LETTERS Treatment of Refractory Mesial Temporal Lobe Epilepsy To the Editor: Dr Engel and colleagues1 presented important additional evidence on the superiority of surgical therapy over antiepileptic drugs (AEDs) in the treatment of refractory mesial temporal lobe epilepsy (MTLE). Their results corroborate and expand the findings of a previous randomized controlled trial,2 which led the American Academy of Neurology to issue a practice parameter in 2003 recommending surgery as the treatment of choice for pharmacoresistant MTLE.3 While the greater efficacy of surgical treatment for seizure control in MTLE is well established, the question of timing of surgery is still controversial. Clinicians generally perceive surgery as a last resort due to concern regarding the risks of adverse effects following surgical intervention and either fail to refer patients or refer them too late. Although not a universal finding, memory impairment has often been reported after an anterior temporal lobe resection and may compromise the patient’s well-being and social functioning, even when seizure-free. However, MTLE is now regarded as a progressive disease and therefore it is critical to assess the comparative effect on health-related quality of life (HRQOL) and the psychosocial status of patients undergoing each treatment approach to make an informed decision concerning the use of surgery or pharmacotherapy. With the premature termination of the trial after only 38 patients were enrolled, the comparative effect of early surgery on cognition and HRQOL remains unanswered. The declared primary outcome of the Early Randomized Surgical Epilepsy Trial (ERSET) was seizure freedom, but the large planned sample size (200 patients) is not justifiable based on the expected difference in the primary outcome because there was previous evidence2 indicating that the surgical approach is superior in cases of refractory MTLE. In fact, supplementary material previously published describing the study design for ERSET4 confirms that “sample size was instead chosen largely to address the important secondary aim of examining treatment group differences in mean change in HRQOL.” Moreover, in 1999, when the original plan for ERSET was published, it stated that, at the end of 2 years, the primary outcome measure would be a quantitative assessment of HRQOL; seizure recurrence was defined as a secondary outcome.5 Early surgery can benefit patients with MTLE. Future trials with larger samples and longer follow-up should address the issue of whether surgery can also improve HRQOL compared with the natural history of the disease in appropriately selected patients with MTLE, in addition to providing better seizure control compared with medication. Renata R. Kieling, MD Andre´ Palmini, MD, PhD Eliseu Paglioli, MD, PhD ©2012 American Medical Association. All rights reserved.
Author Affiliations: Porto Alegre Epilepsy Surgery Program, Pontificia Universidade Cato´lica do Rio Grande do Sul, Porto Alegre, Brazil (
[email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kieling reported receiving medication for a trial of attention-deficit/hyperactivity disorder from Novartis. Dr Palmini reported serving as a board member and receiving payment for lectures and travel from Novartis, Abbott, Janssen-Cilag, and Eli Lilly; receiving payment for manuscript preparation from Novartis, Abbott, and Janssen-Cilag; and receiving payment for organization of preceptorships and workshops paid to fund fellowships from Novartis and Biogen. Dr Paglioli reported no disclosures. 1. Engel J Jr, McDermott MP, Wiebe S, et al; Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930. 2. Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318. 3. Engel J Jr, Wiebe S, French J, et al; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons. 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. Neurology. 2003; 60(4):538-547. 4. Engel J Jr, McDermott MP, Wiebe S, et al; Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy. Epilepsia. 2010; 51(10):1978-1986. 5. Engel J Jr. The timing of surgical intervention for mesial temporal lobe epilepsy: a plan for a randomized clinical trial. Arch Neurol. 1999;56(11):13381341.
To the Editor: The efficacy of epilepsy surgery (73% seizurefree) in the best-possible surgical candidates was corroborated by Dr Engel and colleagues.1 Their trial also showed that surgery can cause irreversible deficits because a statistically reliable decline in performance on memory tests was more frequent in the surgical group (36% in delayed recall and 55% in naming) than in the medical group (0% and 7%, respectively).1 Other aspects of the trial might deserve some clarification. The reported incidence of visual field defects is between 68% and 100% after anterior temporal lobectomy, and in 25% to 46% of patients it may be severe enough to fail driver’s license tests.2 However, I could not find any mention of this subject in the study by Engel et al.1 No patient achieved seizure freedom in the medical group, which is surprising given that the patients had failed only 2 AED trials and had a whole year to attempt new trials.1 In a GUIDELINES FOR LETTERS. Letters discussing a recent JAMA article should be submitted within 4 weeks of the article’s publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 5 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/instructions. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http://manuscripts.jama.com (note: do not include “www” before the URL). For technical assistance, please contact
[email protected]. Letters Section Editor: Jody W. Zylke, MD, Senior Editor. JAMA, June 20, 2012—Vol 307, No. 23 2483
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LETTERS
previous study that compared epilepsy surgery with continued pharmacotherapy, 8% of the medical group became seizure-free even though this sample had previously failed 6 AED trials and had just 1 month to adjust to treatment.3 Moreover, a retrospective study found that 21% of surgical candidates excluded for surgery after presurgical evaluation subsequently achieved seizure freedom with medical therapy.4 As shown by a prospective observational study, after the failure of 2 AED trials, approximately 17% of patients could be expected to become seizure-free following each of the next 3 AED trials.5 Engel et al1 provided the number of AEDs used by their patients at baseline and at the end of the study, but it would be important to know the mean number (and range) of AED trials performed in the medical group before randomization and during the subsequent year. The trial by Engel et al1 was atypical in that the patients included were low in number and highly selected, almost one-third of the patients in the medical group received surgery, and the trial was stopped prematurely. Consequently, this trial will be insufficient “to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management” in early focal refractory epilepsy. Perhaps a large, prospective observational, multicenter study that reflects clinical practice, with identical standardized outcome measures for any intervention, would better inform patients about their preferred treatment option at any time in the course of AED resistance. Juan Gomez-Alonso, MD, PhD Author Affiliation: Servicio de Neurologia, Hospital Universitario Xeral-Cı´es, Vigo, Spain (
[email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving honoraria for lectures or for participation on advisory panels, or both, from Eisai, GlaxoSmithKline, and UCB Pharma; and receiving reimbursement for travel expenses from Eisai, GlaxoSmithKline, UCB Pharma, and Novartis. 1. Engel J Jr, McDermott MP, Wiebe S, et al; Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930. 2. Yogarajah M, Focke NK, Bonelli S, et al. Defining Meyer’s loop-temporal lobe resections, visual field deficits and diffusion tensor tractography. Brain. 2009; 132(pt 6):1656-1668. 3. Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318. 4. Selwa LM, Schmidt SL, Malow BA, Beydoun A. Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy. Epilepsia. 2003;44(12):1568-1572. 5. Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology. 2008;70(1):54-65.
In Reply: We appreciate the concern of Dr Kieling and colleagues regarding the small number of participants in ERSET. Our original plan was to make HRQOL the primary outcome measure, but we changed this to seizure freedom at the request of the National Institutes of Health review panel prior to approval for funding. Nevertheless, we believe our data support a benefit of surgery on HRQOL. Although the effect at 24 months did not reach statistical significance based on the primary intention-to-treat analysis (P = .08), significant differences were found at all earlier time points 2484
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(P ! .009) and at 24 months when postsurgery data from participants in the medical group who received surgery were excluded. The observed effects on secondary outcomes such as driving and socialization further justify a conclusion that early surgery results in psychosocial benefits relative to continued medical management. Dr Gomez-Alonso raised several important issues. Although memory declines were observed over the shortterm on some tests in the surgical group and these do tend to persist over time, patients who did not undergo surgery and who continue to have seizures also show decline over a more prolonged period. The study was terminated before sufficient numbers of patients were enrolled to determine definitively whether the immediate cognitive effects of surgery ultimately differed from the longer-term effects of continued seizures. Additional studies are needed. The standardized anteromesial resection rarely causes visual field deficits large enough to impair function. Small superior quadrantic cuts were identified in 3 participants in the surgical group, but these were not clinically significant. We agree that it is unusual that none of the patients in the medical group became seizure-free given that they were cycled through a rigid schedule of AEDs, as described in the Methods section of the article,1 and pharmacotherapy was reviewed by a blinded independent committee. However, the 95% upper confidence bound for the true percentage of seizurefree cases in this group was 12% based on our small sample size. Also, there was 1 participant in this group who was seizurefree for the last 50 weeks of follow-up. Although a few studies have reported the effectiveness of pharmacotherapy following multiple AED trials to be greater than expected, characterization of these patients and the duration of seizure freedom have not been reported. In any event, efficacy of continued pharmacotherapy in patients who fail 2 AED trials would not be expected to approach the seizure freedom rate of 85% and improvement in HRQOL from surgery as suggested by our study. Consequently, we believe that the trial results are sufficient to conclude that surgery is superior to continued medical management early in the course of MTLE. In addition, we agree that a larger prospective study with longer follow-up time is necessary to fully define the advantages and disadvantages of early surgical intervention for pharmacoresistant epilepsy. Such a study might become possible if the ERSET results are an incentive for more patients with early pharmacoresistant epilepsy to be referred to surgery centers in the future than has been the practice in the past. Jerome Engel Jr, MD, PhD Michael P. McDermott, PhD John T. Langfitt, PhD Author Affiliations: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California (Dr Engel;
[email protected]); and University of Rochester, Rochester, New York (Drs McDermott and Langfitt). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Engel reported receiving an institutional grant from the National Institutes of Health (NIH); serving
©2012 American Medical Association. All rights reserved.
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LETTERS as a consultant to Medtronics, Valeant, Acorda, the US Food and Drug Administration, and Best Doctors; receiving fees for expert testimony; receiving fees for serving on lecture/speakers bureaus for Esai, Johnson & Johnson, Novartis, and Lippincott; receiving of patent fees (WO2009/123734A1 and WO2009/ 123735A1); receiving royalties from Wolters Kluwer, Wiley Blackwell, Elsevier, and MedLink; and receiving reimbursement for travel accommodations/meeting expenses from UCB Pharmaceuticals. Drs McDermott and Langfitt reported receiving an institutional grant from the National Institute of Neurological Disorders and Stroke (NINDS). Dr McDermott also reported receiving reimbursement for travel accommodations/meeting expenses for this study from the NINDS; serving as consultant to Boehringer-Ingelheim, Pfizer, Teva Pharmaceutical Industries, Smith and Nephew, Synosia, and Impax Pharmaceuticals; receiving grant support or having pending grant support from Medivation, NeuroSearch Sweden AB, BoehringerIngelheim, and Pfizer. Dr Langfitt also reported receiving reimbursement for travel accommodations/meeting expenses from the NIH; serving as consultant to the NINDS, University of California, San Francisco, Elekta, Northern Illinois University, University of Cincinnati, and the NIH’s Center for Scientific Review; receiving grant support or having pending grant support from the NINDS and the Agency for Healthcare Research and Quality; and receiving fees for the development of educational presentations from the NIH. 1. Engel J Jr, McDermott MP, Wiebe S, et al; Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy. Epilepsia. 2010; 51(10):1978-1986.
Posttraumatic Stress Disorder and Opioid Use Among US Veterans To the Editor: Dr Seal and colleagues1 demonstrated that veterans of Iraq and Afghanistan with posttraumatic stress disorder (PTSD) who were receiving higher-dose opioid prescriptions were more likely to be receiving concurrent prescriptions for sedative-hypnotic medications, primarily benzodiazepines. The relative risk for concurrent use of opioid and sedative-hypnotic medications was high for veterans with PTSD diagnoses (adjusted RR, 5.46; 95% CI, 4.91-6.07) compared with those with no mental health diagnoses. The authors also found that receiving prescription opioids was associated with an increased risk of adverse clinical outcomes, especially among those with PTSD. In an outpatient population of veterans that predated the conflicts in Iraq and Afghanistan (1998-2001), receipt of highdose anxiolytic benzodiazepine prescriptions (top 5% of average daily doses) was strongly associated with PTSD diagnoses and concurrently dispensed prescriptions of oxycodone and acetaminophen.2 In veterans with PTSD and alcoholism seen as outpatients, high-dose anxiolytic benzodiazepine prescriptions were associated with concurrent prescriptions of oxycodone and acetaminophen, 2 concurrent anxiolytic benzodiazepine prescriptions, younger age, and prior drug abuse or dependence diagnoses.3 In light of these findings, it would be useful to know whether the adverse clinical outcomes associated with opioid prescriptions found by Seal et al1 may have been driven by concurrent, high-dose benzodiazepine prescriptions. If this were the case, it is possible that the adverse clinical outcomes reported could be attributed to 1 or both of these psychoactive medications. John A. Hermos, MD Author Affiliation: VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts (
[email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
©2012 American Medical Association. All rights reserved.
1. Seal KH, Shi Y, Cohen G, et al. Association of mental health disorders with prescription opioids and high-risk opioid use in US veterans of Iraq and Afghanistan. JAMA. 2012;307(9):940-947. 2. Hermos JA, Young MM, Lawler EV, Stedman MR, Gagnon DR, Fiore LD. Characterizations of long-term anxiolytic benzodiazepine prescriptions in veteran patients. J Clin Psychopharmacol. 2005;25(6):600-604. 3. Hermos JA, Young MM, Lawler EV, Rosenbloom D, Fiore LD. Long-term, highdose benzodiazepine prescriptions in veteran patients with PTSD: influence of preexisting alcoholism and drug-abuse diagnoses. J Trauma Stress. 2007;20(5): 909-914.
In Reply: Dr Hermos notes that the high proportion (41%) of Iraq and Afghanistan veterans with pain and PTSD diagnoses in Veterans Affairs health care prescribed both opioids and sedative hypnotics is similar to his finding of a strong association between benzodiazepine and concurrent prescriptions of oxycodone and acetaminophen and PTSD in prior-era veterans.1 He speculates that higher rates of adverse clinical outcomes in veterans with PTSD and pain prescribed opioids may be driven by the concurrent prescription of benzodiazepines. To investigate this question, we conducted additional analyses in 141 029 Iraq and Afghanistan veterans who had received a pain diagnosis during their first year in Veterans Affairs health care from 2005 through 2008. We followed up patients for 1 year from index pain diagnosis and assessed whether they had received an opioid or benzodiazepine prescription, or both, for 20 days or more and whether or not they had sustained 1 or more adverse clinical outcomes (wounds or injuries; opioid-related accidents and overdoses; alcohol and non–opioid drug-related accidents and overdose; self-inflicted injuries; and violence-related injuries). Veterans with pain and PTSD were significantly more likely to be prescribed opioids only, benzodiazepines only, or both than veterans with pain and no mental health diagnoses or pain and mental health diagnoses other than PTSD. In addition, regardless of whether or not they received an opioid and/or benzodiazepine medication, nearly all adverse clinical outcomes were more prevalent in veterans with pain and PTSD compared with other groups of veterans with pain. In Iraq and Afghanistan veterans with pain and PTSD, the prevalence of any adverse clinical outcome was lowest in veterans with neither opioid nor benzodiazepine prescriptions (5.1%), was higher in those with opioid prescriptions only (9.2%) and in veterans with benzodiazepine prescriptions only (9.8%), and was highest in veterans prescribed both opioids and benzodiazepines (15.1%). The prevalence of adverse clinical outcomes was attenuated for veterans with pain and non-PTSD mental health diagnoses (3.5% for neither, 7.7% for opioids only, 5.4% for benzodiazepines only, and 7.8% for both opioids and benzodiazepines) and in veterans with pain and no mental health diagnoses (3.2% for neither, 7.5% for opioids only, 1.9% for benzodiazepines only, and 7.8% both opioids and benzodiazepines). We were limited by an administrative data set from which we could ascertain prescription dispensing data, JAMA, June 20, 2012—Vol 307, No. 23 2485
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