W. Jann Brown

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.

Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat

The present study examined the bilateral synaptic rearrangements of presumed gamma-aminobutyric acid (GABAergic) inhibitory axons and mossy fiber (presumed excitatory) recurrent collaterals following intrahippocampal kainic acid (KA) injection. Glutamate decarboxylase immunoreactivity (GAD-IR) was used to study inhibitory axon terminal sprouting, following 0.5 microgram KA/0.2 microliter injected unilaterally into the posterior hippocampus of rats (n = 16), with survival periods of 14, 28, and 120 days. The age-matched control animals (n = 9) received intrahippocampal 0.2 microliter saline (sham, n = 4) or no injection (normal, n = 5). To study mossy fiber synaptic rearrangements, 0.5 microgram KA/0.2 microliter volumes were injected unilaterally into the posterior hippocampus of rats (n = 10), with survival periods from 14, 28, and 120 days, and Timm sulfide-stained tissue sections were compared to age-matched sham (n = 4) or normal controls (n = 4). At 14 through 120 days after posterior KA injection, GAD-IR puncta were significantly increased in the ipsi- and contralateral inner molecular layers (IML) of the fascia dentata (FD) when compared to sham or normal controls. KA lesion also induced mossy fiber recurrent collateral sprouting into the ipsi- and contralateral FD IMLs. The loss of both the commissural and ipsilateral associational afferents to the FD apparently induced sprouting into their ipsi- and contralateral termination zones by granule cell mossy fibers and GAD-IR axons, thus establishing an abnormal circuitry near the observed pathology in the kainate model of epilepsy. Although reactive synaptogenesis of mossy fibers producing monosynaptic excitation may be one mechanism for KA epileptogenicity, the concurrent sprouting of GABAergic terminals in the same IML zone of the FD suggests that anomalous inhibitory synapses may contribute to chronic KA hippocampal hyperexcitability.

ORGANIC MERCURIAL ENCEPHALOPATHY: IN VIVO AND IN VITRO EFFECTS OF METHYL MERCURY ON SYNAPTOSOMAL RESPIRATION

—A reproducible model of subacute methyl mercury (MeHg) intoxication was developed in the adult rat following the daily intragastric administration of 10 mg methyl mercury/kg body wt. Synaptosomes isolated from animals during the latent phase of mercury neurotoxicity (6‐10 days) demonstrated no significant change in respiratory control, State 3, State 4, or 2,4‐dinitrophenol stimulated respiration with succinate, glutamate or pyruvate plus malate. During the neurotoxic phase, a significant decline in respiratory control was evident with all substrates. Cerebellar synaptosomes revealed qualitatively similar but quantitatively greater inhibition of 2,4‐dinitrophenol stimulated respiration during the latent and neurotoxic phases with glutamate.

GABAergic neurons are spared after intrahippocampal kainate in the rat

The present study used Nissl stains and glutamate decarboxylase immunoreactivity (GAD-IR) to quantify the acute and chronic toxicity of kainic acid (KA) on focal and remote hippocampal principal neurons (i.e., pyramidal and granule cells) and on putative inhibitory neurons (GAD-IR or GABAergic) following intrahippocampal KA administration. Concentrations of 0.5, 1.0, 1.25 or 1.5 micrograms KA/0.2 microliters were injected unilaterally into the posterior hippocampus of rats (n = 32), with survival periods of 1, 3, 5, 14, 21, 30 and 60 days. The age-matched control animals (n = 10) received an intrahippocampal injection of 0.2 microliter saline (sham control, n = 4) or no injection (normal, n = 6). The ipsilateral (KA+) cell counts demonstrated a selective vulnerability of CA3 and CA4 pyramidal neurons which was maximal at 14 days and unchanged to 60 days. However, in the same region, putative inhibitory (GAD-IR) neurons were resistant to the neurotoxic effects of KA. Contralateral (KA-) pyramidal cell and GAD-IR neuron densities were equivalent to controls. The present data demonstrate a selective resistance to KA by GABA neurons compared to the vulnerability of pyramidal neurons. Because GABA neurons are relatively spared in the KA focus, loss of GABAergic inhibitory neurons is probably not a mechanism for the seizure sensitivity in the KA model.

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.

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.

Estrogen receptors in acoustic neurilemmomas

Acoustic neurilemmomas are more frequent, larger, and more vascular in women, and such lesions have a rapidly progressive clinical course in pregnant women; these findings suggest that the growth of these neoplasms may bear a relationship to certain hormone levels. Tissues from 8 patients with acoustic neurilemmoma (3 men and 5 women) were studied by a new fluorescent steroid histochemical technique to detect the presence of estrogen receptors in or on neoplastic cells. Estrogen receptor protein has also been found in meningioma cells in women. Neurilemmoma of the acoustic nerve is the second neoplasm of the central nervous system in which such receptors have been demonstrated.

Relief of Seizures from a Predominantly Posterior Temporal Tumor with Anterior Temporal Lobectomy

Summary: We report the relief of intractable complex partial seizures in a patient with a posteromesial temporal lobe hamartoma after anterior temporal lobectomy, despite minimal tumor removal. We suggest that the key to successful treatment is the mainly medial, or limbic, location of the tumor, which apparently requires anterior limbic structures for full clinical expression of seizures. We conclude that excision anterior to a posterior temporal lesion can result in seizure relief and that a medial tumor location may be important for successful treatment.

Spectrofluorometric determination of β-glucuronidase activity

Abstract A fluorometric method is described for the assay of β-glucuronidase in tissue homogenates using 1-naphthyl-β- d -glucuronide as substrate. The method is sensitive, rapid, and easily applicable to small amounts of tissue. Values for Michaelis constants and inhibitor constants for the competitive inhibition of the enzyme by d -saccharo-1,4-lactone are presented. A comparison of the β-glucuronidase activity in Triton X-100 activated samples of mouse liver using 1-naphthyl-β- d -glucuronide and phenolphthalein β-glucuronide as substrates revealed an average ratio of micromoles 1-naphthol liberated to micromoles phenolphthalein liberated of 1.53:1. Comparative β-glucuronidase activity values were obtained for unfractionated 0.25 M sucrose homogenates of liver, spleen, kidney, and brain, and measurements of the percentage activation by Triton X-100 determined at pH 4.5 and 5.1.