Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy)

1st line – ethosuximide

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ACUTE
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typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy)
1st line – 

ethosuximide

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

Ethosuximide may cause blood dyscrasias, dermatological reactions (including severe reactions such as Stevens-Johnson syndrome), immune thrombocytopenia, changes in hepatic and renal function, and suicidal ideation.

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. There are limited data available on ethosuximide in pregnancy.[52]​ However, birth defects have been reported. A consultant should be consulted for guidance on the use of specific drugs in pregnancy.

Primary options

ethosuximide: children 3-6 years of age: 250 mg orally once daily initially, may increase by 250 mg/day increments every 4-7 days according to response and serum drug levels, usual dose 20 mg/kg/day given in 2 divided doses, maximum 1500 mg/day; children ≥6 years of age: 250 mg orally twice daily initially, may increase by 250 mg/day increments every 4-7 days according to response and serum drug levels, usual dose 20 mg/kg/day given in 2 divided doses, maximum 1500 mg/day; adults: 250 mg orally twice daily initially, may increase by 250 mg/day increments every 4-7 days according to response and serum drug levels, usual dose 250-750 mg twice daily, maximum 1500 mg/day

2nd line – valproic acid or lamotrigine

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ACUTE
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typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy)
2nd line – 

valproic acid or lamotrigine

Valproic acid or lamotrigine are alternative options for patients with childhood absence epilepsy (CAE) with typical absence seizures only, 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]

Valproic acid can cause hepatotoxicity and pancreatitis, thrombocytopenia or pancytopenia, hyperammonaemia, fatigue, weight gain, and hair thinning. Periodic monitoring of FBCs and liver transaminases should be strongly considered. Trough drug levels can help with assessing compliance and effectiveness of therapy. Valproic acid should be used with extreme caution in children aged <2 years, due to increased risk of hepatotoxicity in this age group.

Lamotrigine can cause diplopia, ataxia, and insomnia. Rare cases of hepatotoxicity or multi-organ failure have been reported. When initiating treatment, a slow titration is necessary to avoid Stevens-Johnson syndrome.

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. 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. Valproic acid and its derivatives 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 three months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Lamotrigine has not been associated with an increased risk of major congenital malformations or an increased risk of neurodevelopmental disorders or delay.[56]​ Folic acid supplementation is recommended preconceptionally and during pregnancy.[52]​ A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

Primary options

valproic acid: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adults: 15 mg/kg/day orally given in 1-3 divided doses initially, increase by 5-10 mg/kg/day increments every 7 days according to response and serum drug levels, maximum 60 mg/kg/day given in 2-3 divided doses

OR

lamotrigine: children ≥2 years of age and adults: consult specialist for guidance on dose

3rd line – combination anticonvulsant therapy

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ACUTE
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typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy)
3rd line – 

combination anticonvulsant therapy

If seizures persist despite maximal dose of monotherapy, addition of a second anticonvulsant may be considered. The choice of the additional anticonvulsant should be made in consultation with a specialist.

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

1st line – valproic acid or lamotrigine or levetiracetam

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ACUTE
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typical absence seizures with a history of generalised tonic-clonic seizures (CAE, JAE, JME)
1st line – 

valproic acid or lamotrigine or levetiracetam

If there is any history of generalised tonic-clonic seizures (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and juvenile myoclonic epilepsy [JME]), 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 is not appropriate.[45][49]​​​​[50]​​​ [ Cochrane Clinical Answers logo ] ​ A combination of valproic acid and lamotrigine may be used in resistant cases.[49]

Valproic acid can cause hepatotoxicity and pancreatitis, thrombo/pancytopenia, hyperammonaemia, fatigue, weight gain, and hair thinning. Periodic monitoring of FBCs and liver transaminases should be strongly considered. Trough drug levels can help with assessing compliance and effectiveness of therapy. Valproic acid should be used with extreme caution in children aged younger than 2 years, due to increased risk of hepatotoxicity in this age group.

Lamotrigine can cause diplopia, ataxia, and insomnia. Rare cases of hepatotoxicity or multi-organ failure have been reported. When initiating treatment, a slow titration is necessary to avoid Stevens-Johnson syndrome.

Levetiracetam can cause hepatotoxicity, hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and psychiatric and behavioural abnormalities (including suicidal ideation).

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. 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. Valproic acid and its derivatives must only be used in female patients of childbearing potential if certain precautionary measures are in place (e.g., only used if no suitable alternatives, a pregnancy prevention programme is in place); consult your local guidance for more information. Precautionary measures may also be required in male patients owing to a potential risk that use in the three months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Lamotrigine has not been associated with an increased risk of major congenital malformations or an increased risk of neurodevelopmental disorders or delay.[58] Folic acid supplementation is recommended preconceptionally and during pregnancy.[52]​ A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

Primary options

valproic acid: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adults: 15 mg/kg/day orally given in 1-3 divided doses initially, increase by 5-10 mg/kg/day increments every 7 days according to response and serum drug levels, maximum 60 mg/kg/day given in 2-3 divided doses

OR

lamotrigine: children ≥2 years of age and adults: consult specialist for guidance on dose

OR

levetiracetam: children and adults: consult specialist for guidance on dose

Consider – topiramate or zonisamide

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ACUTE
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typical absence seizures with a history of generalised tonic-clonic seizures (CAE, JAE, JME)
Consider – 

topiramate or zonisamide

Additional treatment recommended for SOME patients in selected patient group

Second-line agents that can be added to first-line monotherapy 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.

Adverse effects of topiramate include word-finding difficulties or cognitive problems, weight loss, nephrolithiasis, and anhidrosis. Rarely, it can precipitate acute angle-closure glaucoma. Therefore, eye pain should be treated as an emergency.

Adverse effects of zonisamide include cognitive slowing, abdominal pain, nephrolithiasis, and weight loss.

For women and girls of childbearing potential, safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. Topiramate may increase the risk of child neurodevelopmental disorders and has been associated with cleft lip and being small for gestational age.[52][53]​​​ Zonisamide has been associated with an increased risk of fetal growth restriction.[56] Levetiracetam has not been associated with an increased risk of major congenital malformations or an increased risk of neurodevelopmental disorders or delay. However, antenatal exposure to levetiracetam may be associated with an increased risk of ADHD.[58] Folic acid supplementation is recommended preconceptionally and during pregnancy.[52]​ A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

Primary options

topiramate: children ≥2 years of age and adults: consult specialist for guidance on dose

OR

zonisamide: children ≥16 years of age and adults: consult specialist for guidance on dose

atypical absence seizures

1st line – valproic acid or lamotrigine or topiramate

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ACUTE
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atypical absence seizures
1st line – 

valproic acid or lamotrigine or topiramate

Valproic acid, lamotrigine, and topiramate are all indicated for first-line treatment of atypical absence seizures, syndromes with generalised epilepsies, or multiple seizure types.

Valproic acid can cause hepatotoxicity and pancreatitis, thrombo/pancytopenia, hyperammonaemia, fatigue, weight gain, and hair thinning. Periodic monitoring of FBCs and liver transaminases should be strongly considered. Trough drug levels can help with assessing compliance and effectiveness of therapy. Valproic acid should be used with extreme caution in children aged less than 2 years, due to increased risk of hepatotoxicity in this age group.

Lamotrigine can cause diplopia, ataxia, and insomnia. Rare cases of hepatotoxicity or multi-organ failure have been reported. When initiating treatment, a slow titration is necessary to avoid Stevens-Johnson syndrome.

Adverse effects of topiramate include word-finding difficulties or cognitive problems, nephrolithiasis, and anhidrosis. Rarely, it can precipitate acute angle-closure glaucoma. Therefore, eye pain should be treated as an emergency.

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. 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. Valproic acid and its derivatives must only be used in female patients of childbearing potential if certain precautionary measures are in place (e.g., only used if no suitable alternatives, a pregnancy prevention programme is in place); consult your local guidance for more information. Precautionary measures may also be required in male patients owing to a potential risk that use in the three months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Lamotrigine has not been associated with an increased risk of major congenital malformations or an increased risk of neurodevelopmental disorders or delay.[56] Topiramate may increase the risk of child neurodevelopmental disorders and has been associated with cleft lip and being small for gestational age.[52][53]​​​ Folic acid supplementation is recommended preconceptionally and during pregnancy.[52]​ A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

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

Primary options

valproic acid: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adults: 15 mg/kg/day orally given in 1-3 divided doses initially, increase by 5-10 mg/kg/day increments every 7 days according to response and serum drug levels, maximum 60 mg/kg/day given in 2-3 divided doses

OR

lamotrigine: children ≥2 years of age and adults: consult specialist for guidance on dose

OR

topiramate: children ≥2 years of age and adults: consult specialist for guidance on dose

Consider – levetiracetam or zonisamide

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ACUTE
|
atypical absence seizures
Consider – 

levetiracetam or zonisamide

Additional treatment recommended for SOME patients in selected patient group

Typically, zonisamide and levetiracetam are second-line agents that are added as adjunct therapy to first-line therapy. Consideration may be given to weaning the first-line agent when seizures are under control.

Levetiracetam can cause hepatotoxicity, hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and psychiatric and behavioural abnormalities (including suicidal ideation).

Adverse effects of zonisamide include cognitive slowing, abdominal pain, nephrolithiasis, and weight loss.

For women and girls of childbearing potential, the safety of anticonvulsants in pregnancy must be taken into account when choosing a suitable drug. Levetiracetam has not been associated with an increased risk of major congenital malformations or an increased risk of neurodevelopmental disorders or delay. However, antenatal exposure to levetiracetam may be associated with an increased risk of ADHD.[58] Zonisamide has been associated with an increased risk of fetal growth restriction.[56] Folic acid supplementation is recommended preconceptionally and during pregnancy.[52]​ A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

Primary options

levetiracetam: children and adults: consult specialist for guidance on dose

OR

zonisamide: children ≥16 years of age and adults: consult specialist for guidance on dose

ONGOING

refractory to treatment

1st line – specialist referral

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ONGOING
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refractory to treatment
1st line – 

specialist referral

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

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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