JAMA Epilepsy Editorial.pdf

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current as of December 2, 2008.Online article and related content

http://jama.ama-assn.org/cgi/content/full/300/21/2548

. 2008;300(21):2548-2550 (doi:10.1001/jama.2008.756)JAMAJerome Engel, Jr

Surgical Treatment for Epilepsy: Too Little, Too Late?

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Neurology; Epilepsy; Surgery; Surgical Interventions; Neurosurgery

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EDITORIAL Editorials represent the opinionsof the authors andJAMAand

not those of the American Medical Association.

Surgical Treatment for EpilepsyToo Little, Too Late?Jerome Engel Jr, MD, PhD

EPILEPSY IS ONE OF THE MOST COMMON SERIOUS NEU-rological conditions. According to a study by theWorld Health Organization, epilepsy accounts for 1%of the global burden of disease based on disability-

adjusted life-years (DALYs), productive years lost due to dis-ability or premature death.1 This is equivalent to lung can-cer in men and breast cancer in women. Among primary

disorders of the brain, epilepsy ranks with depression andother affective disorders, Alzheimer disease and other de-mentias, and substance abuse. Of the worlds population,0.5% to 1.0% has active epilepsy, and pharmacotherapy isunsuccessful in controlling seizures in 20% to 40% of pa-tients.2 In the United States, 80% of the cost of epilepsy isattributable to patients with medically intractable sei-zures.3 Temporal lobe epilepsy is the most common causeof pharmacoresistant seizures4 and may constitute half ormore of the patients in the United States with medically in-tractable epilepsy.5 On the other hand, temporal lobe epi-lepsy is theform of epilepsymosteasily andeffectively treatedwith surgery; 60% to 90% of patients can expect to becomefree of disabling seizures postoperatively.6-8 Appropriately

applied surgical treatment, therefore, is crucial for reduc-ing the health burden represented by epilepsy.

Surgical treatment for epilepsy, however, is arguablythe most underused of all effective therapeutic interven-tions. It is estimated that more than 100 000 patients inthe United States with temporal lobe epilepsy may becandidates for surgical treatment, although fewer than2000 received therapeutic surgical resections in 1990.9 A2001 Western Ontario randomized controlled trialinvolving patients with temporal lobe epilepsy confirmedmany published surgical series findings that surgicaltreatment is more likely to eliminate disabling seizuresand improve quality of life than pharmacotherapy.8 As a

result of this finding and a literature review, the Ameri-can Academy of Neurology issued a practice parameter in2003 recommending surgery as the treatment of choicefor medically intractable temporal lobe epilepsy.7

Although no evidence exists to substantiate whether theWestern Ontario trial and the American Academy of Neu-

rology practice parameter has increased surgical treatmentfor temporal lobe epilepsy in the United States, unpub-lished data from the National Association of Epilepsy Cen-ters indicate that the number of anterior temporal resec-tion for epilepsy performed in the United States is notappreciably greater in 2008 than it was in 1990 (Robert J.Gumnit, MD, president, National Association of EpilepsyCenters, written communication, November 2, 2008). Fur-thermore, those who eventually undergo surgery are not re-ferred until an average of 22 years after onset.10 Not only

are most surgical candidates never referred for surgery butthose who are often undergo surgery too late to prevent ir-reversible disabling psychological and social consequencesof epilepsy.11 In theory, for many of these patients early sur-gical intervention could prevent a lifetime of disability, aswell as premature death.12

A clinical trial to establish the putative positive effect ofsurgical intervention on the mortality rate associated withmedically intractable temporal lobe epilepsy would re-quire following up a large population of patients for manyyears, making such a trial prohibitively expensive. Conse-quently,Choi and colleagues13 useda decisionanalyticmodelto quantitatively predict survival following surgical therapy

compared with continued medical management of patientswith temporal lobe epilepsy and report their results in thisissue ofJAMA. Their data indicate that for a 35-year-old pa-tient, surgical therapy would be associated with an in-crease in life expectancy of 5.0 years and 7.5 in quality-adjusted life-years. These results should provide a furtherincentive for physicians to refer potential surgical candi-dates to epilepsy surgery centers but most likely underes-timate the benefit, given that the authors chose age 35 yearsfor their analysis based on the current practice of perform-ing surgery more than 20 years after the onset of epilepsy.The authors also acknowledge that a major limitation in theirmodel is the lack of data on the natural history of pharma-

coresistant temporal lobe epilepsy. This knowledge deficitcould also account for the fact that surgical treatment is stillpracticed too little and too late.

See also pp 2497 and 2527 and Patient Page.

Author Affiliations: Departments of Neurology, Neurobiology, and PsychiatryandBiobehavioral Sciences, and the Brain Research Institute, David Geffen School ofMedicine at University of California, Los Angeles.Corresponding Author: Jerome Engel Jr,MD, PhD, Departmentof Neurology,DavidGeffen School of Medicine at UCLA, 710Westwood Plaza, LosAngeles, CA 90095-1769 ([email protected]).

2548 JAMA, December 3, 2008Vol 300, No. 21 (Reprinted) 2008 American Medical Association. All rights reserved.

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The inability to reliablyidentifymedical intractability earlyin the course of temporal lobe epilepsy is perhaps the ma-jor reason for the long delay in patient referral to epilepsysurgery centers. With the introduction of many new anti-epileptic drugs over the past 2 decades, it appears that theduration 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 theUniversity of California-Los Angeles Center for Health Sci-ences had epilepsy for more than 20 years.14 It would nowbe impractical to prove that any given patient with epi-lepsy has seizures that are refractory to all available medi-cations in every possible combination. The concept of medi-cally intractable epilepsy, therefore, no longer has practicalmeaning for the clinician and has been replaced by the con-cept of surgically remediable epilepsy syndromes.15 Tem-poral lobe epilepsy is the prototype of a surgically remedi-able epilepsy syndrome, a condition with a well-definedpathophysiology and anatomical substrate, a known poorresponse to medical therapy, and an excellent response

to a standardized surgical intervention based on noninva-sive evaluation. Early surgical intervention for these syn-dromes offers the best opportunity to prevent the develop-ment of irreversible disabling psychological and socialconsequences of recurrent seizures and premature death.

The remaining obstacle to effective early application ofsurgical therapy for temporal lobe epilepsy, therefore, is in-sufficient information regarding the natural history of thisdisorder to permit reliableearly prediction of continued phar-macoresistance in individual patients. Although one studyhassuggestedthat less than 3% of patients with epilepsy willultimately become seizure free after 2 trials of antiepilepticdrugs have faileddue to inefficacy and not intolerance,16 oth-

ers have since documented up to a 15% to 20% response tocontinued pharmacotherapy in this population.17-20 A largemulticenter observational study would be needed to deter-mine the actual percentage of patients with temporal lobeepilepsy who will remain pharmacoresistant after failure of2 antiepileptic drugs and to identify factors that could re-liably predict persistent pharmacoresistance.

In the meantime, given the complexity of issuesinvolved in the consideration of referral for epilepsy sur-gery, the uncertainty of the persistence of pharmacoresis-tance and the critical importance of early intervention,what are primary care physicians and general neurologiststo do? It is perhaps simpler to put thoughts of surgical

therapy aside initially and begin by distinguishing rela-tively benign epilepsies from serious epilepsies. Theformer are easily treated with the first 1 or 2 antiepilepticdrugs tried, resulting in no disabling seizures and noadverse effects. The more serious epilepsies are those inwhich epileptic seizures or adverse effects continue andcompromise work, school, interpersonal relationships, orquality of life, despite adequate trials of a few appropriateantiepileptic drugs at maximum tolerable doses. Ideally,

such patients should be referred for second opinions toepilepsy centers, where epilepsy specialists would thenevaluate the surgical therapy option.

Referral to an epilepsy center, particularly if early surgi-cal therapy might be appropriate, is most important for pa-tients with surgically remediable syndromes such as tem-

poral lobe epilepsy, as well as those with focal seizures dueto localized resectable neocortical lesions, and infants andyoung children with severe epilepsies caused by more dif-fuse lesions that are limited to 1 hemisphere. In most cases,these diagnoses can be suspected based on magnetic reso-nance imaging scans and seizure semiology, even when in-terictal electroencephalographic abnormalities are incon-sistent. Early in the course of temporal lobe epilepsy,however, the magnetic resonance imaging scan results canbe normal and more detailed testing at an epilepsy centerincluding long-term video-electroencephalographic moni-toring, positron emission tomography, ictal single-photonemission computed tomography, magnetoencephalogra-phy, magnetic resonance spectroscopy, and occasionally in-

tracranial recordingmay be necessary to determine whetheran anteromesial temporal resection would most likely ren-der a patient free of disabling seizures.

Patients with medically refractory epilepsy who do notmeet criteria for diagnosis of a surgically remediable syn-drome, as defined herein, might still benefit from surgicaltherapy. For these patients, the presurgical evaluation al-most always requires intracranial monitoring, which in-creases the risk and cost, while the likelihood of a seizure-free result can be only 50% or less.21 The decision to proceedwith surgery in this situation can be difficult, as illustratedby the Clinical Crossroadsdiscussionby Schomer andBlack,22

also published in this issue of JAMA. One of the authors

recommendations for this patient is vagus nerve stimula-tion, given the patients lack of a focal lesion and the po-tential risks of surgery. Although vagus nerve stimulationcan reduce seizure frequency and severity, it rarely resultsin seizure freedom. Further testing would be indicated tobetter determine the patients actual risk from a resectiveprocedure, which could offer a much greater chance of aseizure-free outcome. Ultimately, the patient will need todecide whether the risks are worth the possible benefits, asignificant challenge in the face of limited data.

Surgical treatment for epilepsy remains underused, andwhen surgery is performed, it is often delayed until it istoo late to reverse associated severe disabilities. The study

by Choi et al

13

underscores, but most likely underesti-mates, the benefits of surgical therapy for temporal lobeepilepsy. More information is needed to better understandthe natural history of intractable temporal lobe epilepsyand to identify factors that reliably predict which patientswill continue to have persistent seizures and therebyenable an accurate prediction of surgical benefit early inthe course of antiepileptic drug treatment, before the dis-abling psychological and social consequences of recurrent

EDITORIAL

2008 American Medical Association. All rights reserved. (Reprinted) JAMA,December 3, 2008Vol 300, No. 21 2549



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seizures become irreversible. In the meantime, however,the best approach to facilitate early surgical treatment,when appropriate, would be for primary care physiciansand general neurologists to refer patients who continue tohave disabling seizures after a few antiepileptic drugs havefailed to an epilepsy center for additional evaluation. Epi-

leptologists at these centers are specifically trained to carryout the testing necessary to determine whether early surgi-cal therapy is a viable option.

Financial Disclosures: Dr Engel reports that he has received honoraria for lec-tures, participation on advisory panels, or both from Cyberonic, Dainippon,Eisai, Elan, Johnson & Johnson, Neuropace, Novartis, Pfizer, UCB Pharma, andValiant.

REFERENCES

1. Murray GJ, Lopez AD.Global Comparative Assessments in the Health Sector:Disease Burden, Expenditure, Intervention Packages.Geneva, Switzerland: WorldHealth Organization; 1994.2. Berg AT. Understanding the delay before epilepsy surgery: who develops in-tractable 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 UnitedStates: an estimatefrom population-based clinicaland survey data. Epilepsia. 2000;41(3):342-351.4. Semah F,Picot M-C, AdamC, etal. Is the underlying cause ofepilepsya majorprognostic factor for recurrence? Neurology. 1998;51(5):1256-1262.5. Engel J Jr. Etiology as a risk factor for medically refractory epilepsy: a case forearly surgical intervention.Neurology. 1998;51(5):1243-1244.6. Engel J Jr, Van Ness P, Rasmussen TB, Ojemann LM. Outcome with respect toepileptic 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 lo-calized neocortical resections for epilepsy. Neurology. 2003;60(4):538-547.

8. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial ofsurgery 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 surgicalcandidate? In: Engel J Jr, ed. Surgical Treatment of the Epilepsies.2nd ed. NewYork, NY: Raven Press; 1993:23-34.10. Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsyto become intractable? Neurology. 2003;60(2):186-190.11. Engel J Jr. Finally, a randomized controlled trial of epilepsy surgery. N Engl JMed. 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 tem-poral 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. BauerJ, BuchmllerL, ReuberM, Burr W. Which patients becomeseizure freewith antiepileptic drugs? an observationalstudy in 821 patients with epilepsy.ActaNeurol Scand. 2008;117(1):55-59.18. Callaghan BC, Anaud K, Hesdorffer D, Hauser WA, French JA. Likelihood ofseizure remissionin an adult population withrefractory epilepsy.AnnNeurol. 2007;62(4):382-389.19. Liimatainen SP, Raitanen JA, Ylinen AM, Peltola MA, Peltola JT. The benefitof activedrugtrialsis dependenton theaetiology in refractory focal epilepsy [pub-lished correction in J Neurol Neurosurg Psychiatry. 2008;79(9):1086]. J NeurolNeurosurg Psychiatry. 2008;79(7):808-812.20. Luciano AL, Shorvon SD. Results of treatment changes in patients withapparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62(4):375-381.21. Spencer SS, Sperling MR, Shewman DA, Kahane P. Intracranial electrodes.In: Engel J Jr, ed. Epilepsy: A Comprehensive Textbook. Philadelphia, PA: WoltersKluwer; 2008:1791-1815.22. Schomer DL, Black PM. A 24-year-old woman with intractable seizures: re-view of surgery for epilepsy. JAMA. 2008;300(21):2527-2538.

EDITORIAL

2550 JAMA, December 3, 2008Vol 300, No. 21 (Reprinted) 2008 American Medical Association. All rights reserved.


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