SEIZURES AND EPILEPSY IN ADOLESCENTS AND ADULTS
• Obtain a thorough history, especially from witnesses of the paroxysmal event.
• Perform a thorough physical and neurologic examination.
• Laboratory testing includes blood glucose, complete blood cell count, electrolytes, liver function tests, and toxicology screening.
• Perform lumbar puncture if central nervous system (CNS) infection is suspected
• Neuroimaging should be performed, preferably magnetic resonance imaging (MRI). Computed tomography (CT) is acceptable in the acute setting to exclude hemorrhage; neoplasms may be missed by head CT.
• Routine electroencephalogram (EEG) with sleep deprivation and activation procedures should be performed when possible.
• Select an antiepileptic drug (AED) based on seizure type and epilepsy syndrome.
• Consider side-effect profile and the patient’s unique characteristics.
• Consider convenience (dosing schedule) and cost.
• Aim for monotherapy whenever possible.
• “Start low and go slow” when initiating AED therapy.
• Overlap drugs when switching AEDs and gradually withdraw the first drug when the second is effective.
• Refer to an epilepsy center for consideration of surgery if seizures are refractory to two AEDs.
• After a minimum 2-year seizure-free period, consider withdrawing AEDs for epilepsy of unknown etiology or syndromes known to resolve.
All patients with epilepsy experience seizures, but not all patients with a seizure have epilepsy. An epileptic seizure is a transient occurrence of signs and symptoms resulting from abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, and psychosocial consequences of this condition. The diagnosis of epilepsy requires the occurrence of at least one epileptic seizure. In practice, however, epilepsy is most commonly diagnosed after two or more unprovoked seizures.
Seizures can be acute symptomatic or unprovoked. Acute symptomatic seizures occur at the time of a systemic insult, such as during alcohol withdrawal or in the setting of severe hypoglycemia, or in close temporal association with a brain insult, such as in acute head trauma. The condition leading to the seizure is thought to disrupt normal brain neuronal physiology in a transient fashion.
Unprovoked seizures occur in the absence of such precipitating factors. Recurrent provoked seizures do not constitute epilepsy and therefore do not require treatment with antiepileptic medication.
Epilepsy has many causes including structural (e.g., tumors, strokes, vascular abnormalities), metabolic, infectious, and genetic. Often, no clear cause can be determined. Several epilepsy syndromes have been recognized with clustering of symptoms and signs in epilepsies, which aids in accurate diagnosis and management of seizure disorders.
Epilepsy is a common disease affecting about 50 million people worldwide. The lifetime risk for developing epilepsy is estimated at about 3% to age 80 years. The average annual incidence of epilepsy is about 55 per 100,000 population in the United States and in Europe.
The highest incidence rates are in infants younger than 1 year and in those older than 60 years. Men tend to be affected slightly more than women. Studies in several countries have shown similar prevalence and incidence rates as in the United States. The lifetime risk of a single seizure from any cause is estimated at about 10%.
A standardized classification system for seizures and epilepsy was developed to create a common language and facilitate communication among clinicians and researchers as well as to aid in diagnosis and management. The International League against Epilepsy (ILAE) classifications were first published in 1960 and last updated officially in 2016 for seizures and in 2014 for epilepsies and are mostly based on concepts formulated prior to modern neuroimaging and genomic research. The ILAE Commission on Classification and Terminology revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. The two major categories of seizures, generalized and partial, are redefined as generalized and focal.
Generalized seizures originate within, and rapidly engage, bilaterally distributed networks. Focal seizures originate within networks limited to one hemisphere of the brain. The classification of generalized seizures has been simplified, specifically with the elimination of neonatal seizures as a subcategory and with a simplified subclassification of absence seizures (Box 1). The distinction between the different types of focal seizures based on level of consciousness (e.g., simple partial, complex partial, and partial seizures secondarily generalized) is eliminated in the revised classification scheme. Focal seizures are now described based on their manifestations, such as dyscognitive or focal motor (Box 2).
|Classification of Seizures|
Tonic–clonic (in any combination)
• Absence with special features
• Myoclonic absence
• Eyelid myoclonia
• Myoclonic atonic
• Epileptic spasms
|Descriptors of Focal Seizures According to Degree of Impairment during Seizure|
|Without impairment of consciousness or awareness
• With observable motor (“focal motor”) or autonomic (“autonomic”) components (replaces the term “simple partial seizure”)
With impairment of consciousness or awareness (“dyscognitive”) (replaces the term “complex partial seizure”)
Evolving to a bilateral, convulsive seizure (involving tonic, clonic, or tonic and clonic components) (replaces the term “secondarily generalized seizure”)
In the former classification scheme, epilepsies were subdivided into three categories based on etiology: idiopathic, symptomatic, or cryptogenic syndromes, indicating a presumed genetic cause, underlying brain lesion, or suspected but unidentified brain lesion,
respectively. In the revised classification scheme, these are now referred to as genetic, structural–metabolic, and unknown (Box 3). Genetic epilepsy is the direct result of a known or presumed genetic defect. In structural–metabolic epilepsy there is a distinct structural or metabolic condition that is associated with a significantly increased risk of developing epilepsy. Unknown epilepsy suggests that the underlying cause is not yet identified.
|Terminology for Underlying Cause|
Childhood absence epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy
Epilepsy of infancy with migrating focal seizures
Myoclonic epilepsy in infancy
Benign rolandic epilepsy
Benign occipital epilepsy of the Gastaut type
Another change in the revised classification is the recognition of the concept of “electroclinical syndrome” to mean a complex of clinical features, signs, and symptoms that together define a distinctive, recognizable clinical disorder. These are based on typical age of onset, EEG characteristics, seizure types, and other characteristics. The diagnosis of these syndromes helps determine treatment and prognosis.
Making a diagnosis of epilepsy has important medical and psychosocial implications for patients. An incorrect diagnosis of epilepsy has many negative consequences, including unnecessary restrictions on driving, working, and recreational activities; exposure to potentially toxic antiepileptic drugs (AEDs); and dealing with societal stigma associated with a chronic disease. An accurate diagnosis of epilepsy is based on obtaining a thorough history, conducting a thorough physical and neurologic examination, and performing appropriate testing.
Detailed descriptions from the patient and a witness about the triggering factors, prodromal symptoms, ictal phase, and postictal phase are of paramount importance. Common triggering factors are sleep deprivation, stress, drug intake, and alcohol withdrawal.
Witnesses should be questioned about altered consciousness, duration of each phase, automatism, or head turning as well as any abnormal movements such as tonic, tonic–clonic, or myoclonic activity and the spread of the abnormal movements if they start focally; falling; urinary or bowel incontinence; and tongue biting. Postictal confusion, fatigue, sleeping, focal neurologic signs, and muscle aches often follow a generalized tonic–clonic (GTC) seizure; it is extremely rare for someone to recover full consciousness immediately after a GTC seizure.
Additional important features of the history to obtain include age at onset of events, family history of seizures, birth trauma or injury, childhood febrile illnesses and associated seizures, and history of significant head injury. An important clue to the diagnosis and localization of epilepsy lies in the detailed description of events that take place during recurrent paroxysmal events (semiology) and consistent clinical features with little variation between events (stereotypy).
The presence of an aura, a subjective sensation or motor phenomenon that precedes a generalized or focal seizure, also favors the diagnosis of epilepsy. An aura is actually a focal seizure without impairment of consciousness. The characteristics of an aura may also provide clues to the localization or origin of a seizure. For example, sensations of déjà vu, epigastric rising, and exaggerated emotions of fear or fright are common auras of temporal lobe epilepsy. Muscle and motor activity, forced eye deviation, and speech arrest or disturbances are typically seen in frontal lobe epilepsy. Parietal lobe epilepsies can have auras of paresthesias or sensory phenomena, whereas occipital lobe epilepsy can have positive basic visual phenomena such as flashes or colors experienced as an aura.
Several features of the history and physical or neurologic examination, such as the presence of specific generalized or focal neurologic deficits, predict a higher risk of seizure recurrence and help classify the type of seizure or epilepsy. For instance, the finding of transient unilateral hemiparesis when examining a patient soon after a suspected seizure, or a clinical history to support such a finding, is consistent with a Todd paralysis and suggests a focal-onset seizure involving the motor cortex contralateral to the weakness.
The evaluation of a first seizure is aimed at determining whether it was provoked by a transient cause and thus is an acute symptomatic seizure, or if it was unprovoked, resulting from underlying epilepsy. In the initial evaluation it is crucial to exclude acute life-threatening etiologies such as infection, neoplasm, or hemorrhage. Basic laboratory tests are usually indicated including blood glucose, complete blood count, electrolytes (particularly sodium), liver function tests, and toxicology screening to exclude infections, electrolyte abnormalities, organ dysfunction, and drug intoxication/withdrawal. A lumbar puncture should be performed if a CNS infection is suspected, such as in a febrile patient.
A routine electroencephalogram (EEG) is an essential component of the initial work-up of a patient with suspected epilepsy. Although an EEG can show many different abnormalities, true epileptiform activity, spike and slow-wave complexes and sharp waves, have a high correlation with clinical seizures.
In a nonemergent situation, performing an MRI is important in the initial work-up of a patient with suspected epilepsy, especially when focal seizures are suspected. MRI is more sensitive and more likely to show significant abnormalities than is CT. If MRI is not available or in an acute or emergent setting, a noncontrast head CT may be substituted. Finding a lesion with the potential for being the seizure focus would correlate with focal seizures. A common example of this is mesial temporal sclerosis characterized by atrophy and gliosis of the hippocampus in the temporal lobe. Histopathologically, this is represented by neuronal loss and gliosis of the hippocampus and several mesial temporal structures. Mesial temporal sclerosis correlates with temporal lobe epilepsy and has been associated with good surgical resection outcomes. High resolution cuts through the temporal lobes on MRI have been shown to detect mesial temporal sclerosis.
The evaluation of recurrent seizures is aimed at defining the underlying cause of epilepsy or the epilepsy syndrome. Evaluation is similar to that for a single unprovoked seizure; however, the therapeutic and prognostic implications for a patient with epilepsy are very different. A routine EEG is indicated because it can reveal interictal focal or generalized epileptiform discharges and aid in classifying the seizure type and epilepsy syndrome. However, a normal EEG does not exclude clinical epilepsy. The yield of recording epileptiform activity on routine EEG can be improved by performing the test with sleep deprivation and recording a period of sleep.
Activation procedures of intermittent photic stimulation and hyperventilation should also be performed whenever possible to increase the yield of finding EEG abnormalities. Nevertheless, in patients ultimately shown to have epilepsy, the initial EEG shows epileptiform activity in about 50% of recordings. The yield increases with repeat studies, but only to a point, and doing more than four routine EEGs on a single patient is unlikely to be helpful in capturing epileptiform activity.
The diagnostic evaluation of intractable epilepsy is discussed in a later section.
In making a diagnosis of a seizure or epilepsy, it is important to consider other conditions that can mimic seizures. Psychogenic nonepileptic seizures are the most common condition misdiagnosed as epilepsy, followed by syncope. Other transient and often recurrent conditions that can be misdiagnosed as epilepsy include migraine, transient ischemic attack (TIA), transient global amnesia, dizziness or vertigo, delirium, sleep disorders, and movement disorders.
Psychogenic nonepileptic seizures, formerly called pseudoseizures or psychogenic seizures, present a particular challenge to health care providers when evaluating atypical seizure-like events. It can be especially difficult to distinguish between true epileptic seizures and psychogenic nonepileptic seizures because both can occur in the same patient. Some features that suggest psychogenic nonepileptic seizures include lack of response to AEDs, comorbid personality or psychological disorders, certain ictal movements such as pelvic thrusting and back arching, and ictal eye closure. Ictal stuttering, bringing a stuffed animal to the epilepsy monitoring unit, pseudosleep, a history of fibromyalgia or chronic pain, a history of physical, emotional, or sexual abuse, and having a seizure during an outpatient epilepsy clinic visit have all been associated with the diagnosis of psychogenic nonepileptic seizures.
Syncope is typically characterized by sudden atonic loss of consciousness. Convulsive syncope is a variant that can easily be confused with an epileptic seizure. Abnormal movements including tonic posturing and clonic or myoclonic activity occur during convulsive syncope in response to sudden and transient cerebral anoxia and ischemia. EEG during an attack shows diffuse slowing of the background rhythms but no epileptiform activity. Syncope is distinguished from an epileptic seizure by the presence of presyncopal symptoms (nausea, flushing, and lightheadedness), brief loss of consciousness, and the return of normal cognition within seconds after arousal. Motor symptoms such as clonic jerking or stiffening often accompany prolonged syncope, especially if the patient is maintained in an upright position, and can resemble an epileptic seizure; however, consciousness returns immediately after syncope despite the motor symptoms, whereas it does not return for at least minutes after a GTC seizure.
Migraine headaches can be accompanied by complex visual phenomena or sensorimotor symptoms, which could be confused with seizures. However, visual auras associated with seizures usually evolve and last seconds, whereas migraine auras tend to develop over minutes. Postictal headaches may be confused with migraine.
Complicated migraine with hemiparesis may be mistaken for postictal Todd paralysis. A history of migraine headaches and preservation of normal consciousness help identify the spells as migraine. Rarely, basilar migraines and acute confusional migraine are accompanied by loss of consciousness.
TIAs should almost never be mistaken for seizures because TIAs usually cause focal negative phenomena, such as weakness, numbness, aphasia, or ataxia, whereas seizures usually cause positive phenomena such as jerking, tingling, automatisms, or movements.
Rarely, TIA can have positive symptoms, as in limb-shaking TIA. These consist of brief myoclonic or rhythmic motor activity corresponding to transient cerebral ischemia due to focal arterial stenosis supplying the motor cortex. TIAs of vertebrobasilar artery territory origin occasionally cause loss of consciousness and falls that could be confused with seizures, but vertebrobasilar TIA is usually accompanied by neighborhood signs. Transient global amnesia, which is sudden-onset alteration of anterograde memory and confusion, can mimic seizures and nonconvulsive status epilepticus. Patients with transient global amnesia can perform complex tasks such as calculating, reading, and writing despite appearing confused, whereas patients with nonconvulsive status epilepticus cannot.
Some sleep disorders, movement disorders, and hypoglycemia can mimic seizures. Cataplexy attacks of narcolepsy precipitated by emotional stimuli manifest with sudden loss of muscle tone but preservation of consciousness. Other narcolepsy symptoms such as excessive daytime sleepiness, hypnagogic hallucinations, and sleep paralysis help to make the diagnosis. Parasomnias, arousal disorders, and periodic limb movements in sleep can rarely be confused with epileptic seizures. Hemifacial spasms could be mistaken for simple partial seizures, and myoclonus, which can be epileptic or nonepileptic, can also be difficult to distinguish from seizures. EEG can play a role in making the correct diagnosis.
The decision whether or not to treat is just as important as what drug to use. In general, patients with an acute symptomatic seizure do not require treatment with AEDs, because they are thought to have a transient reversible etiology causing their seizure as opposed to having underlying epilepsy. They are best managed by treating the provoking factor (e.g., correcting an electrolyte abnormality or discontinuing an offending drug or medication). If an acute symptomatic etiology cannot be found, then the patient’s seizure most likely represents underlying epilepsy. Still, the rate of recurrence after a first such seizure ranges in the literature from about 30% to 55%.
Factors that have been shown to increase risk of recurrence include a remote symptomatic etiology, abnormal neurologic examination, and first seizure onset out of sleep. Family history of seizures or epilepsy and EEG abnormalities have been shown to increase risk in some, but not all, studies. If any of these factors are present, treatment may be warranted even after a single event. In addition, early treatment should be considered in any patient for whom the consequences of a recurrent seizure would be significant, such as related to driving, working, or general safety. Once two or more seizures have occurred, risk of recurrence is well over 50%, closer to about 70% in most studies, and treatment with AEDs is recommended.
The treatment of epilepsy involves choosing among the many AED options available (currently 14 first-line AEDs in the United States) by considering spectrum of efficacy, pharmacokinetic and pharmacodynamic properties, and the patient’s comorbidities (Tables 1 and 2). The goal of therapy should be complete seizure freedom with no side effects. This goal can be achieved by following some basic principles.
Dosage and Side Effect Profile of Commonly Prescribed
Abbreviations: AED = antiepileptic drug; VPA = valproic acid.
3 Exceeds dosage recommended by the manufacturer.
Choice of Antiepileptic Drug in Special Situations
|Special Situation||Drug of Choice||Comments|
|Partial seizures||Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, gabapentin|
|Refractory partial seizures||Lacosamide, pregabalin, zonisamide||Second-line treatment|
|Generalized epilepsies||Lamotrigine, topiramate, valproic acid,1 zonisamide1||Avoid valproic acid in women|
|Absence seizures||Ethosuximide, lamotrigine,1 valproic acid, topiramate1||Ethosuximide is the choice for only pure absence seizures and is insufficient in other associated generalized tonic–clonic or myoclonic seizures|
|Juvenile myoclonic epilepsy||Valproic acid,1 topiramate,1 lamotrigine,1 zonisamide,1 levetiracetam||Avoid valproic acid in women|
|Myoclonic seizures||Clonazepam, valproic acid,1 levetiracetam||Lamotrigine occasionally exacerbates myoclonic seizures|
|Women of childbearing potential||Lamotrigine, topiramate, levetiracetam, oxcarbazepine||Avoid enzyme-inducing agents that alter steroid hormones and OCP levels; use OCPs with ≥ 50 µg of estrogen; OCPs increase the elimination of lamotrigine
Significant increased risk of teratogenicity with valproic acid
|Elderly patients||Lamotrigine, gabapentin, levetiracetam, topiramate||Avoid polypharmacy and highly protein-bound AEDs and AEDs with high drug–drug interactions|
|Bipolar disorder||Valproic acid,1 carbamazepine, lamotrigine, topiramate1|
|Migraine||Valproic acid, topiramate||Consider the choice according to sex, side-effect profile, and seizure type|
|Chronic pain||Pregabalin,1 gabapentin1|
|Neuropathic pain||Carbamazepine,1 gabapentin,1 pregabalin|
Abbreviations: AED = antiepileptic drug; OCP = oral contraceptive pill.
1 Not FDA approved for this indication.
First, choose a drug that is effective for the seizure type or epilepsy syndrome. All current AEDs, except ethosuximide (Zarontin), are effective against focal onset seizures. Five AEDs are broad spectrum and are effective against both focal onset and generalized seizures: valproate (Depakene), lamotrigine (Lamictal), topiramate (Topamax), zonisamide (Zonegran),1 leviteracetam (Keppra). Choose a broad- spectrum drug when seizure type is unknown. Head-to-head studies can favor a single drug, but there is no consistent evidence for superiority of one drug over another. Some recommendations can be made based on common clinical experience and the SANAD (Standard and New Antiepileptic Drugs) open-label clinical trials that compared some AEDs in a large number of patients (see Table 1).
Next, consider the drug side-effect profile and the patient’s unique characteristics. Comorbidities such as depression, migraine or other chronic pain, and obesity can guide AED choice based on side-effect profiles. Consider convenience (drug-dosing schedule) and cost when selecting an AED. Less-frequent dosing leads to better compliance.
Aim for monotherapy whenever possible to decrease risk of side effects. It is best to “start low and go slow” when initiating therapy. Most side effects are experienced at the start of therapy and can be avoided by starting with a low enough dosage and increasing more slowly than recommended by the manufacturer. The maintenance dosages cover a wide range because there is no set final dosage for any of the AEDs.
Finally, push the dose until seizure freedom is achieved or side effects occur. This is the only way to determine that the drug is ineffective. If side effects do occur, reduce the dosage to the maximum tolerated.
Serum drug levels are available for conventional and essentially all new AEDs, but the levels of new AEDs are of very limited utility because they are effective over a wide range of serum levels. Most patients do not need routine monitoring of blood levels. Drug levels can provide a general guide and can help guide dosage increases by warning that toxicity can occur with further increases if levels are in the upper limit of the established therapeutic range. If seizure control is not improved or side effects occur at low dosages, then checking a serum level can help to uncover unexpectedly low levels due to fast metabolism or noncompliance, a problem especially common among adolescents. Ultimately, management decisions should be based on clinical history and not serum drug levels.
When switching from one AED to another, drugs should be overlapped, with the new drug increased to the target dosage to determine that it is effective before gradually withdrawing the first drug. This affords at least some protection from seizures at all times.
After a minimum 2-year seizure-free period, a trial of drug withdrawal may be considered in certain patients, especially in those with an unknown etiology. Patients who have a normal MRI and EEG and who do not have primary generalized epilepsy likely have a lower risk of seizure recurrence after drug withdrawal. Drug withdrawal is usually not logical in patients who have an epilepsy syndrome with a known lifelong tendency to seizures, such as juvenile myoclonic epilepsy.
It is important to note that AEDs as a class have been associated with a risk of suicidality, leading to an FDA warning issued in 2008; however, people with epilepsy have a greater risk of mood disorders, anxiety, and suicidality than in the general population, and the relationship among these factors is complex.
Characteristics of Specific Antiepileptic Drugs
Phenytoin (Dilantin, Phenytek) is the most widely used and familiar AED despite having the most problematic side effects. Mechanism of action is thought to be through use-dependent sodium channel blockade. The metabolism of phenytoin is saturable, which means that it shows zero-order kinetics at high blood levels. Very steep elevations in the blood level can occur with even small dosage increases when the blood level is near 20 µg/mL, despite the occurrence of a linear increase in blood level with dosage increases when blood levels are below 20 µg/mL. For example, the blood level may be 10 µg/mL with 200 mg/day and then increase to 15 µg/mL with 300 mg/day and then increase to 20 µg/mL with 400 mg/day, but with an increase to 500 mg/day the level might skyrocket to more than 30 µg/mL if metabolism is saturated.
Phenytoin’s idiosyncratic side effects of hepatitis and blood dyscrasias are rare. Cumulative side effects of phenytoin occur over many years and include gum hypertrophy, hirsutism, coarsening of features, ataxia due to cerebellar atrophy, peripheral neuropathy, and osteoporosis. All patients on phenytoin should receive calcium and vitamin D because phenytoin induces the metabolism of vitamin D, thus lowering its level and causing osteoporosis. Phenytoin is prone to drug–drug interactions, and it increases clearance of oral contraceptives and decreases their effectiveness.
Intravenous phenytoin solution is very basic (pH 11), which often causes venous irritation and can cause purple glove syndrome and severe acute necrosis leading to amputation. Intravenous phenytoin is mixed in polyethylene glycol, causing bradycardia and hypotension, which limits the rate of infusion to less than 50 mg/minute. This can be a significant problem in the treatment of status epilepticus or frequent seizures.
Fosphenytoin (Cerebyx) is a phenytoin prodrug in which the phosphate group is rapidly cleaved off upon entering the bloodstream, yielding phenytoin. It is mixed in an aqueous solution and has a more neutral pH; thus it is much better tolerated and can be given as fast as 150 mg/minute.
Carbamazepine (Carbatrol, Tegretol), like phenytoin, is metabolized by the liver and induces hepatic metabolism. It also undergoes autoinduction, inducing its own metabolism for up to 3 weeks after initiating it, so that steady-state blood levels are not achieved for several weeks. Carbamazepine has a relatively narrow therapeutic window, with usual therapeutic blood levels of between 4 µg/mL and 12 µg/mL. It has a similar mechanism of action to phenytoin’s. It is indicated for simple partial, complex partial, and GTC seizures. It commonly causes acute toxicity (ataxia, diplopia, and lethargy) with only a small increase in the dosage.
Carbamazepine does not have cumulative side effects, but it rarely causes serious idiosyncratic side effects including blood dyscrasias, hepatitis, and hyponatremia. Mild leukopenia is common and does not require intervention unless the white blood cell count falls below 3000 per mm3. Very rarely it can cause bone marrow suppression with aplastic anemia. Extended-release preparations (Carbatrol, Tegretol XR), which can be dosed twice daily, are preferable to standard preparations, which must be dosed every 8 hours. Like phenytoin, it increases the clearance of oral contraceptives and decreases their effectiveness.
Valproic acid is available as valproic acid and sodium divalproex (Depakote) and in an extended-release form (Depakote ER). Valproic acid affects many systems and so has several potential mechanisms of action, including through sodium-channel blockade and augmenting γ-aminobutyric acid (GABA) inhibition. It is most commonly used for primary generalized seizures such as in juvenile myoclonic epilepsy1 and syndromes with absence seizures, but it is also effective for focal seizures. It often causes dyspepsia and other gastrointestinal side effects. Sodium divalproex is immediately cleaved to valproate in the stomach, but this preparation has much better gastrointestinal tolerance. Valproate is usually dosed every 8 hours because of its relatively short half-life. Depakote ER was approved for once-daily dosing for migraine headaches, but it is actually released over fewer than 24 hours, so twice-daily dosing is more useful for the treatment of epilepsy. Valproate is available as an intravenous preparation (Depacon), dosed identically to the oral forms.
Valproate is usually well tolerated, but it occasionally causes weight gain, alopecia, tremor, and thrombocytopenia. It can cause potentially fatal hepatitis and pancreatitis. Hepatitis occurs in only 1 in 40,000 adult patient exposures, but it is much more common in children (as many as 1 in 500) who are taking multiple AEDs and have mental retardation, possibly because they have an undiagnosed metabolic abnormality. It has been suggested that l-carnitine (levocarnitine, Carnitor)1 supplementation might reduce the risk of hepatitis.
Although this has not been demonstrated, it is prudent for children who have unknown causes of mental retardation and who are taking valproate to take carnitine.
The overall risk of birth defects associated with valproate is approximately 10%, and the rate is only approximately 2% in the general population and seemingly not more than approximately 4% for any other AED. Of even greater concern is that valproate is more often associated with neural tube defects such as spina bifida. Folic acid supplementation at 4 mg/day is recommended because it reduces the risk of neural tube defects in all pregnant women. Valproate is a poor choice for women of childbearing potential, and if they are on valproate, they should use an effective method of birth control and take folic acid.
Phenobarbital has fallen out of favor as an AED because it occasionally induces lethargy, depression, and learning difficulties. However, it is usually well tolerated in adults, is effective for partial- onset and primary GTC seizures, is inexpensive, and can be given intravenously. It can be dosed once per day and has a very long half- life, which is an advantage in poorly compliant patients. Primidone (Mysoline) is an infrequently used prodrug of phenobarbital that also has its own antiseizure effects but less often causes lethargy.
Ethosuximide is unique because it is the only AED that is effective exclusively for absence seizures and is not effective for other types of seizures. It is usually well tolerated, but occasionally it causes nausea, anorexia, headache, and blood dyscrasias. It can be dosed once per day because of its very long half-life, but it is usually better tolerated dosed twice daily.
Felbamate (Felbatol) is highly effective for the most intractable epilepsies, such as the Lennox–Gastaut syndrome, as well as for partial-onset seizures despite frequent side effects of anorexia, insomnia, and agitation and the common occurrence of AED interactions. However, it can cause aplastic anemia and fulminant hepatitis, so it is only indicated for intractable epilepsy, in cases where the potential benefit outweighs the risk of potentially fatal side effects. Its use should probably be limited to epilepsy centers.
Gabapentin (Neurontin) is very well tolerated and has no pharmacokinetic interactions because it is renally excreted unchanged. It is indicated for partial seizures with and without secondary generalization. It has engendered an unwarranted poor reputation as an AED because some have thought that it is ineffective. Clinical studies have examined doses that statistically reduced the frequency of seizures with minimal side effects but were not high enough to determine the maximum tolerated dosage; thus it was approved and initially used at relatively low dosages of 900 to 1800 mg/day.
However, clinical experience suggests that dosages of as much as 3600 mg/day may be required to be effective for most patients. On the other hand, very high dosages might not increase blood levels because drug absorption may be saturated at dosages above 4000 mg/day.
Lamotrigine (Lamictal) is particularly useful because it is effective for partial seizures, generalized seizures, and Lennox-Gastaut syndrome. It is severely affected by hepatic enzyme-inducing or enzyme- inhibiting AEDs so that its dosing is drastically different depending on concomitant AEDs. When taken alone (or with a combination of an enzyme inducer and inhibitor), the half-life of lamotrigine is about 25 hours, but this is reduced to 12 hours when it is taken with enzyme inducers (such as phenytoin, phenobarbital, carbamazepine) and prolonged to as much as 60 hours when taken with valproate, an enzyme inhibitor. Oral contraceptives decrease the half-life to 12 hours, necessitating dosage adjustment.
The only potentially serious side effect of lamotrigine is rash. Mild rash is common and was present in as many as 1 in 50 children and 1 in 1000 adults during initial clinical studies. The rash can be life threatening in the form of Stevens–Johnson syndrome or toxic epidermal necrolysis, but the incidence of serious rash, as lamotrigine is used today, is probably only about 1 in 40,000. The rash is most likely to occur after the first 3 weeks of therapy, but it can occur at any time, and it is most common with high initial doses and titration rates and when taken with valproic acid. A slow titration rate decreases the risk of rash. In fact, the rate is so slow that patients are unlikely to see an effect for many weeks or months and can require encouragement from the physician. When a rash is reported, the patient must be examined immediately, and serious consideration must be given to stopping the drug.
Levetiracetam Keppra is very well tolerated and has not been associated with serious side effects. It occasionally causes significant irritability and/or depression that necessitates stopping the drug. It can be titrated relatively rapidly so that its effectiveness in a patient can be determined in a short time. It is primarily excreted unchanged, so it does not have significant drug interactions. Levetiracetam is available in an intravenous preparation, dosed the same as the oral form.
Oxcarbazepine (Trileptal) is a derivative of carbamazepine, and its mechanism of action is similar to carbamazepine’s. The primary CNS side effects of carbamazepine are due to epoxide-10,11- carbamazepine, a metabolite produced by oxidation. Oxcarbazepine cannot undergo this conversion and thus does not produce this metabolite. Therefore, it is better tolerated than carbamazepine and is less likely to cause diplopia and ataxia, although it is not clear whether it causes less sedation. The incidence of blood dyscrasias also appears lower than with carbamazepine, but hyponatremia seems more common than with carbamazepine. It does not induce AED- metabolizing liver enzymes (although it does affect other liver enzymes) or undergo autoinduction. The daily dose cannot be directly converted from the carbamazepine dose. It is effective as monotherapy, so it is likely that in the future oxcarbazepine will entirely replace carbamazepine.
Tiagabine (Gabitril) is approved as add-on therapy for partial-onset seizures. It is the only AED that was designed for a specific mechanism of action; it inhibits the reuptake of GABA in the synaptic cleft. It has a very short serum half-life, but it affects the GABA transporter for at least 12 hours so it can be dosed twice a day. Some patients require more frequent dosing. It is not associated with any end-organ toxicity, but it can exacerbate myoclonic and absence seizures and precipitate nonconvulsive status epilepticus in those who are predisposed, usually patients with generalized epilepsy. Thus, it is uncommonly prescribed.
Topiramate (Topamax) is effective for partial seizures and some types of generalized seizures, especially the Lennox–Gastaut syndrome. It has acquired an unwarranted reputation for causing cognitive side effects. The source of this is probably the design of clinical studies, which appropriately determined the maximum tolerated dose by finding the dose at which an unacceptable incidence of side effects occurs. Considering all topiramate clinical studies together, the incidence of subject dropout in those treated with more than 400 mg/day was twice that of the group treated with less than 400 mg/day, which was approximately equal to dropout in the placebo group. This indicates that the average maximum tolerated dose is about 400 mg/day, so it should usually be used at a dose lower than this. Topiramate is a weak carbonic anhydrase inhibitor and can cause kidney stones and metabolic acidosis; the use of other carbonic anhydrase inhibitors is relatively contraindicated. Acute narrow-angle glaucoma has been reported in a few cases and requires immediate discontinuation.
Zonisamide (Zonegran) appears to be effective for both focal and some generalized1 epilepsies. It is approved as adjunctive treatment for partial seizures in adults. Its pharmacology is not well described, but it is metabolized by multiple mechanisms and has a very long half-life, which might allow it to be dosed once per day. It rarely causes kidney stones. It also can cause oligohydrosis (reduced sweating) and has rarely been associated with blood dyscrasias.
Pregabalin (Lyrica) is approved as adjunctive treatment of partial seizures in adults. It is not metabolized significantly, so it is excreted unchanged in urine. It does not bind to plasma proteins. Common side effects are dizziness, weight gain, pedal edema, and somnolence.
Vigabatrin (Sabril) is approved for infantile spasms in children ages 1 month to 2 years and for adult use in combination with other medications to treat complex partial seizures that have not responded adequately to previous drug therapies. It reversibly inhibits the major degradative enzyme for GABA (GABA-transaminase). It does not bind to plasma proteins. It is eliminated primarily by the kidneys. The side effects can be serious. Peripheral visual field defects can be seen in about 25% to 50% of adults and about 15% of children. Psychotic disorders and hallucinations are rare but also can be seen. Therefore it is recommended to have cognitive and age-appropriate vision testing at baseline and repeated at intervals. If it is effective, then it will be effective within 12 weeks. If there is significant reduction in seizures or the patient becomes seizure free, then the continuation of therapy depends on the risk-to-benefit ratio, and the patient or the caregiver should be involved in decision making. If there is no benefit after 12 weeks of treatment, it should be discontinued. Its use should be limited primarily to epilepsy centers.
Rufinamide (Banzel) is approved as adjunctive therapy for seizures associated with Lennox–Gastaut syndrome, a severe form of epilepsy. The proposed mechanism of action is the limitation of sodium- dependent action potential firing. There seem to be a good cognitive and psychiatric adverse effect profile and few drug interactions.
Rufinamide use is most appropriate when Lennox–Gastaut patients have failed other therapies.
Lacosamide (Vimpat) is approved as adjunctive therapy in the treatment of partial-onset seizures in adults. It has a unique mechanism of action with selective enhancement of voltage-gated sodium channel slow inactivation. Lacosamide has a favorable pharmacokinetic profile with near 100% bioavailability, minimal protein binding, and few drug–drug interactions. The most common adverse effects include diplopia, headache, dizziness, and nausea. At high doses, lacosamide can induce P-R interval prolongation. It is dosed twice a day and is available in an intravenous formulation.
Clobazam (Onfi) was recently approved in the United States for adjunctive treatment of seizures associated with Lennox–Gastaut syndrome. Clobazam is an antiepileptic of the benzodiazepine class. The most common adverse effects are sedation related (sedation, somnolence, drowsiness). Clobazam is dosed twice daily and should be dosed according to body weight. It is primarily metabolized in the liver, and thus dosing should be adjusted in those with hepatic impairment.
Ezogabine (Potiga), a potassium-channel opener, is approved as an adjunctive treatment of partial-onset seizures in adults. Urinary retention was reported in approximately 2% of patients in clinical trials. In October 2013, the FDA added a boxed warning due to risks of retinal abnormalities, potential vision loss, and skin discoloration that may occur with use of ezogabine. This drug should therefore be limited only to patients who have failed several alternative treatments and for whom the benefits outweigh the potential risk of vision loss.
All patients taking ezogabine should have baseline and periodic (every 6 months) visual monitoring by an ophthalmic professional.
Perampanel (Fycompa), an AMPA glutamate receptor antagonist, is approved as an adjunctive treatment of partial-onset seizure in patients aged 12 years and older. Perampanel is extensively metabolized by the liver. Dose adjustments are recommended in those with mild and moderate hepatic impairment, and the drug should not be used in patients with severe hepatic or renal impairment, including those on hemodialysis. Common side effects include dizziness, somnolence, headache, fatigue, irritability, gait disturbance and falls. There is a boxed warning of serious neuropsychiatric effects including alteration of mood and aggression. Perampanel is classified as a Schedule III drug by the U.S. Drug Enforcement Administration (DEA) due to its potential for abuse.
Eslicarbazepine (Aptiom) was approved by the United States FDA in 2013 as an adjunctive treatment of partial-onset seizures in adults. It is structurally similar to carbamazepine and oxcarbazepine. It is believed to act through preferential blockade of voltage-gated sodium channels in rapidly firing neurons, but there may be additional mechanisms of action. Common side effects include dizziness, drowsiness, headache, nausea, and diplopia. Eslicarbazepine has also been associated with an increase in the PR interval, abnormal liver function tests, and hyponatremia.
Special Patient Populations
Women with epilepsy face unique challenges throughout their lifespan related to the interaction of hormones, epilepsy, and AEDs. Women with epilepsy have increased rates of infertility due to intrinsic hormone changes, anovulatory cycles, irregular menstrual cycles, and sexual dysfunction. This can be compounded by the effects of AEDs, especially valproate, which is associated with polycystic ovary disease, as well as the enzyme-inducing AEDs, which can alter endogenous steroids.
Enzyme-inducing AEDs can decrease the efficacy of oral contraceptives (OCs), leading to unwanted pregnancies. Valproate, gabapentin, lacosamide, levetiracetam, pregabalin, tiagabine, and zonisamide do not affect OCs. Oxcarbazepine has an inconsistent effect, and topiramate at higher doses (greater than 200 mg) decreases OCs’ efficacy. The benefits of OCs with higher hormone concentration remain unproven, and therefore a back-up barrier method or changing to a non–enzyme-inducing AED is recommended to prevent unwanted pregnancy. OCs can significantly reduce the serum concentration of lamotrigine, leading to breakthrough seizures, but the effect is variable.
The risk of major congenital malformations related to AEDs is a major concern for women with epilepsy. In general, the risk to the fetus from seizures, especially convulsions, is thought to be greater than the risk to the fetus from AEDs. It is generally recommended to continue AEDs at the lowest effective dose and to avoid polypharmacy. Birth defects occur in 1.6% to 2.3% of all live births in the general population. With the exception of valproic acid, rates of major congenital malformations for women taking AEDs are about twice those of the general population. Patients should be reassured that more than 90% of women with epilepsy have normal, healthy children.
Valproic acid is the AED that clearly has the higher teratogenicity rate (6.2%–10.7%). It has also been shown to reduce cognitive outcomes. Therefore it should not be used as a first-line treatment in women of childbearing potential. All women of childbearing potential, with or without epilepsy, should take at least 0.4 mg of folic acid daily prior to conception and during pregnancy to decrease the risk of major congenital malformations.
Breast-feeding is a common postpartum concern for women with epilepsy. Primidone (Mysoline) and levetiracetam probably transfer into breast milk in amounts that may be clinically important, whereas valproate, phenobarbital, phenytoin, and carbamazepine likely do not. The effects on infant health and development are unknown, however, and most experts believe that taking AEDs does not generally contraindicate breast-feeding because the probable benefits outweigh the risks.
Enzyme-inducing AEDs induce the metabolism of vitamin D, increasing the risk of osteoporosis. Long-term AED use has been associated with an increased risk of fracture, particularly in women. Therefore, supplemental vitamin D and calcium should be recommended.
Elderly patients with epilepsy have several unique characteristics. Altered physiology during aging and possible polypharmacy for other medical conditions need to be considered when selecting an AED. The incidence of epilepsy is high among elderly people, increasing after the age of 75 years. The recognition of seizures may be difficult owing to atypical clinical presentations. The most common presumed cause is stroke. Alzheimer’s disease and head injury are other common causes. Complex partial and simple partial seizures are the most common presentation, especially in the form of memory lapses, confusion, change in mental status, and staring.
When initiating an AED, lower dosages are required owing to decreased renal and hepatic clearance. An age-related decrease in serum albumin increases the free fraction of the protein-bound AEDs.
Phenytoin is particularly poorly tolerated in the elderly and in addition can have a prolonged half-life so that levels are unexpectedly high. Some new AEDs are better tolerated and less likely to cause drug interactions. Gabapentin is particularly desirable because it has no drug interactions. Lamotrigine, oxcarbazepine, and levetiracetam are also usually well tolerated and often selected as first-line agents in this age group.
An estimated one third of people with epilepsy do not respond adequately to AEDs. Patients with refractory epilepsy, defined by failure of two AEDs, should be referred to an epilepsy center for diagnosis and consideration of the many therapeutic options currently available. In addition to a careful history and physical examination directed at determining seizure type, neuroanatomic site of seizure origin, and the epilepsy syndrome or etiology, the most important diagnostic test for evaluating intractable seizures is prolonged simultaneous video and EEG monitoring. Video EEG may need to continue for days or weeks to capture enough spells to make a correct diagnosis. Tools such as MRI of the brain with special acquisition protocols, positron emission tomography (PET), and single photon- emission CT (SPECT) may be used to help reveal abnormalities that are not obvious on routine imaging.
Surgery to resect the epilepsy focus is the only currently available method of curing epilepsy. The seizure-free outcomes after epilepsy surgery have been reported at about 52% at 5 years and 47% at 10 years. Extratemporal resections have an unfavorable outcome compared with temporal resections. Devices such as vagal nerve stimulation have an increasingly important role in the treatment of refractory epilepsy and have been shown to significantly reduce seizure frequency. Continuous deep brain stimulation, which uses electricity to stimulate the anterior nucleus of the thalamus, is not yet approved by the FDA. Responsive cortical stimulation is a treatment option for patients with refractory focal epilepsy and a well defined seizure focus when surgery is not possible. The device monitors and interrupts abnormal electrical activity in the brain before a seizure occurs and was approved by the U.S. FDA in 2013.
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1 Not FDA approved for this indication.