Seizure Arrest Research Articles

Multilobar Epilepsy Surgery in Childhood and Adolescence: Predictors of Long-Term Seizure Freedom.

Although multilobar resections correspond to one-fifth of pediatric epilepsy surgery, there are little data on long-term seizure control. To investigate the long-term seizure outcomes of children and adolescents undergoing multilobar epilepsy surgery and identify their predictors. In this retrospective study, we considered 69 consecutive patients that underwent multilobar epilepsy surgery at the age of 10.0± 5.0 yr (mean±SD). The magnetic resonance imaging revealed a lesion in all but 2 cases. Resections were temporo-parieto(-occipital) in 30%, temporo-occipital in 41%, parieto-occipital in 16%, and fronto-(temporo)-parietal in 13% cases. Etiologies were determined as focal cortical dysplasia in 67%, perinatal or postnatal ischemic lesions in 23%, and benign tumors in 10% of cases. At last follow-up of median 9 yr (range 2.8-14.8), 48% patients were seizure free; 33% were off antiepileptic drugs. 10% of patients, all with dysplastic etiology, required reoperations: 4 of 7 achieved seizure freedom. Seizure recurrence occurred mostly (80%) within the first 6 mo. Among presurgical variables, only an epileptogenic zone far from eloquent cortex independently correlated with significantly higher rates of seizure arrest in multivariate analysis. Among postsurgical variables, the absence of residual lesion and of acute postsurgical seizures was independently associated with significantly higher rates of seizure freedom. Our study demonstrates that multilobar epilepsy surgery is effective regarding long-term seizure freedom and antiepileptic drug withdrawal in selected pediatric candidates. Epileptogenic zones-and lesions-localized distant from eloquent cortex and, thus, fully resectable predispose for seizure control. Acute postsurgical seizures are critical markers of seizure recurrence that should lead to prompt reevaluation.

Participation of GABAB receptors in cortical postictal excitability in immature rats

Arrest of seizures is due to an active inhibition and is followed in mature brain by period of refractoriness markedly present one min after the end of seizures. To study changes in cortical excitability after epileptic seizures we used electrical stimulation of sensorimotor cortical area in immature rats – 25-day-old ones with mature postictal refractoriness and 12-day-old where postictal potentiation of afterdischarges (ADs) is present instead of refractoriness at one minute after the end of the conditioning AD. GABAB receptor antagonist CGP35348 was found to partly suppress postictal refractoriness. In present study not only an antagonist CGP46381 (3 and 10mg/kg i.p.) but also positive allosteric modulator of GABAB receptors CGP7930 (20 and 40mg/kg i.p.) were used to study the role of GABAB receptors in both age groups. They were injected immediately after testing AD and 10min later the two stimulations were repeated. CGP46381 partly antagonized postictal refractoriness in 25-day-old rats but did not significantly affect ADs in 12-day-old animals. CGP7930 did not significantly change ADs duration in either age group.GABAB receptors participate in mechanism of postictal refractoriness but did not play an important role in 12-day-old rats where potentiation instead of refractoriness is present.

CLINICAL AND ELECTROENCEPHALOGRAPHIC CHARACTERISTICS OF IDIOPATHIC CHILDHOOD FOCAL EPILEPSY WITH CENTROTEMPORAL SPIKES

Idiopathic childhood focal epilepsy with centrotemporal spikes, which is more known as rolandic epilepsy (RE), is age- and localization-related epilepsy with childhood onset, which is characterized mainly by short-lasting hemifacial and oropharyngeal seizures generally occurring when awakening or falling asleep, by the normal neurological status of patients, by specific electroencephalographic changes and complete arrest of seizures during therapy or when achieving puberty. RE is the most common epilepsy in childhood. Its prevalence is 21 per 100,000 healthy children. It is characterized by an onset that is clearly related to age. In 85 % of cases, RE occurs at 4–10 years of age with its peak at about 9 years. The clinical manifestations of this form of epilepsy are several types of seizures, such as oropharyngolaryngeal, hemifacial, faciobrachial, secondarily generalized convulsive, unilateral seizures with the possible development of short duration Todd’s paresis. Other types of seizures (absence, atonic, and myoclonic ones) are uncharacteristic of RE. They may occur occasionally on aggravation resulting from the use of carbamazepine or oxcarbazepine or permanently on transformation into pseudo-Lennox syndrome. According to the definition, focal neurological symptoms and behavioral and intellectual disorders are absent in patients with RE. However, there have been recent observations suggesting that speech, cognitive, and behavioral disorders may occur (at the same time rarely) in children with RE. Magnetic resonance imaging (MRI) fails to reveal the abnormality in the vast majority of cases. The described MRI changes in nearly 10 % of the patients with RE are an incidental finding and irrelevant to the course of the disease. Valproate in small doses is a first-choice drug; if it is inefficient, levetiracetam, topiramate, or a combination of valproate and ethosuximide are administered. Sulthiame (ospolot) as monotherapy is used in Germany. Based on their findings and the data available in the literature, the authors consider the etiology, pathogenesis, clinical manifestations of RE and its diagnosis, treatment principles, and prognosis. The specific features of the electroencephalographic pattern in this disease are detailed.

Adenosine Release during Seizures Attenuates GABAAReceptor-Mediated Depolarization

Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity.

Trigger self-control and seizure arrest in the Andrews/Reiter behavioral approach to epilepsy: A retrospective analysis of seizure frequency

The aim of this retrospective study is to describe changes of seizure frequency in epilepsy patients who participated in the Andrews/Reiter behavioral intervention for epilepsy. For this uncontrolled retrospective study, data were extracted from patients' medical journals. Intention-to-treat-analyses were restricted to patients with sufficient documentation supporting a diagnosis of probable or definite epilepsy. Main outcome variable was a comparison of mean seizure frequency at baseline and toward completion of the program. The seizure frequency of 30 (50%) patients showed a clinically meaningful improvement (>50% reduction of seizures) toward the end of the intervention. Twenty-two (37%) patients became seizure-free at the end of the intervention. In summary, a clinically meaningful reduction in reported seizure frequency was observed in epilepsy patients who received the Andrews/Reiter intervention for epilepsy. Prospective trials are needed to further investigate the program's efficacy and to study epileptic seizure triggers.

GABA-B receptor antagonist CGP 35348 interferes with an arrest of cortical epileptic afterdischarges in developing rats

Epileptic seizures activate not only excitatory but also inhibitory systems what results in an arrest of seizures. Our recent data indicate that GABAergic inhibition plays an important role in this process in cortically elicited seizures. We started to study the role of GABA-B receptors in cortical epileptic afterdischarges (ADs) in immature rats 12, 18 and 25 days old with implanted electrodes. Low-frequency stimulation of sensorimotor cortical area was repeated with increasing intensities of stimulation current. Thresholds for movements directly elicited by stimulation, for spike-and-wave type of AD, for clonic seizures accompanying this type of ADs and for transition into limbic type of AD were decreased by the 200mg/kg dose of a GABA-B receptor antagonist CGP35348 in all three age groups. Duration of ADs was markedly increased by 50, 100 as well as 200mg/kg dose of CGP35348. The effects were best expressed in 18-day-old rats. To conclude, GABA-B receptors play an important role in generation and especially in arrest of cortical seizures in immature rats.

Systemic administration of adenosine ameliorates pentylenetetrazol‐induced chemical kindling and secondary behavioural and biochemical changes in mice

Adenosine is one of the inhibitory neuromodulators in the brain and is considered to be responsible for seizure arrest and postictal refractoriness. Adenosine, adenosine receptor agonists, and adenosine uptake blockers are known to reduce the severity and duration of amygdala-kindled seizures. The present study was carried out to elucidate the anticonvulsant and neuromodulatory effect of systemic adenosine on the pentylenetetrazol (PTZ)-induced chemical kindling in mice. Kindling was induced by chronic administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.) on every other day for a total period of 9 days. Adenosine was administered daily, 30 min before PTZ or vehicle. The kindling score was recorded immediately following PTZ administration according to a prevalidated scoring scale. Various behavioral and biochemical estimations were performed on day 10 (i.e. 24 h after the last dose of PTZ). Chronic PTZ treatment progressively increased the seizure score with the maximum score reached on day 9. Behavioral analysis found hyperlocomotor activity, anxiogenic response, hyperalgesia and amnesia in kindled mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation (malondialdehyde levels), nitrite (NO(2-) levels), adenosine deaminase (ADA) and total RNA levels and decreased catalase, reduced glutathione (GSH) levels in brain homogenates, and a depletion of adrenal ascorbic acid. Daily treatment with adenosine (25 and 50 mg/kg, i.p.) for 9 days led to a significant decrease in PTZ-induced kindling score and also reversed various behavioral and biochemical alterations produced by PTZ. The results of the present study suggested that systemic adenosine administration reversed the behavioral and biochemical alterations induced by chronic PTZ.

Can fever treat epileptic encephalopathies?

To describe resistant epileptic encephalopathies that significantly improved after an acute febrile episode (FE). We reviewed the clinical history of patients with daily pharmacoresistant seizures referred to the Saint-Vincent de Paul Hospital in the last 5 years. Four patients experienced seizure arrest in relation with a febrile episode. The four patients suffered from epileptic encephalopathy. Three were symptomatic, one cryptogenic. They presented spasms and atypical absences, beginning after the age of 1 year. All seizures stopped at the onset of fever, and significant EEG improvement was observed. The seizure-free period ranged from 2 to 24 months. The close link between the occurrence of FE and the disappearance of seizures and EEG improvement, contrasting with the previous pharmacoresistance of this epileptic encephalopathy, supports a non fortuitous association. Several mechanisms could explain this phenomenon, including viral etiology, hyperthermia, inflammatory-immune reaction and ACTH release. Better understanding this phenomenon could open new therapeutic perspectives.

The role of nonpharmaceutic conservative interventions in the treatment and secondary prevention of epilepsy.

Nonpharmacologic conservative treatments receive too little attention. Depending on the clinical condition of the patients, they may be used alone or in conjunction with other therapies. Their target is the single seizure rather than the epileptic condition as such. They belong mainly to one of three domains. NONSPECIFIC PREVENTION OF SEIZURES: The first step is the identification of factors facilitating the occurrence of seizures. In the second step, strategies to control these factors are developed. Most common are disturbances of the sleep-wake cycle, especially reduction of sleep. Patients should follow a regular sleep schedule with deviations of not >2 h. Sometimes a sleep calendar is helpful. Night shifts are not compatible with seizure prevention in these cases. Sleep disturbances as a facilitating factor of seizures are particularly common in juvenile idiopathic generalized epilepsies, in which their avoidance is in many cases an indispensable part of the therapeutic regimen, along with appropriate drug treatment. They are the most common precipitating factor in adolescents and adults with a first epileptic [mostly generalized tonic-clonic (GTC)] seizure. In these instances, their avoidance is central to the secondary prevention of epilepsy developing from the single seizure, whereas the prescription of antiepileptic drugs (AEDs) is rarely effective. Other nonspecific facilitators of seizures include uncontrolled use of alcohol and extraordinary stress. Patients must learn how to cope with stressful events. SPECIFIC PREVENTION OF SEIZURES: In reflex epilepsies, specific precipitants of seizures are the targets of interventions. Thus, most patients with primary reading epilepsy begin to have, with prolonged reading, perioral reflex myoclonias, which enable them to stop reading and thus to avoid a GTC seizure. In photosensitive patients, seizures are often precipitated by television. These can be avoided by viewing from a distance and using a remote control, small screens in a well-lit room, and preferably with a 100-Hz line shift. Environmental flicker stimulation often comes unexpectedly, and it is advisable that the patients always wear sunglasses in brightly lighted surroundings. Polarized glasses seem to be more protective than plain sunglasses. If the patient has only photically induced seizures, treatment by specific prevention alone may be sufficient, but if spontaneous seizures also occur, drugs must be given in addition. ARREST OF SEIZURES: Focal seizures that develop sufficiently slowly to leave the patient time to react may be interrupted by "countermeasures." These, again, may be nonspecific (acting by relaxation, concentration, or a combination of both) or specific. The latter are individually tailored, based either on spontaneous experiences of the patient or on the anatomy of ictogenesis. Seizure propagation is blocked when a major part of the neurons involved is activated and not recruitable for spread of the epileptic discharge. Seizure arrest rarely is used alone but usually in combination with partially successful pharmacotherapy.

Use of intramuscular midazolam for status epilepticus

Although intravenous (i.v.) administration of antiepileptic drugs is the preferred route of therapy in status epilepticus, intramuscular (i.m.) delivery may provide a valuable alternative when there are obstacles to venous access. Compared to other treatment options such as rectal drug administration, which is as challenging as the i.v. route in a convulsing patient, the i.m. route is easier and less invasive. The two most commonly used first-line anticonvulsants, diazepam and lorazepam, may be administered i.m., but are absorbed from the i.m. site more slowly than midazolam. Midazolam, a fairly new benzodiazepine, is a potent anticonvulsant with a fast onset of effect. Because of its water solubility, midazolam is rapidly absorbed from the injection site and has excellent local tolerability. The pharmacodynamic effects of midazolam can be seen within seconds of its administration, and seizure arrest is usually attained within 5 to 10 min. Case reports and a recent randomized trial that demonstrate the successful use of i.m. midazolam in the termination of epileptic seizures are reviewed.

The development of epilepsy in the paediatric brain

The immature central nervous system (CNS) is more susceptible to the development of seizures than its adult counterpart. Developmental studies of experimental seizures have suggested that young animals have unique behavioural seizure patterns, including the presence of bilateral, though asymmetric, convulsions. There are differences in the mechanisms responsible for the generation of seizures, propagation patterns and seizure arrest and recurrences. These differences are due to local factors as well as factors that affect neural systems consisting of long neuronal circuits. The substantia nigra, a site involved in the control of seizures, will be used as an example to demonstrate how evolving neurobiological processes modulates the suppression or exacerbation of seizures with age. Evidence will also be presented indicating that early in life, seizures may not produce hippocampal damage. An understanding of the age-related differences is important for the development of rational approaches to treating seizures and their consequences.

Direct measurement of extracellular lactate in the human hippocampus during spontaneous seizures.

The effect of clinical, spontaneous-onset seizures on extracellular fluid lactate was investigated by the method of lactography, the in vivo on-line measurement of lactate levels using microdialysis. Studies of experimental animals have suggested that generation of extracellular lactate as measured by microdialysis is an index of local glucose utilization and is dependent on the activity of neurons under physiological conditions. Patients with medically refractory complex partial epilepsy underwent stereotactic implantation of combination depth electrode/microdialysis probes into both hippocampi for 7-16 days. During spontaneous complex partial seizures with secondary generalization, extracellular lactate levels rose by 91 +/- 32%. Moreover, this increase persisted for 60-90 min. During a unilateral hippocampal seizure that did not propagate to the contralateral hippocampus, the increase in lactate content was restricted to the side of seizure activity. Between seizures, extracellular lactate levels correlated with the frequency of interictal spikes. In summary, these data suggest that brief clinical seizures increase nonoxidative glucose metabolism significantly as measured by the generation of extracellular lactate. Furthermore, the increase in extracellular lactate levels is limited to the site of seizure activity. Lactate is transported extracellularly via a lactate/proton cotransporter, therefore, the rise in extracellular lactate level may mediate the drop in pH0 associated with seizure activity. As acidification of the extracellular compartment has an inhibitory effect on neuronal excitability, the rise in extracellular lactate content may be a mechanism of seizure arrest and postictal refractoriness. Moreover, extracellular lactate may also mediate the decreased seizure susceptibility associated with frequent interictal spikes.

Effect of hypoxia on bicuculline seizures of rat: NMR spectroscopy and bioluminescence imaging.

Previous studies suggested that hypoxia reduces the severity of brain injury after epileptic seizures. To test this hypothesis, the effect of hypoxic arrest of epileptic seizures on brain metabolism was investigated in rats by combining in vivo NMR spectroscopy with imaging techniques for the pictorial evaluation of energy metabolism and pH. Seizures were produced by i.v. injection of bicuculline, and measurements were compared in animals with and without 5 min exposure to 5% oxygen after the onset of seizures. Transient hypoxia persistently reduced seizure activity, even after return to normoxia. Hypoxia or seizure alone had little effect on brain metabolism but the combination of both led to marked albeit reversible deterioration of energy and acid/base status. In normoxic animals pictorial measurements of energy state 2 h after the onset of seizures revealed a regional decline of ATP in the hippocampus. In animals in which seizures were arrested by transient hypoxia ATP depletion was additionally observed in the border zones of vascular territories. These results demonstrate that hypoxic arrest of seizure activity leads to the aggravation of metabolic disturbances and is therefore not suited to preventing permanent brain injury.

Pathophysiological mechanisms of brain damage from status epilepticus.

Human status epilepticus (SE) is consistently associated with cognitive problems, and with widespread neuronal necrosis in hippocampus and other brain regions. In animal models, convulsive SE causes extensive neuronal necrosis. Nonconvulsive SE in adult animals also leads to widespread neuronal necrosis in vulnerable regions, although lesions develop more slowly than they would in the presence of convulsions or anoxia. In very young rats, nonconvulsive normoxic SE spares hippocampal pyramidal cells, but other types of neurons may not show the same resistance, and inhibition of brain growth, DNA and protein synthesis, and of myelin formation and of synaptogenesis may lead to altered brain development. Lesions induced by SE may be epileptogenic by leading to misdirected regeneration. In SE, glutamate, aspartate, and acetylcholine play major roles as excitatory neurotransmitters, and GABA is the dominant inhibitory neurotransmitter. GABA metabolism in substantia nigra (SN) plays a key role in seizure arrest. When seizures stop, a major increase in GABA synthesis is seen in SN postictally. GABA synthesis in SN may fail in SE. Extrasynaptic factors may also play an important role in seizure spread and in maintaining SE. Glial immaturity, increased electronic coupling, and SN immaturity facilitate SE development in the immature brain. Major increases in cerebral blood flow (CBF) protect the brain in early SE, but CBF falls in late SE as blood pressure falters. At the same time, large increases in cerebral metabolic rate for glucose and oxygen continue throughout SE. Adenosine triphosphate (ATP) depletion and lactate accumulation are associated with hypermetabolic neuronal necrosis. Excitotoxic mechanisms mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors open ionic channels permeable to calcium and play a major role in neuronal injury from SE. Hypoxia, systemic lactic acidosis, CO2 narcosis, hyperkalemia, hypoglycemia, shock, cardiac arrhythmias, pulmonary edema, acute renal tubular necrosis, high output failure, aspiration pneumonia, hyperpyrexia, blood leukocytosis and CSF pleocytosis are common and potentially serious complications of SE. Our improved understanding of the pathophysiology of brain damage in SE should lead to further improvement in treatment and outcome.

Adenosine: a potential mediator of seizure arrest and postictal refractoriness.

Adenosine is a potent inhibitory neuromodulator and has been proposed as an endogenous anticonvulsant. Depth electrodes modified to include a microdialysis probe were implanted for 10 to 16 days in the hippocampi of 4 patients with intractable complex partial epilepsy to test the hypothesis that during seizures extracellular adenosine reaches levels that may depress epileptiform activity. Samples were collected bilaterally at 3-minute intervals before, during, and after a single, spontaneous-onset seizure in each patient. All seizures commenced in one hippocampus and propagated to the contralateral hippocampus. Extracellular adenosine levels increased by 6- to 31-fold with the increase significantly greater in the epileptogenic hippocampus. During seizures, levels of adenosine in the dialysate reached concentrations as high as 2.5 microM, reflecting extracellular concentrations of approximately 65 microM. Adenosine at concentrations of 40 to 50 microM depresses epileptiform activity in vitro, so the levels we report may suppress seizure activity in vivo. Moreover, adenosine levels remain elevated above basal values for the entire 18-minute postictal period. These data support the role of adenosine in mediating seizure arrest and postictal refractoriness and suggest that treatments which facilitate adenosine may be effective in preventing seizures.

The effect of diazepam on neonatal seizure: in vivo 31P and 1H NMR study.

It is assumed that when anticonvulsants arrest seizure, there is rapid return of brain high energy phosphates and brain lactate to control values. To test this hypothesis, diazepam was administered to neonatal dogs during flurothyl-induced seizure. In vivo 31P nuclear magnetic resonance spectroscopy disclosed that diazepam quickly arrested electrographic seizure and restored brain phosphocreatine and inorganic phosphate to baseline values. In contrast, in vivo 1H nuclear magnetic resonance spectroscopic measurements showed that arrest of seizure with diazepam did not return brain lactate to control values. The sustained increase in cerebral blood flow and prolonged elevation of brain lactate, acetate, valine, and succinate in the postictal period indicate that metabolic recovery of the brain occurs over an extended period of time after the normalization of EEG, phosphocreatine, and brain pH.

Substantia nigra lesions in mercaptopropionic acid induced status epilepticus: a light and electron microscopic study.

Light microscopic and ultrastructural changes of substantia nigra were studied in paralyzed ventilated rats with status epilepticus induced by mercaptopropionic acid. Some rats were killed at the end of seizure activity and others were examined in varying intervals after the arrest of seizure. The earliest changes were reduction in the size of the neuronal nuclei and chromatin clumping followed by simultaneous distention of axons and dendrites. There was also enlargement of the neuronal perikarya associated with microvacuolation. This neuronal microvacuolation corresponded ultrastructurally to swollen mitochondria with disrupted cristae. These changes were followed by progressive neuronal shrinkage and astrocytic swelling. The swollen astrocytic processes together with swollen neurites gave a spongy appearance to the involved area. The lesion thereafter progressively enlarged and evolved into an area of frank necrosis containing abundant macrophages. This lesion is morphologically different from that produced in cortex and hippocampus by seizure activity or due to the direct effect of excitotoxins. The significance of substantia nigra pars reticularis changes and their pathogenesis are discussed.

Functional hemispherectomy for treatment of epilepsy associated with hemiplegia: rationale, indications, results, and comparison with callosotomy.

Hemispherectomy is effective in arresting seizures associated with maximal or near maximal hemiparesis. This procedure, however, carries an unacceptable 33% risk of late complications due to cerebral hemosiderosis. Anatomically partial but functionally complete hemispherectomy was devised to avoid these complications. The frontal or occipital lobes, or both, were left in place with the blood supply intact but with connections to commissures and brainstem divided. The central strip and parietal and temporal lobes were removed. Twenty patients were so treated with a follow-up of 4 to 13 years (average, 7.3 years) in 14. Ten of these are seizure free, 1 had a single nocturnal seizure, 1 had occasional focal twitching, and 2 had a worthwhile but lesser reduction in the seizure tendency. None has developed cerebral hemosiderosis, to date. In appropriately selected patients, functional hemispherectomy is an effective procedure preferable to callosotomy or to partial hemispherectomy. When there is no independent ictal discharge from the opposite hemisphere, arrest of seizures may be expected, leading to improvement in cognitive functioning (mean increase, 10 IQ points), social behavior, and a reduction in or discontinuation of anticonvulsant medication. In these patients, gait and hand use remain unchanged.

Endogenous anticonvulsant substances

Epileptic seizures will normally arrest abruptly and spontaneously, and the brain will remain refractory to further seizures for some time thereafter. This paper reviews the possible mechanisms underlying this seizure arrest and refractoriness. The data suggests that neuronal fatigue is not involved in either of these processes, whereas the role of ions and excitatory systems are unclear. Rather, seizure arrest and refractoriness may come about by the seizure-induced release and/or activity of multiple endogenous anticonvulsant substances. The spontaneous arrest of the seizure may involve the purine adenosine, in addition to other unknown mechanisms. Seizure refractoriness involves multiple systems, the most important of which, on the available evidence, are prostaglandins and opioid peptides and possibly benzodiazepine systems, although other neuropeptides and the purines may also be involved. The implications of these conclusions to anti-epileptic drug development and status epilepticus are discussed.

Cerebral pO 2 , pCO 2 and pH: changes during convulsive activity and their significance for spontaneous arrest of seizures.

SUMMARYThe present study on rats and cats aimed to clarify the role played by hypoxia, hypercapnia and acidosis in spontaneous arrest of seizures. In most experiments cortical pO2 declined during seizure activity, whereas pCO2 increased. Occasionally, however, reverse reactions occurred. Since the increase in cortical blood flow varied over a wide range, it could account for the fact that gas tension did not always change in the same direction or to the same degree during a seizure. Cessation of seizure activity was independent of the degree and direction of the changes in gas tension. When seizures were arrested by experimentally produced hypoxia, cortical and spinal neurons always showed a distinct depolarization. When convulsive discharges were suppressed by artificial increase in PCO2 most units were concomitantly hyperpolarized. When seizures ceased spontaneously, both cortical and spinal neurons showed a steep re‐ and hyperpolarization, independent of concomitant fluctuations in local gas tension. The findings lead to the conclusion that the degree of hypoxia and hypercapnia usually encountered during prolonged seizure activity does not reach the critical level sufficient to depress seizure activity. It must be assumed that spontaneous seizure termination is based, primarily, on neuronal processes.RESUMECette étude se propose de préciser, chez les rats et les chats, le rôle de l'hypoxie, de l'hypercapnie et de l'acidose dans l'arrêt des crises spontanées. Dans la majorité des expériences, Ia pO2 au niveau cortical diminue pendant la crise, tandis que la pCO2 augmente, quoique occasionnellement, on ait observé le contraire. La très grande variabilité de l'augmentation de la circulation sanguine cérébrale pouvait rendre compte du fait que pendant une crise, la tension des gaz ne changeait pas toujours dans le même sens ou dans les mêmes limites. L'arrêt de la crise était indépendant du degré et du type des modifications de la tension des gaz. Lorsque les crises étaient arrêtées à la suite d'une anoxie provoquée expérimentalement, on a toujours observé une dépolarisation des neurones corticaux spinaux. Lorsque les décharges convulsives étaient supprimées par une augmentation artificielle de la pCO2, la majorité des neurones était parallèlement hyperpolarisée. Lorsque les crises s'arrêtaient spontanément, les neurones du cortex et de la moelle montraient une rapide repolarisation et ensuite une hyperpolarisation indépendamment des fluctuations concomitantes de la tension des gaz. Ces données amènent à la conclusion que le degré d'hypoxie et d'hypercapnie qu'on observe habituellement pendant des crises prolongées n'atteint pas un niveau suffisant pour déprimer l'activité paroxystique.On doit en tirer la conclusion que l'arrêt spontané d'une crise est dûà des processus nerveux.