FULL-LENGTH ORIGINAL RESEARCH

Ictal spread of medial temporal lobe seizures with and without secondary generalization: An intracranial electroencephalography analysis *Ji Yeoun Yoo, *Pue Farooque, *William C. Chen, *Mark W. Youngblood, *Hitten P. Zaveri, †Jason L. Gerrard, †Dennis D. Spencer, *Lawrence J. Hirsch, and *†‡Hal Blumenfeld Epilepsia, 55(2):289–295, 2014 doi: 10.1111/epi.12505

SUMMARY

Dr. Ji Yeoun Yoo, M.D. was an epilepsy fellow at Yale, and is now an assistant professor of Neurology at the Icahn School of Medicine at Mount Sinai.

Objective: Secondary generalization of seizures has devastating consequences for patient safety and quality of life. The aim of this intracranial electroencephalography (icEEG) study was to investigate the differences in onset and propagation patterns of temporal lobe seizures that remained focal versus those with secondary generalization, in order to better understand the mechanism of secondary generalization. Methods: A total of 39 seizures were analyzed in nine patients who met the following criteria: (1) icEEG-video monitoring with at least one secondarily generalized tonic– clonic seizure (GTCS), (2) pathologically proven hippocampal sclerosis, and (3) no seizures for at least 1 year after anteromedial temporal lobe resection. Seizures were classified as focal or secondary generalized by behavioral analysis of video. Onset and propagation patterns were compared by analysis of icEEG. Results: We obtained data from 22 focal seizures without generalization (FS), and 17 GTCS. Seizure-onset patterns did not differ between FS and GTCS, but there were differences in later propagation. All seizures started with low voltage fast activity, except for seven seizures in one patient (six FS, one GTCS), which started with sharply contoured theta activity. Fifteen of 39 seizures started from the hippocampus, and 24 seizures (including six seizures in a patient without hippocampal contacts) started from other medial temporal lobe areas. We observed involvement or more prominent activation of the posterior-lateral temporal regions in GTCS prior to propagation to the other cortical regions, versus FS, which had no involvement or less prominent activation of the posterior lateral temporal cortex. Occipital contacts were not involved at the time of clinical secondary generalization. Significance: The posterior-lateral temporal cortex may serve as an important “gateway” controlling propagation of medial temporal lobe seizures to other cortical regions. Identifying the mechanisms of secondary generalization of focal seizures could lead to improved treatments to confine seizure spread. KEY WORDS: Temporal lobe seizure, Secondary generalization, Propagation, Intracranial electroencephalography, Posterior lateral temporal cortex, SUDEP.

Accepted November 4, 2013; Early View publication January 13, 2014. Departments of *Neurology, †Neurosurgery, and ‡Neurobiology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Address correspondence to Hal Blumenfeld, Yale Departments of Neurology, Neurobiology, Neurosurgery, 333 Cedar Street, New Haven, CT 06520-8018, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy

Generalized tonic–clonic seizures (GTCS), either primary generalized or secondarily generalized from focal seizures (FS), have devastating consequences for patient safety and quality of life. The occurrence and frequency of GTCS is the most important risk factor for sudden unexpected depth in epilepsy (SUDEP)1 and seizure-related serious injuries.2,3 With considerable advances in our understanding about the clinical and physiologic factors of SUDEP and

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290 J. Y. Yoo et al. its risk factors,4 increased attention has been drawn to understand the mechanism of secondary generalization of FS. This is particularly the case for temporal lobe epilepsy, which is the most frequent drug-resistant form of epilepsy. Some studies have investigated the clinical features associated with temporal lobe GTCS by comparing continuous video-electroencephalography (EEG) and magnetic resonance imaging (MRI) in patients with FS versus GTCS,5 and by observing the occurrence of ictal dystonia during temporal lobe seizures to determine the role of basal ganglia in preventing secondary generalization.6 The ictal electrographic spread pattern of temporal lobe seizures has been studied7–11; however, so far no study has systematically compared the onset and propagation pattern of FS versus GTCS. There is growing evidence that GTCS are not truly generalized.12–16 The intracranial EEG (icEEG) provides a unique opportunity to study seizure propagation and areas of involvement in GTCS. Recent icEEG studies have demonstrated that the onset of secondary generalization does not involve the cortex globally.17,18 We sought to study icEEG in a relatively homogeneous group of temporal lobe seizures to investigate the differences in onset and propagation patterns between seizures that remained focal versus those with secondary generalization. Localizing the area that might be responsible for preventing or permitting secondary generalization may lead to the development of better treatment strategies and targets for medical devices or procedures in an attempt to prevent seizure spread.

Methods Patients All procedures were in accordance with the institutional review board for human studies at Yale University School of Medicine. Informed consent was obtained from all subjects. Inclusion and exclusion criteria were chosen to identify a relatively homogenous group of patients with confirmed mesial temporal lobe epilepsy who had undergone icEEG and video monitoring. Patients with the following inclusion criteria were used: (1) icEEG monitoring performed between 1995 and 2010 at Yale, and where at least one GTCS was recorded; (2) pathology demonstrating hippocampal sclerosis; and (3) no seizures during a minimum follow-up period of 1 year after anteromedial temporal lobe resection. A total of 39 seizures from 9 patients were analyzed. Seven seizures that involved only the hippocampal depth or anterior medial temporal regions without spreading to other regions were excluded from analysis. Anatomic localization of electrode positions Depth electrodes were typically used to study the hippocampus, whereas strips were used to study the adjacent mesial temporal structures such as the entorhinal cortex and parahippocampal gyrus; in addition, grids and strips were commonly used to study other regions. Intracranial elecEpilepsia, 55(2):289–295, 2014 doi: 10.1111/epi.12505

trode locations were planned preoperatively based on clinical information in each case; therefore, electrode positions were not standardized. MRI scans were performed on all patients after intracranial electrode implantation using three-dimensional (3D) volume inversion recovery prepped fast spoiled gradient recalled echo (IR-FSPGR) imaging on a 1.5 T system. Surface reconstructions were then obtained with lateral, medial, anterior, posterior, and inferior views of both hemispheres to determine the positions of all electrode contacts. Boundaries between each lobe have been described previously,19 and within the temporal lobe, the areas were further divided into anterior, mid, and posterior regions. The brain surface was segmented into the following anatomic regions for both ipsilateral and contralateral hemispheres: medial temporal, anterior lateral temporal, middle lateral temporal, posterior lateral temporal, and frontal, parietal, and occipital. Electrode contacts identified on the MRI scans were assigned to these regions for icEEG analysis. Intracranial electroencephalography recordings icEEG signals were recorded continuously using Telefactor Beehive systems (Telefactor/Grass/Natus Medical Inc., San Carlos, CA, U.S.A.) or Bio-Logic Systems 128-channel clinical EEG and video monitoring equipment (Bio-Logic Systems Corp./Natus Medical Inc., San Carlos, CA, U.S.A.). Amplifier systems were either single-ended with ground and reference tied together, or with a separate ground and reference, with 128 EEG channels acquired at 12 bit (Telefactor/Grass) or 16 bit (Bio-logic) A/D conversion, 200 Hz sampling (256 Hz for Bio-Logic system), 90 dB or better common-mode rejection ratio, with low-frequency filter setting of 0.1 Hz and high-frequency filter setting of 70 Hz. Electroencephalography analysis The video-icEEG recordings were independently reviewed by two neurologists specializing in epilepsy (J.Y. and P.F.), and any differences were then resolved by joint consensus. Only seizures that clearly progressed to bilateral tonic arm with or without tonic leg posturing that gradually transitioned to bilateral clonic activity were classified as GTCS. It has been described that the final phases of secondary generalized temporal lobe seizures are more stereotyped than the initial clinical signs of generalization.20 The onset of secondary generalization was defined based on video data demonstrating behavioral vocalization, facial clonus, and tonic head/eye deviation. Each location was considered to be involved or activated in the spread pattern if there were spike and slow or sharp and slow waves, spike or polyspike discharges, or low voltage fast activity. The regions were considered to be not involved or inactive if there was no change from the baseline, or showed theta-delta irregular slow waves, adopted and modified from the icEEG rating scale developed by Blumenfeld et al.19 The onset was classified as hippocampal onset when the seizure activity started

291 Ictal Spread of Medial Temporal Lobe Seizures from the hippocampal depth. If there was no activity on the hippocampal depth and seizure activity started from the medial temporal electrode contacts, the seizure onset was classified as nonhippocampal onset. In one patient, a hippocampal depth electrode was not placed and the seizures were included as nonhippocampal onset. For statistical analysis of categorical variables, Fisher’s exact tests were carried out. P values of

Ictal spread of medial temporal lobe seizures with and without secondary generalization: an intracranial electroencephalography analysis.

Secondary generalization of seizures has devastating consequences for patient safety and quality of life. The aim of this intracranial electroencephal...
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