Jeffrey P. Lieb

Temporal lobe volumetric cell densities in temporal lobe epilepsy.

Summary: Volumetric cell densities in 13 different sub‐fields of the temporal lobe were calculated to test various hypotheses about mesial and lateral temporal lobe sclerosis in patients with complex partial epilepsy. In patients benefitting (primary group) from anterior temporal lobectomy (ATL), sclerosis was greater (fewer cells) in anterior than in posterior hippocampus. By contrast, the patients lacking full benefit (nonprimary group) from ATL had decreased numbers of neurons equally distributed from anterior to posterior hippocampus, indicating that zones of mesial temporal cell loss are linked to zones of epilep‐togenicity. These data support a model of focal hippo‐campal epilepsy originating from zones of cell loss and synaptic reorganization that is epileptic. There were no differences in cell densities in gyrus hippocampi or in lateral temporal gyri when patients with temporal lobe epilepsy and controls were compared. Hippocampal cell densities in mesial temporal lobe were not reduced in psychomotor epileptic patients with extrahippocampal foci consisting of foreign tissue. Variables in seizure histories were not correlated with Ammons horn cell densities, indicating that most of the sclerosis preceded the seizures, which did virtually no significant further damage to hippocampus with repeated partial or generalized seizures.

Distribution of Pyramidal Cell Density and Hyperexcitability in the Epileptic Human Hippocampal Formation

Summary: Pyramidal cell densities in various regions of the anterior and posterior hippocampal formation were measured from en bloc temporal lobe resections and compared with presurgical stereoelectroencephalography (SEEG) data derived from depth electrodes in 12 patients with temporal lobe epilepsy. These data were compared with cell densities observed in four nonepileptic control patients. Patients who consistently exhibited anterior focal changes in the SEEG accompanying onset of ictus had cell densities that were selectively reduced in the anterior hippocampal formation but normal with respect to controls in the posterior hippocampal formation. Patients who exhibited more regional changes in the SEEG at onset of ictus had reduced cell densities in both the anterior and posterior hippocampal formation. Patients who exhibited focal spike activity in the anterior hippocampal formation as their predominant interictal SEEG pattern also had selectively reduced cell densities in the anterior hippocampal formation, while patients with widespread spiking throughout the hippocampal formation had reduced cell densities both anteriorly and posteriorly. These data support the concept that epileptogen‐esis occurs in or near those areas of epileptic hippocampus that are most damaged. Hippocampal sclerosis must be viewed as related to adjacent hyperexcitable or epileptogenic neurons and not solely as a passive result of repeated anoxia or ischemia.

Interhemispheric propagation time of human hippocampal seizures. I. Relationship to surgical outcome.

Summary: This study evaluated ictal stereotaxic electroencephalogram (SEEG) records in 75 patients with complex partial seizures who later received anterior temporal lobectomy and were evaluated for long‐term seizure relief. The time required for seizures to propagate from the putatively epileptogenic hippocampal formation to the contralateral hippocampal formation was measured from 615 ictal SEEG records. These interhemispheric propagation times were then compared with the degree of post‐lobectomy seizure relief. Poor postsurgical seizure relief was associated with seizure propagation times of ≤5 s. Relief or reduction of seizures after surgery was associated with seizure propagation times >50 s. These relationships were also found to occur in a subset of 56 patients who did not exhibit interhemispheric propagation times of <0.5 s, thus indicating that interhemispheric propagation times in the range of 0.5–5 s is a negative prognostic sign even in the absence of “bilaterally synchronous” ictal SEEG onsets. The finding of longer interhemispheric propagation times in patients who were improved by surgery may be accounted for by the greatly reduced size, or absence, of the hippocampal commissure in humans and suggests that the corpus callosum is a major, albeit indirect, route by which hippocampal foci may propagate seizure activity contralaterally. The finding of shorter interhemispheric propagation times in patients who did poorly after surgery may be accounted for by the existence of foci outside the region of excision with more direct access to callosal pathways or, alternatively, by the presence of damage in a more seizure‐prone contralateral hippocampus.

Temporo-spatial patterns of pre-ictal spike activity in human temporal lobe epilepsy.

The statistical properties of pre-ictal EEG spike activity in medial temporal lobe sites were analyzed in 6 patients with medically refractory complex partial seizures. A total of 24 1 h pre-ictal periods (2-6 periods per patient) were evaluated by quantifying the rate of occurrence of individual spatial patterns of spike activity derived from a subset (n = 6) of the recording channels. The channels chosen for analysis always included those medial temporal lobe sites which were documented to be most likely to initiate seizures, as well as their respective contralateral homologues. Each 1 h pre-ictal period was divided into 360 10 sec bins which were then visually classified into 1 of 64 possible spatial patterns of spike activity. These patterns, in turn, were grouped into 1 of 5 general spatial patterns and evaluated for trends across 3 20 min pre-ictal segments. Pooling these data across patients yielded the following results: (1) Focal patterns of spike activity tended to decline significantly in rate of occurrence several minutes prior to seizures, while the rate of independent contralateral patterns did not change. (2) The rate of occurrence of patterns of bilateral loosely coupled spike activity (involving focal and contralateral sites) increased significantly across the 20 min pre-ictal segments and was clearly augmented during the 20 min prior to seizures. These findings indicate that the degree of bilateral independence in medial temporal lobe spike activity tends to decrease several minutes prior to the localized onset of temporal lobe seizures; such changes may reflect the mechanisms responsible for the inter-ictal-ictal transition.

Surface and Deep EEG Correlates of Surgical Outcome in Temporal Lobe Epilepsy

Summary: Interictal and ictal EEG characteristics derived from limited surface montages and medial temporal lobe sites were compared with long‐term seizure relief following anterior temporal lobectomy in 52 epileptics. Patients were classified into one of four surgical outcome groups, ranging from seizure free to no clinical improvement. For each patient, interictal records were analyzed according to deep and surface spike characteristics and background activity. Ictal records were analyzed according to the proportion of episodes initiated in a unilateral or bilaterally synchronous fashion, the proportion of surface or deep onsets, the variability of onset location, and the morphology of seizure onsets. Interictal EEG variables that correlated with surgical outcome included: (a) various types of bilaterally synchronous surface/deep spikes; (b) diffuse background slowing; (c) sharp waves; and (d) the presence of multiple independent deep spike patterns in the lobe chosen for resection. Relevant ictal EEG variables included: (a) episodes initiated in a bilaterally synchronous fashion; (b) variability in seizure onset location; (c) the proportion of precisely focal onsets from deep sites; (d) the proportion of surface onsets: and (e) the proportion of onsets from the side chosen for resection. Multivariate analysis of these data with linear, stepwise, discriminate analysis and adaptive, nonlinear. distribution‐free pattern recognition demonstrated that: (a) both interictal and ictal EEG characteristics can independently predict surgical outcome at levels significantly better than chance; (b) ictal and interictal EEG data contain non‐redundant information for making such predictions; and (c) nonlinear pattern recognition techniques are capable of deriving the most accurate rules for predicting the effects of surgery.

Sleep state and seizure foci related to depth spike activity in patients with temporal lobe epilepsy

Depth spike activity was evaluated from medial temporal lobe sites using computer spike recognition techniques in all-night sleep records derived from 10 patients with medically refractory complex partial seizures. Sleep stages were classified into 1 of 4 groups: wakefulness, REM sleep, light sleep and deep sleep. Some disturbance in the periodicity of the sleep cycle was noted in most patients, but the relative proportions of REM sleep, light sleep and deep sleep were close to that reported for normals. Depth spike activity was observed to be most frequent in a majority of sites during deep sleep in 6 patients and during light sleep in 3 patients. In 1 patient equal numbers of sites showed maximal activation during light sleep and deep sleep. In 4 patients, certain sites in the more epileptogenic lobe demonstrated a maximal rate during waking or REM sleep. All patients reported in this study were considered to be suitable for temporal lobectomy. In contrast to the results obtained from a previous study, the side with the site demonstrating maximal mean spike rate did not necessarily correspond to the side chosen for lobectomy. Significant correspondence across patients between the more epileptogenic lobe and maximal spike rate was not found during waking and was further reduced during light sleep and deep sleep. The correspondence was, however, significant during REM sleep and for the side containing the site demonstrating the smallest activation in mean spike rate during light sleep or deep sleep relative to waking. These results indicate that an analysis of sleep induced changes in depth spike activity can be useful in improving predictions concerning epileptogenicity. Quantification of other aspects of the interictal EEG, such as background activity, may further improve such predictions.

Inter-hemispheric propagation of human mesial temporal lobe seizures: a coherence/phase analysis

Intra- and inter-hemispheric propagation of ictal discharges was analyzed with computer techniques in 10 patients with complex partial seizures of mesial temporal lobe origin in whom depth electrodes had been stereotaxically implanted. Coherence and phase analysis of seizure discharges was used to detect the emergence of linear relationships between all possible pairs of surface and depth recording derivations both between and within hemispheres. This analysis included mesial temporal, lateral temporal, and frontal lobe sites during both the onset and inter-hemispheric propagation of 28 ictal episodes. Although strong intra-hemispheric coherences and linear phase spectra reliably emerged in both the epileptogenic and non-epileptogenic hemispheres during seizure onset and contralateral spread, these relationships were usually not observed for inter-hemispheric comparisons. Only 3 of 10 patients demonstrated some degree of consistency in the emergence of significant wideband coherences and linear phase spectra between left and right mesial temporal sites during the inter-hemispherics propagation of ictal discharges. Mesial temporal lobe sites which demonstrated such a relationship included the amygdala, pes hippocampi, and parahippocampal gyrus. In 7 of 10 patients, lateral temporal derivations were sampled during ictal events; the emergence of linear relationships between left and right lateral temporal derivations during inter-hemispheric propagation was observed for only two. Various frontal lobe sites were monitored in 3 of the 10 patients; the emergence of linear relationships was observed only between left and right orbitofrontal derivations in the one patient for whom this region was sampled. These results suggest that the hippocampal commissure, parts of the corpus callosum, and parts of the anterior commissure may be relatively unimportant for the inter-hemispheric propagation of mesial temporal seizures in man. Future studies in non-human primates may reveal that ictal discharges which originate in the mesial temporal region propagate preferentially via brain-stem pathways to contralateral homologous regions.

Neuropathological Findings Following Temporal Lobectomy Related to Surface and Deep EEG Patterns

Summary: Interictal and ictal characteristics of preoperative EEG recordings, derived from limited surface montages and medial temporal lobe sites, were compared with the results of pathological studies done on resected lobes obtained from 44 patients with complex partial seizures. Pathological material was divided into four groups: (a) sclerosis (mesial temporal or restricted to pes hippocampi); (b) neoplasia (mainly hamartomas); (c) miscellaneous lesions; and (d) no significant lesions. Interictal EEG correlates of no pathology included bilaterally synchronous surface spikes (with or without simultaneous deep spikes) and independent surface spikes (with or without simultaneous deep spikes) on the side of lobectomy. Ictal EEG correlates of no pathology included unilateral surface or surface/deep onsets, bilaterally synchronous surface onsets, more than one onset location, and suppression at onset. Focal onsets correlated with sclerosis. Frequent interictal spike activity in the non‐lobectomized lobe and fast buildup at onset of ictus suggested neoplasia. Many of the EEG correlates of no pathology are known to correlate with poor postsurgical seizure relief, due probably in part to the fact that absence of pathology in the resected specimen is a negative prognostic sign. Patients with sclerosis could be distinguished from patients with no demonstrable pathology with 81% cross‐validation classification accuracy using a distribution‐independent, nonlinear classifier. Both interictal and ictal EEG measures were used by the classifier, and one may conclude that ictal and interictal EEG recordings contain nonredundant information for predicting the presence and type of underlying pathology.

Quantitative analysis of depth spiking in relation to seizure foci in patients with temporal lobe epilepsy

Abstract The statistical properties of interictal EEG spiking in medial temporal lobe sites were analyzed in 14 patients with medically refractory complex partial seizures in whom 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 lobectomy as judged by electrographic seizure recordings. While the relation between 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 time of seizure onset was usually not 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.

Changes in intelligence following temporal lobectomy: relationship to EEG activity, seizure relief, and pathology.

Summary: Pre‐ and posttemporal lobectomy measures of intelligence and memory in 36 patients with medically refractory complex partial seizures were compared with (1) various aspects of presurgical ictal and interictal EEG activity derived from surface and deep electrodes, (2) postlobectomy seizure relief, and (3) pathological findings in the resected lobe. With respect to interictal EEG data, bilaterally synchronous surface spikes (accompanied or unaccompanied by simultaneous deep spikes) and sharp waves were significantly correlated with lower prelobectomy intelligence scores and a drop in these scores following lobectomy. With respect to ictal EEG data, bilaterally synchronous and multifocal onsets were significantly correlated with a postlobectomy drop in intelligence scores. Patients with poor postlobectomy seizure relief tended to have lower presurgical intelligence scores and a drop in intelligence scores following lobectomy. The patients most likely to show a postlobectomy drop in intelligence were those demonstrating some combination of poor seizure relief, an absence of pathology in the resected specimen, or EEG signs indicative of poor seizure relief. Postlobectomy changes in intellectual status are therefore not necessarily exclusively attributable to the amount of postlobectomy seizure relief experienced by these patients, but might be due to a combination of factors.