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(See also Neurologic Disorders in Children: Febrile Seizures and see also Neurologic Disorders in Children: Neonatal Seizure Disorders.)
A seizure is an abnormal, unregulated electrical discharge that occurs within the brain's cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered awareness, abnormal sensations, focal involuntary movements, or convulsions (widespread violent involuntary contraction of voluntary muscles).
About 2% of adults have a seizure at some time during their life. Two thirds of these people never have another one.
Definitions:
Terminology can be confusing.
Epilepsy (also called epileptic seizure disorder) is a chronic brain disorder characterized by recurrent (≥ 2), unprovoked seizures (ie, not related to reversible stressors). Epilepsy is often idiopathic, but various brain disorders, such as malformations, strokes, and tumors, can cause symptomatic epilepsy.
Nonepileptic seizures are provoked by a temporary disorder or stressor (eg, metabolic disorders, CNS infections, cardiovascular disorders, drug toxicity or withdrawal). In children, fever can provoke a seizure (see Neurologic Disorders in Children: Febrile Seizures).
Symptomatic seizures are due to a known cause (eg, brain tumor, stroke). Symptomatic seizures are most common among neonates (see Neurologic Disorders in Children: Neonatal Seizure Disorders) and the elderly.
Psychogenic seizures (pseudoseizures) are symptoms that simulate seizures in patients with psychiatric disorders but that do not involve an abnormal electrical discharge in the brain.
Etiology
Common causes of seizures (see Table 1: Seizure Disorders: Causes of Seizures ) vary by age of onset:
In reflex epilepsy, a rare disorder, seizures are triggered predictably by an external stimulus, such as repetitive sounds, flashing lights, video games, or even touching certain parts of the body.
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Table 1
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| Causes of Seizures |
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Condition
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Examples
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Autoimmune disorders
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Cerebral vasculitis, multiple sclerosis (rarely)
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Cerebral edema
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Eclampsia, hypertensive encephalopathy
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Cerebral ischemia or hypoxia
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Cardiac arrhythmias, carbon monoxide toxicity, nonfatal drowning, near suffocation, stroke, vasculitis
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Head trauma*
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Birth injury, blunt or penetrating injuries
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CNS infections
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AIDS, brain abscess, falciparum malaria, meningitis, neurocysticercosis, neurosyphilis, rabies, tetanus, toxoplasmosis, viral encephalitis
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Congenital or developmental abnormalities
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Cortical malformations, genetic disorders (eg, fifth day fits†, lipid storage diseases such as Tay-Sachs disease), neuronal migration disorders (eg, heterotopias), phenylketonuria
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Drugs and toxins‡
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Cause seizures: Camphor, cocaine and other CNS stimulants, cyclosporine, lead, pentylenetetrazol, picrotoxin, strychnine, tacrolimus
Lower seizure threshold: Aminophylline, antidepressants (particularly tricyclics), sedating antihistamines, antimalarial drugs, some antipsychotics (eg, clozapine), buspirone, fluoroquinolones, theophylline
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Expanding intracranial lesions
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Hemorrhage, hydrocephalus, tumors
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Hyperpyrexia
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Drug toxicity (eg, with amphetamines or cocaine), fever, heatstroke
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Metabolic disturbances
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Commonly, hypocalcemia, hypoglycemia, hyponatremia
Less commonly, aminoacidurias, hepatic or uremic encephalopathy, hyperglycemia, hypomagnesemia, hypernatremia
In neonates, vitamin B6 (pyridoxine) deficiency
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Pressure-related
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Decompression illness, hyperbaric O2 treatments
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Withdrawal syndromes
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Alcohol, anesthetics, barbiturates, benzodiazepines
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*Posttraumatic seizures occur in 25 to 75% of patients who have brain contusion, skull fracture, intracranial hemorrhage, prolonged coma, or focal neurologic deficits.
†Fifth day fits (benign neonatal seizures) are tonic-clonic seizures occurring between 4 and 6 days of age in otherwise healthy infants; one form is inherited.
‡When given in toxic doses, various drugs can cause seizures.
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Classification
Seizures are classified as generalized or partial.
Generalized:
In generalized seizures, the aberrant electrical discharge diffusely involves the entire cortex of both hemispheres from the onset, and consciousness is usually lost. Generalized seizures result most often from metabolic disorders and sometimes from genetic disorders. Generalized seizures include the following:
Partial seizures:
In partial seizures, the excess neuronal discharge occurs in one cerebral cortex, and most often results from structural abnormalities. Partial seizures may be
Partial seizures may be followed by a generalized seizure (called secondary generalization), which causes loss of consciousness. Secondary generalization occurs when a partial seizure spreads and activates the entire cerebrum bilaterally. Activation may occur so rapidly that the initial partial seizure is not clinically apparent or is very brief.
Symptoms and Signs
Seizures may be preceded by an aura. Auras may consist of sensory, autonomic, or psychic sensations (eg, paresthesias, a rising epigastric sensation, abnormal smells, a sensation of fear, a déjà vu sensation).
Most seizures end spontaneously in 1 to 2 min. Generalized seizures are often followed by a postictal state, characterized by deep sleep, headache, confusion, and muscle soreness; this state lasts from minutes to hours. Sometimes the postictal state includes Todd's paralysis (a transient neurologic deficit, usually weakness, of the limb contralateral to the seizure focus).
Most patients appear neurologically normal between seizures, although high doses of the drugs used to treat seizure disorders, particularly anticonvulsants, can reduce alertness. Any progressive mental deterioration is usually related to the neurologic disorder that caused the seizures rather than to the seizures themselves. Rarely, seizures are unremitting.
Partial seizures:
There are several types of partial seizures.
Simple partial seizures cause motor, sensory, or psychomotor symptoms without loss of consciousness. Specific symptoms reflect the affected area of the brain (see Table 2: Seizure Disorders: Manifestations of Partial Seizures by Site). In jacksonian seizures, focal motor symptoms begin in one hand, then march up the arm. Other focal seizures affect the face first, then spread to an arm and sometimes a leg. Some partial motor seizures begin with an arm raising and the head turning toward the moving arm.
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Table 2
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| Manifestations of Partial Seizures by Site |
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Focal Manifestation
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Site of Dysfunction
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Bilateral tonic posture
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Frontal lobe (supplementary motor cortex)
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Simple movements (eg, limb twitching, jacksonian march)
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Contralateral frontal lobe
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Head and eye deviation with posturing
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Supplementary motor cortex
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Abnormal taste sensation (dysgeusia)
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Insula
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Visceral or autonomic abnormalities (eg, epigastric aura, salivation)
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Insular-orbital-frontal cortex
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Olfactory hallucinations
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Anteromedial temporal lobe
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Chewing movements, salivation, speech arrest
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Amygdala, opercular region
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Complex automatic behaviorisms
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Temporal lobe
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Visual hallucinations (formed images)
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Posterior temporal lobe or amygdala-hippocampus
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Localized sensory disturbances (eg, tingling or numbness of a limb or 1⁄2 the body)
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Parietal lobe (sensory cortex)
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Visual hallucinations (unformed images)
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Occipital lobe
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Epilepsia partialis continua, a rare disorder, causes focal motor seizures that usually involve the arm, hand, or one side of the face; seizures recur every few seconds or minutes for days to years at a time. In adults, the cause is usually a structural lesion (eg, stroke). In children, it is usually a focal cerebral cortical inflammatory process (eg, Rasmussen encephalitis), possibly caused by a chronic viral infection or autoimmune processes.
Complex partial seizures are often preceded by an aura. During the seizure, patients may stare. Consciousness is impaired, but patients have some awareness of the environment (eg, they purposefully withdraw from noxious stimuli). The following may also occur:
Motor symptoms subside after 1 to 2 min, but confusion and disorientation may continue for another 1 or 2 min. Postictal amnesia is common. Patients may lash out if restrained during the seizure or while recovering consciousness if the seizure generalizes. However, unprovoked aggressive behavior is unusual.
Left temporal lobe seizures may cause verbal memory abnormalities; right temporal lobe seizures may cause visual spatial memory abnormalities.
Generalized seizures:
Consciousness is usually lost, and motor function is abnormal from the onset.
Infantile spasms (see Neurologic Disorders in Children: Infantile Spasms) are characterized by sudden flexion and adduction of the arms and forward flexion of the trunk. Seizures last a few seconds and recur many times a day. They occur only in the first 5 yr of life, then are replaced by other types of seizures. Developmental defects are usually present.
Typical absence seizures (formerly called petit mal seizures) consist of 10- to 30-sec loss of consciousness with eyelid fluttering; axial muscle tone may or may not be lost. Patients do not fall or convulse; they abruptly stop activity, then just as abruptly resume it, with no postictal symptoms or knowledge that a seizure has occurred. Absence seizures are genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many times a day. Seizures often occur when patients are sitting quietly, can be precipitated by hyperventilation, and rarely occur during exercise. Neurologic and cognitive examination results are usually normal.
Atypical absence seizures usually occur as part of the Lennox-Gastaut syndrome, a severe form of epilepsy that begins before age 4 yr. They differ from typical absence seizures as follows:
Many patients have a history of damage to the nervous system, developmental delay, abnormal neurologic examination results, and other types of seizures. Atypical absence seizures usually continue into adulthood.
Atonic seizures occur most often in children, usually as part of Lennox-Gastaut syndrome. Atonic seizures are characterized by brief, complete loss of muscle tone and consciousness. Children fall or pitch to the ground, risking trauma, particularly head injury.
Tonic seizures occur most often during sleep, usually in children. The cause is usually the Lennox-Gastaut syndrome. Tonic (sustained) contraction of axial muscles may begin abruptly or gradually, then spread to the proximal muscles of the limbs. Tonic seizures usually last 10 to 15 sec. In longer tonic seizures, a few, rapid clonic jerks may occur as the tonic phase ends.
Tonic-clonic seizures may be primarily or secondarily generalized. Primarily generalized seizures typically begin with an outcry; they continue with loss of consciousness and falling, followed by tonic contraction, then clonic (rapidly alternating contraction and relaxation) motion of muscles of the extremities, trunk, and head. Urinary and fecal incontinence, tongue biting, and frothing at the mouth sometimes occur. Seizures usually last 1 to 2 min. There is no aura. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.
Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be repetitive, leading to a tonic-clonic seizure. The jerks may be bilateral or unilateral. Unlike other seizures with bilateral motor movements, consciousness is not lost unless the myoclonic seizure progresses into a generalized tonic-clonic seizure.
Juvenile myoclonic epilepsy is an epilepsy syndrome characterized by myoclonic, tonic-clonic, and absence seizures. It typically appears during adolescence. Seizures begin with a few bilateral, synchronous myoclonic jerks, followed in 90% by generalized tonic-clonic seizures. They often occur when patients awaken in the morning, especially after sleep deprivation or alcohol use. Absence seizures may occur in one third of patients.
Febrile seizures occur, by definition, with fever and in the absence of intracranial infection; they are considered a type of provoked seizure. They affect about 4% of children aged 3 mo to 5 yr (see Neurologic Disorders in Children: Febrile Seizures). Benign febrile seizures are brief, solitary, and generalized tonic-clonic in appearance. Complicated febrile seizures are focal, last > 15 min, or recur ≥ 2 times in < 24 h. Overall, 2% of patients with febrile seizures develop a subsequent seizure disorder. However, incidence of seizure disorders and risk of recurrent febrile seizures are much greater among children with complicated febrile seizures, preexisting neurologic abnormalities, onset before age 1 yr, or a family history of seizure disorders.
Status epilepticus:
Generalized convulsive status epilepticus involves at least one of the following:
The previous definition of > 30-min duration was revised to encourage more prompt identification and treatment. Untreated generalized seizures lasting > 60 min may result in permanent brain damage; longer-lasting seizures may be fatal. Heart rate and temperature increase. Generalized convulsive status epilepticus has many causes, including rapid withdrawal of anticonvulsants and head trauma.
Complex partial status epilepticus and absence status epilepticus often manifest as prolonged episodes of mental status changes. EEG may be required for diagnosis.
Diagnosis
Evaluation must determine whether the event was a seizure vs another cause of obtundation, a pseudoseizure, or syncope), then identify possible causes or precipitants. Patients with new-onset seizures are evaluated in an emergency department; they can sometimes be discharged after thorough evaluation. Those with a known seizure disorder may be evaluated in a physician's office.
History:
Patients should be asked about unusual sensations, suggesting an aura and thus a seizure, and about typical seizure manifestations. However, other conditions, such as suddenly decreased brain circulation (eg, due to ventricular arrhythmia) can have similar manifestations, including loss of consciousness and some myoclonic jerks.
History should include information about the first and any subsequent seizures (eg, duration, frequency, sequential evolution, longest and shortest interval between seizures, aura, postictal state, precipitating factors). All patients should be asked about risk factors for seizures:
Patients should also be asked about rare triggers (eg, repetitive sounds, flashing lights, video games, touching certain parts of the body) and about sleep deprivation, which can lower the seizure threshold.
Physical examination:
A bitten tongue, incontinence (eg, urine or feces in clothing), or, in patients who have lost consciousness, prolonged confusion suggest seizure.
In pseudoseizures, generalized muscular activity and lack of response to verbal stimuli may at first glance suggest generalized tonic-clonic seizures. However, pseudoseizures can usually be distinguished from true seizures by clinical characteristics:
Physical examination rarely indicates the cause when seizures are idiopathic but may provide clues when seizures are symptomatic (see Table 3: Seizure Disorders: Clinical Clues to the Causes of Symptomatic Seizures).
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Table 3
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| Clinical Clues to the Causes of Symptomatic Seizures |
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Finding
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Possible Cause
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Fever and stiff neck
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Meningitis
Subarachnoid hemorrhage
Meningoencephalitis
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Papilledema
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Increased intracranial pressure
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Loss of spontaneous venous pulsations
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Increased intracranial pressure (with less sensitivity*)
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Focal neurologic defects (eg, asymmetry of reflexes or muscle strength)
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Structural abnormality (eg, tumor, stroke)
Postictal paralysis
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Generalized neuromuscular irritability (eg, tremulousness, hyperreflexia)
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Drug toxicity (eg, sympathomimetics)
Withdrawal syndromes (eg, of alcohol or sedatives)
Certain metabolic disorders (eg, hypocalcemia, hypomagnesemia)
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Skin lesions (eg, axillary freckling or café-au-lait spots, hypomelanotic skin macules, shagreen patches)
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Neurocutaneous disorders (eg, neurofibromatosis, tuberous sclerosis)
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*About 20% of people with normal intracranial pressure lose spontaneous venous pulsations.
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Testing:
Testing is done routinely, but normal results do not necessarily exclude a seizure disorder. Thus, the diagnosis may ultimately be clinical. Testing depends on the status of seizures and results of the neurologic examination.
If patients have a known seizure disorder and examination results are normal or unchanged, little testing is required except for blood anticonvulsant levels, unless patients have symptoms or signs of a treatable disorder such as trauma, infection, or a metabolic disorder. If seizures are new-onset or if examination results are abnormal for the first time, neuroimaging is required.
Head CT is usually done immediately to exclude a mass or hemorrhage. Some experts say that CT can be deferred and possibly avoided in children with typical febrile seizures whose neurologic status rapidly returns to normal.
Follow-up MRI is recommended when CT is negative. It provides better resolution of brain tumors and abscesses and can detect cortical dysplasias, cerebral venous thrombosis, and herpes encephalitis. An epilepsy-protocol MRI of the head uses high-resolution coronal T1 and T2 sequences, which can detect hippocampal atrophy or sclerosis. MRI can detect some common causes of seizures, such as malformations of cortical development in young children and mesial temporal sclerosis, traumatic gliosis, and small tumors in adults.
EEG is critical in the diagnosis of epileptic seizures, particularly of complex partial or absence status epilepticus, when EEG may be the most definitive indication of a seizure. EEG may detect epileptiform abnormalities (spikes, sharp waves, spike and slow-wave complexes, polyspike and slow-wave complexes). Epileptiform abnormalities may be bilateral and generalized in patients with generalized seizures and may be localized in patients with partial seizures. EEG findings may include the following:
However, normal EEG cannot exclude the diagnosis of epileptic seizures, which must be made clinically. EEG is less likely to detect abnormalities if seizures are infrequent. The initial EEG may detect an epileptiform abnormality in only 30 to 55% of patients with a known epileptic seizure disorder. Serial EEG may detect epileptiform abnormalities in up to 80 to 90% of such patients. In general, serial EEG with extended recording times and with tests done during sleep deprivation greatly increases the chance of detecting epileptiform abnormalities in patients with epileptic seizures. Inpatient combined video-EEG monitoring, usually for 2 to 7 days, records EEG activity and clinical behavior simultaneously. It is the most sensitive EEG testing available and is thus useful in differentiating epileptic from nonepileptic seizures.
Testing is also done to check for other disorders:
If seizures are refractory and surgical resection is being considered, advanced imaging tests may be done in epilepsy centers. Functional MRI can identify functioning cortex and guide surgical resection. If EEG and MRI do not clearly identify the epileptic focus, magnetoencephalography (MEG) with EEG (called magnetic source imaging, or MSI) may localize the lesion, avoiding the need for invasive intraoperative mapping procedures. Single-photon emission CT (SPECT) during the peri-ictal period may detect increased perfusion in the seizure focus and help localize the area to be surgically removed. Because injection of contrast is required at the time of seizure, patients must be admitted for continuous EEG-video monitoring when SPECT is done during the peri-ictal period.
Neuropsychologic testing may help identify functional deficits before and after surgery and help predict social and psychologic prognosis and capacity for rehabilitation.
Prognosis
With treatment, seizures are eliminated in one third of patients with epileptic seizures, and frequency of seizures is reduced by > 50% in another third. About 60% of patients whose seizures are well-controlled by drugs can eventually stop the drugs and remain seizure-free.
Sudden unexplained death in epilepsy (SUDEP) is a rare complication of unknown cause.
Treatment
Optimal treatment is to eliminate the causes whenever possible. If the cause cannot be corrected or identified, anticonvulsants are often required, particularly after a 2nd seizure; usefulness of anticonvulsants after a single seizure is controversial, and risks and benefits should be discussed with the patient. Because the risk of a subsequent seizure is low, drugs may be withheld until a 2nd seizure occurs, particularly in children. In children, certain anticonvulsants cause important behavior and learning problems.
During a generalized tonic-clonic seizure, injury should be prevented by loosening clothing around the neck and placing a pillow under the head. Attempting to protect the tongue is futile and likely to damage the patient's teeth or the rescuer's fingers. Patients should be rolled onto their left side to prevent aspiration. These measures should be taught to the patient's family members and coworkers.
Because partial seizures can become generalized, patients are at risk of losing consciousness and thus should be advised to take certain precautions. Until seizures are controlled, patients should refrain from activities in which loss of consciousness could be life threatening (eg, driving, swimming, climbing, operating power tools, bathing in a bathtub). After seizures are completely controlled (typically for > 6 mo), many such activities can be resumed if appropriate safeguards (eg, lifeguards) are used, and patients should be encouraged to lead a normal life, including exercise and social activities. In a few states, physicians must report patients with seizures to the Department of Motor Vehicles. However, most states allow automobile driving after patients have been seizure-free for 6 mo to 1 yr.
Patients should be advised to avoid cocaine and some other illicit drugs (eg, phencyclidine, amphetamines), which can trigger seizures, and to avoid alcohol. Some drugs (eg, haloperidol, phenothiazines) may lower seizure threshold and should be avoided if possible.
Family members must be taught a commonsense approach toward the patient. Overprotection should be replaced with sympathetic support that lessens negative feelings (eg, of inferiority or self-consciousness); invalidism should be prevented. Institutional care is rarely advisable and should be reserved for severely cognitively impaired patients and for patients with seizures so frequent and violent despite drug treatment that they cannot be cared for elsewhere.
Acute seizures and status epilepticus:
Most seizures remit spontaneously in several minutes or less and do not require emergency drug treatment. Status epilepticus and most seizures lasting > 5 min require drugs to terminate the seizures, with monitoring of respiratory status. Endotracheal intubation is necessary if there is any indication of airway compromise. IV access should be quickly obtained, and lorazepam 0.05 to 0.1 mg/kg IV is given at a rate of 2 mg/min. Larger doses are sometimes required. However, if seizures continue after about 8 mg is given, fosphenytoin 15 to 20 PE (phenytoin equivalents)/kg IV is given at a rate of 100 to 150 PE/min; phenytoin 15 to 20 mg/kg IV at a rate of 50 mg/min is a 2nd choice. Additional seizures require an additional 5 to 10 PE/kg of fosphenytoin or 5 to 10 mg/kg of phenytoin. If IV access cannot be obtained, options include IM fosphenytoin and sublingual or rectal benzodiazepines.
Seizures that persist after use of lorazepam and phenytoin define refractory status epilepticus. Recommendations for a 3rd anticonvulsant vary and include phenobarbital, propofol, midazolam, and valproate. Phenobarbital 15 to 20 mg/kg IV at 100 mg/min (3 mg/kg/min in children) is given; continued seizures require another 5 to 10 mg/kg. A loading dose of valproate 10 to 15 mg/kg IV is an alternative. At this point, if status epilepticus has not abated, intubation and general anesthesia are necessary. The optimal anesthetic to use is controversial, but many physicians use propofol 15 to 20 mg/kg at 100 mg/min or pentobarbital 5 to 8 mg/kg (loading dose) followed by infusion of 2 to 4 mg/kg/h until EEG manifestations of seizure activity have been suppressed. Inhalational anesthetics are rarely used. After initial treatment, the cause of status epilepticus must be identified and treated.
Posttraumatic seizures:
Drugs are given to prevent seizures if head injury causes significant structural injury (eg, large contusions or hematomas, brain laceration, depressed skull fracture) or a Glasgow Coma Scale (GCS) score of < 10. These drugs reduce risk of seizures during the first week after injury but do not prevent permanent posttraumatic epilepsy months or years later. They should be stopped after 1 wk unless seizures occur. If seizures begin > 1 wk after head injury, long-term treatment with drugs is required.
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Principles of long-term treatment:
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.) Some general principles apply:
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.
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, ineffective 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 2nd drug helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of anticonvulsants 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 yr. At that time, stopping the drug may be considered. Most of these drugs can be tapered by 10% every 2 wk. Relapse is more likely in patients who have had any of the following:
Of patients who relapse, about 60% do so within 1 yr, and 80% within 2 yr. Patients who have a relapse when they are not taking anticonvulsants should be treated indefinitely.
Drug choice for long-term treatment:
The drugs preferred vary according to type of seizure (see Table 4: Seizure Disorders: Choice of Drugs for Seizures). For more detailed drug-specific information, see Table 5: Seizure Disorders: Drugs Used in Seizure Disordersa.
For partial seizures and generalized tonic-clonic seizures, the newer anticonvulsants (eg, clonazepam, felbamate, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zosinamide) are no more effective than the established drugs. However, the newer drugs tend to have fewer adverse effects and to be better tolerated.
Infantile spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate is preferred, followed by clonazepam. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal regimen is controversial. ACTH 20 to 60 units IM once/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 is usually recommended. Carbamazepine, oxcarbazepine, or gabapentin can exacerbate the seizures.
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 anticonvulsants 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, drugs are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.
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Table 5
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| Drugs Used in Seizure Disordersa
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Drugb
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Indications
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Children
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Adultsc
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Therapeutic Levels
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Toxic Levels
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Some Adverse Effects
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Acetazolamide
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Refractory absence seizures
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4–15 mg/kg bid (not to exceed 1 g/day)
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4–15 mg/kg bid (not to exceed 1g/day)
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8–14 μg/mL(34–59 μmol/L)
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> 25 μg/mL(> 106 μmol/L)
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Renal calculi, dehydration, metabolic acidosis
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Carbamazepined
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Partial seizures
Generalized seizures
Mixed seizures
(Not absence or myoclonic seizures)
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< 6 yr: 5–10 mg/kg bid (tablets)
2.5–5 mg/kg qid (suspension)
6–12 yr: 100 mg bid (tablets)
2.5 mL (50 mg) qid (suspension)
> 12 yr: 200 mg bid (tablets)
5 mL (100 mg) qid (suspension)
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200–600 mg bid
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4–12 μg/mL (17–51 μmol/L)
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> 14 μg/mL (> 59 μmol/L)
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Diplopia, dizziness, nystagmus, GI upset, dysarthria, lethargy, low WBC count (3000–4000/μL)
Idiosyncratic: Granulocytopenia, thrombocytopenia, liver toxicity, aplastic anemia
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Clonazepam
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Atypical absence seizures in Lennox-Gastaut syndrome
Atonic and myoclonic seizures
Possibly absence seizures refractory to ethosuximide
Infantile spasms
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Initially, 0.01mg/kg bid to tid (maximum: 0.05 mg/kg/day), increased by 0.25–0.5 mg q 3 days until seizures are controlled or adverse effects occur
For maintenance, usually 0.03–0.06 mg/kg tid
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Initially, 0.5 mg tid
For maintenance, up to 5–7 mg tid (maximum: 20 mg/day)
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25–30 ng/mL
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> 80 ng/mL
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Drowsiness, ataxia, behavioral abnormalities, partial or complete tolerance to beneficial effects (usually in 1–6 mo); serious reactions rare
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Divalproex
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Same as for valproate
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Initially, 5 mg/kg bid or tid, increased by 5–10 mg/kg/day at weekly intervals (usual maintenance: 10–20 mg/kg tid)
For extended-release, total daily dose that is 8–20% higher, given once/daye
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5 mg/kg tid, increased slowly—eg, by 1.67–3.33 mg/kg tid at weekly intervals, especially if other drugs are being taken (maximum: 20 mg/kg tid)
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Ethosuximide
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Absence seizures
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3–6 yr: 250 mg once/day (usual maximum: 20–40 mg/kg/day)
> 6 yr: Initially, 250 mg bid, increased by 250 mg/day as needed q 4–7 days (usual maximum: 1500 mg/day)
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250 mg bid, increased in 250-mg increments q 4–7 days (usual maximum: 1500 mg/day)
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40–100 μg/mL (283–708 μmol/L)
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> 100 μg/mL (> 708 μmol/L)f
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Nausea, lethargy, dizziness, headache
Idiosyncratic: Leukocytopenia or pancytopenia, dermatitis, SLE
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Felbamate
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Refractory partial seizures
Atypical absence seizures in Lennox-Gastaut syndrome
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Initially, 15 mg/kg/day (maximum: 45 mg/kg/day)
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Initially, 400 mg tid (maximum: 3600 mg/day)
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30–60 μg/mL (125–250 μmol/L)
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N/A
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Headache, fatigue, liver failure, aplastic anemia (rare)
Requires written informed consent
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Fosphenytoin
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Status epilepticus, same indications as for IV phenytoin
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10–20 PE/kg IV or IM once (maximum infusion rate: 150 PE/min; heart and BP monitoring needed at maximum rate but not at slower rates)
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Same as for children
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10–20 μg/mL (40–80 μmol/L)
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> 25 μg/mL (> 99 μmol/L)
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Ataxia, dizziness, somnolence, headache, pruritus, paresthesias
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Gabapentin
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3–12 yr: Partial seizures (as adjunctive therapy)
≥ 12 yr: Partial seizures with and without secondarily generalized tonic-clonic seizures (as adjunctive therapy)
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3–12 yr: 12.5–20 mg/kg bid (usual maximum: 50 mg/kg bid)
≥ 12 yr: 300 mg tid (usual maximum: 1200 mg tid)
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300 mg tid (usual maximum: 1200 mg tid)
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Not determined
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Not determined
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Drowsiness, dizziness, weight gain, headache
3–12 yr: Somnolence, aggressive behavior, mood lability, hyperactivity
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Lamotrigineg
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≥ 2 yr: Partial seizures (as adjunctive therapy)
Primary generalized tonic-clonic seizures (as adjunctive therapy)
Generalized seizures in Lennox-Gastaut syndrome (as adjunctive therapy)
≥ 16 yr: Partial or secondarily generalized seizures, used as substitution monotherapy after withdrawal of concomitantly used enzyme-inducing anticonvulsantsh or valproatei
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< 16 yr: With enzyme-inducing anticonvulsants and without valproate: Initially, 1 mg/kg bid for 2 wk, followed by 2.5 mg/kg bid for 2 wk, then 5 mg/kg bid (usual maximum: 15 mg/kg or 250 mg/day)
With enzyme-inducing anticonvulsants and valproate: Initially, 0.1 mg/kg bid for 2 wk, followed by 0.2 mg/kg bid for 2 wk, then 0.5 mg/kg bid (usual maximum: 5 mg/kg or 250 mg/day)
With valproate and without enzyme-inducing anticonvulsants: Initially, 0.1–0.2 mg/kg bid for 2 wk, followed by 0.1–0.25 mg/kg bid for 2 wk, then 0.25–0.5 mg/kg bid (usual maximum: 2 mg/kg or 150 mg/day)
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With enzyme-inducing anticonvulsants and without valproate: 50 mg once/day for 2 wk, followed by 50 mg bid for 2 wk, then increased by 100 mg/day q 1–2 wk to usual maintenance dose (150–250 mg bid)
With valproate (with or without enzyme-inducing anticonvulsants): 25 mg once every other day for 2 wk, followed by 25 mg once/day for 2 wk, then increased by 25–50 mg/day q 1–2 wk to usual maintenance dose (100 mg once/day to 200 mg bid)
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No significant relationship observed between blood levels and pharmacologic effect
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Commonly, headache, dizziness, drowsiness, insomnia, fatigue, nausea, vomiting, diplopia, ataxia, tremorj, rash (in 2–3%), rash progressing to Stevens-Johnson syndrome (in 1/50–100 children and 1/1000 adults), menstrual abnormalities
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Levetiracetam
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≥ 4 yr: Partial seizures (as adjunctive therapy)
> 6 yr: Primary generalized tonic-clonic seizures (as adjunctive therapy)
> 12 yr: Myoclonic seizures (as adjunctive therapy)
Juvenile myoclonic epilepsy (as adjunctive therapy)
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250 mg bid (maximum: 1500 mg bid)
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500 mg bid (maximum: 2000 mg bid)
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No significant relationship observed between blood levels and pharmacologic effect
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Fatigue, weakness, ataxia, mood and behavioral changes
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Oxcarbazepine
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4–16 yr: Partial seizures (as adjunctive therapy)
Adults: Partial seizures
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Initially, 4–15mg/kg bid, then over 2 wk, increased to 15 mg/kg bid (usual maintenance dosage)
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300 mg bid, increased by 300 mg bid q 1 wk as needed to 1200 mg bid
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15–25 μg/mL
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Fatigue, nausea, abdominal pain, dizziness, somnolence, leukopenia, diplopia, hyponatremia (in 2.5%)
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Phenobarbital
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Generalized tonic-clonic seizures
Partial seizures
Status epilepticus
Neonatal seizures
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Neonates: 3–4 mg/kg once/day, then increasedk
Infants: 5–8 mg/kg once/day
1–5 yr: 3–5 mg/kg once/day
6–12 yr: 4–6 mg/kg once/dayl
For status epilepticus: 10–20 mg/kg IV (maximum infusion rate: 100 mg/min or 2 mg/kg/min)
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1.5–4 mg/kg at bedtime
For status epilepticus: 15–20 mg/kg IV (maximum infusion rate: 60 mg/min or 2 mg/kg/min)
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10–40 μg/mL (43–129 μmol/L)
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> 40 μg/mL (> 151 μmol/L)
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Drowsiness, nystagmus, ataxia, learning difficulties
Children: Paradoxical hyperactivity
Idiosyncratic: Anemia, rash
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Phenytoin
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Tonic-clonic seizures
Complex partial seizures
Prevention of seizures secondary to head trauma
Convulsive status epilepticus
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Neonates: Initially, 2.5 mg/kg bid (usual maintenance: 2.5–4 mg/kg bid)
For status epilepticus (given IV):
6 mo–3 yr: 8–10 mg/kg
4–6 yr: 7.5–9 mg/kg
7–9 yr: 7–8 mg/kg
10–16 yr: 6–7 mg/kg
(For all ages, maximum infusion rate: 1–3 mg/kg/min)
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4–7 mg/kg at bedtime
For status epilepticus: 15–20 mg/kg IV (maximum infusion rate: 50 mg/min)
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10–20 μg/mL (40–80 μmol/L)
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> 25 μg/mL (> 99 μmol/L)
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Megaloblastic anemia, gingival hyperplasia, osteopenia, hirsutism, adenopathy, loss of bone density
At high blood levels: Nystagmus, ataxia, dysarthria, lethargy, irritability, nausea, vomiting, confusion
Idiosyncratic: Rash, exfoliative dermatitis, seizure exacerbation (rare)
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Pregabalin
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Adults: Partial seizures (as adjunctive therapy)
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N/A
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Initially, 50 mg tid or 75 mg bid, increased as needed and tolerated to 200 mg tid or 300 mg bid (maximum: 600 mg/day)
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No significant relationship observed between blood levels and pharmacologic effect
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Dizziness, somnolence, ataxia, blurred vision, diplopia, tremor, weight gain
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Primidone
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Partial and generalized tonic-clonic seizures
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< 8 yr: Initially, 50–125 mg at bedtime, increased by 50–125 mg/day q 3–7 days (usual maintenance: 3–8 mg/kg tid)
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Initially, 100–125 mg at bedtime, followed by 100–125 mg bid on days 4–6 and 100–125 mg tid on days 7–9, then 250 mg tid
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5–12 μg/mL (23–55 μmol/L)
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> 15 μg/mL (> 69 μmol/L)
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Same as for phenobarbital
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Tiagabine
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≥ 12 yr: Partial seizures (as adjunctive therapy)
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≥ 12 yr: 4 mg once/day, increased by 4 mg/day as needed q 1 wk to 16 mg bid or 8 mg qid (maximum: 32 mg/day)
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4 mg once/day, increased by 4–8 mg/day q 1 wk to 28 mg bid or 14 mg qid (maximum: 56 mg/day )
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No significant relationship observed between blood levels and pharmacologic effect
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Dizziness, light-headedness, confusion, slowed thinking, fatigue, tremor, sedation, abdominal pain
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Topiramate
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≥ 2 yr: Partial seizures
Atypical absence seizures
Primary generalized tonic-clonic seizures
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2–16 yr: 0.5–1.5 mg/kg bid (maximum: 25 mg/day)
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50 mg once/day, increased by 25–50 mg/day q 1–2 wk intervals (usual maximum: 200 mg bid)
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5–20 mg/mL (probably)
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Decreased concentration, paresthesias, fatigue, speech dysfunction, confusion, anorexia, weight loss, metabolic acidosis, nephrolithiasis (in 1–5%), psychosis (in 1%)
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Valproate
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Absence seizures (typical and atypical)
Partial seizures
Tonic-clonic seizures
Myoclonic seizures
Juvenile myoclonic epilepsy
Infantile spasms
Neonatal or febrile seizures
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Initially, 5 mg/kg bid or tid, increased by 5–10 mg/kg/day at weekly intervals (usual maintenance: 10–20 mg/kg tid)
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5 mg/kg tid, increased slowly—eg, by 1.67–3.33 mg/kg tid at weekly intervals, especially if other drugs are being taken (maximum: 20 mg/kg tid)
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50–100 μg/mL (347–693 μmol/L) before am dose
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> 150 μg/mL (> 1041 μmol/L)
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Nausea and vomiting, GI intolerance, weight gain, reversible alopecia (in 5%), transient drowsiness, transient neutropenia, tremor
Idiosyncratic: Hyperammonemic encephalopathy
Rarely, fatal hepatic necrosis in young neurologically impaired children treated with multiple anticonvulsants
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Vigabatrin
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Partial seizures (as adjunctive therapy)
Infantile spasms
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Titrated up to 100 mg/kg/day in 1 wk, then usual maintenance dose of 100–150 mg/kg/day
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Initially, 0.5–1.0 g/day, increased by 0.5–1.0 g q 1–2 wk to usual maintenance dose of 2–4 g/day
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No significant relationship observed between blood levels and pharmacologic effect
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Drowsiness, dizziness, headache, fatigue, irreversible visual field defects (requires regular visual field evaluations)
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Zonisamide
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≥ 16 yr: Partial seizures (as adjunctive therapy)
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100 mg once/day, increased up to 100 mg/day q 2 wk (maximum: 300 mg bid)
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15–40 μg/mL (at > 30 μg/mL, possible increase in CNS adverse effects)
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> 40 μg/mL
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Sedation, fatigue, dizziness, ataxia, confusion, cognitive impairment (eg, impaired word finding), weight loss, anorexia, nausea
Less commonly, depression, psychosis, urinary calculi, oligohidrosis
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a Broad-spectrum anticonvulsants include lamotrigine, levetiracetam, topiramate, valproate, and zonisamide.
b Route is po unless otherwise specified.
c Dose is based on a weight of 70 kg if not specified.
d Starting dose is the same for regular and extended-release tablets.
e There may be fewer adverse effects with extended (slow)-release formulation, which may improve adherence.
f Toxic levels are not well established.
g Lamotrigine may have special synergistic effect when used with valproate.
h Enzyme-inducing anticonvulsants include carbamazepine, phenytoin, and phenobarbital.
i Metabolism of the first anticonvulsant is increased by enzyme-inducing anticonvulsants and decreased by enzyme-inhibiting anticonvulsants.
j Incidence of rash is reduced with slower rates of dosage escalation (especially if lamotrigine is added to valproate).
k Increases in dose are based on clinical response and blood levels.
l Divided doses may be used.
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PE = phenytoin equivalents.
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Adverse drug effects:
All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash, and none is completely safe during pregnancy (see Table: Pregnancy Complicated by Disease: Seizure Disorders in Pregnancy).
For patients taking carbamazepine, CBC should be monitored routinely for the first year of therapy. Decreases in WBC count and dose-dependent neutropenia (neutrophil count < 1000/μL) are common. Sometimes, if no other drug can be readily substituted, decreasing the dose can manage these effects. However, if the WBC count decreases rapidly, the drug should be stopped.
Patients taking valproate should have liver function tests every 3 mo for 1 yr; if serum transaminases or ammonia levels increase significantly (> 2 times the upper limit of normal), the drug should be stopped. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.
Carbamazepine, phenytoin, and valproate are pregnancy category D drugs (ie, teratogenicity occurs in animal and human pregnancies). Risk of neural tube defects is somewhat greater with valproate than other commonly used anticonvulsants. The newer drugs are category C (ie, teratogenicity occurs in animals, but human risk is unknown).
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 anticonvulsants during pregnancy. Yet, because uncontrolled generalized seizures during pregnancy can lead to fetal injury and death, continued treatment with drugs is generally advisable (see Pregnancy Complicated by Disease: Seizure Disorders in Pregnancy). The risk should be put in perspective: Alcohol is more toxic to the developing fetus than any anticonvulsant. 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 anticonvulsants.
Surgery:
About 10 to 20% of patients have intractable seizures refractory to medical treatment and are potential surgical candidates. If seizures originate from a focal, resectable area in the brain, resection of the epileptic focus usually improves seizure control markedly. If the focus is in the anteromesial temporal lobe, resection eliminates seizures in about 60% of patients. After surgical resection, some patients remain seizure-free without taking anticonvulsants, but many still require the drugs, but in reduced doses and possibly as monotherapy. Because surgery requires extensive testing and monitoring, these patients are best treated in specialized epilepsy centers.
Vagus nerve stimulation:
Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device (vagus nerve stimulator) is used as an adjunct to drug therapy in patients who have intractable seizures and are not candidates for epilepsy surgery. This procedure reduces the number of partial seizures by ≥ 50% in about 40%. After the device is programmed, patients can activate it with a magnet to abort an imminent seizure. Adverse effects include deepening of the voice during stimulation, cough, and hoarseness. Complications are minimal. Duration of effectiveness is unclear.
Last full review/revision March 2008 by Bola Adamolekun, MD
Content last modified November 2012
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