Clinical and electroencephalographic effects of topiramate in patients with epilepsy and healthy volunteers.

Although topiramate, one of the newer drugs used in treating epilepsy, is effective in reducing seizure frequency and has a wide spectrum of action, it often induces intolerable adverse effects, predominantly related to the central nervous system. Information that would help document adverse reactions early, thus allowing topiramate doses to be adjusted during the drug titration and maintenance phases, could be obtained from electroencephalogram (EEG) studies. We studied the clinical effects and EEG changes induced by topiramate in patients with refractory partial epilepsy receiving the drug as add-on therapy. To exclude effects related to the other drugs and to epilepsy itself, we compared data from patients and healthy volunteers. After receiving topiramate, 22.6% of patients became seizure free and 29% had their seizures reduced by 50% or more. Topiramate nevertheless induced noteworthy adverse reactions, the main problems being sedative and cognitive changes. Also, in healthy volunteers, a single 100-mg dose of topiramate induced mild adverse reactions, mainly affecting concentration and attention, with difficulties in speech and writing. In patients with epilepsy, the EEG changes induced by topiramate consisted of increased delta and theta activities and decreased activity in the rapid bands. This recognizable topiramate-induced EEG pattern was again evident in the healthy volunteers, in whom we also detected a significant reduction in the alpha frequency rhythm. Our results confirm that topiramate needs to be introduced gradually while patients undergo close neuropsychologic and neurophysiologic monitoring to detect adverse sedative and cognitive reactions early. The EEG correlate of these events seems to be increased activity in the slower frequency bands.

Systemic lupus erythematosus and myoclonic epileptic manifestations.

Systemic lupus erythematosus (SLE) frequently involves the central nervous system (CNS) and, in fact, epileptic manifestations may be one of the earliest symptoms of SLE. These early occurrences of epilepsy, however, can easily be misdiagnosed as indication of pure epileptic syndrome when the SLE diagnosis is still largely incomplete. We present a young girl who developed myoclonic photosensitive seizures at the onset of the illness, erroneously diagnosed as manifestation of a "pure" epileptic syndrome. Shortly after the onset of an anticonvulsant therapy (lamotrigine), there was a remarkable impairment of the general clinical condition: at that time a diagnosis of SLE was made and a specific treatment began. However, the seizures persisted and evolved toward status epilepticus which needed pentobarbitone therapy in an intensive care unit (ICU). After recovery, the girl gradually got better and during the 23 months of follow-up she received only corticosteroid therapy and did not experience seizures nor SLE relapses.

Vigabatrin versus carbamazepine and phenytoin in kainic acid-treated pubescent rats.

The effects of the administration of two doses (1,000 and 1,500 mg kg-1) of gamma-vinyl-GABA (GVG), have been tested in pubescent rats, systemically injected with kainic acid (KA). The changes in spontaneous behaviour before KA injection, the behavioural and epileptic manifestations (Wet Dog Shakes, Limbic Seizures and Status Epilepticus) and the lethality rate caused by KA were taken into account and compared to those observed in controls and in carbamazepine (CBZ) or phenytoin (PHT) treated animals. While GVG appeared to reduce the incidence of the epileptic manifestations and the subsequent mortality, particularly when higher doses of the drug were used, CBZ exerted a proconvulsant action and PHT did not substantially modify the parameters considered. Moreover, GVG, but not CBZ and PHT, induced remarkable sedative effects which disappeared within 48 h. The different anticonvulsant profile of GVG, CBZ and PHT were correlated to their different modes of action, since GVG acts by enhancing the inhibitory GABA-mediated processes, while CBZ and PHT act by reducing the excitatory processes.

Seizure susceptibility in immature rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate.

The administration of the alkylating neurotoxin methylazoxymethanol acetate (MAM) to pregnant rats on day 15 of gestation induces, in the offspring, a marked micrencephaly, characterized by an impaired formation of interneurons at cortical, hippocampal and striatal levels. Since in man developmental CNS malformations are often associated with severe epileptogenic encephalopathies with seizures appearing in the first months or years of life, we have studied the development of kainic-acid- and bicuculline-induced seizures in 15- and 30-day-old rats, prenatally exposed to MAM. Compared to controls, a higher susceptibility to seizures has been found in micrencephalic rats aged 15 days, while no significant differences have been observed in those aged 30 days. It is hypothesized that the cerebral global anatomical dysgenesis caused by MAM underlies the higher seizure susceptibility shown by animals during the first periods of life. Successively, the processes of adjustment occurring between the cerebral regions affected by the neurotoxic action of MAM and the afferent and efferent pathways spared by the substance may re-establish adequate interneuronal relationships and, therefore, a normal convulsive susceptibility.

Prenatal cocaine: seizure susceptibility in rat offspring.

Proconvulsant and convulsant effects of cocaine have been described in various experimental models of epilepsy. We have studied the susceptibility to bicuculline and pentylenetetrazol-induced seizures in developing 10-, 20- and 30-day old rats, gestationally exposed to cocaine. Incidence and latency of appearance of the epileptic manifestations, their evolution toward status epilepticus and successive recovery or death, have been evaluated and compared to the same parameters obtained in control animals of the same ages. Results have demonstrated that 10-day-old rats that had been exposed to cocaine are significantly less sensitive than control animals to the convulsant action of both bicuculline and pentylenetetrazole while no substantial differences between the two groups have been found at the successive ages. It is possible that modifications of various neurotransmitter systems caused by prenatal cocaine exposure modify neuronal excitability at least at early stages of development.

Age-related anticonvulsant activity of NMDA in the rat caudate-putamen.

Striatal pathways are important for modulating the threshold for seizures in the rat forebrain. N-Methyl-D-aspartate (NMDA), an excitatory amino acid derivative and powerful anticonvulsant agent, when injected into the brain, has been shown to protect adult rats against kindling and pilocarpine-induced seizures when injected into the caudate-putamen. The present study examines whether the anticonvulsant action of NMDA in the caudate-putamen varies with age. Bilateral striatal administration of NMDA was effective in suppressing bicuculline-induced seizures in rats older than 23 days of age. The results suggest that striatal pathways involved in the anticonvulsant activity of NMDA in the caudate-putamen are not functionally active in developing rats before the 4th week of life.

Effects of carbamazepine on bicuculline- and pentylenetetrazol-induced seizures in developing rats.

The anticonvulsant effect of carbamazepine (CBZ) was examined in 10-, 18- and 25-day-old Wistar albino rats into which bicuculline or pentylenetetrazol had been systemically injected to induce generalized epileptic manifestations typical for the specific age of the animals. The results showed that: a) in developing rats, CBZ appears to be more effective in the pentylenetetrazol than the bicuculline model of epilepsy; b) in both models of epilepsy the efficacy of CBZ increases with the age of the animals; and c) among the various epileptic manifestations, the tonic phase is the most sensitive to the anticonvulsant effect of CBZ. These conclusions are correlated with the different levels of cerebral maturation of the animals, and are discussed with reference to the mechanisms of action of CBZ and bicuculline or pentylenetetrazol.

The utility of ambulatory EEG monitoring in typical absence seizures.

In this study 8 hours ambulatory EEG monitoring (A/EEG) was performed in 25 outpatients with electroclinical evidence of absence attacks, in order to evaluate the possibility of objective quantification of the epileptic discharges, their distribution during the daytime and their relationship with evident behavioral correlates. A comparison between data obtained by A/EEG and standard EEG (S/EEG) was also made. The results have shown that: 1) it was possible to perform real quantification of the epileptic discharges only through the A/EEG test; 2) the two peaks of a greater incidence of the epileptic discharges corresponded to the execution of relaxing activities and ones requiring a low level of attentiveness; 3) a large number of epileptic generalized discharges did not exhibit a signal pattern like that of a "seizure", although they were of long duration; and 4) in six patients who showed the normalization of S/EEG and the disappearance of the absences after one month of valproate therapy, A/EEG revealed the persistence of epileptic discharges. These data demonstrate that A/EEG is a very useful technique for the quantification of paroxysmal discharges and that it may be of importance in the management of this kind of epileptic disorder.

Effects of progabide on bicuculline-induced epileptic seizures in developing rats.

The effects of progabide, a direct gamma-aminobutyric acid (GABA) receptor agonist, on bicuculline-induced seizures have been tested in developing rats, ages 7-28 days, to study the correlation between the antiepileptic effectiveness of this drug and the level of functional maturation of the GABAergic system. The incidence, latency of appearance, and behavioral characteristics of the epileptic manifestations, their evolution toward status epilepticus, and the percentage of recovery from status epilepticus have been evaluated in rats that had received a single injection (treatment) or three successive daily administrations (pretreatment) of progabide. The results have been compared with those obtained in a control group of animals in which only bicuculline had been injected. In rats ages 7-14 days the treatment appears to be substantially ineffective in protecting animals against bicuculline seizures and their consequences, probably because of the substantial immaturity of the GABAergic system at birth and during the first days of life. At this age, repetitive administrations of progabide cause a protective anticonvulsant action more remarkable than the single injection, particularly when using the higher doses of the substance. In 15-28-day-old rats, the treatment significantly reduces the lethality from status epilepticus but does not substantially modify the incidence of seizures, their latency of appearance, or their evolution toward status epilepticus. As in younger animals, in these rats also pretreatment is more effective than treatment against bicuculline seizures, whatever dose of progabide is used. At this age, therefore, the anticonvulsant properties of progabide appear to be more remarkable than in the previous age, probably because of a higher level of development of the GABAergic system, according to biochemical data on the GABAergic system ontogenesis.

Long-term effects of early status epilepticus on the acquisition of conditioned avoidance behavior in rats.

The acquisition of active avoidance behavior in a shuttle-box apparatus was studied in 45-day-old rats. In these animals a single episode of status epilepticus had been induced by the systemic administration of kainic acid (KA) or pentylenetetrazole (PTZ), when they were 10 or 25 days old. The results were compared with those obtained from animals in which, at the same ages, only saline solution had been injected. In KA-treated rats a decrement of right responses and a prolonged reaction time were observed, with these results more evident in animals treated earlier (10 days). Parallel with the behavioral alterations, the histological, morphometric and morphological examinations revealed neuronal and glial abnormalities at the neocortical level, while no lesions were found in the hippocampus. PTZ-treated rats showed no behavioral alteration nor histological abnormality. The different findings obtained after KA and PTZ injection suggest that not only status epilepticus per se, but the mechanism of action and the neurotoxicity of the convulsant agent, are very important in impairing late performances.

Bicuculline- and allylglycine-induced epilepsy in developing rats.

The development of bicuculline- and allylglycine-induced epilepsy has been studied in developing rats (6 to 30 days old). The results showed that during the first period of life, in both experimental models, the behavioral modifications were atypical and poorly correlated to corresponding epileptic EEG changes. Successively, a gradual evolution of the electroclinical patterns was observed, with similar characteristics in both bicuculline- and allylglycine-treated animals. Only from the 3rd week did electroclinical patterns similar to those of adult animals and more specific for the type of the convulsant agent appear. These data suggest that during the 1st 2 weeks after birth, the level of global cerebral immaturity, rather than the type of the epileptogenic substance, is the prominent element in the characterization of epileptic manifestations. From the 3rd week, the more advanced level of anatomical, biochemical, and neurophysiologic maturation of the CNS allows a more selective involvement of various cerebral structures with subsequent well defined epileptic features.

Effects of gamma-globulin therapy in severely epileptic children.

The effects of gamma-globulin therapy have been studied from clinical, immunological, and electrographic perspectives in 10 children affected by severe organic epilepsy. After the first or the second injection of large doses of IgG, an appreciable reduction in seizure frequency and an improvement in behavioral and psychological performance were observed in seven children. These clinical modifications were not correlated with an important decrease of the EEG epileptic elements, but in most cases they were associated to an increase in alpha activity and/or in power of the predominant EEG frequency. These changes were observed during the entire treatment period and tended to disappear when therapy was interrupted. No significant changes in both immunological data and plasma levels of antiepileptic drugs accompanied the clinical and EEG changes.

Status epilepticus and brain maturation.

The development of a limbic and a generalized tonic-clonic form of epilepsy, induced by systemic injections of kainic acid and pentylenetetrazol respectively, has been studied in developing rats. The purpose of this research was to investigate the correlations between the maturational stages of the CNS and the electro-clinical manifestations of epilepsy and status epilepticus. In both models of epilepsy, the electro-clinical patterns of seizures typical of the adult animal were reached as early as the third week of life. During the first weeks, atypical behavioural and EEG epileptic manifestations were observed. An attempt has been made to compare the experimental results with the electro-clinical epileptic signs of the infant, in order to suggest some neurophysiological explanations of the peculiar aspects of infantile epilepsy.

Intracortical and intrahippocampal injections of kainic acid in developing rats: an electrographic study.

Electrographic patterns induced by neocortical and hippocampal microinjections of kainic acid (KA) have been studied in curarized 4-30-day-old rats. In younger (4-6-day-old) animals, both hippocampal and neocortical KA application induced, with a long delay, the appearance of sequences of slow spikes, simultaneously occurring in the cortex and hippocampus. The same pattern was observed in about 60% of animals 7-9 days old. In the remaining 40% of the rats of this age, epileptic abnormalities, initially localized in the neocortical or hippocampal injection site were obtained. The latter pattern always appeared in 10-14-day-old rats. In some of these status epilepticus was also reached. In older (15-30 days) animals, the hippocampal injection caused the appearance of hippocampal seizures, always evolving into status epilepticus. In neocortically injected animals, cortical bursts of polyspikes appeared, with or without hippocampal involvement. After 40-60 min, typical hippocampal seizures occurred, later leading to status epilepticus. The simultaneous hippocampal and neocortical response observed in younger rats is attributed to a massive activation of the immature brain structures. The focal response seems to be correlated with a maturational process of glutamate and/or kainate receptors at both hippocampal and neocortical levels. This process is completed during the third week, when a typical selective activation of the limbic structures is obtained.

A simple method for implanting electrodes in freely moving neonatal rats.

A simple method for implanting cortical and subcortical electrodes in very young rats is described, which does not interfere with the behavior of the animal during the experiment. The cortical electrodes are anchored to the skull by a spiral whose first loop is introduced between the inner layer of the skull and the dura mater. The subcortical electrodes have a loop which rests above the skull. Both the spirals of the cortical electrodes and the loops of subcortical electrodes are then embedded in dental acrylic.