- Email: [email protected]
Relationship between hypometabolic patterns and ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: An FDG–PET study
Epilepsy Research (2009) 84, 187—193
journal homepage: www.elsevier.com/locate/epilepsyres
Relationship between hypometabolic patterns and ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: An FDG—PET study Eun Mi Lee a, Ki Chun Im b, Ji Hyun Kim c, Jung Kyo Lee d, Seok Ho Hong d, Young Joo No a, Sang-Ahm Lee a, Jae Seung Kim b, Joong Koo Kang a,∗ a
Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea b Department of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea c Department of Neurology, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea d Department of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Received 10 October 2007; received in revised form 4 November 2008; accepted 1 February 2009 Available online 13 March 2009
KEYWORDS Mesial temporal lobe epilepsy; PET; Hypometabolism; Ictal scalp EEG; Dystonic posture
∗
Summary This study was to explore the relationship between scalp ictal EEG patterns and interictal hypometabolic patterns in hippocampal sclerosis-associated mesial temporal lobe epilepsy (HS-MTLE) and determine the clinical significance of interictal hypometabolic patterns. Twenty-five patients were classified into 2 groups based on initial ictal discharge (IID) frequency on scalp EEG: (a) those with a sustained regular 5- to 9-Hz rhythm with a restricted temporal or subtemporal distribution (group 1, N = 9); and (b) those with an irregular 2- to 5-Hz rhythm with a widespread distribution (group 2, N = 16). Using statistical parametric mapping, the PET results of each group were compared with age- and sex-matched controls to identify regions of significant hypometabolism, and the clinical characteristics were compared. Group 1 showed focal hypometabolism confined to the ipsilateral temporal lobe, whereas group 2 showed widespread hypometabolism in the ipsilateral temporal lobe, insular cortex and anterior part of the putamen. The two groups showed no significant differences in clinical characteristics. Among semiologic features, dystonic limb posturing was more frequently observed in group 2 (p = 0.03). In summary, scalp EEG IID patterns in HS-MTLE can be important in determining hypometabolic patterns on interictal PET. Differences in hypometabolic patterns may reflect preferential pathways of ictal propagation rather than intrinsic epileptogenic regions. © 2009 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +82 2 3010 3448; fax: +82 2 474 4691. E-mail address: [email protected] (J.K. Kang).
0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2009.02.005
188
Introduction Scalp EEG initial ictal discharge (IID) frequency has been shown to be important in localizing epileptogenic regions in TLE (Risinger et al., 1989; Ebersole and Pacia, 1996; Pacia and Ebersole, 1997). These discharges most commonly appear as rhythmic waves during complex partial seizures (CPS) of temporal lobe origin (Blume et al., 1984; Sharbrough, 1993; Ebner and Hoppe, 1995; Steinhoff et al., 1995; King et al., 1997). In hippocampal sclerosis-associated mesial temporal lobe epilepsy (HS-MTLE), two distinct lateralizing scalp ictal EEG patterns have been observed: (a) a restricted temporal or subtemporal distribution, 5- to 9-Hz IID (type 1); and (b) a widespread irregular, 2- to 5-Hz IID (type 2) (Ebersole and Pacia, 1996). We recently demonstrated that scalp EEG IID frequency in HS-MTLE can be important in determining ictal hyperperfusion patterns and reflect preferential pathways of ictal propagation rather than intrinsic epileptogenic regions (Kim et al., 2007). Interictal temporal hypometabolism ipsilateral to the epileptic focus has been shown by positron emission tomography (PET) to be present in 80—97% of MTLE patients (Spencer, 1994; Semah et al., 1995; Adam et al., 1996; Ryvlin et al., 1998). The pathophysiology of interictal hypometabolism and its clinical relevance, however, are incompletely understood. The topography of interictal hypometabolism may be related to brain areas generating the clinical expression of ictal onset and spread (Savic et al., 1997; Dupont et al., 1998; Koutroumanidis et al., 2000) and may reflect the preferential networks involved by ictal discharges (Chassoux et al., 2004). However, it has not been documented yet that patterns of interictal hypometabolism on PET may also be dependent on scalp IID frequency patterns in homogeneous group of patients with HS-MTLE; rather restricted interictal hypometabolism in IID type I versus wider interictal hypometabolism in IID type II according to IID frequency, suggesting presence of the preferential networks. To test the hypothesis that hypometabolic patterns may differ in relation to scalp EEG IID such as type I or II and reflect the preferential networks involved by ictal discharges, we have explored the relationship between scalp ictal EEG patterns and interictal hypometabolism patterns in a well-defined group of HS-MTLE patients with seizurefree after surgery. We also assessed the clinical significance of interictal hypometabolism patterns according to scalp IID patterns.
E.M. Lee et al. dalohippocampectomy (ATL-AH) with a minimum follow-up of 1 year; and (5) surgical pathology demonstrating hippocampal sclerosis without dual pathology. Exclusion criteria included: (1) more than one type of scalp EEG IID pattern (i.e., a mixture of type 1 and type 2 patterns) in the same patient during video-EEG monitoring; (2) non-lateralizing ictal scalp EEG; (3) bilateral HS based on visual assessment of MRI; (4) side-to-side discrepancy between ictal EEG initiation and PET hypometabolism; and (5) patients who were not seizure-free (Engel’s classification II, III, IV), indicating that the epileptogenic zone had not been resected following ATL-AH (Engel et al., 1993). During the video-EEG monitoring, antiepileptic drugs were gradually tapered off or completely withdrew to record ictal events. Two experienced interpreters (E.M.L. and J.K.K.) independently reviewed the video-EEG monitoring data of all patients. In cases of discordance in determining ictal EEG patterns, a third interpreter (J.H.K) made the final decision. HS was diagnosed by visual assessment of high-resolution MRI, based on a combination of unilateral hippocampal atrophy and increased T2 signal in the atrophic hippocampus (Jackson et al., 1993). Parameters obtained for all patients included demographic and clinical characteristics (e.g., sex, age at epilepsy surgery, age at seizure onset, duration of epilepsy), follow-up period after surgery, seizure duration and seizure semiology. Semiological analyses included the presence of motionless staring, oroalimentary automatism, unilateral or bilateral limb automatism, and dystonic limb posturing contralateral to the side of HS, and secondarily generalized seizures. Seizure duration was calculated from the time of identifiable change of EEG activity, whether or not preceding clinical onset, to the end of ictal EEG activity. For secondarily generalized seizures, the end of a complex partial seizure was defined as the time just before the clinical manifestation of the generalized seizure. Dystonic posturing was defined as sustained unnatural posturing with a tonic component involving one upper extremity (Rusu et al., 2005). We did not consider the chronology of ictal symptoms. Individual seizure semiology was considered present if it was observed at least one-half of recorded seizures. A total of 160 seizures consistent with their habitual seizures were analyzed. One neurosurgeon (J.K.L.) performed ATL-AH on all patients in the same manner. For those undergoing dominant ATL, 4.0 cm of the temporal lobe was excised; for non-dominant ATL, 4.0—5.0 cm was excised. The hippocampus was removed microsurgically, usually to the level of the posterior midbrain. Surgical specimens of the hippocampus and temporal neocortex were evaluated for the presence of hippocampal sclerosis and cortical malformation, respectively.
MRI analysis
Methods
MRI scans were visually analyzed by two neurologists (E.M.L. and J.K.K.) blinded to clinical data. They assessed the side and degree of hippocampal atrophy (mild, moderate, or severe), associated temporal lobe atrophy, and signal changes (i.e., hypersignal with blurring between gray and white matter on T2-weighted sequences) in the temporal lobe (Chassoux et al., 2004).
Patients
Ictal scalp EEG acquisition and classification
We retrospectively selected a homogeneous group of patients undergoing temporal lobectomy for medically intractable HS-MTLE at the Asan Medical Center from 2001 to 2005. Inclusion criteria included: (1) electro-clinical features typical of MTLE patients who had more than 3 ictal events during long-term video-EEG monitoring; (2) unilateral HS on high-resolution MRI; (3) stereotypic scalp EEG IID patterns (i.e., type 1 or type 2 IID patterns), irrespective of secondary generalized seizures, during all seizures recorded by video-EEG monitoring; (4) excellent surgical outcome (Engel’s classification I) following anterior temporal lobectomy and amyg-
Electrodes were placed according to the 10-20 International System, along with supplementary subtemporal (F9/10, FT9/10, T9/10) and sphenoidal electrodes (SP1/2). Digitally acquired ictal recordings were reviewed on a conventional anterior-posterior bipolar montage and verified on a referential montage with a high frequency filter of 70 Hz and a low frequency filter of 1.0 Hz (Kim et al., 2007). Ictal EEG onset was defined by the presence of well-recognized, sustained rhythmic waves distinct from background. Two lateralizing ictal patterns were identified: (1) those who had a sustained, regular 5—9 Hz rhythm with well-lateralized temporal or subtemporal
EEG and interictal hypometabolic patterns HS-MTLE
189
Figure 1 An example of ictal-onset EEG of group 1: progressive buildup of a regular 7 Hz initial ictal discharge (IIDs) with a restricted left temporal/subtemporal distribution. This ictal EEG is displayed with a Pz reference montage and 3- to 17-Hz bandpass filtering. Vertical time scale at 1-s intervals. distribution (type 1) was designated as group 1 (Fig. 1); and (2) those who had an irregular 2—5 Hz rhythm, sometimes appearing as periodic discharges, with widespread temporal distribution (type 2) was designated as group 2 (Fig. 2).
PET scans PET images were acquired using an ECAT EXACT HR + scanner (CTISiemens, Knoxville, Tennessee, USA). The system provides 63 planes (2.46 mm slice thickness) and a 15.5 cm longitudinal field of view. After a fast of at least 6 h, all participants were injected with an intravenous dose of 370 MBq (10 mCi) of FDG over 30—60 s. After a 5-min transmission scan for segmented attenuation correction with a rotating 68 Ge source, an emission scan was acquired for 15 min in three-dimensional mode. All emission images were reconstructed with ordered subset expectation maximization (OSEM) using 16 subsets and 6 iterations. PET scans were performed with minimal auditory stimulation in a dimly lit room and with the participants’ eyes closed. EEG was not performed during FDG uptake. But we carefully monitored for head movements and ictal events. Patients were also asked to report any seizures experienced on the day of the scan. Patients were also asked to report any seizures experienced on the day of the scan, whether before or after the FDG injection. A second examination was considered for patients with such seizures if the images were inconclusive.
Statistical parametric mapping (SPM) analysis of 18 F-fluoro-2-deoxy-D-glucose PET Prior to statistical analysis, all images were spatially normalized to a PET template using the SPM2 implemented in Matlab 6.5 (Mathworks Inc., Natick, MA, USA). Spatially normalized images were smoothed using an isotropic Gaussian kernel with an 8-mm full-width at halfmaximum. Image intensity was normalized between participants to control for inter-participant variability in global brain activity. Before analysis, PET images from the right HS-MTLE patients were flipped onto the left side to enable group analysis. Individual SPM analysis was first performed in order to detect some potential variability within each group that may affect the group analysis results. Statistical analyses were performed in two steps. Significant decreases in regional glucose metabolism in the patient groups were estimated by comparing their normalized PET images with those of 18 healthy controls (6 females; mean age, 31.9 ± 6.2 years; range, 23—39 years). A two-sided t-test of SPM was performed to assess the group difference. The analysis produced a t statistic for each voxel and t values were transformed to the standard distribution. Statistical significance was set at a threshold of p < 0.005, uncorrected for multiple comparisons, with the added requirement that at least 50 contiguous voxels exceeded this statistical level. The Montreal Neurological Institute (MNI) coordinates of cluster peak were transformed to standard Talairach coordinates (Talairach and Tournoux, 1988).
Figure 2 An example of ictal onset EEG of group 2: buildup of a regular 3- to 4-Hz initial ictal discharge (IID) with a widespread left temporal/subtemporal and parasagittal distribution, followed by 6- to 7-Hz rhythmic activity. This is displayed with a Pz reference montage and 3- to 17-Hz bandpass filtering. Vertical time scale at 1-s intervals.
190
E.M. Lee et al.
Table 1
Clinical characteristics and semiologic features in each group.
Patient number (male:female) Age at operation (year) Age at onset (year) Epilepsy duration Follow-up period (months) Seizure frequency (per month) Seizure duration (s) Motionless staring Oroalimentary automatism Limb automatism Contralateral limb dystonic posture Total number of recorded seizures Secondary GTC MRI finding (hippocampal atrophy) Mild Moderate Severe MRI finding (signal change) Yes No
Group 1
Group 2
p-value
4:5 31.56 ± 6.21 19.89 ± 9.56 11.67 ± 8.79 41.22 ± 15.51 2.61 ± 1.41 64.76 ± 21.33 8/9 (88.9%) 3/9 (33.3%) 2/9 (22.2%) 1/9 (11.1%) 7.44 ± 4.69 1.0 ± 1.5
8:8 30.69 ± 6.23 15.56 ± 8.04 15.25 ± 8.08 35.06 ± 9.20 2.29 ± 2.23 65.04 ± 23.11 12/16 (75.0%) 10/16 (62.5%) 5/16 (31.3%) 10/16 (62.5%) 5.81 ± 2.86 1.19 ± 1.68
0.79 0.79 0.24 0.31 0.22 0.8 0.98 0.62 0.23 1 0.03 0.29 0.78 0.62
3 (33.3%) 3 (33.3%) 3 (33.3%)
3 (18.8%) 8 (50.0%) 5 (31.2%)
7 (77.8%) 2 (22.2%)
14 (87.5%) 2 (12.5%)
0.60
GTC: generalized tonic-clonic seizure.
Statistical analysis Continuous, normally distributed variables, including age at operation, onset age, epilepsy duration, seizure duration and follow-up period were compared using independent t-tests. Categorical variables, such as presence of risk factors and semiologic features, were compared using Fisher’s exact test. Data storage and analysis were performed using SPSS software (Statistical Package for the Social Science, version 12.0, Chicago, IL, USA). Statistical significance was defined as p ≤ 0.05.
dyslamination in the temporal neocortex was negative in all patients. Unilateral hippocampal atrophy was found on the right side in 12 patients and on the left side in 13 and was classified as mild in 6 (24.0%), moderate in 11 (44.0%) and severe in 8 (32.0%) patients. Associated signal changes on T2-weighted sequences were detected in 21 of 25 patients (84.0%). None had ipsilateral hemispheric atrophy. The degree of HA (p = 0.62) and signal change on T2 weighted image on temporal lobe (p = 0.60) did not differ between the two groups.
Results Patient groups Of the 25 patients (13 females; mean age, 31 ± 6.1 years; range, 19—39 years) with unilateral HS and MTLE semiology, who underwent interictal PET scans and ATL-AH, 9 (5 females, 4 right HS) were classified as group 1, and 16 (8 females, 8 right HS) as group 2. Intracranial EEG recordings were performed on 4 patients in group 2 and one in group 1 using bilateral hippocampal depths and temporal subdural strips. In all 5 patients, ictal onset was started from hippocampal depth electrodes. The interpretation of ictal EEG by the 2 primary interpreters was concordant in 21 (87.5%) patients and discordant in 3 (12.5%). Demographics and clinical characteristics are summarized in Table 1. No differences between groups 1 and 2 were observed in age at operation (p = 0.79), age at seizure onset (p = 0.24), duration of epilepsy (p = 0.31), or mean follow-up period (41.22 ± 15.51 months vs 35.06 ± 9.20 months; p = 0.22). Pathologic examination of the resected specimen at the time of surgery confirmed that all patients had HS without dual pathology. A careful search for focal cortical dysplasia and
Semiologic analyses Mean seizure duration did not differ between groups 1 and 2 (64.76 ± 21.33 s vs 65.04 ± 23.11 s; p = 0.98). Semiologic analyses showed no between-group differences in the frequency of motionless staring only (8 of 9 (88.9%) vs 12 of 16 (75.0%); p = 0.62), oroalimentary automatism (3 of 9 (33.3%) vs 10 of 16 (62.5%); p = 0.23), and limb automatism (2 of 9 (22.2%) vs 5 of 16 (31.3%); p = 1.0). Dystonic limb posturing contralateral to the side of HS was significantly more frequent in group 2 (10 of 16, 62.5%) than in group 1 (1 of 9, 11.1%; p = 0.03).
SPM analysis of PET Individual data did not show significant heterogeneity within each group, but individual PET data in group 2 usually showed wider hypometabolism than those in group 1. In group analysis, group 1 showed focal hypometabolism in the ipsilateral temporal lobe including hippocampus at a significance level of uncorrected p < 0.005 (Fig. 3A). In group
EEG and interictal hypometabolic patterns HS-MTLE
191
Figure 3 Hypometabolism topography in the two groups (A, group 1; B, group 2) compared to 18 healthy controls using SPM2 (threshold: p < 0.005, uncorrected for extent). Focal hypometabolism was observed in the ipsilateral temporal lobe in group 1 (A), whereas widespread hypometabolism was observed in the ipsilateral temporal lobe, putamen and insular cortex in group 2 (B).
2, widespread hypometabolism was observed in the ipsilateral temporal lobe, insular cortex and putamen at the same threshold (Fig. 3B).
Discussion The main finding of the present study is that IID of rather restricted, regular high-frequency (5—9 Hz) rhythm resulted in interictal hypometabolism confined mainly to the ipsilateral temporal lobe (group 1), whereas IID of widespread, irregular low-frequency (2—5 Hz) rhythm was associated with widespread interictal hypometabolism in the ipsilateral putamen and insular cortex, as well as ipsilateral temporal lobe hypometabolism (group 2). Involvement of the ipsilateral basal ganglia in group 2 has important implications for understanding the semiology of MTLE, suggesting a higher incidence of dystonic limb posturing. These findings suggest that interictal hypometabolism in relation to scalp ictal IID frequencies not only localize seizure-onset zone but also reflect the preferential pathway of ictal propagation. Thus, scalp EEG IID could be a determinant of a hypometabolism pattern in unilateral HS-MTLE. Based on electro-clinical correlation in patients with unilateral HS-MTLE, the degree and topography of hypometabolism clearly differed among those with mesial, anterior mesio-lateral, and widespread involvement (Chassoux et al., 2004), suggesting a correlation between topography of hypometabolism and electroclinical pattern. That is, focal ictal semiology was associated with restricted interictal temporal hypometabolism, whereas diverse ictal semiology was related to widespread interictal hypometabolism. Although our findings of wider interictal hypometabolism in group 2 than in group 1 is in line with their results, hypometabolic areas in our cases were relatively restricted to local areas in both groups compared to previous studies (Chassoux et al., 2004; Rusu et al., 2005). This discrepancy between the studies may be due to the different patient population included. We included
only a homogeneous group of patients who had HS-MTLE and obtained seizure-free (Engel’s classification class I) after surgery, resulting in relatively restricted interictal hypometabolic area in patients with type I (group 1) and, even, type II (group 2). Previous studies included patients with HS-MTLE, but also included patients with other etiologies and patients with not seizure-free (even though they obtained good surgical outcome) or non-operation, resulting in including some patients with wider epileptogenic zone and wider hypometabolic areas in PET compared to our study (Chassoux et al., 2004; Rusu et al., 2005). Another explanation for restricted hypometabolic area in our cases, especially in group 2, is that the inclusion criteria of dystonic posturing was milder than those of previous studies (Chassoux et al., 2004; Rusu et al., 2005). These also contributed to including patients with mild and less frequent dystonic posturing, resulting in less involvement of the basal ganglia even in group 2. The important difference between our study and previous studies is also that we classified homogeneous HS-MTLE patients according to their scalp IID patterns without considering their clinical features. One may argue that low-frequency IID of group 2 in our study may be ascribed to temporal neocortical-onset seizure because irregular widespread 2- to 5-Hz discharges (type 2) have been frequently associated with temporal neocortical onset seizures (Ebersole and Pacia, 1996; Pacia and Ebersole, 1997). However, all of our patients, including those in group 2, had substantial MRI evidence of HS and excellent seizure outcomes after surgery. In addition, pathologic examination failed to show any abnormalities in the temporal neocortex of group 2 patients, suggesting that all of these patients had hippocampus-onset seizures. Ictal dystonic posturing during a CPS is the most reliable lateralizing feature in MTLE (Kotagal et al., 1989) and is related to the spread of ictal discharges to the caudate, putamen, and thalamus, as demonstrated by PET (Dupont et al., 1998) and SPECT (Newton et al., 1992; Joo
192 et al., 2004; Mizobuchi et al., 2004). Lesions of the putamen and globus pallidus commonly caused dystonia, particularly when the putamen was involved. Hypometabolism in the ipsilateral putamen may account for the higher incidence of dystonic limb posturing observed in our group 2. These findings suggest that low frequency IID in HS-MTLE is related to hypometabolism of the ipsilateral putamen and tends to produce ictal semiology of dystonic limb posturing. Our results, however, are in disagreement with previous findings (Rusu et al., 2005), showing that ictal dystonia was associated with faster ictal rhythms. This discrepancy may be due to differences in inclusion criteria and patient classification. In the earlier study, patients with dystonic posturing had longer seizure duration, secondary generalization and an association with oroalimentary automatism than did patients without dystonic posturing (Rusu et al., 2005). In our study, however, there were no differences, except for scalp EEG IID patterns, associated with the different rate of dystonic posture in the two groups. These findings suggested that, although seizure duration of scalp EEG IID type 2 was not longer than that of type 1, the former may have preferential pathway or a tendency to involve widespread areas of the brain including the subcortical structure such as the ipsilateral putamen, providing further supports to our hypothesis that IID type 1 results in confined interictal hypometabolism and ictal hyperperfusion, whereas IID type 2 is associated with wider interictal hypometabolism and ictal hyperperfusion. Another interesting finding in the present study was that group 2 had interictal hypometabolism in the ipsilateral insular cortex compared to group 1. Since the anterior insular cortex is connected to the temporal and orbitofrontal cortices and the amygadala (Mesulam and Mufson, 1982), MTLE seizures may involve the insula (Isnard et al., 2000; Bouilleret et al., 2002). Because the clinical characteristics of the two groups were similar, clinical significance involving the insular cortex was not clear. Further study will be needed to reveal these issues. Compared with epileptogenic zones identified on structural MR imaging, hypometabolic areas on PET are usually larger, often spreading over extra-temporal cortical areas, including subcortical structures (Arnold et al., 1996; Savic et al., 1997; Dupont et al., 1998). Recent findings have shown a concordance between ictal SPECT hyperperfusion and interictal FDG—PET hypometabolism in TLE, suggesting that seizures were generated and spread in interictally hypometabolic regions (Bouilleret et al., 2002). Thus, hypometabolic areas identified on interictal PET may include not only the seizure onset zone but also areas of functional deficit or preferential pathways of seizure spread. By reflecting chronic functional disturbances related to seizures, interictal PET studies may show a correlation between metabolic patterns and seizure spread pathways in MTLE. Temporal hypometabolism has been correlated with the severity of hippocampal atrophy (Gaillard et al., 1995; Semah et al., 1995), but a strong relationship with the metabolic pattern was not observed (O’Brien et al., 1997, Chassoux et al., 2004). We also detected no between-group differences in HS severity or signal changes of the temporal lobe, although we did not perform a volumetric measurement of hippocampal and temporal lobe atrophy. These
E.M. Lee et al. findings suggest that the degree of hippocampal atrophy or associated signal change does not appear to be a determinant of metabolic changes. Our study had several limitations. Specific semiology was considered present if it observed ≥50% of all recorded seizures, a somewhat arbitrary classification. In addition, the number of patients in each group was small, making the statistical powers relatively weak. Additional large-scale detailed studies are necessary in the future. In conclusion, we demonstrated that scalp EEG IID may be a determinant of hypometabolism pattern in patients with unilateral HS-MTLE. We observed a correlation between hypometabolism topography and scalp EEG IID frequency, supporting the hypothesis that neuronal networks are involved in ictal discharges and metabolic changes.
Acknowledgements The authors thank the technical assistants of Epilepsy Monitoring Unit in Asan Medical Center for their help to obtain good quality of video-EEG monitoring data. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References Adam, C., Clémenceau, S., Semah, F., Hasboun, D., Samson, S., Aboujaoude, N., Samson, Y., Baulac, M., 1996. Variability of presentation in medial temporal lobe epilepsy: a study of 30 operated cases. Acta Neurol. Scand. 94, 1—11. Arnold, S., Schlaug, G., Niemann, H., Ebner, A., Lüders, H., Witte, O.W., Seitz, R.J., 1996. Topography of interictal glucose hypometabolism in unilateral mesiotemporal epilepsy. Neurology 46, 1422—1430. Blume, W.T., Young, G.B., Lemieux, J.F., 1984. EEG morphology of partial epileptic seizures. Electroencephalogr. Clin. Neurophysiol. 57, 295—302. Bouilleret, V., Dupont, S., Spelle, L., Baulac, M., Samson, Y., Semah, F., 2002. Insular cortex involvement in mesiotemporal lobe epilepsy: a positron emission tomography study. Ann. Neurol. 51, 202—208. Chassoux, F., Semah, F., Bouilleret, V., Landre, E., Devaux, B., Turak, B., Nataf, F., Roux, F.X., 2004. Metabolic changes and electro-clinical patterns in mesio-temporal lobe epilepsy: a correlative study. Brain 127, 164—174. Dupont, S., Semah, F., Baulac, M., Samson, Y., 1998. The underlying pathophysiology of ictal dystonia in temporal lobe epilepsy: an FDG—PET study. Neurology 51, 1289—1292. Ebersole, J.S., Pacia, S.V., 1996. Localization of temporal lobe foci by ictal EEG patterns. Epilepsia 37, 386—399. Ebner, A., Hoppe, M., 1995. Noninvasive electroencephalography and mesial temporal sclerosis. J. Clin. Neurophysiol. 12, 23—31. Engel Jr., J., Van Ness, P.C., Rasmussen, T.B., 1993. Outcome with respect to epileptic seizures. In: Engel Jr., J. (Ed.), Surgical Treatment of the Epilepsies, 2nd ed. Raven Press, New York, pp. 609—621. Gaillard, W.D., Bhatia, S., Bookheimer, S.Y., Fazilat, S., Sato, S., Theodore, W.H., 1995. FDG—PET and volumetric MRI in the evaluation of patients with partial epilepsy. Neurology 45, 123—126. Isnard, J., Guenot, M., Ostrowsky, K., Sindou, M., Mauguiere, F., 2000. The role of the insular cortex in temporal lobe epilepsy. Ann. Neurol. 48, 614—623.
EEG and interictal hypometabolic patterns HS-MTLE Jackson, G.D., Berkovic, S.F., Duncan, J.S., Connelly, A., 1993. Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am. J. Neuroradiol. 14, 753—762. Joo, E.Y., Hong, S.B., Lee, E.K., Tae, W.S., Kim, J.H., Seo, D.W., Hong, S.C., Kim, S., Kim, M.H., 2004. Regional cerebral hyperperfusion with ictal dystonic posturing: ictal-interictal SPECT subtraction. Epilepsia 45, 686—689. Kim, J.H., Im, K.C., Kim, J.S., Lee, S.A., Lee, J.K., Khang, S.K., Kang, J.K., 2007. Ictal hyperperfusion patterns in relation to ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: a SPECT study. Epilepsia 48, 270—277. King, D., Spencer, S.S., McCarthy, G., Spencer, D.D., 1997. Surface and depth EEG findings in patients with hippocampal atrophy. Neurology 48, 1363—1367. Kotagal, P., Lüders, H.O., Morris, H.H., Dinner, D.S., Wyllie, E., Godoy, J., Rothner, A.D., 1989. Dystonic posturing in complex partial seizures of temporal lobe onset: A new lateralizing sign. Neurology 39, 196—201. Koutroumanidis, M., Hennessy, M.J., Seed, P.T., Elwes, R.D., Jarosz, J., Morris, R.G., Maisey, M.N., Binnie, C.D., Polkey, C.E., 2000. Significance of interictal bilateral temporal hypometabolism in temporal lobe epilepsy. Neurology 54, 1811—1821. Mesulam, M.M., Mufson, E.J., 1982. Insula of the old world monkey I. Architectonics on the insulo-orbito-temporal component of the paralimbic brain. J. Comp. Neurol. 212, 1—22. Mizobuchi, M., Matsuda, K., Inoue, Y., Sako, K., Sumi, Y., Chitoku, S., Tsumaki, K., Takahashi, M., 2004. Dystonic posturing associated with putaminal hyperperfusion depicted on subtraction SPECT. Epilepsia 45, 948—953. Newton, M.R., Berkovic, S.F., Austin, M.C., Reutens, D.C., McKay, W.J., Bladin, P.F., 1992. Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures. Neurology 42, 371—377. O’Brien, T.J., Newton, M.R., Cook, M.J., Berlangieri, S.U., Kilpatrick, C., Morris, K., Berkovic, S.F., 1997. Hippocampal
193 atrophy is not a major determinant of regional hypometabolism in temporal lobe epilepsy. Epilepsia 38, 74—80. Pacia, S.V., Ebersole, J.S., 1997. Intracranial EEG substrates of scalp ictal patterns from temporal lobe foci. Epilepsia 38, 642—654. Risinger, M.W., Engel Jr., J., Van Ness, P.C., Henry, T.R., Crandall, P.H., 1989. Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings. Neurology 39, 1288—1293. Rusu, V., Chassoux, F., Landre, E., Bouilleret, V., Nataf, F., Devaux, B.C., Turak, B., Semah, F., 2005. Dystonic posturing in seizures of mesial temporal origin: electroclinical and metabolic patterns. Neurology 65, 1612—1619. Ryvlin, P., Bouvard, S., Le Bars, D., De Lamérie, G., Grégoire, M.C., Kahane, P., Froment, J.C., Mauguiere, F., 1998. Clinical utility of flumazenil-PET versus [18 F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy. A prospective study in 100 patients. Brain 121, 2067—2081. Savic, I., Altshuler, L., Baxter, L., Engel Jr., J., 1997. Pattern of interictal hypometabolism in PET scans with fludeoxyglucose F 18 reflects prior seizure types in patients with mesial temporal lobe seizures. Arch. Neurol. 54, 129—136. Semah, F., Baulac, M., Hasboun, D., Frouin, V., Mangin, J.F., Papageorgiou, S., Leroy-Willig, A., Philippon, J., Laplane, D., Samon, Y., 1995. Is interictal temporal hypometabolism related to mesial temporal sclerosis? A positron emission tomography/magnetic resonance imaging confrontation. Epilepsia 36, 447—456. Sharbrough, F.W., 1993. Scalp-recorded ictal patterns in focal epilepsy. J. Clin. Neurophysiol. 10, 262—267. Spencer, S.S., 1994. The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 35 (Suppl. 6), S72—S89. Steinhoff, B.J., So, N.K., Lim, S., Luders, H.O., 1995. Ictal scalp EEG in temporal lobe epilepsy with unitemporal versus bitemporal interictal epileptiform discharges. Neurology 45, 889—896. Talairach, J., Tournoux, P., 1988. Co-Planar Stereotaxic Atlas of the Brain. 3-Dimensional Proportional System: An Approach to Cerebral Imaging. George Thieme, Stuttgart.
journal homepage: www.elsevier.com/locate/epilepsyres
Relationship between hypometabolic patterns and ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: An FDG—PET study Eun Mi Lee a, Ki Chun Im b, Ji Hyun Kim c, Jung Kyo Lee d, Seok Ho Hong d, Young Joo No a, Sang-Ahm Lee a, Jae Seung Kim b, Joong Koo Kang a,∗ a
Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea b Department of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea c Department of Neurology, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea d Department of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Received 10 October 2007; received in revised form 4 November 2008; accepted 1 February 2009 Available online 13 March 2009
KEYWORDS Mesial temporal lobe epilepsy; PET; Hypometabolism; Ictal scalp EEG; Dystonic posture
∗
Summary This study was to explore the relationship between scalp ictal EEG patterns and interictal hypometabolic patterns in hippocampal sclerosis-associated mesial temporal lobe epilepsy (HS-MTLE) and determine the clinical significance of interictal hypometabolic patterns. Twenty-five patients were classified into 2 groups based on initial ictal discharge (IID) frequency on scalp EEG: (a) those with a sustained regular 5- to 9-Hz rhythm with a restricted temporal or subtemporal distribution (group 1, N = 9); and (b) those with an irregular 2- to 5-Hz rhythm with a widespread distribution (group 2, N = 16). Using statistical parametric mapping, the PET results of each group were compared with age- and sex-matched controls to identify regions of significant hypometabolism, and the clinical characteristics were compared. Group 1 showed focal hypometabolism confined to the ipsilateral temporal lobe, whereas group 2 showed widespread hypometabolism in the ipsilateral temporal lobe, insular cortex and anterior part of the putamen. The two groups showed no significant differences in clinical characteristics. Among semiologic features, dystonic limb posturing was more frequently observed in group 2 (p = 0.03). In summary, scalp EEG IID patterns in HS-MTLE can be important in determining hypometabolic patterns on interictal PET. Differences in hypometabolic patterns may reflect preferential pathways of ictal propagation rather than intrinsic epileptogenic regions. © 2009 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +82 2 3010 3448; fax: +82 2 474 4691. E-mail address: [email protected] (J.K. Kang).
0920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2009.02.005
188
Introduction Scalp EEG initial ictal discharge (IID) frequency has been shown to be important in localizing epileptogenic regions in TLE (Risinger et al., 1989; Ebersole and Pacia, 1996; Pacia and Ebersole, 1997). These discharges most commonly appear as rhythmic waves during complex partial seizures (CPS) of temporal lobe origin (Blume et al., 1984; Sharbrough, 1993; Ebner and Hoppe, 1995; Steinhoff et al., 1995; King et al., 1997). In hippocampal sclerosis-associated mesial temporal lobe epilepsy (HS-MTLE), two distinct lateralizing scalp ictal EEG patterns have been observed: (a) a restricted temporal or subtemporal distribution, 5- to 9-Hz IID (type 1); and (b) a widespread irregular, 2- to 5-Hz IID (type 2) (Ebersole and Pacia, 1996). We recently demonstrated that scalp EEG IID frequency in HS-MTLE can be important in determining ictal hyperperfusion patterns and reflect preferential pathways of ictal propagation rather than intrinsic epileptogenic regions (Kim et al., 2007). Interictal temporal hypometabolism ipsilateral to the epileptic focus has been shown by positron emission tomography (PET) to be present in 80—97% of MTLE patients (Spencer, 1994; Semah et al., 1995; Adam et al., 1996; Ryvlin et al., 1998). The pathophysiology of interictal hypometabolism and its clinical relevance, however, are incompletely understood. The topography of interictal hypometabolism may be related to brain areas generating the clinical expression of ictal onset and spread (Savic et al., 1997; Dupont et al., 1998; Koutroumanidis et al., 2000) and may reflect the preferential networks involved by ictal discharges (Chassoux et al., 2004). However, it has not been documented yet that patterns of interictal hypometabolism on PET may also be dependent on scalp IID frequency patterns in homogeneous group of patients with HS-MTLE; rather restricted interictal hypometabolism in IID type I versus wider interictal hypometabolism in IID type II according to IID frequency, suggesting presence of the preferential networks. To test the hypothesis that hypometabolic patterns may differ in relation to scalp EEG IID such as type I or II and reflect the preferential networks involved by ictal discharges, we have explored the relationship between scalp ictal EEG patterns and interictal hypometabolism patterns in a well-defined group of HS-MTLE patients with seizurefree after surgery. We also assessed the clinical significance of interictal hypometabolism patterns according to scalp IID patterns.
E.M. Lee et al. dalohippocampectomy (ATL-AH) with a minimum follow-up of 1 year; and (5) surgical pathology demonstrating hippocampal sclerosis without dual pathology. Exclusion criteria included: (1) more than one type of scalp EEG IID pattern (i.e., a mixture of type 1 and type 2 patterns) in the same patient during video-EEG monitoring; (2) non-lateralizing ictal scalp EEG; (3) bilateral HS based on visual assessment of MRI; (4) side-to-side discrepancy between ictal EEG initiation and PET hypometabolism; and (5) patients who were not seizure-free (Engel’s classification II, III, IV), indicating that the epileptogenic zone had not been resected following ATL-AH (Engel et al., 1993). During the video-EEG monitoring, antiepileptic drugs were gradually tapered off or completely withdrew to record ictal events. Two experienced interpreters (E.M.L. and J.K.K.) independently reviewed the video-EEG monitoring data of all patients. In cases of discordance in determining ictal EEG patterns, a third interpreter (J.H.K) made the final decision. HS was diagnosed by visual assessment of high-resolution MRI, based on a combination of unilateral hippocampal atrophy and increased T2 signal in the atrophic hippocampus (Jackson et al., 1993). Parameters obtained for all patients included demographic and clinical characteristics (e.g., sex, age at epilepsy surgery, age at seizure onset, duration of epilepsy), follow-up period after surgery, seizure duration and seizure semiology. Semiological analyses included the presence of motionless staring, oroalimentary automatism, unilateral or bilateral limb automatism, and dystonic limb posturing contralateral to the side of HS, and secondarily generalized seizures. Seizure duration was calculated from the time of identifiable change of EEG activity, whether or not preceding clinical onset, to the end of ictal EEG activity. For secondarily generalized seizures, the end of a complex partial seizure was defined as the time just before the clinical manifestation of the generalized seizure. Dystonic posturing was defined as sustained unnatural posturing with a tonic component involving one upper extremity (Rusu et al., 2005). We did not consider the chronology of ictal symptoms. Individual seizure semiology was considered present if it was observed at least one-half of recorded seizures. A total of 160 seizures consistent with their habitual seizures were analyzed. One neurosurgeon (J.K.L.) performed ATL-AH on all patients in the same manner. For those undergoing dominant ATL, 4.0 cm of the temporal lobe was excised; for non-dominant ATL, 4.0—5.0 cm was excised. The hippocampus was removed microsurgically, usually to the level of the posterior midbrain. Surgical specimens of the hippocampus and temporal neocortex were evaluated for the presence of hippocampal sclerosis and cortical malformation, respectively.
MRI analysis
Methods
MRI scans were visually analyzed by two neurologists (E.M.L. and J.K.K.) blinded to clinical data. They assessed the side and degree of hippocampal atrophy (mild, moderate, or severe), associated temporal lobe atrophy, and signal changes (i.e., hypersignal with blurring between gray and white matter on T2-weighted sequences) in the temporal lobe (Chassoux et al., 2004).
Patients
Ictal scalp EEG acquisition and classification
We retrospectively selected a homogeneous group of patients undergoing temporal lobectomy for medically intractable HS-MTLE at the Asan Medical Center from 2001 to 2005. Inclusion criteria included: (1) electro-clinical features typical of MTLE patients who had more than 3 ictal events during long-term video-EEG monitoring; (2) unilateral HS on high-resolution MRI; (3) stereotypic scalp EEG IID patterns (i.e., type 1 or type 2 IID patterns), irrespective of secondary generalized seizures, during all seizures recorded by video-EEG monitoring; (4) excellent surgical outcome (Engel’s classification I) following anterior temporal lobectomy and amyg-
Electrodes were placed according to the 10-20 International System, along with supplementary subtemporal (F9/10, FT9/10, T9/10) and sphenoidal electrodes (SP1/2). Digitally acquired ictal recordings were reviewed on a conventional anterior-posterior bipolar montage and verified on a referential montage with a high frequency filter of 70 Hz and a low frequency filter of 1.0 Hz (Kim et al., 2007). Ictal EEG onset was defined by the presence of well-recognized, sustained rhythmic waves distinct from background. Two lateralizing ictal patterns were identified: (1) those who had a sustained, regular 5—9 Hz rhythm with well-lateralized temporal or subtemporal
EEG and interictal hypometabolic patterns HS-MTLE
189
Figure 1 An example of ictal-onset EEG of group 1: progressive buildup of a regular 7 Hz initial ictal discharge (IIDs) with a restricted left temporal/subtemporal distribution. This ictal EEG is displayed with a Pz reference montage and 3- to 17-Hz bandpass filtering. Vertical time scale at 1-s intervals. distribution (type 1) was designated as group 1 (Fig. 1); and (2) those who had an irregular 2—5 Hz rhythm, sometimes appearing as periodic discharges, with widespread temporal distribution (type 2) was designated as group 2 (Fig. 2).
PET scans PET images were acquired using an ECAT EXACT HR + scanner (CTISiemens, Knoxville, Tennessee, USA). The system provides 63 planes (2.46 mm slice thickness) and a 15.5 cm longitudinal field of view. After a fast of at least 6 h, all participants were injected with an intravenous dose of 370 MBq (10 mCi) of FDG over 30—60 s. After a 5-min transmission scan for segmented attenuation correction with a rotating 68 Ge source, an emission scan was acquired for 15 min in three-dimensional mode. All emission images were reconstructed with ordered subset expectation maximization (OSEM) using 16 subsets and 6 iterations. PET scans were performed with minimal auditory stimulation in a dimly lit room and with the participants’ eyes closed. EEG was not performed during FDG uptake. But we carefully monitored for head movements and ictal events. Patients were also asked to report any seizures experienced on the day of the scan. Patients were also asked to report any seizures experienced on the day of the scan, whether before or after the FDG injection. A second examination was considered for patients with such seizures if the images were inconclusive.
Statistical parametric mapping (SPM) analysis of 18 F-fluoro-2-deoxy-D-glucose PET Prior to statistical analysis, all images were spatially normalized to a PET template using the SPM2 implemented in Matlab 6.5 (Mathworks Inc., Natick, MA, USA). Spatially normalized images were smoothed using an isotropic Gaussian kernel with an 8-mm full-width at halfmaximum. Image intensity was normalized between participants to control for inter-participant variability in global brain activity. Before analysis, PET images from the right HS-MTLE patients were flipped onto the left side to enable group analysis. Individual SPM analysis was first performed in order to detect some potential variability within each group that may affect the group analysis results. Statistical analyses were performed in two steps. Significant decreases in regional glucose metabolism in the patient groups were estimated by comparing their normalized PET images with those of 18 healthy controls (6 females; mean age, 31.9 ± 6.2 years; range, 23—39 years). A two-sided t-test of SPM was performed to assess the group difference. The analysis produced a t statistic for each voxel and t values were transformed to the standard distribution. Statistical significance was set at a threshold of p < 0.005, uncorrected for multiple comparisons, with the added requirement that at least 50 contiguous voxels exceeded this statistical level. The Montreal Neurological Institute (MNI) coordinates of cluster peak were transformed to standard Talairach coordinates (Talairach and Tournoux, 1988).
Figure 2 An example of ictal onset EEG of group 2: buildup of a regular 3- to 4-Hz initial ictal discharge (IID) with a widespread left temporal/subtemporal and parasagittal distribution, followed by 6- to 7-Hz rhythmic activity. This is displayed with a Pz reference montage and 3- to 17-Hz bandpass filtering. Vertical time scale at 1-s intervals.
190
E.M. Lee et al.
Table 1
Clinical characteristics and semiologic features in each group.
Patient number (male:female) Age at operation (year) Age at onset (year) Epilepsy duration Follow-up period (months) Seizure frequency (per month) Seizure duration (s) Motionless staring Oroalimentary automatism Limb automatism Contralateral limb dystonic posture Total number of recorded seizures Secondary GTC MRI finding (hippocampal atrophy) Mild Moderate Severe MRI finding (signal change) Yes No
Group 1
Group 2
p-value
4:5 31.56 ± 6.21 19.89 ± 9.56 11.67 ± 8.79 41.22 ± 15.51 2.61 ± 1.41 64.76 ± 21.33 8/9 (88.9%) 3/9 (33.3%) 2/9 (22.2%) 1/9 (11.1%) 7.44 ± 4.69 1.0 ± 1.5
8:8 30.69 ± 6.23 15.56 ± 8.04 15.25 ± 8.08 35.06 ± 9.20 2.29 ± 2.23 65.04 ± 23.11 12/16 (75.0%) 10/16 (62.5%) 5/16 (31.3%) 10/16 (62.5%) 5.81 ± 2.86 1.19 ± 1.68
0.79 0.79 0.24 0.31 0.22 0.8 0.98 0.62 0.23 1 0.03 0.29 0.78 0.62
3 (33.3%) 3 (33.3%) 3 (33.3%)
3 (18.8%) 8 (50.0%) 5 (31.2%)
7 (77.8%) 2 (22.2%)
14 (87.5%) 2 (12.5%)
0.60
GTC: generalized tonic-clonic seizure.
Statistical analysis Continuous, normally distributed variables, including age at operation, onset age, epilepsy duration, seizure duration and follow-up period were compared using independent t-tests. Categorical variables, such as presence of risk factors and semiologic features, were compared using Fisher’s exact test. Data storage and analysis were performed using SPSS software (Statistical Package for the Social Science, version 12.0, Chicago, IL, USA). Statistical significance was defined as p ≤ 0.05.
dyslamination in the temporal neocortex was negative in all patients. Unilateral hippocampal atrophy was found on the right side in 12 patients and on the left side in 13 and was classified as mild in 6 (24.0%), moderate in 11 (44.0%) and severe in 8 (32.0%) patients. Associated signal changes on T2-weighted sequences were detected in 21 of 25 patients (84.0%). None had ipsilateral hemispheric atrophy. The degree of HA (p = 0.62) and signal change on T2 weighted image on temporal lobe (p = 0.60) did not differ between the two groups.
Results Patient groups Of the 25 patients (13 females; mean age, 31 ± 6.1 years; range, 19—39 years) with unilateral HS and MTLE semiology, who underwent interictal PET scans and ATL-AH, 9 (5 females, 4 right HS) were classified as group 1, and 16 (8 females, 8 right HS) as group 2. Intracranial EEG recordings were performed on 4 patients in group 2 and one in group 1 using bilateral hippocampal depths and temporal subdural strips. In all 5 patients, ictal onset was started from hippocampal depth electrodes. The interpretation of ictal EEG by the 2 primary interpreters was concordant in 21 (87.5%) patients and discordant in 3 (12.5%). Demographics and clinical characteristics are summarized in Table 1. No differences between groups 1 and 2 were observed in age at operation (p = 0.79), age at seizure onset (p = 0.24), duration of epilepsy (p = 0.31), or mean follow-up period (41.22 ± 15.51 months vs 35.06 ± 9.20 months; p = 0.22). Pathologic examination of the resected specimen at the time of surgery confirmed that all patients had HS without dual pathology. A careful search for focal cortical dysplasia and
Semiologic analyses Mean seizure duration did not differ between groups 1 and 2 (64.76 ± 21.33 s vs 65.04 ± 23.11 s; p = 0.98). Semiologic analyses showed no between-group differences in the frequency of motionless staring only (8 of 9 (88.9%) vs 12 of 16 (75.0%); p = 0.62), oroalimentary automatism (3 of 9 (33.3%) vs 10 of 16 (62.5%); p = 0.23), and limb automatism (2 of 9 (22.2%) vs 5 of 16 (31.3%); p = 1.0). Dystonic limb posturing contralateral to the side of HS was significantly more frequent in group 2 (10 of 16, 62.5%) than in group 1 (1 of 9, 11.1%; p = 0.03).
SPM analysis of PET Individual data did not show significant heterogeneity within each group, but individual PET data in group 2 usually showed wider hypometabolism than those in group 1. In group analysis, group 1 showed focal hypometabolism in the ipsilateral temporal lobe including hippocampus at a significance level of uncorrected p < 0.005 (Fig. 3A). In group
EEG and interictal hypometabolic patterns HS-MTLE
191
Figure 3 Hypometabolism topography in the two groups (A, group 1; B, group 2) compared to 18 healthy controls using SPM2 (threshold: p < 0.005, uncorrected for extent). Focal hypometabolism was observed in the ipsilateral temporal lobe in group 1 (A), whereas widespread hypometabolism was observed in the ipsilateral temporal lobe, putamen and insular cortex in group 2 (B).
2, widespread hypometabolism was observed in the ipsilateral temporal lobe, insular cortex and putamen at the same threshold (Fig. 3B).
Discussion The main finding of the present study is that IID of rather restricted, regular high-frequency (5—9 Hz) rhythm resulted in interictal hypometabolism confined mainly to the ipsilateral temporal lobe (group 1), whereas IID of widespread, irregular low-frequency (2—5 Hz) rhythm was associated with widespread interictal hypometabolism in the ipsilateral putamen and insular cortex, as well as ipsilateral temporal lobe hypometabolism (group 2). Involvement of the ipsilateral basal ganglia in group 2 has important implications for understanding the semiology of MTLE, suggesting a higher incidence of dystonic limb posturing. These findings suggest that interictal hypometabolism in relation to scalp ictal IID frequencies not only localize seizure-onset zone but also reflect the preferential pathway of ictal propagation. Thus, scalp EEG IID could be a determinant of a hypometabolism pattern in unilateral HS-MTLE. Based on electro-clinical correlation in patients with unilateral HS-MTLE, the degree and topography of hypometabolism clearly differed among those with mesial, anterior mesio-lateral, and widespread involvement (Chassoux et al., 2004), suggesting a correlation between topography of hypometabolism and electroclinical pattern. That is, focal ictal semiology was associated with restricted interictal temporal hypometabolism, whereas diverse ictal semiology was related to widespread interictal hypometabolism. Although our findings of wider interictal hypometabolism in group 2 than in group 1 is in line with their results, hypometabolic areas in our cases were relatively restricted to local areas in both groups compared to previous studies (Chassoux et al., 2004; Rusu et al., 2005). This discrepancy between the studies may be due to the different patient population included. We included
only a homogeneous group of patients who had HS-MTLE and obtained seizure-free (Engel’s classification class I) after surgery, resulting in relatively restricted interictal hypometabolic area in patients with type I (group 1) and, even, type II (group 2). Previous studies included patients with HS-MTLE, but also included patients with other etiologies and patients with not seizure-free (even though they obtained good surgical outcome) or non-operation, resulting in including some patients with wider epileptogenic zone and wider hypometabolic areas in PET compared to our study (Chassoux et al., 2004; Rusu et al., 2005). Another explanation for restricted hypometabolic area in our cases, especially in group 2, is that the inclusion criteria of dystonic posturing was milder than those of previous studies (Chassoux et al., 2004; Rusu et al., 2005). These also contributed to including patients with mild and less frequent dystonic posturing, resulting in less involvement of the basal ganglia even in group 2. The important difference between our study and previous studies is also that we classified homogeneous HS-MTLE patients according to their scalp IID patterns without considering their clinical features. One may argue that low-frequency IID of group 2 in our study may be ascribed to temporal neocortical-onset seizure because irregular widespread 2- to 5-Hz discharges (type 2) have been frequently associated with temporal neocortical onset seizures (Ebersole and Pacia, 1996; Pacia and Ebersole, 1997). However, all of our patients, including those in group 2, had substantial MRI evidence of HS and excellent seizure outcomes after surgery. In addition, pathologic examination failed to show any abnormalities in the temporal neocortex of group 2 patients, suggesting that all of these patients had hippocampus-onset seizures. Ictal dystonic posturing during a CPS is the most reliable lateralizing feature in MTLE (Kotagal et al., 1989) and is related to the spread of ictal discharges to the caudate, putamen, and thalamus, as demonstrated by PET (Dupont et al., 1998) and SPECT (Newton et al., 1992; Joo
192 et al., 2004; Mizobuchi et al., 2004). Lesions of the putamen and globus pallidus commonly caused dystonia, particularly when the putamen was involved. Hypometabolism in the ipsilateral putamen may account for the higher incidence of dystonic limb posturing observed in our group 2. These findings suggest that low frequency IID in HS-MTLE is related to hypometabolism of the ipsilateral putamen and tends to produce ictal semiology of dystonic limb posturing. Our results, however, are in disagreement with previous findings (Rusu et al., 2005), showing that ictal dystonia was associated with faster ictal rhythms. This discrepancy may be due to differences in inclusion criteria and patient classification. In the earlier study, patients with dystonic posturing had longer seizure duration, secondary generalization and an association with oroalimentary automatism than did patients without dystonic posturing (Rusu et al., 2005). In our study, however, there were no differences, except for scalp EEG IID patterns, associated with the different rate of dystonic posture in the two groups. These findings suggested that, although seizure duration of scalp EEG IID type 2 was not longer than that of type 1, the former may have preferential pathway or a tendency to involve widespread areas of the brain including the subcortical structure such as the ipsilateral putamen, providing further supports to our hypothesis that IID type 1 results in confined interictal hypometabolism and ictal hyperperfusion, whereas IID type 2 is associated with wider interictal hypometabolism and ictal hyperperfusion. Another interesting finding in the present study was that group 2 had interictal hypometabolism in the ipsilateral insular cortex compared to group 1. Since the anterior insular cortex is connected to the temporal and orbitofrontal cortices and the amygadala (Mesulam and Mufson, 1982), MTLE seizures may involve the insula (Isnard et al., 2000; Bouilleret et al., 2002). Because the clinical characteristics of the two groups were similar, clinical significance involving the insular cortex was not clear. Further study will be needed to reveal these issues. Compared with epileptogenic zones identified on structural MR imaging, hypometabolic areas on PET are usually larger, often spreading over extra-temporal cortical areas, including subcortical structures (Arnold et al., 1996; Savic et al., 1997; Dupont et al., 1998). Recent findings have shown a concordance between ictal SPECT hyperperfusion and interictal FDG—PET hypometabolism in TLE, suggesting that seizures were generated and spread in interictally hypometabolic regions (Bouilleret et al., 2002). Thus, hypometabolic areas identified on interictal PET may include not only the seizure onset zone but also areas of functional deficit or preferential pathways of seizure spread. By reflecting chronic functional disturbances related to seizures, interictal PET studies may show a correlation between metabolic patterns and seizure spread pathways in MTLE. Temporal hypometabolism has been correlated with the severity of hippocampal atrophy (Gaillard et al., 1995; Semah et al., 1995), but a strong relationship with the metabolic pattern was not observed (O’Brien et al., 1997, Chassoux et al., 2004). We also detected no between-group differences in HS severity or signal changes of the temporal lobe, although we did not perform a volumetric measurement of hippocampal and temporal lobe atrophy. These
E.M. Lee et al. findings suggest that the degree of hippocampal atrophy or associated signal change does not appear to be a determinant of metabolic changes. Our study had several limitations. Specific semiology was considered present if it observed ≥50% of all recorded seizures, a somewhat arbitrary classification. In addition, the number of patients in each group was small, making the statistical powers relatively weak. Additional large-scale detailed studies are necessary in the future. In conclusion, we demonstrated that scalp EEG IID may be a determinant of hypometabolism pattern in patients with unilateral HS-MTLE. We observed a correlation between hypometabolism topography and scalp EEG IID frequency, supporting the hypothesis that neuronal networks are involved in ictal discharges and metabolic changes.
Acknowledgements The authors thank the technical assistants of Epilepsy Monitoring Unit in Asan Medical Center for their help to obtain good quality of video-EEG monitoring data. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References Adam, C., Clémenceau, S., Semah, F., Hasboun, D., Samson, S., Aboujaoude, N., Samson, Y., Baulac, M., 1996. Variability of presentation in medial temporal lobe epilepsy: a study of 30 operated cases. Acta Neurol. Scand. 94, 1—11. Arnold, S., Schlaug, G., Niemann, H., Ebner, A., Lüders, H., Witte, O.W., Seitz, R.J., 1996. Topography of interictal glucose hypometabolism in unilateral mesiotemporal epilepsy. Neurology 46, 1422—1430. Blume, W.T., Young, G.B., Lemieux, J.F., 1984. EEG morphology of partial epileptic seizures. Electroencephalogr. Clin. Neurophysiol. 57, 295—302. Bouilleret, V., Dupont, S., Spelle, L., Baulac, M., Samson, Y., Semah, F., 2002. Insular cortex involvement in mesiotemporal lobe epilepsy: a positron emission tomography study. Ann. Neurol. 51, 202—208. Chassoux, F., Semah, F., Bouilleret, V., Landre, E., Devaux, B., Turak, B., Nataf, F., Roux, F.X., 2004. Metabolic changes and electro-clinical patterns in mesio-temporal lobe epilepsy: a correlative study. Brain 127, 164—174. Dupont, S., Semah, F., Baulac, M., Samson, Y., 1998. The underlying pathophysiology of ictal dystonia in temporal lobe epilepsy: an FDG—PET study. Neurology 51, 1289—1292. Ebersole, J.S., Pacia, S.V., 1996. Localization of temporal lobe foci by ictal EEG patterns. Epilepsia 37, 386—399. Ebner, A., Hoppe, M., 1995. Noninvasive electroencephalography and mesial temporal sclerosis. J. Clin. Neurophysiol. 12, 23—31. Engel Jr., J., Van Ness, P.C., Rasmussen, T.B., 1993. Outcome with respect to epileptic seizures. In: Engel Jr., J. (Ed.), Surgical Treatment of the Epilepsies, 2nd ed. Raven Press, New York, pp. 609—621. Gaillard, W.D., Bhatia, S., Bookheimer, S.Y., Fazilat, S., Sato, S., Theodore, W.H., 1995. FDG—PET and volumetric MRI in the evaluation of patients with partial epilepsy. Neurology 45, 123—126. Isnard, J., Guenot, M., Ostrowsky, K., Sindou, M., Mauguiere, F., 2000. The role of the insular cortex in temporal lobe epilepsy. Ann. Neurol. 48, 614—623.
EEG and interictal hypometabolic patterns HS-MTLE Jackson, G.D., Berkovic, S.F., Duncan, J.S., Connelly, A., 1993. Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am. J. Neuroradiol. 14, 753—762. Joo, E.Y., Hong, S.B., Lee, E.K., Tae, W.S., Kim, J.H., Seo, D.W., Hong, S.C., Kim, S., Kim, M.H., 2004. Regional cerebral hyperperfusion with ictal dystonic posturing: ictal-interictal SPECT subtraction. Epilepsia 45, 686—689. Kim, J.H., Im, K.C., Kim, J.S., Lee, S.A., Lee, J.K., Khang, S.K., Kang, J.K., 2007. Ictal hyperperfusion patterns in relation to ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: a SPECT study. Epilepsia 48, 270—277. King, D., Spencer, S.S., McCarthy, G., Spencer, D.D., 1997. Surface and depth EEG findings in patients with hippocampal atrophy. Neurology 48, 1363—1367. Kotagal, P., Lüders, H.O., Morris, H.H., Dinner, D.S., Wyllie, E., Godoy, J., Rothner, A.D., 1989. Dystonic posturing in complex partial seizures of temporal lobe onset: A new lateralizing sign. Neurology 39, 196—201. Koutroumanidis, M., Hennessy, M.J., Seed, P.T., Elwes, R.D., Jarosz, J., Morris, R.G., Maisey, M.N., Binnie, C.D., Polkey, C.E., 2000. Significance of interictal bilateral temporal hypometabolism in temporal lobe epilepsy. Neurology 54, 1811—1821. Mesulam, M.M., Mufson, E.J., 1982. Insula of the old world monkey I. Architectonics on the insulo-orbito-temporal component of the paralimbic brain. J. Comp. Neurol. 212, 1—22. Mizobuchi, M., Matsuda, K., Inoue, Y., Sako, K., Sumi, Y., Chitoku, S., Tsumaki, K., Takahashi, M., 2004. Dystonic posturing associated with putaminal hyperperfusion depicted on subtraction SPECT. Epilepsia 45, 948—953. Newton, M.R., Berkovic, S.F., Austin, M.C., Reutens, D.C., McKay, W.J., Bladin, P.F., 1992. Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures. Neurology 42, 371—377. O’Brien, T.J., Newton, M.R., Cook, M.J., Berlangieri, S.U., Kilpatrick, C., Morris, K., Berkovic, S.F., 1997. Hippocampal
193 atrophy is not a major determinant of regional hypometabolism in temporal lobe epilepsy. Epilepsia 38, 74—80. Pacia, S.V., Ebersole, J.S., 1997. Intracranial EEG substrates of scalp ictal patterns from temporal lobe foci. Epilepsia 38, 642—654. Risinger, M.W., Engel Jr., J., Van Ness, P.C., Henry, T.R., Crandall, P.H., 1989. Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings. Neurology 39, 1288—1293. Rusu, V., Chassoux, F., Landre, E., Bouilleret, V., Nataf, F., Devaux, B.C., Turak, B., Semah, F., 2005. Dystonic posturing in seizures of mesial temporal origin: electroclinical and metabolic patterns. Neurology 65, 1612—1619. Ryvlin, P., Bouvard, S., Le Bars, D., De Lamérie, G., Grégoire, M.C., Kahane, P., Froment, J.C., Mauguiere, F., 1998. Clinical utility of flumazenil-PET versus [18 F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy. A prospective study in 100 patients. Brain 121, 2067—2081. Savic, I., Altshuler, L., Baxter, L., Engel Jr., J., 1997. Pattern of interictal hypometabolism in PET scans with fludeoxyglucose F 18 reflects prior seizure types in patients with mesial temporal lobe seizures. Arch. Neurol. 54, 129—136. Semah, F., Baulac, M., Hasboun, D., Frouin, V., Mangin, J.F., Papageorgiou, S., Leroy-Willig, A., Philippon, J., Laplane, D., Samon, Y., 1995. Is interictal temporal hypometabolism related to mesial temporal sclerosis? A positron emission tomography/magnetic resonance imaging confrontation. Epilepsia 36, 447—456. Sharbrough, F.W., 1993. Scalp-recorded ictal patterns in focal epilepsy. J. Clin. Neurophysiol. 10, 262—267. Spencer, S.S., 1994. The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 35 (Suppl. 6), S72—S89. Steinhoff, B.J., So, N.K., Lim, S., Luders, H.O., 1995. Ictal scalp EEG in temporal lobe epilepsy with unitemporal versus bitemporal interictal epileptiform discharges. Neurology 45, 889—896. Talairach, J., Tournoux, P., 1988. Co-Planar Stereotaxic Atlas of the Brain. 3-Dimensional Proportional System: An Approach to Cerebral Imaging. George Thieme, Stuttgart.