The following reports are based on a symposium held in Denver at the 54th Annual Meeting of the American Academy of Neurology.

Data from large, prospective clinical trials can guide physicians in initiating and discontinuing antiepileptic drugs (AEDs) in children and adults who present with seizures. In general, AEDs are initiated once the risks of seizure recurrence outweigh treatment risks; in a seizure-free patient, AEDs are withdrawn after the risks of treatment continuation outweigh the risks of further seizures. However, physicians face neurologic, psychologic, and legal ramifications in making these decisions, according to Joseph I. Sirven, MD, Director of the Epilepsy Center at the Mayo Clinic in Scottsdale, Arizona.

To determine when to initiate medication, Dr. Sirven said that “the goal is to choose an action to deliver an outcome the patient finds desirable. Physicians estimate the risk of seizures versus the risk of starting a medication, and then the patient compares the risks of each and chooses the desirable risk.” The best treatment is individualized, with the patient (whenever possible) agreeing to the decision. “The patient makes the ultimate choice—you present options,” Dr. Sirven remarked.

INITIATION OF AEDs IN ADULTS

Before initiating AEDs in adults, physicians should first consider risks related to untreated seizures, Dr. Sirven advised. Generalized tonic clonic seizures are most likely to be associated with increased rates of sudden death in epilepsy, and suicide resulting from comorbid depression can also occur. Head injuries, fractures, and burns can result from seizures in adults with epilepsy, as can motor vehicle accidents. Laboratory and imaging studies and neurologic testing suggest that seizures—particularly status epilepticus—cause brain injury and secondary epileptogenesis, although clinical relevance has not yet been determined. Other seizure-related risks are psychosocial—employment discrimination, lower marriage rates, concerns about participating in leisure activities and sports, and comorbid mood disorders.

Medication-related risks are another factor to consider. “A risk of serious reaction to medication is about 1 in 30,000, and 15% will have a reaction to medication sufficient to warrant discontinuation,” he said. “There is the possibility of teratogenicity, and then, of course, just because you take a medication does not make it effective.”

Risk of recurrence after a first seizure is approximately 30%, although findings have ranged from 16% to 61%. Indications for treatment after a first seizure include abnormal EEG, structural lesions related to stroke or tumor, generalized tonic-clonic seizures, occupational risk, and status epilepticus. Dr. Sirven noted that individuals who are experiencing alcohol withdrawal or drug abuse or who have an acute illness, low sodium or calcium, or a postimpact seizure should not be treated after a first seizure. Other exceptions include patients with seizures caused by benign epilepsy syndromes or those who have excessive sleep deprivation.

After two seizures, the risk of recurrence is approximately 80% to 90%. “Almost all patients should be treated at that point,” said Dr. Sirven. “The problem is, when do you define two seizures? If they had it a year ago and then another one this year, is that enough? Those are questions we don’t know clearly from the issue of space and timing of those seizures. But the recurrence risk based on these population studies is believed to be very high.” Those with simple, partial, or widely spaced seizures may not need to be treated, he added.

Dr. Sirven also addressed whether patients should be treated for seizure prevention or prophylaxis—ie, prior to neurosurgical procedures or after the diagnosis of a tumor, stroke, trauma, or subarachnoid hemorrhage. “It’s clear that in posttraumatic epilepsy, there may be a role in preventing seizures if they have had [prior] seizures but not in prophylaxing against epilepsy,” he said. Initiating an AED as prophylaxis against epileptogenesis is also not likely to help.

INITIATION OF AEDs IN CHILDREN

Dennis J. Dlugos, MD, Assistant Professor of Neurology at the Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, said that a key point to remember in initiating AEDs in children is that “the decision-making process is very different from an adult, partly because children don’t drive but also because children’s brains are different.”

The accepted definition of epilepsy in children is two or more unprovoked seizures. An unprovoked seizure is one that has no immediate precipitant, such as fever, acute head trauma, or central nervous system infection, and is categorized as either remote symptomatic or cryptogenic/idiopathic, although a new classification has been proposed that would replace cryptogenic with “probably symptomatic.”

“Typically, remote symptomatic seizures are the consequence of a history of an infection, a stroke, hypoxic ischemic encephalopathy, or head trauma,” as well as significant static encephalopathy or lesions on neuroimaging, Dr. Dlugos said. Cryptogenic seizures are those with no known etiology, whereas “idiopathic seizures have a clear or suspected genetic etiology, such as childhood absence epilepsy or juvenile myoclonic epilepsy,” he said. Children with cryptogenic/idiopathic seizures “almost always have normal neuroimaging and are otherwise well.”

THE FIRST UNPROVOKED SEIZURE

A valuable, prospective cohort study of 407 children enrolled after a first unprovoked seizure (or cluster of seizures within 24 hours), was conducted by Shlomo Shinnar, MD, PhD, and colleagues at Montefiore Medical Center, Albert Einstein College of Medicine, in the Bronx, New York. The study found that 182 children (45%) had a second seizure within 10 years, with the second seizure usually occurring within two years. Children ranged in age from one month to 19 years and were followed for a mean of 9.6 years. Cumulative risk of second seizure was 29% for the first year, 37% at two years, 43% at five years, and 45% at 10 years. Cumulative risk of a third seizure was 57% at one year, 63% at two years, and 72% at five years. Dr. Dlugos urged cautious interpretation of data regarding risk of a third seizure, however, noting that after their second seizure, 44% of children were treated with AEDs.

Nearly 40% of children whose first seizure was cryptogenic/idiopathic had a second seizure, compared with 72% of those whose first seizure was remote symptomatic. Risk factors for recurrence of a cryptogenic/idiopathic seizure were abnormal EEG and first seizure while asleep and, for remote symptomatic seizure, prior febrile seizure or age younger than 3.

Half of the 48 children who presented with status epilepticus had a second seizure, with 21% having recurrent status epilepticus. However, if the first seizure was not status epilepticus, the risk of recurrent status epilepticus was 1%. For the entire cohort, risk factors for seizure recurrence were remote symptomatic etiology, abnormal EEG, having a first seizure while asleep or a prior febrile seizure, and Todd’s paresis.

“The most favorable group from this cohort—with a five-year recurrence risk of 21%—was children with a cryptogenic/idiopathic etiology, a first seizure while awake, and a normal EEG,” Dr. Dlugos said. “The least favorable group—with a two-year recurrence rate of more than 90%—was children with remote symptomatic etiology and a first seizure before age 3.”

AEDs AND FIRST SEIZURE

Regarding treatment efficacy after a first partial seizure, a trial of 31 children in Nova Scotia, conducted by Peter Camfield, MD, and colleagues in the Department of Pediatrics at Dalhousie Medical School, Halifax, found that of 14 children treated with carbamazepine, 43% were seizure-free for one year with acceptable side effects, whereas 29% stopped the drug because of side effects. Of the 17 untreated children, 41% were seizure-free for one year, Dr. Dlugos said.

In a trial of 419 children older than 2 with a first unprovoked tonic clonic seizure, 215 were treated with AEDs and 24% had a recurrence within two years. Of the 204 not treated, 42% had a recurrence in two years. Despite this difference, long-term outcome between the groups was similar, he added.

As for when to start daily AEDs following a first seizure in a child, Dr. Dlugos responded, “Almost never. The risk of recurrence is all over the map, 20% to 95%, and you can tease out in your individual patients where they fit, but nobody is guaranteed to have a recurrence, and it is impossible to judge seizure frequency after one seizure.” Furthermore, he noted that seizures may recur, “but it could be a year, two years, five years. Do you really want to start a daily medicine even if the risk of recurrence is high but the next seizure might not be coming for months or years? I say no.”

Dr. Dlugos noted one possible exception—children younger than 3 with a remote symptomatic etiology whose first seizure is status epilepticus. “That’s scary,” he said. “It’s pretty tough to send the parents home after a bout of nocturnal, unprovoked status with nothing. But you don’t necessarily have to start daily AEDs. You could consider prescribing rectal diazepam.”

AEDs AND MULTIPLE SEIZURES

Dr. Dlugos stated that AEDs should not always be administered after two seizures either. “Remember, a third seizure is not guaranteed, and it could be months to years. No AED is totally benign.” Factors to consider include etiology, seizure type, duration, and frequency; psychosocial issues; and patient/parent preference. “How anxious is the child about it? Did the seizure happen in school? Is he or she afraid of having a seizure in the cafeteria, having a seizure at the prom? Sometimes those things sway you,” he said. “Again, you can consider prescribing rectal diazepam to prevent recurrent prolonged seizures.”

After three seizures, Dr. Dlugos said treatment will “often but not always” be initiated. “With time, the decision to treat or not to treat will become clear. In many cases, there’s no rush.” Although daily AEDs may not be needed, “if you’re not going to treat after three or more seizures, make sure the parents are on board, make sure the child’s on board, and document why you did it,” he advised.

DISCONTINUING AEDs

David Chadwick, MD, affiliated with the Walton Centre for Neurology and Neurosurgery in Liverpool, United Kingdom, addressed the topic of discontinuation of AEDs in adults and children. “By and large, physicians are very keen on starting therapy. They tend not to study stopping therapy quite so enthusiastically for reasons that are not entirely clear,” he said.

Studies have shown that approximately 70% of patients diagnosed and treated for epilepsy will achieve long-term remission once AEDs are withdrawn, he said. Determining at what point treatment withdrawal should be recommended and how to withdraw treatment remain critical issues and can be the most difficult aspects of decision making.

The Medical Research Council Antiepileptic Drug Withdrawal Study found “the most influential prognostic factor for recurrence was the period of time [that a patient was] seizure free,” Dr. Chadwick said. Patients rated the best outcome as being off AEDs and not having seizures. However, patients were as unhappy about continuing to have seizures as they were to remain on AEDs. “That’s telling us something about the role of antiepileptic drugs in the stigma associated with epilepsy,” Dr. Chadwick said. Patients who were seizure free for a median of three years and continued to take medication had an annual seizure risk of 10%.

TEENAGE TAMPERING?

Based on the Medical Research Council study, discontinuation of AEDs “anytime after two years seems quite reasonable,” Dr. Chadwick said.“Pediatricians are much more aggressive than adult physicians, and they like to start thinking about stopping treatment over shorter periods of time [eg, after one year]. It’s perfectly reasonable to taper treatment off over a two- to three-month period.”

Although the decision to withdraw treatment has to be made by the patient (or his or her family), Dr. Chadwick made a plea for as many children as possible to be withdrawn from AEDs, especially before they start driving. “If you have adolescents who are 14, 15, 16, and they are doing well and they are seizure-free, taper them even if they are nervous. Tell them, ‘There will never be an easier time in your life to taper. If you don’t do it now, you’re going to be trapped on medicine you may not need.’”

Return to table of contents