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.
Довідкові матеріали загального характеру
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
Принципи тривалого лікування
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.
Some medications (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 medication. Some patients have symptoms of medication toxicity when blood levels of a medication are low; others tolerate high levels without symptoms. If seizures continue, the daily dose is increased by small increments.
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.
Цінні поради та підводні камені
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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.
Вибір лікарського препарату для довготривалого лікування
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
Lamotrigine
Levetiracetam
Topiramate
Valproate
Zonisamide
For focal-onset seizures and generalized-onset tonic-clonic seizures, the newer antiseizure medications (eg, clobazam, clonazepam, felbamate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) are no more effective than the established medications. However, the newer medications 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 medication 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, medications are not recommended unless children have a subsequent seizure in the absence of febrile illness. Previously, many physicians gave phenobarbital or other antiseizure medications 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 medications are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.
Вибір лікарських препаратів для лікування судомних нападів
Type | Medications | Use |
|---|---|---|
Generalized-onset tonic-clonic seizures | Divalproex Valproate | First-line monotherapy |
Lamotrigine Levetiracetam Topiramate | Second-line monotherapy or adjunctive therapy | |
Lacosamide Perampanel Zonisamide | Adjunctive therapy | |
Phenobarbital | 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 | Carbamazepine Fosphenytoin Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Topiramate | First-line monotherapy |
Cenobamate Divalproex Eslicarbazepine Gabapentin Lacosamide Perampanel Pregabalin Valproate Zonisamide | Second-line monotherapy or adjunctive therapy | |
Clobazam Felbamate Tiagabine Vigabatrin | Third-line monotherapy or adjunctive therapy | |
Phenobarbital | Although effective, often considered less desirable because it is sedating and can cause behavioral problems in children | |
Typical nonmotor (absence) seizures | Divalproex Ethosuximide Lamotrigine Valproate | First-line monotherapy |
Clobazam Levetiracetam Topiramate Zonisamide | Also effective | |
Atypical nonmotor (absence) seizures Nonmotor seizures associated with other seizure types | Divalproex Felbamate Lamotrigine Topiramate Valproate | First-line monotherapy |
Clonazepam | Also effective, but often development of tolerance | |
Acetazolamide | Reserved for refractory cases | |
Epileptic (infantile) spasms Atonic seizures Myoclonic seizures | Divalproex Valproate | First-line monotherapy |
Vigabatrin | Risk of irreversible visual field defects | |
Clonazepam | Second-line | |
Dravet syndrome* | Cannabidiol Clobazam Topiramate Valproate | Adjunctive therapy. |
Tonic and/or atonic seizures in Lennox-Gastaut syndrome | Divalproex Lamotrigine Topiramate Valproate | First-line monotherapy |
Cannabidiol | Adjunctive therapy | |
Clobazam Felbamate Zonisamide | Sometimes alternative or adjunctive therapy for atonic seizures | |
Juvenile myoclonic epilepsy | Divalproex Valproate | First-line monotherapy |
Lamotrigine† Levetiracetam Topiramate Zonisamide | Second-line monotherapy or adjunctive therapy | |
Unclassifiable seizures | Divalproex Valproate | First-line monotherapy |
Lamotrigine | Second-line monotherapy | |
Levetiracetam Topiramate Zonisamide | Third-line monotherapy or adjunctive therapy | |
Status epilepticus | Fosphenytoin Phenytoin Levetiracetam Valproate | After initial lorazepam |
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. | ||
* Carbamazepine, phenytoin, and lamotrigine can worsen myoclonus and exacerbate seizures in patients with Dravet syndrome. | ||
† Lamotrigine can aggravate myoclonic seizures in some patients with juvenile myoclonic epilepsy. | ||
Побічні ефекти
The different adverse effects of antiseizure medications may influence the choice of medication for an individual patient. For example, antiseizure medications 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 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.
Some types of seizures may be worsened by certain antiseizure medications. For example, pregabalin and lamotrigine may worsen myoclonic seizures; carbamazepine may worsen absence, myoclonic, and atonic seizures.
Some antiseizure medications (phenobarbital, carbamazepine, phenytoin) are potent inducers of the cytochrome P450 (CYP450) system and may lead to reduced blood levels of several medications, including oral contraceptives, anticoagulants, antiretrovirals, cytotoxic therapy and some other antiseizure medications. They may also lead to lower vitamin D levels, increasing the risk of osteoporosis.
Other adverse effects vary by medication (see Specific Antiseizure Medications).
Використання протисудомних препаратів під час вагітності
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.
Risk of teratogenicity is lower with monotherapy and varies by medication; 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 Medications With Adverse Effects During Pregnancy). Risk of neural tube defects is somewhat greater with valproate than other commonly used antiseizure medications. Risk with some of the newer medications (eg, lamotrigine) seems to be less.
Специфічні протисудомні препарати
Medication Name | Indications | Adverse Effects |
|---|---|---|
Acetazolamide | Refractory absence seizures | Renal calculi, dehydration, metabolic acidosis |
Cannabidiol | 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 |
Carbamazepine | 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 |
Cenobamate | 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 |
Clobazam | 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 |
Clonazepam | 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* |
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 |
Eslicarbazepine | 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 |
Ethosuximide | Absence seizures | Nausea, lethargy, dizziness, headache Idiosyncratically, leukocytopenia or pancytopenia, dermatitis, systemic lupus erythematosus |
Felbamate | Refractory focal-onset seizures, atypical absence seizures in Lennox-Gastaut syndrome | Headache, fatigue, liver failure; rarely, aplastic anemia |
Fosphenytoin | Status epilepticus | Ataxia, dizziness, somnolence, headache, pruritus, paresthesias |
Gabapentin | 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 |
Lacosamide | 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 |
Lamotrigine | 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 medication (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 |
Levetiracetam | 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 |
Oxcarbazepine | 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%). |
Perampanel | 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 |
Phenobarbital | Generalized-onset tonic-clonic seizures, focal-onset seizures, status epilepticus, neonatal seizures | Drowsiness, nystagmus, ataxia, In children, learning difficulties, paradoxical hyperactivity Idiosyncratically, anemia, rash |
Phenytoin | 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 |
Pregabalin | Adjunctive therapy for focal-onset seizures | Dizziness, somnolence, ataxia, blurred vision, diplopia, tremor, weight gain Exacerbation of myoclonic seizures |
Tiagabine | Adjunctive therapy for focal-onset seizures in patients ≥ 12 years | Dizziness, light-headedness, confusion, slowed thinking, fatigue, tremor, sedation, nausea, abdominal pain |
Topiramate | 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 |
Vigabatrin | Adjunctive therapy for focal-onset seizures Epileptic spasms | Drowsiness, dizziness, headache, fatigue, irreversible visual field defects (requires regular visual field evaluations) |
Zonisamide | 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. | ||
Додаткова інформація
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.
