Current Literature In Clinical Science
Ammon’s Horns of a Dilemma: A LITTle Less is More
Laser Interstitial Thermal Therapy for Medically Intractable Mesial Temporal Lobe Epilepsy. Kang JY, Wu C, Tracy J, Lorenzo M, Evans J, Nei M, Skidmore C, Mintzer S, Sharan AD, Sperling MR. Epilepsia 2016;57:325– 334.
OBJECTIVE: To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with magnetic resonance imaging (MRI)-guided stereotactic laser interstitial thermal therapy (LiTT). METHODS: We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug-resistant mTLE who underwent MRI-guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volumebased analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure-free and not seizure-free groups. RESULTS: Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval [CI] 30.1-75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9-88.4%) at 2-year follow-up. Median follow-up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure-free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure-free and non-seizure-free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted. SIGNIFICANCE: We conclude that MRI-guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.
Commentary Our patients often find themselves on the horns of a dilemma: the choice between seeking seizure-freedom through resective surgery, but at the risk of disability due to the possible occurrence of new deficits. In particular, with open resective surgery (eg, anterior temporal lobectomy, ATL) for mesial temporal lobe epilepsy (MTLE) patients are offered the high probability of seizure freedom (~75% as per a recent metaanalysis [1]), but face certain risks. These include decline in verbal memory, especially in the setting of relatively preserved preoperative memory (2), and deficits in naming or object recognition, as recently highlighted (3). Any advance in surgical treatment that improves the ratio, if you will, of seizure-free outcomes to the occurrence of deficits works to mitigate the dilemma that patients face - and that often precludes them from accepting the surgical alternative. Although it has been shown that when ATL achieves seizure freedom it improves quality of life even in the setting of verbal memory decline (4), Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 249–250 © American Epilepsy Society
there is little doubt that such patients would be better off with seizure freedom without new or worsened deficits. Thus, we must constantly strive to improve surgical treatments in order to improve the ratio of benefits to deficits. Laser interstitial thermal therapy (LITT) is a less invasive way to extirpate mesial temporal structures for the treatment of MTLE. Through a minimal incision and twist drill hole a laser fiber is stereotactically inserted into the hippocampus, typically via the long axis, to create a laser-induced thermocoagulative ablation of the hippocampus and amygdala. The heating is guided by MRI thermometry, which allows near realtime estimation of the heating, and thus a reliable prediction of the ‘irreversible damage zone’; this estimate is very highly correlated to lesion on post ablation MRI imaging. Typically, only the hippocampus and amygdala are targeted, whereas in open resective surgery the parahippocampal gyrus is also removed. We don’t yet know if the latter should be targeted for ablation as well, but results from a series of radiofrequency ablations suggests not (5). Both patients with and without mesial temporal sclerosis (MTS) are candidates for the procedure, although one would suspect the latter would not do as well, as is the case in some surgical series. My group published the first series of 13 MTLE patients who underwent LITT, show-
249
LITT for Mesial Temporal Lobe Epilepsy
ing 7 of 13 (54%) patients, and 6 of 9 (67%) of those with MTS were seizure free 6 months following surgery (6). We have also demonstrated that the instance of decline in naming or object recognition is strikingly reduced after LITT as compared with open resective surgery (3). Kang et al. reported the outcome of 20 patients with MTLE who underwent the same procedure, from 6 months to 2 years following surgery. They reported that 8 of 15 (53%, 95% CI 30.1–75.2%) were seizure free after 6 months (the outcomes on the last 5 patients - #16–20 - were at 1.3–5.3 months, too early to evaluate), reminiscent of our own results. It should be noted that one of their non–seizure-free patients had a temporal lobe glioma outside of the ablation zone and a strong argument should be made to exclude this patient (8 of 14, 57%). Their reported outcome at 1 year was not as good (4 of 11, 36.4%, 95% CI 14.9–64.8%), but they saw seizure freedom in three of five patients at 2 years (60%, 95% CI 22.9–88.4%). This is a very small series of a novel therapy. It is important to remember that our goal is to fairly evaluate it, as we would any new therapy, against our present treatment approaches, with the above elaborated goals in mind. In this regard, it is extremely important to adhere to statistical principles, and not draw premature conclusions, either for or against the therapy. There are several critical points to consider in this context: 1) The outcome that we use to evaluate and compare surgical treatments for epilepsy is the Engel scale at 1 year, not 6 months or 2 years; this allows us to compare treatments with the only (sufficiently powered) randomized controlled trial of surgical treatment of MTLE, the Wiebe et al. (7) study that showed 64% of operated patients became seizure free at one year after ATL. Thus, the 6-month outcomes reported by both Kang et al. and by Willie et al. (5) are only promising indicators, not comparators to be used against the 1-year outcomes of ATL. The proportion of seizure-free patients at 1 year (4 of 11) reported by Kang et al. is the only number of true importance as a comparator, but consider these additional points. 2) Confidence intervals are reported for a reason: they reflect what we can confidently conclude from a series of data. Thus, the CIs above reveal that, for all we know, the 1-year outcomes for LITT for MTLE are as poor as 14.9% or as good as 64.8% effective. The large span of the CI reflects the low number of patients in this group. 3) LITT is a new technology that requires the user to learn how to most effectively use it, and the authors were among the first to use LITT for MTLE. This is a report of their entire experience, and thus encompasses their learning curve. The longer the outcome interval the more proportionally represented are the earlier versus the later cases on the learning curve, which can be seen in the difference between outcomes in the 1-year versus 6-month group (bearing in mind, too, that only 1 of 11 patients that was seizure free at 6 months had a seizure between 6 and 12 months.) 4) Finally, analysis of LITT for MTLE should be limited to patients without lesions outside the mesial temporal lobe. Kang et al. analyzed the relationship of lesion volumes to outcome. Although a worthy endeavor, finding a correlation in such a small series with the above confounds is highly improbable, and ‘absence of evidence is not evidence of absence’.
250
Also, the findings with respect to decline in verbal memory in the five dominant LITT patients are not particularly surprising: this would be expected even in the less invasive approach to extirpation of mesial temporal structures. It would have been nice to see tests of lateral temporal lobe functions, such as naming and (on the nondominant side) object recognition, which we have found is spared in LITT as compared with open resections (2). As Kang et al. conclude, the “results suggest that MRIguided stereotactic [LITT] is a safe and reasonable alternative to ATL.” This will remain true until we have a larger, prospective series of patients to analyze, and indeed those efforts are underway. We must also do a more complete job of characterizing the advantages with respect to neurocognitive outcomes, longer term outcomes, and short- and long-term costs. In the end, it is also important to bear in mind that our comparator group is not only open resection, but also continued medical treatment. Epilepsy surgery is highly underpenetrated among bona fide surgical candidates, who chose (or whose doctors chose) continued medical treatment alone over surgical treatment. For these patients, 54% chance of seizure-freedom with minimal risk of neurological deficits, and with a procedure that does not lead to significant issues with postoperative pain and associated concerns, removes the (Ammon’s) horns from the dilemma, and represents a marked advance in the treatment of epilepsy. by Robert E. Gross, MD, PhD References 1. Josephson CB, Dykeman J, Fiest KM, Liu X, Sadler RM, Jette N, Wiebe S. Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery. Neurology 2013;80:1669–1676. 2. Baxendale S, Thompson PJ, Sander JW. Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function. Epilepsia 2013;54:e131– e134. 3. Drane DL, Loring DW, Voets NL, Price M, Ojemann JG, Willie JT, Saindane AM, Phatak V, Ivanisevic M, Millis S, Helmers SL, Miller JW, Meador KJ, Gross RE. Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy. Epilepsia 2015;56:101–113. 4. Langfitt JT, Westerveld M, Hamberger MJ, Walczak TS, Cicchetti DV, Berg AT, Vickrey BG, Barr WB, Sperling MR, Masur D, Spencer SS. Worsening of quality of life after epilepsy surgery: effect of seizures and memory decline. Neurology 2007;68:1988–1994. 5. Malikova H, Liscak R, Vojtech Z, Prochazka T, Vymazal J, Vladyka V, Druga R. Stereotactic radiofrequency amygdalohippocampectomy: does reduction of entorhinal and perirhinal cortices influence good clinical seizure outcome? Epilepsia 2011;52:932–940. 6. Willie JT, Laxpati NG, Drane DL, Gowda A, Appin C, Hao C, Brat DJ, Helmers SL, Saindane A, Nour SG, Gross RE. Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. Neurosurgery 2014;74:569–584, discussion 584–565. 7. 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;345:311–318.
Ammon’s Horns of a Dilemma: A LITTle Less is More
Laser Interstitial Thermal Therapy for Medically Intractable Mesial Temporal Lobe Epilepsy. Kang JY, Wu C, Tracy J, Lorenzo M, Evans J, Nei M, Skidmore C, Mintzer S, Sharan AD, Sperling MR. Epilepsia 2016;57:325– 334.
OBJECTIVE: To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with magnetic resonance imaging (MRI)-guided stereotactic laser interstitial thermal therapy (LiTT). METHODS: We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug-resistant mTLE who underwent MRI-guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volumebased analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure-free and not seizure-free groups. RESULTS: Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval [CI] 30.1-75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9-88.4%) at 2-year follow-up. Median follow-up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure-free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure-free and non-seizure-free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted. SIGNIFICANCE: We conclude that MRI-guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.
Commentary Our patients often find themselves on the horns of a dilemma: the choice between seeking seizure-freedom through resective surgery, but at the risk of disability due to the possible occurrence of new deficits. In particular, with open resective surgery (eg, anterior temporal lobectomy, ATL) for mesial temporal lobe epilepsy (MTLE) patients are offered the high probability of seizure freedom (~75% as per a recent metaanalysis [1]), but face certain risks. These include decline in verbal memory, especially in the setting of relatively preserved preoperative memory (2), and deficits in naming or object recognition, as recently highlighted (3). Any advance in surgical treatment that improves the ratio, if you will, of seizure-free outcomes to the occurrence of deficits works to mitigate the dilemma that patients face - and that often precludes them from accepting the surgical alternative. Although it has been shown that when ATL achieves seizure freedom it improves quality of life even in the setting of verbal memory decline (4), Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 249–250 © American Epilepsy Society
there is little doubt that such patients would be better off with seizure freedom without new or worsened deficits. Thus, we must constantly strive to improve surgical treatments in order to improve the ratio of benefits to deficits. Laser interstitial thermal therapy (LITT) is a less invasive way to extirpate mesial temporal structures for the treatment of MTLE. Through a minimal incision and twist drill hole a laser fiber is stereotactically inserted into the hippocampus, typically via the long axis, to create a laser-induced thermocoagulative ablation of the hippocampus and amygdala. The heating is guided by MRI thermometry, which allows near realtime estimation of the heating, and thus a reliable prediction of the ‘irreversible damage zone’; this estimate is very highly correlated to lesion on post ablation MRI imaging. Typically, only the hippocampus and amygdala are targeted, whereas in open resective surgery the parahippocampal gyrus is also removed. We don’t yet know if the latter should be targeted for ablation as well, but results from a series of radiofrequency ablations suggests not (5). Both patients with and without mesial temporal sclerosis (MTS) are candidates for the procedure, although one would suspect the latter would not do as well, as is the case in some surgical series. My group published the first series of 13 MTLE patients who underwent LITT, show-
249
LITT for Mesial Temporal Lobe Epilepsy
ing 7 of 13 (54%) patients, and 6 of 9 (67%) of those with MTS were seizure free 6 months following surgery (6). We have also demonstrated that the instance of decline in naming or object recognition is strikingly reduced after LITT as compared with open resective surgery (3). Kang et al. reported the outcome of 20 patients with MTLE who underwent the same procedure, from 6 months to 2 years following surgery. They reported that 8 of 15 (53%, 95% CI 30.1–75.2%) were seizure free after 6 months (the outcomes on the last 5 patients - #16–20 - were at 1.3–5.3 months, too early to evaluate), reminiscent of our own results. It should be noted that one of their non–seizure-free patients had a temporal lobe glioma outside of the ablation zone and a strong argument should be made to exclude this patient (8 of 14, 57%). Their reported outcome at 1 year was not as good (4 of 11, 36.4%, 95% CI 14.9–64.8%), but they saw seizure freedom in three of five patients at 2 years (60%, 95% CI 22.9–88.4%). This is a very small series of a novel therapy. It is important to remember that our goal is to fairly evaluate it, as we would any new therapy, against our present treatment approaches, with the above elaborated goals in mind. In this regard, it is extremely important to adhere to statistical principles, and not draw premature conclusions, either for or against the therapy. There are several critical points to consider in this context: 1) The outcome that we use to evaluate and compare surgical treatments for epilepsy is the Engel scale at 1 year, not 6 months or 2 years; this allows us to compare treatments with the only (sufficiently powered) randomized controlled trial of surgical treatment of MTLE, the Wiebe et al. (7) study that showed 64% of operated patients became seizure free at one year after ATL. Thus, the 6-month outcomes reported by both Kang et al. and by Willie et al. (5) are only promising indicators, not comparators to be used against the 1-year outcomes of ATL. The proportion of seizure-free patients at 1 year (4 of 11) reported by Kang et al. is the only number of true importance as a comparator, but consider these additional points. 2) Confidence intervals are reported for a reason: they reflect what we can confidently conclude from a series of data. Thus, the CIs above reveal that, for all we know, the 1-year outcomes for LITT for MTLE are as poor as 14.9% or as good as 64.8% effective. The large span of the CI reflects the low number of patients in this group. 3) LITT is a new technology that requires the user to learn how to most effectively use it, and the authors were among the first to use LITT for MTLE. This is a report of their entire experience, and thus encompasses their learning curve. The longer the outcome interval the more proportionally represented are the earlier versus the later cases on the learning curve, which can be seen in the difference between outcomes in the 1-year versus 6-month group (bearing in mind, too, that only 1 of 11 patients that was seizure free at 6 months had a seizure between 6 and 12 months.) 4) Finally, analysis of LITT for MTLE should be limited to patients without lesions outside the mesial temporal lobe. Kang et al. analyzed the relationship of lesion volumes to outcome. Although a worthy endeavor, finding a correlation in such a small series with the above confounds is highly improbable, and ‘absence of evidence is not evidence of absence’.
250
Also, the findings with respect to decline in verbal memory in the five dominant LITT patients are not particularly surprising: this would be expected even in the less invasive approach to extirpation of mesial temporal structures. It would have been nice to see tests of lateral temporal lobe functions, such as naming and (on the nondominant side) object recognition, which we have found is spared in LITT as compared with open resections (2). As Kang et al. conclude, the “results suggest that MRIguided stereotactic [LITT] is a safe and reasonable alternative to ATL.” This will remain true until we have a larger, prospective series of patients to analyze, and indeed those efforts are underway. We must also do a more complete job of characterizing the advantages with respect to neurocognitive outcomes, longer term outcomes, and short- and long-term costs. In the end, it is also important to bear in mind that our comparator group is not only open resection, but also continued medical treatment. Epilepsy surgery is highly underpenetrated among bona fide surgical candidates, who chose (or whose doctors chose) continued medical treatment alone over surgical treatment. For these patients, 54% chance of seizure-freedom with minimal risk of neurological deficits, and with a procedure that does not lead to significant issues with postoperative pain and associated concerns, removes the (Ammon’s) horns from the dilemma, and represents a marked advance in the treatment of epilepsy. by Robert E. Gross, MD, PhD References 1. Josephson CB, Dykeman J, Fiest KM, Liu X, Sadler RM, Jette N, Wiebe S. Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery. Neurology 2013;80:1669–1676. 2. Baxendale S, Thompson PJ, Sander JW. Neuropsychological outcomes in epilepsy surgery patients with unilateral hippocampal sclerosis and good preoperative memory function. Epilepsia 2013;54:e131– e134. 3. Drane DL, Loring DW, Voets NL, Price M, Ojemann JG, Willie JT, Saindane AM, Phatak V, Ivanisevic M, Millis S, Helmers SL, Miller JW, Meador KJ, Gross RE. Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy. Epilepsia 2015;56:101–113. 4. Langfitt JT, Westerveld M, Hamberger MJ, Walczak TS, Cicchetti DV, Berg AT, Vickrey BG, Barr WB, Sperling MR, Masur D, Spencer SS. Worsening of quality of life after epilepsy surgery: effect of seizures and memory decline. Neurology 2007;68:1988–1994. 5. Malikova H, Liscak R, Vojtech Z, Prochazka T, Vymazal J, Vladyka V, Druga R. Stereotactic radiofrequency amygdalohippocampectomy: does reduction of entorhinal and perirhinal cortices influence good clinical seizure outcome? Epilepsia 2011;52:932–940. 6. Willie JT, Laxpati NG, Drane DL, Gowda A, Appin C, Hao C, Brat DJ, Helmers SL, Saindane A, Nour SG, Gross RE. Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. Neurosurgery 2014;74:569–584, discussion 584–565. 7. 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;345:311–318.
