposure to levetiracetam and ADHD.[58]​ Data for other drugs show an increased risk of fetal growth restriction associated with zonisamide.[56]​ Risks associated with other anticonvulsants are uncertain due to limitations in the data.[56][59][60]​ There are limited data available on ethosuximide in pregnancy.[52]​ However, birth defects have been reported.

Folic acid supplementation

Women of childbearing potential who are taking anticonvulsants are advised to take folic acid supplementation daily preconceptionally and during pregnancy to decrease the risk of neural tube defects and possibly improve neurodevelopmental outcomes in the offspring.[52]

Drug discontinuation

Seizure freedom for long periods of time can occur with anticonvulsant therapy. Patients taking anticonvulsants who achieve seizure freedom may eventually wish to discontinue their drug treatment to avoid the adverse effects, psychological implications, and cost of ongoing treatment.

There is no statistically significant evidence to guide the timing of anticonvulsant discontinuation in adults. For adults who have been seizure-free for at least 2 years, clinicians should discuss the risks and benefits of drug discontinuation with the patient, including the risks of seizure recurrence and treatment resistance. Individual patient characteristics and preferences should be taken into account. Abrupt drug discontinuation is inadvisable, but, beyond this, there is little evidence to guide the speed of tapering drug treatment in adults.[61]

For children who have been seizure-free for at least 18-24 months, and who do not have an electroclinical syndrome suggesting otherwise, discontinuation of the anticonvulsant may be considered, as this does not clearly increase risk of seizure recurrence.[62]​ The risks and benefits of discontinuation should be discussed with the patient and family.​ Evidence for optimal rate of tapering of anticonvulsants in children is very limited.[63]​ Provided that an EEG does not show epileptiform activity, discontinuation should be offered at a rate no faster than 25% every 10-14 days.[62]​​

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