Edward B. Bromfield*

Barbara A. Dworetzky




  • 1. The term “epilepsy” is derived from Greek epilepsia: a taking hold of or seizing.

  • 2. Ancient accounts over 2,500 years ago by Babylonians and Egyptians. Detailed descriptions in “On the Sacred Disease” attributed to Hippocrates in the 5th century BC. Use of “sacred” possibly meant to be ironic, as Hippocrates is regarded as wishing to replace the earlier, supernatural explanations of epilepsy, with a natural one dependent on brain function.

  • 3. Late 19th century:

    • a. Jackson: Model of focal seizure beginning as aura and evolving to psychomotor or convulsive seizure, and use of aura symptoms to localize seizure onset within gray matter of the brain.

    • b. Gowers: Detailed descriptions of epileptic syndromes and related disorders; concept that “seizures beget seizures.”

  • 4. Mid 20th century:

    • a. Berger, Walter, and Lennox: Ability to record human electroencephalogram (EEG) from scalp and correlate with epilepsy.

    • b. Penfield and Jasper: Surgical resection facilitated by identification of epileptic focus on the basis of clinical manifestations and electrocorticography (EEG recorded from the brain surface) and identification of functional cortical regions by cortical electrical stimulation.

    • c. Merritt and Putnam: Determination that phenytoin was an antiepileptic drug using an animal seizure model.

    • d. Gastaut: Advances in syndromic classification and treatment.

  • 5. Late 20th century:

    • a. Widespread use of simultaneous video-EEG recording, allowing accurate correlations of EEG and behavior.

    • b. Neuroimaging, allowing visualization of lesions responsible for seizure generation and facilitating surgical treatment of epilepsy.

    • c. Development of many new antiepileptic drugs by screening and synthesis based on knowledge of seizure mechanisms.

    • d. Emergence of epileptology as a defined specialty within neurology and the development of comprehensive epilepsy management programs, including long-term monitoring and epilepsy surgery.

  • 6. 21st century:

    • a. Identification of genetic bases of many syndromic epilepsies.

    • b. Implantable stimulation techniques (e.g., vagal nerve stimulation) for treatment-resistant epilepsy.


  • 1. Seizure: The clinical manifestation of an abnormal, excessive, and hypersynchronous electrical discharge of a population of cortical neurons.

  • 2. Epilepsy: A brain disorder characterized by recurrent seizures that are unprovoked by systemic or neurologic insults.

  • 3. Epileptic syndrome: A particular form of epilepsy, often implying specific causes, clinical manifestations, and prognosis.

  • 4. Aura: The earliest part of a seizure and typically, the only experience recalled by the patient.

  • 5. Convulsion: The motor manifestations of a seizure, usually consisting of rhythmic tonic followed by clonic movements and postures.

  • 6. Postictal period: Time between the end of the seizure and recovery to the baseline state.

  • 7. Status epilepticus (SE): 30 or more minutes of continuous or recurrent seizures without recovery.


Seizure Types

The fundamental types of seizures are (a) partial, or “focal,” seizures that are presumed to originate in a specifiable lobe or hemisphere of the brain and (b) generalized seizures that start simultaneously throughout the entire cortex, or at least in widespread areas of both hemispheres. A further distinction is made between (c) simple and (d) complex seizures, the former signifying preservation of normal consciousness throughout the seizure and the latter indicating an alteration of consciousness, including confusional states, behavioral aberrations, and unresponsiveness.

The following is a simplified version of the 1981 seizure classification system of the International League against Epilepsy (ILAE):

  • 1. Partial seizures (seizures beginning locally)

    • a. Simple partial seizures: Consciousness not impaired; all but those with motor manifestations are experienced by the patient as a subjective sensory or psychic occurrence. Usual duration of 5 to 30 seconds; EEG pattern may show focal or unilateral rhythmic discharges.

      • 1) Motor (e.g., localized tonic or dystonic posturing or clonic jerking)

      • 2) Somatosensory or special sensory (e.g., localized tingling, flashing lights, unpleasant odor)

      • 3) Autonomic (e.g., rising epigastric sensation)

      • 4) Psychic-cognitive (e.g., déjà vu, jamais vu, unprovoked fear)

    • b. Complex partial seizures (CPS): Consciousness is impaired or lost; frequently including repetitive, automatic-appearing repetitive movements, termed “automatisms” (source of the previously used term “psychomotor seizures”). Usual duration is 30 to 180 seconds; EEG pattern—typically bilateral rhythmic discharge but often with a focal or unilateral onset.

      • 1) CPS beginning as a simple partial seizure (see list item 1.a. above)

      • 2) CPS with impairment of consciousness at onset

    • c. Partial seizures, secondarily generalized: Partial seizure progressing to complete loss of consciousness with bilateral tonic posturing followed by clonic contractions; the latter gradually slow down before stopping. Usual duration is 50 to 120 seconds following initial partial seizure; EEG pattern—focal or bilateral rhythmic discharge prior to generalization, then widespread polyspikes typically obscured by muscle artifact from onset of tonic phase, evolving into bursts of polyspikes and muscle artifact as clonic jerks appear.

  • 2. Generalized seizures (bilaterally symmetric and without focal onset) including grand mal seizures; almost always complex by definition because of simultaneous loss or alteration of consciousness.

    • a. Typical absence (petit mal): Arrest of behavioral activity with staring and minor motor activity (e.g., blinking); usual duration 5 to 10 seconds, rarely up to 30 seconds, longer absences may be accompanied by automatisms; EEG pattern of 3 Hz (rarely up to 6 Hz) generalized spike-wave complexes.

    • b. A typical absence: Compared with typical absence, often less complete but longer and more gradual behavioral arrest and recovery; EEG pattern of slow (1.5 to 2.5 Hz) spike-wave complexes.

    • c. Myoclonic: Brief, shocklike jerking of muscles on both sides of body; duration, less than 1 second; EEG pattern of generalized polyspike-wave complex.

    • d. Clonic: Series of myoclonic jerks; duration variable; EEG pattern of repeated myoclonic jerks.

    • e. Tonic: Stiffening or contraction in a fixed posture, often with abduction of the shoulders and partial flexion of the elbows; usual duration 10 to 20 seconds, but often cluster; EEG pattern of rapid, diffuse polyspikes, often following a slow wave.

    • f. Tonic-clonic (grand mal, convulsion): Stereotyped sequence of bilateral stiffening followed by clonic contractions; usual duration 50 to 120 seconds; EEG pattern of low-amplitude polyspikes increasing in amplitude until obscured by muscle artifact, then in bursts corresponding to clonic jerks.

    • g. Atonic: Sudden loss of postural tone, usually with altered awareness; duration 5 to 30 seconds; EEG pattern of rapid, low-voltage spikes following a slow wave, or slow-spike/polyspike-wave complexes.

  • 3. Unclassified epileptic seizures (usually because there is inadequate clinical data on which to base classification).

Epilepsy Syndromes

  • 1. Epilepsy syndromes are classified predominantly by the seizure type, partial or generalized, and by the underlying cause of the epilepsy.

  • 2. Epilepsy is termed “idiopathic” if there is normal interictal neurologic function and mental ability, usually implying a genetic predisposition to seizures.

  • 3. Epilepsy is “symptomatic” if the seizures result from an underlying condition (e.g., brain injury, cortical malformation, or inborn error of metabolism).

  • 4. If there is a presumed cause that cannot be found, the process is termed “cryptogenic.”

  • 5. Several of the common epilepsy syndromes are listed in Table 2-1.


  • 1. Seizures have a 9% to 10% cumulative lifetime incidence (3% to 4% febrile, 3% other acute symptomatic, 2% to 3% epileptic) in almost all populations.

  • 2. The incidence of epilepsy is 30 to 50/100,000; cumulative incidence 2% to 3% by age 75; prevalence 0.5% to 0.8%.

  • 3. There is a bimodal incidence for both seizures and epilepsy with the highest rate in the first year of life and increasing again after age 60.


The hypersynchronous neuronal discharge that characterizes a seizure is the result of an imbalance between excitation and inhibition. Genetic epilepsies typically affect the structure and function of neurotransmitter receptors and their associated ion channels. The mechanisms by which cortical injuries produce epilepsy are unknown but
probably are related to alterations in function and connectivity of excitatory and inhibitory neurons at the margins of the injury.

TABLE 2-1 Modified International League Against Epilepsy Classification of Epilepsy Syndromes

Localization-related (partial, focal) epilepsies



Benign childhood epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms



Chronic progressive epilepsia partialis continua of childhood (Rasmussen encephalitis)


Symptomatic or cryptogenic:

Temporal, frontal, parietal, or occipital epilepsies

Generalized epilepsies



Benign neonatal familial convulsions

Benign myoclonic epilepsy in childhood

Childhood absence epilepsy

Juvenile absence epilepsy

Juvenile myoclonic epilepsy


Cryptogenic or symptomatic epilepsies:

West syndrome (infantile spasms)

Lennox-Gastaut syndrome


Situation-related syndromes

Febrile convulsions

Alcohol/drug related


Epilepsy with specific modes of presentation (reflex epilepsies)

Physiologic Mechanisms

  • 1. Cellular: Alterations in distribution or function of ion channels, or in neurotransmitter synthesis, metabolism, or uptake.

  • 2. Extracellular: Alterations in ionic environment (partially mediated by glial cells) or synaptic structure.

  • 3. Network: Alterations in synaptic organization; alterations in number or function of inhibitory or excitatory neuronal populations. There is evidence that absence seizures result from aberration in the thalamocortical network that underlies sleep spindle generation.

Molecular Mechanisms

  • 1. Main inhibitory neurotransmitter: γ-aminobutyric acid (GABA), which is a pleomorphic class of receptors linked to the chloride channel, activation of which hyperpolarizes neurons.

  • 2. Main excitatory transmitter: Glutamate acts via several ionotropic (creating ion pores) receptors that are often divided into three groups on the basis of experimental agonists (N-methyl D-aspartate [NMDA], AMPA, and kainic acid). Glutamate also acts on metabotropic receptors affecting intracellular processes more slowly via G-proteins.


  • 1. The current view is that a collection of genes and polymorphisms, coding mainly for neurotransmitter receptors and their associated ion channels, determine an individual’s “seizure threshold.” This threshold influences the likelihood that an individual will develop epilepsy after a brain injury or from a systemic or neurologic derangement.

  • 2. There are also rare Mendelian syndromes with mutations affecting critical receptors or channels (e.g., autosomal dominant nocturnal frontal lobe epilepsy and the nicotinic acetylcholine receptor, juvenile myoclonic epilepsy [JME] families with mutations in the GABR1 gene).

  • 3. Common epilepsy syndromes (childhood absence epilepsy [CAE] and most cases of JME) are likely due to the participation of a small number of genes.

  • 4. Inborn errors of metabolism or of brain development that are frequently accompanied by epilepsy may also have a Mendelian basis (e.g., tuberous sclerosis, lissencephaly syndromes).


Natural History

  • 1. A single unprovoked seizure has a 2-year recurrence rate of 23% to 71%. The recurrence rate after second seizure is 73%; risk factors for recurrence include family history of epilepsy or an abnormal neurologic examination, somatic dysmorphisms, imaging, or EEG. Recurrent seizures and the presence of some of these additional features implicate a diagnosis of epilepsy.

  • 2. Many childhood-onset epilepsy syndromes remit spontaneously (e.g., benign childhood epilepsy with centrotemporal spikes [BECTS], childhood absence epilepsy [CAE]).

  • 3. Adolescent-onset idiopathic syndromes (e.g., juvenile myoclonic epilepsy [JME], juvenile absence epilepsy [JAE]) and symptomatic cases are less likely to remit.

  • 4. Although most epilepsies that respond initially to medical treatment are controlled, there is no evidence that early treatment alters the natural history.

Response to Medical Treatment

  • 1. Approximately half (58% if idiopathic, 44% symptomatic or cryptogenic) of new cases respond to the first well-tolerated drug.

  • 2. Patients who continue to have seizures despite adequate treatment with one drug have only a 10% to 30% chance of complete response to another one and multiple medications are often instituted (see further on).

Nonmedical Treatment

  • 1. Ketogenic diet

    • a. A high-fat diet that produces metabolic changes mimicking starvation can produce marked seizure reductions in 30% to 50% of children with various seizure types (usually cryptogenic or symptomatic generalized epilepsy syndromes).

    • b. Short-term risks of the diet include weight loss, renal stones, acidosis, hemolytic anemia, lethargy, and elevated liver function tests; treatment is usually initiated in the hospital and maintained with the assistance of a dietitian.

    • c. Much less information is available concerning feasibility, effectiveness, and long-term safety in adults of the ketogenic diet or of less restrictive high-fat, low-carbohydrate diets.

  • 2. Resective surgery

    • a. Medically refractory patients with an identifiable seizure focus (localization-related epilepsy) should be considered for resection of the epileptic focus.

    • b. In appropriately selected candidates, long-term seizure-free rates range from 60% to 80%. The best prognosis is for those with structural lesions, even subtle ones, especially mesial temporal sclerosis.

  • 3. Palliative procedures

    • a. For those who are not candidates for resective surgery, several procedures have been shown to produce worthwhile benefit in many patients, although complete seizure remission, in only a few.

    • b. These include disconnection procedures such as corpus callosotomy (section of the major interhemispheric commissures, often the anterior two-thirds of the corpus callosum), multiple subpial transections (shallow longitudinal cuts presumed to sever cortical-cortical connections while leaving intact the descending projection fibers needed to preserve function), or insertion of vagus nerve stimulator (VNS).

    • c. The VNS, which delivers controllable stimulations at programmable intervals to the left vagus nerve, produces a 50% decrease in seizure frequency in 25% to 45% of patients. It is most appropriate for patients 12 years of age or older with partial seizures, but younger patients and those with generalized epilepsies may respond.

    • d. Neurostimulation of deep gray nuclei such as the anterior nucleus of the thalamus has been somewhat successful with 35% to 76% seizure reduction.

  • 4. Complementary and alternative therapies: Such activities as relaxation techniques, yoga, or exercise are under investigation, as are some herbal medicines and dietary supplements. While some of these may prove beneficial, and relaxation and related techniques appear safe, caution must be exercised with herbal preparations, since some have potentially harmful effects (including lowering the seizure threshold) or may interact with antiepileptic drugs [AEDs].

Medication Withdrawal

  • 1. In general, patients who have had no seizures for at least 2 years can be considered for medication withdrawal, with the expectation that there will be a recurrence in 20% to 40%.

  • 2. Those patients with only one seizure type, which responded promptly and was controlled for many years on modest doses of one medication, have the best prognosis, particularly if they have normal neurologic examinations, imaging studies, and EEG. Even a small risk of recurrence may be unacceptable to people with certain lifestyles or occupations that put them at risk for brief loss of consciousness.

  • 3. Specific epilepsy syndromes, such as BECTS or JME confer different recurrence risk than the overall statistics quoted in list item 1 above.


Differential Diagnosis

  • 1. Transient events that mimic partial or generalized seizures include

    • a. Syncope, especially “convulsive syncope” with clonic shaking or tonic extension with pallor after the patient has fallen to the ground

    • b. Migraine (migraine with aura or basilar migraine)

    • c. Transient ischemic attack (TIA) (carotid or vertebrobasilar, particularly the uncommon carotid syndrome of “limb-shaking” TIA)

    • d. Movement disorder (tremor, nonepileptic myoclonus, dyskinesia)

    • e. Sleep disorders (specifically narcolepsy-cataplexy syndrome and somnambulism)

    • f. Toxic-metabolic disturbances (distinct from those that can cause seizures), particularly with tremulousness or asterixis

    • g. Psychiatric disorders (dissociative states, psychogenic nonepileptic seizures, or pseudoseizures, panic attacks)


  • 1. History: Helpful aspects are recent or remote serious brain injury or illness; sleep deprivation or fever; presence, nature, and duration of warning before seizure and whether either the entire event or the warning was ever experienced before; witness accounts including level of responsiveness, motor manifestations, duration of event and recovery; patient and witness assessment of functioning afterward, particularly focal symptoms, incontinence, mouth/tongue biting, muscle soreness.

  • 2. Physical examination: Mental status, focal features, signs of infection or trauma.

  • 3. Laboratory studies: Electrolytes, calcium, magnesium, glucose, renal and liver function tests, toxic screen, and complete blood count (CBC, CPK).

  • 4. Ancillary tests: Neuroimaging (magnetic resonance imaging [MRI] preferred to computed tomography [CT]), EEG (as soon as available), lumbar puncture if infection suspected.


Antiepileptic Drugs

  • 1. Principles of use:

    • a. The differences between drugs in efficacy are less than the differences in pharmacokinetics, drug-drug interactions, adverse effects, and cost.

    • b. Several drugs work approximately equally well in any given clinical seizure type.

    • c. Unless a rapid therapeutic effect is essential, choose a low starting dose and slow upward titration. This is especially true when treating elderly, frail, or medically ill patients.

    • d. In general, increase the dose until an adequate observation period establishes that seizures are controlled or until dose-related side effects develop. In the latter case, decrease back to the previous dose and monitor response. If seizures are not controlled, another appropriate AED should be initiated and titrated, usually while weaning the patient off the first drug (i.e., monotherapy is always preferable to polytherapy unless there is no alternative).

    • e. Sometimes, increases in dose result in increased seizures. The dose should be reduced and the drug is replaced by an alternative AED.

    • f. Off-label use is justifiable if approved AEDs are not successful or the risk with the off-label alternative appears lower than that with the approved AED.

    • g. The most common drug interactions involving AEDs are based on induction, or, less commonly, inhibition, of the hepatic mixed-function oxidase or P450 enzyme system or other interactions that involve glucuronidation pathways. As a group, the older AEDs have much stronger effects on these systems than do the newer ones, although several of the latter are substrates whose metabolism is affected by addition or withdrawal of the older drugs.

    • h. Serum drug concentrations (drug levels) can be useful in verifying compliance or in providing an initial target for patients with infrequent seizures, but if used mechanically as a guide to dosing these can hinder rather than help in achieving the goal of treatment: no seizures and no side effects (and ultimately, optimizing quality of life). Even for the older AEDs, published therapeutic
      ranges have limited scientific support, and individuals may have therapeutic responses or adverse effects either below or above this range. For the newer AEDs, therapeutic ranges are even more provisional, but these are included in the following discussions for completeness.

  • 2. Specific AEDs: The common medications for seizures are categorized in several ways. Classifications based on biochemical mechanism are logical but of limited clinical value in that several drugs work by more than one mechanism and, for many, the mechanisms are poorly understood. We find it more useful to group the drugs by their spectrum of action for specific seizure types:

    • a. The first and the largest group of AEDs is effective against partial seizures, including simple and complex types as well as secondarily generalized seizures. Most, if not all, of these also prevent primarily generalized tonic-clonic seizures; however, they are not effective against, and may worsen, other generalized seizure types, including absence and myoclonic seizures. Drugs in this class include carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PHB), primidone (PRM), gabapentin (GBP), oxcarbazepine (OXC), tiagabine (TGB), and pregabalin (PGB).

    • b. The second group is the “broad-spectrum” AEDs with activity against a variety of generalized and partial seizures. The most familiar drug with this characteristic is valproate (VPA). A similar broad spectrum has been attributed to some newer drugs such as lamotrigine (LTG), topiramate (TPM), levetiracetam (LEV), zonisamide (ZNS), felbamate (FBM), and the older drug methsuximide (MSX), as well as for recently approved lacosamide (LAC) and rufinamide (RFA).

    • c. The third group includes drugs that do not easily fit in the above categories, including ethosuximide (ESX), a narrow-spectrum AED with established efficacy against only typical generalized absence seizures. (Interestingly, the closely related methosuximide has a broader spectrum and is effective against partial seizures as well.) There are other less commonly used adjunctive drugs, not strictly speaking antiepileptics, that have special uses, such as acetazolamide (ACZ), ACTH for infantile spasms, pyridoxine, and perhaps allopurinol.

    • d. Finally, there are medications used in seizure clusters and status epilepticus, alcohol, and other drug-related seizures. These include intravenous (IV), sublingual, and rectal benzodiazepines, fosphenytoin, midazolam, propofol, and anesthetic agents.

Drugs for Partial and Tonic-Clonic Seizures


  • 1. Advantages: Considered a first-choice drug for partial and tonic-clonic seizures; familiarity; slow-release preparations allow twice a day (b.i.d.) dosing.

  • 2. Disadvantages: Need to titrate slowly to avoid dose-related adverse effects, pharmacokinetic interactions (P450 enzyme inducer and substrate).

  • 3. Major adverse effects:

    • a. Dose-related: dizziness, diplopia, nausea, sedation, mild leukopenia, hyponatremia, bradyarrhythmias (elderly)

    • b. Idiosyncratic: rash (including Stevens-Johnson syndrome [SJS]), agranulocytosis, hepatic failure, pancreatitis, lupus-like syndrome

    • c. Chronic: osteopenia (possibly preventable with vitamin D and calcium supplementation)

  • 4. Teratogenicity: Poses a risk including 0.5% to 1% neural tube defects (unclear whether extra folate is preventative).

  • 5. Initiation and titration: 100 to 200 mg at night (hs) or 100 mg b.i.d.; increase after 3 to 7 days to 200 mg b.i.d. Can check blood tests after 1 week on this dose: CBZ level, CBC/differential, electrolytes (Na), and perhaps albumin and aspartate
    aminotransferase (AST) levels. Dose can be increased at 3- to 7-day intervals to obtain a level of 4 to 12 mg/L; level is typically rechecked in 4 to 6 weeks, as autoinduction of enzymes may necessitate further increases. Usual maintenance doses in adults are as follows: 600 to 1,600 mg/d, up to 2,400 mg/d. In children, start at 5 to 10 mg/kg/d, maintenance 15 to 20 mg/kg/d, up to 30 mg/kg/d.

  • 6. Pharmacokinetics: Half-life: 12 to 20 hours (shorter with enzyme-inducing drugs; autoinduction also occurs, with level falling after 2 to 6 weeks on stable dose), protein binding: 70% to 80%.

  • 7. Usual therapeutic range: 4 to 12 mg/L.

  • 8. Preparations: Tegretol tablets 100 and 200 mg, generic 200-mg tablets, suspension 100 mg/5 mL (can solidify in tube feedings), generic 200 mg; slow-release preparations including Tegretol-XR 100-, 200-, and 400-mg caplets, and Carbatrol 200- and 300-mg capsules.


  • 1. Advantages: More rapid titration than CBZ, b.i.d. dosing, minor interactions, no known hepatic or hematologic adverse effects; approved as initial monotherapy for partial seizures.

  • 2. Disadvantages: Dose-related effects similar to those of CBZ; although induces P450 only weakly, it can lower hormone (e.g., contraceptive) levels.

  • 3. Comment: Very similar chemically to CBZ but not converted into epoxide metabolite, which accounts for many adverse effects of CBZ.

  • 4. Major adverse effects:

    • a. Dose-related: dizziness, diplopia, hyponatremia, somnolence, ataxia, gastrointestinal (GI) upset

    • b. Idiosyncratic: rash (25% cross-reactivity with CBZ)

    • c. Chronic: none known

  • 5. Teratogenicity: Unknown (lack of epoxide metabolite may suggest favorable relative to CBZ).

  • 6. Initiation and titration: Adults—150 to 300 mg b.i.d., increasing by 300 to 600 mg every 1 to 2 weeks to target of 1,200 to 2,400 mg/d; children (older than 4 years)—8 to 10 mg/kg/d titrated to 20 to 40 mg/kg/d. Note: conversion from CBZ can be rapid, over 1 day to 2 weeks, at a ratio of 300-mg OXC to 200-mg CBZ.

  • 7. Pharmacokinetics: Half-life of 2 hours but converted into active monohydroxyderivative (MHD) with half-life of 8 to 10 hours; protein binding: 40%.

  • 8. Therapeutic range: 10 to 35 mg/L (MHD).

  • 9. Preparations: Trileptal or generic tablets 150, 300, 600 mg; syrup 300 mg/5 mL.


  • 1. Advantages: Arguably a first-choice drug for partial and tonic-clonic seizures, although used less in Europe than in United States; physician familiarity and long history in medical use; long duration of action, especially with slow-release preparations—usually b.i.d. dosing, but can be daily (q.d.); parenteral loading options. Usually effective against generalized tonic as well as tonic-clonic seizures, although not against absence or myoclonic seizures.

  • 2. Disadvantages: As the dose of phenytoin increases, plasma levels rise to a disproportionate degree due to saturation of metabolic pathway, referred to as nonlinear or zero-order kinetics; pharmacokinetic interactions (strong P450 inducer); chronic cosmetic and other adverse effects.

  • 3. Major adverse effects:

    • a. Dose-related: dizziness, ataxia, diplopia, nausea

    • b. Idiosyncratic: rash, including SJS; blood dyscrasias; hepatic failure; lupus-like syndrome

    • c. Chronic: gingival hyperplasia, hirsutism, osteopenia, pseudolymphoma, and controversially, lymphoma, cerebellar degeneration

  • 4. Teratogenicity: Yes.

  • 5. Initiation and titration: Adults—In nonemergent situations, can load orally; two doses of 500 mg or three doses of 300 mg can be taken 4 to 6 hours apart. Parenteral loading can be achieved IV (15 mg/kg, or 20 mg/kg for SE, not more than 50 mg/min; precursor drug fosphenytoin may be preferable for status). When loading is not needed, can initiate estimated maintenance dose of 300 to 400 mg/d, usually in two doses, checking levels in 1 to 2 weeks. Because of zero-order kinetics, increases must be proportionately less as the level rises; for example, if the steady-state level on 300 mg/d is 12 mg/L, then 330 mg/d, a 10% dose increase, may be sufficient to raise the level to 18, a 50% increase. Pediatrics: 4 to 5 mg/kg/d, up to 8 mg/kg or more depending on level.

  • 6. Pharmacokinetics: Half-life depends on the serum concentration and is longer at higher concentrations, for example, 20 to 30 hours when in usual therapeutic range; protein binding: 90% (lower with renal failure or hypoalbuminemia).

  • 7. Usual therapeutic range: 10 to 20 mg/L (arguably 5 to 25 mg/L).

  • 8. Preparations: Dilantin tablets 50 mg, Dilantin and generic extended-release capsules 30 and 100 mg, and suspension 125 mg/5 mL (must be adequately mixed in bottle); Phenytek capsules 200 and 300 mg. Fosphenytoin used for rapid loading IV.


  • 1. Advantages: Rapid titration, relatively well tolerated, no pharmacokinetic interactions, additional uses (neuropathic pain).

  • 2. Disadvantages: Three or four times daily (t.i.d. and q.i.d., respectively) dosing recommended (although it can be given b.i.d.); perceived as less efficacious than other AEDs, although data are conflicting.

  • 3. Major adverse effects:

    • a. Dose-related: sedation, dizziness, ataxia

    • b. Idiosyncratic: weight gain, rash (rare), behavioral changes in children, myoclonus

    • c. Chronic: none known

  • 4. Teratogenicity: Unknown.

  • 5. Initiation and titration: 300 mg hs, increasing by 300 mg every 1 to 7 days to target of 1,800 to 3,600 mg/d; in elderly, 100 mg hs or b.i.d., increasing in 100-to 200-mg increments; pediatrics (older than 3 years), 10 to 20 mg/kg/d increasing to target of 30 to 60 mg/d.

  • 6. Pharmacokinetics: Half-life: 5 to 7 hours (but brain kinetics likely slower); protein binding: none.

  • 7. Therapeutic range: 4 to 16 mg/L.

  • 8. Preparations: Neurontin or generic capsules 100, 300, 400 mg; tablets 600 and 800 mg; solution 250 mg/5 mL.


  • 1. Advantages: No pharmacokinetic interactions, additional uses (neuropathic pain).

  • 2. Disadvantages: Relatively slow titration due to sedation.

  • 3. Major adverse effects:

    • a. Dose-related: sedation (may potentiate ethanol, benzodiazepine effects), dizziness, ataxia

    • b. Idiosyncratic: weight gain, rash (rare), myoclonus

    • c. Chronic: none known

  • 4. Teratogenicity: Unknown.

  • 5. Initiation and titration: 75 to 100 mg hs, increasing by a similar amount mg every 1 to 2 week to target of 300 to 600 mg/d; adjust for renal impairment.

  • 6. Pharmacokinetics: Half-life: 4 to 7 hours (but brain kinetics likely slower); protein binding: none.

  • 7. Provisional therapeutic range: 4 to16 mg/L

  • 8. Preparations: capsules 25, 50, 75, 100, 150, 200, 225, 300 mg.


  • 1. Advantages: May have antianxiety or analgesic effects; can sometimes be given b.i.d.

  • 2. Disadvantages: Sedating; risk of nonconvulsive SE; P450 induction.

  • 3. Major adverse effects:

    • a. Dose-related: dizziness, somnolence, nausea, cognitive slowing

    • b. Idiosyncratic: rash, mood changes, generalized nonconvulsive SE (doses 48 mg/d or greater)

    • c. Chronic: unknown

  • 4. Teratogenicity: Unknown.

  • 5. Initiation and titration: 2 to 8 mg/d, increasing by 2 to 8 mg/d at weekly intervals to target of 24 to 56 mg/d in two to four doses; pediatrics (older than 12 years): 4 mg/d, increasing by 4 mg/wk to target of 20 to 32 mg/d.

  • 6. Pharmacokinetics: Half-life: 4 to 9 hours, protein binding: 96%.

  • 7. Provisional therapeutic range: 0.1 to 0.3 mg/L.

  • 8. Preparations: Gabitril filmtabs 2, 4, 12, 16, 20 mg.


  • 1. Advantages: Long half-life (daily dosing), inexpensive.

  • 2. Disadvantages: Drowsiness, cognitive and behavioral side effects, interactions (induces P450).

  • 3. Major adverse effects:

    • a. Dose-related: sedation, depression, cognitive impairment

    • b. Idiosyncratic: rash, hyperactivity (children), hepatic failure (rare), aplastic anemia (rare)

    • c. Chronic: osteoporosis, connective tissue disorders (e.g., frozen shoulder)

  • 4. Teratogenicity: Yes.

  • 5. Initiation and titration: 90 to 250 mg/d, can load IV with up to 20 mg/kg (<100 mg/hr for SE), but sedation is universal; check steady-state levels in 2 to 3 weeks (4 to 5 weeks in presence of VPA); pediatrics: 2 to 7 mg/kg/d.

  • 6. Pharmacokinetics: Half-life: 72 to 168 hours (less in children; more when coadministered with VPA).

  • 7. Usual therapeutic range: 10 to 40 mg/L.

  • 8. Preparations: Tablets 15, 30, 60 (or 62.5), 100 mg; suspension 15 or 20 mg/5 mL; parenteral 30, 60, 130 mg/mL.


  • 1. Advantages: Parent compound may have efficacy beyond that of phenobarbital metabolite, at least against myoclonic seizures; effective against tremor at low doses.

  • 2. Disadvantages: Possibly more sedating than phenobarbital alone; must be taken in divided doses, usually t.i.d. or q.i.d.; strongly induces P450.

  • 3. Comment: Metabolized to PHB.

  • 4. Major adverse effects:

    • a. Dose-related: same as PHB

    • b. Idiosyncratic: same as PHB

    • c. Chronic: same as PHB

  • 5. Teratogenicity: Yes.

  • 6. Initiation and titration: 100 to 125 mg hs, increasing by 125 to 250 mg every 2 to 7 days to target of 500 to 1,500 mg/d; pediatrics: 50 mg/d increasing to 10 to 25 mg/kg/d.

  • 7. Pharmacokinetics: Half-life: 6 to 22 hours (72 to 168 hours for PHB metabolite); P450 inducers promote conversion to PHB.

  • 8. Usual therapeutic range: 5 to 12 mg/L (10 to 40 mg/L for PHB).

  • 9. Preparations: Mysoline and generic tablets 50 and 250 mg; suspension 250 mg/5 mL.

Drugs for Generalized Seizures

Including absence and myoclonic. These drugs also are effective against tonic-clonic partial seizures.


  • 1. Advantages: Familiarity, best-established broad-spectrum AED; beneficial effects on migraine, bipolar illness; slow-release preparations allow b.i.d. or possibly daily dosing.

  • 2. Disadvantages: Acute and chronic adverse effects, particularly weight gain; interactions (P450 inhibitor, also competes for protein-binding sites).

  • 3. Major adverse effects:

    • a. Dose-related: GI upset, anorexia, tremor, thrombocytopenia

    • b. Idiosyncratic: pancreatitis (up to one in 200), hepatic failure (especially infants on polytherapy), stupor and coma, depression, rash, hyperammonemia, thrombocytopenia/thrombocytopathy

    • c. Chronic: weight gain, hair loss or change in texture; possibly polycystic ovarian syndrome

  • 4. Teratogenicity: Yes, including 1% to 2% incidence of neural tube defects.

  • 5. Initiation and titration: 250 mg b.i.d. to t.i.d., increasing by 250 to 500 mg weekly to target of 750 to 2,000 mg/d (higher if also on enzyme-inducing drugs); pediatrics: 10 to 15 mg/kg/d, increasing by 5 to 10 mg/kg/wk to 15 to 30 mg/kg/d (maximum, 60 mg/kg/d).

  • 6. Pharmacokinetics: Half-life: 10 to 20 hours; up to 95% protein bound, less at higher levels; partial P450 inhibitor, elevating particularly PHB and LTG.

  • 7. Usual therapeutic range: 50 to 120 mg/L.

  • 8. Preparations: Depakene or generic valproic acid capsules 250 mg, syrup 250 mg/5 mL; depakote delayed-release tablets, 125, 250, and 500 mg; depakote sprinkles slow-release capsules, 125 mg; depakote-ER extended-release capsules 250 and 500 mg; Depacon infusion 100 mg /5 mL.


May 28, 2016 | Posted by in NEUROLOGY | Comments Off on Epilepsy
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