Journal of the Neurological Sciences 340 (2014) 183–190

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Clinico-pathological factors influencing surgical outcome in drug resistant epilepsy secondary to mesial temporal sclerosis B.V. Savitr Sastri a, A. Arivazhagan a, Sanjib Sinha b, Anita Mahadevan c, R.D. Bharath d, J. Saini d, R. Jamuna e, J. Keshav Kumar e, S.L. Rao e, B.A. Chandramouli a, S.K. Shankar c, P. Satishchandra b,⁎ a

Department of Neurosurgery, NIMHANS, Bengaluru, India Department of Neurology, NIMHANS, Bengaluru, India Department of Neuropathology, NIMHANS, Bengaluru, India d Department of Neuroimaging and Interventional Radiology, NIMHANS, Bengaluru, India e Department of Clinical Psychology, NIMHANS, Bangalore, India b c

a r t i c l e

i n f o

Article history: Received 7 October 2013 Received in revised form 11 March 2014 Accepted 12 March 2014 Available online 19 March 2014 Keywords: Hippocampal sclerosis Epilepsy surgery Temporal lobe epilepsy Outcome Pathology Dual pathology

a b s t r a c t Background: Mesial temporal sclerosis (MTS) is the most common cause of drug resistant epilepsy amenable for surgical treatment and seizure control. Methods: This study analyzed the outcome of patients with MTS following anterior temporal lobectomy and amygdalohippocampectomy (ATL-AH) over 10 years and correlated the electrophysiological and radiological factors with the post operative seizure outcome. Results: Eighty seven patients were included in the study. Sixty seven (77.2%) patients had an Engel Class 1 outcome, 9 (11.4%) had Class 2 outcome. Engel's class 1 outcome was achieved in 89.9% at 1 year, while it reduced slightly to 81.9% at 2 years and 76.2% at 5 year follow up. Seventy seven (88.5%) patients had evidence of hippocampal sclerosis on histopathology. Dual pathology was observed in 19 of 77 specimens with hippocampal sclerosis, but did not influence the outcome. Factors associated with an unfavorable outcome included male gender (p = 0.04), and a higher frequency of pre-operative seizures (p = 0.005), whereas the presence of febrile seizures (p = 0.048) and loss of hippocampal neurons in CA4 region on histopathology (p = 0.040) were associated with favorable outcome. The effect of CA4 loss on outcome is probably influenced by neuronal loss in other subfields as well since isolated CA4 loss was rare. Abnormal post operative EEG at the end of 1 week was found to be a significant factor predicting unfavorable outcome (p = 0.005). On multivariate analysis, the preoperative seizure frequency was the only significant factor affecting outcome. Conclusions: The present study observed excellent seizure free outcome in a carefully selected cohort of patients with MTS with refractory epilepsy. The presence of dual pathology did not influence the outcome. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The syndrome of mesial temporal sclerosis (MTS) is the most common indication for surgical treatment of refractory epilepsy [1]. The results of surgery in such patients are encouraging with over two thirds showing improvement in seizure control following resection. In India, about 450,000 patients will be potential candidates for epilepsy surgery [2]. Approximately 60–70% of these patients have MTS [2]. While several clinical studies report good outcomes in this cohort of patients with MTS, there is difficulty in comparing these studies due to variability in several parameters including duration of follow up, and temporal profile of seizure remission [3–23]. Literature abounds with several clinical studies evaluating outcome in these patients with MTS, but there is a ⁎ Corresponding author at: NIMHANS, Bangalore, India. Tel.: + 91 80 26995001; fax: + 91 80 26564830. E-mail address: [email protected] (P. Satishchandra).

http://dx.doi.org/10.1016/j.jns.2014.03.026 0022-510X/© 2014 Elsevier B.V. All rights reserved.

paucity of studies that address pathological factors affecting outcome of surgery for temporal lobe epilepsy (TLE). We reviewed all patients with medically refractory epilepsy secondary to MTS who were surgically treated at our center to identify the various clinical and pathological factors, if any, which influenced the outcome in this cohort. 2. Materials and methods This retrospective study evaluated 87 patients who underwent surgical treatment for refractory epilepsy secondary to MTS between 1998 and 2008. They were recruited and underwent evaluation in the ‘Refractory Epilepsy Clinic’ at the National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore, for drug resistant TLE. The study was approved by the institutional ethics committee. The clinical data was collated after review of the medical records of the patients. This included the age of onset of epilepsy, duration and

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semiology, history of febrile convulsions, birth injury and family history of epilepsy. A comprehensive presurgical evaluation included serial 10– 20 scalp EEG recording, video EEG for confirming the localization and the semiology of seizure, MRI with specific protocol for complex partial seizures along with volumetry in relevant cases, detailed neuropsychological evaluation and other routine blood hemogram and biochemistry. All patients were discussed in the weekly epilepsy conference and a decision for surgery was made after reviewing the clinical, electrophysiological and imaging data. All patients were subjected to standard anterior temporal lobectomy with amygdalohippocampectomy. The presurgical evaluation and surgery were carried in accordance with an established protocol developed as part of a ‘Comprehensive Epilepsy Surgical Program’. The pathological specimens were reviewed by the neuropathologist blinded to the clinical data. All patients underwent a post operative EEG 1 week following surgery. Patients were followed up at the Refractory Epilepsy Clinic at 3 month intervals. EEG and psychometry were performed at the end of 1 year following surgery according to protocol. Post surgical outcome indicating the class of seizure freedom, change in the dose of antiepileptic drugs, cognitive/neuropsychological change (if any), follow up EEG and neuropsychological assessment were noted. Postoperative seizure outcome was assessed according to Engel's outcome scale. Patients were also contacted via mail or telephonic interviews and their current status with respect to seizure control and antiepileptic drug dosages was ascertained. The pathological specimens were reviewed by the neuropathologist as per the protocol outlined below. The resected temporal lobe and hippocampus were collected en bloc, fresh from the operation theater. The specimen was oriented anatomically using the subpial surface as a marker for the superior aspect and sliced serially in the coronal plane. The slices were examined serially for any grossly visible lesion and the cortical ribbon thickness examined for variation in thickness or grossly evident dysplasia. The hippocampus was sliced serially in the coronal plane and examined for any gross deformity and shrinkage. Representative samples from the hippocampus and temporal lobectomy specimen were processed for paraffin embedding and histological sectioning. Two to three micrometer thick sections were stained with hematoxylin–eosin, cresyl violet and Luxol Fast blue (for myelin) and immunohistochemistry with antibodies to delineate neuronal (NeuN, 1:50, Millipore USA and phosphorylated neurofilament, 1:100, Nova Castra Labs, USA) and Glial alterations (GFAP, 1:500, Nova Castra labs, USA). The histological sections were evaluated for dentate gyrus alterations, degree of neuronal loss in various subfields (CA1–4) of Ammon's horn, and astrocytosis and graded in accordance with Blumcke's grading system [24]. The temporal lobe was examined for the presence of cortical dysplasia or other dual pathology and classified in accordance with recent ILAE classification [24,25]. The clinical, electrophysiological, radiological and histopathological data was tabulated and correlated with seizure outcome to evaluate their effect, if any. Results were subjected to statistical analysis using SPSS v15.0. The statistical tests used were the Pearson's chi square, Mann–Whitney U test (non parametric data), and Student's t test (parametric data) for univariate analysis. Multivariate analysis was done using a binomial logistic regression model. 3. Results 3.1. Demographic, clinical and presurgical evaluation data The age of the patients at the time of surgery ranged from 10 years to 49 years (mean age of 26.4 ± 8.68). Most of the patients belonged to the age group between 11 and 30 years. The male to female ratio was 1.35:1. Thirty seven patients (42.5%) had history of febrile seizures in their childhood, while four patients (4.6%) had history of perinatal insult (hypoxic-ischemic events at birth—2, neonatal jaundice—1,

maternal febrile illness—1). Family history of seizure disorder in first degree relatives was recorded in 3 patients (3.4%). Cognitive decline on preoperative testing was noted in 9.2% (n = 8) of patients and concomitant psychiatric disorders on treatment were present in 3 patients (3.4%). The age at seizure onset ranged from 1 to 29 years (mean 10.57 ± 6.0 years) with over half developing seizures in the first decade of life. The duration of seizures at the time of surgical intervention ranged from 2 years to 36 years (mean 15.68 ± 7.75 years, median 16 years). Seizure semiology was complex partial seizures in 55 (63.2%) and with secondary generalization in 32 patients. In 28 (32.2%) patients, there was a change in ictal semiology from initial generalized seizures to complex partial seizures during the course of the illness. Patients had been on treatment for varying periods of time prior to referral for surgery (range: 2–36 years, mean 15.68 ± 7.75 years) and received a minimum of two antiepileptic drugs. Most of the patients were on three or more antiepileptic drugs at the time of surgery, 47.1% had a seizure frequency of 1–3/month, 42.5% had seizure frequency of 1–6/week while 9.2% of patients had more than one seizure per day. MRI and EEG data were concordant with the side of lateralization in 80 patients (92.0%). Of the seven patients with discordance, three underwent ictal and inter ictal SPECT to determine lateralization, while four underwent surgery according to the side of MRI lateralization. The results of presurgical evaluation and their utility in deciding the side of surgery is shown in Supplementary Table ST1. Forty one patients underwent left sided surgery (47.1%) and 46 underwent right sided surgery. Intraoperative electrocorticography was performed in 21 patients (24.1%). Postoperative seizures were noted in 8 patients (9.2%) within the first week of surgery. There was no procedure related mortality in this series. 3.2. Pathology Hippocampal sclerosis of varying degrees was detected in 77 of 87 patients. On application of Blumcke's grading system, MTS Type 1a was the most common (55.2%) (Fig. 1B), followed by MTS Type 2 (17.2%) (Fig. 1D), and MTS Type 1b (12.6%) (Fig. 1C) while Type 3 (3.4%) was the least common. In 10 patients (11.5%), no neuronal loss was detected in the hippocampus (Blumcke's grade 0) (Fig. 1A). Evaluation of the dentate gyrus also revealed a spectrum of changes, ranging from normal (Fig. 2A) to patchy loss of neurons in 28 patients (32.1%) (Fig. 2B), ischemic change in 21 (24.1%), laminar duplication in eight (Fig. 2D), while two patients had meganeurons in the midst of normal granule cells. Granule cell dispersal of varying degrees was observed in 21 patients (24.6%) (Fig. 2C).Interestingly among the 77 cases of hippocampal sclerosis, additional pathological changes (dual pathology) were noted in the temporal lobe in 19 patients (24.68%), and included cortical laminar disorganization (n = 5) (Fig. 2F), cortical ectopia (n = 4), granule cell ectopia (n = 1) (Fig. 2G), and malformations of cortical development (n = 8). Neoplasm was detected only in one case in the form of dysembryoblastic neuroepithelial tumor (Fig. 3A–D). In patients without evidence of hippocampal sclerosis (Blumcke's grade 0), the ischemic changes were noted in the hippocampal pyramidal neurons as well as in the temporal cortex. In four cases, scattered neurons were seen in the temporal while matter, indicating microdysgenesis. 3.3. Follow up and outcome The overall follow up ranged from 0.3 to 129 months (median— 37 months) post surgery. Three patients were lost for follow up immediately after discharge and 33 patients (38%) had a follow up of over 5 years.

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Fig. 1. Ammon's horn sclerosis. Hippocampectomy showing varying grades of hippocampal sclerosis with Neu N immunostaining, varying from Grade 0 (A) wherein there is no loss of pyramidal neurons in Ammon's horn, Type 1a (B) with loss of Ammon's horn neurons in CA1, CA3 and CA4 subfields with relative sparing of CA2 neurons. In Type 1b (C), there is severe loss of neurons in all subfields of Ammon's horn whereas in Type 2 (D), neuronal loss is restricted to CA1 subfield sparing other subfields. [NeuN immunoperdoxidase—magnification scale bar].

The patients who had a follow up of at least 12 months (n = 79) following surgery were considered for outcome analysis. The time of follow up for this outcome analysis group ranged from 12 months to 129 months (median follow up—47 months). Seizure outcome was documented using Engel's class at the time of last follow up is depicted in Table 1. The seizure outcome at 1 year, 2 years and 5 years was also calculated. Outcome at 1 year was known in 79 patients, while the outcome at 2 years and 5 years was documented in72 patients and 42 patients respectively. We noted that Engel's class 1 outcome was achieved in 89.9% at 1 year, while it reduced slightly to 81.9% at 2 years and 76.2% at 5 year follow up (Table 2). Twenty five (28.7%) patients were completely weaned off all the medications following surgery. Two patients, one each with outcome of Engel's class 3a and 4a, were evaluated with VEEGs at follow up following documentation of poor seizure control. The VEEG revealed seizures originating from the temporal leads on the same side as surgery, suggesting a possible residual focus. They were planned for revaluation for the feasibility of resurgery, but the patients refused the same. Repeat MR imaging available in one patient revealed only post operative changes. Three patients expired due to unrelated causes 1 year following surgery. The seizure outcome was classified as favorable or unfavorable, based on the Engel class. Patients with Engel's class of 1 and 2 were grouped as favorable outcome and those with Engel's class of 3 and 4 were grouped as unfavorable outcome. Accordingly 88.6% (70/79) patients had favorable outcome and 11.3% (9/79) had unfavorable outcome (Table 1). 3.4. Factors affecting outcome The influence of clinicopathological factors on the outcome of the patients was analyzed (Tables 3 and 4). Patients with a history of febrile

seizures in childhood had better seizure control (p = 0.048). Patients with a higher seizure frequency before surgery had unfavorable outcome (p = 0.005). Age at onset, seizure duration, number of AEDs and the occurrence of acute post operative seizure had no bearing on the outcome. Amongst the pathological findings, loss of neurons in CA4 subfield was associated with favorable outcome (p = 0.040). Discordance between MRI and EEG findings was noted in six patients but this did not significantly alter the outcome, though it tended towards significance (χ2 = 3.079; p = 0.078), suggesting that discordant EEG and MRI data might point towards an unfavorable outcome. However the numbers of patients in this group were too small to make any categorical inference. Post-operative EEG prior to discharge was abnormal in 15 patients, six of whom had unfavorable outcome and this was found to be significant (χ2 = 8.046; p = 0.005). Interestingly, no significant difference in the outcomes was found between patients with or without hippocampal sclerosis (Blumcke's Grade 0). The presence of co-existing cortical dysplasia in the temporal neocortex found in 14 patients (20%) also did not adversely affect outcome (p = 0.69).Multivariate analysis was performed using a Binomial Logistic Regression model. The only factor found to be a significant predictor of unfavorable outcome was the preoperative seizure frequency (p = 0.019, odds ratio = 3.888).

4. Discussion About 50 million people worldwide suffer from epilepsy at any given point of time. Of these, 80% live in resource restricted countries [26]. The incidence of epilepsy in low-income countries ranges from 50 to 190 per 100,000 people and constitutes a significant health care and public health problem [27–29]. The syndrome of Mesial Temporal Lobe Sclerosis (MTS) has been described elaborately in literature [30,

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Fig. 2. A–D: Spectrum of dentate gyrus pathology. A: Normal compact 5–6 layered dentate gyrus granule cells; B: Significant loss of dentate gyrus granule cells causing marked thinning (arrow) (25/F Engel 1a, 30 months); C: Dispersion of granule cells forming small aggregates in the molecular layer (arrows). (16/F Engel 2a, 129 months); D: Dispersion and migration of dentate granule neurons causing double layering of dentate gyrus (arrows) (23/F Engel 3a, 21 months). E–G:Dual pathology. E,F: Disorganization and loss of laminar organization seen in the temporal cortex seen on Neu N immunostaining (F) compared to the laminar organization of normal temporal cortex (E). This was unaccompanied by dysplastic changes in neurons; G: Granule cell heterotopic focus (asterix) seen within the hilar region of hippocampus. [A: H&E×160, B:H&E×160, C:HE×80, D: H&E×80, E,F: Neu N immunoperoxidase, G: HE: E–G: magnification—scale bar].

31]. It constitutes the most commonly reported indication for surgical intervention in the treatment of epilepsy [1,2]. The results of seizure outcome following surgery for MTS have been uniformly good in several large series with most centers reporting good outcome with respect to seizure control of over 60% [3–23]. Hemb M et al. reported in their series of 108 patients that the seizure freedom after 12 and 18 years was 65% and 62% respectively, demonstrating the consistent longstanding benefits of surgery in MTS [32]. An understanding of the factors influencing the outcome following surgery in these patients will aid in selecting the correct cohort for intervention as well as proper counseling in terms of prognosis. Some recent studies have reported predictors of survival in their patient cohorts [33–35]. The demographic data in our study correlated well with that reported in literature. There are however, a few interesting observations. The

onset of seizures, in over half the cases was in childhood (mean age at onset being 10.57 ± 6.0 years), implying that this is primarily a disease that begins at an early age, as shown in literature [30,36]. Most patients had long standing epilepsy, the mean duration of seizures prior to presentation being 15.68 ± 7.75 years with a median value of 16 years. This is often due to inordinate delay in seeking medical assistance in most developing countries, or delayed referral to a tertiary or specialized center leads to such patients having refractory seizures, despite being on polypharmacy with evidence of good compliance [37,38]. Even in the Western countries, the duration of epilepsy prior to surgery is more or less similar with a substantial proportion of patients suffering for over 20 years [39]. This statistics has not shown any change over the last two decades [40]. The number of patients who were on treatment with three or more drugs in this study was over 71%. In literature, the

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Fig. 3. Dysembryoblasticneuroepithelial tumor ((16/F Engel 2a, 129 months)). Whole mount preparation of hippocampus reveals expansion of dentate hilum and CA1 zone (circled) by pale nodules of tumor (A) that on higher magnification show characteristic columns of small monomorphic tumor cells arranged in columns separated by mucinous stroma (B) forming the specific glioneuronal elements that contain synaptophysin labeled processes (C) and floating neurons between the columns that are labeled by phosphorylated neurofilament (D, arrow). [A: H&E×10, B: H&E×80, C: synaptophysin immunoperoxidase ×240, D: neurofilament ×300].

initial response to anticonvulsant drug therapy has been shown to be highly predictive of long-term outcome. Almost two-thirds of patients respond to anticonvulsant therapy. Approximately 47% respond on one drug alone; about 13% require two drugs while 4% require three drugs or more to achieve remission [41]. Generally, it has been observed that the chances of achieving seizure control beyond three drugs are 5 to 10% [42,43]. The pathological changes in the hippocampectomy specimens were evaluated in accordance with the recently described Blumke's grading [24].We compared the distribution of cases amongst the grades in the present study to that reported by Blumcke et al. The classical type of MTS (1a) was the most frequent in the present study whereas the severe MTS type (1b) is the predominant histology in the previously reported series. As this is a relatively recent classification compared to the earlier Wyler grading, there is a paucity of literature of the distribution of cases in each subgroup. In addition, granule cell dispersion in the dentate gyrus was reported in 44% of cases in a study in 2007 [44].We

Table 1 Seizure outcome based on Engel's class: score. Engel's class

Frequency

Percent

1a 1b 1c 1d Total Grade class 1 2a 2b Total Grade Class 2 3a 4a Total

47 3 2 9 61 7 2 9 5 4 79

59.5 3.8 2.5 11.4 77.2 8.9 2.5 11.4 6.3 5.1

noted granule cell dispersion in the dentate gyrus in 24.5% cases. Other changes in the dentate gyrus were noted in 70.1% of cases when compared to 81.3% in literature [44]. Extrahippocampal pathology (dual pathology) in the temporal lobe was noted in 24.67% of cases in the present series. This was in concurrence with the previous reports in literature (range: 5 to 48%). The most commonly reported dual pathology in literature comprises malformations of cortical development and focal cortical dyplasias. Neoplasms and vascular malformations are rarely seen [45–51]. In our series, none of these patients with dual pathology on histopathological examination of the resected specimens demonstrated any extrahippocampal lesion other than MTS in MR imaging. In literature, the sensitivity of MRI in detecting a second pathology coexistent with MTS is between 5 and 20% with the rates for malformations of cortical development being lower when compared to vascular malformations or tumors [52, 53]. We noted that the presence of dual pathology in our series did not result in worse prognosis. It has been reported earlier in literature that in the presence of dual pathology, resection of only the extra hippocampal lesion or only the hippocampus can result in poor outcome. Cascino et al. noted that results were poor if only the extrahippocampal lesion was resected [46]. Li et al. in a multicenter study documented that resection of the lesion and the mesial temporal structures resulted in seizure freedom in 73% patients, while lesionectomy or resection of mesial temporal structures alone resulted in seizure freedom in only 12.5% and 20% respectively [54]. Therefore it is evident that seizure outcome is comparable in dual pathology if complete resection encompassing both pathologies were performed [46,51]. Anterior temporal lobectomy with amygdalohippocampectomy would address removal of dual pathologies better when compared to selective amygdalohippocampectomy. In the present study, 88.6% of patients achieved Engel Class 1 and 2 outcome, with 77.2% of patients in Engel Class 1. We also noted that Engel's class 1 outcome was achieved in 89.9% at 1 year, 81.9% at 2 years and 76.2% at 5 year follow up. The seizure outcome in the

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Table 2 Yearwise seizure outcome based on Engel's class. Outcome analysis

Engel's class 1 N (%)

Engel's class 2 N (%)

Engel's class 3 N (%)

Engel's class 4 N (%)

Overall outcome (N = 79) Outcome at 1 year follow up (N = 79) Outcome at 2 year follow up (N = 72) Outcome at 5 year follow up (N = 42)

61 (77.2) 71 (89.9) 59 (81.9) 32 (76.2)

10 (12.7) 5 (6.3) 7 (9.7) 6 (14.3)

4 (5.1) 2 (2.5) 4 (5.6) 3 (7.1)

4 (5.1) 1 (1.3) 2 (2.8) 1 (2.4)

present series is comparable to the previous reports in literature. The proportion of patients with complete seizure freedom following surgery in various studies (the number of patients included in different series vary from 25 to 434) ranged from 48% to 78% [3–23]. A Spanish study recently reported 86.1% favorable seizure outcome at 2 year follow up, with 68.8% of patients achieving Engels Class 1 [55]. In the present study, a history of febrile seizures was found to be a favorable clinical factor. The association of febrile seizures with mesial temporal sclerosis has been well documented [56–59]. Other clinical factors noted in literature include a history of status epilepticus, family history of epilepsy, history of a perinatal insult and versive seizures [23,60,61]. Most other clinical data such as duration of seizures, characteristics of aura or the seizure itself were not clearly associated with either a favorable or unfavorable outcome [60,62,63]. We however, noted that the frequency of seizures while on antiepileptic drugs prior to surgery was an independent predictor of outcome on multivariate analysis in the present study. Discordant MRI and EEG lateralization has been shown to be a poor predictor of outcome in a number of studies [16,64–66]. In our study, 6 patients with discordance in the lateralization had unfavorable outcome (p = 0.078). However, the number of cases is too few to confirm a categorical relationship. It is recommended that patients who do not demonstrate concordance in the findings of presurgical evaluation, especially electrophysiology and imaging undergo further evaluation with PET, SPECT, MEG, invasive V-EEG monitoring, protocol based 3T imaging, etc. to ascertain concordance. An abnormal immediate post operative EEG (performed 1 week following surgery in this study) was seen to be a significant factor in predicting unfavorable outcome, reflected in other studies as well [23,55,67,68].

When the Blumcke grading of hippocampal sclerosis was first proposed in 2007, the reasons cited for its preference over the existing Wyler classification were the ease of administration of the grade and an early study demonstrating good correlation with outcome following amygdalohippocampectomy [24]. In Wyler's scoring system with five grades, though widely used, the thresholds for determining the grades were arbitrary. The proposed interval between Grades I and II is too wide (10% and 50%) leading to significant inter-observer variation. Hence, Blumcke's grading was used in the present study. However, we failed to find a correlation with Blumcke's grade and outcome in the present study. We also noted a higher prevalence of Grade 1a (classical MTS) in our patients compared to Grade 1b in Blumcke's series [24]. Whether this is a reflection of a smaller study population studied or reflects ethnic differences in the type of hippocampal sclerosis prevalent in the Indian population in comparison to the West is unclear and needs further investigation. Recent studies have attempted to correlate the pathological factors to the seizure outcome in MTS [69–71]. da Costa Neves et al. reported that granule cell dispersion occurred in 45.5% of the cases. Neuronal loss was severe in patients with granule cell dispersion. However, this finding did not influence the seizure outcome [69]. Interestingly, another study documented that a quantitative assessment of neuronal loss patterns in hippocampus could predict seizure outcome [70]. When studying preservation of neurons in specific sectors of the Ammon's horn, an earlier study from our institute had noted loss in the CA3 sector to be suggestive of unfavorable outcome; however, the total number of included patients in this study was too small to generate statistical significance [72]. On evaluating neuronal loss in the present study, it was

Table 3 Clinical factors affecting outcome. Factor

Good N = 70

Poor N = 9

P value

Inference

Age at surgery (y) Gender Male (n = 45) Female (n = 34) Age at onset of seizures (y) Febrile seizures Present (n = 33) Absent (n = 46) Type of seizure CPS (n = 51) CPS with generalization (n = 28) Duration of seizures (m) Frequency of seizures 1–3 per month(n = 39) 1–6 per week(n = 32) 1–3 per day(n = 5) 4–10 per day (n = 2) N 10 per day but not status epilepticus (n = 1) Number of AEDs 1 (n = 1) 2 (n = 24) 3 (n = 39) 4 (n = 14) 5 (n = 1) Side of surgery Left (n = 38) Right (n = 41) Post-operative seizures Present (n = 8) Absent (n = 62)

26.7 ± 8.7

27.9 ± 10.3

.81

Not significant

37 33 10.7 ± 6.1

8 1 9.2 ± 4.7

0.040

Males have a poorer outcome

.467

Not significant

32 38

1 8

0.048

Presence of febrile seizure is a good prognostic factor

45 25 15.9 ± 8

6 3 15.7 ± 5.3

0.88

Not significant

.941

Not significant

38 27 4 1 0

1 5 1 1 1

0.005

More the number of seizures worse the prognosis

1 21 35 12 1

0 3 4 2 0

0.978

Not significant

34 36

4 5

0.816

Not significant

8 53

0 9

0.285

Not significant

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189

Table 4 Pathological factors affecting outcome. Factor

Good (N = 70)

Poor (N = 9)

Blumcke's grading 0 (n = 9) 7 2 1a (n = 41) 39 2 1b (n = 11) 10 1 2 (n = 15) 12 3 3 (n = 3) 2 1 Presenceofdentate gyrus pathological changes (granule cell dispersion/loss/duplication) Present (n = 61) 55 6 Absent (n = 9) 8 1 Dentategyrus granule cell dispersion Present 18 45 Absent 1 6 CA1 preserved (n = 1) 1 0 Neuronal loss (n = 69) 62 7 CA2 preserved (n = 32) 27 5 Neuronal loss (n = 38) 36 2 CA3 preserved (n = 14) 11 3 Neuronal loss (n = 56) 52 4 CA4 preserved (n = 11) 8 3 Neuronal loss (n = 58) 54 4

noted that loss of CA4 neurons was a good prognostic factor. This finding has not been previously reported in literature. However, in only three of the cases, CA4 loss was isolated whereas in all others, CA4 loss was associated with loss in other sub fields (most often CA1, followed by CA3 and CA2). In the three cases with isolated CA4 loss, outcome was good in two and poor in one. Hence, good prognosis in cases with CA4 neuronal loss could probably be influenced by loss in other sectors. As loss of neurons in the CA4 region occurred in cases with established or extensive mesial temporal sclerosis, surgical removal of the pathology probably resulted in better outcome.

5. Conclusion The present study highlights the excellent seizure free outcome in a carefully selected cohort of patients with MTS with refractory epilepsy, achieved by a comprehensive phase 1 epilepsy surgery program. We report various clinical, electrophysiological factors influencing outcome. We report the novel association of loss of hippocampal neurons in the CA4 region on histopathology with favorable outcome. Further research on pathological factors influencing the outcome in a larger series is suggested which can provide further insights into this functionally and socially disabling disease. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2014.03.026.

Conflict of interest None.

Financial disclosure Nil.

Acknowledgments The authors wish to gratefully acknowledge the technical support of Mrs. Rajasakti V, Mr. Prasanna Kumar, and Mr. Shivaji Rao, Human Brain Tissue Repository (Brain Bank), NIMHANS for assistance in histopathological preparation and immunohistochemistry as well as Mr. K. Manjunath, Department of Neuropathology, NIMHANS for assistance in microphotography and montage preparation for the manuscript.

p

Inference

0.252

Not significant

0.905

Not significant

0.42

Not significant

0.737

Not significant

0.150

Not significant

0.111

Not significant

0.040

Loss of neurons of CA4 region is a good prognostic factor

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Clinico-pathological factors influencing surgical outcome in drug resistant epilepsy secondary to mesial temporal sclerosis.

Mesial temporal sclerosis (MTS) is the most common cause of drug resistant epilepsy amenable for surgical treatment and seizure control...
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