The Role of New Antiepileptic Drugs

Case Scenarios: EpilepsyThe treatment of seizures with antiepileptic drugs (AEDs) was initiated >150 years ago with the introduction of bromide therapy.1 As different agents became more readily available, physicians started prescribing AEDs for patients based on specific seizure types. Early medications with approved efficacy included phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone, and valproic acid. These AEDs have been shown to be effective for a wide range of seizure types and remain first-line therapy options for all newly diagnosed epilepsy.Only ~70% of patients achieve seizure control while on these AEDs, however.^{2 In addition, many of the older AEDs are limited by serious adverse side effects, numerous drug interactions, and challenging pharmacokinetics.}3In the past 10 years, the FDA has approved several medications to expand the treatment options for epilepsy.4,5 Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and now zonisamide and pregabalin are all widely available options for seizures in the United States. With the introduction of these medications, many health care providers are now seeking updated evidence-based guidelines for the treatment of epilepsy.Diagnosis

Epilepsy and seizure disorders are among the most common neurologic problems in the world. An estimated 3% of the people in the United States will have epilepsy at some point in their lives.6A seizure is defined as a sudden, excessive discharge of electrical activity in the brain that causes a change in a person's feelings, perception, or behavior. Epilepsy is a chronic process that causes a person to have recurrent seizures. Seizures and epilepsy are best understood when classified into 3 categories: partial seizures, generalized seizures, and status epilepticus.Partial seizures arise from electrical activity in discrete regions of the brain. Hippocampal sclerosis is the most common focal lesion in adults with partial seizures.7 Simple partial seizures can cause motor (eg, progressive jerking, mild paralysis), sensory (eg, hallucinations), autonomic (eg, flushing, sweating), and psychic (eg, fear) symptoms. One's consciousness, however, is intact throughout the attack.

Complex partial seizures are similar to simple partial seizures, but one's consciousness is impaired during the attack. In addition, complex partial seizures are associated with automatisms (eg, lip smacking, chewing, "picking" movements of the hand). Electroencephalography (EEG) shows a burst of repetitive spikes in the right temporal region.

Generalized seizures arise from both cerebral hemispheres, with no detectable focal deficits as found in partial seizures. Within the hemispheres, alterations can be found within neuronal networks or intrinsic neuronal function.7

Absence (petit mal) seizures usually occur only in children. They are characterized by 5 to 30 seconds of loss of consciousness, often with eye or muscle fluttering. The children often appear to be staring or daydreaming, then suddenly resume normal activity. Unlike other seizures, absence seizures are not found to have a postictal or confusion state after the attack. EEG shows 3-Hz spikewave activity over both hemispheres.

Tonic-clonic (grand mal) seizures are the seizures often seen on television. The patient has muscle stiffening throughout the body (in the tonic phase), often causing a fall, followed by rapid and rhythmic muscle jerking in the arms and usually the legs (in the clonic phase). Tongue biting and incontinence often are noted, and recovery from the postictal phase is slow. EEG shows 10-Hz activity, followed by slow waves.

Status epilepticus is a medical emergency when any seizure occurs repeatedly without a return to consciousness between seizures. It often occurs spontaneously or after the sudden withdrawal from antiepileptic medications.

To diagnose any type of seizure, physical examination should be performed, with emphasis on neurologic findings. EEG is used to help confirm diagnosis, to classify seizures, and to locate the site of the seizure. The best time to perform EEG is while the patient is experiencing the actual seizure.Treatment Guidelines

Both the United States and the United Kingdom have recently attempted to develop updated treatment guidelines for epilepsy with the inclusion of modern AEDs. In the United States, the Therapeutic and Technology Assessment Subcommittee and the Quality Standards Subcommittee of the American Academy of Neurology, in collaboration with the American Epilepsy Society, did an extensive literature search to find evidence-based trials of 7 new AEDs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide).4,5

Relevant studies were then reviewed by a panel of experts to evaluate the efficacy, tolerability, and safety of the modern AEDs. The National Institute for Clinical Excellence Committee performed a similar search in the United Kingdom. Only the US results will be reviewed here.

For the treatment of newly diagnosed partial seizures, the current literature suggests that the new AEDs appear similar to older medications in efficacy but better in tolerability (Table 1). There is insufficient evidence, however, directly comparing the old agents with the new agents or the new agents with each other. As a result, for the treatment of partial seizures the guidelines still recommend an older AED or lamotrigine, gabapentin, oxcarbazepine, or topiramate. The actual choice among these agents should be individualized for each specific patient, based on side effects, cost, and tolerability.

Refractory partial seizures were defined as those failing to respond to 3 or more drugs. In these cases, the experts found that all of the new AEDs show efficacy as adjunctive therapy. In addition, the US panel recommended the use of oxcarbazepine, topiramate, and lamotrigine as possible options for monotherapy in refractory partial epilepsy. This recommendation was made despite the relatively limited availability of regulated clinical trials.

Guidelines for newly diagnosed generalized seizures also remain incomplete. The US panel did recommend the inclusion of lamotrigine as an option for newly diagnosed generalized seizures in children. This suggestion was based on class II evidence (on a scale of I to IV, with I being the best rating). Otherwise, an older AED is still the treatment of choice.

For refractory generalized seizures, only topiramate was recommended for treatment in children and adults. Gabapentin was ruled as ineffective for refractory generalized seizures. These recommendations were based on very limited clinical trials, however. A summary of these results is provided in Table 2.

It is important to point out that there were discrepancies between the US and the more conservative UK and Scottish Intercollegiate Network guidelines. These conflicting recommendations can intuitively be explained by possible preferences among the different panelists, as well as the lack of scientific literature available. Future studies should focus on comparing the new AEDs as monoand/or adjunctive therapy in a long-term, randomized clinical trial.

Summary

Antiepileptic medications have been in use for more than a century. Older AEDs have proven their efficacy in most newly diagnosed seizures, but they also carry the burden of potential adverse effects and drug interactions.

The recent FDA approval of new AEDs has called for updated evidence-based guidelines. According to the new US guidelines, the treatment of newly diagnosed partial seizures should start with an older AED or lamotrigine, gabapentin, oxcarbazepine, or topiramate. For refractory partial seizures, an older AED or oxcarbazepine, topiramate, or lamotrigine should be used. For newly diagnosed generalized seizures, treatment should be with an older AED or lamotrigine. Finally, the panel recommends either an older AED or topiramate for the treatment of refractory generalized epilepsy.

All new AEDs are indicated as adjunctive therapy for all seizure types. With the limited availability of randomized clinical trials, health care providers should consider these guidelines in addition to safety, tolerability, and cost for each individual patient.

References

• Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE Treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizure and syndromes. Epilepsia. 2006:47;1094-1120.
• Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3:618-621.
• Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. Curr Opin Neurol. 2006;19:175-180.
• French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I; treatment of new onset epilepsy. Neurology. 2004;62:1252-1260.
• French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy. Neurology. 2004;62:1261-1273.
• Annegers JF. The epidemiology of epilepsy. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001:131-138.
• Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349:1257-1266.