Electroencephalography and Clinical Neurophysiology, 1978, 44:641--663

641

© Elsevier/North-Holland Scientific Publishers Ltd.

QUANTITATIVE ANALYSIS OF DEPTH SPIKING IN R E L A T I O N TO SEIZURE FOCI IN PATIENTS WITH T E M P O R A L LOBE EPILEPSY* JEFFREY P. LIEB, STEPHEN C. WOODS, ANTONIO SICCARDI**, PAUL H. CRANDALL, DONALD O. WALTER and BARBARA LEAKE Reed Neurological Research Center, Division of Neurological Surgery and Brain Research Inst:tute, UCLA Center for the Health Sciences, Los Angeles, Calif. 90024 (U.S.A.)

(Accepted for publication: October 27, 1977) Electroencephalographers engaged in the interpretation of EEG recordings obtained from patients with medically refractory seizures in w h o m depth electrodes have been stereotaxically placed, are generally in agreem e n t that those recordings obtained during spontaneous ictus provide the most important information for the localization of epileptogenic sites (Walter 1973; Rossi 1973; Talairach and Bancaud 1966; Crandall et al. 1971; Gloor 1975). While some electroencephalographers consider the electrical abnormalities which occur in the interictal depth EEG of these patients to contain useful background information which can be integrated with the information obtained from recordings taken during seizures (Rossi 1973; Gloor 1975; Ludwig et al. 1975b), others are more inclined to rely solely on the EEG obtained during clinical events (Talairach and Bancaud 1966; Walter 1973). There are various reasons why the abnormalities observed in the interictal EEG have been regarded as less than optimal for the purpose of localizing sites responsible for the initiation of seizures: (1) these abnormalities typically "demonstrate a wide diversity of morphologies, both within and between patients; (2) such abnormalities are often widely dispersed anatomically; (3) it is not known whether such abnormalities * Supported by U.S. Public Health Service Grants NS 02808 and NS 11379. ** Present address: Center for Cerebral Neurophysiology of the National Research Council, Institute of Neurosurgery of the University, Genoa (Italy).

originated at the recording ~,;ite or have been propagated there (Rossi 1973). These difficulties in interpreting the localizing significance of interictal abnormali'ties are readily apparent in recordings taken from bilateral medial temporal lobe sites in patients whose seizures are suspected to originate in these areas (Walter 1973). Such patients c o m m o n l y exhibit i:aterictal abnormalities in both temporal lobes and it is often not readily apparent whether they tend to predominate in one temporal lobe. Additionally, such abnormalitie~ may appear to occur independently both within and between temporal lobes, thus yielding an impression of great complexity in the record. It is important to recognize, however, that the electrographic patterns which accompany clinical seizures in these patients may, in any given patient, appear to originate in the depths of either temporal lobe or from a cortical site during different episodes. Additionally, the locus of origin of seizure onset ma~, not always be apparent in the EEG which accompanies the patient's seizure episodes. Such potential variability and uncertainty in the locus of seizure onset requires that ,;everal recordings of EEG activity accompanying spontaneous seizures be obtained for each patient in order to determine the consistency of localization or lateralization across attacks (Crandall et al. 1971; Walter 1973; Gloor 1975). The uncertainty of locus of seizure, onset in these patients lends practical significance to an investigation of the relation between the

642

characteristics of interictal discharges and such loci. It is possible that an analysis of interictal electrical discharges may prove useful in making predictions about the type and location of electroencephalographic onsets that tend to occur during a sampling of each patient's seizures. Numerous aspects of interictai epileptic potentials may be measured. These include morphology, amplitude, relation to background activity, time relations between potentials recorded from different sites, and rate and variability of discharge. The application of computer-oriented techniques for analysis of EEG permits quantitative measurements of any of these aspects (Kellaway and Petersen 1976). Much progress has been made in the past few years in the automatic detec'tion and analysis of interictal spikes and sharp waves (Bickford et al. 1968; Buckley et al. 1968; Carrie 1972a,b, 1975a,b, 1976; Hill and Townsend 1973; Lopes da Silva and coworkers 1973, 1975, 1976; Walter et al. 1973; Smith 1974; Siccardi and Lieb 1974; Eftang et al. 1975; Gevins et al. 1975; Gotman and Gloor 1976). The present study consists of an analysis of computer-detected depth spike activity in a series of patients with intractable complex partial seizures of suspected temporal lobe origin in whom EEG recording electrodes had been chronically implanted for diagnostic purposes.* These patients were judged for suitability of surgical treatment on the basis of a sample of spontaneous EEG seizure episodes, many of which were known to be * All patients were fully informed about the procedure to be used and gave their consent after undergoing interviews and examining explicit consent forms prepared by the neurosurgeon (P.H.C.). These examinations have been approved by the Human Subject Research Committee of the U.C.L.A. Center for the Health Sciences. The informed consent followed the guidelines of the National Institutes of Health (1971, 1974). These procedures were in concurrence with the recommendations from the Declaration of Helsinki in basic principles and as clinical research combined with professional care.

J.P. LIEB ET AL.

accompanied by clinical phenomena. Spike analyses in each patient were compared with locus and, in some cases, time of seizure onset. This approach also permitted a comparison of such analyses with neuropathological studies of excised tissue. The results obtained support the hypothesis that parameters of interictal spiking in medial temporal lobe sites such as rate and interspike interval variability are closely related to the locus of initiation of the ictal electroencephalographic signal.

Method

Patients and recording techniques The 14 patients reported in this study are part of a series of 103 patients with uncontrolled psychomotor epilepsy in whom depth EEG recording electrodes had been sterotaxically implanted. The principal objective in this series has been the localization of epileptogenic foci, as a basis for surgical treatment (Crandall et al. 1963). The stereotaxic coordinates for electrode implantation were derived from the Talairach atlases (Talairach et al. 1958), and radiologic localization of electrode placement was utilized (Rand et al. 1964). Electrodes were implanted bilaterally in anterior, mid, and posterior hippocampal pes, in anterior, mid, and posterior hippocampal gyrus, in amygdala, and occasionally in cingulate or supplementary motor cortex. Additionally, surface electrodes were implanted in the outer table of the calvarium, in regions identified by the International 10-20 System (Jasper 1958), at the same time patients received depth electrodes. Depth electrodes were bipolar pairs with tip separation of 2 mm and tip exposure of 1 mm. Post-operatively, medication was gradually lowered to facilitate the recording of spontaneous seizures; most of the analyses of interictal EEG in the present study were thus carried out on data derived from periods of reduced medication. EEG recordings were obtained with either

DEPTH SPIKING IN T E M P O R A L LOBE EPILEPSY

direct 'hard-wired' monitoring of patients in a shielded room utilizing a polygraph (16 channel, Grass) and magnetic tape recorder (14 channel, Ampex) or by monitoring the patients on the ward with a 14-channel PWM-FM telemetry system (Dymond et al. 1976; Lieb et al. 1976a) (Benton Instrument Co., Saratoga, California). During 'hardwired' recording the patients were monitored for the occurrence of seizures; in some patients, a split-screen videotape system (Sony) was used to monitor patient behavior and the EEG simultaneously (Walsh, 1975). During telemetry monitoring, the telemetry pack was mounted on the patient's head; an analoguedigital EEG seizure-detection device (Babb et al. 1974) was used to signal the nurses' station that the patient might be having an attack. Patients were also instructed to signal the occurrence of an attack and to note its time of occurrence. In recent patients, videotape monitoring of patient behavior during telemetering has been utilized. In the present study, patients were monitored for periods of 1--8 weeks before the electrodes were removed. Those patients in whom an operable temporal lobe focus could be identified during the period in which the electrodes were in place, became candidates for anterior temporal lobectomy. En bloc removal of the mesial temporal lobe structures from which depth recordings were obtained were made available for neuropathological studies for comparison with electrographic data (Brown 1973).

Analysis of data An automatic spike detection system (COUNTR) was programmed for the PDP-12 minicomputer and was used to detect varying types of sharp-transient epileptiform activity which occurred in the EEG derived from the depth electrodes in each patient. COUNTR utilizes the 'second-derivative' technique for the detection of unusually sharp transients in the ongoing EEG. This approach was based on the fact that interictal spikes are waveforms with peaks that are often relatively sharper than background activity. This is especially

643

appropriate in recordings obtained from depth sites, where interictal paroxysmal activity often stands out very clearly in relation to background activity (Abraham and Ajmone Marsan 1958). Second-derivative transformation of the ongoing EEG signal acts to selectively amplify the rapid changes in slope which occur as a part of the spike waveform. The present second-derivative system is similar to others that 'look back' at the recent history of the EEG, estimating in a continuous fashion the average and degree of variation in sharpness of background activity preceding the waveform being judged (Carrie 1972a,b, 1973, 1975a,b, 1976; Siccardi and Lieb 1974). COUNTR is currently a single channel system; this required multiple passes in real-time of tape recorded data, one for each depth channel, in order to detect all the depth spiking that occurred within a recording session. The operation of COUNTR is as follows: Incoming EEG is prefiltered (3 dB down at 40 cycles/sec) and is then transformed through an analog device (double pseudo-differentiator). The output of this device is then digitized by the computer at 400 samples/sec (analog/ digital conversion). The absolute values of the differences between each sample and each of the preceding 11 samples is computed. The maximum of these 11 absolute values is defined as the 'peak-to-peak' (PTP) of the second-derivative of the EEG signal within this 30-msec window. Computation of the PTP emphasizes monophasic and biphasic sharp waveforms which occur in the transformed EEG. Spike detection is begun during a period containing mainly background activity. During its operation, COUNTR compares the current PTP with a previously determined 'checking level' in order to determine whether or not the PTP represents background activity. If the PTP is less than the current checking level, it is considered to be background activity and will then be used in future computations of the checking level and a 'threshold level' for spike detection. Independently, the PTP is compared with the

644 current threshold level for spike detection. If it exceeds threshold, its time of occurrence is stored on digital tape for future analysis. When threshold level is exceeded, a refractory period begins during which no further spike detection will be done; for the present study, this refractory period was set at 160 msec, thus limiting the rate at which detection could occur to 6.25/sec. The checking level and threshold level are c o m p u t e d from the recent history of the EEG as follows: Checking level = No * Standard deviation + Mean, {where No is an input parameter and the standard deviation and mean of a sample of PTPs are c o m p u t e d from a time window closely preceding the PTP under consideration. The duration of the window for the present study was set at 2.5 sec and the standard deviation and mean were r e c o m p u t e d every 2.5 sec). Threshold level for spikes = N~ * Standard Deviation + Mean, (where NI is an input parameter greater than No). In order to determine the optimal value of N~ for setting the threshold level of spike detection, a preliminary study of the performance characteristics of C O U N T R was carried o u t on 15 min of EEG data derived from the right anterior pes hippocampi in each of 3 patients. With respect to the checking level, No was set equal to 3 in order to limit the a m o u n t of paroxysmal activity going into the computation of the threshold. N~ was varied from 4 to 20. One of the authors (B.L.) independently judged which waveforms in each of the 3 records appeared to be unequivocal spikes, based on the criteria of Chatrian et al. (1974). The number of waveforms in the 3 records judged to be spikes varied from 97 to 484. Fig. 1 shows the performance characteristics of COUNTR at the varied threshold settings for the 3 records. The plots are drawn so that correct spike identification is weighted as being twice as desirable as the avoidance of false spike identification. The

J.P. LIEB ET AL. optimal threshold level in each plot is the point on the curve closest in distance to perfect performance (all hits and no false alarms). The average of the optimal threshold level across the three records was closest to 9 and this setting was therefore used in all of the spike analyses for the 14 patients in this study. No was 3 for most of the records; it was occasionally increased to 4 when it became evident that, in some channels, fluctuations in background activity were often exceeding the checking level and thereby indirectly reducing the estimate of the threshold level enough to generate substantial numbers of false spike identifications. Fig. 2 demonstrates some of the types of depth spiking that were c o m m o n l y observed in these patients and their detection b y COUNTR. As is evident in the figure, morphology and rate of spiking was quite varied, even within a channel. Spiking was sometimes observed to occur on a suppressed background, while in other sites background activity was normal. In some sites, the spikes were isolated, while in others they were polyphasic in shape. The polyphasic events varied considerably in amplitude and, at times, were indistinguishable from spindles. Neither spindles nor irregular background activity were found to produce substantial numbers of false spike identifications. False alarms resulted mainly from computer detection of sharp waves while misses tended to result from events occurring during the 160-msec refractory period. The duration chosen for the refractory period was, however, considered desirable since clusters of sharp transients occurring within such an epoch would n o t be counted as multiple events. Such clusters of sharp transients have n o t been considered to possess the same epileptic significance as regularly occurring monophasic depth spikes (Colicchio et al. 1973). Since artifact rejection routines were not incorporated into COUNTR, all raw EEG records were visually inspected in order to select epochs for analysis that were either free, or almost free, of artifactual rapid

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Fig. 2. Detection of various types of depth spiking by COUNTR. The leading edges of the positive pulses indicate the point in time at which a spike occurrence was detected and stored on digital tape. Wider pulses indicate multiple detections. Note that the morphology of spiking varied considerably. (A) and (E) primarily biphasic spiking; (B) rapid, primarily monophasic, spiking; (C) and (D) isolated and clustered spiking; (F) sharp spikes and associated slow-waves with relatively low amplitudes in comparison to background activity; (G) intermingled sharp and slow spikes on a suppressed background; (H) and (I) polyphasic spike activity of varying amplitudes; the low amplitude events were often indistinguishable from spindles and were much less likely to be counted as spikes.

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DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY

647

TABLE I The region of onset of electrographic episodes is compared with the interictal spike characteristics in each of 14 patients. The origin of each episode is classified as having originated in left depth, right depth, surface, or in a bilaterally synchronous fashion. The side containing the sites exhibiting maximum mean rate, minimum standard deviation of interspike intervals and minimum coefficient of variation is indicated for each analysis epoch. Electrographic Episodes: Region of Onset

Interictal Spike Characteristics Maximum Mean Minimal Interval Minimum Rate Standard Coefficient of Deviation Variation

Patient

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transients. The m o s t c o m m o n t y p e s o f artifact were d u e t o cable m o v e m e n t d u r i n g direct recordings, or d u e t o f a u l t y transmission during t e l e m e t r y recordings. In s o m e instances s h a r p - t r a n s i e n t a r t i f a c t was e l i m i n a t e d f r o m the r e c o r d b y briefly s t o p p i n g the central processing u n i t (CPU) o f the c o m p u t e r d u r i n g their a p p e a r a n c e o n t h e r e c o r d a n d t h e n restarting the CPU i m m e d i a t e l y afterwards. The l e n g t h o f the r e c o r d s selected f o r analysis in each p a t i e n t varied f r o m 29 t o 3 0 0 min, and the n u m b e r o f sessions a n a l y z e d varied f r o m 1 t o 4 (see Table I). The behavioral state

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o f the patients during the e p o c h s selected f o r analysis varied. During e p o c h s selected f r o m t e l e m e t r y , t h e y were o f t e n n o t observed. D u r i n g e p o c h s selected f r o m h a r d w i r e d r e c o r d i n g s t h e y were usually a w a k e with periods o f drowsiness and occasional sleep. Each train o f d e t e c t e d spikes was a n a l y z e d t o c o m p u t e m e a n rate o f spiking, s t a n d a r d deviation o f inter-spike intervals, and the ratio o f the s t a n d a r d deviation t o the rate ( ' c o e f f i c i e n t o f v a r i a t i o n ' ) ( S T A P - 1 2 , Wyss a n d H a n d w e r k e r 1 9 7 1 ) . Time-rate plots and a u t o c o r r e l o g r a m s ( N t h o r d e r interval histo-

648

J.P. LIEB ET AL.

obtained with depth and surface electrodes. Spike activity was prominent bilaterally in depth and gave the appearance of independence between the two sides. The morphology of spiking was varied across channels. Fig. 4, Part I, shows the start of telemetry-recorded seizure activity accompanying an aura in the patient. Fifteen cycles/sec seizure activity appeared in the left anterior pes hippocampi (shown at the arrow) and then propagated subtly to other left depth structures. There is a gap of 25 sec between Parts I and II during which seizure activity continued in the left anterior pes in the form of rapid spiking followed by suppression. Part II shows a prominent seizure discharge throughout the left depth. This episode was thus a clear example of seizure activity initiated unilaterally in depth in an apparently focal fashion and propagating to other depth sites on the same side. During the 21-day period during which depth electrodes remained in place, 9 electrographic seizure-like episodes were recorded from this patient. Their general region of onset is specified in Table I. Seven of these episodes were known to be accompanied by auras; the clinical accompaniments of

grams) were also plotted for each spike train (HSTPLT, Woods, 1975).

Results

Data from selected patients Examples of EEG activity during ictal and interictal periods and spike analyses of interictal EEG will be shown for two patients. Both patients demonstrated prominent bilaterally independent spiking in their interictal EEG records. Depth recordings appeared to successfully localize the seizure focus in the first patient (J.D.F.), while in the second patient (R.L.) the origin of seizure onset was usually not apparent in the EEG. The first patient (J.D.F.) was a 36-year-old right handed male who was well until the age of 16 when he experienced the onset of d~j~ vu attacks; these eventually became secondary generalized seizures as well. Medication was successful in controlling the generalized seizures but he continued to have repeated complex partial seizures. There was no antecedent etiology for the seizures. Fig. 3 is an example of interictal EEG activity

INTERICTAL ACTIVITY : BILATERAL DEPTH SPIKING

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DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY

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the other 2 episodes are~unknown. The precise locus of origin of onset of these episodes was often evident in the electrographic record: 6 episodes began in an apparently focal fashion in the left anterior pes hippocampi and 1 episode began in a similar focal fashion in the left posterior hippocampal gyrus. The precise origin of the other 2 episodes was n o t clear; 1 of these episodes began in a regional fashion in the left depth while the other appeared to begin bilaterally from the surface.

Three separate depth spike analyses were done on this patient over a period of 4 days. Fig. 5 is an analysis done on the third day. This figure consists of multi-channel plots of spike rate versus time, short- and long-epoch autocorrelograms, and descriptive statistics c o m p u t e d from the spiking in each channel. This spike analysis is based on hardwired recordings derived from 120 rain of interictal activity. The recording was begun at about 1 4 5 0 : 0 0 h, and the state of the patient varied

650

J.P. LIEB ET AL

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Fig. 5. A depth spike analysis based on a 120-min interictal hardwired recorded epoch in patient J.D.F. The state of the patient varied throughout the record. The most active site was the left anterior pes hippocampi; this site also displayed the lowest standard deviation of interspike intervals as well as the lowest coefficient of variation. No periodicities in spike occurrence were uncovered by either the 1- or 40-rain autocorrelograms. The autocorrelograms shown here and in Fig. 8 have been approximately normalized with respect to the total number of spkes in each site; this was accomplished by scaling the figures within a column up or down to approximately the same size and by using an evenly dispersed fraction of the events in the more active spike trains for constructing the histograms. Each vertical scale indicates 10 counts.

DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY

651

to initiate a seizure episode in an apparently focal fashion. In none of the analyses were the short- or long-epoch autocorrelograms observed to bring out any hidden periodicities in any of the spike trains. This patient's episodes were considered to be primarily the result of a left deep temporal seizure focus and he later underwent a left temporal craniotomy and anterior temporal lobectomy. Microscopic examination of the resected lobe revealed an anterior hippocampal sclerosis. The second patient (R.L.) was a 15-year-old right handed male. His seizures began at the age of 12 years with generalized convulsions. Since undergoing treatment with anticonvulsant medications, no further generalized convulsions have occurred, and his seizures became p s y c h o m o t o r in character. Some of these were preceded by epigastric auras, some were set off by emotional states, particular words, or smells. The seizures included staring and complex movements of the fingers, mumbling, smacking of the lips, and sometimes organized automatic activity. His seizures were not controlled by medications

from alertness to sleep. The patient was alert throughout the interictal periods used for the other 2 spike analyses that were performed. It was found that the rate of spiking increased over the 4-day period during which the 3 records were taken. This increase in spike activity may have been due to a continuing reduction of levels of anticonvulsant medication in the patient's blood; his medication had been reduced and primidone eliminated a b o u t 1 week prior to the recordings analyzed. In spite of the general increase in spike rate over time, the relationship of spike characteristics among the different channels remained fairly stable across time. It is of interest that for each spike analysis, the highest spike rate, lowest interspike variability, and lowest coefficient of variation in spiking was found to occur in the left anterior pes hippocampi, the site where most of the patient's seizure episodes appeared to begin. The second highest spike rate, second lowest interspike variability, and second lowest coefficient of variation in spiking was observed to occur consistently in the left posterior hippocampal gyrus, which was the only other site observed

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Fig. 6. Bilaterally independent depth spike activity in patient R.L. during an interictal period. Note the similarity between this record and that shown in Fig. 3; both records demonstrate marked bilateral spike abnormalities as well as variability in spike morphology.

652

J.P. LIEB ET AL.

and occurred at a rate of no less than 5/month. A mass lesion was shown up b y EMI scan in the left medial occipital region near the cingulum. The nature of this lesion was unclear. There was no antecedent etiology for the seizures. Fig. 6 is an example of interictal EEG activity obtained with depth and surface electrodes. As in the previous patient, spike activity was prominent bilaterally in depth and appeared to occur independently between

R.L.

the two sides. The morphology of the spiking varied across channels. The initial part of Fig. 7, Part I, shows interictal activity just preceding the start of a telemetry-recorded clinical seizure; depth spiking was prominent bilaterally. At a b o u t 15--20 sec into the record, seizure activity developed bilaterally in surface and in depth with no clear indication of any locus of origin. Part II is a direct continuation of the record, during which the intensity of the seizure discharge continued

AGE 16

0609

MALE 16 JUNE 76

CLINICAL SEIZURE 9th DAY POST-OP

LT, CING. LT. AMYG LT. ANT. PES LT. MID HIP GYRUS RT. AMYG RT. ANT. PES RT. POST PIES RT. MIO HIP GYRUS F7-T3 T3-T5 F8 -T4 T4 -T6

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Fig. 7. The EEG telemetry record accompanying a spontaneous clinical seizure in patient R.L. In Part I, bilateral interictal abnormalities are evident in the depth record and are followed by a build-up in rhythmic activity which occurs in a generalized fashion in surface and in depth. This build-up continues in Part II and develops into rapid, high voltage discharge in surface and in depth. See text for a behavioral description of the episode.

DEPTH SPIKING IN T E M P O R A L LOBE EPILEPSY

R.L. 15 June 76

Spike rate vs. time ~120 min--------~ ~ 22

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653

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Fig.8. Adepth spike analysis based o n a 120-rain interictal recorded epoch in patient R.L. The patient was alert t h r o u g h o u t the recording. The right anterior pes hippocampi was the most active site and d e m o n s t r a t e d the smallest variability in interspike intervals as well as the lowest coefficient of variation.

654 to build. Clinically, the episode endured for 60 sec during which he was unresponsive to verbal or painful stimuli. His eyes deviated to the right. His arms and legs were outstretched and exhibited tonic-clonic movements. During the 19-day period in which depth electrodes remained in place, 13 electrographic seizurelike episodes were recorded from this patient. Six of these episodes were known to be accompanied by clinical phenomena. The patient was unresponsive during all the observed episodes. The episodes varied in form but were often accompanied by generalized tonic-clonic movements. As indicated in Table I, no region of electrographic onset of the episodes was evident from the record in most cases. Depth spike analyses were done on this patient on 2 consecutive days. Fig. 8 is an analysis done on the first day. The duration of the epochs analyzed for each day were 120 and 115 min respectively. Both records were begun at about 1450:00 h and the patient was alert during each recording. Comparison of the 2 analyses indicated a general increase in the a m o u n t of spike activity and a decrease in inter-spike interval variability and coefficient of variation over the 2-day period. On both days, the maximal rate in spiking occurred in right depth sites. With respect to the autocorrelograms, no periodicities of less than 1 min were observed. Only some weak periodicities were apparent at about 30 min in right depth sites for the second analysis. This patient's episodes were considered to originate primarily in a generalized fashion due, possibly, to the existence of multiple seizure foci. He was not considered a suitable candidate for surgery.

General findings The finding that the relationship among sites demonstrating spiking was a stable one across a period of days in patients J.D.F. and R.L., also applied to the other patients in whom spike analyses were done on more than one day. (See Table I; patients S.P., R.E.,

J.P. LIEB ET AL. L.M. and T.F..) In general it appears that the analysis of one recording epoch might be sufficient to indicate which sites are the most active and demonstrate the least variability of interspike intervals. Table I compares the apparent region of seizure onset with the properties of interictal spiking in each patient. The electrographic seizure episodes recorded from each patient during the period their depth electrodes were in place are classified, on the basis of the available montage, as having originated from left depth, right depth, surface, or in a bilaterally synchronous fashion. Many of these electrographic episodes were observed to be accompanied by clinical phenomena. All of the electrographic seizure episodes were clearly distinguishable from both background EEG and interictal epileptiform activity in that such seizure activity typically consisted of high frequency, very regular waveforms which often exhibited a build-up of amplitude in the affected area and propagated to other regions (Lieb et al. 1976b). For each spike analysis period in each patient, the side containing the depth site with the maximum mean rate, the minimum standard deviation of interspike intervals, and the minimum coefficient of variation, is indicated. Eight of the patients shown in Table I (J.D.F., L.M., M.S., M.Sh., S.P., T.F., M.C. and R.E.) exhibited electrographic seizure activity indicative of a surgically treatable unilateral deep temporal seizure focus; of this group, all except R.E. have undergone unilateral temporal lobectomy. As is evident from the table, for all of the surgically treatable patients, the side exhibiting apparent seizure initiation was also the side containing the depth sites exhibiting maximal mean rate, minimal standard deviation of interspike intervals, and minimal coefficient of variation. Similarly, in those patients who were not deemed surgically treatable by unilateral temporal lobectomy but whose depth originating episodes predominated on one side of the other (R.L., T.J., H.O. and M.O.), spiking exhibited maximal mean rates, minimal standard

DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY

deviation of interspike intervals, and minimal coefficient of variation almost exclusively in depth sites on the predominating side. In those patients (J.D.F., L.M., M.S., S.P. and R.E.) who exhibited electrographic seizure episodes which sometimes (or exclusively) appeared to demonstrate a precise focal onset of seizure activity from a particular depth site, which then propagated to other depth sites, it was found that the initiating depth

36,

(A)

655

sites produced spiking at a greater rate and lower standard deviation than any of the other sites within the same temporal lobe. Fig. 9 summarizes the statistical properties of depth spiking in: (I) temporal lobes which appeared to be clearly capable of generating electrographic seizure episodes from depth sites, (II) temporal lobes initiating no electrographic seizure episodes and (III) temporal lobes in patients in which more than 50% of

(B)

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Fig. 9. Distribution of the (A) mean rates, (B) standard deviations of interspike intervals, and (C) coefficients of variation across all depth sites and all epochs analyzed. This was done for: (I) temporal lobes which appeared to be clearly capable of generating electrographic seizure episodes in patients whose episodes did not primarily arise in a bilateral fashion: (II) temporal lobes not observed to initiate electrographic episodes; and (III) temporal lobes from patients in which more than 50% of all the recorded episodes began in a bilaterally synchronous fashion. Group I consists of: J.D.F. (left side), L.M. (right side), M.S. (right side), M.Sh. (right side), S.P. (right side), T.F. (right side), R.E. (left side), M.O. (both sides), H.O. (both sides) and A.P. (both sides). Group II consists of L.M. (left side), M.S. (left side), M.Sh (left side), J.D.F. (right side), S.P. (left side), T.F. (left side), R.E. (right side). Group III consists of R.L. (both sides), T.J. (both sides), M.C. (both sides) and K.K. (both sides). Note that Group I temporal lobes yielded distributions that were distinctly different from those derived from Group II and Group III temporal lobes.

656

all the recorded electrographic seizure episodes began in an apparently bilaterally synchronous fashion. For each of these 3 temporal lobe classifications, the distribution of: (A) mean rates, (B) standard deviations of interspike intervals and (C) coefficients of variation across depth sites within that classification are shown. These distributions indicate that the statistical properties of spiking in temporal lobes apparently capable of generating electrographic seizure episodes are quite discriminable from the other 2 classifications. For any temporal lobe depth site, a mean rate greater than 0.6/sec, a standard deviation of interspike intervals of less than 5 sec or a coefficient of variation of less than 10 is indicative of a strong likelihood that electrographic seizure episodes will appear to be generated from that temporal lobe. In order to determine whether the information derived from depth spiking differentiated between the 8 patients who eventually became candidates for temporal l o b e c t o m y (L.M., M.S., M.Sh., J.D.F., S.P., M.C., T.F. and R.E.) and the 5 patients who never became candidates for surgical treatment for epilepsy (R.L., T.J., M.O., H.O. and A.P.), the degree of lateralization in the rate of spiking between temporal lobes was c o m p u t e d for each patient and plotted as a distribution (Fig. 10). (Patient K.K. is not included in this analysis since she eventually received a suprasylvian cortical excision.) The degree of lateralization in each patient was obtained by taking the ratio of the r o o t mean square of mean spike rate across depth sites in the more active temporal lobe to the root mean square of mean spike rate across depth sites in the less active temporal lobe. In patients in which more than 1 spike analysis epoch was obtained, the average of the lateralization ratios obtained for those epochs was used. Fig. 10 shows that a lateralization ratio of less than 2 is indicative of a patient whose seizure records will appear to demonstrate either multifocal or unlocalized seizure foci and thus n o t be suitable for surgery. The lateralization ratio in those patients considered suitable for unilateral

J.P. LIEB ET AL. SURGICAL CANDIDATES

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Fig. 10. The distribution of the degree of lateralization of spiking across the 8 patients who, on the basis of their seizure records, were deemed suitable candidates for temporal lobectomy (J.D.F., L.M., M.S., M.Sh., S.P., T.F., M.C. and R.E.) was compared with that of patients not deemed suitable for surgery (R.L., T.J., M.O., H.O. and A.P.). All in the first group have thus far received surgery except patient R.E. Patient K.K. received a frontal lobe excision and is not included in either graph. The technique for computing the degree of spike lateralization in each patient is described in the text. Note that there is no overlap in these distributions, thus indicating that the degree of spike lateralization is a good predictor of the suitability of patients for surgery.

temporal l o b e c t o m y varied over a wide range, but was always greater than 2. Evidence of neuropathological changes was reported in all of the patients who underwent unilateral temporal lobectomy. (L.M., M.S., M.Sh., J.D.F., S.P., T.F. and M.C.). Hippocampal specimens were available for examination in 3 of these patients (M.S., M.Sh. and J.D.F.) and hippocampal sclerosis was observed in each case.

D E P T H S P I K I N G IN T E M P O R A L L O B E E P I L E P S Y

657 iCoeff.

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Fig. 11. 55-min epochs prior to, and following, an epigastric aura exhibiting a right depth onset in patient S.P.. No trends in spike rate either preceding or following the episodes were evident. The statistical properties of the spiking give no evidence o f change following the episode.

Relationship of depth spiking to the time of seizure onset The relationship between depth spiking and the time of seizure onset was investigated for a total of 9 electrographic seizure episodes

in 5 patients (M.C., R.L., T.J., J.D.F. a n d ' S.P.). Clear-cut changes in depth spiking were generally not evident prior to the onset of an episode. Fig. 11 shows spike analyses done on 55-min epochs immediately prior to, and

658

J.P. L I E B E T AL.

R.L. 11 June 76

seizure episode

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no data

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Fig. 12. T h e r e l a t i o n s h i p b e t w e e n spike r a t e a n d seizure e p i s o d e s over a 6-h t e l e m e t e r e d r e c o r d in p a t i e n t R.L.. T h e p a t i e n t was n o t o b s e r v e d d u r i n g this p e r i o d a n d his b e h a v i o r a l s t a t e b e t w e e n a n d d u r i n g t h e e p i s o d e s is n o t k n o w n . Periods m a r k e d ' N o D a t a ' were t h e result o f t e m p o r a r y signal loss in t h o s e c h a n n e l s . Spike c o u n t i n g was d o n e right u p t o t h e m o m e n t it b e c a m e e v i d e n t t h a t a n e l e c t r o g r a p h i c e p i s o d e was beginning. F o l l o w i n g each episode, spike c o u n t i n g was r e s u m e d f o l l o w i n g a p e r i o d o f p o s t ictal d e p r e s s i o n lasting 3 0 - - 6 0 sec. T h e rate o f spiking appears, in general, t o b e u n r e l a t e d t o t h e t i m e o f o c c u r r e n c e o f a n episode.

DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY following, an epigastric aura in patient S.P.. The electrographic onset of this episode occurred in a regional fashion in the right depth. The post-aura spike analysis epoch began following a short period (60 sec) of post-ictal depression which followed the episode. It is evident f r o m inspection of the spike rate vs. time plots in Fig. 11 that no clear-cut changes occurred in the rate of spiking either before or after the episode. The descriptive statistics shown in the figure confirm the visual impression of no differences between pre-aura and post-aura spike occurrence properties. Fig. 12 shows the relationship between spike rate and a series of electrographic seizure episodes recorded b y telemetering over a period of just under 6 h in patient R.L.. The patient was unobserved during this period and the clinical concomitants of these episodes and the behavioral state of the patient are thus unknown. The region of earliest onset of seizure activity was n o t clear in the electrographic record of the first 3 episodes; in the fourth episode, seizure activity appeared initially in the surface leads. Inspection of this figure reveals no systematic changes in spike activity related to the occurrence of the electrographic episodes that are consistent across channels and repeatable across episodes. The time between episodes is indicative of a periodicity of a b o u t 80 min.

Discussion

The data presented here lend clear support to the hypothesis that depth spike occurrence properties are closely related to the electrographically defined locus of seizure onset in patients whose seizures apparently originate in medial temporal lobe sites. Specifically, the temporal lobe in each patient which appeared to either exclusively or predominantly initiate seizure episodes was found to contain depth sites which produced spike activity with the maximal rate, minimal variation in interspike-intervals, and minimal coefficient of variation. Certain values of the

659 descriptive statistics employed can be used to indicate whether or not a temporal lobe will eventually generate an episode. Additionally, the degree of lateralization in depth spiking appears to be a useful indicator of whether or not the patient will prove to be suitable for surgery on the basis of activity recorded during ictus. The close relationship observed here between interictal spiking and the apparent locus of electrographic seizure origin may be related to the cellular firing properties that have been observed in experimental seizure foci. Wyler et al. (1975) reported that cells recorded from chronic alumina foci in awake monkeys varied considerably in their tendency to produce high frequency bursts of firing. Cells exhibiting the highest proportion of bursting behavior over time were found to be the most difficult to operantly condition and the most likely to respond with bursting to either anti- or orthodromic stimulation. Assuming that cells exhibiting a high proportion of bursting activity are responsible for, and most numerous in, those loci capable of generating seizures, a higher rate of spiking recorded in the interictal EEG from such loci would be expected. Evidence that such neurons are the least modifiable by changes in behavioral state, would also imply that spiking recorded in the interictal EEG from such loci should also occur at a less variable rate than in other, less epileptogenic, foci. Behaviorally induced synaptic input may be less effective in modifying the electrical activity of the most highly epileptogenic regions due to the partial denervation of cells in these regions (Scheibel and Scheibel, 1973). Autocorrelation of the interictal spike trains in these patients generally failed to reveal any marked periodicities in the range of 1--75 min. These data, taken in conjunction with those of Stevens et al. (1971, 1972) which indicated that there is an underlying 90-min periodicity in spike activity, support the hypothesis that significant systematic variations in epileptic activity are due primarily to processes related to the sleep-cycle. In one

660 patient (R.L.) in which a series of electrographic seizure episodes were recorded and related to spike rate (Fig. 16), the intervals separating the episodes were in the vicinity of 90 min and also support this hypothesis. While the present data support the idea that the analysis of depth spiking may be useful in lateralizing and localizing the medial temporal regions most likely to initiate seizure episodes, the analysis of clear-cut spiking in the surface EEG, used to accomplish the same ends, would very likely be subject to error. This is due to the fact that depth spiking is very often not evident at the surface. This deficiency is clearly illustrated in a study of Crandall {1975) which was based on visual analysis of the surface record. In that study, 23.5% of those patients whose pre-implant scalp EEGs had exhibited unilateral temporal abnormalities, were found to have an opposite lateralization when depth electrode studies were later done. Several factors may account for the loss of information about depth spiking in the surface EEG. Such factors would include the distance of the active site from the surface, how widespread the spiking is in depth, and how synchronized the spiking is in depth (Gloor 1975; Pfurtscheller and Cooper 1975). An approach to analyzing the surface record which would more likely be successful would involve the identification of those waveforms likely to correlate with depth spiking; the use of autoregressive predictive filtering for the detection of non-stationarities appears to be a useful approach to this problem (Lopes da Silva et al. 1973, 1975, 1976). Additionally, spike analyses of scalp records during reduced medications might also prove fruitful since Ludwig and Ajmone Marsan (1975a) have shown that reduced medication can often produce specific focal activation of epileptiform activity that may be crucial for localization. The present study had too few patients in whom temporal lobectomy was performed and long-term follow-ups were available, to comment upon the usefulness of depth spike

J.P. LIEB ET AL. analysis in prognosticating the outcome of surgery. Ultimately, the optimal set of criteria for interpreting the clinical significance of the statistical patterns of depth spiking must be derived from an analysis of the outcome of surgery as well as pathological studies of resected tissue. The present study, by comparing the properties of depth spiking with the electrographic seizure records, must therefore be considered preliminary. It should also be noted that the criteria used for the interpretation of electrographic seizure records are also dependent on follow-up studies of surgical outcome and pathology, and are thus modifiable. Nonetheless the data presented here do suggest that surgical patients with lateralization ratios less than 2 and spike properties in the non-resected lobe close to those values found here to be indicative of eventual seizure initiation in that lobe, would be less likely to show a favorable outcome as measured by improvement in either seizure rate or, perhaps, psychological functioning. The development of optimal criteria for interpreting both depth spike patterns and the electrical seizure patterns accompanying ictus may eventually demonstrate that both types of information should be taken into account in order to obtain the best possible surgical outcome. Future studies of depth recordings should focus on this problem since, as hypothesized by Rossi (1973), the attempt to treat patients solely on the basis of the analysis of the ictal electroencephalographic signal may yield less satisfactory results than if depth spike information were taken into account. The data reported here are not indicative of any marked relationship between spike activity in depth and the time of seizure onset. Others studies in which animals with experimentally induced epilepsy (Ralston 1958; Elazar and Blum 1974; Angeleri et al. 1972) and human epileptics (Angeleri et al. 1970; Stevens et al. 1972) have been investigated, have reported various relationships between interictal EEG abnormalities and time of seizure onset. Such relationships may have been more apparent in the present study if

DEPTH SPIKING IN TEMPORAL LOBE EPILEPSY activity preceding and following multiple episodes had been observed for each patient. The much more apparent relationship between interictal spiking and the electrographically inferred locus of seizure onset indicates that the neuronal aggregate which produces spiking at any given locus reflects the long-term relative threshold of that site for seizure initiation b u t does n o t reflect the time of seizure initiation, perhaps because independent factors, such as the chance occurrence of synchrony across several sites, determine the time at which that threshold will be reached.

Summary The statistical properties of interictal EEG spiking in medial temporal lobe sites were analyzed in 14 patients with medically refractory complex partial seizures in w h o m the anatomical origins of seizure episodes had been inferred through the assessment of electrographic seizure records. An automatic spike recognition system programmed for a minicomputer was optimized and used to quantify spike abnormalities. The relationship of spike properties across recording sites within patients was found to exhibit stability across a period of days. Within each patient, the temporal lobe which appeared to be most likely to initiate electrographic seizure episodes was found to contain a site or sites exhibiting the maximum mean spike rate, the minimum standard deviation of interspike intervals, and the minimum coefficient of variation in spiking. Certain values of these measures of spiking may be indicative of a strong likelihood of eventual seizure initiation from 'the region being monitored. The degree of lateralization of depth spike activity was found to correlate perfectly with the suitability of patients from unilateral temporal l o b e c t o m y as judged by electrographic seizure recordings. While the relation b e t w e e n depth spike occurrence and the apparent origin of seizure episodes was found to be a very close one, a relation between depth spike occurrence and

661 time of seizure onset was usually n o t evident. These data indicate the usefulness of interictal depth spike activity in predicting the electrographic locus of depth originating seizure episodes as well as the potential usefulness of such information in forming a surgical prognosis.

Rdsumd

Analyse quantitative des d~charges de pointes profondes en relation avec les foyers de crises chez des malades avec gpilepsie du lobe temporal Les propridtds statistiques des ddcharges de pointes EEG intercritiques situdes dans le lobe temporal mddian ont dtd analysdes chez 14 malades avec crises partielles complexes rdfractaires aux mddicaments chez lesquels l'origine anatomique des dpisodes critiques a dtd infdrde de l'interprdtation des enregistrements dlectrographiques des crises. Un systdme de reconnaissance automatique de pointes, programmd pour mini-ordinateur a dtd optimisd et utilisd pour quantifier les anomalies de type pointe. La relation entre propridtds des pointes aux points d'enregistrements chez les malades s'est avdrde stable sur une pdriode de plusieurs jours. Chez chaque malade, le lobe temporal qui apparaissait le plus susceptible d'initier des dpisodes dlectrographiques s'est avdrd contenir un ou plusieurs points montrant le taux m o y e n maximum de ddcharges de pointes, la ddviation standard minimale des intervalles inter-pointes et le coefficient de variation de ddcharges minimum. Certaines valeurs de ces mesures de ddcharges de pointes peuvent indiquer une forte probabilitd que les crises ddbutent au niveau de la rdgion enregistrde. Le degr~ de latdralisation de l'activitd profonde de ddcharges de pointes s'est avdrd correspondre parfaitement avec l'indication de lobectomie temporale unilatdrale apprdcide par enregistrement dlectrographique des crises. Tandis que la relation entre survenue de pointes en

662

profondeur et origine apparente des crises s'est averse tr~s ~troite, une relation entre survenue des pointes en profondeur et m o m e n t s de d~but de la crise n'~tait habituellement pas ~vident. Ces donn~es indiquent l'utilit~ d'enregistrer en profondeur l'activit~ interictale de pointes pour pr~dire le lieu ~lectrographique des 6pisodes critiques d'origine profonde, et l'utilit~ potentielle d'une telle information pour formuler un pronostic chirurgical. The authors gratefully acknowledge the assistance of the staff of the Clinical Neurophysiology Project, whose efforts made this research possible: Mr. Jeffrey Walker, Mr. Peter Turek, Mrs. Mary Price, Miss Jean Lewis, Mr. Everett Cart, Mr. Daniel Stoller and Mr. Elmo Mariani. Miss Joan Hopgood typed the manuscript. Computer Facilities were made available by the laboratory of Dr. M.A.B. Brazier (supported by U.S.P.H.S. Grant NS 11379) and by the Data Proceasing Laboratory of the Brain Research Institute (supported by U.S.P.H.S. Grant NS 02501). Neuropathological studies were made by Dr. W. Jann Brown.

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