J Neurol DOI 10.1007/s00415-014-7625-z

ORIGINAL COMMUNICATION

Functional neuroimaging findings in patients with lateral and mesio-lateral temporal lobe epilepsy; FDG-PET and ictal SPECT studies Eun Yeon Joo • Dae Won Seo • Seung-Chyul Hong • Seung Bong Hong

Received: 9 October 2014 / Revised: 21 December 2014 / Accepted: 22 December 2014 Ó Springer-Verlag Berlin Heidelberg 2015

Abstract The differentiation of combined mesial and lateral temporal onset of seizures (mesio-lateral TLE, MLTLE) from lateral TLE (LTLE) is critical to achieve good surgical outcomes. However, the functional neuroimaging features in LTLE patients based on the ictal onset zone utilizing intracranial EEG (iEEG) in a large series have not been investigated. We enrolled patients diagnosed with MLTLE (n = 35) and LTLE (n = 53) based on the site of ictal onset zone from iEEG monitoring. MLTLE is defined when ictal discharges originate from the mesial and lateral temporal cortices independently, whereas seizures of LTLE arise exclusively from the lateral temporal cortex. Compared to patients with LTLE, patients with MLTLE were more likely to have 18Ffluorodeoxyglucose positron emission tomography (FDGPET) hypometabolism and hyperperfusion on ictal singlephoton emission computed tomography (SPECT) restricted to the temporal areas. MLTLE patients had more frequent aura or secondarily generalized seizures than LTLE patients. No significant differences were found in scalp EEG, MRI, and Wada asymmetry between groups. The overall seizure-free rate was good (73.8 %, mean followup = 9.7 years), which was not different (Engel class I,

E. Y. Joo  D. W. Seo  S. B. Hong (&) Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea e-mail: [email protected]; [email protected] S.-C. Hong (&) Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea e-mail: [email protected]

74.3 % in MLTLE vs. 73.6 % in LTLE). Postsurgical memory function was spared in LTLE patients, while visual memory was impaired in MLTLE patients when their mesial temporal structures were sufficiently resected. It suggests that functional neuroimaging (interictal PET and ictal and interictal SPECT) may play a crucial role to differentiate between MLTLE and LTLE. Keywords Lateral temporal lobe epilepsy  Mesio-lateral temporal lobe epilepsy  Functional neuroimaging  Surgical outcome  Intracranial EEG  FDG-PET  SPECT  Memory

Introduction Temporal lobe epilepsy (TLE) can be subclassified according to area of seizure onset zone on intracranial EEG (iEEG) into mesial TLE, lateral TLE (LTLE), and combined mesio-lateral TLE (MLTLE). The last is present if there are independent mesial and lateral seizure onset zones demonstrated on iEEG, or if iEEG does not allow a precise differentiation between mesial and lateral ictal onset. Differentiating LTLE from MLTLE is critical in order to achieve good surgical outcome and possibly avoid memory impairments by sparing the mesial temporal structures. The term mesio-lateral temporal lobe seizures has been proposed previously [1–5]. The clinical differences between mesial, lateral, and mesio-lateral groups have been studied in 53 partial epilepsy patients with iEEG recordings [3]. It suggests that another subtype of TLE involving both mesial and lateral temporal regions exists in addition to LTLE and mesial TLE. However, functional neuroimaging, such as brain positron emission tomography (PET) or single-photon emission computed tomography (SPECT),

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was not included in those studies. One study analyzed the interictal PET of hypometabolism according to electroclinical patterns in 50 patients with unilateral hippocampal sclerosis and consistent features of mesial TLE [6]. To the best of our knowledge, there have been no studies to characterize functional neuroimaging finding and surgical outcome of MLTLE and LTLE in a large series. The aim of the study was to investigate the differences of the functional neuroimaging features in addition to clinical, electrophysiological, and neuropsychological findings between MLTLE and LTLE patients, and whether the postoperative seizure and memory outcomes of MLTLE patients differ from LTLE patients.

Methods

were performed in 72 patients (31 in MLTLE and 41 in LTLE). Analyses of clinical seizures during scalp EEG monitoring We reviewed patients’ seizures carefully. The presence of aura was determined by the patient’s memory or by the presence of the patient’s pressing a seizure button before seizures. Scalp video EEG monitoring The 10/10 system of scalp electrodes and sphenoidal electrodes (if required) was placed. AEDs were usually reduced or completely stopped in order to facilitate the recording of seizures.

Presurgical evaluations Interictal EEG classification [7] An intractable patient undergoes a comprehensive presurgical evaluation, which consists of a complete neurologic examination, scalp video EEG monitoring, and brain magnetic resonance imagings (MRI) during the 1st admission period. Ictal and interictal SPECT studies were additionally performed in case of TLE, when interictal spikes or ictal onset zone were not localized on unilateral temporal area suggesting the mesial temporal origin. If a TLE patient has normal brain MRI or no definite hippocampal lesions (with neocortical temporal abnormalities) on MRIs, the patient is planned to perform 18Ffluorodeoxyglucose-PET (FDG-PET), neuropsychological test, and Wada test during the 2nd admission period. All data from 1st and 2nd admission periods are reviewed and discussed at the epilepsy management conference, and the surgical plan of the strategy including iEEG monitoring is set to remove the epileptic foci. Patients’ characteristics We retrospectively evaluated a group of 466 consecutive TLE patients who had undergone resective surgery between March 1994 and March 2009 at one universityaffiliated hospital. A total of 109 TLE patients who had undergone iEEG monitoring to localize the epileptogenic foci and determine the respective margin were enrolled. All patients had been intractable before surgery despite proper and sufficient antiepileptic drug (AED) treatment. Clinical characteristics registered for each patient included age of seizure onset, age at surgery, duration of epilepsy, history of febrile seizures, monthly seizure frequency, and the number of antiepileptic drugs (AEDs) at surgery. Interictal PET was done in 76 patients (31 in MLTLE and 45 in LTLE), and both interictal and ictal SPECTs

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Interictal epileptiform discharges (IED) were counted and analyzed over entire recording days and classified into temporal or extratemporal IED. Since tapering of AEDs and sleep restriction in video-EEG monitoring unit definitely affect the numbers and distribution of IED, and the policy about medication tapering and sleep restriction in the unit was set and applied to patients uniformly as possible. On the first day of admission the medication is not tapered and habitual sleep time and amount are allowed to the patients. On second day, slowly tapering of medication without sleep restriction is permitted. From 3rd day, tapering or stopping of medication with or without sleep restriction is tried, yet it may depend on the patients’ situations and the numbers of seizures. Temporal IED (T-IED) indicated uni- or bi-temporal IED or, when temporal IED was present, as a 75 % or more preponderance over the extratemporal IEDs. Temporal and extratemporal IED (ExT-IED) indicated when IEDs from ipsi- or contralateral extratemporal regions were present with over 25 % preponderance to T-IED. Ictal EEG classification [7] during scalp EEG recording Temporal ictal onset zone (T-IOZ) was defined when the location of the ictal discharges was uni- or bi-temporal, and the amplitude ratio of the temporal vs. parasagittal chain was higher than 2:1 in bipolar montages and higher than 2:1 for the 2 sides in referential montages. Hemispheric ictal onset zone (H-IOZ) was defined if the location of ictal discharges arose from a lateralized hemisphere, and the amplitude ratio of the temporal vs. parasagittal chain was lower than 2:1 in bipolar montages and lower than 2:1 for the two sides in referential montages.

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iEEG monitoring iEEG monitoring were performed using a combination of grids/strips and depth electrodes. The anatomical targeting of electrodes was established in each patient according to available non-invasive information and hypotheses about the localization of the epileptogenic zone. Grid and strips were placed in lateral and mesio-basal temporal regions. Concomitantly, implantation of depth electrodes was performed in limited numbers of patients (8 MLTLE and 5 LTLE). Depth electrodes were inserted into uni- or bi-lateral mesial temporal regions (amygdala and hippocampal head, body, and tail), and the locations of electrodes were confirmed by intraoperative photographs and post-implantation surface-rendered electrodes’ images. The onset of ictal EEG discharge during iEEG monitoring was defined as any paroxysmal, sustained pattern that was distinct from background activity and accompanied with clinical seizures [8]. The final diagnosis was determined by the site of ictal onset discharges in at least 3 habitual seizures during iEEG monitoring regardless of the locations of the brain lesions: (1) MLTLE is defined when ictal discharges originate from the depth or grid/strip electrodes implanted on the mesial temporal regions and from grid/strip electrodes on the lateral neocortical temporal cortex independently, whereas (2) LTLE is defined when ictal discharges arise only from grid/ strip electrodes on the lateral neocortical temporal cortex. Intracarotid pentobarbital test (Wada test) Wada memory scores were calculated using the choice recognition memory test. The formula used was the number of items remembered correctly 10 min after a pentobarbital injection divided by the total number of items, which was 12 in our case [9]. A difference of 3 points or more (C25 %) in the retention memory scores between left and right injection was defined as asymmetric, and a difference of less than 3 points (25 %) was defined as symmetric [7]. Neuropsychological tests All patients received pre- and 1-year postoperative neuropsychological battery including the Korean California verbal learning test (K-CVLT) for verbal memory [10] and the Rey Complex Figure Test (RCFT) for non-verbal and visual memory [11]. Brain MRI MRI scanning was performed using a GE Signa 1.5-Tesla scanner (GE Medical Systems, Inc., Milwaukee, WI, USA). All subjects underwent Spoiled Gradient Echo (SPGR), T2-

weighted, and Fluid-Attenuated Inversion Recovery (FLAIR) imaging protocols. Coronal SPGR MR Images were obtained using the following scanning variables: 1.6 mm thickness, no gap, 124 slices, repetition time/echo time (TR/TE) = 30/7 ms, flip angle (FA) = 45°, number of excitations (NEX) = 1, matrix = 256 9 192, and field of view (FOV) = 22 9 22 cm. The voxel dimension of the SPGR MR images was 0.86 9 0.86 9 1.6 mm. Oblique coronal FLAIR MRI was performed using a slice thickness of 4.0 mm, gap of 1.0-mm, 32 slices, TR/TE = 10,002/ 127.5 ms, 1 NEX, matrix = 256 9 192, and FOV = 20 9 20 cm. Oblique coronal T2-weighted MR images were obtained with a slice thickness of 3.0 mm, gap of 0.3 mm, 56 slices, TR/TE = 5,300/99 ms, FA = 90°, 3 NEX, matrix = 256 9 192, and FOV = 20 9 20 cm. 18

F-FDG-PET studies

The FDG-PET images were obtained (GE Advance PET scanner, GE Medical Systems, Inc.) after patients had fasted for 4 or more hours and then received an intravenous injection of 7–10 mCi (259–370 MBq) of FDG. EEG during the uptake period demonstrated no EEG seizure activity in any patient. Apparent hypometabolism was determined semiquantitatively by visual assessment using calibrated color scales (Fig. 1). A graduated color scale in 2 % increments was used for display and analysis. Temporal hypometabolism was defined when the metabolism of the uni- or bi-temporal lobe(s) showed a 20 % or more reduction compared with the extratemporal regions showing normal metabolism [7]. Temporal and extratemporal hypometabolism was defined when the metabolisms of unior bi-temporal and extratemporal lobes showed a 20 % or more reduction compared with other extratemporal regions showing normal glucose metabolism [7] (Fig. 2). Interictal and ictal SPECT studies Brain SPECT scans were performed 30–60 min after the injection of 25 mCi 99mTc-ethyl cysteinate dimer (ECD) using a 3-headed Triad XLT system (Trionix Research Laboratory, Inc., Twinsburg, OH). Interictal SPECT studies were performed when the patients had no documented seizure activity for 24 h. For ictal studies, patients received the radiotracer injection during seizures. Ictal–interictal SPECT Subtraction Co-registered to MR images (SISCOM) analysis was performed on an offline workstation using ANALYZE 7.5 (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN), and the procedures had been previously described [12]. Localized meant definite localized hyperperfusion in the temporal lobe ipsilateral to resection, and Non-localized indicated no hyperperfusion in the temporal lobe, hyperperfusion only in extratemporal regions, or small

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Fig. 1 Intracranial ictal EEG findings in a mesio-lateral temporal lobe epilepsy (MLTLE) patient. A 43-year-old male with a structural lesion in the left inferior temporal gyrus. He had frequent complex partial seizures with or without secondarily generalized tonic–clonic seizures. This figure depicts two separate ictal discharges on his intracranial EEG. During seizure type I, ictal discharges (fast and repetitive spikes) started from the left lateral temporal grid electrodes (white circles with dashed lines), which were adjacent to the lesion

(white circles) and spreaded to the ipsilateral lateral temporal cortex. Seizure type II occurred during sleep. Ictal discharges (fast activities) orginated from the strip electrode located on left mesial temporal region (parahippocampal gyrus, white circle with black dot) and then built up in left hemisphere. Coronal MRI image with fluid-attenuated inversion recovery revealed the cavernous hemangioma in left middle temporal gyrus

hyperperfused spots in temporal and extratemporal regions. One neurologist (Joo EY) and one neuroimaging analyst (Tae WS) reviewed PET and SPECT results independently blind to patient’s information. Since the opinions from two experts were different, final decision was revised by the formal reports from the department of nuclear medicine.

Mann–Whitney U test for continuous variables and with a Chi-square test for categorical variables. A multiple logistic regression was performed to identify the significant factors in determining MLTLE or LTLE. Preoperative group differences in memory were calculated by analysis of variance (ANOVA), and postoperative changes were calculated by performing separate repeated measures (with the factor of surgery) and a multivariate analysis of variance (MANOVA) for verbal and visual memory domains choosing group (MLTLE vs. LTLE) and side of surgery (left vs. right) as independent variables. Data storage and statistical analyses were performed with SPSS 17.0 (SPSS, Inc., Chicago, IL). A p value \0.05 was considered significant.

Surgery and surgical outcome The resection margins of the temporal cortex were determined by the ictal onset zone with or without adjacent brain regions of frequent interictal spikes and early ictal propagation on the iEEG monitoring. All patients had a follow-up period of 2 years or more. Surgical seizure outcome was determined by outpatient clinic interview or by telephone interview using Engel’s classification.

Results Statistical analysis The clinical characteristics of the MLTLE and LTLE patients were compared with a Student’s t test or the

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Among 109 TLE patients, 35 patients were finally diagnosed with MLTLE, 53 with LTLE, and 21 with mesial TLE. Mesial TLE patients were excluded in this study.

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Fig. 2 SISCOM and FDG-PET findings in an MLTLE and an LTLE patient. a Left upper 2 SISCOM images show increased cerebral perfusion in the left mesial and lateral temporal regions during seizure, and the right upper 2 FDG-PET images depict interictal hypometabolism in the left mesial and lateral temporal regions in an

MLTLE patient. b Lower row shows ictal hyperperfusion in the left middle–inferior temporal gyrus and posterior basal temporal regions (left 2 SISCOM images) and interictal hypometabolism in the left hemisphere, especially in the lateral and basal temporal and frontoparietal regions (right 2 FDG-PET images) in an LTLE patient

Patients’ characteristics

appeared to be slightly higher (62.8 %) than that of LTLE (54.7 %) (p = 0.449), but not significant. In 19 MLTLE (86.3 %, 19/22) and 19 LTLE (65.5 %, 19/29) patients who had asymmetric Wada memory scores, contralateral sides of their memory laterality were concordant to the epileptic foci (suitable for resection of epileptic mesial temporal structure). All patients except two with LTLE were right-handed, and their language center was mostly located in the left hemisphere (33 in MLTLE and 50 in LTLE).

There were no differences in clinical characteristics between MLTLE and LTLE groups. The detailed data are summarized in Table 1. Scalp video EEG monitoring On history, MLTLE patients showed more frequent auras (65 % nonspecific, 35 % olfactory, psychic, vertiginous, or abdominal), but the secondarily generalized tonic–clonic seizures with head version were more frequent in LTLE patients (Table 2). Nearly half of both groups showed ExTIED on scalp EEGs similarly (p = 0.960). The ExT-IEDs were recorded most frequently on the frontal regions (34.3 %, F3 or F4) in LTLE patients, whereas it was recorded on the frontopolar regions (28.1 %, FP1 or FP2) in MLTLE patients. LTLE patients tended to have more frequent H-IOZ (60.4 %) than MLTLE patients (45.8 %) (p = 0.176), which did not reach statistical significance. Intracarotid pentobarbital test (Wada test) Asymmetric Wada memory scores indicate lateralized memory dominance. In MLTLE patients, the proportion of patients with asymmetric Wada memory scores

Neuropsychological tests Preoperatively, verbal and visual memory was not significantly different between MLTLE and LTLE patients. Postoperatively, visual memory deterioration in MLTLE patients was definite as opposed to LTLE patients who did not change (Table 3). Brain MRI Sixteen patients with MLTLE and 33 with LTLE showed normal or nonspecific MRI findings. In 19 with lesional MLTLE, 13 showed abnormal signals or shapes in the mesial temporal regions (hippocampus, amygdala, and parahippocampal gyrus), and 6 had benign tumor or

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J Neurol Table 1 Clinical characteristics

Group MLTLE

AEDs antiepileptic drugs, MLTLE mesio-lateral temporal lobe epilepsy, LTLE lateral temporal lobe epilepsy * p \ 0.05, Fisher’s exact test or Paired t test

LTLE

p

Male:female

19:16

35:18

0.271

Age at seizure onset

17.2 ± 10.6

16.5 ± 8.3

0.759

Age at the time of surgery

29.9 ± 10.9

26.9 ± 10.3

0.241

Duration of epilepsy (years)

12.7 ± 8.3

10.4 ± 7.8

0.232

A history of febrile convulsions

15, 42.8 %

21, 39.6 %

0.826

Number of AEDs before surgery

2.4 ± 1.0

2.2 ± 1.0

0.271

Preoperative seizure frequency, per month

8.5 ± 24.5

13.4 ± 26.1

0.440

Postoperative follow-up period (years)

10.0 ± 4.3

9.5 ± 4.2

0.586

2–5 years, n (%)

6 (17.2)

11 (20.7)

5–10 years, n (%)

11 (31.4)

16 (30.2)

10–16 years, n (%) Side of surgery, left:right

18 (51.4) 19:16

26 (49.1) 31:22

0.201

Engel’s classification, I:II–IV

26:9

39:14

0.623

Table 2 Summary of presurgical evaluations

Group MLTLE

LTLE

p

Aura

20 (57.1)

19 (35.8)

0.040*

sGTCs with head version

18 (2.8)

40 (75.4)

0.018*

Scalp EEG interictal spikes Temporal

20 (57.1)

30 (56.6)

0.960

15 (42.9)

23 (43.4)

Temporal

19 (54.2)

21 (39.6)

Hemispheric

16 (45.8)

32 (60.4)

Asymmetric:symmetric

22(62.8):13 (37.2)

29 (54.7):24 (45.2)

0.449

Concordant:discordant

19 (54.2):16 (45.8)

19 (35.8):34 (64.2)

0.087

33 (94.2):2 (5.8)

50 (94.3):3 (5.7)

0.991

19 (54.2)

20 (37.7)

0.126

Seizure Semiology

Temporal and extratemporal Scalp EEG ictal onset zone

0.176

Wada test Memory laterality

Values are n (%) ‘Concordant’ means that memory dominance (asymmetric memory scores) is consistent with the side of epileptic foci sGTCs secondarily generalized tonic–clonic seizures, EEG electroencephalography, MRI magnetic resonance imaging, FDG-PET fluorodeoxyglucose positron emission tomography, SISCOM ictal–interictal SPECT subtraction co-registered to MR images * p \ 0.05, Fisher’s exact test or paired t test

Language center Left:right Brain MRI Symptomatic Cryptogenic FDG-PET, hypometabolism (n = 76) Temporal only Temporal and extratemporal SISCOM, hyperperfusion (n = 72)

33 (62.3) N = 45 15 (33.3)

10 (32.2)

30 (66.7)

0.005*

N = 31

N = 41

Mean radiotracer injection time

25.0 ± 9.3 s

24.8 ± 8.5 s

0.093

Mean seizure duration during injection

51.5 ± 27.4 s

40.5 ± 16.8 s

0.037*

Localized

19 (61.2)

14 (34.1)

0.032*

Non-localized

12 (38.8)

27 (65.9)

angiomas in the lateral temporal regions (4 with lesions in mesial and lateral temporal structures). Among 20 with lesional LTLE, 10 had benign tumor, 5 cavernous angioma,

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16 (45.8) N = 31 21 (67.7)

and 5 had encephalomalacia in the lateral temporal lobe. The ratio of patients with MRI lesions and without lesions was not different between groups (p = 0.126).

J Neurol Table 3 Comparison of preand postoperative memory

Domain memory

Test time

Groups MLTLE

Verbal learning (trials 1–5)

Pre

55.6/8.5

51.2/9.9

2.7 (n.s.)

49.3/10.7

52.3/11.0

0.6 (n.s.)

11.0 (0.003)*

0.1 (n.s.)

Pre

11.2/3.7

10.0/3.1

1.4 (n.s.)

Post

9.6/4.0

10.3/3.7

0.4 (n.s.)

2.5 (n.s.)

0.1 (n.s.)

Pre

11.6/3.1

10.6/3.3

1.3 (n.s.).

Post

10.3/3.9

11.1/3.9

0.5 (n.s.).

2.7 (n.s.)

0.2 (n.s.)

Pre

94.8/4.6

93.1/7.8

0.8 (n.s.)

Post

93.0/7.2 2.0 (n.s.)

92.9/10.0 0.0 (n.s.)

0.0 (n.s.)

Pre

17.8/6.6

15.3/7.5

2.0 (n.s.)

Post

13.7/5.6

17.2/6.6

3.2 (n.s.)

4.7 (0.041)*

0.7 (n.s.)

MANOVA F (sign.) Verbal delayed recall MANOVA F (sign.) Verbal discriminability (SS) MANOVA F (sign.) Visual immediate recall Pre preoperative baseline assessment, Post 1-year postoperative follow-up assessment, SS standardized score, F F-test analysis of variance (ANOVA), MANOVA multivariate analysis of variance, sign. significant, n.s. non-significant * p \ 0.05

18

MANOVA F (sign.) Visual delayed recall

Pre

18.2/6.2

15.2/7.2

2.0 (n.s.)

Post

13.9/4.9

16.6/6.4

2.2 (n.s.)

5.9 (0.023)*

0.4 (n.s.)

MANOVA F (sign.) Visual recognition MANOVA F (sign.)

F-FDG-PET

PET study was performed in 31 MLTLE (88.5 %) and 45 LTLE patients (85.0 %). All patients who underwent PET in this study had areas of hypometabolism. Patients with normal PET with/or without normal SISCOM findings were not willingly considered to be surgical candidates. Exclusively temporal hypometabolism was found in 67.7 % of MLTLE and in 33.3 % of LTLE patients. Temporal and extratemporal hypometabolism was found in 66.7 % of LTLE and in 32.2 % of MLTLE patients. Moreover, mesial temporal hypometabolism was observed in 28 patients with MLTLE (90.3 %), but in only 13 LTLE patients (28.9 %) (p \ 0.05). SISCOM Interictal SPECT was done in 34 MLTLE and 44 LTLE patients, and ictal SPECT (with SISCOM analysis) was performed in 31 MLTLE (88.5 %) and 41 LTLE patients (77.3 %). Temporal hyperperfusion (localized) was observed in 61.2 % of MLTLE and 34.1 % of LTLE patients, which implied that SISCOM was helpful in the localization of epileptic foci in MLTLE (p = 0.032).

ANOVA F (sign.)

Post MANOVA F (sign.) Verbal immediate recall

LTLE

Pre

19.1/1.6

19.6/1.5

0.6 (n.s.)

Post

18.9/2.5

20.1/1.8

3.0 (n.s.)

0.2 (n.s.)

2.3 (n.s.)

Surgery, surgical outcome, and pathology All MLTLE patients had undergone resections of the lateral and mesial temporal regions. Total resection of the hippocampus was performed in 30 MLTLE patients, in whom 10 had abnormal hippocampal shape or signal and 6 had tumor invasion into the hippocampus on MRIs. The remaining 14 MLTLE patients with a normal hippocampus on MRI showed asymmetry of Wada memory scores and mesial temporal hypometabolism on FDG-PET. Partial resection of the hippocampus was done in another 5 MLTLE patients. All LTLE patients underwent resection of lateral temporal cortices, including lesions and epileptic foci. The mean length of the postoperative follow-up was 9.7 ± 4.2 years (range 2–16) as a whole (mean 10.0 years in MLTLE and 9.5 year in LTLE), which was longer than previous studies [13–15]. The long-term seizure-free rate was good (Engel class I, 74.3 % in MLTLE and 73.6 % in LTLE), and it was not different between two groups. Sixtyfive patients (73.8 %, 65/88) became seizure free (Engel class I), whereas the remaining 23 (26.2 %, 23/88) did not render seizure free (Engel II–IV). The surgical outcomes were not different between two groups (Engel class for the LTLE group: I, 39; IIA, 2; IIB,

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3; III, 3; IV, 6; for the MLTLE group: I, 26; IIA, 1; IIB, 2; III, 0; IV, 6). A pathological evaluation of the mesial and lateral temporal structures was available for 35 MLTLE patients. Of mesial temporal specimens, 18 showed hippocampal sclerosis, 13 focal cortical dysplasia, and 4 benign tumor/ angiomas. Of lateral temporal specimens, 28 had mild or focal cortical dysplasia (80 %), 6 had benign tumor/angiomas, and 1 had gliosis. Among lateral temporal specimens of 55 LTLE patients, 35 had mild or focal cortical dysplasia (66.0 %), 15 had benign tumor/angiomas, and 3 had gliosis. A multiple logistic regression identified the presence of aura (p = 0.047), visible MRI lesions (p = 0.040), and FDG-PET hypometabolism restricted to the temporal lobe (p = 0.020), as independent factors for differentiating MLTLE from LTLE.

Discussion There is no doubt that precise differentiation between LTLE and TLE with combined mesial and lateral temporal onset seizures would be essential to expect good surgical outcome. Numerous studies have reported clinical, electrophysiological, and imaging features of TLE [1–5]. It was reported that 37 mesial TLE patients with lateral temporal onset of seizures were more likely to have a lateralized memory deficit and an early risk factor occurring before the age of 2 years compared to 11 LTLE patients, and there were no other differences in semiology, scalp EEG, or seizure outcome between them [4]. In another study, 21 LTLE patients who became seizure free by resection of the lateral neocortex plus the mesial temporal structures showed the characteristics of mesial TLE of the patients, but 15 of 21 patients showed normal or nonspecific findings in brain MRI [5]. Nevertheless, it is not always clear to classify subgroups of TLE with available data. In this study, we hypothesized that functional neuroimaging may be useful to analyze LTLE and observed that interictal FDG-PET and ictalinterictal SPECT findings were significantly different to distinguish MLTLE from LTLE. Patients with suspicious lateral or mesio-lateral TLE routinely underwent interictal and ictal SPECT for SISCOM during the scalp EEG monitoring. One or 2 months later, they were admitted to the general ward to perform interictal PET, neuropsychological test, and Wada test. This presurgical program has continued for last 20 years in this epilepsy center and applied to most TLE patients without exception. The data obtained from this steady program could provide the clinical relevance of the results for the presurgical decision-making process, specifically

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whether to pursue epilepsy surgery, and/or to consider iEEG. The MLTLE patients showed more frequent hypometabolism of both mesial and lateral temporal regions, whereas LTLE patients had frequent hypometabolism in extratemporal regions rather than temporal lobe. Moreover, temporal (mesial and lateral) hypometabolism was revealed to be a significant independent factor to differentiate MLTLE from LTLE. Previously, metabolic differences had been shown among different subtypes of temporal lobe seizures and suggested that hypometabolism in TLE may be related to ictal discharge generation and spread pathways [6], but their subjects were all mesial TLE with unilateral hippocampal sclerosis. More frequent extratemporal hypometabolism in LTLE patients might be related to the faster spreads of ictal discharges to extratemporal regions during LTLE seizures [16]. Moreover, extratemporal cortical hypometabolism outside the seizure focus, in particular hypometabolism in the contralateral cerebral cortex, may be associated with a poorer postoperative seizure outcome in mesial TLE [17]. The patterns of ictal hyperperfusion in SPECT studies apparently reflect not only the anatomic origin of the epileptic discharges, but also adjacent cortical regions they spread [12, 18]. Thus, localized temporal hypometabolism on FDG-PET and temporal hyperperfusion on SISCOM may more suggest MLTLE than LTLE. It would be undoubtful that functional neuroimaging findings may provide the rationale for iEEG exploration of mesial temporal regions in suspected LTLE patients before deciding standard lobectomy and amygdalohippocampectomy for mesial TLE. We observed that MLTLE and LTLE patients had different frequencies of aura and secondarily GTCs; however, other presurgical data (scalp EEG, Wada, and MRI findings) were not different between them. It may support the necessity of functional neuroimaging in the presurgical evaluation of LTLE patients who had auras suggesting mesial temporal origin or of mesial TLE patients who have frequent secondarily GTCs. In this series, we experienced 15 TLE patients with definite mesial temporal lesions who had undergone iEEG monitoring to explore lateral temporal cortex based on the functional neuroimaging findings (extratemporal hypometabolism on FDG-PET and/or nonlocalized SISCOM). In 10 of them, ictal onset zones that independently involved lateral or mesial temporal regions were observed (diagnosed as MLTLE). They were decided to have standard temporal lobectomy and additional corticectomy of lateral temporal regions and all became seizure free (Engle 1). Meanwhile, it needs to address that 5 patients with MLTLE who showed non-localized SISCOM findings did have temporal and extratemporal hypometabolism in PET and 4 of them were revealed to have poor surgical outcome (Engle II–IV). Coincidentally, all of

J Neurol

them did not have brain lesions on MRI (cryptogenic). The diagnosis of MLTLE of them was made mainly based on the iEEG findings and accompanied clinical seizures. It reflects that this comprehensive presurgical evaluation may have limitations to contribute further information to define and remove epileptic foci completely. The strategy for determining resection margins was not different between MLTLE and LTLE. In this series, concomitant depth electrodes were implanted in mesial temporal regions in very limited patients. We acknowledge that it would be hard to differentiate the mesial onset seizures from EEG on grid/strip electrodes located in basal temporal regions and in the absence of direct hippocampal recordings, a seemingly lateral temporal onset may in fact be propagated from the mesial structures. In the early periods of surgery in this center, implantation of depth electrodes was not practically available. In the absence of depth electrodes into hippocampus, ictal onset discharges arising from grid or strip electrodes contacting to parahippocampal gyrus were regarded as ictal onsets of mesial temporal regions. Total resection of the hippocampus was performed in 30 out of 35 MLTLE. Five patients with a partially resected hippocampus had benign tumors in the lateral and mesial temporal regions. Three of them became seizure free (Engel class I), while the other two had persistent seizures postsurgically (Engel class IIIB, IV). Overall numbers of left-side resection were larger (n = 50) than right side (n = 38); however, the ratio of left and right was not significantly different between groups (p = 0.201). No definite difference was not observed in the distribution of poor surgical outcome (Engel II–IV) according to resection side (left:right = 5:4 in MLTLE, 8:6 in LTLE). In MLTLE patients, the most common pathology was hippocampal sclerosis (51.4 %, 18/35) in the mesial temporal region and only 13 of them (37.1 %) showed abnormal shape or signal in mesial temporal structures. Presurgical verbal and visual memory was not significantly different between MLTLE and LTLE patients. The MLTLE patients showed significant decrease of visual memory postsurgically, while verbal memory was spared. LTLE patients did not reveal memory decline after surgery. These findings showed that the hippocampus may be epileptogenic in MLTLE patients in the absence of visible MRI lesions of mesial temporal regions and that it may result in unavoidable postsurgical memory decline in those patients. Although it is not certain why verbal memory was not impaired in MLTLE patients after surgery, it is presumed that the lesser resection extent of left-sided (dominant) hippocampus and basal temporal regions compared to right-sided TLE surgery [12] may play a role to preserve the memory.

It is noteworthy that the mean postsurgical follow-up period was long (mean 9.7 years) and the overall surgical outcomes of both LTLE and MLTLE patients were excellent compared to previous ones [4, 5, 19–22].

Conclusion Distribution of interictal FDG-PET hypometabolism and hyperperfusion of ictal-interictal SPECT (SISCOM) differs in patients with MLTLE and LTLE. Acknowledgments The authors thank Woo Suk Tae PhD (neuroimaging analyst), Department of Radiology, Kangwon National University, Korea for his interpretation of imaging findings, Ms. Suwha Yoon for her devotion in data collection, and Ms. Eunhwa Kim for her assistance with statistical analyses. This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (No. A110097). Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest with respect to the present work. Ethical standard This study has been approved by the appropriate committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Functional neuroimaging findings in patients with lateral and mesio-lateral temporal lobe epilepsy; FDG-PET and ictal SPECT studies.

The differentiation of combined mesial and lateral temporal onset of seizures (mesio-lateral TLE, MLTLE) from lateral TLE (LTLE) is critical to achiev...
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