New AAN/AES Guideline on First Unprovoked Seizure in Adults

Pauline Anderson

April 20, 2015

The American Academy of Neurology (AAN) and the American Epilepsy Society (AES) have released a new guideline on the prognosis and treatment of first unprovoked seizures.

The guideline "is not a simple black and white recommendation," said first author Alan Krumholtz, MD, professor of neurology, University of Maryland School of Medicine and director of the Veterans Affairs Epilepsy Center of Excellence for the Northeast Region and the Maryland Health Care System, Baltimore.

It's very important, said Dr Krumholtz, that physicians work with patients who have experienced a first unprovoked seizure to see what treatment approach is best for them.

"Clinicians should weigh individualized seizure recurrence risk against the benefits regarding the adverse effects of AEDs [antiepileptic drugs] and consider informed and educated patient preferences."

Another author of the guideline, Jacqueline French, MD, professor, Department of Neurology and co-director of the Epilepsy Research and Epilepsy Clinical Trials at the New York University Comprehensive Epilepsy Center, agreed that it's important not to have "a knee jerk reaction one way or the other — to treat or not treat," following a first unprovoked seizure.

Adults with an unprovoked first seizure are at 21% to 45% greater risk for a recurrence within 2 years, with this risk being especially high during the first year, the guideline notes.

Factors associated with this increased risk for recurrence include a prior stroke or other brain insult, an electroencephalogram (EEG) with an epileptiform abnormality, a significant brain-imaging abnormality, and a nocturnal seizure. The risk appears to be lower for patients treated immediately with AED).

The new evidence-based guideline was published online April 20 in Neurology, and released here at the American Academy of Neurology (AAN) 67th Annual Meeting.

To Treat or Not to Treat

Neurologists have been grappling with whether to treat a first unprovoked seizure or wait until a patient experiences a second seizure. They and their patients have to balance the possible ramifications of being diagnosed with a seizure condition, including not being able drive or work, with the risk of sustaining another seizure, which could lead to physical or neurologic injury, even death.

Members of the guideline authors carried out a literature review, identified and rated 47 relevant articles, and linked recommendations to evidence strength based primarily on studies rated class I or II.

They classified unprovoked seizures into two broad categories: a seizure of unknown etiology or a seizure in relation to a demonstrated pre-existing brain legion or progressive central nervous system disorder. They identified two prognostic class I and 8 prognostic class II studies addressing the probability than an adult with an unprovoked first seizure would have recurrent seizure.

The analysis showed that the cumulative incidence of seizure recurrence increases over time, with most occurring within the first 1 to 2 years after the initial seizure and the greatest risk in the first year — for example 32% at 1 year and just 46% by 5 years.

The risk for seizure recurrence about doubles under certain circumstances. For example, a prior brain insult such as a seizure was associated with an increased relative rate of seizure recurrence at 1 to 5 years of 2.55 (95% confidence interval [CI], 1.44 - 4.51) compared with that in patients with seizures of unknown cause.

Strong evidence also suggests that having an EEG showing signs of epilepsy is associated with increased risk. The relative rate increase for seizure recurrence at 1 to 5 years was 2.16 (95% CI, 1.07 - 4.38) compared with patients without such EEG abnormalities.

There was moderate evidence for other factors increasing the recurrence risk. Having abnormal brain imaging results had a hazard ratio at 1 to 4 years of 2.44 (95% CI, 1.09 - 5.44) compared with not having imaging abnormalities. And having a nocturnal seizure had an odds ratio at 1 to 4 years of 2.1 (95% CI, 1.0 - 4.3) compared with a seizure while awake.

"If the seizure has a focal onset, that already says that there may be some faulty wiring, so if you don't see any focal onset; the EEG is completely normal; and the MRI is completely normal, in those situations the likelihood of a recurrent seizure goes down to about 20% or 25%," Dr French told Medscape Medical News.

Many people would accept that 25% risk but others would consider it too high, she said. She pointed out that if a patient decides to start medication, and comes off that medication later, they might still face that 25% risk.

However, she pointed out that mediations today are less "toxic" than they were in the past. "It used to be a really big decision to go on a medication; now, the good news is that we have medications that are really well tolerated."

But unfortunately these newer medications still don't change the underlying disease. "They treat the symptoms, which in many cases is just as good. If you can take a pill every day and not have seizures."

The review found moderate evidence that immediate treatment can lower the risk for another seizure within the first 2 years after a first unprovoked seizure.

There was an absolute risk reduction in seizure recurrence of 35% (95% CI, 23% - 46%) for immediate vs delayed AED treatment in pooled 2-year data in adults presenting with an unprovoked first seizure.

Long-Term Prognosis

As for seizure remission over the longer term — over 3 years — the review showed that compared with delaying treatment until a second seizure occurs, immediate AED treatment is unlikely to improve the chance of attaining sustained seizure remission.

While seizure recurrence can cause such serious psychological and social consequences as loss of driving privileges and limitations on employment, one controlled class II study comparing immediate AED treatment with treatment deferred until after a seizure recurrence found no significant difference in standard 2-year quality-of-life measures.

The new guideline comes at a time when the current standard definition of epilepsy is changing. The International League Against Epilepsy has proposed the definition be expanded to encompass people with an unprovoked seizure and at least a 60% risk for seizure recurrence over the next 10 years.

"It used to be that you needed to have two seizures to have epilepsy," said Dr French. "Many clinicians have been trained that a single seizure is not epilepsy and therefore should not be treated."

According to the guideline, the incidence of adverse events from AEDs in adults initially treated with a single AED for an unprovoked first seizure is reportedly 7% to 31%. The adverse events appear to be mild and many are reversible when doses are lowered or patients are switched to another AED. At the time of the studies, AEDs included phenytoin, phenobarbital, carbamazepine, valproic acid, and lamotrigine.

The authors pointed out that the newer AEDs may have fewer and different adverse events.

They stressed the importance of patients appreciating how long they may need to be receiving an AED and the risks of AED discontinuation.

The guideline was endorsed by the American Neurological Association and the World Federation of Neurology. A 2007 practice guideline addressed the evaluation of an unprovoked first seizure in adults.

Because neurologists are not always the first clinicians to see patients following a first unprovoked seizure, the new guideline "needs to be promoted and available to all physicians," including primary care and emergency department doctors, said Dr Krumboltz.

Dr French stressed that a first seizure may not be a convulsion but could be small spells of confusion or strong feelings of déjà vu that can often be missed. She told the story of a 50-year-old women presenting with confusion and feelings of déjà vu. She was sent to an internist, a psychiatrist, and finally a neurologist before MRI found a brain tumor.

An estimated 150,000 adults present annually with an unprovoked first seizure in the United States.

Asked for a comment, Amy Brooks-Kayal, MD, president of the AES, professor of pediatrics, neurology, and pharmacological sciences, and chief of the Division of Neurology, Children's Hospital Colorado, took issue with the term AEDs. She said medications given to patients with epilepsy should be called antiseizure rather than antiepileptic medications.

"They don't fundamentally change epilepsy or the underlying cause," she told Medscape Medical News. Although the newer medicines are better in terms of the risk for neurocognitive side adverse events "fundamentally they don't change the percentage of people who don't respond to medical therapy which unfortunately remains at least 30%."

A "great need" in the field of epilepsy is the development of disease-modifying therapies, said Dr Brooks-Kayal.

This guideline was developed with financial support from the American Academy of Neurology. A complete list of financial disclosures is available with the original article.

Neurology. Published online April 22, 2015. Abstract

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