Generalised seizures in adults

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

The main goal of treatment with anticonvulsant medication is to achieve maximum seizure control as efficiently as possible (preferably monotherapy) with no or minimal adverse effects. A structured approach to treatment is helpful. Timely referral of patients with treatment-resistant epilepsy to a comprehensive epilepsy specialty centre is important.[54][55]

Acute management of status epilepticus (defined as either 5 minutes or more of continuous seizure activity, or two or more discrete seizures between which there is incomplete recovery of consciousness) is beyond the scope of this topic. See Status epilepticus.

Treatment of acute repetitive seizures

Acute repetitive seizures (also known as seizure clusters) affect up to half of patients with epilepsy, and can significantly disrupt patients' lives, but their prevalence is underappreciated and seizure action plans are often lacking.[56][57][58]

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 favoured, provided that the patient is awake and co-operative, and the risk of aspiration is low or not a concern.[56][57][60]

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 to treat acute repetitive seizures.[61]

The patient should be continued on a suitable oral formulation of an anticonvulsant once stabilised.

Long-term treatment: general approach

The treatment approach should be individualised, based on the epilepsy syndrome as well as patient preference and characteristics (e.g., age, sex, comorbidities, and potential drug interactions).[62]

Starting treatment

After a first generalised tonic-clonic seizure (GTCS), the treatment approach depends on identifying the cause of the seizure.[63] For a one-time seizure event in which a provoking factor has been determined and reversed, there is no need to institute therapy specific for epilepsy.

For a first unprovoked seizure, the results of the history/physical examination, electroencephalogram (EEG), and magnetic resonance imaging (MRI) guide therapeutic decisions, based on the identification of an epilepsy syndrome. The decision whether to start immediate treatment should take into account the risk of recurrence versus potential adverse effects of therapy, and patient preference.[63][64][65]

Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure, but does not affect the proportion of patients in remission in the long term.[63][66]

After a second unprovoked seizure, therapy is generally recommended, regardless of the epilepsy syndrome.

Choice of anticonvulsant drug

Choice of anticonvulsant drug should focus on tolerability and be individualised. The main criteria are efficacy and adverse effects, but other factors should also be taken into account, including the underlying aetiology of the seizure; the age and sex of the patient; co-morbidities; and drug interactions, mechanism of action, adherence, dosing, and formulations.[67] Clinical decision tools are available that can help guide choice of anticonvulsant treatment, but these should not supersede clinical judgement.[68] Any anticonvulsant may be used if it is the most suitable choice for a particular patient.

With an appropriate medication delivered as monotherapy, the patient may become seizure-free, regardless of the epilepsy syndrome or the specific drug chosen. Seizure-free rates are approximately 50% to 60% in patients with secondary GTCSs, and 60% or higher in patients with primary GTCSs; these rates have not changed with newer anticonvulsants.[69][70][71][72]

Monotherapy limits the risks of adverse effects, idiosyncratic reactions, and pharmacological interactions. Typically, the newer anticonvulsants are associated with fewer, less severe adverse effects, as well as fewer drug-drug interactions.[73][74]

Considerations for women of childbearing potential and pregnant women

Care should be taken with anticonvulsant treatment for any woman of childbearing potential. Choice of anticonvulsant for pregnant women 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. Women with epilepsy should receive pre-conception counselling.[75][76][77][78][79][80][81]

In particular:

Avoid anticonvulsants with documented risks of major and minor fetal malformations or a negative impact on cognitive development, such as valproic acid and its derivatives, topiramate, phenobarbital, and phenytoin. The latest data on teratogenicity should be consulted.[80][81] Data on the teratogenic potential of newer anticonvulsants may not be available or may be limited.[82]
For women taking birth control pills, avoid anticonvulsants with enzyme-inducing properties (e.g., carbamazepine, phenytoin, phenobarbital, primidone), as these can lower contraceptive efficacy and lead to an increased failure rate.[83]

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. These drugs are contraindicated in 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 these drugs 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.[84] Topiramate exposure in pregnancy is associated with cleft lip and being small for gestational age.[81]

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.[85][86]

Safety of other anticonvulsants in pregnancy

The American Academy of Neurology recommends that clinicians consider using lamotrigine, levetiracetam, or oxcarbazepine 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.[81] 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.[82] A later study has suggested an association between antenatal exposure to levetiracetam and attention-deficit hyperactivity disorder.[87] One systematic review has reported adverse fetal and neonatal outcomes following in utero exposure to oxcarbazepine.[88]

Data for other drugs show an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, and phenytoin; possible adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin; and an increased risk of fetal growth restriction associated with phenobarbital and zonisamide. One study suggested that pregabalin might slightly increase the risk of major congenital malformations.[89] Risks associated with other anticonvulsants were uncertain due to limitations in the data.[82]

Folic acid supplementation

Women with epilepsy are advised to take high-dose folic acid before conception and during pregnancy, because some anticonvulsant drugs may affect folate metabolism.[76][90][91][92]

Folic acid supplementation (to help prevent neural tube defects in the developing fetus) is a routine recommendation for all women planning pregnancy. Any risk associated with folic acid supplementation is generally thought to be low. However, one cohort study reported that antenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.[93] Evidence about the benefits of high-dose folic acid supplementation before and during pregnancy for women with epilepsy is inconclusive.[75][77][90]

Care for pregnant women with epilepsy

Pregnant women with epilepsy should be under the care of a multidisciplinary team that includes a high-risk obstetric specialist, and care should be co-ordinated through joint obstetric and neurology clinics.[76] Risk of caesarean delivery, late pregnancy bleeding, premature contractions, or premature labour and delivery are probably not substantially increased in women taking anticonvulsant drugs who do not smoke.[80]

Monitoring of blood anticonvulsant levels is recommended, as pharmacokinetics are affected during pregnancy, and significant declines in levels may occur. Increased drug doses may be required.[77][94]

An anatomical ultrasound should be performed between 14 and 18 weeks of pregnancy, and serum alpha-fetoprotein level measured, to check for possible fetal abnormalities. The need for amniocentesis is on a case-by-case basis.

Long-term treatment: patients with ≥2 unprovoked GTCSs without syndromic diagnosis

In some patients who have GTCSs, the physician may not be able to confirm the cause; that is, there are no obvious findings to suggest a specific epilepsy syndrome. For example, there may be no abnormalities on EEG or MRI. However, initiation of treatment is required with the most effective and safest possible medication.

Consult a specialist for guidance on choice of anticonvulsant for pregnant women (see ‘Considerations for women of childbearing potential and pregnant women’ section).

Primary treatment options for patients with ≥2 unprovoked GTCSs without syndromic diagnosis

In cases where GTCSs are suspected without syndromic diagnosis, there are a number of first-line therapies with comparable efficacy. Medication choice will depend on adverse-effect profile and/or contraindications. Primary options include valproic acid, lamotrigine, levetiracetam, topiramate, oxcarbazepine, and carbamazepine.[95][96]

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 for whom valproic acid may not be an appropriate therapy due to teratogenicity.[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, and for women of of childbearing potential.

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

Other treatment options for patients with ≥2 unprovoked GTCSs without syndromic diagnosis

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.

Long-term treatment: patients age <65 years with ≥2 unprovoked GTCSs with focal-onset epilepsy

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

Consult a specialist for guidance on choice of anticonvulsant for pregnant women (see 'Considerations for women of childbearing potential and pregnant women' section).

Primary treatment options for patients <65 years of age with ≥2 unprovoked GTCSs with focal-onset epilepsy

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

The newer medicines 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] Topiramate should generally be avoided for women of childbearing potential.

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 treatment options for patients <65 years of age with ≥2 unprovoked GTCSs with focal-onset epilepsy

These 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.

Long-term treatment: patients age >65 years with ≥2 unprovoked GTCSs with focal-onset epilepsy

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

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 first-line therapy for older patients with findings on either EEG or MRI suggestive of symptomatic focal-onset epilepsy.[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.

Long-term treatment: patients with ≥2 unprovoked GTCSs with generalised-onset epilepsy

In patients with findings on either EEG or MRI 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]

Consult a consultant for guidance on choice of anticonvulsant for pregnant women (see 'Considerations for women of childbearing potential and pregnant women' section).

Valproic acid and topiramate should generally be avoided as first-line treatment for older patients: valproic acid affects hepatic enzymatic action and binds to plasma proteins, and topiramate may worsen cognitive deficits.

Alternative anticonvulsant monotherapy

Any patient with any epilepsy syndrome that does not respond to an adequate trial of an appropriate first-line medication has an increased risk of inadequate response to subsequent pharmacotherapy.[69]

Monotherapy with a drug with a different mechanism of action should be considered if first-line therapy is not effective.

If the first-line drug was not tolerated (due to adverse effects), the alternative agent should be chosen with special consideration for the patient's health profile. An anticonvulsant not listed for first-line therapy may be considered, if it is the most suitable choice for a particular patient.[121]

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 it is not typically used as first-line therapy.[122][123]

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, 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.[124] In general, combinations are selected based on pharmacokinetics, drug-drug interactions, and cumulative adverse-effect concerns.[74]

Cochrane reviews, other systematic reviews, and trials assessing add-on therapy for drug-resistant epilepsy report the following; in all cases more evidence is needed:

Adjunctive lamotrigine reduced seizure rate in patients with refractory GTCSs. [ ]
Brivaracetam as add-on therapy for patients with drug-resistant epilepsy is 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, 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 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] [ ]

In older patients with focal-onset epilepsy in whom second-line therapy is not effective, a further trial of monotherapy with a medication with proven efficacy in focal-onset epilepsy may be preferred to dual therapy, depending on the patient’s clinical situation (seizure frequency, comorbidities, etc.).

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.

Treatment effectiveness and adherence

A significant proportion of patients do not become seizure-free after two separate monotherapy trials and/or a dual therapy trial with appropriate anticonvulsant medications at optimal doses. The likelihood of achieving freedom from seizures by further trials is small.[55][62] Determining treatment failure depends on baseline seizure frequency: it is easier to judge a lack of response in a patient who has six seizures a month than in someone who has six seizures a year.[55] Medicine adherence, the time frame for reaching therapeutic dosing, and drug tolerability also have to be taken into account.

Adherence with therapy is a challenge for many patients.[28] [ ] Patients with relatively few seizures may have no ill effects if a single dose is missed but, with time, occasional missed doses may result in recurrent seizures. Reasons for non-adherence include adverse effects (especially drowsiness and nausea), cognitive difficulties, cost, and lack of understanding about the need for medication. Behavioural interventions may be helpful, but more research is needed.[28] [ ]

Treatment-resistant epilepsy

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 an 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]

Surgical resection

A patient with GTCSs may be a candidate for surgical resection if the seizures originate from a single primary ictal focus.[139][140][141]

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]

Neurostimulation

In patients for whom surgical resection is considered unsuitable, or who decline surgery, techniques such as vagus nerve stimulation, deep brain 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] However, complete seizure freedom is rarely achieved using vagus nerve stimulation, and one quarter of patients do not receive any benefit from therapy.[146][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] A trial is under way to investigate efficacy in reducing primary generalised seizures in patients with drug-resistant idiopathic generalised epilepsy.[157]

Drug discontinuation

Seizure freedom for long periods of time can occur with an anticonvulsant or after surgical treatment.

Patients who achieve seizure freedom may eventually wish to discontinue anticonvulsant medications 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 medication discontinuation with the patient, including the risks of seizure recurrence and treatment resistance. Individual patient characteristics and preferences should be considered. Patients who are seizure-free after epilepsy surgery and are considering medication discontinuation should be informed that the risk of seizure occurrence is uncertain due to a lack of evidence.[158][159] Abrupt medication discontinuation is inadvisable, but, beyond this, there is little evidence to guide the speed of medication taper.[160]

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