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WASHINGTON -- When an adult with no seizure history has one that can't be attributed to a definite cause such as head trauma or hypoglycemia, the situation "poses difficult diagnostic and treatment questions," according to a new joint guideline from the American Academy of Neurology (AAN) and the American Epilepsy Society (AES).

But moderately credible evidence (Level B) suggests that initiating anti-epileptic drug treatment reduces the risk of a second seizure in the next 2 years, the guideline authors stated, although it may not improve quality of life and appears not to provide long-term (greater than 3 years) remission from seizures.

The guideline was released here at the and published in the April 21 issue of its journal, . AES members will also find it on that group's website and in the May/June issue of its publication. The guideline has been endorsed as well by the and the .

Led by , of the University of Maryland School of Medicine in Baltimore, and , of NYU Langone Medical Center in New York City, the guideline authors found strong (Level A) evidence that a first unprovoked seizure carries clinically significant risk of a second seizure within 2 years, in the range of 21% to 45%. About half of individuals experience a recurrent seizure at some point, the literature indicates.

At an AAN press briefing on the new guideline, French said the groups' hope is that the guideline will educate physicians who currently don't consider treating first unprovoked seizures.

"Many [clinicians] have been trained that a single seizure is not epilepsy and should not be treated," she said, noting that a consensus has now emerged that "a single seizure can indeed by epilepsy."

At the same time, however, she and Krumholz agreed that treating the first seizure is not always appropriate, but rather depends heavily on a patient's tolerance of adverse effect risk and the importance to that patient of avoiding a second seizure.

Overall, about 10% of adults experience a seizure at some point during their lives, including those with known triggers; some 4% of all adults experience two or more unprovoked seizures, qualifying them for a diagnosis of epilepsy. Krumholz estimated that about 150,000 adults experience a first unprovoked seizure in the U.S. each year.

Factors increasing risk of recurrence include a history (not necessarily recent) of stroke or head trauma, seizure occurring during sleep, EEG recordings with epileptiform patterns, and abnormalities in brain imaging.

Data from five studies of drug therapy started immediately after a first unprovoked seizure suggest that it reduces the 2-year risk of recurrence by 35% (95% CI 23%-46%), Krumholz and colleagues calculated.

Only one of those studies evaluated quality of life, though, and it found no difference between those treated immediately and those with delayed or no treatment. But Krumholz and colleagues noted that the question of driving, a major quality-of-life issue for many adult patients, has not been addressed in most studies. The sole study to make mention of it found that patients treated immediately were more likely to retain driving privileges.

Also, the authors identified only two studies examining effects of immediate anti-epileptic drug (AED) therapy on long-term recurrence, neither of which showed a clear benefit. "Immediate AED treatment as compared with treatment delayed until a second seizure occurs is unlikely to improve the chance of attaining sustained seizure remission over the longer term (>3 years)," they concluded.

Importantly, the guideline did not recommend any specific agent for first seizures or discuss efficacy differences between the many available drugs for this indication.

With respect to safety, Krumholz and colleagues also did not seek to distinguish between particular drugs, but they noted that adverse effects with all of them are common. "Patients should be advised that their risk for AED adverse effects ranges from 7% to 31% (Level B) and that these adverse effects are predominantly mild and reversible," they wrote.

Also not included in the guideline was detailed information on the diagnostic workup necessary to establish that a first unprovoked seizure is in fact that. Many "first" seizures turn out, when a detailed history is obtained, to actually have been a patient's second or third or fourth, and the question of whether a seizure was provoked (generally defined as triggered by an acute event within the past week) typically involves EEG and imaging studies. Krumholz said a covered much of the needed diagnostic work.

The guideline did recommend avenues for future research. These include prospective studies to examine specific interventions (including counseling) with endpoints including quality of life. Also needed are more data on recurrence risks and the extent to which treatments affect them to create more accurate models that can be tailored to individual patients.

Krumholz and colleagues called as well for more studies of adverse effects associated with AEDs in the first-unprovoked-seizure population, with special attention to newer agents for which the side-effect profiles are less well established.

Finally, the authors indicated that future research should examine discontinuation of drug therapy in patients with long-term freedom from recurrence. "It is important for patients to appreciate how long they may need to be on an AED once it has been started and the risks of AED discontinuation, as this type of information may help guide a patient's decision-making about AED initiation," the authors noted.

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