No single drug controls all types of seizures, and different patients require different drugs. Some patients require multiple drugs. (See also the practice guideline for the treatment of refractory epilepsy from the American Academy of Neurology and the American Epilepsy Society [ 1 General references No single drug controls all types of seizures, and different patients require different drugs. Some patients require multiple drugs. (See also the practice guideline for the treatment of refractory... read more , 2 General references No single drug controls all types of seizures, and different patients require different drugs. Some patients require multiple drugs. (See also the practice guideline for the treatment of refractory... read more ].)
Rarely, an antiseizure drug that is effective for one seizure type may aggravate another seizure type.
1. Kanner AM, Ashman E, Gloss D, et al: Practice guideline update: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 91 (2):74–81, 2018. doi: 10.1212/WNL.0000000000005755 Epub 2018 Jun 13.
2. Kanner AM, Ashman E, Gloss D, et al: Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy. Epilepsy Curr 18 (4):269–278, 2018. doi: 10.5698/1535-7518.104.22.1689
Principles of Long-Term Treatment
There are some general principles for using antiseizure drugs (also called antiepileptic or anticonvulsant drugs):
A single drug, usually the first or second one tried, controls epileptic seizures in about 60% of patients.
If seizures are difficult to control from the outset (in 30 to 40% of patients), ≥ 2 drugs may eventually be required.
If seizures are intractable (refractory to an adequate trial of ≥ 2 drugs), patients should be referred to an epilepsy center to determine whether they are candidates for surgery.
Some drugs (eg, phenytoin, valproate), given IV or orally, reach the targeted therapeutic range very rapidly. Others (eg, lamotrigine, topiramate) must be started at a relatively low dose and gradually increased over several weeks to the standard therapeutic dose, based on the patient’s lean body mass. Dose should be tailored to the patient’s tolerance of the drug. Some patients have symptoms of drug toxicity when blood drug levels are low; others tolerate high levels without symptoms. If seizures continue, the daily dose is increased by small increments.
The appropriate dose of any drug is the lowest dose that stops all seizures and has the fewest adverse effects, regardless of blood drug level. Blood drug levels are only guidelines. Once drug response is known, following the clinical course is more useful than measuring blood levels.
Pearls & Pitfalls
If toxicity develops before seizures are controlled, the dose is reduced to the pretoxicity dose. Then, another drug is added at a low dose, which is gradually increased until seizures are controlled. Patients should be closely monitored because the 2 drugs can interact, interfering with either drug’s rate of metabolic degradation. The initial drug is then slowly tapered and eventually withdrawn completely.
Use of multiple drugs should be avoided if possible because incidence of adverse effects, poor adherence, and drug interactions increases significantly. Adding a second drug helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of antiseizure drugs is altered by many other drugs, and vice versa. Physicians should be aware of all potential drug-drug interactions before prescribing a new drug.
Once seizures are controlled, the drug should be continued without interruption until patients have been seizure-free for at least 2 years. At that time, stopping the drug may be considered. Most of these drugs can be tapered by 10% every 2 weeks.
Relapse is more likely in patients who have had any of the following:
A seizure disorder since childhood
Need for > 1 drug to be seizure-free
Previous seizures while taking an antiseizure drug
Focal-onset or myoclonic seizures
Underlying static (nonprogressive) encephalopathy
Abnormal electroencephalogram (EEG) results within the last year
Structural lesions (seen on imaging studies)
Of patients who relapse, about 60% do so within 1 year, and 80% within 2 years. Patients who have a relapse when they are not taking antiseizure drugs should be treated indefinitely.
Antiseizure Drug Choice for Long-Term Treatment
The drugs preferred vary according to type of seizure (see table Choice of Drugs for Seizures Choice of Drugs for Seizures ). For more detailed drug-specific information, see Specific Antiseizure Drugs .
Traditionally, drugs have been separated into older and newer groups based on when they became available. However, some so-called newer drugs have been available for many years now.
Broad-spectrum antiseizure drugs (which are effective for focal-onset seizures and various types of generalized-onset seizures) include
For focal-onset seizures and generalized-onset tonic-clonic seizures, the newer antiseizure drugs (eg, clobazam, clonazepam, felbamate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) are no more effective than the established drugs. However, the newer drugs tend to have fewer adverse effects and to be better-tolerated.
Epileptic (formerly, infantile) spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate or vigabatrin is preferred, followed by clonazepam. For epileptic spasms, corticosteroids for 8 to 10 weeks are often effective. The optimal regimen is controversial. Adrenocorticotropic hormone (ACTH) 20 to 60 units IM once a day may be used. A ketogenic diet (a very high fat diet that induces ketosis) may help but is difficult to maintain.
For juvenile myoclonic epilepsy, life-long treatment with valproate or another antiseizure drug is usually recommended. Carbamazepine, oxcarbazepine, or gabapentin can exacerbate the seizures. Lamotrigine can be used as second-line monotherapy (eg, for women of childbearing age) or adjunctive therapy for juvenile myoclonic epilepsy; however, it can aggravate myoclonic seizures in some patients with juvenile myoclonic epilepsy.
For febrile seizures, drugs are not recommended unless children have a subsequent seizure in the absence of febrile illness. Previously, many physicians gave phenobarbital or other antiseizure drugs to children with complicated febrile seizures to prevent nonfebrile seizures from developing, but this treatment does not appear effective, and long-term use of phenobarbital reduces learning capacity.
For seizures due to alcohol withdrawal, antiseizure drugs are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.
The different adverse effects of antiseizure drugs may influence the choice of drug for an individual patient. For example, antiseizure drugs that cause weight gain (eg, valproate) may not be the best option for an overweight patient, and topiramate or zonisamide may not be suitable for patients with history of kidney stones.
Some adverse effects of antiseizure drugs can be minimized by increasing the dose gradually.
Overall, the newer antiseizure drugs have advantages, such as better tolerability, less sedation, and fewer drug interactions.
All antiseizure drugs may cause an allergic scarlatiniform or morbilliform rash.
Some types of seizures may be worsened by certain antiseizure drugs. For example, pregabalin and lamotrigine may worsen myoclonic seizures; carbamazepine may worsen absence, myoclonic, and atonic seizures.
Other adverse effects vary by drug (see Specific Antiseizure Drugs ).
Antiseizure drug use during pregnancy
Antiseizure drugs are associated with an increased risk of teratogenicity.
Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, limb or digit hypoplasia) occurs in 4% of children of women who take antiseizure drugs during pregnancy.
Yet, because uncontrolled generalized-onset seizures during pregnancy Seizure Disorders in Pregnancy Seizure disorders may impair fertility. But certain antiseizure drugs may make oral contraceptives less effective, resulting in unintentional pregnancy. The dose of antiseizure drugs may have... read more can lead to fetal injury and death, continued treatment with drugs is generally advisable. Women should be informed of the risks of antiseizure drugs to the fetus, and the risk should be put in perspective: Alcohol is more toxic to the developing fetus than any antiseizure drug.
Many antiseizure drugs decrease folate and B12 serum levels; oral vitamin supplements can prevent this effect. Taking folate supplements before conception helps reduce risk of neural tube defects Overview of Congenital Neurologic Anomalies Congenital brain anomalies usually cause severe neurologic deficits; some may be fatal. Some of the most serious neurologic anomalies (eg, anencephaly, encephalocele, spina bifida) develop in... read more and should be recommended to all women who are of childbearing age and who take antiseizure drugs.
Risk of teratogenicity is less with monotherapy and varies by drug; none is completely safe during pregnancy. Risk with carbamazepine, phenytoin, and valproate is relatively high; there is evidence that they have caused congenital malformations in humans (see table Some Drugs With Adverse Effects During Pregnancy Some Drugs With Adverse Effects During Pregnancy ). Risk of neural tube defects is somewhat greater with valproate than other commonly used antiseizure drugs. Risk with some of the newer drugs (eg, lamotrigine) seems to be less.
Specific Antiseizure Drugs
Refractory absence seizures
Renal calculi, dehydration, metabolic acidosis
Adjunctive therapy for seizures in Lennox-Gastaut syndrome and Dravet syndrome in patients ≥ 2 years
Somnolence, hepatocellular injury with elevated aminotransferases, anorexia, fatigue, insomnia, diarrhea
Focal-onset, generalized-onset tonic-clonic, and mixed seizures (but not absence, myoclonic, or atonic seizures)
Diplopia, dizziness, nystagmus, gastrointestinal (GI) upset, dysarthria, lethargy, a low white blood cell (WBC) count (3000 to 4000/mcL), hyponatremia, severe rash, including Stevens-Johnson syndrome (in 5%)
Idiosyncratic adverse effects: granulocytopenia, thrombocytopenia, liver toxicity, aplastic anemia
Adjunctive therapy for focal-onset seizures with or without focal-to-bilateral tonic-clonic generalization
Contraindicated in patients with familial short QT syndrome
Dizziness, diplopia, somnolence, fatigue
Rarely, drug reaction with eosinophilia and systemic symptoms (DRESS), shortening of QT interval, suicidal ideation
Adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome and for refractory focal-onset seizures with or without focal-to-bilateral tonic-clonic generalization
Somnolence, sedation, constipation, ataxia, suicidal thoughts, drug dependency, irritability, dysphagia
Atypical absence seizures in Lennox-Gastaut syndrome, atonic and myoclonic seizures, epileptic spasms
Possibly absence seizures refractory to ethosuximide
Drowsiness, ataxia, behavioral abnormalities, partial or complete tolerance to beneficial effects, usually in 1 to 6 months*
Same indications as valproate: Absence seizures (typical and atypical), focal-onset seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, epileptic spasms, neonatal or febrile seizures, tonic or atonic seizures in Lennox-Gastaut syndrome
Nausea, vomiting, GI intolerance, weight gain, reversible alopecia, transient drowsiness, transient neutropenia, tremor
Idiosyncratically, hyperammonemic encephalopathy
Rarely, fatal hepatic necrosis, particularly in young neurologically impaired children treated with multiple antiseizure drugs
Focal-onset seizures as monotherapy or adjunctive therapy
Not recommended for use in patients with severe hepatic impairment
Dizziness, diplopia, somnolence, hyponatremia, suicidal ideation, dermatologic reactions (including Stevens-Johnson syndrome); significant drug reactions possible
Nausea, lethargy, dizziness, headache
Idiosyncratically, leukocytopenia or pancytopenia, dermatitis, systemic lupus erythematosus
Refractory focal-onset seizures, atypical absence seizures in Lennox-Gastaut syndrome
Headache, fatigue, liver failure; rarely, aplastic anemia
Ataxia, dizziness, somnolence, headache, pruritus, paresthesias
Adjunctive therapy for focal-onset seizures in patients aged 3 to 12 years and as adjunctive therapy for focal-onset seizures with or without focal-to-bilateral tonic-clonic seizures in patients aged ≥ 12 years
Drowsiness, dizziness, weight gain, headache
In patients aged 3 to 12 years, somnolence, aggressive behavior, mood lability, hyperactivity
Second-line monotherapy or adjunctive therapy for focal-onset seizures in patients ≥ 17 years
Dizziness, diplopia, suicidal thoughts
Adjunctive therapy for focal-onset seizures in patients ≥ 2 years, generalized-onset seizures in Lennox-Gastaut syndrome, generalized-onset tonic-clonic seizures
In patients ≥ 16 years, substitution monotherapy for focal-onset or focal-to-bilateral tonic-clonic seizures after a concomitantly used enzyme-inducing antiseizure drug (eg, carbamazepine, phenytoin, phenobarbital) or valproate is stopped
Headache, dizziness, drowsiness, insomnia, fatigue, nausea, vomiting, diplopia, ataxia, tremor, menstrual abnormalities, rash (in 2 to 3%), which progresses to Stevens-Johnson syndrome in 1/50 to 100 children and 1/1000 adults
Exacerbation of myoclonic seizures in adults
Adjunctive therapy for focal-onset seizures in patients ≥ 4 years, generalized-onset tonic-clonic seizures in patients > 6 years, myoclonic seizures in patients > 12 years, and juvenile myoclonic epilepsy
Fatigue, weakness, ataxia, mood and behavioral changes
Focal-onset seizures in patients aged 4 to 16 years as adjunctive therapy and for focal-onset seizures in adults
Fatigue, nausea, abdominal pain, headache, dizziness, somnolence, leukopenia, diplopia, hyponatremia (in 2.5%).
Adjunctive therapy for focal-onset seizures and generalized-onset tonic-clonic seizures in people who have epilepsy and are ≥ 12 years
Not indicated for use in children < 4 years
Aggressiveness, mood and behavioral changes, suicidal ideation, dizziness, somnolence, fatigue, irritability, falls, headache, nausea, vomiting, abdominal pain, weight gain, gait disturbances
Generalized-onset tonic-clonic seizures, focal-onset seizures, status epilepticus, neonatal seizures
Drowsiness, nystagmus, ataxia,
In children, learning difficulties, paradoxical hyperactivity
Idiosyncratically, anemia, rash
Focal-to-bilateral tonic-clonic seizures, focal impaired-awareness seizures, convulsive status epilepticus
Prevention of seizures secondary to head trauma
Megaloblastic anemia, gingival hyperplasia, hirsutism, adenopathy, loss of bone density
With high blood levels of, phenytoin, nystagmus, ataxia, dysarthria, lethargy, irritability, nausea, vomiting, confusion
Idiosyncratically, rash, exfoliative dermatitis
Rarely, exacerbation of seizures
Adjunctive therapy for focal-onset seizures
Dizziness, somnolence, ataxia, blurred vision, diplopia, tremor, weight gain
Exacerbation of myoclonic seizures
Adjunctive therapy for focal-onset seizures in patients ≥ 12 years
Dizziness, light-headedness, confusion, slowed thinking, fatigue, tremor, sedation, nausea, abdominal pain
Focal-onset seizures in patients ≥ 2 years, atypical absence seizures
Second-line monotherapy or adjunctive therapy for primarily generalized tonic-clonic seizures
Decreased concentration, paresthesias, fatigue, speech dysfunction, confusion, anorexia, weight loss, reduced sweating, metabolic acidosis, nephrolithiasis (in 1 to 5%), psychosis (in 1%)
Absence seizures (typical and atypical), focal-onset seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, epileptic spasms, neonatal or febrile seizures, tonic or atonic seizures in Lennox-Gastaut syndrome
Not generally recommended for women of childbearing age
Nausea, vomiting, GI intolerance, weight gain, reversible alopecia (in 5%), transient drowsiness, transient neutropenia, tremor
Idiosyncratically, hyperammonemic encephalopathy
Rarely, fatal hepatic necrosis‡, particularly in young neurologically impaired children treated with multiple antiseizure drugs
Adjunctive therapy for focal-onset seizures
Drowsiness, dizziness, headache, fatigue, irreversible visual field defects (requires regular visual field evaluations)
Adjunctive therapy for focal-onset seizures in patients ≥ 16 years, alternative or adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome
Depression, psychosis, urinary calculi, oligohidrosis
* Serious reactions to clonazepam are rare.
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
1. Kanner AM, Ashman E, Gloss D, et al: Practice guideline update: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
2. Kanner AM, Ashman E, Gloss D, et al: Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy.