Generalised seizures in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

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

acute repetitive seizures: in the community

1st line – benzodiazepine

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1st line –

benzodiazepine

There is no well-established definition of acute repetitive seizures, which adds to the challenge of recognising them.[59] One frequently used clinical definition is three or more seizures within 24 hours for patients whose habitual seizure frequency is fewer than three seizures per day, with return to full alertness between seizures. Other definitions include two or more seizures in 6 hours, two or more seizures in 24 hours, or two to four seizures in less than 48 hours.[58][59]

Carers and family members should be trained to administer treatments as soon as possible in the community when the seizure clusters are identified, without the need for the patient to attend the hospital. Treatment options include diazepam rectal gel, intranasal formulations of midazolam and diazepam, and buccal midazolam. These benzodiazepine formulations have shown reasonable efficacy, equal to or better than that of intravenous formulations, in most patients. Oral benzodiazepines (e.g., lorazepam) can be used if the above formulations are not available or in patients in whom the rectal route is less favored, provided that the patient is awake and co-operative, and the risk of aspiration is low or not a concern.[56][57][60]

Primary options

diazepam rectal: 0.2 mg/kg rectally as a single dose

diazepam nasal: body weight 14-27 kg: 5 mg intranasally as a single dose; body weight 28-50 kg: 10 mg intranasally as a single dose; body weight 51-75 kg: 15 mg intranasally as a single dose; body weight ≥76 kg: 20 mg intranasally as a single dose

midazolam nasal: 5 mg (1 spray) intranasally as a single dose

midazolam: 10 mg buccally as a single dose

Secondary options

lorazepam: 4 mg orally as a single dose, may repeat once after 10-15 minutes

acute repetitive seizures: in the hospital

1st line – parenteral benzodiazepine or anticonvulsant

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1st line –

parenteral benzodiazepine or anticonvulsant

There is no well-established definition of acute repetitive seizures. One frequently used definition is three or more seizures within 24 hours for patients whose habitual seizure frequency is fewer than three seizures per day, with return to full alertness between seizures. Other definitions include two or more seizures in 6 hours, two or more seizures in 24 hours, or two to four seizures in less than 48 hours.[59]

In a hospital setting, intravenous benzodiazepines and intravenous formulations of anticonvulsants such as phenytoin (or fosphenytoin), valproic acid, levetiracetam, lacosamide, and brivaracetam can be used.[61] Choice of medication should take into account the age and sex of the patient, and any comorbidities. The patient should be continued on a suitable oral formulation of an anticonvulsant once stabilised.

Pregnant women with epilepsy should be under the care of a multidisciplinary team that includes a high-risk obstetric consultant.[76] Choice of anticonvulsant needs to balance the risks of generalised tonic-clonic seizures (GTCSs) to the health of the woman and fetus against potential teratogenic effects of the drug treatment, and should be guided by consultant advice.[75][76][77][80][81] Some anticonvulsants are contraindicated in pregnancy due to an increased risk of major congenital malformations and/or child neurodevelopmental disorders.[79][82][89]

Primary options

diazepam: 5-10 mg intravenously every 5-10 minutes according to response, maximum 30 mg/total dose

lorazepam: 4 mg intravenously as a single dose, may repeat once after 10-15 minutes

phenytoin: 15-20 mg/kg intravenously as a loading dose, followed by an additional dose of 5-10 mg/kg after 10-20 minutes according to response

fosphenytoin: 15-20 mg (phenytoin equivalents)/kg intravenously as a loading dose, followed by an additional dose of 5-10 mg (phenytoin equivalents)/kg after 10-20 minutes according to response

valproic acid: 20-40 mg/kg intravenously as a single dose, may give an additional dose of 20 mg/kg according to response, maximum 3000 mg/dose

levetiracetam: 60 mg/kg intravenously as a single dose, maximum 4500 mg/dose

lacosamide: consult specialist for guidance on dose

brivaracetam: consult specialist for guidance on dose

ONGOING

≥2 unprovoked generalised tonic-clonic seizures (GTCSs) without syndromic diagnosis

1st line – anticonvulsant monotherapy

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1st line –

anticonvulsant monotherapy

These patients have no abnormalities on electroencephalogram or MRI.

An appropriately chosen single medication is likely to be effective for most patients. Monotherapy ensures the lowest risk of adverse effects and drug-drug interactions. There are a number of therapies with comparable efficacy. Treatment should always be tailored to the needs of the patient, taking into account adverse-effect profile; contraindications; age and sex; the underlying aetiology of the seizures; the pharmacokinetic properties, mechanism of action, and available formulations of drugs; and comorbidities and any other medications. Any anticonvulsant, including those not listed here, may be used if it is the most suitable choice for a particular patient.

Pregnant women with epilepsy should be under the care of a multidisciplinary team that includes a high-risk obstetric specialist.[76] Choice of anticonvulsant needs to balance the risks of GTCSs to the health of the woman and fetus against potential teratogenic effects of the drug treatment, and should be guided by specialist advice.[75][76][77][80][81] Some anticonvulsants are contraindicated in pregnancy due to an increased risk of major congenital malformations and/or child neurodevelopmental disorders (e.g., valproic acid and its derivatives, topiramate, phenobarbital, phenytoin).[79][81][82][89] Monitoring of blood anticonvulsant levels is recommended as pharmacokinetics are affected during pregnancy.[77] High-dose folic acid supplementation is recommended.[76][90][91]

Valproic acid has proven efficacy for GTCSs and is widely used.[97][98][99] High-quality evidence from one Cochrane review supports the use of sodium valproate as first-line treatment for patients with GTCSs (with or without other generalised seizure types).[96] [ ] Valproic acid should generally be avoided as first-line treatment for older patients, as it affects hepatic enzymatic action and binds to plasma proteins.

Lamotrigine and levetiracetam are suitable alternatives to valproic acid, particularly for women of childbearing potential.[81][95][96][100] [ ]

Topiramate and oxcarbazepine also have demonstrated effectiveness as monotherapy for new-onset seizures.[95][97][101][102][103] [ ] Topiramate should generally be avoided as first-line treatment for older patients because it may worsen cognitive deficits.

Carbamazepine is a reasonable choice, but should be avoided when generalised-onset epilepsy is a possible diagnosis; it should not be considered a standard broad-spectrum anticonvulsant.[97][101][102]

Other options include zonisamide, lacosamide, brivaracetam, and phenytoin, although evidence is limited.[97][104][105] The adverse-effect and toxicity profile of phenytoin is a significant issue for a number of patients, and particular caution should be used if there is suspicion of generalised-onset epilepsy syndrome.

Gabapentin and pregabalin are further options, although they appear to be less effective than some other anticonvulsants.[106][107]

Phenobarbital should be avoided in almost all cases due to adverse effects.

In general, the medication is initiated at a low, easily tolerated dose, and gradually titrated upwards. Dose should be adjusted according to response and serum drug level. An appropriate trial of a single agent is represented by the achievement of a sufficiently high dose. Patients should be monitored for efficacy and adverse effects.

Primary options

valproic acid: 10-15 mg/kg/day orally given in 1-3 divided doses initially, increase gradually according to response, maximum 60 mg/kg/day

lamotrigine: consult specialist for guidance on dose

levetiracetam: 500 mg orally twice daily initially, increase gradually according to response, maximum 3000 mg/day

topiramate: 25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 400 mg/day

oxcarbazepine: 300 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 2400 mg/day

carbamazepine: 200 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 1600 mg/day

Secondary options

zonisamide: 100 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day

lacosamide: 100 mg orally twice daily initially, increase gradually according to response, maximum 400 mg/day

brivaracetam: 50 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day

phenytoin: 15-20 mg/kg orally as a loading dose given in 3 divided doses every 2-4 hours, followed by 4-7 mg/kg/day (or 300-400 mg/day) given in 2-3 divided doses

Tertiary options

gabapentin: 300 mg orally three times daily initially, increase gradually according to response, maximum 3600 mg/day

pregabalin: 75 mg orally twice daily or 50 mg orally three times daily initially, increase gradually according to response, maximum 600 mg/day

2nd line – alternative anticonvulsant monotherapy

Back

2nd line –

alternative anticonvulsant monotherapy

If first-line therapy is not effective, monotherapy with a different broad-spectrum anticonvulsant is indicated. A drug with a different mechanism of action should be considered.

If the first drug was not tolerated (due to adverse effects), a second agent should be chosen with special consideration for the patient's health profile and tolerance. The anticonvulsants listed above for first-line monotherapy are most suitable for this patient population, and choice of second-line therapy should come from that list in most cases. However, any anticonvulsant may be considered if it is the most suitable choice for a particular patient. For example, perampanel is approved by the US Food and Drug Administration as monotherapy for patients with focal-onset epilepsy (with or without secondarily generalised seizures) but is not typically used as first-line therapy.[122][123]

Any new information that aids in defining the epilepsy syndrome should be used to select the best suited medication.

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

The current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly. The specific pharmacokinetic profiles for each of the drugs should be researched prior to instructing the patient on how to switch. A written schedule is often required to help patient compliance. Patients should be counselled that there is an increased risk of seizures during this transition period.

Dose should be adjusted according to response and serum drug level.

3rd line – anticonvulsant dual therapy

Back

3rd line –

anticonvulsant dual therapy

If seizure freedom has not been attained after two monotherapy trials at optimal doses, a dual therapy trial may be initiated, using either a combination of two of the monotherapy options (see above) or an anticonvulsant that is used primarily for adjunctive treatment in combination with one of the monotherapy options. A combination of two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of drugs that have been shown to have anticonvulsant agonistic effects, is preferred.

Evidence to guide choice of dual therapy is limited, and more trials are needed.[124] In general, combinations are selected based on pharmacokinetics, drug-drug interactions, and cumulative adverse-effect concerns.[74]

Adjunctive lamotrigine reduced seizure rate frequency in patients with refractory GTCSs, but the evidence was judged insufficient to inform clinical practice.[161] [ ]

Brivaracetam as add-on therapy for patients with drug-resistant epilepsy was effective in reducing seizure frequency (but only one of the assessed studies included participants with generalised epilepsy).[125]

Adjunctive clobazam might reduce seizure frequency in patients with drug-resistant epilepsy, and may be most effective for patients with focal-onset seizures. However, evidence is of very low quality and it is unclear which population will benefit most.[126]

There is some evidence that perampanel is an effective adjunctive therapy for GTCSs in patients with focal-onset and generalised-onset epilepsy.[127][128]

Adjunctive cenobamate is reported to reduce the frequency of focal-onset seizures, but data are limited.[129]

Adjunctive lacosamide was reported to be effective in treating primary GTCSs in a double-blind, randomised, placebo-controlled trial.[130]

Cochrane reviews have also investigated the effectiveness of a number of other anticonvulsants (e.g., topiramate, levetiracetam, zonisamide, gabapentin, pregabalin) as add-on therapy for drug-resistant focal seizures, but as yet there is little evidence regarding their effectiveness for treating generalised seizures.[131][132][133][134][135] [ ]

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

At this stage of epilepsy treatment, it is also appropriate to investigate the possibility of localisation-related epilepsy in any patient who has not had a formal epilepsy syndrome diagnosed. A patient with a well-localised epileptic focus should be considered a candidate for resective epilepsy surgery or neurostimulation, and be referred to a tertiary epilepsy centre.

A dose adjustment may be required when using two anticonvulsants together; consult a specialist for guidance on dose.

Dose should be adjusted according to response and serum drug level.

≥2 unprovoked GTCSs with focal-onset epilepsy

adults <65 years

1st line – anticonvulsant monotherapy

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1st line –

anticonvulsant monotherapy

The electroencephalogram or MRI is suggestive of focal-onset epilepsy.

An appropriately chosen medication in monotherapy is likely to be effective for most patients. Monotherapy ensures the lowest risk of adverse effects and drug-drug interactions. There are a number of therapies with comparable efficacy. Treatment should always be tailored to the needs of the patient, taking into account adverse-effect profile; contraindications; age and sex; the underlying aetiology of the seizures; the pharmacokinetic properties, mechanism of action, and available formulations of drugs; and comorbidities and any other medications. Any anticonvulsant, including those not listed here, may be used if it is the most suitable choice for a particular patient.

Carbamazepine and valproic acid have demonstrated efficacy for symptomatic focal-onset epilepsy.[97][98][108] Lamotrigine compares favourably with carbamazepine.[96][102][109]

The newer medications have superior tolerability and pharmacokinetic profiles, but have not been shown to be more effective than the older agents.[74][100]

The effectiveness of topiramate and oxcarbazepine is comparable to that of several older anticonvulsants.[97]

Levetiracetam monotherapy has been demonstrated to be effective in a mixed population of patients with GTCSs; network meta-analysis supports its use in patients with focal-onset seizures.[96][110]

Zonisamide monotherapy was non-inferior to controlled-release carbamazepine in a phase 3, randomised, double-blind, parallel-group study of patients with newly diagnosed focal epilepsy.[111] Long-term follow-up (≥24 months) found that zonisamide monotherapy was safe and maintained treatment efficacy in this patient population.[112]

Other options include phenytoin, lacosamide, eslicarbazepine, brivaracetam, gabapentin, and pregabalin.[104][105][106][113] Phenytoin has demonstrated efficacy for focal to bilateral tonic-clonic seizures, but its adverse-effect and toxicity profiles are less favourable than those of some other options.

Primary options

carbamazepine: 200 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 1600 mg/day

valproic acid: 10-15 mg/kg/day orally given in 1-3 divided doses initially, increase gradually according to response, maximum 60 mg/kg/day

lamotrigine: consult specialist for guidance on dose

topiramate: 25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 400 mg/day

oxcarbazepine: 300 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 2400 mg/day

levetiracetam: 500 mg orally twice daily initially, increase gradually according to response, maximum 3000 mg/day

zonisamide: 100 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day

Secondary options

gabapentin: 300 mg orally three times daily initially, increase gradually according to response, maximum 3600 mg/day

pregabalin: 75 mg orally twice daily or 50 mg orally three times daily initially, increase gradually according to response, maximum 600 mg/day

lacosamide: 100 mg orally twice daily initially, increase gradually according to response, maximum 400 mg/day

eslicarbazepine acetate: 400 mg orally once daily initially, increase gradually according to response, maximum 1600 mg/day

brivaracetam: 50 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day

phenytoin: 15-20 mg/kg orally as a loading dose given in 3 divided doses every 2-4 hours, followed by 4-7 mg/kg/day (or 300-400 mg/day) given in 2-3 divided doses

2nd line – alternative anticonvulsant monotherapy

Back

2nd line –

alternative anticonvulsant monotherapy

If first-line therapy is not effective, monotherapy with a different anticonvulsant with proven efficacy in focal-onset epilepsy is indicated. A drug with a different mechanism of action should be considered.

If the first drug was not tolerated (due to adverse effects), a second agent should be chosen with special consideration for the patient's health profile and tolerance. The anticonvulsants listed above for first-line monotherapy are most suitable for this patient population, and choice of second-line therapy should come from that list in most cases. However, any anticonvulsant may be considered if it is the most suitable choice for a particular patient.[121] For example, perampanel is approved by the US Food and Drug Administration as monotherapy for patients with focal-onset epilepsy (with or without secondarily generalised seizures), but is not typically used as first-line therapy.[122][123]

Any new information that aids in defining the epilepsy syndrome should be used to select the best suited medication.

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

The current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly. The specific pharmacokinetic profiles for each of the drugs should be researched prior to instructing the patient on how to switch. A written schedule is often required to aid patients in adherence. Patients should be counselled that there is an increased risk of seizures during this transition period.

Dose should be adjusted according to response and serum drug level.

3rd line – anticonvulsant dual therapy

Back

3rd line –

anticonvulsant dual therapy

If seizure freedom has not been attained after two monotherapy trials at optimal doses, a dual therapy trial may be initiated, using either a combination of two of the monotherapy options (see above) or an anticonvulsant that is used primarily for adjunctive treatment (e.g., clobazam) in combination with one of the monotherapy options. A combination of two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of drugs that have been shown to have anticonvulsant agonistic effects, is preferred.

Evidence to guide choice of dual therapy is limited.[124] In general, combinations are chosen based on pharmacokinetics, drug-drug interactions, and cumulative adverse-effect concerns.[74]

Adjunctive lamotrigine reduced seizure rate frequency in patients with refractory GTCSs.[161] [ ]

There is some evidence that perampanel is an effective adjunctive therapy for GTCSs in patients with focal-onset and generalised-onset epilepsy.[127][128]

Adjunctive cenobamate is reported to reduce the frequency of focal-onset seizures, but data are limited.[129]

Cochrane reviews have investigated the effectiveness of a number of anticonvulsant drugs (e.g., topiramate, levetiracetam, zonisamide, gabapentin, pregabalin) as add-on therapy for drug-resistant focal seizures, but as yet there is little evidence regarding their effectiveness for treating generalised seizures.[131][132][133][134][135] [ ]

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

A dose adjustment may be required when using two anticonvulsants together; consult a specialist for guidance on dose.

Dose should be adjusted according to response and serum drug level.

4th line – surgical resection or neurostimulation

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4th line –

surgical resection or neurostimulation

Treatment-resistant epilepsy is defined as the persistence of seizures after trials of at least two appropriate anticonvulsant drugs (as monotherapies or in combination) that are used at efficacious daily dose.[55][136] Patients with treatment-resistant epilepsy should be referred to an epilepsy specialty centre for consideration for epilepsy surgery or neurostimulation.[55][137][138]

A patient with GTCSs may be a suitable candidate for surgical resection if the seizures originate from a single primary ictal focus.[139][141][162]

Minimally invasive alternatives to traditional resective surgery include laser interstitial thermal therapy (LITT) and radiofrequency ablation; both of these approaches avoid the need for craniotomy, but the seizure-freedom rates are very slightly lower than with traditional resective surgery.[55][142][143] Functional MRI may be used for pre-surgical mapping.[47]

In patients with seizures that originated from a primary ictal focus for whom surgical resection is considered unsuitable, or who decline surgery, techniques such as deep brain stimulation, vagus nerve stimulation, and responsive neurostimulation may be used. There is currently no good evidence to guide selection of one of these modalities over another.[55][144][145]

Vagus nerve stimulation is an effective and safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection.[146][147][148][149]

Deep brain stimulation has been shown to be effective for refractory epilepsy, although responses vary markedly between patients.[150][151][152][153] Targets for deep brain stimulation include the anterior and centromedian nuclei of the thalamus.

The responsive neurostimulation system is an option for patients with treatment-resistant epilepsy who have one to two unresectable foci.[154][155][156]

adults >65 years

1st line – anticonvulsant monotherapy

Back

1st line –

anticonvulsant monotherapy

Older patients can be particularly susceptible to adverse effects and often have tolerability issues, especially at higher doses or with polypharmacy.[114][115][116]

Anticonvulsant options are listed based on established efficacy and optimal tolerability. However, treatment should always be tailored to the needs of the patient, taking into account age and sex; the underlying aetiology of the seizures; the pharmacokinetic properties, mechanism of action, and available formulations of drugs; and comorbidities and any other medications. Any anticonvulsant, including those not listed here, may be used if it is the most suitable choice for a particular patient.

Most older anticonvulsants interact with other medications, affect hepatic enzymatic action, and bind to plasma proteins. Lamotrigine, levetiracetam, gabapentin, and pregabalin have fewer interactions, which makes them suitable candidates for initial therapy for older patients.[97][102][117] [ ] Other options include carbamazepine and brivaracetam.[105][118]

Because drug metabolism slows in many patients as they age, medication dosing should be adjusted accordingly and the patient should be closely monitored for signs of toxicity. Lower starting and target doses, and slower titration, are recommended for all medications.

Dose should be adjusted according to response and serum drug level.

Primary options

lamotrigine: consult specialist for guidance on dose

levetiracetam: 500 mg orally twice daily initially, increase gradually according to response, maximum 3000 mg/day

Secondary options

gabapentin: 300 mg orally three times daily initially, increase gradually according to response, maximum 3600 mg/day

pregabalin: 75 mg orally twice daily or 50 mg orally three times daily initially, increase gradually according to response, maximum 600 mg/day

Tertiary options

carbamazepine: 200 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 1600 mg/day

brivaracetam: 50 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day

2nd line – alternative anticonvulsant monotherapy

Back

2nd line –

alternative anticonvulsant monotherapy

If first-line therapy is not effective, monotherapy with a different anticonvulsant that has proven efficacy for focal-onset epilepsy in older patients is indicated.

If the first drug was not tolerated (due to adverse effects), a second agent should be chosen with special consideration for the patient's health profile and tolerance.

The anticonvulsants listed above for first-line monotherapy are most suitable for this patient population, and choice of second-line therapy should come from that list in most cases. However, any anticonvulsant may be considered if it is the most suitable choice for a particular patient.

Any new information that aids in defining the epilepsy syndrome should be used to select the best suited medication.

The current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly. The specific pharmacokinetic profiles for each of the drugs should be researched prior to instructing the patient on how to switch. A written schedule is often required to aid patients in adherence. Patients should be counselled that there is an increased risk of seizures during this transition period.

Dose should be adjusted according to response and serum drug level.

3rd line – alternative anticonvulsant monotherapy

Back

3rd line –

alternative anticonvulsant monotherapy

If the first- and second-line medications have been ineffective, it is appropriate to try another medication indicated as monotherapy for the treatment of focal-onset epilepsy, such as one of those listed here, or to try anticonvulsant dual therapy (see below). Choice of treatments will depend on the patient’s clinical situation (seizure frequency, comorbidities, etc.).

Options for alternative monotherapy include valproic acid, oxcarbazepine, zonisamide, topiramate, phenytoin, lacosamide, perampanel, and eslicarbazepine.

Before choosing an agent in an older patient, consider possible drug-drug interactions (e.g., due to P450 enzyme induction or inhibition), metabolism, and other adverse effects (e.g., topiramate and zonisamide should only be used with great caution in patients with cognitive problems).

When switching treatment, the current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly. The specific pharmacokinetic profiles for each of the drugs should be researched prior to instructing the patient on how to switch. A written schedule is often required to aid patients in adherence. Patients should be counselled that there is an increased risk of seizures during this transition period.

Dose should be adjusted according to response and serum drug level.

Primary options

valproic acid: 10-15 mg/kg/day orally given in 1-3 divided doses initially, increase gradually according to response, maximum 60 mg/kg/day

oxcarbazepine: 300 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 2400 mg/day

Secondary options

zonisamide: 100 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day

topiramate: 25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 400 mg/day

phenytoin: 15-20 mg/kg orally as a loading dose given in 3 divided doses every 2-4 hours, followed by 4-7 mg/kg/day (or 300-400 mg/day) given in 2-3 divided doses

lacosamide: 100 mg orally twice daily initially, increase gradually according to response, maximum 400 mg/day

eslicarbazepine acetate: 400 mg orally once daily initially, increase gradually according to response, maximum 1600 mg/day

perampanel: 2 mg orally once daily at bedtime initially, increase gradually according to response, maximum 12 mg/day

3rd line – anticonvulsant dual therapy

Back

3rd line –

anticonvulsant dual therapy

If the first- and second-line medications have been ineffective, dual anticonvulsant therapy is an alternative option to trying an alternative medication as monotherapy.

Dual therapy may use either a combination of two of the monotherapy options or an anticonvulsant that is used primarily for adjunctive treatment (e.g., clobazam) in combination with one of the monotherapy options. A combination of two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of drugs that have been shown to have anticonvulsant agonistic effects, is preferred.

Evidence to guide choice of dual therapy is limited.[124] In general, combinations are chosen based on pharmacokinetics, drug-drug interactions, and cumulative adverse-effect concerns.[74]

Adjunctive lamotrigine reduced seizure rate frequency in patients with refractory GTCSs.[161]

There is some evidence that perampanel is an effective adjunctive therapy for GTCSs in patients with focal-onset and generalised-onset epilepsy.[127][128]

Adjunctive cenobamate is reported to reduce the frequency of focal-onset seizures, but data are limited.[129]

A dose adjustment may be required when using two anticonvulsants together; consult a specialist for guidance on dose.

Dose should be adjusted according to response and serum drug level.

4th line – surgical resection or neurostimulation

Back

4th line –

surgical resection or neurostimulation

A patient with GTCSs may be a suitable candidate for surgical resection if the seizures originate from a single primary ictal focus.[139][141][162]

Vagus nerve stimulation is an effective and safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection.[146][147][148][149]

The responsive neurostimulation system is an option for patients with treatment-resistant epilepsy who have one to two unresectable foci.[154][155][156]

≥2 unprovoked GTCSs with generalised-onset epilepsy

1st line – anticonvulsant monotherapy

Back

1st line –

anticonvulsant monotherapy

Findings on electroencephalogram or MRI are suggestive of generalised-onset epilepsy.

Valproic acid is the standard first-line treatment for GTCSs.[118][119] Other agents with proven efficacy are lamotrigine, levetiracetam, and topiramate.[95][96][119][120] [ ] Brivaracetam is a further option.[105]

Valproic acid and topiramate should be used with caution in older patients: valproic acid affects hepatic enzymatic action and binds to plasma proteins, and topiramate may worsen cognitive deficits.

In general, the medication is initiated at a low, easily tolerated dose, and gradually titrated upwards. Dose should be adjusted according to response and serum drug level. An appropriate trial of a single agent is represented by achievement of a sufficiently high dose; for some patients, this may be the listed maximum dose. Patients should be monitored for both efficacy and adverse effects.

Primary options

valproic acid: 10-15 mg/kg/day orally given in 1-3 divided doses initially, increase gradually according to response, maximum 60 mg/kg/day

topiramate: 25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 400 mg/day

lamotrigine: consult specialist for guidance on dose

levetiracetam: 500 mg orally twice daily initially, increase gradually according to response, maximum 3000 mg/day

Secondary options

brivaracetam: 50 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day

2nd line – alternative anticonvulsant monotherapy

Back

2nd line –

alternative anticonvulsant monotherapy

If first-line therapy is not effective, monotherapy with a different anticonvulsant is indicated. A drug with a different mechanism of action should be considered.

If the first drug was not tolerated (due to adverse effects), a second agent should be chosen with special consideration for the patient's health profile and tolerance.

Any new information that aids in defining the epilepsy syndrome should be used to select the best suited medication.

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

The current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly. The specific pharmacokinetic profiles for each of the drugs should be researched prior to instructing the patient on how to switch. A written schedule is often required to aid patients in adherence. Patients should be counselled that there is an increased risk of seizures during this transition period.

Dose should be adjusted according to response and serum drug level.

3rd line – anticonvulsant dual therapy

Back

3rd line –

anticonvulsant dual therapy

Evidence to guide choice of dual therapy is limited.[124] In general, combinations are selected based on pharmacokinetics, drug-drug interactions, and cumulative adverse-effect concerns.[74]

Adjunctive lamotrigine reduced seizure frequency in patients with refractory GTCSs.[161] [ ]

Adjunctive clobazam might reduce seizure frequency in patients with drug-resistant epilepsy. However, the evidence is of very low quality and it is unclear which population will benefit most.[126]

There is some evidence that perampanel is an effective adjunctive therapy for GTCSs in patients with generalised-onset epilepsy.[122][123]

Adjunctive lacosamide was reported to be effective in treating primary GTCSs in a double-blind, randomised, placebo-controlled trial.[130]

Consult a specialist for guidance on choice of anticonvulsant for pregnant women.[76][81]

A dose adjustment may be required when using two anticonvulsants together; consult a specialist for guidance on dose.

Dose should be adjusted according to response and serum drug level.

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Generalised seizures in adults

Treatment algorithm

acute repetitive seizures: in the community

benzodiazepine

Primary options

Secondary options

acute repetitive seizures: in the hospital

parenteral benzodiazepine or anticonvulsant

Primary options

≥2 unprovoked generalised tonic-clonic seizures (GTCSs) without syndromic diagnosis

anticonvulsant monotherapy

Primary options

Secondary options

Tertiary options

alternative anticonvulsant monotherapy

anticonvulsant dual therapy

≥2 unprovoked GTCSs with focal-onset epilepsy

anticonvulsant monotherapy

Primary options

Secondary options

alternative anticonvulsant monotherapy

anticonvulsant dual therapy

surgical resection or neurostimulation

anticonvulsant monotherapy

Primary options

Secondary options

Tertiary options

alternative anticonvulsant monotherapy

alternative anticonvulsant monotherapy

Primary options

Secondary options

anticonvulsant dual therapy

surgical resection or neurostimulation

≥2 unprovoked GTCSs with generalised-onset epilepsy

anticonvulsant monotherapy

Primary options

Secondary options

alternative anticonvulsant monotherapy

anticonvulsant dual therapy