Non-epileptic Control Research Articles

Responsiveness of genetically epilepsy-prone rats to intracerebroventricular morphine-induced convulsions

The sensitivity of intracerebroventricular morphine-induced convulsions was determined in members of the severe seizure (GEPR-9) and moderate seizure (GEPR-3) colonies of genetically epilepsy-prone rats as well as in non-epileptic control rats. GEPR-9s were more sensitive to morphine-induced wet-dog shakes, rearing with bilateral forelimb clonus and generalized clonus than controls or GEPR-3s. GEPR-3s were less sensitive to morphine-induced wet-dog shakes and rearing with bilateral forelimb clonus than controls. Both high and extremely low doses of morphine in GEPR-9s elicited tonic extensor convulsions resembling the characteristic sound-induced convulsion of GEPR-9s. The results suggest that opiotergic systems may contribute to the pathophysiology of the seizure-prone condition in GEPR-9s. Further, differences in responsiveness of opiotergic systems in GEPR-3s and GEPR-9s may partially account for differences in seizure severity in the characteristic sound-induced seizures of these two types of GEPRs.

Nocturnal plasma prolactin and cortisol levels in epileptics with complex partial seizures and primary generalized seizures.

The nocturnal pattern of plasma prolactin (PRL) and cortisol in male epileptics with complex partial seizures and primary generalized seizures was studied by all-night polygraphic recordings with continuous video monitoring and sequential blood sampling at 30-minute intervals. Mean nocturnal plasma PRL concentrations in both groups of epileptics were significantly elevated when compared with nonepileptic control subjects studied in a similar fashion. Eight subclinical and three clinical partial seizures were recorded during sleep. Although a tenfold increase of plasma PRL level occurred following a short brief clinical complex partial seizure, there was no direct correlation between single subclinical partial seizures and nocturnal fluctuations of plasma PRL concentrations. We did not observe recognizable plasma cortisol changes following partial seizures during sleep, nor significant differences of mean nocturnal plasma cortisol levels between epileptics and controls. The data obtained in this environmentally controlled study indicate that postictal elevation of plasma PRL is a specific phenomenon related to seizure discharges; however, failure of such a rise does not exclude partial seizures.

Sleep studies in benign epilepsy of childhood with rolandic spikes. I. Sleep pathology.

Polygraphic all-night sleep records of 11 children with typical benign epilepsy of childhood with rolandic spikes (BERS) and those of eight nonepileptic controls were investigated with regard to sleep pathology. Basic properties of sleep organization and electromorphology were preserved in both groups. Seventeen quantitative sleep parameters were measured. Except for more waking in the BERS group, no sleep parameter showed significant differences between the BERS and the control group, but differences existed in comparison to normative values. We interpret our results as showing that in BERS epileptic neuronal malfunctioning does not affect sleep organization in a characteristic manner. The lack of detrimental interactions between epileptic neuronal behavior and pathological sleep alterations may be an additional cause of the benign course of BERS.

Effect of interictal epileptiform discharges on nocturnal plasma prolactin concentrations in epileptic patients with complex partial seizures.

To investigate the effect of interictal epileptiform discharges (IEDs) on plasma prolactin (PRL) level, we studied 18 epileptic patients with complex partial seizures (CPS) who did not experience clinical or subclinical ictal events during all-night monitoring with polygraphic recording and video imaging. The density of IEDs peaked during non-REM stages and was significantly reduced during REM stage. Mean plasma PRL concentrations in epileptic patients, when sampled at 30-min intervals, showed a moderate but significant elevation during non-REM (p less than 0.001) and awake stages (p less than 0.005), but not during REM stage, when compared with 10 nonepileptic control subjects studied in a similar fashion. The data obtained in this physiologically controlled environment indicate that the cumulative effect of IEDs may modify PRL regulatory mechanisms, resulting in a modest elevation of plasma concentrations independent of ictal discharges.

Indices of noradrenergic function in the central nervous system of seizure-naive genetically epilepsy-prone rats.

Norepinephrine concentrations and tyrosine hydroxylase activity were determined in the brains of moderate-seizure and severe-seizure genetically epilepsy-prone rats (GEPRs) and in nonepileptic control rats. Both moderate-seizure (GEPR-3) and severe-seizure (GEPR-9) animals had widespread abnormalities in brain norepinephrine concentrations. Abnormalities in tyrosine hydroxylase activity were restricted to the midbrain. The state of abnormal seizure susceptibility, but not severity, in the GEPR may be determined by noradrenergic deficits in the hypothalamus/thalamus. Both seizure severity and susceptibility may be determined by noradrenergic deficits in the telencephalon, midbrain, and pons-medulla. Seizure severity but not susceptibility may be determined by noradrenergic abnormalities in the cerebellum.

IX. The development of kindled seizures is accelerated in the genetically epilepsy-prone rat

The kindling phenomenon was examined in genetically epilepsy-prone (GEPR) and non-epileptic control Sprague-Dawley rats. Kindling stimulations were administered three times a day until each rat had exhibited three Class 5 kindled motor seizures. The mean total number of kindling stimulations required for each experimental group to exhibit three motor seizures of each motor seizure class was determined. The results indicated that the early stage of kindling development was accelerated significantly in both the GEPR-3 and GEPR-9 rats, compared to non-epileptic control rats. Later stages of kindling development were accelerated in GEPR-9 but not GEPR-3 rats. Thus a differential acceleration of kindling development was exhibited by GEPR-3 and GEPR-9 rats. The results suggest the possibility that some brain region(s) involved in the early stage of kindling development may be hyperexcitable in both GEPR-3 and GEPR-9 rats. Other brain region(s) involved with the later stages of kindling development may be more excitable in GEPR-9 rats. These putative alterations may, in part, contribute to the seizure prone state of GEPR rats and the differential seizure responses of GEPR-3 and GEPR-9 rats.

Stability of alpha-1 adrenoceptors in surgically excised human brain

Alpha-1 adrenoceptor sites were measured in membranes prepared from nonepileptic superficial cortex following temporal lobectomy for lesions in deep medial structures. There was no significant change in receptor density (Bmax) or affinity (Kd) when paired samples were either frozen immediately or kept at room temperature for 24 hours before freezing and storage at −70°C. Regional variability in the Bmax or Kd of alpha-1 adrenoceptor binding was not observed in serial samples from lateral temporal cortex. We previously reported a localized decrease in alpha-1 adrenoceptors in epileptic foci when compared to adjacent nonepileptic tissue obtained from the same patient. As nonepileptic control tissue from an adjacent gyrus is frequently not available in the same specimen, the stability of alpha-1 adrenoceptors justifies the use of postmortem brain for comparative studies.

Angular bundle kindling is accelerated in rats with a genetic predisposition to acoustic stimulus-induced seizures

Limbic kindling was examined in genetically epilepsy-prone (GEPR) and non-epileptic control rats. The early stage of kindling development was accelerated in both groups of GEPR rats compared to controls. Later stages of kindling were accelerated in GEPR-9 but not GEPR-3 rats. These results indicate that GEPR rats have an enhanced susceptibility to limbic kindling and suggest that limbic brain alterations may contribute to acceleration of the early stage kindling development in GEPR rats.

Influence of reduced oxygen availability on cerebral metabolic changes during bicuculline-induced seizures in rats.

The objective of the present work was to study cerebral energy metabolism at threshold levels of hypoxia, i.e., degrees of hypoxia that abolish cerebral electrical activity, in the "normal" and in the epileptic brain. Seizures were induced by intravenous bicuculline and cerebral oxygen availability was reduced by a combination of lowered PO2 and reduced blood pressure to give a transformation of the burst suppression pattern to either one with single spikes or overt EEG flattening. Nonepileptic control animals were exposed to degrees of hypoxia that gave either a markedly depressed EEG pattern with sparse slow waves or EEG flattening. Epileptic and nonepileptic groups proved comparable in terms of calculated oxygen availability and cerebral oxygen consumption at the threshold of "transmission failure." At levels of hypoxia that markedly attenuated or completely abolished seizure discharge, the cerebral metabolic changes were more marked than in comparable nonepileptic animals. These changes comprised an imminent severe perturbation of cerebral cortical phosphorylation potential, a pronounced lactic acidosis with a precipitous redox change, and a marked accumulation of ammonia. The more labile energy balance of the epileptic brain may indicate that the "seizure state" either increases cellular energy demands in spite of the electrical silence or reduces the efficiency of ATP production at the prevailing oxygen availability. It is conceivable that energy failure elicited by complicating hypoxia can aggravate or precipitate brain cell damage in epilepsy.

Obstetric outcome in women with epilepsy

A comparison of 150 pregnancies in women with epilepsy and 150 pregnancies in matched nonepileptic control women showed similar rates of pregnancy-induced hypertension, albuminuria, premature contractions, premature labor, and bleeding in pregnancy. Duration of labor, blood loss at delivery, cesarean section rates, and vacuum extraction rates were also similar among epileptic and control groups. There were five perinatal deaths in the epileptic group and two in the control group. A fetal heart rate tracing during a maternal grand mal seizure showed bradycardia, reduced short-term and long-term variability, and late decelerations suggesting asphyxia. It is concluded that grand mal seizures during pregnancy should be avoided by the use of antiepileptic drugs. Women with epilepsy require antenatal neurological and obstetric follow-up during pregnancy.

Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation.

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 epileptogenesis 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.

5-HIAA in cerebrospinal fluid of patients with status epilepticus.

Cerebrospinal fluid concentration of 5-hydroxyindolacetic acid (5-HIAA) was determined in 15 patients soon after recovery from status epilepticus. Similarly, patients with generalised epilepsy and persons without epilepsy, serving as controls, were also studied. The level of 5-HIAA was significantly reduced in all epileptic patients with or without status epilepticus, as compared with the nonepileptic control group. However, there was no statistical difference between patients with status epilepticus and those with generalised epilepsy. Among patients with epilepsy, low 5-HIAA levels in CSF could not be correlated with frequency or severity of seizures, or with antiepileptic drugs. A link between CSF 5-HIAA and susceptibility of humans to epilepsy may indicate a possible future therapeutic approach.

Influence of systemic factors on experimental epileptic brain injury. Structural changes accompanying bicuculline-induced seizures in rats following manipulations of tissue oxygenation or alpha-tocopherol levels.

A previous study from the laboratory showed that status epilepticus induced by bicuculline administration to ventilated rats produced astrocytic swelling and nerve cell changes ("type 1 and 2 injury") particularly in layers 3 and 5 of the neocortex (Söderfeldt et al. 1981). The type 1 injured neurons were characterized by condensation of cyto- and karyoplasm and the less common type 2 cells were characterized by swelling of endoplasmic reticulum including the nuclear envelope. In the present study we explored whether changes in cerebral oxygen availability altered the extent or character of the cellular alterations. Animals with 2 h of status epilepticus were made either hyperoxic (administration of 100% O2), hypoxic (arterial pO2 50 mm Hg) or hypotensive (arterial blood pressure of either 70-75 or 50 mm Hg). Furthermore, we explored whether "oxidative" damage occurred by manipulating tissue levels of alpha-tocopherol, a known free radical scavenger. Non-epileptic control animals exposed to comparable degrees of hypoxia or hypotension showed no or minimal structural alterations. In the epileptic animals the results were as follows. Hyperoxia did not change the quality or extent of the structural alterations previously observed in normoxic epileptic animals. Neither administration nor deficiency of vitamin E did modify this pattern of alterations. In hypoxia the extent of cell damage was the same or somewhat larger than in normoxic, epileptic animals. In addition, neurons often showed cytoplasmic microvacuoles due to swelling of mitochondria. The hypoxic animals also showed swelling of astrocytic nuclei with clumped chromatin. Changes similar to those observed in hypoxic animals also appeared in moderate hypotension (mean arterial blood pressure 50 mm Hg), whereas mild hypotension (70-75 mm Hg) did not change the character of the tissue injury from that seen in hyperoxic or normoxic epileptic rats. The present results demonstrate that the neuronal cell damage that can be observed when the brain is fixed by perfusion after status epilepticus of 2 h duration is not exaggerated by hyperoxia or vitamin E deficiency nor is it ameliorated by a moderate restriction in cerebral oxygen supply or by vitamin E administration. If anything, hypoxia (or moderate hypotension) appears to increase the extent of damage and it clearly alters its ultrastructural characteristics. However, although the results fail to support the notion that epileptic cell damage is "oxidative", definite conclusions must await information on the cell damage that remains upon arrest of the epileptic activity.

Epilepsy and the concentrations of plasma amino acids in humans

We have examined the correlation between the presence of epilepsy in humans, and plasma amino acid levels. Subjects were divided into those having pure generalized tonic-clonic seizures (grand mal group), those having generalized tonic-clonic seizures plus other types of epilepsy (mixed group), and those suffering from epilepsies other than grand mal (no grand mal group). Compared to non-epileptic controls, the grand mal group had significantly higher fasting plasma levels of aspartate (100% increase) and glutamate (380% increase) but significant decreases were seen with phenylalanine (?23%), lysine (?27%), and tryptophan (?30%). The no grand mal group showed similar changes except for lysine. The mixed group showed elevations in glutamate, but decreases only in cysteine and methionine. In response to a high protein meal, plasma levels of alanine, cysteine and methionine rose significantly less for the no grand mal group compared to the control group. Increases in aspartate and glutamate concentrations strongly correlated with the prescription of phenytoin. However, the concentrations of these amino acids were not significantly correlated with the actual plasma levels of phenytoin.

Fetal hydantoin syndrome: Current status

IN THE 70 YEARS since the introduction of the first anticonvulsant, phenobarbital, a large and diverse group of drugs has been developed to control seizures. Among the most efficacious and widely used of these agents is phenytoin (Dilantin, hydantoin), an agent in clinical use for more than 40 years. It has been estimated that two million patients in the United States receive phenytoin on a long-term basis/ Extensive literature exists regarding the magnitude of risk for fetal abnormality in the offspring of mothers with convulsive disorders. In all of these epidemiologic studies, the frequency of abnormalities in the offspring of treated epileptic women has exceeded that for offspring of normal (nonepileptic) controls (Table). 2~6 In most cases this difference has been statistically significant, with relative risk estimates ranging from 2 to 3. Unfortunately, sample sizes in these studies have been marginal for any reliable conclusions to be madeJ 6 In all studies, sample sizes have been insufficient to allow stratification by more than a few maternal Or paternal variables, and all combinations of drug therapy or convulsive disorders have been analyzed together. Consideration of the dosage and timing of drug exposures has not been specified. Epidemiologic studies have thus far failed to answer the question: Is the risk for congenital abnormalities in the offspring of treated epileptic women related to drug therapy or to the underlying convulsive disorder or genetic factors? Two areas of study suggest that a portion of the increased risk may be attributable to drug therapy. As illustrated in the Table, in retrospective studies the frequency of abnormality in the offspring of treated epileptic women is consistently greater than in the offspring of

Left and right temporal lobe epileptics: a controlled investigation of some psychological differences.

Twenty-two young adults with clinically and electroencephalographically diagnosed temporal lobe epilepsy were selected from an outpatient neurology source; 11 with focal epileptic activity in the right temporal lobe and 11 with left temporal lobe involvement were included. All patients had normal intelligence and comparable educational and socioeconomic backgrounds. Matched nonepileptic controls were also tested. Subjects were given psychological tests assessing differences in cognitive style and affect communication. Greater reliance on the ear ipsilateral to discharge focus in a dichotic listening paradigm was discovered, confirming appropriate lateralization assignment. Left lateralized patients exhibited a more reflective cognitive style than controls; right lateralized patients were more impulsive. Previously confirmed associations between impulsivity and externalized aggressive responses suggest the hypothesis that externalization of aggressive responses may occur more often among right lateralized patients. Left lateralized patients exhibited a more reflective cognitive style than controls; right lateralized patients were more impulsive. Previously confirmed associations between impulsivity and externalized aggressive responses suggest the hypothesis that externalization of aggressive responses may occur more often among right lateralized patients. Left lateralized patients made more atypical assignments of affect labels to emotionally evocative descriptions. Right laterlized patients tended to assign affect labels as controls. A greater potential for disturbance in the verbal communication of affect among left laterlized patients is suggested.

Diphenylhydantoin (dilantin) gingival hyperplasia: drug-induced abnormality of connective tissue.

Various degrees of gingival overgrowth may occur in individuals taking diphenylhydantoin, a drug used widely in the treatment of epilepsy. The tissue overgrowth is made up predominantly of collagen, and may therefore be a useful model for analysis of fibrosis and some other connective tissue abnormalities. Fibroblasts derived from the overgrown tissue exhibit a level of protein synthetic activity approximately twice that of comparable cells obtained from nonepileptic control individuals and from the gingiva of age-matched epileptics taking the drug but not exhibiting gingival enlargement. In addition, 20% of the protein synthesized by cells from the affected tissue is collagen, whereas collagen accounts for only about 11% of the total protein produced by control cells of both types. The drug appears to induce or select for fibroblasts characterized by enhanced levels of protein synthesis and collagen production. This alteration persists through several cell replications in vitro in the absence of drug.

Significance of Purkinje cell density in seizure suppresion by chronic cerebellar stimulation.

Cerebellar biopsy specimens were obtained at the time of cerebellar electrode installation in three epileptic patients. Cerebellar autopsy specimens also were examined from four epileptic patients and from five patients without epilepsy or neurologic disease. All specimens from seizure patients showed isomorphic gliosis of the cerebellar cortices. Significantly lower Purkinje cell densities were found in epileptic patients as compared with nonepileptic control patients. Our two epileptic patients showing marked Purkinje cell loss before cerebellar stimualtaion appeared to have better seizure control during stimulation than the patient who had only mild reduction in Purkinje cell density. These data suggest that augmentation of Purkinje cell inhibitory discharges in not the dominant mechanism for seizure suppression during cerebellar stimulation. Comparison of cerebellar specimens obtained during electrode installation with those obtained later during electrode revisions may have been prognostic significance.

Human epileptic brain Na, K ATPase activity and phenytoin concentrations.

An abnormal flux of monovalent cations may be related to the epileptogenic process in man. One possible mechanism for deranged electrolyte metabolism in epileptic brain is an abnormality in sodium, potassium-dependent adenosine triphosphatase (Na, K ATPase). We found the activity of Na, K ATPase to be significantly less in epileptic human corfex than in nonepileptic cortex. Histological changes have been simultaneously evaluated in epileptic brain. A second membrane-bound enzyme, acetylcholinesterase (AChE), was also assayed as a marker for neuronal membranes and found not to correlate with the epileptogenicity of human brain. In addition, the concentrations of the anticonvulsant compound phenytoin have been determined in the serum and cerebral cortex of epileptic and nonepileptic patients. The ratio of phenytoin in cortex to serum concentration is significantly lower in epileptic patients than in nonepileptic controls.

Glutamic Acid and its Salts inPetit MalEpilepsy

The following experiments on glutamic acid were carried out in view of the conflicting reports of Price, Waelsch and Putnam (1943), Waelsch and Price (1944), and Goodman et al. (1948) on its effect in epilepsy. A number of preliminary experiments were made which suggested that there was an apparent difference between the effects of glutamic acid and sodium glutamate. Such a difference does not appear to have been considered by most other investigators. It was decided therefore to try to determine whether a possible reason for the difference was the effect of the sodium ion on water balance, since this is known to be related to the tendency to seizures (McQuarrie et al., 1932, Swinyard et al., 1946, and Weinland, 1949). For comparison potassium glutamate was given in a way to be described below. The experiments will be reported under the following headings:1.The acute E.E.G. and clinical effects of intravenous sodium glutamate.2.The short term (one week) E.E.G. and clinical effects of glutamic acid, its sodium and potassium salts and a placebo.3.Longer term clinical effects in out-patients.4.Biochemical studies of the blood and urine levels of glutamic acid by paper chromatography of 7 epileptic patients and 5 non-epileptic control subjects, including salt and water balance studies of patients and controls.