No single medication controls all types of seizures, and different patients require different medications. Some patients require multiple medications. (See also the practice guideline for the treatment of refractory epilepsy from the American Academy of Neurology and the American Epilepsy Society [1, 2].)
Rarely, an antiseizure medication that is effective for one seizure type may aggravate another seizure type.
General references
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: 10.5698/1535-7597.18.4.269
Principles of Long-Term Treatment
There are some general principles for using antiseizure medications (also called antiepileptic medications or anticonvulsants):
A single medication, 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 medications may eventually be required.
If seizures are intractable (refractory to an adequate trial of ≥ 2 medications), patients should be referred to an epilepsy center to determine whether they are candidates for surgery.
The appropriate dose of any medication is the lowest dose that stops all seizures and has the fewest adverse effects, regardless of blood level of a medication. Blood levels of medications are only guidelines. Once medication 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 medication is added at a low dose, which is gradually increased until seizures are controlled. Patients should be closely monitored because the 2 medications can interact, interfering with either medication’s rate of metabolic degradation. The initial medication is then slowly tapered and eventually withdrawn completely.
Use of multiple medications should be avoided if possible because incidence of adverse effects, poor adherence, and medication interactions increases significantly. Adding a second medication helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of antiseizure medications is altered by many other medications, and vice versa. Physicians should be aware of all potential drug-drug interactions before prescribing a new medication.
Once seizures are controlled, the medication should be continued without interruption until patients have been seizure-free for at least 2 years. At that time, stopping the medication may be considered. Most of these medications 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 medication to be seizure-free
Previous seizures while taking an antiseizure medication
Focal-onset or myoclonic seizures
Underlying static (nonprogressive) encephalopathy
Abnormal electroencephalogram (EEG) results within the last year
Structural lesions (seen on imaging studies)
Patients who have a relapse when they are not taking antiseizure medications should be treated indefinitely.
Choice of Medication for Long-Term Treatment
The preferred medications vary according to type of seizure (see table Choice of Medications to Treat Seizures). Other factors that influence choice of medication include adverse effects, interactions with other medications, comorbidities, childbearing plans, and patient preferences.
Traditionally, antiseizure medications have been separated into older and newer groups based on when they became available. However, some so-called newer medications have been available for many years now.
Broad-spectrum antiseizure medications (which are effective for focal-onset seizures and various types of generalized-onset seizures) include
Valproate
For focal-onset seizures and generalized-onset tonic-clonic seizures,
Epileptic (formerly, infantile) spasms, atonic seizures, and myoclonic seizures
For juvenile myoclonic epilepsy,
For febrile seizures,
For seizures due to alcohol withdrawal, antiseizure medications are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.
Choice of Medications to Treat Seizures
Type | Medications | Use |
|---|---|---|
Generalized-onset tonic-clonic seizures | Divalproex Valproate | First-line monotherapy |
Second-line monotherapy or adjunctive therapy | ||
Adjunctive therapy | ||
Although effective, often considered second-line monotherapy because it is sedating and can cause behavioral and learning problems in children | ||
Various types of focal-onset and focal-to-bilateral tonic-clonic seizures | First-line monotherapy | |
Divalproex Valproate | Second-line monotherapy or adjunctive therapy | |
Third-line monotherapy or adjunctive therapy | ||
Although effective, often considered less desirable because it is sedating and can cause behavioral problems in children | ||
Typical nonmotor (absence) seizures | Divalproex Valproate | First-line monotherapy |
Also effective | ||
Atypical nonmotor (absence) seizures Nonmotor seizures associated with other seizure types | Divalproex Valproate | First-line monotherapy |
Also effective, but often development of tolerance | ||
Reserved for refractory cases | ||
Epileptic (infantile) spasms Atonic seizures Myoclonic seizures | Divalproex Valproate | First-line monotherapy |
Risk of irreversible visual field defects | ||
Second-line | ||
Dravet syndrome* | Valproate | Adjunctive therapy. |
Tonic and/or atonic seizures in Lennox-Gastaut syndrome | Divalproex Valproate | First-line monotherapy |
Adjunctive therapy | ||
Sometimes alternative or adjunctive therapy for atonic seizures | ||
Juvenile myoclonic epilepsy | Divalproex Valproate | First-line monotherapy |
Second-line monotherapy or adjunctive therapy | ||
Unclassifiable seizures | Divalproex Valproate | First-line monotherapy |
Second-line monotherapy | ||
Third-line monotherapy or adjunctive therapy | ||
Status epilepticus | Valproate | |
Note: Ezogabine has been withdrawn from the market because of limited use; the medication had a boxed warning for retinal abnormalities and potential vision loss. | ||
Adverse effects
Some adverse effects of antiseizure medications can be minimized by increasing the dose gradually.
Overall, the newer antiseizure medications have advantages, such as better tolerability, less sedation, and fewer medication interactions.
All antiseizure medications may cause an allergic scarlatiniform or morbilliform rash.
Other adverse effects vary by medication (see Specific Antiseizure Medications).
Antiseizure medication use during pregnancy
Antiseizure medications 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 medications during pregnancy.
Yet, because uncontrolled generalized-onset seizures during pregnancy can lead to fetal injury and death, continued treatment with medications is generally advisable. Women should be informed of the risks of antiseizure medications to the fetus, and the risk should be put in perspective: Alcohol is more toxic to the developing fetus than any antiseizure medication.
Many antiseizure medications 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 and should be recommended to all women who are of childbearing age and who take antiseizure medications.
Some Medications With Adverse Effects During Pregnancy
Specific Antiseizure Medications
Medication Name | Indications | Adverse Effects |
|---|---|---|
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, 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, medication reaction with eosinophilia and systemic symptoms (DRESS), shortening of QT interval, suicidal ideation | |
Absence seizures 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, medication dependency, irritability, dysphagia | |
Atypical absence seizures in Lennox-Gastaut syndrome, atonic and myoclonic seizures, epileptic spasms | Drowsiness, ataxia, behavioral abnormalities, partial or complete tolerance to beneficial effects, usually in 1 to 6 months* | |
Divalproex | 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 medications |
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 medication reactions possible | |
Absence seizures | 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 | |
Status epilepticus | 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 Adjunctive therapy for primary generalized tonic-clonic seizures in patients ≥ 4 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 | 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 | |
Status epilepticus 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 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%) | |
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 Status epilepticus 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 medications |
Adjunctive therapy for focal-onset seizures Epileptic spasms | 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 | |
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
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.
Kanner AM, Ashman E, Gloss D, et al: Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy.
