PHILADELPHIA—An individual patient’s characteristics strongly influence the treatment strategy for newly diagnosed epilepsy, according to an overview presented at the 69th Annual Meeting of the American Epilepsy Society. Neurologists should consider the risks and benefits of treatment versus no treatment, as well as the risks and benefits of given medications. The patient’s age, gender, medical history (eg, history of serious medication-related rash), comorbidities (eg, overweight status), and genotype also may affect drug selection. Drug efficacy and side-effect profile are other necessary considerations, and a neurologist also should adjust the dose to fit the patient.
The literature contains little high-quality evidence that could guide the choice of therapy, however. A systematic review conducted by a task force of the International League Against Epilepsy (ILAE) identified approximately 70 randomized studies in adults, children, and elderly patients with focal epilepsy. Only six of these studies met Class I criteria. Similarly, of a large number of studies examining generalized epilepsies, only one study in participants with childhood absence epilepsy met Class I criteria, and the other studies were of low quality (Class III). “We really need better-quality studies, specifically for persons with generalized epilepsy,” said Emilio Perucca, MD, PhD, Professor of Pharmacology at the University of Pavia Medical School in Italy.
When Is Treatment Indicated?
The risk of seizure recurrence is the main consideration affecting the decision about whether to initiate treatment. Treatment initiation is usually indicated after the occurrence of two unprovoked seizures separated by more than 24 hours. In line with the ILAE’s 2014 clinical definition of epilepsy, treatment also may be justified after one unprovoked seizure and a probability of further seizures similar to the general recurrence risk (ie, at least 60%) after two unprovoked seizures, occurring over the next 10 years.
A 2006 study by Kim et al analyzed outcomes in more than 1,400 patients with single seizures and early epilepsy who were randomized to immediate or deferred treatment. Compared with deferred treatment, immediate treatment significantly reduced the risk of seizure recurrence for patients at high risk. For patients at low risk of seizure recurrence (eg, those with one generalized tonic-clonic seizure and no other evidence suggesting a special risk of seizure recurrence), immediate treatment did not significantly change outcomes, compared with deferred treatment. “It’s the risk of seizure recurrence that should drive our consideration of whether treatment is indicated or not,” said Dr. Perucca. A patient’s likelihood of achieving sustained seizure freedom is independent of whether treatment is initiated immediately or delayed, he added.
Which Is the Right Medicine?
If treatment is indicated, the neurologist should choose a medicine that is effective against the patient’s particular seizure type. Drugs such as carbamazepine, phenytoin, and oxcarbazepine treat focal epilepsy effectively. Some drugs selectively used to treat focal epilepsy also are effective against primary generalized tonic-clonic seizures, but they may aggravate myoclonic and absence seizures, particularly in patients with genetic (idiopathic) generalized epilepsies. Relatively broad-spectrum drugs such as lamotrigine, topiramate, and levetiracetam are efficacious against focal seizures and some generalized seizure types. The broad-spectrum drug with “unsurpassed efficacy against generalized seizures is valproate,” said Dr. Perucca.
If more than one therapy is effective against the seizure type, the neurologist should examine potential differences in their magnitudes of efficacy. A study from the 1980s suggests that carbamazepine and phenytoin are more effective than primidone and phenobarbital for the treatment of focal seizures. Phenobarbital, however, showed comparable effectiveness to carbamazepine and phenytoin against secondary generalized tonic-clonic seizures in the same study.
A subsequent investigation compared carbamazepine with valproic acid in patients with complex partial seizures. The drugs had comparable efficacy for the treatment of secondary generalized tonic-clonic seizures. For complex partial seizures, however, carbamazepine provided better control and was superior in four out of five efficacy end points that the researchers measured. Carbamazepine also had better long-term tolerability than valproate.
As newer antiepileptic drugs have been introduced, researchers have compared them with the first generation of medicines. Overall, none of the newer drugs have proven more effective against focal seizures than the older drugs. Most investigations used carbamazepine as the reference older-generation agent. Furthermore, researchers found clear signals that gabapentin and vigabatrin, two newer therapies, were less effective than carbamazepine.
The large, unblinded Standard and New Antiepileptic Drugs (SANAD) study compared carbamazepine with lamotrigine, oxcarbazepine, topiramate, and gabapentin in patients with focal seizures. Patients who received lamotrigine, carbamazepine, or oxcarbazepine had the best outcomes. Topiramate had inferior tolerability, and gabapentin had inferior seizure control.
Among patients with newly diagnosed focal epilepsy with onset in old age, however, lamotrigine and gabapentin are superior to carbamazepine, according to a double-blind study. Carbamazepine had poor tolerability in this population, “and we know that the elderly are more susceptible to side effects,” said Dr. Perucca. A similar double-blind study found that levetiracetam was superior to carbamazepine in elderly patients, again because of tolerability.