Medication Summary
The goals of pharmacotherapy are to prevent epileptic seizures, reduce morbidity, and prevent complications. Antiepileptic drugs, corticotropin ACTH, and vigabatrin are indicated.
Vitamins, water soluble
Class Summary
Vitamins are used to meet dietary requirements and are used in metabolic pathways, as well as in DNA and protein synthesis.
Pyridoxine (Aminoxin, Pyri-500)
Involved in synthesis of GABA within the CNS.
Anticonvulsants
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Zonisamide (Zonegran)
Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Evidence indicates it is also effective in myoclonic and other generalized seizure types.
Phenobarbital
Important to use minimal amount required and to wait for anticonvulsant effect to develop before giving second dose. Start with loading dose and continue with maintenance dosage.
Clonazepam (Klonopin)
Long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). Reaches peak plasma concentration at 2-4 h after oral or rectal administration.
Vigabatrin (Sabril)
This agent inhibits GABA transaminase, which increases levels of the inhibitory molecule GABA within the brain.
Valproic acid (Depacon, Depakene, Stavzor)
Chemically unrelated to other drugs that treat seizure disorders. Although mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect.
For conversion to monotherapy, concomitant antiepilepsy drug dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may start at initiation of therapy or can be delayed by 1-2 weeks if there is concern that seizures may occur with a reduction. Monitor patients closely during this period for increased seizure frequency.
As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses of less than 60 mg/kg/d.
Lamotrigine (Lamictal)
Efficacy as adjunctive therapy against seizures associated with Lennox-Gastaut syndrome was demonstrated in 2 controlled trials and multiple open-label studies. Valuable for patients with Lennox-Gastaut syndrome despite risk of idiosyncratic dermatologic reactions. Consider for use as soon as diagnosis of Lennox-Gastaut syndrome is made. Proper attention to concomitant medications, low starting dose, and very slow titration can minimize risk of dermatologic reactions. Initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.
Topiramate (Topamax)
In a multicenter, double-blind, placebo-controlled trial, found to be safe and effective as adjunctive therapy (target dose 6 mg/kg/d) for patients with Lennox-Gastaut syndrome. In a long-term open-label extension portion of this trial (mean dosage 10 mg/kg/d), drop attacks were reduced by more than half in 55% of patients, and 15% of patients were free of drop attacks for longer than 6 months at the last visit.
Rufinamide (Banzel)
Antiepileptic agent but structurally unrelated to current antiepileptics. Modulates sodium channel activity, particularly prolongation of the channel's inactive state. Significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.
Felbamate (Felbatol)
Oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine receptor binding. Has little activity at MK-801 receptor-binding site of NMDA receptor-ionophore complex. However, felbamate is antagonist at strychnine-insensitive glycine recognition site of NMDA receptor-ionophore complex. Not indicated as first-line antiepileptic treatment. Recommended for use only in patients whose epilepsy is so severe that benefits outweigh risks of aplastic anemia or liver failure. Most adverse effects during adjunctive therapy may resolve as dosage of concomitant antiepileptic drugs decrease.
Found to be safe and effective in patients with Lennox-Gastaut syndrome in randomized, double-blind, placebo-controlled adjunctive therapy trial; 12-month follow-up study in patients who completed controlled part of study confirmed long-term efficacy; although effective, significant risk of idiosyncratic reactions associated with use make it third-line or fourth-line drug for Lennox-Gastaut syndrome.
Carbamazepine (Carbatrol, Equetro, Epitol, Tegretol)
Anticonvulsant action may involve depressing activity in nucleus ventralis anterior of thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. Reduces sustained high-frequency repetitive neural firing. Potent enzyme inducer that can induce own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before drug instituted. Therapeutic plasma levels are between 4-12 mcg/mL for analgesic and antiseizure response. Peak serum levels in 4-5 h. Half-life (serum) in 12-17 h with repeated doses. Metabolized in liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites excreted through feces and urine.
Indicated for complex partial seizures and trigeminal neuralgia. Following a therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 months.
Oxcarbazepine (Trileptal)
The pharmacological activity of oxcarbazepine is primarily by the 10-monohydroxy metabolite (MHD) of oxcarbazepine. May block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. This drug's anticonvulsant effect may also occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children (< 8 y) have a 30-40% increased clearance compared with older children and adults. Children younger than 2 years have not been studied in controlled clinical trials.
Phenytoin (Dilantin, Phenytek)
May act in motor cortex, where may inhibit spread of seizure activity. Activity of brain stem centers responsible for tonic phase of grand mal seizures may also be inhibited.
Individualize dose. Administer larger dose before bedtime if dose cannot be divided equally.
Ethosuximide (Zarontin)
Effective only against absence seizures. Has no effect on generalized tonic-clonic, atonic-akinetic, or partial seizures. Mechanism of action is based on reducing current in T-type calcium channels found on thalamic neurons. Spike-and-wave pattern during petit mal seizures thought to be initiated in thalamocortical relays by activation of these channels.
Clobazam
Benzodiazepine that binds to benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the CNS, including the limbic system and reticular formation. GABA inhibits neuronal excitability by increasing neuronal membrane permeability to chloride ions. This increase in permeability results in hyperpolarization of the neuronal membrane and causes the membrane to become more stable.
Corticosteroids
Class Summary
These agents have profound and varied metabolic effects.
Corticotropin (H.P. Acthar)
Stimulates adrenal cortex to produce and secrete adrenocortical hormones.
Used in infants with infantile spasms (West syndrome). Estimated overall efficacy (percentage of infants with infantile spasms due to any cause reaching seizure freedom) is 50-67%. Associated with serious, potentially life-threatening adverse effects.
Must be administered IM, which is painful to infant and unpleasant for parent to perform. Daily dosages expressed as U/d (most common), U/m2/d, or U/kg/d.
Prospective single-blind study demonstrated no difference in effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk, tapering over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk, tapering over 1 wk) with respect to spasm cessation and improvement in patient's EEG. Hypertension was more common with larger doses.
Precise mechanism for infantile spasms unknown. Theorized that corticotropin suppresses corticotropin-releasing hormone (CRH), which is an excitatory neuropeptide. Infants with infantile spasms may have increased CRH.
Prednisolone (Millipred, Orapred, Prelone)
Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. May be beneficial in the treatment of carpal tunnel syndrome
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Atonic seizure. Abrupt loss of muscle tone is followed by clonic rhythmic movements. This type of seizure is typical for the symptomatic generalized epilepsies of the Lennox-Gastaut type.
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Electroencephalogram demonstrating hypsarrhythmia in infantile spasms. Note the chaotic high-amplitude background.
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Electroencephalogram demonstrating hypsarrhythmia. Note the electrodecremental response that is associated with a spasm in infantile spasms (ie, West syndrome).
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Slow (< 2.5 Hz) electroencephalographic spike and wave discharges associated with atypical absence seizures (ie, Lennox-Gastaut syndrome).
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Slow (< 2.5 Hz) electroencephalographic spike and wave discharges in atypical absence epilepsy (ie, Lennox-Gastaut syndrome).
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Spike, generalized. Significant spikes usually are followed by a slow wave, as shown here. This example also illustrates that generalized spikes are typically maximal frontally. This is typical of primary (ie, idiopathic, genetic) epilepsies. If burst lasted 3 seconds or more, it could be classified as spike-wave complexes.
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Slow spike-wave complexes. In addition to being slower, they are also less monomorphic than 3-Hz spike-wave complexes. With other findings, this often is seen in symptomatic/cryptogenic epilepsies of Lennox-Gastaut type.
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Slow spike-wave complexes. In addition to being slower, they are also less monomorphic than 3-Hz spike-wave complexes. With other findings, this often is seen in symptomatic/cryptogenic epilepsies of Lennox-Gastaut type.
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Hypsarrhythmia. High-amplitude slowing with no organized background and multifocal spikes (left and right frontal in this sample). This is phenotype of first year of life and is associated with West syndrome (ie, infantile spasms).
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Hypsarrhythmia. High-amplitude slowing (note scale) with no organized background and multifocal spikes (right frontal and left occipital in this sample). This is phenotype of first year of life and is associated with West syndrome (ie, infantile spasms).
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Generalized paroxysmal fast activity and electrodecrement. This pattern is characteristic of symptomatic/cryptogenic epilepsies of Lennox-Gastaut type and may be subclinical or associated with tonic or atonic seizures.
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Typical generalized tonic seizure in an adult patient with a "symptomatic" (now termed structural-metabolic) generalized epilepsy of the Lennox-Gastaut type.
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Typical generalized tonic seizure in a patient with a "symptomatic" (now termed structural-metabolic) generalized epilepsy of the Lennox-Gastaut type and severe static encephalopathy with cerebral palsy.
