Comparison of short-term outcome between surgical and clinical treatment in temporal lobe epilepsy: A prospective study

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1 Seizure (2006) 15, Comparison of short-term outcome between surgical and clinical treatment in temporal lobe epilepsy: A prospective study Clarissa L. Yasuda a,b, Helder Tedeschi a,b, Evandro L.P. Oliveira a,b, Guilherme C. Ribas a,b, Alberto L.C. Costa a,tânia A.M.O. Cardoso a, Maria A. Montenegro a, Carlos A.M. Guerreiro a, Marilisa M. Guerreiro a, Li M. Li a, Fernando Cendes a, * a Department of Neurology, State University of Campinas, Campinas, SP , Brazil b Division of Neurosurgery, Department of Neurology, State University of Campinas, Campinas, SP , Brazil Received 16 February 2005; received in revised form 8 October 2005; accepted 31 October 2005 KEYWORDS Temporal lobe epilepsy; Partial seizures; Surgery; Antiepileptic drugs; Treatment; Outcome; Adverse effects Summary Objective: To compare the efficacy of medical and surgical treatment for refractory mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE). Methods: A prospective controlled non-randomized study of 26 patients with MTLE who underwent surgical treatment and 75 patients with MTLE who underwent medical treatment between August 2002 and October All patients failed to achieve seizure control with at least two first line antiepileptic drugs (AED) for partial seizures before entering the study. We used Kaplan Meier survival analyses as a function of time of seizure recurrence to obtain estimates of 95% confident interval of seizure freedom and log-rank test to compare the status of seizure control between the two groups. Results: The cumulative proportion of patients free of all seizures (Engel s class IA) was higher in the surgical group (73%) compared to the clinical group (12%) ( p < ). In the surgical group, 2 of 26 patients (7.7%) had transient adverse effects and 2 of 26 patients (7.7%) had a permanent deficit related to the surgical procedure. In the clinical group 7 patients (9.3%) major adverse events during follow-up, including burns and status epilepticus. Conclusions: Surgical treatment for patients with MTLE who failed to achieve seizure control with two previous AED regimens was more efficient than medical treatment with further trials of AED. # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. * Corresponding author /$ see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 36 C.L. Yasuda et al. Introduction Epilepsy affects between 0.5 and 2% of the general population. 1 5 The accumulated urban prevalence in Brazil was recently estimated in 18.6/1000 inhabitants. 6 It is the second most frequent neurological condition, 7 and its worldwide burden is compared to that of breast cancer in women and lung cancer in men. 7 9 Epileptic syndromes presenting with partial seizures account for 50 70% of all epilepsies and are refractory to adequate drug therapy 3,7 in approximately 60% of these patients. 2,3,10,11 Surgery for intractable focal epilepsy has been proposed for more than a century, 12 and more recent technological advances have made possible to expand the number of patients who may benefit from surgery The overall rate of significant improvement with the surgery for temporal lobe epilepsy (TLE) is %, 18,19 but the rate of patients free of seizures is lower, varying from 63 to 77%. 9,18 21 Despite the good results with low rates of complications, 9,22 26 surgery is still underused, particularly in developing countries. One of the reasons for this is probably related to the lack of studies confirming the safety and efficacy of surgery as compared to multiple trials of antiepileptic drugs (AEDs) and the failure of primary care physicians on identifying the possible candidates. 9 For most patients who failed to achieve seizure control after first-line AEDs, surgery is still considered the last resort, being offered late in life, rendering psychosocial rehabilitation unlikely. 22 In this study, we compared the rates of seizure freedom between medical and surgical treatment in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE) who have failed to obtain seizure control with at least two AED regimens. Methods This is a prospective controlled non-randomized study designed to compare patients with refractory MTLE submitted to medical and surgical treatment at the Epilepsy Service of State University of Campinas, Brazil. We consecutively included all the patients with diagnosis of MTLE with MRI evidence of hippocampal sclerosis seen at the outpatient clinic for refractory epilepsy at our institution, during the period between August 2002 and October 2004, who fulfilled the following criteria: older than 12 years of age, clinical and EEG features of MTLE, 11 failure of seizure control with at least two AED regimens and seizure frequency at least one seizure per month over the year before entry in the study. We excluded patients with any additional progressive disease, such as malignancy or neurodegenerative disorders and those with previous epilepsy surgery. Patients were explained that participation in this study would not interfere with their medical treatment or with the possibility of surgical treatment and that they could withdraw from the study at any time. They underwent our routine outpatient investigation, including electroencephalography (EEG), magnetic resonance imaging (MRI) (T1-weighted axial, coronal and sagittal, proton-density, T2-weighted and fluid-attenuated inversion recovery sequences), neuropsychological and psychological assessments. Some patients with unclear origin of ictal discharges were admitted to the hospital for video-eeg and ictal SPECT when necessary before surgery. Clinical and surgical groups The clinical group consisted of all patients included in the study while they were waiting for completing their pre-surgical investigation, or waiting for surgical procedure after having completed their presurgical investigation, as well as those who rejected the surgical treatment for personal reasons, including religious aspects and fear of complications. Apart from the personal rejection, they had no other different risk factors and they were all equally considered surgical candidates. The surgical group consisted of all refractory MTLE patients who were operated during the study period. Patients from both groups were explained to complete a seizure calendar. The descriptions of events were examined by at least two epileptologists who reached a consensus to classify as a seizure or not. Interventions Three experienced neurosurgeons performed the selective transsylvian amygdalohippocampectomy. 27 We recorded the details of each surgery and also all the per operative complications. After surgery they received standard post-operative care and were instructed to maintain the same AEDs dosage used before for at least one year, even if they were free of seizures. They were followed monthly during the first 3 months, every 2 months until 6 months and every 4 months after 6 months. During this follow-up the epileptologists took into account individual requirements, including correction of serum electrolytes and adjustments of the dosage of AEDs in order to avoid side effects. The clinical group has been followed since the baseline with clinical visitations every 2 4 months.

3 Comparison between surgical and clinical treatment in temporal lobe epilepsy 37 Patients received either monotherapy with a first line AED different from the ones used before baseline, or a combination of AED (polytherapy). For these patients the epileptologists made the necessary and appropriated AED adjustments and combinations, according to individual maximal tolerance. We made telephone calls for patients who missed the visits. Patients from both groups were instructed to return for unscheduled visits or contact us by telephone in case of any unexpected side effect, accident, or increase in seizure frequency. Statistical analysis We used T-test and paired T-test and to analyze differences of continuous variables between groups and Pearson x 2 and Fisher exact tests to analyze frequency distribution. To compare the status of seizure control between the two groups we used Kaplan Meier event-free survival analyses to obtain estimates of 95% confident intervals of seizure freedom and log-rank test to compare the results between the two groups. We chose the Kaplan Meier method of analysis because it is an appropriate method to compare the performances of different procedures in short-term analysis. This method permits us to include in the same analysis individuals with variations in follow-up duration and also those individuals who did not experience the outcome event during the period of study. We chose the Mantel log-rank test to compare the results from the survival distribution and to confirm that the differences were greater than expected by chance. 19,28 Results We studied 101 consecutive patients from our Epilepsy s Clinic, according to our inclusion criteria described above. There were 75 patients in the clinical group and 26 patients in the surgical group. Before the baseline, there were no significant differences between the two groups in terms of gender distribution ( p =0.91),age(p = 0.13), antecedent of previous status epilepticus ( p = 0.71) or accidents during the follow-up ( p = 0.54), including burns and falls with head injury. At the baseline of the study, patients from the surgical group showed an earlier onset of seizures in life ( ) compared to the clinical group ( ) ( p = 0.03). The monthly average seizure frequency in the year before the baseline was significantly higher in the surgical group than in the clinical group ( p = 0.001) (Table 1). The mean follow-up (range) was 12.7 (range 2 24) months for the surgical group and 12.7 (range 3 24) months for the clinical group ( p = 0.96). In the surgical group all the 26 patients underwent transsylvian selective amygdalohippocampectomy (16 on the left and 10 on the right side). In 15 patients surgery was decided on the basis of unilateral EEG discharges on serial routine and prolonged EEG, coincident with ipsilateral Table 1 Characteristics of patients Variable Clinical group (N = 75) Surgical group (N = 26) Statistics Age (years) at the study entry T-test; p = 0.13 Age (years) at the onset of seizures T-test; p = 0.03 Male/Female 35%/65% 38.5%/61.5% Yates corrected x 2 ; p = 0.91 History of status epilepticus 4% Fisher s exact test; p = 0.57 Duration of follow-up (months) Mean T-test; p = 0.96 Range Monthly seizure frequency in the year T-test; p = before the entrance in the study (mean S.D.) Monthly seizure frequency at the last T-test; p = 0.13 follow-up (mean SD) Intragroup comparisons between entrance and last follow-up Not significant ( p = 0.40) Significant ( p = 0.02) Paired T-test with Bonferroni adjusted Accidents (burns, falls with head injury) during the follow up Plus-minus values are means S.D. probability 5.3% _ Fisher s exact test; p = 0.57

4 38 C.L. Yasuda et al. hippocampal atrophy and memory dysfunction on neuropsychological evaluation. 29 In 11 patients in whom interictal epileptiform discharges were scarce or who had bitemporal interictal discharges we performed video-eeg for recording seizures and ictal SPECT when necessary. None of these patients required invasive investigation with intracranial EEG recording. 30,31 Eleven of 15 (73.3%) patients who did not have video-eeg monitoring became seizure free and 8 of 11 (72.7%) patients who underwent video-eeg monitoring became seizure free ( p = 1.0). Overall, 19 of 26 (73.1%) operated patients were seizure free (Engel I-A), 5 of 26 (19.2%) improved (Engel Ib-II) and 2 of 26 (7.7%) remained with disabling seizures (Engel III-IV). Two of the 26 (7.7%) operated patients had transient complications related to the surgical procedure: one had a post-operative small epidural hematoma which was operated on and she recovered without sequel; and one patient had a infection in the surgical wound which was treated successfully. Two of the 26 (7.7%) patients had complications related to the surgical procedure which lead to permanent deficits: one had thrombophlebitis of the right central retinal vein and artery which led to amaurosis of the right eye; and one patient presented mild memory deficits without compromising his daily life. In the clinical group 7 of the 75 (9.3%) patients had significant complications related to seizures during the follow-up: two had severe (second and third degree) burns; two had falls with head injury, and 3 had status epilepticus (Table 1). No neurological deficits occurred in the clinical group. No patients were lost to follow-up or died during the period of the study. It was necessary to switch the AEDs doses or combinations in 35 patients of the clinical group (47%), with the doses adjusted to maximal tolerated doses. After surgery we needed to lower the AEDs doses in 12 of 26 (46%) patients due to the side effects, most commonly excessive somnolence, dizziness and diplopia. In the surgical group we needed to increase the AEDs doses in only 4 of 26 (15%) patients due to persistent seizures after the surgery. In the remaining patients from the surgical group, the AEDs were maintained in the same dosage as before surgery. In the surgical group the average monthly seizure frequency after the surgery ( ) was significantly lower than the average monthly seizure frequency in the year before the surgery ( ) ( p = 0.02). In the clinical group, the average of monthly seizure frequency ( ) over the year before the study was Figure 1 Kaplan Meier event-free survival curves comparing the cumulative percentages of patients in the two groups who were free of seizures. In the surgical group more patients were free of seizure (P < by the logrank test). not different as compared to that of at the last follow-up ( ) ( p = 0.41). Nine of the 75 (12%) patients in the clinical group became seizure free during the study period, and 7 (9.3%) patients had at least 50% reduction in seizure frequency. Therefore, the overall improvement rate in the clinical group was 21.3%. The cumulative proportion of patients free of all seizures (Engel s class IA) 18 was higher in the surgical group with 19 of 26 patients (73.1%) compared to the clinical group with 9 of 75 (12%) ( p < ) (Fig. 1). Discussion Our study confirms the efficacy and superiority of surgical treatment to control seizures in patients with MTLE, even in a country with limited resources. The surgical treatment achieved a better rate of success despite the higher frequency of seizures registered during the year before the surgery. Our rate of freedom of seizures during the study period in the surgical group was of 73.1% versus 12% in the clinical group. The overall improvement in the surgical group (92.3% in Engel I + II) was also higher than the improvement in the clinical group (21.3% of patients with at least 50% reduction in seizure frequency) in accordance with previous studies. 13,18,26,32 40 After surgery, some patients (46%) who were free of seizures could not tolerate the side effects and

5 Comparison between surgical and clinical treatment in temporal lobe epilepsy 39 this fact lead us to reduce their AEDs. A similar situation was already reported by Griffin et al. 41 Although surgical morbidity was relatively high, with 2 of the 26 (7.7%) patients having permanent deficits, complications were also frequent in the clinical group (9.3%) 9,24 26,37,42,43 One limitation of our study, compared to that of Wiebe et al., 9 is that our patients were not randomized. However, our waiting list for surgical procedures and for pre-surgical evaluation is quite long due to the fact that our hospital serves a highly dense populated area in a country with few centers for epilepsy surgery. In addition, several of our patients reject surgery for religious or cultural reasons. These two factors allowed us to include prospectively a series of patients in the clinical group with similar characteristics and duration of followup. In fact, our clinical group had almost three times more patients than the surgical group, although all were potentially surgical candidates. One of the differences between groups at baseline was the higher seizure frequency in the surgical group. This indicates a bias towards more severe epilepsy in the surgical group and would be in favor of a better seizure outcome in the clinical group. However, our results were in the opposite direction of this potential bias. Another issue that may be raised is that the follow-up period varies widely within both groups, although it is similar between groups. This is explained by the fact that patients entered in the study at different time points during the period of observation. For example, a patient that entered in the beginning of the study had 24 months of followup and another patient that entered two months before the end of the study period had only 2 months of follow-up. In addition, the duration of seizure free intervals during the study period also varied widely among patients. In statistics, this is called progressive censored observations. 28 Fortunately, the Kaplan Meier survival analyses is a robust and appropriate method for analyzing progressive censored observations even in a relatively small number of patients when there are no confounding variables. 28 In this study, the surgical treatment proved to be superior to medical treatment in terms of seizure control in a short-term follow-up. 9,18,34 Prolonged treatment with AEDs does not offer good chances of seizure relief and does not preclude social and physical disability. The overall improvement in terms of seizure control with the surgical treatment may offer new perspectives for these patients with refractory MTLE regarding social rehabilitation, improvement in quality of life and even in employment status. 9,13 References 1. Annegers JF. The epidemiology of epilepsy. 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