Moderate hyperhomocysteinemia in patients treated for epilepsy.

Homocystein (Hcy) is regarded as a neuroexcitatory substance, which is therefore used as an epileptogenic agent in experimental epileptology. Experiments "in vivo" as well as "in vitro" revealed its relation to NMDA glutamate receptors, and its potential neurotoxicity. From the clinical aspect, hyperhomocysteinemia (HHcy), mostly as a marker of the risk factor in the vascular damage, was often studied in patients treated with antiepileptic drugs (AE). However, the neuroexcitatory influence of mild HHcy (up to 30 micromol/l) was rarely discussed. Out of a group of 123 adult patients on long-term conventional AE we analyzed 8 patients (7 men and one woman) with moderate to severe HHcy (30.7-109.0 micromol/l) retrospectively and 2-5 years after HHcy normalization. All of them suffered from partial and/or secondary generalized seizures accompanied by neuropsychological impairment depending on the aetiology of the disease. The patients were characterized by a concurrence of several factors: (1) All of them received conventional AEs inducing the cytochrome P 450 at the time HHcy was diagnosed. (2) Molecular-genetic tests showed enzymopathic impairment (methylentetrahydrofolate reductase-MTHFR mutation of the gene C677 T) also in all eight, homozygous in 7 cases and heterozygous in 1 case. (3) All patients were found to have a vitamin deficit or marginal values of at least one of the vitamins under study, especially folate and/or vitamin B6 and 812. With reference to clinical and EEG features, the potential neuroexcitatory influence of Hcy is discussed taking into account its effect on pathogenetic factors.

Phenytoin as a risk factor in gingival hyperplasia.

Fifty-four out-patients with epilepsy who had been taking phenytoin for more than one year were examined for gingival hyperplasia. Approximately 76% of patients showed either mild or no gingival hyperplasia. Lesion severity was then compared statistically to phenytoin dosage and drug concentrations as well as to other clinical and laboratory parameters. There was a tendency for gingival hypertrophy to be associated with both increasing dosage of phenytoin per unit of body weight and the duration of phenytoin administration. All patients followed had a statistically significant progressive trend to increasing gingival hyperplasia with higher total and free phenytoin concentration.

[Epilepsy and intelligence. II. Correlation among 13 variables]. / Epilepsie a inteligence. II. Korelace ke trinácti promenným.

In a group of 215 ambulatory adult patients the authors assessed links with full-scale IQ, verbal IQ, performance IQ and different Wechsler-Bellevue sub-tests. They revealed marked correlations in particular with the frequency of grand mal seizures, invalidity and the onset of the disease. More important than the close correlation of IQ and education is the finding that an earlier onset of the disease markedly reduces the opportunities of good education. Less marked but still significant are correlations with the known aetiology of the disease, the duration of the disease, the frequency of other seizures than grand mal and the course of the disease. Dramatically increased correlations with the frequency of other seizures than grand mal were recorded in a sub-group of 77 men whose data on the disease can be considered valid (in WPSI, the Washington Psychosocial Seizure Inventory, values of scale L within the range of 0-3). No marked correlations were found with seizures in relatives. The position of bachelors is often adverse also as far as intellectual performance is concerned. Patients with a history of contact with psychiatry have lower intellectual performance. Patients who admit subjective needs of psychiatric or psychological assistance have a markedly better performance. It is probable that rehabilitation procedures which improve the collaboration and adherence to the therapeutic regime, in particular as regards taking prescribed drugs may promote also better cognitive performance.

[Epilepsy and intelligence. I. Intellectual status in a group of 215 ambulatory patients]. / Epilepsie a inteligence, I. Intelektová úroven v souboru 215 ambulantních pacientu.

A group of 119 men and 96 women, mean age 32.8 years, with a mean onset of the disease at the age 13 years was examined by Wechsler's intelligence test for adults (Wechsler-Bellevue). They assessed the mean intellectual level, total IQ mean = 104.4, s = 15.3. The intellectual performance of female patients had roughly a normal distribution, in men it was shifted slightly to higher zones. The mean absolute difference of the verbal IQ and performance IQ was mean = 8.4, s = 7.0, median = 7. The results are consistent with some more recent data in the literature on good intellectual abilities of the majority of epileptic subjects. The authors discuss the causes of frequent erroneous ideas of laymen and health professionals on an association of epilepsy and intellectual inadequacy. Among others there persists prejudice, problems of patients as regards memory, problems in the psychosocial sphere, psychopathological manifestations, adverse side-effects of drugs, sequelae of transient impairment of consciousness manifested clinically by short-term reduced performance. Real impairment of epileptic patients are assessed best by special neuropsychological methods, however, evaluation of intellectual abilities is necessary.

[Binding of phenytoin to serum albumin in vitro and in vivo]. / Studium vazby fenytoinu na sérový albumin v podmínkách in vitro a in vivo.

The present paper describes an ultrafiltration method of determination of the concentration of free phenytoin (DPH) in serum and its use for the study of the binding equilibrium phenytoin--albumin. The procedure was employed to determine the binding affinity of serum albumin (a) in a group of healthy volunteers (n = 8) in in vitro conditions, (b) in a group of healthy volunteers (a mixed serum, n = 6) and (c) in a group of patients suffering from epilepsy with fits of the generalized type grand mal (n = 15) in in vivo conditions. The calculation of binding parameters was carried out by the method of nonlinear regression analysis with the use of the one-parameter Scatchard's model of the bond. Binding activity of serum albumin in the volunteers of group (a) was N.Ka = 17,500 l/mol, group (b) N.Ka = 18,700 l/mol, and in patients with epilepsy n.Ka = 19,200 l/mol. The results of covariational analysis demonstrated good agreement in the binding parameters of all three groups under study. The paper also discusses the suitability of the binding model used and the mathematical processing and possible use of the binding parameters measured in in vitro conditions for the estimation of the value of the free fraction of the drug in patients with epilepsy.

[Epilepsy and rehabilitation using psychological methods (psychotherapy)]. / Epilepsie a rehabilitace psychologickými prostredky (psychoterapií).

41 subjects (39 patients and two mothers) participated in 1983-1988 in group psychotherapy for ambulatory adult patients focused on psychosocial problems and questions of the therapeutic regime. According to the independent evaluation by the attending physician the individually outlined goal was achieved in 38% of the patients. 31% of the patients left without a special effect, however, participation in the group meant probably a certain enrichment of their life. Another 31% of the patients had a negative attitude to participation in the group. Successful patients attended much longer, had a significantly higher verbal IQ and all responded reliably in Washington's psychosocial seizure inventory--WPSI. Conversely, 27% of the other patients gave invalid responses to WPSI. Psychological procedures should be part of a wider scale of rehabilitation approaches to epilepsy, including occupational rehabilitation and club activities.

[Initial experience with the Czech version of the Washington Psychosocial Seizure Inventory]. / První zkusenosti s ceskou verzí Washingtonského psychosociálniho dotazníku pro záchvatová onemocnení (WPSI).

The Czech version of the Washington psychosocial questionnaire for paroxysmal diseases (WPSI) was presented to 100 ambulatory patients selected at random at the Regional Clinic for Paroxysmal Diseases in Prague (55 men, 45 women). The results are compared with data in the literature on samples from other countries; the Czech sample has mostly median values. Comparison of the sub-groups of the Czech group revealed differences by sex (women had more problems in the scale of family background, men in the scale of vocational adjustment), by the duration of the disease (with a shorter duration of the disease greater financial difficulties were associated), and by the neurologist's evaluation of the development of the disease (on the whole patients with a favourable development of the disease had significantly more often a high score of the lie scale-40.5%). Those patients with a favourable development of the disease who had the score of the lie scale in the normal range had greater difficulties with interpersonal adaptation and adaptation at work than patients with an adverse development of the disease.

Effect of isatin (2,3 dioxoindoline) on physiological and pathological electrographic manifestations and vigilance.

The effect of various doses (40--160 mg/kg) of isatin (2,3-dioxoindoline) on electroencephalographic manifestations of vigilance, groups of rhythmic discharges (episodes) and the incidence of epileptiform pathological activities was studied in repeated chronic experiments on rats with implanted cortical and subcortical electrodes. After all the given doses of isatin the proportion of slow-wave sleep diminished and its onset was delayed (especially REM sleep) and the amount of quiet wakefulness increased. There were more spontaneous rhythmic episodes and their rhythm slowed down. In some cases large doses of isatin produced short groups of discharges without any motor signs; sometimes the episodes changed to epileptic activity composed of spike-wave complexes (2--3 Hz), accompanied by clonic jerks.

Effect of pentobarbital on thalamo- and hippocampocortical processes in rats.

Experiments were carried out on 28 rats immobilized with d-tubocurarine. The effect of three successive doses of pentobarbital (PB--5, 15 and 40 mg.kg-1) on electrocorticographic manifestations (evoked responses, the rhythmic afterdischarge and barbiturate spindles, the self-sustained afterdischarge--SSAD) elicited by electrical stimulation of two thalamic nuclei with a different type of control projection and the hippocampus (CA3) was compared. We found no difference between the effect of PB on cortical electrographic manifestations elicited by stimulation of the dorsomedial part of the ventral nucleus (VDM) and the anterior lateral nucleus (LA) of the thalamus. Cortical responses elicited by stimulation of the hippocampus were heterogeneous and the effect of PB on them was smaller than on thalamocortical responses. Reduction of the hippocampocortical SSAD was likewise not significant until the deepest stage of barbiturate anaesthesia.

Two types of epileptic cortical after-discharges evoked by the stimulation of the hippocampus and thalamic nuclei in rats.

Rhythmic cortical phenomena were evoked by stimulation of hippocampus and/or thalamus in rats. Electrical stimulation of thalamic nuclei (nc. ventralis dorsomedialis VDM and nc. lateralis anterior--LA) by single pulses elicited rhythmic after-discharge ("spindle") as a late component of the cortical response, whereas identical stimulation of hippocampus did not trigger such an activity. Rhythmic stimulation of thalamic nuclei elicited cortical incremental responses more often than stimulation of hippocampus. Epileptic self-sustained after-discharges (AD) occurred after the endo of rhythmic stimulation in 66% of hippocampal stimulations, in 35% of VDM stimulations and in 30% of LA stimulations. AD evoked by stimulation of the hippocampus (long duration discharges of slow serrated waves) differed characteristically from AD following stimulation of the VMD (short duration spike and wave complexes). Stimulation of the LA in half of the cases led to the "hippocampal" pattern of serrated wave after-discharges, in the remaining cases spike-and-wave complexes or a combined AD pattern was recorded.

Effect of isatin (2,3-dioxoindoline) on audiogenic seizures in rats and its relationship to electrographic and behavioural phenomena.

In doses of 160 and 80 mg/kg, isatin (2,3-dioxoindoline) significantly reduced the total incidence of audiogenic epileptic seizures in rats highly sensitive to an acoustic epileptogenic stimulus. The number of severest forms of seizure (running, clonic convulsions) was higher than in the control tests, however. The acoustic epileptogenic stimuls was applied one hour after the i.p. injection of isatin. At that time some postural reflexes were still inhibited after 160 mg isatin/kg, while after smaller doses they were already normal again. One hour after administering isatin there were marked changes in the electroencephalogram, the chief ones being an increase in rhythmic episodic activity against a desynchronization background and a decrease in slow wave sleep activity.

The relationship between vigilance and cortical EEG manifestations after electrical stimulation of the thalamus and hippocampus in unrestrained rats.

The thalamus or hippocampus of unanaesthetized rats with impaired cortical and subcortical electrodes was stimulated with rhythmic series of electrical pulses of 3--15/sec frequency. In both cases, stimulation either did not affect vigilance, or led to a higher degree of wakefulness. The incidence of recruiting responses (RR) and of self-sustained afterdischarges (SSAD) evoked by stimulation of the thalamus was not correlated to the preceding state of vigilance. In stimulation of the hippocampus, a significantly higher incidence of SSAD was found in the quiet waking state. The correlation between the elicitation of RR and SSAD was also significantly the highest after stimulation of the hippocampus during wakefulness.

The influence of pentobarbital upon a cortical epileptogenic focus in rats.

Three subsequent doses of pentobarbital (5, 15, and 40 mg/kg) were applied intraperitoneally in acute experiments in rats with a cortical epileptogenic focus. Histograms of intervals between individual focal discharges were shifted towards longer intervals even after the smallest dose of pentobarbital; the prolongation of intervals was clearly visible after the third dose also in the EEG recording. Shape of primary as well as projected cortical focal discharges after pentobarbital resembled that seen after local application of GABA. Barbiturate spindles which were present after the first and second dose of pentobarbital were regularly triggered by focal discharges. The mechanism of this triggering was probably a thalamocortical one, because marked projected discharges were recorded from various thalamic nuclei from the very beginning of focal activity.

Activation of epileptic electrographic phenomena in the human EEG by nasal air flow.

The activating effect of deep oral breathing (with the nose closed) and nasal hyperventilation (with mouth closed) was examined in 62 patients with three different kinds of epileptic EEG abnormalities: unilateral localized temporal (fronto-temporal, occipito-temporal) abnormalities - group F, bilateral episodic theta-delta abnormalities - group TH, and bilaterally synchronous spike and wave abnormalities - group SW. Nasal hyperventilation was much more effective in group F and TH. Its effect was already significant 30-60 seconds after the start of deep breathing. In the group SW there were no statistically significant differences between the effects of nasal and oral hyperventilation. Unilateral nasal hyperventilation (the other nasal cavity being closed by tamponade) demonstrated a more pronounced activating effect on ipsilateral localized temporal EEG abnormalities. These effects of deep nasal breathing can hardly be explained by metabolic-vascular mechanisms, which probably are involved in the course of oral hyperventilation. On the other hand they are in agreement with animal experiments demonstrating that the mechanical stimulus of nasal air flow operates as a synchronizing impulse for certain rhinencephalic structures.

Stimulation of the thalamus and its effect on electrographic manifestations of the brain in unrestrained rats.

The thalamus was electrically stimulated in unrestrained rats with implanted cortical and subcortical electrodes. Single pulses often triggered rhythmic cortical activity identical with the 8--9/sec spike episodes which occur spontaneously in rats in the walking state. In rhythmic stimulation of the thalamus, self-sustained 3/sec spike-wave paroxysmal activity, with partial clonic jerks, was observed. Specific and non-specific thalamic nuclei participated in the production of these activities.

Stimulation of the hippocampus and its effect on electrographic manifestations of the brain in unrestrained rats.

The dorsal hippocampus was electrically stimulated in unanaesthetized, unrestrained rats with a cobalt-gelatin rod in their cortex. The significance of the hippocampus in the elicitation of both physiological spontaneous rhythmic activity (episodic activity of 8--9/sec frequency bound, in rats, to a state of quiet wakefulness, and "sleep spindles") and pathological rhythmic activity of the self-sustained after-discharge (SSAD) type was determined from the aspect of the EEG and behavioural characteristics. 1. Single electrical pulses (0.1 msec, 1--10 V, 0.3/sec) elicited an evoked potential bilaterally in the somatosensory cortex. Elicitation of rhythmic after-activity (of the type of episodes or sleep spindles) was observed only in some cases in which an adequately strong stimulus was used. 2. Repeated series of rhythmic electrical stimuli following each other at short intervals (2--3 min) led to the formation of SSAD in about one third of the cases and at all stimulation frequencies (3-15/sec), although low frequencies (3--4/sec) were the least effective. The character of the SSAD and simultaneous behavioural phenomena differed fundamentally from those evoked by electrical stimulation of the thalamus (Chocholová et al. 1977). The development of paroxysmal after-activity was signalled by responses of a more or less distinct "recruiting" character during stimulation. On the basis of a comparison of electrographic and behavioural manifestations after electrical stimulation of the thalamus and hippocampus, the possibility of both thalamic and extrathalamic projection from the hippocampus to the cortical region is considered.