Kindled seizure-induced reduction of muscarinic cholinergic receptors in rat hippocampal formation: evidence for localization to dentate granule cells.

The binding of [3H] quinuclidinyl benzilate ( [3H] QNB) to muscarinic cholinergic receptors in dentate gyrus of rat hippocampal formation was analyzed by membrane binding assay and in vitro autoradiography. The destruction of dentate granule cells, either by neonatal irradiation or colchicine injection, resulted in nearly complete elimination of [3H] QNB binding sites in the molecular and granule cell layers. By contrast, neither perforant path transection nor destruction of the septal-hippocampal cholinergic afferents caused a decline of [3H] QNB binding sites. Amygdala kindled seizures resulted in a 30% reduction of [3H] QNB binding sites which was distributed uniformly across the entire molecular and granule cell layers. Thus, most, if not all, of the muscarinic cholinergic receptors present in dentate gyrus appear to reside on the somata and dendritic trees of the dentate granule cells. We propose that this kindled seizure-induced decline of muscarinic receptors represents an endogenous compensatory mechanism designed to stabilize granule cell excitability.

Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure.

Sudden unexpected death (SUD) occurred in an epileptic patient after a seizure. The patient had a witnessed seizure with electrocardiographic evidence of a cardiac arrhythmia. Immediate cardiopulmonary resuscitation in the hospital was ineffective. Autopsy revealed no anatomic cause of death. This case supports a cardiac cause for SUD in this patient. The mechanism of death remains speculative despite its setting in an epilepsy center. The seven-year experience with SUD at the epilepsy center is reviewed.

Memory performance during the Amytal test in patients with non-temporal lobe epilepsy.

PROBLEM: The amobarbital (Amytal) sodium test has been considered an indispensable tool in the presurgical examination of patients for epilepsy surgery. However, the accuracy of the Amytal test for predicting memory deficits, especially the amnestic syndrome, has been questioned. METHOD: The Amytal test was administered bilaterally to three groups of patients with epilepsy: temporal lobe (n = 76), frontal lobe (n = 25), and primary generalized (n = 8). Each injected hemisphere for each patient was graded pass or fail for its ability to support memory. RESULTS: The percentages of hemispheres that failed the Amytal test were 31% for the temporal lobe group, 32% for the frontal lobe group, and 56% for the primary generalized group. CONCLUSIONS: The Amytal test may be a sensitive measure of memory dysfunction. However, the high percentage of failures remains at variance with the rare incidence of the amnestic syndrome, suggesting a low specificity for this test.

Effect of simultaneously ingested milk on phenytoin bioavailability.

Adverse gastrointestinal symptoms from milk may reduce the bioavailability of phenytoin. In a prospective crossover study, we studied the effect of simultaneous ingestion of phenytoin and milk in 12 patients with partial epilepsy and no adverse gastrointestinal symptoms. Serum phenytoin levels were measured at the start of the study and after 2 weeks. Patients then switched regimens, and a third phenytoin level was determined 2 weeks later. Serum phenytoin levels were similar for patients taking phenytoin with either milk or water.

Vagus nerve stimulation therapy for epilepsy in older adults.

The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

A new method of monitoring membrane potential in rat hippocampal slices using cyanine voltage-sensitive dyes.

A novel application of voltage-sensitive dyes is described. Hippocampal slices in vitro accumulated voltage-sensitive cyanine dyes under conditions presumed to cause depolarization and hyperpolarization. Increasing extracellular potassium caused a depression of dye uptake that correlated linearly with the membrane potential calculated from the Goldman equation. Veratrine depressed dye uptake, and this effect was blocked by addition of tetrodotoxin or removal of extracellular sodium. Ouabain also depressed dye uptake. Conversely, hyperpolarizing conditions using reduced extracellular sodium caused increased dye uptake. These results support a voltage-dependent mechanism for the uptake of cyanine dyes in hippocampal slices. Application of this phenomenon as an alternative to 2-deoxyglucose autoradiography for mapping neuronal activity will be presented.

In vivo mapping of drug-induced seizures with voltage-sensitive dye.

The voltage-sensitive dye diO-C2-5 was used to produce an in vivo map of the membrane potential in two types of seizures. Mild limbic seizures were induced in rats with kainic acid; clonic convulsive seizures were induced with bicuculline. Kainic acid animals showed various levels of neural depolarization during their seizures in limbic, thalamic, cortical, and brainstem sites. The bicuculline animals showed uniformly greater levels of neural depolarization during their seizures. The magnitude of these changes relative to controls varied across seizure models and reflected the different underlying neural mechanisms for each model. The ability of the technique to capture local electrical events provides a new tool in which to explore brain activity.

Evidence for an agonist independent down regulation of hippocampal muscarinic receptors in kindling.

Kindling induces a decline of hippocampal muscarinic cholinergic receptors. To test the hypthesis that the decline was mediated by the agonist, acetylcholine, adult male Sprague--Dawley rats were lesioned in the medial septum prior to kindling. Despite the marked destruction of presynaptic cholinergic terminals in the hippocampus, amygdala kindling proceeded normally and the hippocampal muscarinic receptor decline was not blocked. A small but significant decline in choline acetyltransferase activity was demonstrated in non-lesioned kindled rats. It is proposed that the kindling induced decline of hippocampal muscarinic receptors is mediated by repeated neuronal depolarization.

The effects of colchicine in mammalian brain from rodents to rhesus monkeys.

The injection of colchicine into rats and monkeys produced two different types of brain damage. At selected doses, intradentate colchicine preferentially destroyed DGC in rats, whereas damage was less selective and more severe in monkeys. Experiments were performed with different tubulin-binding drugs to investigate the structure-function relationship of tubulin binding and DGC death. The tubulin-binding characteristics of these and other drugs reported in the literature did not correlate with their ability to damage DGC. The role of seizure-induced cell death was investigated by recording the EEG in monkeys and in rats treated with phenobarbital. The data suggest that seizures are an infrequent epiphenomenon of colchicine's action. We proposed that colchicine is not a selective neurotoxin and that it causes brain damage by inducing a non-specific inflammatory response. This response is both dose- and species-dependent. We concluded by discussing the medical implications of the present and proposed uses of colchicine.

Electrolytic entorhinal lesions cause seizures.

The entorhinal cortex is a key site of interneuronal communication between a variety of cortical and subcortical areas and hippocampal formation. Lesioning the entorhinal cortex is commonly used in studies of the hippocampal formation, animal behavior and neuronal plasticity. We have found that electrolytic destruction of the entorhinal cortex consistently produces limbic seizure activity in rats. The propensity of lesions in this area for producing seizure activity may facilitate insights into the normal function of this network of neural connections. This unexpected phenomenon represents a potential confounding variable for all researchers using this method for making brain lesions.

Seizures down-regulate muscarinic cholinergic receptors in hippocampal formation.

Muscarinic cholinergic receptors (MCR) have been previously shown to decline in the hippocampal formation (HPF) of amygdala-kindled rats. Seizures have been proposed as the process responsible for this down-regulation. We now demonstrate similar down-regulation of MCR within HPF in 3 additional methods of inducing seizures: electroconvulsive shock, entorhinal kindling and entorhinal lesion. Two key parameters which causally link the MCR declines with seizures are their time course and reversal with anticonvulsants. The transient decline of MCR induced by entorhinal lesion-induced seizures parallels the time course established in amygdala kindling. Further, phenobarbital could block both these seizures and the MCR declines. Together, this supports the relationship of seizures causing the declines. We postulate that the MCR down-regulation represents an endogenous inhibitory response of neurons that are intensely and repeatedly depolarized during the seizures.

Benzodiazepine receptor declines in hippocampal formation following limbic seizures.

Electrolytic lesions of entorhinal cortex have previously been shown to consistently produce limbic seizures. We report a bilateral and symmetrical decline in benzodiazepine receptor number in dentate gyrus of the hippocampal formation in unilateral entorhinal cortex-lesioned animals. We think this decline is caused by seizures since phenobarbital pretreatment prevented the appearance of limbic seizures and blocked the receptor decline. We postulate that these receptor declines may contribute to decreased endogenous recurrent inhibition (a presumed GABAergic synapse) of dentate granule cells which could lead to their repetitive firing. Thus these benzodiazepine receptor declines may be a consequence of limbic seizures yet increase the likelihood of subsequent seizures.

Epilepsy surgery improves regional glucose metabolism on PET scan. A case report.

A patient with medically intractable complex partial epilepsy was evaluated for epilepsy surgery by electro-encephalograph recording with depth electrodes and 18F-fluorodeoxyglucose positron emission tomography (PET). A small calcified arteriovenous malformation was excised from the left parietal lobe, and the patient became seizure free. Baseline and language stimulation PET scans were obtained preoperatively and 10 months postoperatively. There was a significant increase in glucose metabolism of the left temporal lobe postoperatively, which we interpret as evidence of improved neuronal function. We suggest that this case represents evidence for a functional, and reversible, inhibition of neuronal metabolism by epileptic activity.

Xenon/CT cerebral blood flow studies during continuous depth electrode monitoring in epilepsy patients.

PURPOSE: To observe and describe cerebral blood flow (CBF) alterations immediately following depth electrode stimulation of the temporal lobe in patients with medically intractable epilepsy. MATERIALS AND METHODS: Five patients with partial epilepsy undergoing presurgical evaluation were chosen for xenon/CT cerebral blood flow (Xe/CT CBF) measurement immediately following electrically stimulated seizures via stereotactically placed temporal lobe depth electrodes. Each patient had a baseline Xe/CT CBF study. Four of the five patients had a total of seven temporal lobe stimulations each followed by a Xe/CT CBF study. The other patient had right temporal lobe electrical status epilepticus and was scanned without stimulation or electroencephalogram monitoring. RESULTS: Of the four baseline or interictal scans, no areas of abnormally low flow were detected, but one baseline scan had elevated flows of 115 mL.100 g-1.min-1 in the left temporal lobe. One stimulation elicited 8 seconds of afterdischarge potentials, but no alteration of CBF was detected. One stimulation elicited an aura but no electrographic seizure was detected. This resulted, however, in bitemporal lobe elevation of CBF. The other five temporal lobe stimulations resulted in 17-63 seconds of afterdischarge potentials and all resulted in elevation of CBF to 69-118 mL.100 g-1.min-1. One of these five stimulations resulted in seizure and localized elevation of CBF. Following seizure activity, elevated CBF began to return to baseline levels by 20 minutes. CONCLUSION: This study reveals a direct spatial and temporal relationship of elevated CBF with seizures. This study provides the most direct data to date in human subjects that focal seizure activity elevates CBF. Since seizures are known to increase metabolic activity in the activated tissue, this data also supports the assumption of coupling between CBF and metabolism during the pathologic process of a seizure.

Visual angle of the mind's eye before and after unilateral occipital lobectomy.

Do mental images occur in a spatially mapped (i.e., analog, or array-format) representational medium? Kosslyn's (1978) method was used to measure the visual angle of "the mind's eye" to estimate the extent of the imagery medium before and after unilateral occipital lobectomy. It was found that the overall size of the largest possible image was reduced following the surgery. In addition, only the horizontal extent, and not the vertical extent, of the imagery medium was reduced. Finally, it was determined that the S understood the tasks, was not aware of our predictions, and was unaffected by a strong demand characteristic in a different imagery task. These results are consistent with the hypothesis that imagery occurs in a spatially mapped representational medium dependent on occipital cortex.

Fluorescent voltage-sensitive dyes: applications for neurophysiology.

Voltage-sensitive dyes are a means to optically monitor changes in membrane potential. Their application in research has grown steadily over the last two decades as better dyes have been developed. The techniques presently in use are providing unique information about biologic systems from bacteria to the functional organization of primate occipital cortex. This review provides a history of the dyes, the data supporting their voltage sensitivity, and the techniques required for their use. The limitations in using and interpreting the voltage-sensitive dyes, as well as their diverse applications in all areas of research, especially neurophysiology, are comprehensively presented.

Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death.

Sudden unexpected death represents a significant cause of mortality in people with epilepsy. It derives this significance not because it is the most frequent cause of death but because it is apparently a direct consequence of a seizure. The implication is that epilepsy is an inherently lethal disorder. Seven patients who were studied in an epilepsy surgery program died a sudden unexpected death. This incidence of sudden unexpected death was five times higher than the 1-2/1,000 per year reported in the general epilepsy population. Sudden unexpected death shares some of the characteristics associated with sudden cardiac death, which kills 300,000 people in the United States each year. A cardiac arrhythmia, usually ventricular fibrillation, is the most common terminal event for sudden cardiac death and is the leading candidate as the mechanism for sudden unexpected death. Despite this knowledge, little is known on how to identify a high-risk group of patients for sudden death or how these deaths might be prevented.

Evaluation of the thiopental test in epilepsy surgery patients.

One hundred and three patients underwent a thiopental test during a presurgical evaluation for epilepsy surgery. Depth electrodes were implanted bilaterally into the mesial temporal and mesial frontal lobes. Thiopental was infused at 25 mg/30 s for adults and 0.3 mg/kg/20 s in children until loss of corneal reflexes or a total of 1 g. The absence of beta activity on the EEG, and activation of interictal spiking were two parameters monitored at all recording sites. Positive results were correlated with the anatomy of the ictal epileptic foci. Half of the patients produced increased interictal spiking and three-quarters of them showed absence of beta production in at least one lobe. Despite a reasonably high concordance between ictal foci and the two thiopental parameters, both measures yielded a low sensitivity and specificity. This work, as well as that reported in the literature, was unable to confirm the hypothesis that local damage within the temporal lobe was responsible for positive thiopental test results. An alternative hypothesis is proposed that the thalamus may be a distant source of these findings. Irrespective of the mechanism, the thiopental test must be used cautiously in the evaluation for epilepsy surgery.

Vagal nerve stimulation does not unkindle seizures.

The purpose of this study was to investigate a mechanism of action for the effect of vagal nerve stimulation on reducing seizures in patients with complex partial epilepsy. The hypothesis tested was that vagal nerve stimulation has an antikindling effect on epilepsy. The databases of two large clinical trials (E03, E05) were accessed, and statistical methods were applied using logarithmic transforms and regression analysis. Two parameters--duration of a patient's epilepsy before entering the clinical trial and the patient's seizure density before entering the clinical trial--were used as markers of subsequent seizure control during vagal nerve stimulation. In general, there was not a good fit to the regression lines, and the slope of the lines did not conform to the hypothesis. The hypothesis that vagal nerve stimulation may unkindle epileptic seizures was not supported.

Anesthetic implications of epilepsy, status epilepticus, and epilepsy surgery.

Epilepsy is a clinical paroxysmal disorder of recurring seizures, excluding alcohol or drug withdrawal seizures or such recurring exogenous events as repeated insulin-induced hypoglycemia. Epilepsy has a profound impact on each individual diagnosed with this disease. Seizures have been and are thought to arise as a result of abnormalities in (a) neural circuits, (b) excitation/inhibition balance, (c) potassium, and (d) genetic abnormalities. Therapy for epilepsy is either medical, entailing the use of a variety of antiepileptic drugs, or surgical. An urgent approach to seizure control is indicated when status epilepticus occurs. When all standard therapy fails, general anesthesia can be used to control status epilepticus. Surgery is an option in the treatment of epilepsy and requires extensive preoperative evaluation. The primary concerns for the neuroanesthesiologist anesthetizing the patient with epilepsy are the capacity of anesthetics to modulate or potentiate seizure activity and the interaction of anesthetic drugs with antiepileptic drugs. Proconvulsant and anticonvulsant properties have been reported for nearly every anesthetic. If seizure spikes are to be evoked during seizure surgery, then light anesthesia with a proconvulsant anesthetic is used. Conscious analgesia can be used for awake seizure surgery. However, if electrocorticography is not planned, then a general anticonvulsant anesthetic maintenance regimen is used. The latter technique also may be useful in patients whose anesthetic management is complicated by an incidental history of epilepsy.