Current Literature In Clinical Sciences
Temporal Plus Epilepsy: Epileptic Territory Beyond the Temporal Lobes
Temporal Plus Epilepsy Is a Major Determinant of Temporal Lobe Surgery Failures. Barba C, Rheims S, Minotti L, Guénot M, Hoffmann D, Chabardès S, Isnard J, Kahane P, Ryvlin P. Brain 2016;139:444–451. doi:10.1093/brain/awv372.
Reasons for failed temporal lobe epilepsy surgery remain unclear. Temporal plus epilepsy, characterized by a primary temporal lobe epileptogenic zone extending to neighboured regions, might account for a yet unknown proportion of these failures. In this study all patients from two epilepsy surgery programmes who fulfilled the following criteria were included: (i) operated from an anterior temporal lobectomy or disconnection between January 1990 and December 2001; (ii) magnetic resonance imaging normal or showing signs of hippocampal sclerosis; and (iii) postoperative followup ≥ 24 months for seizure-free patients. Patients were classified as suffering from unilateral temporal lobe epilepsy, bitemporal epilepsy or temporal plus epilepsy based on available presurgical data. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom over time. Predictors of seizure recurrence were investigated using Cox proportional hazards model. Of 168 patients included, 108 (63.7%) underwent stereoelectroencephalography, 131 (78%) had hippocampal sclerosis, 149 suffered from unilateral temporal lobe epilepsy (88.7%), one from bitemporal epilepsy (0.6%) and 18 (10.7%) from temporal plus epilepsy. The probability of Engel class I outcome at 10 years of follow-up was 67.3% (95% CI: 63.4–71.2) for the entire cohort, 74.5% (95% CI: 70.6–78.4) for unilateral temporal lobe epilepsy, and 14.8% (95% CI: 5.9–23.7) for temporal plus epilepsy. Multivariate analyses demonstrated four predictors of seizure relapse: temporal plus epilepsy (P < 0.001), postoperative hippocampal remnant (P = 0.001), past history of traumatic or infectious brain insult (P = 0.022), and secondary generalized tonic-clonic seizures (P = 0.023). Risk of temporal lobe surgery failure was 5.06 (95% CI: 2.36–10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy. Temporal plus epilepsy represents a hitherto unrecognized prominent cause of temporal lobe surgery failures. In patients with temporal plus epilepsy, anterior temporal lobectomy appears very unlikely to control seizures and should not be advised. Whether larger resection of temporal plus epileptogenic zones offers greater chance of seizure freedom remains to be investigated.
Commentary Temporal lobe resections have been performed for drugresistant epilepsy for more than half a century (1). Despite many advances in clinical description of syndromes, imaging, and neurophysiology, a significant percentage of patients do not become seizure free after surgery. On average, only about 65% of patients are seizure free long term (1). The reasons why surgery fails remain speculative. Possible explanations include the following: 1. The temporal lobe was not the true seizure onset zone, and seizures originate somewhere else not included in the resection;
Epilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 305–307 © American Epilepsy Society
2. There is more than one seizure onset zone or dual pathology, and only one focus was resected; 3. Temporal lobe epilepsy (TLE) is actually bilateral and was not identified as such; 4. Our concept of focal epilepsy is an inappropriate model for epilepsy. TLE is a network disease, and not enough network nodes were resected; 5. The resection margin becomes a new focus; 6. Not enough of the epileptogenic tissue that extended out of the temporal lobe into other areas of the brain was resected. Barba et al. try to explain temporal lobe surgery failures by the latter. In their study, they focus on a cohort of patients they define as temporal plus epilepsy (TPE). Of 168 patients who underwent temporal lobe resection at two French epilepsy
305
Temporal Plus Epilepsy
centers, they classified patients as TPE if stereoelectroencephalography (S-EEG) confirmed seizure onset in the temporal lobe and simultaneously in extratemporal regions such as the insula, the orbitofrontal cortex, the frontal operculum, or the temporo-parietal-occipital junction. Patients with TPE (n = 18) were compared with patients with no neurophysiologic or imaging evidence of initial involvement of extratemporal structures (n = 150; TLE). Patients with TPE were less likely to have a history of febrile seizures or to have hippocampal sclerosis on MRI but were more likely to have a history of trauma/ infection and generalized tonic-clonic seizures. They report that only 16.7% of patients with TPE had an Engel class I outcome at last follow-up compared with 76.7% of patients with “pure” TLE. The risk of seizure recurrence was five times higher with TPE than with TLE 10 years after surgery. In a multivariate analysis, the authors identified a history of trauma or infection, a history of secondarily generalized seizures, and evidence of postoperative hippocampal remnants as additional risk factors for seizure recurrence. By examining the above-mentioned possible hypotheses, the poor outcomes reported in the TPE cohort could be explained by several mechanisms. It is possible that simultaneous multilobar EEG onset is a reflection of a distant focus (e.g., an occipital focus) that was not sampled with the limited S-EEG sampling, and the presumed ictal onset zone just represents a spread pattern (explanation 1), the seizure onset zone extends beyond the temporal lobe (explanation 6) or there is dual pathology (explanation 2). There is also the possibility that the TPE network has different properties as compared with TLE and therefore requires different surgical approaches (explanation 4). Even contralateral seizure onset is possible, as no information is presented on whether all patients with TPE had bilateral S-EEG investigations (explanation 3). Evidence from patients chronically implanted with the responsive neurostimulator demonstrated that it took, on average, 41 days until contralateral seizures were recorded (2). If patients had contralateral seizures, they may not have been recorded in the short amount of time during S-EEG even if electrodes were placed bilaterally. It is beyond the scope of the study to address the pathophysiological reason for the surgical failures, but the network hypothesis warrants further thought. As the mesial temporal structures are functionally closely connected to the orbitofrontal, insular, and posterior regions, would resections beyond the temporal lobe benefit the TPE patients further? Which are really the necessary nodes that need to be included in a resection? Are we routinely not resecting enough, and we just get away with what we resect in more than 60% of the cases? It is apparent from the study that patients with TPE do not benefit from a temporal lobectomy alone, and the authors discourage temporal lobectomy for patients with multilobar onset on intracranial EEG. They also confirmed that the hippocampus should be completely resected as is consistent with previous similar reports (3). The question of whether multilobar resections, including other areas of the brain in addition to the temporal lobe, would have changed the outcomes remains unanswered. Most reports about multilobar resections include patients with severe, often symptomatic epilepsy
306
with large multilobar lesions. Those studies report a favorable outcome between 40 and 55% (4, 5). The orbitofrontal, insular, and occipital areas are closely connected to the mesial temporal areas and therefore warrant some consideration for surgical planning. Serletis et al. advocate for multilobar resection in orbitofrontal epilepsy plus temporo-polar epilepsy to ensure a good seizure outcome (6). Appel et al. report that multilobar resections are needed in patients with seizures originating in the occipital areas to achieve seizure freedom (7). Advanced imaging and neurophysiologic methods may in the future give us additional patient-specific information about the epileptogenic network and could guide the extent of resection (8, 9). There seem to be inherently different properties of the epileptic network in patients with a history of generalized tonic-clonic convulsions than in patients without. A history of generalized tonic-clonic convulsions reduces the likelihood of becoming seizure free after surgery, a finding reported by several authors (1, 10). Intracranial EEG studies have shown that TLE patients with and without generalized tonic-clonic seizures have differing involvement of lateral temporal structures (11). This finding suggests that patients with and without generalized tonic-clonic seizures have differing epileptogenic networks, and we should include a history of tonic-clonic seizures into our surgical decision making. In conclusion, our methods, albeit sophisticated and highly technological, remain inadequate to determine what needs to be resected to render the patient seizure free, especially if presurgical diagnostic studies are not concordant or conclusive. Our understanding of the epileptogenic disease process remains incomplete—one more reason to continue to research advanced diagnostic methods and underlying pathophysiology for a better understanding of a yet unresolved problem. by Barbara C. Jobst, MD References 1. Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: A review. JAMA 2015;313:285–293. 2. King-Stephens D, Mirro E, Weber PB, Laxer KD, Van Ness PC, Salanova V, Spencer DC, Heck CN, Goldman A, Jobst B, Shields DC, Bergey GK, Eisenschenk S, Worrell GA, Rossi MA, Gross RE, Cole AJ, Sperling MR, Nair DR, Gwinn RP, Park YD, Rutecki PA, Fountain NB, Wharen RE, Hirsch LJ, Miller IO, Barkley GL, Edwards JC, Geller EB, Berg MJ, Sadler TL, Sun FT, Morrell MJ. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia 2015;56:959–967. 3. Wyler AR, Hermann BP, Somes G. Extent of medial temporal resection on outcome from anterior temporal lobectomy: A randomized prospective study. Neurosurgery 1995;37:982–990; discussion 990–991. 4. Sarkis RA, Jehi L, Najm IM, Kotagal P, Bingaman WE. Seizure outcomes following multilobar epilepsy surgery. Epilepsia 2012;53:44–50. 5. Cho EB, Joo EY, Seo DW, Hong SC, Hong SB. Prognostic role of functional neuroimaging after multilobar resection in patients with localization-related epilepsy. PLoS One 2015;10(8):e0136565. 6. Serletis D, Bulacio J, Alexopoulos A, Najm I, Bingaman W, GonzalezMartinez J. Tailored unilobar and multilobar resections for orbitofrontal-plus epilepsy. Neurosurgery 2014;75:388–397; discussion 397.
Temporal Plus Epilepsy
7. Appel S, Sharan AD, Tracy JI, Evans J, Sperling MR. A comparison of occipital and temporal lobe epilepsies. Acta Neurol Scand 2015;132:284–290. 8. Engel J Jr, Bragin A, Staba R, Mody I. High-frequency oscillations: What is normal and what is not? Epilepsia 2009;50:598–604. 9. Englot DJ, Hinkley LB, Kort NS, Imber BS, Mizuiri D, Honma SM, Findlay AM, Garrett C, Cheung PL, Mantle M, Tarapore PE, Knowlton RC, Chang EF, Kirsch HE, Nagarajan SS. Global and regional functional connectivity maps of neural oscillations in focal epilepsy. Brain 2015;138(pt 8):2249–2262.
10. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langfitt JT, Walczak TS, Pacia SV; Multicenter Study of Epilepsy Surgery. Predicting long-term seizure outcome after resective epilepsy surgery: The multicenter study. Neurology 2005;65:912– 918. 11. Yoo JY, Farooque P, Chen WC, Youngblood MW, Zaveri HP, Gerrard JL, Spencer DD, Hirsch LJ, Blumenfeld H. Ictal spread of medial temporal lobe seizures with and without secondary generalization: An intracranial electroencephalography analysis. Epilepsia 2014;55:289–295.
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Temporal Plus Epilepsy: Epileptic Territory Beyond the Temporal Lobes
Temporal Plus Epilepsy Is a Major Determinant of Temporal Lobe Surgery Failures. Barba C, Rheims S, Minotti L, Guénot M, Hoffmann D, Chabardès S, Isnard J, Kahane P, Ryvlin P. Brain 2016;139:444–451. doi:10.1093/brain/awv372.
Reasons for failed temporal lobe epilepsy surgery remain unclear. Temporal plus epilepsy, characterized by a primary temporal lobe epileptogenic zone extending to neighboured regions, might account for a yet unknown proportion of these failures. In this study all patients from two epilepsy surgery programmes who fulfilled the following criteria were included: (i) operated from an anterior temporal lobectomy or disconnection between January 1990 and December 2001; (ii) magnetic resonance imaging normal or showing signs of hippocampal sclerosis; and (iii) postoperative followup ≥ 24 months for seizure-free patients. Patients were classified as suffering from unilateral temporal lobe epilepsy, bitemporal epilepsy or temporal plus epilepsy based on available presurgical data. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom over time. Predictors of seizure recurrence were investigated using Cox proportional hazards model. Of 168 patients included, 108 (63.7%) underwent stereoelectroencephalography, 131 (78%) had hippocampal sclerosis, 149 suffered from unilateral temporal lobe epilepsy (88.7%), one from bitemporal epilepsy (0.6%) and 18 (10.7%) from temporal plus epilepsy. The probability of Engel class I outcome at 10 years of follow-up was 67.3% (95% CI: 63.4–71.2) for the entire cohort, 74.5% (95% CI: 70.6–78.4) for unilateral temporal lobe epilepsy, and 14.8% (95% CI: 5.9–23.7) for temporal plus epilepsy. Multivariate analyses demonstrated four predictors of seizure relapse: temporal plus epilepsy (P < 0.001), postoperative hippocampal remnant (P = 0.001), past history of traumatic or infectious brain insult (P = 0.022), and secondary generalized tonic-clonic seizures (P = 0.023). Risk of temporal lobe surgery failure was 5.06 (95% CI: 2.36–10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy. Temporal plus epilepsy represents a hitherto unrecognized prominent cause of temporal lobe surgery failures. In patients with temporal plus epilepsy, anterior temporal lobectomy appears very unlikely to control seizures and should not be advised. Whether larger resection of temporal plus epileptogenic zones offers greater chance of seizure freedom remains to be investigated.
Commentary Temporal lobe resections have been performed for drugresistant epilepsy for more than half a century (1). Despite many advances in clinical description of syndromes, imaging, and neurophysiology, a significant percentage of patients do not become seizure free after surgery. On average, only about 65% of patients are seizure free long term (1). The reasons why surgery fails remain speculative. Possible explanations include the following: 1. The temporal lobe was not the true seizure onset zone, and seizures originate somewhere else not included in the resection;
Epilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 305–307 © American Epilepsy Society
2. There is more than one seizure onset zone or dual pathology, and only one focus was resected; 3. Temporal lobe epilepsy (TLE) is actually bilateral and was not identified as such; 4. Our concept of focal epilepsy is an inappropriate model for epilepsy. TLE is a network disease, and not enough network nodes were resected; 5. The resection margin becomes a new focus; 6. Not enough of the epileptogenic tissue that extended out of the temporal lobe into other areas of the brain was resected. Barba et al. try to explain temporal lobe surgery failures by the latter. In their study, they focus on a cohort of patients they define as temporal plus epilepsy (TPE). Of 168 patients who underwent temporal lobe resection at two French epilepsy
305
Temporal Plus Epilepsy
centers, they classified patients as TPE if stereoelectroencephalography (S-EEG) confirmed seizure onset in the temporal lobe and simultaneously in extratemporal regions such as the insula, the orbitofrontal cortex, the frontal operculum, or the temporo-parietal-occipital junction. Patients with TPE (n = 18) were compared with patients with no neurophysiologic or imaging evidence of initial involvement of extratemporal structures (n = 150; TLE). Patients with TPE were less likely to have a history of febrile seizures or to have hippocampal sclerosis on MRI but were more likely to have a history of trauma/ infection and generalized tonic-clonic seizures. They report that only 16.7% of patients with TPE had an Engel class I outcome at last follow-up compared with 76.7% of patients with “pure” TLE. The risk of seizure recurrence was five times higher with TPE than with TLE 10 years after surgery. In a multivariate analysis, the authors identified a history of trauma or infection, a history of secondarily generalized seizures, and evidence of postoperative hippocampal remnants as additional risk factors for seizure recurrence. By examining the above-mentioned possible hypotheses, the poor outcomes reported in the TPE cohort could be explained by several mechanisms. It is possible that simultaneous multilobar EEG onset is a reflection of a distant focus (e.g., an occipital focus) that was not sampled with the limited S-EEG sampling, and the presumed ictal onset zone just represents a spread pattern (explanation 1), the seizure onset zone extends beyond the temporal lobe (explanation 6) or there is dual pathology (explanation 2). There is also the possibility that the TPE network has different properties as compared with TLE and therefore requires different surgical approaches (explanation 4). Even contralateral seizure onset is possible, as no information is presented on whether all patients with TPE had bilateral S-EEG investigations (explanation 3). Evidence from patients chronically implanted with the responsive neurostimulator demonstrated that it took, on average, 41 days until contralateral seizures were recorded (2). If patients had contralateral seizures, they may not have been recorded in the short amount of time during S-EEG even if electrodes were placed bilaterally. It is beyond the scope of the study to address the pathophysiological reason for the surgical failures, but the network hypothesis warrants further thought. As the mesial temporal structures are functionally closely connected to the orbitofrontal, insular, and posterior regions, would resections beyond the temporal lobe benefit the TPE patients further? Which are really the necessary nodes that need to be included in a resection? Are we routinely not resecting enough, and we just get away with what we resect in more than 60% of the cases? It is apparent from the study that patients with TPE do not benefit from a temporal lobectomy alone, and the authors discourage temporal lobectomy for patients with multilobar onset on intracranial EEG. They also confirmed that the hippocampus should be completely resected as is consistent with previous similar reports (3). The question of whether multilobar resections, including other areas of the brain in addition to the temporal lobe, would have changed the outcomes remains unanswered. Most reports about multilobar resections include patients with severe, often symptomatic epilepsy
306
with large multilobar lesions. Those studies report a favorable outcome between 40 and 55% (4, 5). The orbitofrontal, insular, and occipital areas are closely connected to the mesial temporal areas and therefore warrant some consideration for surgical planning. Serletis et al. advocate for multilobar resection in orbitofrontal epilepsy plus temporo-polar epilepsy to ensure a good seizure outcome (6). Appel et al. report that multilobar resections are needed in patients with seizures originating in the occipital areas to achieve seizure freedom (7). Advanced imaging and neurophysiologic methods may in the future give us additional patient-specific information about the epileptogenic network and could guide the extent of resection (8, 9). There seem to be inherently different properties of the epileptic network in patients with a history of generalized tonic-clonic convulsions than in patients without. A history of generalized tonic-clonic convulsions reduces the likelihood of becoming seizure free after surgery, a finding reported by several authors (1, 10). Intracranial EEG studies have shown that TLE patients with and without generalized tonic-clonic seizures have differing involvement of lateral temporal structures (11). This finding suggests that patients with and without generalized tonic-clonic seizures have differing epileptogenic networks, and we should include a history of tonic-clonic seizures into our surgical decision making. In conclusion, our methods, albeit sophisticated and highly technological, remain inadequate to determine what needs to be resected to render the patient seizure free, especially if presurgical diagnostic studies are not concordant or conclusive. Our understanding of the epileptogenic disease process remains incomplete—one more reason to continue to research advanced diagnostic methods and underlying pathophysiology for a better understanding of a yet unresolved problem. by Barbara C. Jobst, MD References 1. Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: A review. JAMA 2015;313:285–293. 2. King-Stephens D, Mirro E, Weber PB, Laxer KD, Van Ness PC, Salanova V, Spencer DC, Heck CN, Goldman A, Jobst B, Shields DC, Bergey GK, Eisenschenk S, Worrell GA, Rossi MA, Gross RE, Cole AJ, Sperling MR, Nair DR, Gwinn RP, Park YD, Rutecki PA, Fountain NB, Wharen RE, Hirsch LJ, Miller IO, Barkley GL, Edwards JC, Geller EB, Berg MJ, Sadler TL, Sun FT, Morrell MJ. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia 2015;56:959–967. 3. Wyler AR, Hermann BP, Somes G. Extent of medial temporal resection on outcome from anterior temporal lobectomy: A randomized prospective study. Neurosurgery 1995;37:982–990; discussion 990–991. 4. Sarkis RA, Jehi L, Najm IM, Kotagal P, Bingaman WE. Seizure outcomes following multilobar epilepsy surgery. Epilepsia 2012;53:44–50. 5. Cho EB, Joo EY, Seo DW, Hong SC, Hong SB. Prognostic role of functional neuroimaging after multilobar resection in patients with localization-related epilepsy. PLoS One 2015;10(8):e0136565. 6. Serletis D, Bulacio J, Alexopoulos A, Najm I, Bingaman W, GonzalezMartinez J. Tailored unilobar and multilobar resections for orbitofrontal-plus epilepsy. Neurosurgery 2014;75:388–397; discussion 397.
Temporal Plus Epilepsy
7. Appel S, Sharan AD, Tracy JI, Evans J, Sperling MR. A comparison of occipital and temporal lobe epilepsies. Acta Neurol Scand 2015;132:284–290. 8. Engel J Jr, Bragin A, Staba R, Mody I. High-frequency oscillations: What is normal and what is not? Epilepsia 2009;50:598–604. 9. Englot DJ, Hinkley LB, Kort NS, Imber BS, Mizuiri D, Honma SM, Findlay AM, Garrett C, Cheung PL, Mantle M, Tarapore PE, Knowlton RC, Chang EF, Kirsch HE, Nagarajan SS. Global and regional functional connectivity maps of neural oscillations in focal epilepsy. Brain 2015;138(pt 8):2249–2262.
10. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langfitt JT, Walczak TS, Pacia SV; Multicenter Study of Epilepsy Surgery. Predicting long-term seizure outcome after resective epilepsy surgery: The multicenter study. Neurology 2005;65:912– 918. 11. Yoo JY, Farooque P, Chen WC, Youngblood MW, Zaveri HP, Gerrard JL, Spencer DD, Hirsch LJ, Blumenfeld H. Ictal spread of medial temporal lobe seizures with and without secondary generalization: An intracranial electroencephalography analysis. Epilepsia 2014;55:289–295.
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