Conference Coverage
Jacqueline A. French, MD
New Epilepsy Classification System
A patient’s epilepsy syndrome is the most important factor when choosing an AED, Dr. French said. According to a new epilepsy classification system published by the International League Against Epilepsy, generalized epilepsy may be further categorized as absence, myoclonic, atonic, tonic, and tonic–clonic. Focal epilepsy (formerly called partial epilepsy) may be categorized as focal aware (formerly simple partial), focal impaired awareness (formerly complex partial), and focal to bilateral tonic–clonic (formerly secondary generalized).
Combined generalized and focal epilepsy is a new category associated with epileptic encephalopathies, such as Dravet syndrome and Lennox-Gastaut syndrome. Finally, “seizures of unknown onset” describes cases where the clinician does not have enough information to determine whether the epilepsy is focal or generalized.
Narrow-spectrum drugs, including carbamazepine, oxcarbazepine, tiagabine, gabapentin, and pregabalin, should only be used in patients with focal epilepsy. “Narrow-spectrum drugs might make generalized seizures worse, or they fail to treat generalized seizures,” Dr. French said. “People with generalized epilepsy, generalized and focal epilepsy combined, or epilepsy of unknown onset should be on broad-spectrum agents—valproic acid, topiramate, lamotrigine, levetiracetam, zonisamide, and perampanel.”
Risk of Adverse Effects
“With any AED, the most common adverse events are dose-related,” Dr. French said. Some adverse events occur during titration and eventually resolve. Some drugs are associated with specific adverse events and therefore should be avoided in certain patient populations.
For instance, carbamazepine, oxcarbazepine, and eslicarbazepine may cause hyponatremia and should be given with caution to at-risk patients, such as the elderly. Likewise, drugs that may cause renal calculi, such as topiramate and zonisamide, should be given with caution to patients with that condition. Enzyme-inducing AEDs that increase cholesterol levels (eg, carbamazepine and phenytoin) should be avoided in patients with cardiovascular risk factors. For patients with weight problems or eating disorders, physicians should bear in mind that valproate, gabapentin, carbamazepine, pregabalin, ezogabine, and perampanel have been known to increase weight, while topiramate, zonisamide, and felbamate have been known to decrease weight.
AEDs that may worsen psychiatric function include levetiracetam, topiramate, zonisamide, tiagabine, phenobarbital, and perampanel. “Make sure that you ask patients when they are on levetiracetam whether they are experiencing increased irritability, although not everyone recognizes their mood changes,” Dr. French said. “Sometimes the spouse will complain, but the person will not.” On the other hand, carbamazepine, valproic acid, lamotrigine, and pregabalin have a tendency to improve psychiatric function—but not always. Psychiatric function “can go either way” with any of the AEDs, she said.
Some patients experience adverse drug effects as a result of add-on therapy. In some cases, a pharmacodynamic interaction between the new and old drugs may be responsible. Removing the add-on drug or the background drug may help. “Sometimes it is a better idea to take away the background drugs,” she said.
Older AEDs—carbamazepine, phenytoin, phenobarbital, and valproic acid—are associated with idiosyncratic adverse effects, including serious rash, liver failure, bone marrow failure, and pancreatitis. While some of the newer drugs also have such risks, the overall rate of idiosyncratic adverse reactions with their use is lower. Thus far, levetiracetam, brivaracetam, gabapentin, and pregabalin have not been associated with major idiosyncratic adverse effects, Dr. French noted.
Drug Initiation and Interactions
“The ability to initiate a drug rapidly is sometimes the driving characteristic that causes some doctors to pick one drug over another,” Dr. French said. Drugs that can be initiated at a therapeutic dose in a single day include phenytoin, levetiracetam, valproic acid, gabapentin, pregabalin, lacosamide, and brivaracetam. Other AEDs, such as carbamazepine, lamotrigine, perampanel, and oxcarbazepine, require gradual initiation over one to 10 weeks. Some drugs that take longer to initiate may be better tolerated overall, she said.
Generally, older AEDs are more likely to cause drug interactions, compared with newer drugs. Phenytoin, phenobarbital, and carbamazepine are enzyme inducers, which may cause problems for patients who are on statins. Valproic acid is a hepatic enzyme inhibitor, and phenytoin and valproic acid can have protein-binding interactions. Oral contraceptives reduce lamotrigine’s efficacy by doubling the clearance of the AED, Dr. French explained. “This can be problematic when women do not tell you when they are going on and off the contraceptive pill. They can have a breakthrough seizure, and it is only after the fact that you realize why that happened,” she said.
Interactions between oral contraceptive are common with other AEDs, as well. She cited a recent retrospective study involving 1,144 women with epilepsy ages 18 to 47 who provided demographic, epilepsy, AED, contraceptive, and pregnancy data. Survey results showed that 65% of their pregnancies were unintended. Oral forms of contraception had greater failure rates than nonoral forms, with intrauterine devices having the lowest failure rate.
—Adriene Marshall
Suggested Reading
Herzog AG, Mandle HB, Cahill KE, et al. Predictors of unintended pregnancy in women with epilepsy. Neurology. 2017;88(8):728-733.
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521.