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Mortality Risk Found to be Reduced by Two-Thirds Following Epilepsy Surgery

ARTICLE IN BRIEF

New data from a large study underscore the need to refer patients with medically-refractory epilepsy for assessment for surgery at an epilepsy center — the risk of mortality was reduced by two-thirds in patients who underwent brain surgery compared with those who received medical treatment.

The risk of mortality is reduced by two-thirds in patients with medication-resistant epilepsy who undergo brain surgery compared with those who receive medical treatment, according to the largest study ever undertaken on the subject.

Although those whose seizures are entirely eliminated by surgery enjoy the greatest mortality benefit, even a simple reduction in seizure frequency confers a substantial risk reduction, according to a new study published in the April 27 online edition of Neurology.

The first author of the study told Neurology Today that he hopes the study will help to break through the resistance that patients and general neurologists alike have shown to obtaining specialist care for epilepsy uncontrolled by two medication trials. As recent studies have found, less than 1 percent of patients with drug-resistant epilepsy are currently referred to epilepsy centers, he said.

“I see many patients in the office who have had uncontrolled seizures for many years, sometimes for decades, and you really have to wonder why they hadn't been referred sooner,” said Michael R. Sperling, MD, FAAN, professor of neurology and director of the Jefferson Comprehensive Epilepsy Center at the Thomas Jefferson University Hospital in Philadelphia.

“We hope this will serve as a wake-up call to neurologists that there is a risk to not referring patients for surgery, said Dr. Sperling, who also serves as editor-in-chief of the journal Epilepsia. “The decision to persist in futile therapy is one with potentially fatal consequences.”

The results of the new study extend results Dr. Sperling reported in a smaller prospective cohort study he published in 2005.

Neurologists who specialize in epilepsy hailed the study's findings and said they underscore the need for non-specialists to follow AAN guidelines recommending that patients whose seizures are not fully controlled by medications be referred to an epilepsy center.

STUDY METHODOLOGY

The study examined death rates among 1,110 epilepsy patients treated at the Graduate Hospital and then the Jefferson Comprehensive Epilepsy Center in Philadelphia between 1986 and 2013, including 1,006 who had been treated surgically and 104 non-surgically. Deaths were ascertained through the epilepsy center database and the Social Security Death Index.

In all, 89 deaths were observed during the follow-up period. Surgically treated patients had a lower mortality rate (8.6 per 1,000 patient-years) than non-surgically treated patients — 25.3 per 1,000 patient-years; p<0.0010.

Following surgery, seizure-free patients had a lower mortality rate (5.2 per 1000 patient years) than non-seizure-free patients —10.4 per 1000 patient years; p=0.03. More frequent postoperative tonic-clonic seizures, more than two per year, were associated with increased mortality (p=0.006), whereas complex partial seizure frequency was not related to death rate. Mortality was not influenced by the surgical resection site, whether it was temporal or extra-temporal (p=0.7).

EXPERT COMMENTARY

“This paper is incredibly important,” said Steven Karceski, MD, assistant professor of neurology and director of clinical trials at the Weill Cornell Epilepsy Center. “It tells us that we can have a tremendous impact by getting these seizures under control. There has been too much complacency, and this study tells us that complacency has a very real cost.”

An accompanying editorial coauthored by Nathalie Jette, MD, of the University of Calgary and Jerome Engel, MD, PhD, of the University of California, Los Angeles, noted that despite surgery's high efficacy and cost effectiveness, no improvement in delays to referral have been observed since the AAN published a practice parameter in 2003 declaring surgery to be the treatment of choice for drug-resistant temporal lobe epilepsy.

The editorial noted, however, that despite its strengths, the study did have a few limitations. First, the cause of death was unknown in over half of the patients, precluding stratification into epilepsy-related versus non epilepsy-related causes.

Second, the editorial continued, “the surgical and the non-surgical group were not matched, with the non-surgical group having more severe epilepsy and more comorbidity, thus resulting in selection bias. In addition, the surgical group is ten times larger than the non-surgical group. Finally, the lack of risk adjustment for comorbidity is an important limitation, as a number of comorbidities are associated with mortality. There even exists a validated epilepsy-specific comorbidity risk adjustment index for mortality that could have been applied as part of the analysis.”

Lara Jehi, MD, research director and head of the outcomes research program at the Cleveland Clinic Epilepsy Center, said that while such limitations are valid, they do not call into question the study's conclusions or its importance to the field.

“This is the best study we have,” Dr. Jehi told Neurology Today. “To look at mortality in a thousand patients, that's a big effort. The value of this study is that it gives us the best possible information to look at mortality in patients who have had surgery versus those who have not. I will definitely be using this paper in conversations with patients.”

Dr. Jehi published an editorial last year in Neurology decrying the persistent gap between AAN guidelines and actual practice on when epilepsy patients should be referred for possible surgery.

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DR. MICHAEL R. SPERLING: “I see many patients in the office who have had uncontrolled seizures for many years, sometimes for decades, and you really have to wonder why they hadnt been referred sooner.”

“The current reality,” she wrote, “is that on average, adult patients who do get surgery have had intractable epilepsy for 20 years or more, and many who come for evaluation never knew they might be surgical candidates.”

In addition to a lack of access to epilepsy surgery — whether due to insurance coverage or geographic distance — Dr. Jehi described what she called a “knowledge gap” among neurologists. Her editorial cited a survey of Canadian neurologists, published in the same issue, which found that about half of them did not understand the definition of drug-resistant epilepsy or the recommendations for when to make a referral for possible surgery. (A patient for whom trials of two medications, over a period of a few years, fail to fully control seizures is considered medication-resistant and should be immediately referred to an epilepsy center, according to AAN guidelines.)

In interviews with Neurology Today, several other epileptologists struck a similar theme, emphasizing the need to remind neurologists or other referring physicians that patients with medically-refractory epilepsy stand to benefit from assessments for surgery at comprehensive epilepsy centers, which often offer psychosocial as well as clinical treatment options.

“Neurologists may feel, despite the publications, that surgery is not right for their patients, that it's too risky,” said Carl W. Bazil, MD, PhD, FAAN, professor of neurology and director of the division of epilepsy and sleep at Columbia University College of Physicians and Surgeons. “They may feel they can take care of it medically. But they owe it to their patients to tell them, ‘If you get your epilepsy cured by surgery, it decreases your chances of death.’ That's a really important message.”

“You may be able to identify individuals with medically-refractory epilepsy after the initial two or three antiepileptic medication trials,” said Gregory D. Cascino, MD, FAAN, Whitney Macmillan, Jr., professor of neuroscience and enterprise director of epilepsy at the Mayo Clinic in Rochester, MN.

“Some patients are not surgical candidates, and some will not even consider surgery. But they don't have the option if they're not referred to a comprehensive epilepsy center.”

EXPERTS: ON DATA SUPPORTING REFERRALS TO COMPREHENSIVE EPILEPSY CENTERS

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DR. STEVEN KARCESKI: “This paper is incredibly important. It tells us that we can have a tremendous impact by getting these seizures under control. There has been too much complacency, and this study tells us that complacency has a very real cost.”

Figure

DR. LARA JEHI: “This is the best study we have. To look at mortality in a thousand patients, thats a big effort. The value of this study is that it gives us the best possible information to look at mortality in patients who have had surgery versus those who have not. I will definitely be using this paper in conversations with patients.”

Figure

DR. CARL W. BAZIL: “Neurologists may feel, despite the publications, that surgery is not right for their patients, that its too risky. They may feel they can take care of it medically. But they owe it to their patients to tell them, ‘If you get your epilepsy cured by surgery, it decreases your chances of death.’ Thats a really important message.”

Figure

DR. GREGORY D. CASCINO: “You may be able to identify individuals with medically-refractory epilepsy after the initial two or three antiepileptic medication trials. Some patients are not surgical candidates, and some will not even consider surgery. But they dont have the option if theyre not referred to a comprehensive epilepsy center.”

LINK UP FOR MORE INFORMATION:

•. Sperling MR, Barshow S, Maromi N, et al.. A reappraisal of mortality after epilepsy surgery http://neurology.org/lookup/doi/10.1212/WNL.0000000000002700. Neurology 2016; Epub 2016 April 27.
    •. Jette N, Engel J. Lest we forget: Refractory epilepsy is a life-threatening disease http://neurology.org/lookup/doi/10.1212/WNL.0000000000002707. Neurology 2016: Epub 2016 April 27.
      •. Engel J, Wiebe S, French J, et al. Practice parameter: Temporal lobe and localized neocortical resections for epilepsy: Report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons http://www.ncbi.nlm.nih.gov/pubmed/12601090. Neurology 2003; 60:538–547.
        •. Sperling MR, Harris A, Nei M, Liporace JD, O'Connor MJ. Mortality after epilepsy surgery http://www.ncbi.nlm.nih.gov/pubmed/16393181. Epilepsia 2005; 46:49–53.
          •. Roberts JI, Hrazdil C, Wiebe S, et al. Neurologists' knowledge of and attitudes toward epilepsy surgery: a national survey http://www.ncbi.nlm.nih.gov/pubmed/25503624. Neurology 2015; 84:159–166.