Focal seizures

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

The main goal of treatment is to achieve maximum seizure control as efficiently as possible (preferably with monotherapy) with no or minimal adverse effects. A structured approach to treatment is helpful.

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 under-appreciated and seizure action plans are often lacking.[59][60]

There is no well-established definition of acute repetitive seizures, which adds to the challenge of recognising them.[61] 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.[61]

Carers 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 hospital. Treatment options include diazepam rectal gel, intranasal formulations of midazolam and diazepam, and a buccal formulation of midazolam (available only in Europe). 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 (adults), provided that the patient is awake and cooperative, and the risk of aspiration is low or not a concern.[59][60]

In a hospital setting, intravenous benzodiazepines and intravenous formulations of anticonvulsant medications such as phenytoin/fosphenytoin, valproic acid, levetiracetam, lacosamide, and brivaracetam can be used to treat acute repetitive seizures.

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

Long-term treatment with anticonvulsants: principles

The decision to start anticonvulsant drug treatment following a first unprovoked seizure should be individualised and based on the patient's preference and circumstances.[62] Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure, but does not improve the likelihood of sustained, long-term seizure remission.[62][63]

Treatment should always be tailored to the needs of the patient, taking into account factors such as age and sex, any comorbidities and other medications, and drug properties.[64] Any anticonvulsant may be used as first-line monotherapy if it is the most suitable choice for a particular patient.

When changing from one anticonvulsant to another, current and new medications should be cross-titrated slowly; agents should not be started or stopped abruptly (the concomitant anticonvulsant is gradually reduced as the new agent is introduced). The pharmacokinetic profile of each drug should be researched before instructing the patient on how to switch. A written schedule helps patient adherence. Dose should be adjusted according to response and serum drug level. Patients should be advised that there is an increased risk of seizures during the transition period.

Long-term treatment: choice of anticonvulsant

The efficacy of anticonvulsants has been established in multi-centre, randomised, double-blind, placebo-controlled trials. However, the number of head-to-head trials is limited.[65] The available data suggest that anticonvulsants used to treat focal seizures have comparable efficacy. Therefore, the choice of anticonvulsant should focus on tolerability and be individualised. In particular, the following should be taken into account:[66]

The age and sex of the patient (including, for women, whether they are of childbearing potential)
The underlying aetiology of the focal seizures
The pharmacokinetic properties, mechanism of action, and available formulations of the drug (e.g., extended-release formulations)
Comorbidities and any other medication the patient is taking.

Typically, newer anticonvulsants are associated with fewer, less severe adverse effects, as well as fewer drug-drug interactions.[66][67]

Considerations in relation to comorbidities and drug properties include the following:

For patients with psychiatric comorbidities: levetiracetam, brivaracetam, topiramate, zonisamide, and perampanel should only be used with great caution and with close monitoring for recurrence or exacerbation of psychiatric symptoms.
For patients with cognitive problems: topiramate and zonisamide should only be used with great caution.
For patients with renal impairment: levetiracetam should be used with caution and on the advice of a specialist neurologist, since this drug is cleared exclusively by the kidney.
For patients who may have underlying liver disease or other comorbidities requiring multiple drug therapy, including P450 enzyme-inducing medication: levetiracetam, gabapentin, and pregabalin may help minimise effects on the liver and reduce the potential for drug-drug interactions. Valproic acid, phenobarbital, phenytoin, and felbamate should not be offered.
For patients with migraine as well as focal seizures: topiramate and valproic acid are both effective as migraine prophylaxis.
For patients with neuropathic pain: anticonvulsants with efficacy for certain neuropathic pain conditions (the most common of which is painful diabetic neuropathy) include gabapentin, pregabalin, oxcarbazepine, and carbamazepine.[68][69][70] [ ]
Anticonvulsants associated with weight gain include valproic acid, gabapentin, and pregabalin, and these should be used with great caution in patients with obesity. Those associated with weight loss include topiramate and zonisamide. For the most part, other anticonvulsants are considered not to affect body weight.
Anticonvulsant dose adjustment and/or slower titration may be needed (e.g., for people with renal or hepatic impairment).

Dual therapy

Considerations for choosing two anticonvulsants to use in combination include:

Maximising therapeutic efficacy by using drugs with different mechanisms of action
Minimising pharmacokinetic and pharmacodynamic drug interactions.

Few clinical trials provide data on which combinations may be more effective or preferable.

Adults aged <60 years (long-term treatment)

Additional considerations for women of childbearing potential and pregnant women are discussed in a separate section below.

Anticonvulsant monotherapy (adults aged <60 years)

A trial of anticonvulsant monotherapy is indicated if the patient has had at least two spontaneous seizures, or one seizure with one of the following: epileptiform activity on electroencephalogram (EEG); structural pathology on brain magnetic resonance imaging (MRI) or computed tomography (CT); seizure out of sleep; focal onset indicated by semiology (i.e., head turning or gaze deviation).[71]

Lamotrigine, levetiracetam, and oxcarbazepine are suitable first-line anticonvulsants for monotherapy.[72][73][74][75][76][77] Results from a pragmatic randomised controlled trial suggest that the adverse reaction profile of lamotrigine may be superior to that of levetiracetam in patients (>5 years of age) with two or more unprovoked seizures.[78]

Other treatment options include lacosamide, eslicarbazepine, brivaracetam, zonisamide, carbamazepine, valproic acid, topiramate, perampanel, and cenobamate.[75][79][80] [ ] Brivaracetam is a derivative of levetiracetam with higher binding affinity for the presynaptic SV2 protein. Behavioural adverse events are likely to be less frequent and less severe with brivaracetam than with levetiracetam, except in patients with a history of psychiatric comorbidities.[81][82][83][84]

Gabapentin and pregabalin are appropriate options for patients with particular comorbidities (e.g., psychiatric comorbidities, hepatic impairment, migraine, neuropathic pain).

Alternative anticonvulsant monotherapy (adults aged <60 years)

If the initial anticonvulsant is not effective or not tolerated, a second monotherapy trial is indicated, choosing a different anticonvulsant that is suitable for this population. A drug with a different mechanism of action should be considered. If the first monotherapy agent is unsuitable due to intolerable adverse effects, the alternative agent should be chosen with special consideration for the patient's health profile and tolerance.

Anticonvulsant dual therapy (adults aged <60 years)

If two separate monotherapy trials at optimal doses do not result in adequate seizure control, a dual therapy trial may be initiated using:

A combination of two 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 two drugs that have been shown to have anticonvulsant agonistic effects, should be used.[70][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] [ ]

Other adjunctive therapies are available, including rufinamide, vigabatrin, tiagabine, and felbamate.[103][104][105][106][107] [ ] [ ] However, rufinamide, vigabatrin, tiagabine, and felbamate are associated with severe adverse effects, and should only be considered when multiple other medications have been attempted and surgery is deemed not to be an option. An epilepsy specialist should be involved if these agents are being considered.

Adults aged ≥60 years (long-term treatment)

The incidence of new-onset seizures in older people is significant.[6] The decision to treat focal seizures in older people is often made after the first unprovoked seizure, because the likelihood of recurrence is higher, and the consequences for the patient of even a single seizure (e.g., falls/hip fracture) may be life-changing.

Anticonvulsant monotherapy (adults aged ≥60 years)

Monotherapy administered at the lowest possible dose is preferred. Older patients are particularly susceptible to adverse effects and often have tolerability issues, especially at higher doses or with polytherapy. Age-related physiological changes may contribute to lower rates of drug metabolism and erratic drug absorption, possibly leading to either toxicity or breakthrough seizures. In addition, many people over the age of 60 years have important medical comorbidities, and take a number of different medications.[64]

Anticonvulsants with more favourable pharmacokinetics and adverse-effect profiles, such as lamotrigine, gabapentin, and levetiracetam, are usually the most appropriate choice for patients aged ≥60 years. Other options include oxcarbazepine, lacosamide, eslicarbazepine, brivaracetam, pregabalin, carbamazepine, zonisamide, valproic acid, perampanel, and cenobamate.[75][79][80] [ ] Doses should be increased gradually according to patient response, and the patient should be closely monitored for signs of toxicity. Treatment should always be tailored to the individual patient.[108][109][110]

The pharmacokinetic properties of some anticonvulsants make them less desirable choices for treating focal seizures in older people. These anticonvulsants include drugs that are P450 enzyme inducers or inhibitors; have high protein binding; or are associated with cognitive adverse events.

Alternative anticonvulsant monotherapy (adults aged ≥60 years)

If the initial anticonvulsant is not effective or not tolerated, a second monotherapy trial is indicated, choosing a different anticonvulsant that has proven efficacy for focal epilepsy in the older population. A drug with a different mechanism of action should be considered. If the first monotherapy agent is unsuitable due to intolerable adverse effects (which can be a particular issue in older patients), the alternative agent should be chosen with special consideration for the patient's health profile and tolerance.

Anticonvulsant dual therapy (adults aged ≥60 years)

If two separate monotherapy trials at optimal doses do not result in adequate seizure control, a dual therapy trial may be initiated after consultation with a specialist neurologist. Two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of two drugs that have been shown to have anticonvulsant agonistic effects, can be used.[70][79][80][87][88][89][91][93][94][95][96][97][100][101][102][104] [ ]

Women of childbearing potential and pregnant women (long-term treatment)

Care should be taken with anticonvulsant treatment for any woman of childbearing potential. A specialist should be consulted for guidance about choice of anticonvulsant for pregnant women. Women with epilepsy should receive pre-conception counselling.[111][112][113]

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.[113][114][115][116] The latest data on teratogenicity should be consulted.[113] Data on the teratogenic potential of newer anticonvulsants may not be available or may be limited.[117]
For women taking the contraceptive pill, 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.[118]

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 specialist 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 three 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.[119] Topiramate exposure in pregnancy is associated with cleft lip and being small for gestational age.[113]

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.[120][121]

Safety of other anticonvulsants in pregnancy

In 2021 the UK Medicines and Healthcare products Regulatory Agency (MHRA) published a review of the safety of the following anticonvulsants in pregnancy: carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and zonisamide.

The review concluded that lamotrigine and levetiracetam, at maintenance doses, are not associated with an increased risk of major congenital malformations. Available studies 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.[113][117] A later study suggested an association between antenatal exposure to levetiracetam and attention-deficit hyperactivity disorder.[122]

Data for other drugs showed: 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. Risks associated with other anticonvulsants are uncertain due to lack of or limitations in the data.[117][123] One subsequent MHRA study suggested that pregabalin might slightly increase the risk of major congenital malformations.[124] One systematic review reported adverse fetal and neonatal outcomes following in-utero exposure to oxcarbazepine.[125]

For lamotrigine, levetiracetam, and any anticonvulsant that can be used during pregnancy, the MHRA recommends using monotherapy at the lowest effective dose, and provides monitoring advice.[117]

Anticonvulsant monotherapy (women of childbearing potential or pregnant)

Suitable anticonvulsants for women of childbearing potential and in pregnancy include lamotrigine and levetiracetam.[113][117] [ ] Other options include oxcarbazepine, lacosamide, and zonisamide.[113]

Alternative anticonvulsant monotherapy (women of childbearing potential or pregnant)

If monotherapy does not give adequate seizure control in a pregnant woman, referral to a specialist neurologist is recommended.

If the initial anticonvulsant is not effective or not tolerated, a second monotherapy trial is indicated, choosing a different anticonvulsant that is suitable for a woman of childbearing potential or a pregnant woman. A drug with a different mechanism of action should be considered. If the first monotherapy agent is unsuitable due to intolerable adverse effects, the alternative agent should be chosen with special consideration for the patient's health profile and tolerance.

Anticonvulsant dual therapy (women of childbearing potential or pregnant)

If two separate monotherapy trials at optimal doses do not result in adequate seizure control, a dual therapy trial may be initiated. For pregnant women, consultation with a specialist neurologist is required.[113][126]

Two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of two drugs that have been shown to have anticonvulsant agonistic effects, can be used for dual therapy.[87][88][91][95][96][97][127] [ ]

Folic acid supplementation

Women with epilepsy should be advised to take high-dose folic acid before conception and during pregnancy.[112][126]

Folic acid supplementation (to help prevent neural tube defects in the developing fetus) is a routine recommendation for all women planning pregnancy, and any risk associated with folic acid supplementation is low. Evidence about the benefits of high-dose folic acid supplementation before and during pregnancy for women with epilepsy is inconclusive.[111][113][128][129]

Care of pregnant women

Pregnant women with epilepsy should be under the care of a multidisciplinary team that includes a high-risk obstetric specialist, and care should be coordinated through joint obstetric and neurology clinics.[112] However, 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.[130]

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.[131][132]

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.

Children (long-term treatment)

Treatment should be managed initially by a specialist paediatric neurologist. Guidelines for the acute treatment of seizures in children are largely independent of aetiology, though hypoglycaemia should never be overlooked.[133]

Once focal seizures are diagnosed in a child, determination of aetiology is important for long-term treatment decisions. For example, certain syndromes, such as the subtype of localisation-related/idiopathic epilepsy known as benign childhood epilepsy with centrotemporal spikes, are often accompanied by few seizures, are age dependent, and are usually self-limiting. For this reason, some have advocated that no anticonvulsant treatment is necessary.[134]

In some cases (e.g., if seizure episodes are infrequent) it may be appropriate for the parent or carer to treat only the prolonged seizure with an acute therapy for aborting the seizure, such as rectal diazepam.

For the localisation-related/symptomatic epilepsies (where aetiologies such as malformations and other lesions are identified), focal seizures are often difficult to control. Early anticonvulsant treatment, often with polytherapy, is the norm in these situations.

Anticonvulsant monotherapy (children)

When selecting an appropriate anticonvulsant for a child, potential effects on cognition, learning, and behaviour should be taken into account. For this reason, long-term treatment with anticonvulsants such as phenobarbital and phenytoin should be avoided.

Levetiracetam and oxcarbazepine are suggested as first-line options; they are effective, and a network meta‐analysis of individual patients' data indicates that they have favourable profiles with regard to cognitive adverse effects.[135] Data on the cognitive effects of newer anticonvulsants may not be available or may be limited.

Other options for monotherapy in children include lamotrigine, lacosamide, eslicarbazepine, brivaracetam, carbamazepine, zonisamide, topiramate, perampanel, clobazam, and (other than for girls of childbearing potential) valproic acid.[79][135][136][137]

Younger children often have more rapid clearance and variability in elimination kinetics of anticonvulsants; this must be factored into dosing regimens. Younger children may require liquid and/or chewable anticonvulsant formulations.

Alternative anticonvulsant monotherapy (children)

If the initial anticonvulsant is not effective or not tolerated, a second monotherapy trial is indicated, choosing a different anticonvulsant that is suitable for children. A drug with a different mechanism of action should be considered. If the first monotherapy agent is unsuitable due to intolerable adverse effects, the alternative agent should be chosen with special consideration for the patient's health profile and tolerance.

Anticonvulsant dual therapy (children)

If two separate monotherapy trials at optimal doses do not result in adequate seizure control, a dual therapy trial may be initiated after consultation with a specialist paediatric neurologist. Two anticonvulsants with different mechanisms of action (with the aim of maximising efficacy and minimising toxicity), or a combination of two drugs that have been shown to have anticonvulsant agonistic effects, can be used.[95][96][97][104][138][139] [ ]

Treatment effectiveness and adherence

Only a relatively small percentage (less than 5%) of patients with persistent focal seizures become completely 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 is not increased by further trials.[140][141]

Determining treatment failure depends largely 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. Medication 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. 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. Some patients are non-adherent because of adverse effects, especially drowsiness and nausea. Others may have memory problems and cannot follow the medication regimen. Some patients cannot afford the cost of their medication and may, therefore, under-dose so that it lasts longer. Others may not like to take medication or may fear medication in general.

Ancillary treatment options

Avoiding sleep deprivation, alcohol, and excessive stress may be helpful at any stage of treatment but cannot substitute for anticonvulsant drug therapy.

Evidence about non-pharmacological interventions is limited. One 2020 Cochrane review found that adjunctive psychological and self‐management interventions improved quality of life and emotional wellbeing and reduced fatigue in adults and adolescents with epilepsy.[142] [ ] One 2019 systematic review reported limited evidence that self-management strategies modestly improved some patient outcomes that are important to people with epilepsy.[143]

The International League Against Epilepsy Psychology Task Force recommends that psychological interventions targeting improvements in quality of life and medication adherence, and a decrease in comorbidity symptoms (anxiety, depression), should be incorporated into comprehensive epilepsy care.[144]

Treatment-resistant epilepsy

For adults and children, failure of at least two anticonvulsants in combination (treatment-resistant or intractable epilepsy) should result in reassessment of the diagnosis. If the diagnosis is not secure, then reinvestigation, possibly with video/EEG monitoring, may be helpful.

If the focal seizure diagnosis is correct and the patient is truly refractory to anticonvulsants, consideration and work-up for epilepsy surgery or neurostimulation should be performed.[145][146]

Consideration of these advanced options should be pursued at an epilepsy specialty centre only.

Surgery

Candidates for epilepsy surgery include patients with lesions on brain MRI, or in whom the epileptogenic area can be localised to one region by a variety of techniques, including EEG. One Cochrane review reported that 64% of people who had surgery for epilepsy achieved a good outcome; however, the quality of evidence was low and the estimate across studies varied from 13.5% to 92.5%.[147]

Minimally invasive alternatives to traditional resective surgery include laser interstitial thermal therapy (LITT), radiofrequency ablation, and stereotactic radiosurgery.[148][149]

Neurostimulation

If the patient has more than one epileptogenic focus, neurostimulation may be considered an alternative to surgery.[150] Options include vagus nerve stimulation and deep brain stimulation.[151][152][153][154][155][156]

Responsive neurostimulation (RNS) therapy, neuromodulation via a cranially implanted device, may be appropriate for some medically refractory patients for whom resective surgery is not a viable option.[157][158][159][160]

Ketogenic diet

An option predominantly, but not exclusively, for children (not to be used in adults aged ≥60 years). The ketogenic diet is high in fat and low in carbohydrates and has been shown to reduce seizure frequency.[161][162][163] [ ] [ ] The diet must be initiated in hospital, under close medical supervision, with monitoring for metabolic acidosis and renal calculi.

Drug discontinuation

Seizure freedom for long periods of time can occur with anticonvulsant therapy or after surgical treatment. Patients taking anticonvulsants who achieve seizure freedom may eventually wish to discontinue their medication 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 taken into account. 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 lack of evidence.[164][165] Abrupt medication discontinuation is inadvisable, but, beyond this, there is little evidence to guide the speed of medication taper in adults.[166]

For children who have been seizure-free for at least 18-24 months, and who do not have an electroclinical syndrome suggesting otherwise, discontinuation of anticonvulsant medication may be considered, as this does not clearly increase risk of seizure recurrence. The risks and benefits of discontinuation should be discussed with the patient and family. Provided that an EEG does not show epileptiform activity, discontinuation should be offered at a rate no faster than 25% every 10-14 days.[164]

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