Surgical Treatment for Epilepsy: Too Little, Too Late?

Jerome Engel, Jr
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current as of December 2, 2008.

JAMA. 2008;300(21):2548-2550 (doi:10.1001/jama.2008.756)

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EDITORIAL

Editorials represent the opinions

of the authors and JAMA and
not those of the American Medical Association.

Surgical Treatment for Epilepsy

Too Little, Too Late?
Jerome Engel Jr, MD, PhD

PILEPSY IS ONE OF THE MOST COMMON SERIOUS NEU-

rological conditions. According to a study by the

World Health Organization, epilepsy accounts for 1%
of the global burden of disease based on disabilityadjusted life-years (DALYs), productive years lost due to disability or premature death.1 This is equivalent to lung cancer in men and breast cancer in women. Among primary
disorders of the brain, epilepsy ranks with depression and
other affective disorders, Alzheimer disease and other dementias, and substance abuse. Of the worlds population,
0.5% to 1.0% has active epilepsy, and pharmacotherapy is
unsuccessful in controlling seizures in 20% to 40% of patients.2 In the United States, 80% of the cost of epilepsy is
attributable to patients with medically intractable seizures.3 Temporal lobe epilepsy is the most common cause
of pharmacoresistant seizures4 and may constitute half or
more of the patients in the United States with medically intractable epilepsy.5 On the other hand, temporal lobe epilepsy is the form of epilepsy most easily and effectively treated
with surgery; 60% to 90% of patients can expect to become
free of disabling seizures postoperatively.6-8 Appropriately
applied surgical treatment, therefore, is crucial for reducing the health burden represented by epilepsy.
Surgical treatment for epilepsy, however, is arguably
the most underused of all effective therapeutic interventions. It is estimated that more than 100 000 patients in
the United States with temporal lobe epilepsy may be
candidates for surgical treatment, although fewer than
2000 received therapeutic surgical resections in 1990.9 A
2001 Western Ontario randomized controlled trial
involving patients with temporal lobe epilepsy confirmed
many published surgical series findings that surgical
treatment is more likely to eliminate disabling seizures
and improve quality of life than pharmacotherapy.8 As a
result of this finding and a literature review, the American Academy of Neurology issued a practice parameter in
2003 recommending surgery as the treatment of choice
for medically intractable temporal lobe epilepsy.7
Although no evidence exists to substantiate whether the
Western Ontario trial and the American Academy of NeuSee also pp 2497 and 2527 and Patient Page.
2548

JAMA, December 3, 2008Vol 300, No. 21 (Reprinted)

rology practice parameter has increased surgical treatment

for temporal lobe epilepsy in the United States, unpublished data from the National Association of Epilepsy Centers indicate that the number of anterior temporal resection for epilepsy performed in the United States is not
appreciably greater in 2008 than it was in 1990 (Robert J.
Gumnit, MD, president, National Association of Epilepsy
Centers, written communication, November 2, 2008). Furthermore, those who eventually undergo surgery are not referred until an average of 22 years after onset.10 Not only
are most surgical candidates never referred for surgery but
those who are often undergo surgery too late to prevent irreversible disabling psychological and social consequences
of epilepsy.11 In theory, for many of these patients early surgical intervention could prevent a lifetime of disability, as
well as premature death.12
A clinical trial to establish the putative positive effect of
surgical intervention on the mortality rate associated with
medically intractable temporal lobe epilepsy would require following up a large population of patients for many
years, making such a trial prohibitively expensive. Consequently, Choi and colleagues13 used a decision analytic model
to quantitatively predict survival following surgical therapy
compared with continued medical management of patients
with temporal lobe epilepsy and report their results in this
issue of JAMA. Their data indicate that for a 35-year-old patient, surgical therapy would be associated with an increase in life expectancy of 5.0 years and 7.5 in qualityadjusted life-years. These results should provide a further
incentive for physicians to refer potential surgical candidates to epilepsy surgery centers but most likely underestimate the benefit, given that the authors chose age 35 years
for their analysis based on the current practice of performing surgery more than 20 years after the onset of epilepsy.
The authors also acknowledge that a major limitation in their
model is the lack of data on the natural history of pharmacoresistant temporal lobe epilepsy. This knowledge deficit
could also account for the fact that surgical treatment is still
practiced too little and too late.
Author Affiliations: Departments of Neurology, Neurobiology, and Psychiatry and
Biobehavioral Sciences, and the Brain Research Institute, David Geffen School of
Medicine at University of California, Los Angeles.
Corresponding Author: Jerome Engel Jr, MD, PhD, Department of Neurology, David
Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 900951769 (engel@ucla.edu).

2008 American Medical Association. All rights reserved.

Downloaded from www.jama.com at Columbia University on December 2, 2008

EDITORIAL

The inability to reliably identify medical intractability early

in the course of temporal lobe epilepsy is perhaps the major reason for the long delay in patient referral to epilepsy
surgery centers. With the introduction of many new antiepileptic drugs over the past 2 decades, it appears that the
duration between epilepsy onset and referral for surgical
treatment may have actually increased; in 1986, only 12.5%
of patients who had undergone temporal lobe surgery at the
University of California-Los Angeles Center for Health Sciences had epilepsy for more than 20 years.14 It would now
be impractical to prove that any given patient with epilepsy has seizures that are refractory to all available medications in every possible combination. The concept of medically intractable epilepsy, therefore, no longer has practical
meaning for the clinician and has been replaced by the concept of surgically remediable epilepsy syndromes.15 Temporal lobe epilepsy is the prototype of a surgically remediable epilepsy syndrome, a condition with a well-defined
pathophysiology and anatomical substrate, a known poor
response to medical therapy, and an excellent response
to a standardized surgical intervention based on noninvasive evaluation. Early surgical intervention for these syndromes offers the best opportunity to prevent the development of irreversible disabling psychological and social
consequences of recurrent seizures and premature death.
The remaining obstacle to effective early application of
surgical therapy for temporal lobe epilepsy, therefore, is insufficient information regarding the natural history of this
disorder to permit reliable early prediction of continued pharmacoresistance in individual patients. Although one study
has suggested that less than 3% of patients with epilepsy will
ultimately become seizure free after 2 trials of antiepileptic
drugs have failed due to inefficacy and not intolerance,16 others have since documented up to a 15% to 20% response to
continued pharmacotherapy in this population.17-20 A large
multicenter observational study would be needed to determine the actual percentage of patients with temporal lobe
epilepsy who will remain pharmacoresistant after failure of
2 antiepileptic drugs and to identify factors that could reliably predict persistent pharmacoresistance.
In the meantime, given the complexity of issues
involved in the consideration of referral for epilepsy surgery, the uncertainty of the persistence of pharmacoresistance and the critical importance of early intervention,
what are primary care physicians and general neurologists
to do? It is perhaps simpler to put thoughts of surgical
therapy aside initially and begin by distinguishing relatively benign epilepsies from serious epilepsies. The
former are easily treated with the first 1 or 2 antiepileptic
drugs tried, resulting in no disabling seizures and no
adverse effects. The more serious epilepsies are those in
which epileptic seizures or adverse effects continue and
compromise work, school, interpersonal relationships, or
quality of life, despite adequate trials of a few appropriate
antiepileptic drugs at maximum tolerable doses. Ideally,
2008 American Medical Association. All rights reserved.

such patients should be referred for second opinions to

epilepsy centers, where epilepsy specialists would then
evaluate the surgical therapy option.
Referral to an epilepsy center, particularly if early surgical therapy might be appropriate, is most important for patients with surgically remediable syndromes such as temporal lobe epilepsy, as well as those with focal seizures due
to localized resectable neocortical lesions, and infants and
young children with severe epilepsies caused by more diffuse lesions that are limited to 1 hemisphere. In most cases,
these diagnoses can be suspected based on magnetic resonance imaging scans and seizure semiology, even when interictal electroencephalographic abnormalities are inconsistent. Early in the course of temporal lobe epilepsy,
however, the magnetic resonance imaging scan results can
be normal and more detailed testing at an epilepsy center
including long-term video-electroencephalographic monitoring, positron emission tomography, ictal single-photon
emission computed tomography, magnetoencephalography, magnetic resonance spectroscopy, and occasionally intracranial recordingmay be necessary to determine whether
an anteromesial temporal resection would most likely render a patient free of disabling seizures.
Patients with medically refractory epilepsy who do not
meet criteria for diagnosis of a surgically remediable syndrome, as defined herein, might still benefit from surgical
therapy. For these patients, the presurgical evaluation almost always requires intracranial monitoring, which increases the risk and cost, while the likelihood of a seizurefree result can be only 50% or less.21 The decision to proceed
with surgery in this situation can be difficult, as illustrated
by the Clinical Crossroads discussion by Schomer and Black,22
also published in this issue of JAMA. One of the authors
recommendations for this patient is vagus nerve stimulation, given the patients lack of a focal lesion and the potential risks of surgery. Although vagus nerve stimulation
can reduce seizure frequency and severity, it rarely results
in seizure freedom. Further testing would be indicated to
better determine the patients actual risk from a resective
procedure, which could offer a much greater chance of a
seizure-free outcome. Ultimately, the patient will need to
decide whether the risks are worth the possible benefits, a
significant challenge in the face of limited data.
Surgical treatment for epilepsy remains underused, and
when surgery is performed, it is often delayed until it is
too late to reverse associated severe disabilities. The study
by Choi et al13 underscores, but most likely underestimates, the benefits of surgical therapy for temporal lobe
epilepsy. More information is needed to better understand
the natural history of intractable temporal lobe epilepsy
and to identify factors that reliably predict which patients
will continue to have persistent seizures and thereby
enable an accurate prediction of surgical benefit early in
the course of antiepileptic drug treatment, before the disabling psychological and social consequences of recurrent
(Reprinted) JAMA, December 3, 2008Vol 300, No. 21

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2549

EDITORIAL

seizures become irreversible. In the meantime, however,

the best approach to facilitate early surgical treatment,
when appropriate, would be for primary care physicians
and general neurologists to refer patients who continue to
have disabling seizures after a few antiepileptic drugs have
failed to an epilepsy center for additional evaluation. Epileptologists at these centers are specifically trained to carry
out the testing necessary to determine whether early surgical therapy is a viable option.
Financial Disclosures: Dr Engel reports that he has received honoraria for lectures, participation on advisory panels, or both from Cyberonic, Dainippon,
Eisai, Elan, Johnson & Johnson, Neuropace, Novartis, Pfizer, UCB Pharma, and
Valiant.
REFERENCES
1. Murray GJ, Lopez AD. Global Comparative Assessments in the Health Sector:
Disease Burden, Expenditure, Intervention Packages. Geneva, Switzerland: World
Health Organization; 1994.
2. Berg AT. Understanding the delay before epilepsy surgery: who develops intractable focal epilepsy and when? CNS Spectr. 2004;9(2):136-144.
3. Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United
States: an estimate from population-based clinical and survey data. Epilepsia. 2000;
41(3):342-351.
4. Semah F, Picot M-C, Adam C, et al. Is the underlying cause of epilepsy a major
prognostic factor for recurrence? Neurology. 1998;51(5):1256-1262.
5. Engel J Jr. Etiology as a risk factor for medically refractory epilepsy: a case for
early surgical intervention. Neurology. 1998;51(5):1243-1244.
6. Engel J Jr, Van Ness P, Rasmussen TB, Ojemann LM. Outcome with respect to
epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. 2nd ed.
New York, NY: Raven Press; 1993:609-621.
7. Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology. 2003;60(4):538-547.

2550 JAMA, December 3, 2008Vol 300, No. 21 (Reprinted)

8. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of

surgery for temporal lobe epilepsy. N Engl J Med. 2001;345(5):311-318.
9. Engel J Jr, Shewmon DA. Overview: who should be considered a surgical
candidate? In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. 2nd ed. New
York, NY: Raven Press; 1993:23-34.
10. Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsy
to become intractable? Neurology. 2003;60(2):186-190.
11. Engel J Jr. Finally, a randomized controlled trial of epilepsy surgery. N Engl J
Med. 2001;345(5):365-367.
12. Sperling MR. The consequences of uncontrolled epilepsy. CNS Spectr. 2004;
9(2):98-109.
13. Choi H, Sell RL, Lenert L, et al. Epilepsy surgery for pharmacoresistant temporal lobe epilepsy: a decision analysis. JAMA. 2008;300(21):2497-2505.
14. Engel J Jr, Cahan L. Potential relevance of kindling to human partial epilepsy.
In: Wada J, ed. Kindling 3. New York, NY: Raven Press; 1986:37-51.
15. Engel J Jr. Current concepts: surgery for seizures. N Engl J Med. 1996;
334(10):647-652.
16. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med.
2000;342(5):314-319.
17. Bauer J, Buchmller L, Reuber M, Burr W. Which patients become seizure free
with antiepileptic drugs? an observational study in 821 patients with epilepsy. Acta
Neurol Scand. 2008;117(1):55-59.
18. Callaghan BC, Anaud K, Hesdorffer D, Hauser WA, French JA. Likelihood of
seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;
62(4):382-389.
19. Liimatainen SP, Raitanen JA, Ylinen AM, Peltola MA, Peltola JT. The benefit
of active drug trials is dependent on the aetiology in refractory focal epilepsy [published correction in J Neurol Neurosurg Psychiatry. 2008;79(9):1086]. J Neurol
Neurosurg Psychiatry. 2008;79(7):808-812.
20. Luciano AL, Shorvon SD. Results of treatment changes in patients with
apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62(4):375381.
21. Spencer SS, Sperling MR, Shewman DA, Kahane P. Intracranial electrodes.
In: Engel J Jr, ed. Epilepsy: A Comprehensive Textbook. Philadelphia, PA: Wolters
Kluwer; 2008:1791-1815.
22. Schomer DL, Black PM. A 24-year-old woman with intractable seizures: review of surgery for epilepsy. JAMA. 2008;300(21):2527-2538.

2008 American Medical Association. All rights reserved.

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