Optimal timing and differential significance of postoperative awake and sleep EEG to predict seizure outcome after temporal lobectomy

Clinical Neurophysiology 129 (2018) 1907–1912

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Optimal timing and differential significance of postoperative awake and sleep EEG to predict seizure outcome after temporal lobectomy Chaturbhuj Rathore a,⇑,1, Pandurang R. Wattamwar a,2, Neeraj Baheti a,3, Malcolm Jeyaraj a,4, Gopal K. Dash a,5, Sankara P. Sarma b, Kurupath Radhakrishnan a,6 a R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India b Achutha Menon Center for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

a r t i c l e

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Article history: Accepted 24 June 2018 Available online 30 June 2018 Keywords: Postoperative EEG Epilepsy surgery Temporal lobectomy Seizure outcome Antiepileptic drug withdrawal

h i g h l i g h t s  EEG done on 7th day following temporal lobectomy is not useful in predicting seizure outcome.  EEG at 3 months and 1 year following surgery has significant value in predicting seizure outcome.  Sleep recording improves the sensitivity of postoperative EEG by 30% without compromising

specificity.

a b s t r a c t Objective: To evaluate the prognostic value of postoperative EEGs to estimate post anterior temporal lobectomy (ATL) seizure outcome. Methods: We studied postoperative EEGs in 325 consecutive patients who had minimum five years of post-ATL followup. Interictal epileptiform discharges (IEDs) present only during sleep were classified as sleep IEDs. We defined favorable final-year outcome as no seizures during the final one year and favorable absolute-postoperative outcome as no seizures during the entire postoperative period. Results: At mean follow-up of 7.3 ± 1.8 years, 281 (86.5%) patients had favorable final-year outcome while 161 (49.5%) had favorable absolute-postoperative outcome. IEDs on three months and one year EEG were associated with unfavorable outcomes while IEDs at 7th day had no association with outcomes. Sleep record increased the yield of IEDs by 30% at each time-point without compromising predictive value. EEG at one year predicted the risk of seizure recurrence on drug withdrawal. Conclusion: While EEG at three months and at one-year after ATL predicted seizure outcome, EEG at 7th day was not helpful. Sleep record increases the sensitivity of postoperative EEG without compromising specificity. Significance: Both awake and sleep EEG provide useful information in postoperative period following ATL. Ó 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Abbreviations: AEDs, antiepileptic drugs; ATL, anterior temporal lobectomy; EEG, electroencephalogram; IED, interictal epileptiform discharges; MRI, magnetic resonance imaging; MTLE, mesial temporal lobe epilepsy; MTS, mesial temporal sclerosis; VEEG, video–electroencephalography. ⇑ Corresponding author at: Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Piparia, Waghodiya, Vadodara 391760, Gujarat, India. Fax: +91 02668 245292. E-mail address: [email protected] (C. Rathore). 1 Present address: Department of Neurology, Smt B K Shah Medical Institute and Research Center, Sumandeep Vidyapeeth, Vadodara, Gujarat, India. 2 Present address: Department of Neurology, United CIIGMA Hospital, Aurangabad, Maharashtra, India. 3 Present address: Department of Neurology, Central India Institute of Medical Sciences, Nagpur, Maharashtra, India. 4 Present address: Department of Neurology, Stanley Medical College, Chennai, Tamil Nadu, India. 5 Present address: Department of Neurology, Narayana Hrudayalaya Hospital, Bengaluru, Karnataka, India. 6 Present address: Amrita Advanced Epilepsy Center, Department of Neurology, Amrita Institute of Medical Sciences, Kochi, Kerala, India. https://doi.org/10.1016/j.clinph.2018.06.014 1388-2457/Ó 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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1. Introduction Postoperative EEG is useful for predicting the seizure outcome and to make decisions about antiepileptic drug (AED) withdrawal following epilepsy surgery (Rathore and Radhakrishnan, 2010; Rathore et al., 2011c). Presence of interictal epileptiform discharges (IEDs) on a single postoperative EEG is associated with an increased risk of unfavorable seizure outcome and a higher risk of seizure recurrence on AED withdrawal following temporal and extratemporal surgeries (Menon et al., 2012; Rathore et al., 2011b, 2011c; Rathore and Radhakrishnan, 2010). Still, a single EEG has relatively lower sensitivity and specificity in predicting seizure outcome following epilepsy surgery. The predictive value of EEG can be further increased by obtaining serial EEGs (Rathore et al., 2011c). In nonsurgical patients, the yield of EEG can also be increased by obtaining a sleep record (Adachi et al., 1998; Leach et al., 2006; Mendez and Brenner, 2006). Whether the prognostic yield of EEG in the postoperative period can also be increased by obtaining a sleep record and if yes, then up to what extent, has not been previously studied. Similarly, it is not clear whether the IEDs in the awake and sleep states have the same prognostic value in the postoperative period. The optimal timing of postoperative EEG is also not certain. Ideally an EEG should be obtained at earliest time following surgery to have the best information about seizure outcome and to make decisions about AED withdrawal. Whether an EEG during the early postoperative period has the same significance as EEG done at later times is not certain (Rathore and Radhakrishnan, 2010). We undertook this study to ascertain the optimal timing of postoperative EEG and the significance of postoperative sleep EEG in a uniform group of patients who underwent anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE).

2. Methods 2.1. Study setting and patient selection This study was carried out at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India. We have previously described our methods of patient selection for ATL for MTLE and the subsequent postoperative protocols (Chemmanam et al., 2009; Lachhwani and Radhakrishnan, 2008; Rathore et al., 2011a; Sylaja et al., 2004). From a prospectively maintained database, we included consecutive patients who underwent ATL for MTLE from March 1995 to December 2005 and had completed a minimum of 5 years of postoperative follow-up. To have a uniform group of patients, only those patients with MTLE who had hippocampal sclerosis on MRI or in whom MRI was normal or showed equivocal findings were selected for this study. Hippocampal sclerosis was defined as the presence of hippocampal atrophy and increased hippocampal signal on T2 weighted and fluid attenuated inversion recovery (FLAIR) sequences. Patients with MTLE associated with other lesions such as vascular malformations and benign tumors, patients with dual pathology, and those with bilateral mesial temporal sclerosis were excluded from this analysis. Similarly, patients with extratemporal and temporal neocortical epilepsies were excluded. The standard presurgical evaluation protocol at our center includes detailed clinical evaluation with special emphasis on seizure semiology, neuropsychological evaluation, long-term video– electroencephalography (VEEG) monitoring for clinical semiology and interictal and ictal EEG data, and 1.5-T high resolution magnetic resonance imaging (MRI) (Chemmanam et al., 2009; Lachhwani and Radhakrishnan, 2008; Rathore et al., 2011a; Sylaja et al., 2004). We made decisions for surgery after thorough

discussion in the multidisciplinary patient management conference. The majority of the patients with unilateral hippocampal sclerosis on MRI were selected for surgery on the basis of noninvasive evaluation. Patients with normal or equivocal MRI findings were also selected for ATL on the basis of noninvasive data, if they satisfied all of the following specific criteria: history of febrile seizures, seizure semiology suggestive of mesial temporal origin, unilateral anterior temporal IEDs (defined as 90% of IEDs lateralized to the side of resection), and well defined ipsilateral temporal ictal onset on EEG. Few patients were subjected to hippocampal depth electrode monitoring before surgery if the noninvasive evaluation data were nonlocalizing or discordant. We performed standard temporal lobectomy for all the patients in which excision of neocortical structures (4.5–5 cm on nondominant side and 3.5 cm on dominant side) was followed by complete excision of amygdala, hippocampus and parahippocampal gyrus. Pathologically, 30% loss of neurons in the CA1 sector of hippocampal formation was defined as hippocampal sclerosis (Rathore et al., 2011c). 2.2. Postoperative follow-up After the ATL, all the patients underwent an EEG before discharge which was usually on 7th postoperative day. Subsequently, all the patients came for follow-up at three months, at one year, and then at yearly intervals. At each follow-up, patients were asked about the seizure outcome through the personal interview. Patients were asked to maintain seizure diaries as a standard practice. After five years of postoperative regular follow-up, patients who remained seizure free and had difficulty in yearly visits were followed up through postal or email interview. In case of any seizure recurrence, patients were advised to contact personally or telephonically. For this study, we defined two outcome measures: favorable final-year outcome was defined as no seizures or auras during the final one year of follow-up. Those patients who had seizures during the final year of followup were classified to have unfavorable final-year outcome. Favorable absolute-postoperative outcome was defined as no seizures or auras during the entire post-ATL follow-up period. Those patients who had seizure any time during whole followup period were classified as having unfavorable absolute-postoperative outcome. 2.3. Postoperative EEG protocol We have previously described our protocol for EEG recording and reporting (Rathore et al., 2011c). For all the patients, we tried to obtain EEG at 7th day, at three months and then at one, two and three years of follow-up. As the majority of the patients have seizure recurrence within first year, we included the EEG done at 7th day, three months and at one year for the analysis in this study. We utilized the Mayo system of EEG classification and coding for EEG abnormalities (Mayo Clinic and Mayo Foundation, 1991). Our EEG protocol consists of partial sleep deprivation on previous night and obtaining at least 40 min of EEG record, both in awake and sleep states (Radhakrishnan et al., 1999; Rathore et al., 2011c). We tried to obtain natural sleep in majority of the patients; however, if required, either chloral hydrate or Triclofos were used as hypnotic agents. We performed activation procedures including intermittent photic stimulation and hyperventilation for all the patients except on the 7th day when hyperventilation was not performed. Only definite spikes or sharp waves were classified as IEDs. We classified IEDs as awake IEDs when these were present only during wakefulness, or both during wakefulness and sleep, while sleep IEDs were defined as IEDs present only during sleep.

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27.3 ± 9.3 years and the mean duration of epilepsy was 17.7 ± 8.7 years. The mean duration of postoperative follow-up was 7.3 ± 1.8 years (median 7 years; range 5–12 years). Of the 325 patients, 291 patients had mesial temporal sclerosis (MTS) on MRI while 34 patients had either normal MRI or equivocal findings. Pathologically, 266 patients had hippocampal sclerosis while 49 patients had nonspecific findings on pathology. Ten patients with definite MTS on MRI had insufficient pathological specimens to make a definite diagnosis. At the last follow-up, 281 (86.5%) patients had favorable finalyear outcome while 161 (49.5%) patients had favorable absolutepostoperative outcome.

2.4. Postoperative AED management As previously described by us, AEDs were withdrawn as per the standard protocol in seizure free patients (Menon et al., 2012; Rathore et al., 2011b). We started AED withdrawal after three months in those patients who were taking two or more AEDs and after one year in those on one AED. AEDs were withdrawn at a consistent rate in majority of the patients. We reduced doses every two months except in patients who were taking three or more AEDs where first drug was withdrawn more rapidly. Some patients, who developed mood fluctuations or insomnia during drug withdrawal, were continued on the minimal dose for six months before complete discontinuation. Patients who were never seizure-free following ATL were managed on individual basis and their AEDs were optimized as per the clinical course.

3.1. Postoperative EEG and seizure outcome Three hundred and twenty five (325) patients had EEGs at both time points of three months and one year following surgery while 307 patients had EEG at 7th postoperative day. IEDs were present in 74 (24.1%) EEGs at 7th day, in 68 (20.9%) EEGs at third month and in 51 (15.7%) EEGs done at one year. Presence of IEDs on EEG at third month and at one year was significantly associated with the unfavorable final-year outcome (p value, 0.0001 and 0.04 respectively) and unfavorable absolute-postoperative outcome (p value, 0.004 and 0.0002 respectively) (Tables 1 and 2). However, the presence of IEDs on the 7th postoperative day EEG was not predictive of seizure outcome (Tables 1 and 2). The sensitivity, specificity, and positive and negative predictive values of the EEG, at different time points, in predicting seizure outcomes are depicted in Tables 1 and 2. For final-year outcome, IEDs at three months and one year following surgery showed a good negative predictive value of 90% with a relatively poor positive predictive value, indicating that absence of IED at these time points have 90% probability of favorable final-year seizure outcome. For absolutepostoperative outcome, EEG at both time points had a positive predictive value of 70% and a negative predictive value of 54%, indicating that presence of IEDs at these time points have 70% probability of unfavorable absolute postoperative outcome.

2.5. Statistical analysis In this study, we compared the seizure outcomes in patients with and without IEDs on postoperative EEGs recorded at different time points. We calculated the sensitivity, specificity, positive and negative predictive values of EEG in predicting seizure outcome at each time point. We repeated these analyses in the subgroup of patients who had both sleep and awake records. We used Fisher exact test, Pearson chi-square test and student’s t test for comparisons. All analyses were performed by using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. and a p value of less than 0.05 was considered significant. 3. Results During the study period, 711 patients underwent epilepsy surgery, which included all types of surgeries. Of which, 384 patients were eligible for inclusion in this study. Of these, 59 patients did not have EEG at all time points. The remaining 325 patients formed the study group. Mean age of the group at the time of ATL was Table 1 Prognostic importance of EEG at different time points for final-year outcome Time point

7 days 3 months 1 year 3 months + 1 year combined

IEDs present

IEDs absent

SF

NSF

SF

NSF

62 (84%) 42 (61%) 39 (76%) 65 (68%)

12 (16%) 26 (39%) 12 (24%) 30 (32%)

206 (88%) 239 (93%) 242 (88%) 216 (94%)

27 (12%) 18 (7%) 32 (12%) 14 (6%)

P value

Sensitivity

Specificity

PPV

NPV

0.298

0.31 (0.18–0.48) 0.59 (0.43–0.73) 0.27 (0.15–0.43) 0.68 (0.52–0.81)

0.77 (0.71–0.82) 0.85 (0.80–0.89) 0.86 (0.81–0.90) 0.77 (0.71–0.82)

0.16 (0.09–0.27) 0.38 (0.27–0.51) 0.24 (0.13–0.38) 0.32 (0.23–0.42)

0.88 (0.83–0.92) 0.93 (0.89–0.96) 0.88 (0.84–0.92) 0.94 (0.90–0.97)

0.0001 0.04 0.0001

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PPV = positive predictive value; SF = seizure free.

Table 2 Prognostic importance of EEG at different time points for absolute-postoperative outcome Time point

7 days 3 months 1 year 3 months + 1 year combined

IEDs present

IEDs absent

SF

NSF

SF

NSF

39 (53%) 23 (44%) 15 (29%) 30 (32%)

35 (47%) 45 (66%) 36 (71%) 65 (68%)

113 (49%) 138 (54%) 146 (53%) 131 (57%)

120 (51%) 119 (46%) 128 (47%) 99 (43%)

P value

Sensitivity

Specificity

PPV

NPV

0.53

0.23 (0.16–0.3) 0.27 (0.21–0.35) 0.22 (0.16–0.29) 0.40 (0.32–0.48)

0.74 (0.67–0.81) 0.86 (0.79–0.91) 0.91 (0.85–0.95) 0.81 (0.74–0.87)

0.47 (0.36–0.59) 0.66 (0.54–0.77) 0.71 (0.56–0.82) 0.68 (0.58–0.77)

0.48 (0.42–0.55) 0.54 (0.47–0.60) 0.53 (0.47–0.59) 0.57 (0.50–0.63)

0.004 0.0002 0.0001

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PPV = positive predictive value; SF = seizure free.

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year following surgery. Sleep record was obtained in 205 (63.1%) patients at three months and in 216 (66.5%) patients at one year. Compared to three months, additional 64 (19.7%) patients had sleep record at one year. Thus overall, 269 (82.8%) patients had at least one sleep record by one year. To study the true differential significance of the awake and sleep records, we restricted further analysis to only those patients who had both awake and sleep records at each time point. At three months, IEDs were present in 48 of 205 (23.4%) patients. Of these, 17 (35%) patients had IEDs only during sleep record. At one year, IEDs were present in 35 (16.2%) patients, of which 15 (43%) had IEDs only during the sleep record. Thus obtaining a sleep record increased the yield of IEDs by 35% at three months and by 43% at one year. Overall, IEDs were present in 70 (26%) of the 269 patients who had at least one sleep record. At three months, both awake and sleep IEDs were associated with unfavorable seizure outcomes (Table 5). Interictal discharges during awake and sleep states had similar negative and positive predictive values for both the outcomes. Presence of IEDs during sleep alone increased the sensitivity of EEG in predicting unfavorable final-year outcome by 36% and absolute-postoperative outcome by 13%. Similar to the overall analysis as presented in

Combining the information from the EEGs done at three months and at one year improved the sensitivity without compromising the specificity of EEG in predicting seizure outcome. 3.2. Utility of EEG in patients who were seizure free at the time of EEG We also calculated the predictive value of EEG in a group of patients who were seizure free at the time of EEG. At three months, 257 patients (79%) patients were seizure free. Presence of IEDs on three month EEG was associated with unfavorable final-year outcome (p value, 0.0001) and unfavorable absolute postoperative outcome (p value, 0.04; Table 3). At one year, 229 (70%) patients were seizure free. Presence of IEDs on one year EEG was again associated with unfavorable final-year outcome (p value, 0.01) and absolute-postoperative outcome (p value, 0.04; Table 4). Predictive values of EEG in this group of patients were similar to the predictive values for the whole group as described above. 3.3. Utility of awake and sleep EEG As EEG at 7th day was not predictive of the outcome, we restricted this analysis to the EEGs done at three months and one

Table 3 Prognostic importance of EEG at three months for different outcomes in patients who were seizure free at the time of EEG Outcome

Final-year outcome Absolute-postoperative outcome

IEDs present

IEDs absent

SF

NSF

SF

NSF

10 (44%) 7 (30%)

13 (56%) 16 (70%)

220 (94%) 127 (54%)

14 (6%) 107 (46%)

P value

Sensitivity

Specificity

PPV

NPV

0.0001

0.48 (0.29–0.68) 0.13 (0.08–0.20)

0.96 (0.92–0.98) 0.95 (0.90–0.98)

0.57 (0.39–0.73) 0.70 (0.49–0.84)

0.94 (0.92–0.96) 0.54 (0.52–0.56)

0.04

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PPV = positive predictive value; SF = seizure free.

Table 4 Prognostic importance of EEG at one year for different outcomes in patients who were seizure free at the time of EEG Outcome

Final-year outcome Absolute-postoperative outcome

IEDs present

IEDs absent

SF

NSF

SF

NSF

6 (60%) 2 (20%)

4 (40%) 8 (80%)

200 (91%) 120 (55%)

19 (9%) 99 (45%)

P value

Sensitivity

Specificity

PPV

NPV

0.01

0.17 (0.05–0.39) 0.08 (0.03–0.14)

0.97 (0.94–0.99) 0.98 (0.94–0.99)

0.40 (0.17–0.69) 0.80 (0.46– 0.95)

0.91 (0.90–0.93) 0.55 (0.53–0.56)

0.04

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PPV = positive predictive value; SF = seizure free.

Table 5 Differential significance of awake and sleep EEG at three months EEG state

Outcome

Awake only

Final-year Outcome Absolute-PO Outcome

Awake + sleep IEDs

Final-year Outcome Absolute-PO Outcome

Sleep only

Final-year Outcome Absolute-PO Outcome

IEDs present

IEDs absent

SF

NSF

SF

NSF

22 (71%) 14 (45%)

9 (29%) 17 (55%)

155 (89%) 97 (56%)

19 (11%) 77 (44%)

29 (60%) 19 (40%

19 (40%) 29 (60%)

148 (94%) 92 (59%)

9 (6%) 65 (41%)

7 (41%) 5 (29%)

10 (59%) 12 (71%)

148 (94%) 92 (59%)

9 (6%) 65 (41%)

P value

Sensitivity

Specificity

PPV

NPV

0.02

0.32 (0.17–0.52) 0.18 (0.11–0.28)

0.88 (0.82–0.92) 0.87 (0.79–0.93)

0.29 (0.15–0.48) 0.55 (0.36–0.72)

0.89 (0.83–0.93) 0.56 (0.48–0.63)

0.68 (0.48–0.83) 0.31 (0.22–0.41)

0.84 (0.77–0.89) 0.83 (0.74–0.89)

0.40 (0.26–0.54) 0.60 (0.45–0.74)

0.94 (0.89–0.97) 0.59 (0.50–0.66)

0.53 (0.29–0.75) 0.16 (0.09–0.26)

0.95 (0.91–0.98) 0.95 (0.88–0.98)

0.59 (0.33–0.81) 0.70 (0.44–0.89)

0.94 (0.89–0.97) 0.59 (0.50–0.66)

0.33 0.0001 0.03 0.0001 0.03

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PO-postoperative; PPV = positive predictive value; SF = seizure free.

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C. Rathore et al. / Clinical Neurophysiology 129 (2018) 1907–1912 Table 6 Differential significance of awake and sleep EEG at one year EEG state

Awake only

Outcome

Final-year Outcome Absolute-PO Outcome

Awake + sleep IEDs

Final-year Outcome Absolute-PO Outcome

Sleep only

Final-year Outcome Absolute-PO Outcome

IEDs present

IEDs absent

SF

NSF

SF

NSF

14 (70%) 5 (25%)

6 (30%) 15 (75%)

176 (90%) 108 (55%)

20 (10%) 88 (45%)

27 (77%) 10 (29%)

8 (23%) 25 (71%)

163 (90%) 103 (57%)

18 (10%) 78 (43%)

12 (80%) 5 (33%)

3 (20%) 10 (67%)

164 (91%) 102 (56%)

17 (9%) 79 (44%)

P value

Sensitivity

Specificity

PPV

NPV

0.02

0.23 (0.1–0.44) 0.15 (0.09–0.23)

0.93 (0.88–0.96) 0.96 (0.89–0.98)

0.3 (0.13–0.54) 0.75 (0.51–0.9)

0.9 (0.84–0.94) 0.55 (0.48–0.62)

0.31 (0.15–0.52) 0.24 (0.17–0.34)

0.86 (0.8–0.9) 0.91 (0.84–0.95)

0.23 (0.11–0.4) 0.71 (0.53–0.85)

0.9 (0.85–0.94) 0.57 (0.49–0.64)

0.1 (0.02–0.33) 0.11 (0.06–0.20)

0.93 (0.87–0.96) 0.95 (0.89–0.98)

0.13 (0.02–0.41) 0.67 (0.37–0.87)

0.9 (0.85–0.94) 0.56 (0.49–0.64)

0.02

0.04 0.002 0.18 0.10

Abbreviations: IEDs = interictal epileptiform discharges; NPV = negative predictive value; NSF = not seizure free; PO-postoperative; PPV = positive predictive value; SF = seizure free.

previous segment, IEDs during wakefulness or sleep alone had good negative predictive value for unfavorable final-year outcome and a good positive predictive value for absolute postoperative outcome. Results for the EEGs done at one year were similar to that of three month EEGs except the IEDs only during sleep were not predictive of unfavorable outcome at this time point (Table 6). Overall presence of IEDs during sleep were better predictive of seizure outcome at three months while awake IEDs were better predictive of seizure outcome at one year. 3.4. EEG and seizure recurrence on AED withdrawal AED withdrawal was attempted in 284 (87.4%) patients. Of these, 83 (29.2%) patients had recurrence on attempted withdrawal. Presence of IEDs at one year EEG was associated with a higher risk of seizure recurrence (17/83 vs 21/201; p value 0.03). The IEDs at seven days and three months were not associated with a higher risk of seizure recurrence on attempted AED withdrawal. The positive predictive value for the EEG at one year was 0.45 (0.29–0.61) and the negative predictive value was 0.73 (0.67–0.79). 4. Discussion The important findings from this study are: (1) EEG done at three months and one year is useful in predicting both final one year and absolute postoperative seizure outcome; (2) EEG done on 7th postoperative day is not useful in predicting the seizure outcome; (3) Obtaining a sleep record improves the yield of IEDs by 30%; (4) Presence of IEDs during sleep has the same prognostic significance as awake IEDs; (5) EEG at one year has a modest value in predicting seizure recurrence on attempted AED withdrawal. We have studied the prognostic significance of an EEG done at 7th postoperative day and compared it with the EEG done at later time points. While the presence of IEDs on postoperative EEG has been consistently shown to be associated with unfavorable seizure outcome, the exact timing of obtaining a postoperative EEG is not certain (Rathore and Radhakrishnan, 2010). The previous investigators have used various time points ranging from three months to one year to undertake an EEG, largely depending upon the protocol followed at an individual center (Rathore and Radhakrishnan, 2010). It is desirable to obtain an early EEG so as to predict the outcome at the earliest. However, our data

shows that an early EEG at 7th day following surgery is not useful in predicting the seizure outcome. The spikes in the early postoperative period may represent acute injury spikes or the activated spikes following the resection, which have not been found to be predictive of seizure outcome (MacDonald and Pillay, 2000). Additionally, early postoperative period is associated with multiple systematic and metabolic factors which by themselves may be associated with activation of IEDs. The only other study which evaluated the prognostic significance of early postoperative EEG also showed similar results (Radhakrishnan et al., 1998). However, this study was focused on the predictors of seizure outcome following ATL and not specifically on postoperative EEG. IEDs on early postoperative EEG can also be compared with the persistent IEDs on acute electrocorticography following resection, which have not been shown to predict the seizure outcome in patients with MTLE (McKhann et al., 2000; Schwartz et al., 1997; Tran et al., 1995). It is possible that many of these injury spikes or activated spikes on early postoperative EEG disappear on follow-up. This is corroborated by the fact that 24% of the EEGs showed IEDs at 7th day as compared to 20% at three months and 16% at one year. Similar results have been shown in a recent study by Di Gennaro and colleagues in patients with MTLE, where 24% patients had IEDs at two months compared to 16% at two years (Di Gennaro et al., 2014). In their study, the presence of IEDs at two months was associated with unfavorable seizure outcome. Taking all data together, we feel that an EEG done between second and third postoperative month is most useful for predicting seizure outcome and this predictive value can be further improved by undertaking an EEG at one year. Our results show that obtaining a sleep record increases the yield of IEDs, thus improving the sensitivity of EEG in predicting seizure outcome without compromising the specificity. The presence of IEDs only during sleep at three months was associated with unfavorable seizure outcomes. This was not evident at one year, probably related to lower number of patients with IEDs at one year. The results do indicate that IEDs during sleep has same prognostic significance as that of awake IEDs and all efforts should be made to obtain a sleep record to maximize the chances of accurate prediction. This study evaluated the differential prognostic significance of IEDs during wakefulness and sleep in the postoperative period which has not been well studied even in nonsurgical patients (Di Gennaro et al., 2014). The predictive value of EEG varies according to the type of the outcome studied. Thus for absolute-postoperative outcome, the best possible outcome with no seizures or auras following surgery, presence of IEDs has good positive predictive value of 70% with a

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relatively modest negative predictive value. For final-year outcome, EEG has a very good negative predictive value. Thus even a single normal EEG is associated with favorable outcome during final one year while a single abnormal EEG is highly predictive of seizure recurrence anytime during the whole postoperative period. These results also indicate that seizure outcome is determined by multiple factors and postoperative EEG can only be used as only one of the tools to predict the seizure outcome (McIntosh et al., 2004; Spencer et al., 2005; Téllez-Zenteno et al., 2005). Presence of IEDs on postoperative EEG has rather modest value in predicting seizure recurrence on attempted AED withdrawal. While the IEDs at one year were associated with a higher risk of seizure recurrence on AED withdrawal, IEDs at three months were not associated with a higher risk. This is likely to be due to the fact that AED withdrawal is usually attempted in seizure free patients and patients with IEDs at three months might have seizure recurrence precluding AED withdrawal. Still, EEG had a negative predictive value of 0.73 indicating that a normal EEG can be taken as favorable factor for attempting AED withdrawal. A uniform group of large number of patients with majority having pathologically verified hippocampal sclerosis and long duration of postoperative follow-up are the main strength of this study. Still, approximately 20% of patients who underwent ATL during the same period could not be included in the study either due to the lack of follow-up or due to the absence of EEG at each time point. In our protocol of doing scalp EEG, we insists upon partial sleep deprivation on the previous night. Hence, the exact contribution of sleep deprivation or actual sleep in the activation of IEDs cannot be determined by this study. Moreover, as this study was focused only the postoperative EEG, we could not study the relative significance of other preoperative and postoperative variables in predicting seizure outcome. 5. Conclusions Postoperative EEG has an important role in the management of patients following ATL for MTLE associated with hippocampal sclerosis. For optimal gains, a postoperative EEG should be done between two to three months following surgery as an early EEG at 7th postoperative day is not predictive of seizure outcome. Every effort should be taken to ensure a sleep record as it increases the sensitivity of EEG in predicting seizure outcome. The presence of IEDs during wakefulness and sleep has same prognostic significance for predicting seizure outcome. Overall, EEG has moderate value in predicting seizure recurrence on attempted AED withdrawal with a good negative predictive value. Conflict of interest None of the authors have potential conflicts of interest to be disclosed.

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