Medication Summary
The chosen antiepileptic drug should have high efficacy, long-term safety, good tolerability, and low interaction potential, and the agent should allow a good quality of life, especially because half of all patients never have another seizure without treatment. [8] These agents prevent seizure recurrence and terminate clinical and electrical seizure activity. [45]
The accepted principle is that one should begin with monotherapy. All newer (second-generation) agents are acceptable choices and are likely just as effective as older agents. An American Academy of Neurology (AAN) evidence-based guideline recommended lamotrigine, oxcarbazepine, topiramate, and gabapentin as appropriate for initial monotherapy; however, this guideline did not include newer antiepileptic drugs, such as levetiracetam and pregabalin.
Selected anticonvulsant trial results
In an early report, phenytoin, carbamazepine, valproate, and phenobarbital were equally effective in treating newly diagnosed epilepsy; however, phenobarbital had more adverse effects. [46] Other authors agree that barbiturates should be avoided because of neurotoxic and cognitive side effects. [8]
SANAD study results
The Standard and New Antiepileptic Drugs (SANAD) study reported that lamotrigine was significantly better in terms of time to treatment failure than the current standard treatment, carbamazepine, and the newer drugs gabapentin and topiramate for treatment of partial seizures. [47] (The study compared carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate.) For time to 12-month remission from seizures, carbamazepine was not significantly advantageous compared with lamotrigine. [47] Lamotrigine also has the lowest incidence of treatment failure and has better outcome than all drugs except oxcarbazepine.
The same SANAD study compared valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy seizures, and found that valproate is the drug of choice and is better tolerated than topiramate. [48]
Epilepsy monotherapy trial results
Another study compared 8 antiepileptic drugs used in 20 randomized trials and reported that in patients with partial seizures, the results favored carbamazepine, oxcarbazepine, and lamotrigine. [49] For generalized tonic-clonic seizures, the results favored valproate and phenytoin. [49]
NEAD study results
Regarding sodium valproate, the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group recommended that sodium valproate not be used as a first-line drug in the treatment of epilepsy for women of child-bearing age because of its side effects. [50]
Anticonvulsant safety and tolerability
Although phenytoin, carbamazepine, valproate, and phenobarbital were initially reported as equally effective in treating newly diagnosed epilepsy, phenobarbital had more adverse effects. [46] In general, barbiturates should be avoided because of neurotoxic and cognitive side effects. [8]
Overall, the newer antiepileptic drugs appear safer and better tolerated; however, they have not been used for as long or in as many patients as the older drugs. None of the common side effects of the older drugs (eg, gum hyperplasia, neuropathy) have been identified; however, ruling out potential new problems with long-term use of the newer antiepileptic drugs is difficult. Head-to-head studies have demonstrated favorable side effect profiles for gabapentin when compared with carbamazepine, and for oxcarbazepine and lamotrigine when compared with both phenytoin and carbamazepine.
All newer antiepileptic drugs, although "officially" approved as adjunctive therapy, are acceptable options for monotherapy (off-label use).
Privitera et al found topiramate 100 mg/d is as effective as therapeutic doses of carbamazepine and sodium valproate and has the fewest discontinuations due to adverse events. [51]
Anticonvulsants
Class Summary
Anticonvulsant agents, including lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproic acid, are commonly used for the treatment of seizures. Initial treatment includes monotherapy. Newer agents are acceptable choices and are likely just as effective as older agents.
Lamotrigine (Lamictal, Lamictal XR, Lamictal ODT)
Lamotrigine is a triazine derivative that inhibits the release of glutamate and voltage-sensitive sodium channels, leading to stabilization of the neuronal membrane. Lamotrigine is indicated for both adjunctive treatment and monotherapy for epilepsy.
Oxcarbazepine (Trileptal)
The pharmacological activity of oxcarbazepine is primarily by the 10-monohydroxy metabolite (MHD) of oxcarbazepine. It 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.
Carbamazepine (Tegretol, Tegretol XR, Epitol, Carbatrol)
Carbamazepine has anticonvulsant actions that may involve depressing activity in the nucleus ventralis anterior of the thalamus, resulting in a reduction of polysynaptic responses and blocking posttetanic potentiation. It reduces sustained high-frequency repetitive neural firing. It is indicated for partial seizures, generalized tonic-clonic seizures, and mixed seizures.
Topiramate (Topamax, Topiragen, Topamax Sprinkles)
Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have a state-dependent sodium channel blocking action, potentiation of the inhibitory activity of the neurotransmitter gamma-aminobutyrate (GABA), and, possibly, blocking of glutamate activity. Topiramate is indicated for both adjunctive treatment and monotherapy for epilepsy.
Levetiracetam (Keppra)
Levetiracetam may inhibit presynaptic calcium channels by binding to a synaptic vesicle glycoprotein, SV2A. Levetiracetam is rapidly and almost completely absorbed after oral intake, with peak plasma concentrations approximately 1 hour after oral administration. It is predominantly excreted unchanged through the kidneys, with only about 27% metabolized.
Valproic acid (Depakote, Depakene, Depacon, Depakote ER, Stavzor)
Valproic acid is chemically unrelated to other drugs used to treat seizure disorders. Although its mechanism of action is not established, the activity of valproic acid may be related to increased brain levels of GABA or enhanced GABA action. This agent may also potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect.
Phenytoin (Dilantin, Phenytek, Dilantin Infatabs)
Phenytoin may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited. The dose administered should be individualized.
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An electroencephalogram (EEG) recording of a temporal lobe seizure. The ictal EEG pattern is shown in the rectangular areas.
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An electroencephalogram (EEG) recording from a patient with primary generalized epilepsy. A burst of bilateral spike and wave discharge is shown in the rectangular area.
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An electroencephalogram (EEG) recording of a seizure from a subdural array in a patient evaluated for epilepsy surgery. The subdural electrodes record from the left anterior temporal (LAT), left middle temporal (LMT), and left posterior temporal (LPT) regions. The EEG seizure pattern is seen best in bipolar EEG channels LAT 3-4 and LMT 3-4 (rectangular areas).
