Paul H. Crandall

Synaptic reorganization by mossy fibers in human epileptic fascia dentata.

This study was designed to identify whether synaptic reorganizations occur in epileptic human hippocampus which might contribute to feedback excitation. In epileptic hippocampi, (n = 21) reactive synaptogenesis of mossy fibers into the inner molecular layer of the granule cell dendrites was demonstrated at the light microscopic and electron microscopic levels. There was no inner molecular layer staining for mossy fibers in autopsy controls (n = 4) or in controls with neocortex epilepsy having no hippocampal sclerosis (n = 2). Comparing epileptics to controls, there were statistically significant correlations between Timm stain density and hilar cell loss. Since hilar neurons are the origin of ipsilateral projections to the inner molecular layer, this suggests that hilar deafferentation of this dendritic zone precedes mossy fiber reafferentation. Quantitative Timm-stained electron microscopy revealed large, zinc-labelled vesicles in terminals with asymmetric synapses on dendrites in the inner molecular and granule cell layers. Terminals in the middle and outer molecular layers did not contain zinc, were smaller and had smaller vesicles. These histochemical and ultrastructural data suggest that in damaged human epileptic hippocampus, mossy fiber reactive synaptogenesis may result in monosynaptic recurrent excitation of granule cells that could contribute to focal seizure onsets.

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.

Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings

We assessed the reliability and accuracy of scalp/sphenoidal recordings for ictal localization by retrospectively analyzing 706 noninvasive ictal recordings from 110 patients who subsequently underwent stereoencephalographic evaluation. Strictly defined unilateral temporal/sphenoidal ictal patterns correctly predicted findings of depth electrode examination in 82 to 94% of cases. These strictly defined predictive patterns could be detected with excellent interrater reliability. The patterns are misleading in only a minority of cases, but cannot be used in isolation for definite ictal localization.

Psychological Status Related to Surgical Control of Temporal Lobe Seizures

Summary: Patients who underwent temporal lobe surgery with diagnosis aided by stereoelectroencephalography (SEEG) were evaluated psychosocial^ before surgery and at one month and one year after surgery. Patients who were not operated on but who also had been evaluated by SEEG served as controls. These patients were evaluated at time periods comparable to those of the operated cases. At one year after surgery, patients whose seizures had been relieved had improved in Degree of Dependency, Work Performance, and Non‐Family Relationships. Patients whose seizures were not controlled by surgery and nonoperated patients did not show any significant change in psychosocial measurements one year postoperatively. Psychosocial improvements were seen regardless of the side of the brain operated. While patients whose seizures were reduced experienced memory deficits of the type associated with side of the temporal lobe resection, the data suggested that there was improvement in intellectual scores and, in the case of right‐sided surgery patients, memory functions associated with the contralateral, intact hemisphere.

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.

The magnetic and electric fields agree with intracranial localizations of somatosensory cortex

We measured the magnetoencephalogram (MEG), electroencephalogram (EEG), and electrocorticogram (ECoG) after stimulation of contralateral median nerve in four patients with partial epilepsy evaluated for surgery. Quantitative localization estimates from equivalent source modeling were compared with locations of central fissure in hand sensorimotor area determined by cortical stimulations, intraoperative photographs, and examination after excision in frontal lobe. We also measured MEG and EEG in nine control subjects. MEG and EEG localizations were within 2.5 cm of the estimated location of central fissure in all 13 subjects. In the three patients who had complete mapping of all three fields, the average distance of localizations from central fissure was approximately 4 mm in both MEG and EEG, 3 mm in ECoG, and 3 mm in combined MEG and EEG. MEG was simpler than EEG, which was simpler than ECoG. MEG resolved ambiguities in both EEG and ECoG. The combination of the three fields added information about the spatiotemporal activity of somatosensory cortex. Localization of central fissure was essential to surgical treatment.

Ketamine-induced electroconvulsive phenomena in the human limbic and thalamic regions.

In nine patients with cortical, limbic and thalamic electrode implants, correlative electrical activity and gross behavior were observed following administration of ketamine, 70 per cent N2O, and thiopental. Ketamine was administered in four dosages: 0.5, 1, 2, and 4 mg/kg. One patient who received 0.5 mg/kg iv manifested depth-clectrode seizure activity without loss of consciousness. Two patients, receiving 1 mg/kg iv, developed increased frequency in their depth-clectrode EECs with transient unconsciousness. All six patients receiving 2 or 4 mg/kg iv developed electrical seizure activity in the limbic and thalamic areas, with uncorrected behavioral manifestations ranging from apparent “unconsciousness” and immobility to actual tonic and clonic motor activity. The surface EEG did not manifest the intense electrical activity in the limbic region at all times. In contrast, administration of 70 per cent N:O and 400 mg thiopental did not induce electrical seizure phenomena. It is suggested that ketamine be used cautiously in patients with seizure disorders.

A comparison of EEG seizure patterns recorded with surface and depth electrodes in patients with temporal lobe epilepsy.

Surface and depth EEG seizure patterns were compared in 34 patients with intractable temporal lobe epilepsy in whom depth EEG electrodes had been chronically implanted in order to localize epileptogenic sites with a view to surgery. EEG records accompanied by clinical seizures, auras, no behavioral changes, as well as records for which no behavioral observations had been made, were judged with respect to the manner in which seizure activity originating unilaterally in the depth of one of the temporal lobes spread to the surface. For each EEG record, the onset of seizure activity in depth was classified as being focal or regional in form, and seizure activity was judged as: (1) not spreading to the surface, (2) spreading bilaterally and synchronously to the surface, (3) spreading initially to the surface ipsilateral to the depth site(s) in which the electrographic seizure first appeared, or (4) spreading initially to the surface contralateral to the depth site(s) in which the seizure activity initially occurred. EEG seizure activity was found to be less likely to propagate to the surface for those records that were either unaccompanied by behavior changes or accompanied only by auras than for those records accompanied by clinical seizures. In records accompanied by clinical seizures, seizure activity commonly propagated to the surface in a bilateral and synchronous fashion and was also found to spread initially to the ipsilateral but not to the contralateral surface. Anatomical and electrophysiological data accounting for the occurrence of ipsilateral spread were discussed. Diagnostic usefulness of surface recordings during clinical seizures in temporal lobe epilepsy was discussed.

Functional connections in the human temporal lobe

SummaryConnections in the human mesial temporal lobe were investigated using brief, single pulses of electrical stimulation to evoke field potential responses in limbic structures of 74 epileptic patients. Eight specific areas within these structures were stereotactically targeted for study, including amygdala, entorhinal cortex, presubiculum, the anterior, middle and posterior levels of hippocampus and the middle and posterior levels of parahippocampal gyrus. These sites were studied systematically in order to quantitatively assess the response characteristics and reliability of responses evoked during stimulation of pathways connecting the areas. Specific measures included response probability, amplitude, latency and conduction velocities. The results are assumed to be representative of typical human limbic pathways since all recordings were made interictally and response probabilities across sites were not found to differ significantly between non-epileptogenic vs. identified epileptogenic regions. Field potentials ranging in amplitude from less than 0.1 to greater than 6.0 mV were evoked ipsilaterally, with mean onset latencies and conduction velocities ranging from 4.4 ms and 3.64 m/s in the perforant pathway connecting entorhinal cortex to anterior hippocampus to 24.8 ms and 0.88 m/s in the pathway connecting the amygdala and middle hippocampus. Stimulation of presubiculum and entorhinal cortex were most effective in evoking widespread responses in adjacent limbic recording sites, whereas posterior parahippocampal gyrus appeared functionally separated from other limbic sites since its probability of influencing ipsilateral sites was significantly lower than any other area. It was particularly noteworthy that stimulation did not evoke responses in any sites in contralateral hippocampal formation; even though a large number of sites were tested with bilateral implantation of homotopic electrodes. The absence of evidence for a functional contralateral limbic projection in the human brain stands in marked contrast to the anatomical and physiological evidence in lower animals for strong contralateral connections between subfields of the hippocampus via the hippocampal commissure. In addition, it correlates well with anatomical evidence for reduced hippocampal commissural connections in lower primates.

Corticosteroid Responses to Limbic Stimulation in Man: Localization of Stimulus Sites

Corticosteroids in human plasma and urine increase after amygdala stimulation, and plasma corticosteroids decrease after hippocampus stimulation. Five subjects underwent unilateral temporal lobectomy, and histopathologic localization of electrode sites was attempted. Localization was successful for six sites: three in basolateral amygdala and three in hippocampus.