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Prognostic factors for surgery of neocortical temporal lobe epilepsy
Seizure (2006) 15, 125—132
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Prognostic factors for surgery of neocortical temporal lobe epilepsy J. Janszky a,b,*, H.W. Pannek a, A. Fogarasi a,c, B. Bone b, R. Schulz a, F. Behne a, A. Ebner a a
Epilepsy Centre Bethel, Bielefeld, Germany ´cs, Pe ´cs, Hungary Department of Neurology, University of Pe c Epilepsy Centre, Bethesda Children’s Hospital, Budapest, Hungary b
Received 11 May 2005; received in revised form 9 September 2005; accepted 5 December 2005
KEYWORDS Epilepsy surgery outcome; Prognosis; Left; Benign tumor; EEG seizure pattern
Summary Objectives: In the current classification of epilepsies two forms of temporal lobe epilepsy (TLE) were included: mesial and lateral (neocortical) TLE. We aimed at identifying prognostic factors for the surgical outcome of lesional neocortical TLE. Methods: We included consecutive patients who had undergone presurgical evaluation including ictal video-EEG and high-resolution MRI, who had TLE due to neocortical lateral epileptogenic lesions, who had a lesionectomy and who had >2-year followup. Results: There were 29 patients who met the inclusion criteria. Twenty of them became postoperatively seizure-free. Patients’ mean age was 34.8 9 years (range 18—52). The age at epilepsy onset was 20.1 8 years. We found that left-sided surgery ( p = 0.048) and focal cortical dysplasia (FCD) on MRI ( p = 0.005) were associated with non-seizure-free outcome, while lateralized/localized EEG seizure pattern ( p = 0.032), tumors on the MRI ( p = 0.013), and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom ( p < 0.001). Multivariate analysis indicated that the side of surgery was not an independent predictor. Conclusion: More than two-thirds of the patients with neocortical TLE became seizure-free postoperatively. Lateralized/localized EEG seizure pattern and tumors on the MRI were associated with postoperative seizure-freedom, while FCD were associated with a poor outcome. The 6-month postoperative outcome is a reliable predictor for the long-term outcome. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel. +36 72535910; fax: +36 72535911. E-mail address: [email protected] (J. Janszky). 1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2005.12.002
126
Introduction Temporal lobe epilepsy (TLE) is the most common type of epilepsy requiring surgical treatment1 and with a favorable surgical prognosis because 60—70% of patients become seizure-free after TLE surgery.2,3 In the current classification of epilepsies and epileptic syndromes two forms of TLE were included: mesial and lateral (neocortical) TLE.4 Compared to mesial TLE, the clinical picture of neocortical TLE is different. The history of febrile seizures is not characteristic.5—7 Auditory and visual auras occur more frequently than in mesial TLE.8,9 Seizures rarely begin with oral automatism5 but a motionless stare7 or motor phenomena5,10 are characteristic early ictal signs. Ictal dystonia6,10—12 occurs infrequently. Interictal and ictal EEG features can also be different from mesial TLE.11,13 Moreover, some studies found that the surgical outcome in neocortical TLE is less favorable than in mesial TLE,11 but others did not find such a difference.14,15 Sudden epileptic death may occur more frequently in neocortical TLE than in mesial TLE.14 The majority of patients with TLE have mesial TLE,16 whereas neocortical TLE occurs in about 10% of all TLE cases.15 Since mesial TLE is the most frequent TLE form, large multivariate studies investigating the surgical outcome in TLE include mostly3,17,18 or exclusively19 mesial TLE patients, whereas neocortical TLE patients make up only a small portion of these studies.20 Because the neocortical and mesial TLE seem to be two different syndromes which require different types of surgery, it is reasonable to assume that different factors may influence the surgical outcome in them. Determination of prognostic factors for surgery is important for counseling our patients in everyday practice. In addition, the identification of prognostic factors may improve general understanding of the pathophysiology of surgical failure and of spatial extension of the epileptogenic zone. In the present study we aimed at identifying prognostic factors which predict the outcome 2 years after epilepsy surgery of TLE with neocortical lesions.
Methods Presurgical evaluation at the Epilepsy Surgery Department of the Epilepsy Centre, Bethel Since observed variables were based on presurgical evaluation of epileptic patients, our procedure is briefly described below.
J. Janszky et al. In patients who were considered possible candidates for epilepsy surgery, a detailed clinical history was taken. Therapy resistance to first-line antiepileptic drugs was evaluated. High-resolution MRI was performed in all patients. MRI pictures in most patients were made by a Siemens Magnetom Impact 1.5-T scanner, and included T1-weighted threedimensional volume, protondensity, FLAIR, and T2-weighted images. Patients underwent continuous video-EEG monitoring lasting 2—10 days. In all patients a psychiatric and a neuropsychological examination, as well as social assessment, was performed. Findings of presurgical evaluation were discussed at a multidisciplinary case conference, where decisions were made concerning the possibility and type of surgery. Patients who underwent epilepsy surgery were re-examined 6 months and 2 years later with an assessment of the seizure outcome as well as with an evaluation of the psychiatric, neuropsychological and social status. Our protocol is for patients to receive antiepileptic drugs (AED) for a minimum of 2 years postoperatively. The dosage and type of AED remain unchanged unless the patients report side-effects.
Patient selection For this study we included all patients who had undergone presurgical evaluation at our center including ictal video-EEG recordings and high-resolution MRI, who were >16 years, who had temporal lobe epilepsy due to neocortical lateral epileptogenic lesions on the MRI, who had had a lesionectomy between 1993 and 2002 and who had >2-year postsurgical follow-up. Patients with mesiotemporal pathology (for example, hippocampal sclerosis) or mesiotemporal resections were not included. All the patients had a detailed clinical history, MRI and longterm video-EEG with ictal and interictal recordings. In order to lateralize the speech representation, speech-activated functional MRI or Wada test was performed in 20 patients. The technical details are described elsewhere.21,22
Data collection The following group of variables were investigated: (1) age at epilepsy onset, (2) duration of epilepsy, (3) presence of secondarily generalized tonic-clonic seizures (SGTCS), (4) seizure semiology, (5) unilateral interictal epileptiform discharges (IED), (6) presence of localized/lateralized EEG seizure pattern, (7) localization and lateralization of the resection, (8) MRI-based diagnosis of the epileptogenic lesion and (9) seizure situation at the 6-month post-
Predictors for surgery outcome in neocortical TLE operative examination. The first three clinical variables were ascertained by asking the patients and (in most cases) their relatives when admitted to the presurgical unit. This history was taken by physicians blinded to the goals of this study. Patients’ previous medical charts were also reviewed. The data on EEG and the seizure semiology was determined by non-invasive continuous video-EEG monitoring. A 32—64 channel EEG recording was used; electrodes were placed according to 10—10 systems, the number of electrodes and their placement varied individually taking into consideration the suspected epileptogenic region and side. The location and frequency of interictal epileptiform discharges (IED) were assessed by visual analysis of interictal EEG samples of 2-min duration every hour. Ictal EEG recordings were stored in separate files and were evaluated independently from the interictal data. Unilateral interictal epileptiform discharges were defined if at least 95% of interictal discharges appeared over one temporal lobe. We defined the seizure-pattern as localized if it appeared exclusively or predominantly over one brain region (Fig. 1). Lateralized seizure pattern was considered if the ictal activity appeared predominantly over one hemisphere. We defined the EEG seizure as nonlateralized if the seizure pattern showed no clear lateralization such as it appeared over both hemispheres symmetrically (Fig. 2).23
Selection of variables The above-mentioned variables were chosen according to their presumed importance in presur-
127 gical evaluation or if they were previously reported as a predictive factor for epilepsy surgery. The results of psychiatric, neuropsychological and sociological assessments were not included.
Outcome assessment Seizure outcome was assessed at regular postoperative examinations (0.5 and 2 years after the operation). We only evaluated the seizure outcome, while the psychiatric, social and neuropsychological outcome was ignored. For this study we divided the patients into two categories: with seizure-free or non-seizure-free outcome. Patients with non-disabling auras without other seizures were considered to be seizure-free. Seizure freedom was defined if the patient was seizure-free in the period of time from the operation to the last outcome assessment, or was seizure free for 18 months prior to the outcome assessment (such as between the 6-month and 2-year postoperative evaluation).
Statistical methods For univariate analyses of categorical variables, Fisher’s exact tests were carried out. The Mann— Whitney U test was used for comparisons of continuous variables. To identify which variables could predict the outcome independently, we performed a multivariate stepwise logistic regression for variables demonstrating a significant effect in univariate analyses. Two-tailed error probabilities smaller than p < 0.05 were considered to be significant.
Figure 1 Lateralized and localized seizure pattern. The rhythmic seizure activity showed a clear predominance over the left-sided temporal electrodes.
128
Figure 2
J. Janszky et al.
Non-lateralized seizure pattern. The rhythmic seizure activity appeared over both hemispheres symmetrically.
Results There were 29 patients who met the inclusion criteria. Twenty of them (69%) became seizure-free within 2 years after the surgery. The mean age of the patients was 34.8 9 years (range 18—52). The age at epilepsy onset was 20.1 8 years (range 4—39). There were 11 women and 18 men. Wada test and/or speech-activated functional MRI was performed in 20 patients (in 11 patients with right-sided and in 9 patients with left-sided epilepsy). Atypical (rightsided) speech lateralization was demonstrated in only one patient with left-sided lesion, in the remaining 19 patients the speech lateralization was left-sided. The lesionectomy was carried out on the left side in 11 and on the right side in 18 patients. Table 1 demonstrates the localization and
the extension of performed lesionectomies. Histological results revealed low grade tumors in 17 (11 gangliogliomas, 3 dysembryoplastic neuroepithelial tumors, 2 low-grade astrocytomas, 1 neurocytoma), focal cortical dysplasia in 4, cavernoma in 5, and posttraumatic lesion in 3 cases. Only one patient underwent invasive monitoring and this patient became seizure-free.
Univariate assessment of prediction Tables 1 and 2 show the results of univariate analyses, identifying variables which were associated with the outcome at 2 years postoperatively. Leftsided surgery and focal cortical dysplasia on MRI were associated with non-seizure-free outcome, while a lateralized/localized seizure pattern on
Table 1 Localization and the extension of performed lesionectomies and their relation to the surgical outcome
Only superior temporal gyrus Only middle temporal gyrus Superior and middle temporal gyrus Middle and inferior temporal gyrus Anterior part of the neocortical temporal region Posterior part of the neocortical temporal region Affected both anterior and posterior parts of the temporal region Extended resection (>5 cm Ø) Circumsrcibed resection (<5 cm Ø)
N (%) in all patients (N = 29)
N (%) in seizurefree patients (N = 20)
N (%) in nonseizure-free patients (N = 9)
Significance level
6 5 10 8 15
4 3 8 5 10
2 2 2 3 5
(22) (22) (22) (33) (56)
NS NS NS NS NS
(21) (17) (34) (28) (52)
(20) (15) (40) (25) (50)
8 (28)
7 (35)
1 (11)
NS
6 (21)
3 (15)
3 (33)
NS
21 (72) 8 (28)
14 (70) 6 (30)
7 (78) 2 (22)
NS NS
Predictors for surgery outcome in neocortical TLE
129
Table 2 Univariate analysis of the variables at 2-year postoperative evaluation
Age (years) Age at epilepsy onset (years) Epilepsy duration (years)
Men Left-sided resection Presence of generalized tonic-clonic seizures Presence of complex partial seizures Tumor on MRI Focal cortical dysplasia on MRI Cavernoma on MRI Posttraumatic injury on MRI Unilateral IED Lateralized/localized seizure pattern Incomplete resection on the postoperative MRI 6-Month seizure-free outcome
Mean (S.D.) in seizurefree patients 2 years after surgery N = 20
Mean (S.D.) in non-seizurefree patients 2 years after surgery N = 9
Significance level
33.2 (6) 18.6 (8) 14.6 (11)
38.3 (9) 23.4 (10) 14.9 (9)
NS NS NS
N (%) in seizure-free patients
N (%) in non-seizure-free patients
Significance level
13 (65) 5 (25) 11 (55)
5 (55) 6 (67) 4 (44)
NS p = 0.048 NS
18 (90)
8 (89)
NS
15 0 4 1 11 20
2 4 1 2 3 6
p = 0.014 p = 0.005 NS NS NS p = 0.032
(75) (0) (20) (5) (55) (100)
(22) (44) (11) (22) (33) (66)
3 (15)
4 (44)
NS
19 (95)
0 (0)
p < 0.001
Abbreviations: IED, interictal epileptiform discharges; MRI, magnetic resonance imaging.
the EEG, a tumor on the MRI, and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom. The localization of the lesionectomy did not influence the outcome (Table 1). One may speculate that due to the neighborhood of eloquent speech centers, left-sided resections can be more circumscribed and the resection more often incomplete and this might be the reason why the resection side showed an association with the outcome. However, we could not demonstrate a statistical relationship between these parameters (Table 3).
Logistic regression analysis In order to determine the independent predictors of outcomes at the four evaluation times, we per-
formed forward selection analyses for those variables which were found to be significant by univariate analysis. The 6-month outcome was not included in the multivariate analysis because it is a postoperative variable and can be highly influenced by the other variables. Moreover, as no patients with focal cortical dysplasia and no patient with an absence of a lateralized/localized seizure pattern has become seizure-free, logistic regression could not be performed on these variables due to the lack of contrast, which makes it mathematically impossible to calculate the odds ratios. Considering the remaining two variables, the side of the resection and the tumor on MRI, only a tumor on the MRI showed a significant association with the outcome by multivariate analysis ( p = 0.013, OR for seizurefree outcome = 1.1, 95% confidence intervals for OR [95% CI]: 1.01—1.85), while the variable left-sided
Table 3 Relationship between side of the resection, the localization and the extension of performed lesionectomies and their relation to the surgical outcome
Circumsrcibed resection (<5 cm Ø) Incomplete resection on the postoperative MRI
N (%) in all patients N = 29
N (%) in patients with right-sided resection N = 18
N (%) in patients with right-sided resection N = 11
Significance level
8 (28)
4 (22)
4 (36)
NS
7 (24)
3 (17)
4 (36)
NS
130
J. Janszky et al.
lesionectomy showed no independent influence on the seizure freedom.
Discussion Two years after surgery of neocortical TLE, 69% of patients became seizure free. This corresponds well with other studies which also found that 60—79% of patients with neocortical TLE have a successful surgery.11,14,15,24 We found that left-sided surgery and focal cortical dysplasia on the MRI were associated with non-seizure-free outcome, while a lateralized/localized seizure pattern on EEG, tumors on the MRI, and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom. Multivariate analysis indicated that the side of surgery was not an independent prognostic factor. Until now, only two studies selectively investigated the surgical prognosis of neocortical TLE. One of them focused only on the intracranial EEG results,24 while the other focused on surgical techniques and histopathological results without using multivariate analyses.15 Furthermore, the latter study conducted by Schramm et al. (2001) included patients in whom the minimal follow-up time was only 1 month, which is an inadequate interval in assessing the outcome and the factors which may have influence on the outcome.15 None of these studies investigated the predictive value of the surface EEG which is one of the most important tools in predicting the outcome of epilepsy surgery.3,17,20,25,26 Table 4 summarizes these studies. In agreement with our study, Schramm et al. (2001) also found that one of the positive predictors for surgery of neocortical TLE was the tumoral etiol-
ogy.15 Another study conducted by Hennessy et al. (2001) investigated the surgical outcome of temporal lobectomy for medically intractable epilepsy associated with focal lesions other than hippocampal sclerosis established by postoperative histology. Although they did not distinguish between mesial and lateral TLE, a standardized temporal lobectomy was performed in all patients. They also found that the presence of tumoral etiology was the best predictor for a seizure-free outcome, while focal cortical dysplasia was associated with poor surgical results.27 Ictal EEG (contralateral seizure pattern or contralateral seizure spread) was found to be a valuable prognostic factor in surgery of mesial TLE proven for surface EEG26 and depth recordings.28 Jung et al. (1999) found that localized intracranial ictal EEG pattern and slow ictal spread were correlated with favorable outcome in neocortical TLE, which is in agreement with our study because we also found that a lateralized/localized seizure pattern seen on ictal scalp EEG was associated with a favorable outcome.24 One patient who was not seizure-free at the 6month postoperative evaluation became seizurefree by the 2-year evaluation, while for the remaining patients, the 6-month and 2-year postoperative outcomes were identical. The fact that the 6-month outcome was an excellent predictor for the 2-year outcome underscores the fact that the postoperative seizure status may not change over time as is seen in mesial TLE.19 One of the limitations of the present study is that the relatively low number of patients resulted in limited statistical power. Thus, some infrequent clinical phenomena (for example, the posttraumatic injury, types of resection, incomplete resection) might have had no chance of reaching statistical
Table 4 Studies selectively investigated the surgical prognosis of neocortical TLE Number of operated patients Minimal follow-up Ratio of postoperatively seizure-free patients Positive predictors
Jung et al. (1999) 24
Schramm et al. (2001) 15
Present study
31
62
29
18 months 67%
1 month 79%
2 years 69%
1. Localized seizure onset on the invasive EEG 2. Anteriotemporal seizure onset 3. Slow ictal propagation time
Tumorous tissue on histological examination
1. Lateralized, localized seizure pattern 2. Tumor on MRI
Negative predictors a
This variable was not found to be significant by multivariate analysis.
1. Cortical dysplasia 2. Left-sided lesionectomy a
Predictors for surgery outcome in neocortical TLE significance because it did not occur at a high enough frequency to reach statistical significance although it occurred more frequently in non-seizure-free patients. In conclusion, we found that more than twothirds of patients with neocortical TLE became seizure-free 2 years after the operation. A lateralized/localized seizure pattern on the EEG and tumors on the MRI were associated with postoperative seizure-freedom, while focal cortical dysplasia on the MRI were associated with a poor surgical outcome. The 6-month postoperative outcome is a very reliable predictor for the long-term (2-year) outcome. Our study may facilitate other studies enrolling larger numbers of patients to confirm our results by investigating data of patients having epilepsy surgery due to neocortical TLE.
Acknowledgments This work was supported by the Humboldt Foundation and a grant from the Deutsche Forschungsgemeinschaft (DFG-Eb 111/2-2). A.F. was supported by the grant #D 048517 from the Hungarian Scientific Research Fund. J.J. was supported by Bolyai Scholarship. We gratefully acknowledge Terri Shore Ebner who carefully reviewed the manuscript as a native English speaker. We wish to thank Hermann Steffen who helped us in data collection and organized the postoperative examinations.
References 1. Engel J, Cascino GD, Shields WD. Surgically remediable syndromes. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincot-Raven Publishers; 1997. p. 1687—96. 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;345:311—8. 3. Radhakrishnan K, So EL, Silbert PL, Jack CR, Cascino GD, Sharbrough FW, et al. Predictors of outcome of anterior temporal lobectomy for intractable epilepsy–—a multivariate study. Neurology 1998;51:465—71. 4. Commission on Classification and Terminology of the Internal League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389— 99. 5. Gil-Nagel A, Risiger MW. Ictal semiology in hippocampal versus extrahippocampal temporal lobe epilepsy. Brain 1997;120:183—92. 6. Foldvary N, Lee N, Thwaites G, et al. Clinical and electrographic manifestations of lesional neocortical temporal lobe epilepsy. Neurology 1997;49:757—63.
131 7. Pacia SV, Devinsky O, Perrine K, et al. Clinical features of neocortical temporal lobe epilepsy. Ann Neurol 1996;40: 724—30. 8. Ebner A. Lateral (neocortical) temporal lobe epilepsy. In: Wolf P, editor. Epileptic seizures and syndromes. Paris: John Libbey and & Company Ltd.; 1994. p. 375—82. 9. Maillard L, Vignal JP, Gavaret M, et al. Semiologic and electrophysiologic correlations in temporal lobe seizure subtypes. Epilepsia 2004;45:1590—4. 10. Pfander M, Arnold S, Henkel A, Weil S, Werhahn KJ, Eisensehr I, et al. Clinical features and EEG findings differentiating mesial from neocortical temporal lobe epilepsy. Epileptic Disord 2002;4:189—95. 11. O’Brien TJ, Kilpatrick TC, Murrie V, Vogrin S, Morris K, Cook MJ. Temporal lobe epilepsy caused by mesial temporal lobe sclerosis and temporal neocortical lesions. Brain 1996; 119:2133—44. 12. Dupont S, Semah F, Boon P, Saint-Hilaire JM, Adam C, Broglin D, et al. Association of ipsilateral motor automatisms and contralateral dystonic posturing: a clinical feature differentiating medial from neocortical temporal lobe epilepsy. Arch Neurol 1999;56:927—32. 13. Boon P, D’Have M, Van Hoey G, Vanrumste B, Vonck K, Adam C, et al. Interictal and ictal source localization in neocortical versus medial temporal lobe epilepsy. Adv Neurol 2000; 84:365—75. 14. Burgeman RS, Sperling MR, French JA, Saykin AJ, O’Connor MJ. Comparison of mesial versus neocortical onset temporal lobe seizures: neurodiagnostic findings and surgical outcome. Epilepsia 1995;36:662—70. 15. Schramm J, Kral T, Grunwald T, Blumcke I. Surgical treatment for neocortical temporal lobe epilepsy: clinical and surgical aspects and seizure outcome. J Neurosurg 2001;94: 33—42. 16. Wieser HG, ILAE Commission on Neurosurgery of Epilepsy. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695—714. 17. Blume WT, Desai HB, Girvin JP, McLachlan RS, Lemieux JF. Effectiveness of temporal lobectomy measured by yearly follow-up and multivariate analysis. J Epilepsy 1994;7: 203—14. 18. Berkovic SF, McIntosh AM, Kalnins RM. Preoperative MRI predicts outcome of temporal lobectomy. Neurology 1995; 45:1358—63. 19. Janszky J, Janszky I, Schulz R, Hoppe M, Behne F, Pannek HW, et al. Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome. Brain 2005;128: 395—404. 20. McIntosh AM, Wilson SJ, Berkovic SF. Seizure outcome after temporal lobectomy: current research practice and findings. Epilepsia 2001;42:1288—307. 21. Jokeit H, Ebner A, Holthausen H, Markowitsch HJ, Moch A, Pannek H, et al. Individual prediction of change in delayed recall of prose passages after left-sided anterior temporal lobectomy. Neurology 1997;49:481—7. 22. Woermann FG, Jokeit H, Luerding R, Freitag H, Schulz R, Guertler S, et al. Language lateralization by Wada test and fMRI in 100 patients with epilepsy. Neurology 2003;61: 699—701. 23. Lu ¨ders HO, Noachtar S. Atlas und Klassifkation der Elektroenzephalographie. Wehr: CIBA-GEIGY Verlag; 1994. 24. Jung WY, Pacia SV, Devinsky R. Neocortical temporal lobe epilepsy: intracranial EEG features and surgical outcome. J Clin Neurophysiol 1999;16:419—25. 25. Janszky J, Jokeit H, Schulz R, Hoppe M, Ebner A. EEG predicts surgical outcome in lesional frontal lobe epilepsy. Neurology 2000;54:1470—6.
132 26. Schulz R, Lu ¨ders HO, Hoppe M, Tuxhorn I, May T, Ebner A. Interictal EEG and ictal scalp EEG propagation are highly predictive of surgical outcome in mesial temporal lobe epilepsy. Epilepsia 2000;41:564—70. 27. Hennessy MJ, Elwes RD, Honavar M, Rabe-Hesketh S, Binnie CD, Polkey CE. Predictors of outcome and pathological con-
J. Janszky et al. siderations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions. J Neurol Neurosurg Psychiatry 2001;70:450—8. 28. Lee KH, Park YD, King DW, Meador KJ, Lorring DW, Murro AM, et al. Prognostic implication of contralateral electrographic seizures in temporal lobe epilepsy. Epilepsia 2000;41:1444—9.
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Prognostic factors for surgery of neocortical temporal lobe epilepsy J. Janszky a,b,*, H.W. Pannek a, A. Fogarasi a,c, B. Bone b, R. Schulz a, F. Behne a, A. Ebner a a
Epilepsy Centre Bethel, Bielefeld, Germany ´cs, Pe ´cs, Hungary Department of Neurology, University of Pe c Epilepsy Centre, Bethesda Children’s Hospital, Budapest, Hungary b
Received 11 May 2005; received in revised form 9 September 2005; accepted 5 December 2005
KEYWORDS Epilepsy surgery outcome; Prognosis; Left; Benign tumor; EEG seizure pattern
Summary Objectives: In the current classification of epilepsies two forms of temporal lobe epilepsy (TLE) were included: mesial and lateral (neocortical) TLE. We aimed at identifying prognostic factors for the surgical outcome of lesional neocortical TLE. Methods: We included consecutive patients who had undergone presurgical evaluation including ictal video-EEG and high-resolution MRI, who had TLE due to neocortical lateral epileptogenic lesions, who had a lesionectomy and who had >2-year followup. Results: There were 29 patients who met the inclusion criteria. Twenty of them became postoperatively seizure-free. Patients’ mean age was 34.8 9 years (range 18—52). The age at epilepsy onset was 20.1 8 years. We found that left-sided surgery ( p = 0.048) and focal cortical dysplasia (FCD) on MRI ( p = 0.005) were associated with non-seizure-free outcome, while lateralized/localized EEG seizure pattern ( p = 0.032), tumors on the MRI ( p = 0.013), and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom ( p < 0.001). Multivariate analysis indicated that the side of surgery was not an independent predictor. Conclusion: More than two-thirds of the patients with neocortical TLE became seizure-free postoperatively. Lateralized/localized EEG seizure pattern and tumors on the MRI were associated with postoperative seizure-freedom, while FCD were associated with a poor outcome. The 6-month postoperative outcome is a reliable predictor for the long-term outcome. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel. +36 72535910; fax: +36 72535911. E-mail address: [email protected] (J. Janszky). 1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2005.12.002
126
Introduction Temporal lobe epilepsy (TLE) is the most common type of epilepsy requiring surgical treatment1 and with a favorable surgical prognosis because 60—70% of patients become seizure-free after TLE surgery.2,3 In the current classification of epilepsies and epileptic syndromes two forms of TLE were included: mesial and lateral (neocortical) TLE.4 Compared to mesial TLE, the clinical picture of neocortical TLE is different. The history of febrile seizures is not characteristic.5—7 Auditory and visual auras occur more frequently than in mesial TLE.8,9 Seizures rarely begin with oral automatism5 but a motionless stare7 or motor phenomena5,10 are characteristic early ictal signs. Ictal dystonia6,10—12 occurs infrequently. Interictal and ictal EEG features can also be different from mesial TLE.11,13 Moreover, some studies found that the surgical outcome in neocortical TLE is less favorable than in mesial TLE,11 but others did not find such a difference.14,15 Sudden epileptic death may occur more frequently in neocortical TLE than in mesial TLE.14 The majority of patients with TLE have mesial TLE,16 whereas neocortical TLE occurs in about 10% of all TLE cases.15 Since mesial TLE is the most frequent TLE form, large multivariate studies investigating the surgical outcome in TLE include mostly3,17,18 or exclusively19 mesial TLE patients, whereas neocortical TLE patients make up only a small portion of these studies.20 Because the neocortical and mesial TLE seem to be two different syndromes which require different types of surgery, it is reasonable to assume that different factors may influence the surgical outcome in them. Determination of prognostic factors for surgery is important for counseling our patients in everyday practice. In addition, the identification of prognostic factors may improve general understanding of the pathophysiology of surgical failure and of spatial extension of the epileptogenic zone. In the present study we aimed at identifying prognostic factors which predict the outcome 2 years after epilepsy surgery of TLE with neocortical lesions.
Methods Presurgical evaluation at the Epilepsy Surgery Department of the Epilepsy Centre, Bethel Since observed variables were based on presurgical evaluation of epileptic patients, our procedure is briefly described below.
J. Janszky et al. In patients who were considered possible candidates for epilepsy surgery, a detailed clinical history was taken. Therapy resistance to first-line antiepileptic drugs was evaluated. High-resolution MRI was performed in all patients. MRI pictures in most patients were made by a Siemens Magnetom Impact 1.5-T scanner, and included T1-weighted threedimensional volume, protondensity, FLAIR, and T2-weighted images. Patients underwent continuous video-EEG monitoring lasting 2—10 days. In all patients a psychiatric and a neuropsychological examination, as well as social assessment, was performed. Findings of presurgical evaluation were discussed at a multidisciplinary case conference, where decisions were made concerning the possibility and type of surgery. Patients who underwent epilepsy surgery were re-examined 6 months and 2 years later with an assessment of the seizure outcome as well as with an evaluation of the psychiatric, neuropsychological and social status. Our protocol is for patients to receive antiepileptic drugs (AED) for a minimum of 2 years postoperatively. The dosage and type of AED remain unchanged unless the patients report side-effects.
Patient selection For this study we included all patients who had undergone presurgical evaluation at our center including ictal video-EEG recordings and high-resolution MRI, who were >16 years, who had temporal lobe epilepsy due to neocortical lateral epileptogenic lesions on the MRI, who had had a lesionectomy between 1993 and 2002 and who had >2-year postsurgical follow-up. Patients with mesiotemporal pathology (for example, hippocampal sclerosis) or mesiotemporal resections were not included. All the patients had a detailed clinical history, MRI and longterm video-EEG with ictal and interictal recordings. In order to lateralize the speech representation, speech-activated functional MRI or Wada test was performed in 20 patients. The technical details are described elsewhere.21,22
Data collection The following group of variables were investigated: (1) age at epilepsy onset, (2) duration of epilepsy, (3) presence of secondarily generalized tonic-clonic seizures (SGTCS), (4) seizure semiology, (5) unilateral interictal epileptiform discharges (IED), (6) presence of localized/lateralized EEG seizure pattern, (7) localization and lateralization of the resection, (8) MRI-based diagnosis of the epileptogenic lesion and (9) seizure situation at the 6-month post-
Predictors for surgery outcome in neocortical TLE operative examination. The first three clinical variables were ascertained by asking the patients and (in most cases) their relatives when admitted to the presurgical unit. This history was taken by physicians blinded to the goals of this study. Patients’ previous medical charts were also reviewed. The data on EEG and the seizure semiology was determined by non-invasive continuous video-EEG monitoring. A 32—64 channel EEG recording was used; electrodes were placed according to 10—10 systems, the number of electrodes and their placement varied individually taking into consideration the suspected epileptogenic region and side. The location and frequency of interictal epileptiform discharges (IED) were assessed by visual analysis of interictal EEG samples of 2-min duration every hour. Ictal EEG recordings were stored in separate files and were evaluated independently from the interictal data. Unilateral interictal epileptiform discharges were defined if at least 95% of interictal discharges appeared over one temporal lobe. We defined the seizure-pattern as localized if it appeared exclusively or predominantly over one brain region (Fig. 1). Lateralized seizure pattern was considered if the ictal activity appeared predominantly over one hemisphere. We defined the EEG seizure as nonlateralized if the seizure pattern showed no clear lateralization such as it appeared over both hemispheres symmetrically (Fig. 2).23
Selection of variables The above-mentioned variables were chosen according to their presumed importance in presur-
127 gical evaluation or if they were previously reported as a predictive factor for epilepsy surgery. The results of psychiatric, neuropsychological and sociological assessments were not included.
Outcome assessment Seizure outcome was assessed at regular postoperative examinations (0.5 and 2 years after the operation). We only evaluated the seizure outcome, while the psychiatric, social and neuropsychological outcome was ignored. For this study we divided the patients into two categories: with seizure-free or non-seizure-free outcome. Patients with non-disabling auras without other seizures were considered to be seizure-free. Seizure freedom was defined if the patient was seizure-free in the period of time from the operation to the last outcome assessment, or was seizure free for 18 months prior to the outcome assessment (such as between the 6-month and 2-year postoperative evaluation).
Statistical methods For univariate analyses of categorical variables, Fisher’s exact tests were carried out. The Mann— Whitney U test was used for comparisons of continuous variables. To identify which variables could predict the outcome independently, we performed a multivariate stepwise logistic regression for variables demonstrating a significant effect in univariate analyses. Two-tailed error probabilities smaller than p < 0.05 were considered to be significant.
Figure 1 Lateralized and localized seizure pattern. The rhythmic seizure activity showed a clear predominance over the left-sided temporal electrodes.
128
Figure 2
J. Janszky et al.
Non-lateralized seizure pattern. The rhythmic seizure activity appeared over both hemispheres symmetrically.
Results There were 29 patients who met the inclusion criteria. Twenty of them (69%) became seizure-free within 2 years after the surgery. The mean age of the patients was 34.8 9 years (range 18—52). The age at epilepsy onset was 20.1 8 years (range 4—39). There were 11 women and 18 men. Wada test and/or speech-activated functional MRI was performed in 20 patients (in 11 patients with right-sided and in 9 patients with left-sided epilepsy). Atypical (rightsided) speech lateralization was demonstrated in only one patient with left-sided lesion, in the remaining 19 patients the speech lateralization was left-sided. The lesionectomy was carried out on the left side in 11 and on the right side in 18 patients. Table 1 demonstrates the localization and
the extension of performed lesionectomies. Histological results revealed low grade tumors in 17 (11 gangliogliomas, 3 dysembryoplastic neuroepithelial tumors, 2 low-grade astrocytomas, 1 neurocytoma), focal cortical dysplasia in 4, cavernoma in 5, and posttraumatic lesion in 3 cases. Only one patient underwent invasive monitoring and this patient became seizure-free.
Univariate assessment of prediction Tables 1 and 2 show the results of univariate analyses, identifying variables which were associated with the outcome at 2 years postoperatively. Leftsided surgery and focal cortical dysplasia on MRI were associated with non-seizure-free outcome, while a lateralized/localized seizure pattern on
Table 1 Localization and the extension of performed lesionectomies and their relation to the surgical outcome
Only superior temporal gyrus Only middle temporal gyrus Superior and middle temporal gyrus Middle and inferior temporal gyrus Anterior part of the neocortical temporal region Posterior part of the neocortical temporal region Affected both anterior and posterior parts of the temporal region Extended resection (>5 cm Ø) Circumsrcibed resection (<5 cm Ø)
N (%) in all patients (N = 29)
N (%) in seizurefree patients (N = 20)
N (%) in nonseizure-free patients (N = 9)
Significance level
6 5 10 8 15
4 3 8 5 10
2 2 2 3 5
(22) (22) (22) (33) (56)
NS NS NS NS NS
(21) (17) (34) (28) (52)
(20) (15) (40) (25) (50)
8 (28)
7 (35)
1 (11)
NS
6 (21)
3 (15)
3 (33)
NS
21 (72) 8 (28)
14 (70) 6 (30)
7 (78) 2 (22)
NS NS
Predictors for surgery outcome in neocortical TLE
129
Table 2 Univariate analysis of the variables at 2-year postoperative evaluation
Age (years) Age at epilepsy onset (years) Epilepsy duration (years)
Men Left-sided resection Presence of generalized tonic-clonic seizures Presence of complex partial seizures Tumor on MRI Focal cortical dysplasia on MRI Cavernoma on MRI Posttraumatic injury on MRI Unilateral IED Lateralized/localized seizure pattern Incomplete resection on the postoperative MRI 6-Month seizure-free outcome
Mean (S.D.) in seizurefree patients 2 years after surgery N = 20
Mean (S.D.) in non-seizurefree patients 2 years after surgery N = 9
Significance level
33.2 (6) 18.6 (8) 14.6 (11)
38.3 (9) 23.4 (10) 14.9 (9)
NS NS NS
N (%) in seizure-free patients
N (%) in non-seizure-free patients
Significance level
13 (65) 5 (25) 11 (55)
5 (55) 6 (67) 4 (44)
NS p = 0.048 NS
18 (90)
8 (89)
NS
15 0 4 1 11 20
2 4 1 2 3 6
p = 0.014 p = 0.005 NS NS NS p = 0.032
(75) (0) (20) (5) (55) (100)
(22) (44) (11) (22) (33) (66)
3 (15)
4 (44)
NS
19 (95)
0 (0)
p < 0.001
Abbreviations: IED, interictal epileptiform discharges; MRI, magnetic resonance imaging.
the EEG, a tumor on the MRI, and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom. The localization of the lesionectomy did not influence the outcome (Table 1). One may speculate that due to the neighborhood of eloquent speech centers, left-sided resections can be more circumscribed and the resection more often incomplete and this might be the reason why the resection side showed an association with the outcome. However, we could not demonstrate a statistical relationship between these parameters (Table 3).
Logistic regression analysis In order to determine the independent predictors of outcomes at the four evaluation times, we per-
formed forward selection analyses for those variables which were found to be significant by univariate analysis. The 6-month outcome was not included in the multivariate analysis because it is a postoperative variable and can be highly influenced by the other variables. Moreover, as no patients with focal cortical dysplasia and no patient with an absence of a lateralized/localized seizure pattern has become seizure-free, logistic regression could not be performed on these variables due to the lack of contrast, which makes it mathematically impossible to calculate the odds ratios. Considering the remaining two variables, the side of the resection and the tumor on MRI, only a tumor on the MRI showed a significant association with the outcome by multivariate analysis ( p = 0.013, OR for seizurefree outcome = 1.1, 95% confidence intervals for OR [95% CI]: 1.01—1.85), while the variable left-sided
Table 3 Relationship between side of the resection, the localization and the extension of performed lesionectomies and their relation to the surgical outcome
Circumsrcibed resection (<5 cm Ø) Incomplete resection on the postoperative MRI
N (%) in all patients N = 29
N (%) in patients with right-sided resection N = 18
N (%) in patients with right-sided resection N = 11
Significance level
8 (28)
4 (22)
4 (36)
NS
7 (24)
3 (17)
4 (36)
NS
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lesionectomy showed no independent influence on the seizure freedom.
Discussion Two years after surgery of neocortical TLE, 69% of patients became seizure free. This corresponds well with other studies which also found that 60—79% of patients with neocortical TLE have a successful surgery.11,14,15,24 We found that left-sided surgery and focal cortical dysplasia on the MRI were associated with non-seizure-free outcome, while a lateralized/localized seizure pattern on EEG, tumors on the MRI, and a favorable seizure situation at the 6-month postoperative evaluation were associated with 2-year postoperative seizure-freedom. Multivariate analysis indicated that the side of surgery was not an independent prognostic factor. Until now, only two studies selectively investigated the surgical prognosis of neocortical TLE. One of them focused only on the intracranial EEG results,24 while the other focused on surgical techniques and histopathological results without using multivariate analyses.15 Furthermore, the latter study conducted by Schramm et al. (2001) included patients in whom the minimal follow-up time was only 1 month, which is an inadequate interval in assessing the outcome and the factors which may have influence on the outcome.15 None of these studies investigated the predictive value of the surface EEG which is one of the most important tools in predicting the outcome of epilepsy surgery.3,17,20,25,26 Table 4 summarizes these studies. In agreement with our study, Schramm et al. (2001) also found that one of the positive predictors for surgery of neocortical TLE was the tumoral etiol-
ogy.15 Another study conducted by Hennessy et al. (2001) investigated the surgical outcome of temporal lobectomy for medically intractable epilepsy associated with focal lesions other than hippocampal sclerosis established by postoperative histology. Although they did not distinguish between mesial and lateral TLE, a standardized temporal lobectomy was performed in all patients. They also found that the presence of tumoral etiology was the best predictor for a seizure-free outcome, while focal cortical dysplasia was associated with poor surgical results.27 Ictal EEG (contralateral seizure pattern or contralateral seizure spread) was found to be a valuable prognostic factor in surgery of mesial TLE proven for surface EEG26 and depth recordings.28 Jung et al. (1999) found that localized intracranial ictal EEG pattern and slow ictal spread were correlated with favorable outcome in neocortical TLE, which is in agreement with our study because we also found that a lateralized/localized seizure pattern seen on ictal scalp EEG was associated with a favorable outcome.24 One patient who was not seizure-free at the 6month postoperative evaluation became seizurefree by the 2-year evaluation, while for the remaining patients, the 6-month and 2-year postoperative outcomes were identical. The fact that the 6-month outcome was an excellent predictor for the 2-year outcome underscores the fact that the postoperative seizure status may not change over time as is seen in mesial TLE.19 One of the limitations of the present study is that the relatively low number of patients resulted in limited statistical power. Thus, some infrequent clinical phenomena (for example, the posttraumatic injury, types of resection, incomplete resection) might have had no chance of reaching statistical
Table 4 Studies selectively investigated the surgical prognosis of neocortical TLE Number of operated patients Minimal follow-up Ratio of postoperatively seizure-free patients Positive predictors
Jung et al. (1999) 24
Schramm et al. (2001) 15
Present study
31
62
29
18 months 67%
1 month 79%
2 years 69%
1. Localized seizure onset on the invasive EEG 2. Anteriotemporal seizure onset 3. Slow ictal propagation time
Tumorous tissue on histological examination
1. Lateralized, localized seizure pattern 2. Tumor on MRI
Negative predictors a
This variable was not found to be significant by multivariate analysis.
1. Cortical dysplasia 2. Left-sided lesionectomy a
Predictors for surgery outcome in neocortical TLE significance because it did not occur at a high enough frequency to reach statistical significance although it occurred more frequently in non-seizure-free patients. In conclusion, we found that more than twothirds of patients with neocortical TLE became seizure-free 2 years after the operation. A lateralized/localized seizure pattern on the EEG and tumors on the MRI were associated with postoperative seizure-freedom, while focal cortical dysplasia on the MRI were associated with a poor surgical outcome. The 6-month postoperative outcome is a very reliable predictor for the long-term (2-year) outcome. Our study may facilitate other studies enrolling larger numbers of patients to confirm our results by investigating data of patients having epilepsy surgery due to neocortical TLE.
Acknowledgments This work was supported by the Humboldt Foundation and a grant from the Deutsche Forschungsgemeinschaft (DFG-Eb 111/2-2). A.F. was supported by the grant #D 048517 from the Hungarian Scientific Research Fund. J.J. was supported by Bolyai Scholarship. We gratefully acknowledge Terri Shore Ebner who carefully reviewed the manuscript as a native English speaker. We wish to thank Hermann Steffen who helped us in data collection and organized the postoperative examinations.
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