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 or 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)
1st line – 

ethosuximide or valproic acid or lamotrigine

A patient with only typical absence seizures is likely to respond to ethosuximide, valproic acid, or lamotrigine as first-line treatments.[42] A Cochrane review concluded that ethosuximide is the optimal initial empirical monotherapy for children and adolescents with absence seizures.[41]

In rare instances, ethosuximide can cause aplastic anaemia, and hepatic or renal failure.

Valproic acid can cause hepatotoxicity and pancreatitis (black box warning), 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 younger than 2 years, due to increased risk of hepatotoxicity in this age group.

When initiating lamotrigine treatment, a slow titration is necessary to avoid Stevens-Johnson syndrome (black box warning). Rare cases of hepatotoxicity or multi-organ failure have been reported. Adverse effects also include diplopia, ataxia, and insomnia.

In both the US and Europe, valproate and its analogues are contraindicated during pregnancy due to the risk of congenital malformations and developmental problems in the child. If it is not possible to stop valproate, treatment may be continued with appropriate specialist care. Valproate and its analogues must not be used in female patients of childbearing potential unless there is a pregnancy prevention programme in place and certain conditions are met.[66] If the patient is taking the drug to prevent major seizures and is planning to become pregnant, the decision of continuing valproate versus changing to an alternate agent should be made on an individual basis.

A review of the safety of anticonvulsants (other than valproate) in pregnancy by the UK Medicines and Healthcare products Regulatory Agency concluded that lamotrigine and levetiracetam, at maintenance doses, are not associated with an increased risk of major congenital malformations. Available studies also do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to lamotrigine or levetiracetam, but data are more limited. Data for other drugs show an increased risk of major congenital malformations associated with topiramate, and an increased risk of fetal growth restriction associated with topiramate and zonisamide. Ethosumide was not studied.[67] A specialist should be consulted for more guidance on the use of specific drugs in pregnancy.

Primary options

ethosuximide: children 3-6 years of age: 15 mg/kg/day (maximum 250 mg) orally given in 2 divided doses initially, increase every 4-7 days according to response, usual maintenance dose is 15-40 mg/kg/day, maximum 1500 mg/day; children >6 years of age, adolescents and adults: refer to consultant for guidance on dosage

Secondary options

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

OR

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

2nd line – topiramate or zonisamide or levetiracetam

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

topiramate or zonisamide or levetiracetam

Second-line agents include topiramate, zonisamide, and levetiracetam.

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.

Adverse effects of levetiracetam include agitation or aggressive behaviour, predominantly in younger children or elderly, and, rarely, psychosis or hallucinations. There are no significant drug interactions. It is renally cleared.

Primary options

topiramate: children 2-16 years of age: 1-3 mg/kg/day orally once daily at night for 1 week initially, increase by 1-3 mg/kg/day increments given in 2 divided doses every 1-2 weeks according to response, maximum 15 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

OR

zonisamide: children <16 years of age: 1-2 mg/kg/day orally given in 2 divided doses initially, increase by 0.5 to 1 mg/kg/day increments every 2 weeks according to response, maximum 8 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

OR

levetiracetam: children 4-16 years of age: 10 mg/kg/dose orally twice daily initially, increase by 10 mg/kg/dose increments every 2 weeks, maximum 60 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

Plus – ketogenic diet

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ACUTE
|
typical absence seizures without a history of generalised tonic-clonic seizures (childhood absence epilepsy)
|
GLUT1 deficiency
Plus – 

ketogenic diet

Treatment recommended for ALL patients in selected patient group

In the subgroup of patients with GLUT1 deficiency, a ketogenic diet is recommended. Patients are monitored and treated by an epileptologist.

This is typically a high-fat, adequate-protein, low-carbohydrate diet, and should be initiated in hospital, under close medical supervision. It may take a couple of months before a clinical response is noted.

Antiepileptic medication is continued initially. If a patient responds very well and has little or no seizure activity, medication is tapered slowly.

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

1st line – valproic acid or lamotrigine

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

valproic acid or lamotrigine

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 less appropriate, and valproic acid and lamotrigine would be preferred first-line agents.[41] [ Cochrane Clinical Answers logo ]

Valproic acid can cause hepatotoxicity and pancreatitis (black box warning), 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.

When initiating lamotrigine treatment, a slow titration is necessary to avoid the serious complication of Stevens-Johnson syndrome (black box warning). Rare cases of hepatotoxicity or multi-organ failure have been reported. Adverse effects also include diplopia, ataxia, and insomnia.

In both the US and Europe, valproate and its analogues are contraindicated during pregnancy due to the risk of congenital malformations and developmental problems in the child. If it is not possible to stop valproate, treatment may be continued with appropriate specialist care. Valproate and its analogues must not be used in female patients of childbearing potential unless there is a pregnancy prevention programme in place and certain conditions are met.[66] If the patient is taking the drug to prevent major seizures and is planning to become pregnant, the decision of continuing valproate versus changing to an alternate agent should be made on an individual basis.

A review of the safety of anticonvulsants (other than valproate) in pregnancy by the UK Medicines and Healthcare products Regulatory Agency concluded that lamotrigine and levetiracetam, at maintenance doses, are not associated with an increased risk of major congenital malformations. Available studies also do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to lamotrigine or levetiracetam, but data are more limited. Data for other drugs show an increased risk of major congenital malformations associated with topiramate, and an increased risk of fetal growth restriction associated with topiramate and zonisamide.[67] 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; adults and children ≥10 years of age: 15 mg/kg/day orally given in 1-3 divided doses initially, increase by 5-10 mg/kg/day increments every 7 days as tolerated and according to response

OR

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

Consider – topiramate or zonisamide or levetiracetam

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

topiramate or zonisamide or levetiracetam

Additional treatment recommended for SOME patients in selected patient group

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.

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.

Adverse effects of levetiracetam include agitation or aggressive behaviour, predominantly in younger children or elderly, and, rarely, psychosis or hallucinations. There are no significant drug interactions. It is renally cleared.

Primary options

topiramate: children 2-16 years of age: 1-3 mg/kg/day orally once daily at night for 1 week initially, increase by 1-3 mg/kg/day increments given in 2 divided doses every 1-2 weeks according to response, maximum 15 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

OR

levetiracetam: children 4-16 years of age: 10 mg/kg/dose orally twice daily initially, increase by 10 mg/kg/dose increments every 2 weeks, maximum 60 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

OR

zonisamide: children <16 years of age: 1-2 mg/kg/day orally given in 2 divided doses initially, increase by 0.5 to 1 mg/kg/day increments every 2 weeks according to response, maximum 8 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

atypical absence seizures

1st line – valproic acid or lamotrigine or topiramate

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ACUTE
|
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 (black box warning), 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.

When initiating lamotrigine treatment, a slow titration is necessary to avoid the serious complication of Stevens-Johnson syndrome (black box warning). Rare cases of hepatotoxicity or multi-organ failure have been reported. Adverse effects also include diplopia, ataxia, and insomnia.

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.

In both the US and Europe, valproate and its analogues are contraindicated during pregnancy due to the risk of congenital malformations and developmental problems in the child. If it is not possible to stop valproate, treatment may be continued with appropriate specialist care. Valproate and its analogues must not be used in female patients of childbearing potential unless there is a pregnancy prevention programme in place and certain conditions are met.[66] If the patient is taking the drug to prevent major seizures and is planning to become pregnant, the decision of continuing valproate versus changing to an alternate agent should be made on an individual basis.

A review of the safety of anticonvulsants (other than valproate) in pregnancy by the UK Medicines and Healthcare products Regulatory Agency concluded that lamotrigine and levetiracetam, at maintenance doses, are not associated with an increased risk of major congenital malformations. Available studies also do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to lamotrigine or levetiracetam, but data are more limited. Data for other drugs show an increased risk of major congenital malformations associated with topiramate, and an increased risk of fetal growth restriction associated with topiramate and zonisamide.[67] 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; adults and children ≥10 years of age: 15 mg/kg/day orally given in 1-3 divided doses initially, increase by 5-10 mg/kg/day increments every 7 days as tolerated and according to response

OR

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

OR

topiramate: children 2-16 years of age: 1-3 mg/kg/day orally once daily at night for 1 week initially, increase by 1-3 mg/kg/day increments given in 2 divided doses every 1-2 weeks according to response, maximum 15 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

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.

Adverse effects of levetiracetam include agitation or aggressive behaviour, predominantly in younger children or elderly, and, rarely, psychosis or hallucinations. There are no significant drug interactions. It is renally cleared.

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

Primary options

levetiracetam: children 4-16 years of age: 10 mg/kg/dose orally twice daily initially, increase by 10 mg/kg/dose increments every 2 weeks, maximum 60 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

OR

zonisamide: children <16 years of age: 1-2 mg/kg/day orally given in 2 divided doses initially, increase by 0.5 to 1 mg/kg/day increments every 2 weeks according to response, maximum 8 mg/kg/day; adolescents and adults: refer to consultant for guidance on dosage

ONGOING

refractory to treatment

1st line – specialist referral

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ONGOING
|
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 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.

Drugs usually more appropriate for focal seizures, such as carbamazepine and phenytoin, are generally felt to worsen generalised seizures, including absence seizures.

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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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