Hyperthermia-induced Seizures Research Articles

Interleukin‐10 is associated with resistance to febrile seizures: Genetic association and experimental animal studies

Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) beta, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls. The promoter SNPs of four inflammatory cytokine genes (IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs (IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models. The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10-administered rats was significantly higher than that in the saline-treated control ones (p = 0.027). The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1beta, confers resistance to FS.

Long-term behavioral outcome after early-life hyperthermia-induced seizures

Febrile seizures (FS) are among the most common types of seizures in the developing brain. It has been suggested that FS cause cognitive deficits that proceed into adulthood, but the information is conflicting. The aim of the present study was to determine whether experimental FS have long-term cognitive or behavioral deficits. FS were induced by hyperthermia (30 minutes, approximately 41 degrees C) in 10-day-old rat pups, and behavioral testing was performed. Hippocampus-dependent water maze learning, locomotor activity, and choice reaction time parameters (e.g., reaction time) were generally not affected by FS. However, more detailed analysis revealed that reaction times on the right side were slower than those on the left in controls, whereas this was not observed after FS. Early-life experimental FS did not cause overt cognitive and behavioral deficits, which is in line with previous work, but eliminated the lateralization effect in reaction time known to occur in normal controls, an effect that may be due to the combination of FS and kainic acid or to FS alone.

Interleukin-1β enhances susceptibility to hyperthermia-induced seizures in developing rats

Cytokines have been shown to influence susceptibility to febrile seizures and epilepsy. In this study, the role of interleukin-1β (IL-1β) was examined in developing rats. IL-1β and interleukin-1 receptor antagonist (IL-1ra) were administered to developing rats, and seizures were induced by moist warm air. Twenty male Lewis rats (21–23 days old) were divided into two groups (IL-1β and saline control groups) and two holes were made in the skull for EEG electrodes. We applied human recombinant IL-1β intra-nasally 1 h before seizures induced by moist warm air. The brain temperature at the appearance of seizure discharges on EEG, and the latency time from the hyperthermia onset until the appearance of seizure discharges on EEG were measured. And the same study using IL-1ra was performed. The median brain temperature for the IL-1β group, 42.6 °C (range: 41.8–43.0), was significantly lower than that for the control, 42.9 (42.3–43.4) ( P = 0.043). The brain temperature for the IL-1ra group, 43.3 (42.8–43.7), was significantly higher than that for the control, 42.9 (42.2–43.5) ( P = 0.011), and the latency time for the IL-1ra group, 398 s (270–561), was significantly longer than that for the control, 325 (252–462) ( P = 0.035). These results demonstrate that IL-1β promotes hyperthermia-induced seizures in developing rats.

Hyperthermic seizure induces persistent alteration in excitability of the dentate gyrus in immature rats

Febrile seizure (FS) is the most common type of seizure that occurs during early childhood. It has been proposed that atypical FS (prolonged, multiple, or lateralized) results in the development of recurrent complex partial seizures accompanied by Ammon's horn sclerosis or mesial temporal sclerosis, which is the most common of the intractable epilepsy. To elucidate the characteristics of epileptogenesis or acquired epilepsy following FS, we performed prospective long-term studies using hyperthermia-induced seizure model. Rat pups (postnatal 11 day old) were induced to hyperthermia (41–43 °C in core temperature) by exposure to a 175 W mercury vapor lamp. Six–nine weeks after hyperthermic seizure, the dentate gyrus showed impairments of paired-pulse inhibitions and excitability ratio. In addition, newly generated granule cells and synaptogenesis were observed in this region. Ten–twelve weeks after hyperthermic seizure, animals (~ 68%) showed electroencephalographic seizure activity with increased VGLUT-1 immunoreactivity in the dentate gyrus. Parvalbumin immunoreactivity was markedly reduced in the hilus. These findings indicate that in this model the epileptogenic changes in the dentate gyrus may be based on the persistent alterations in excitability via neurogenesis, synaptogenesis, and impaired GABA B receptor-mediated inhibition.

Cytogenesis in the dentate gyrus after neonatal hyperthermia‐induced seizures: What becomes of surviving cells?

Febrile seizures (FS) are early-life seizures thought to play a role in epileptogenesis. By labeling cells that were dividing immediately following experimental FS, we previously demonstrated that significantly more of these newborn cells in the dentate gyrus (DG) survived 8 weeks later, relative to animals that did not experience FS. The purpose of the present study was to determine the long-term fate of these newborn cells. On postnatal day (PN) 10, hyperthermia-induced seizures (HT, +/-42 degrees C core temperature) were evoked in Sprague-Dawley rats and littermates were used as normothermia controls (NT, +/-35 degrees C core temperature). From PN11 to PN16, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. At PN66, we evaluated the number of BrdU-labeled cells in the DG that colocalized with the neuronal marker NeuN, glial marker glial fibrillary acidic protein (GFAP), neuronal excitatory amino acid transporter 3 (EAAT3), GABAergic neuronal marker glutamic acid decarboxylase 67 (GAD67) or microglia marker tomato lectin (TL). In all rats, almost all BrdU-labeled cells in the DG, that showed double-labeling, colocalized with NeuN, and rarely with GFAP, GAD67, or TL. In NT controls and HT rats that did not experience seizures ("HT-no seizures"), approximately 23% of BrdU-labeled cells colocalized with EAAT3, which was significantly different from 14% in HT rats that did experience seizures (HT + FS). Early-life seizures decrease the population of newborn cells that survive and mature into EAAT3-positive neurons and do not affect the GABAergic cell population. This may affect hippocampal physiology in young adulthood.

Interleukin-6 attenuates hyperthermia-induced seizures in developing rats

Previous studies indicated that several cytokines influenced the seizure propensity in convulsive disorders and were the cause of encephalopathies in childhood. We studied the role of one inflammatory cytokine, interleukin-6 (IL-6), in hyperthermia-induced seizures in developing rats. Twenty-four male Lewis rats (23–28 days old) were divided into three groups ( n = 8/IL-6 (500 ng), IL-6 (50 ng), and saline control groups). We applied human recombinant IL-6 intra-nasally to developing rats 1 h before seizures induced by moist heated air (50 °C). The seizure latency was defined as the time from hyperthermia onset until the appearance of continuous seizure discharges on electroencephalography (EEG), and the seizure duration as the duration of continuous spike and wave discharges on EEG. Five of the eight rats in the IL-6 (500 ng) group, two in the IL-6 (50 ng) group, and one in the control group exhibited no seizure discharges during the 360 s heating period. In these cases, the seizure latency time was regarded as 360 s and the seizure duration time as 0 s. The median seizure latency for the IL-6 (500 ng) group, 360 s (range: 256–360), was significantly longer than that for the control one, 249 (121–360) ( P < 0.05). The seizure duration for the IL-6 (500 ng) group, 0 s (0–20), was significantly shorter than that for the control one, 33 (0–76) ( P < 0.025). Also, the adenosine receptor antagonist, aminophylline, prevented these effects of IL-6 on hyperthermia-induced seizures. These results indicate that IL-6 plays an anti-convulsive role through the adenosine system in hyperthermia-induced seizures, which might be relevant as to human febrile seizures.

Hyperthermia-induced seizures modify the GABA(A) and benzodiazepine receptor binding in immature rat brain.

Effects of hyperthermia-induced seizures (HS) on GABA(A) and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced in 10-days-old rats by a regulated stream of moderately heated air directed 50 cm above the animals. Rats were killed 30 min, 24 h or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABA(A) and BDZ receptor binding. GABA(A) binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in the cingulate, frontal, posterior parietal, entorhinal, temporal and perirhinal cortices; striatum, accumbens, substantia nigra pars compacta and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal, anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABA(A) and BDZ binding in immature brain. HS-induced GABA(A) and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals.

Decreased IH in Hippocampal Area CA1 Pyramidal Neurons after Perinatal Seizure‐inducing Hypoxia

The hyperpolarization-activated cation current (IH) has been proposed to play a role in some forms of epileptogenesis, as it critically regulates synaptic integration and intrinsic excitability of principal limbic neurons and can be pathologically altered after experimentally induced seizures. In hippocampal CA1 pyramidal neurons, IH is functionally decreased after kainate-induced status epilepticus in adult rats but is increased after hyperthermia-induced seizures in immature rat pups. This study aimed to determine whether and how IH may be altered in CA1 pyramidal neurons after seizure-inducing global hypoxia in the neonatal brain. Seizures were induced in rat pups on postnatal day 10 by 14- to 16-min exposure to 5-7% O2. Whole-cell patch-clamp recordings were obtained from hippocampal CA1 pyramidal neurons in slices 30 min to 3 days after hypoxia treatment, and from control age-matched littermates. IH was isolated under voltage-clamp by subtracting current responses to hyperpolarizing voltage steps before and during application of the IH blocker ZD 7288 (100 microM). IH was significantly decreased in pyramidal neurons from the hypoxia-treated group compared with controls (p<0.001; 19 controls; 15 hypoxia). Analyses of tail currents and activation kinetics indicated no statistically significant differences between groups in the voltage dependence or time constants of activation. These data indicate that a single episode of neonatal hypoxia that induces seizures can persistently decrease IH in CA1 pyramidal neurons, raising this as a potential contributing mechanism to epileptogenesis in this setting. Our findings further indicate that the consequences of seizures for IH may depend more on seizure etiology than on maturational stage.

Persistent changes in action potential broadening and the slow afterhyperpolarization in rat CA1 pyramidal cells after febrile seizures

Febrile (fever-induced) seizures (FS) are the most common form of seizures during childhood and have been associated with an increased risk of epilepsy later in life. The relationship of FS to subsequent epilepsy is, however, still controversial. Insights from animal models do indicate that especially complex FS are harmful to the developing brain and contribute to a hyperexcitable state that may persist for life. Here, we determined long-lasting changes in neuronal excitability of rat hippocampal CA1 pyramidal cells after prolonged (complex) FS induced by hyperthermia on postnatal day 10. We show that hyperthermia-induced seizures at postnatal day 10 induce a long-lasting increase in the hyperpolarization-activated current I(h). Furthermore, we show that a reduction in the amount of spike broadening and in the amplitude of the slow afterhyperpolarization following FS are also likely to contribute to the hyperexcitability of the hippocampus long term.

Decrease of Hippocampal GABAB Receptor–Mediated Inhibition after Hyperthermia‐induced Seizures in Immature Rats

Whether febrile seizures have detrimental consequences on the brain is still controversial. We hypothesized that neuronal inhibition in the hippocampus is altered after hyperthermia-induced seizures in immature rats. Rats were given a single seizure by a heat lamp on postnatal day (PND) 15, or repeated seizures by heated air on PND 13 to 15. Fourteen or 30 days after the seizure(s), laminar field potentials were recorded by 16-channel silicon probes in CA1 and the dentate gyrus (DG), in response to the paired-pulse stimulation of the CA3 and medial perforant path, and analyzed as current source density. Gamma-aminobutyric acid (GABA)(B)-receptor antagonist CGP35348 was injected intracerebroventricularly (icv). At 14 but not at 30 days after a single or after repeated hyperthermia-induced seizures, paired-pulse facilitation (PPF) of the CA1 population spikes at 100 to 200 ms interpulse intervals (IPIs) was significantly increased in seizure as compared with control rats, irrespective of the types of induced seizures. CGP35348 icv also resulted in PPF at 100 to 200 ms IPIs in CA1 of control rats, but CGP35348 had no effect on PPF in seizure rats. At 30 days after repeated seizures, paired-pulse inhibition in the DG was significantly increased at 30-ms IPI, and PPF was increased at 200-ms IPI. CGP35348 increased paired-pulse inhibition in the DG in repeated-seizure rats but not in control rats. We conclude that hyperthermia-induced seizures in immature rats induced a decrease of GABA(B) receptor-mediated inhibition in CA1 and DG that lasted > or =14 to 30 days after hyperthermic seizure(s).

Hyperthermia-induced seizures modify the GABAA and benzodiazepine receptor binding in immature rat brain.

Effects of hyperthermia-induced seizures (HS) on GABAA and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced in 10-day-old rats by a regulated stream of moderately heated air directed 50 cm above the animals. Rats were killed 30 min, 24 h, or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABAA and BDZ receptor binding. GABAA binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in the cingulate, frontal, posterior parietal, entorhinal, temporal, and perirhinal cortices; striatum, accumbens, substantia nigra pars compacta, and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal, anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABAA and BDZ binding in immature brain. HS-induced GABAA and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals.

Freeze lesion-induced focal cortical dysplasia predisposes to atypical hyperthermic seizures in the immature rat.

To determine the effects of focal cortical dysplasia on the behavioral and electrographic features of hyperthermia-induced seizures (HSs) in rats. A right sensorimotor cortex freeze lesion was induced in postnatal day 1 (P1) rat pups, and HSs were provoked at P10 under continuous monitoring of core temperature; EEGs were recorded from the right amygdala during and after hyperthermia. Controls included both sham-operated at P1 and naïve rats. HSs began with jaw myoclonus, followed by hindlimb clonus and generalized convulsions (GCs), and terminated by a period of posthyperthermia depression. The threshold temperature and latency of jaw myoclonus were similar across the groups. However, both the threshold temperature and latency of GCs were significantly lower in lesioned pups than in controls (40.5 +/- 0.5 degrees C, n = 24, vs. 42.0 +/- 0.2 degrees C, n = 21; p < 0.001; 6.7 +/- 0.6 min, n = 20, vs. 8.4 +/- 0.6 min, n = 22; p < 0.05). In lesioned pups, the threshold and latencies for jaw myoclonus and hindlimb clonus were similar, whereas in controls, the progression from one to the other was marked by significant differences in both parameters. Posthyperthermia depression was longer in lesioned (13.3 +/- 1.2 min, n = 21) than in control (8.0 +/- 0.8 min, n = 20; p < 0.0001) pups. Ictal EEG activity was recorded during both behavioral seizures and posthyperthermia depression. An HS in rats with a localized freeze lesion results in lower threshold GC and prolonged ictal manifestations, thus supporting a pathophysiologic link between focal cortical dysplasia and atypical febrile seizures, conditions that have a high prevalence in children with mesial temporal lobe epilepsy.

Increased expression of gamma-aminobutyric acid transporter-1 in the forebrain of infant rats with corticotropin-releasing hormone-induced seizures but not in those with hyperthermia-induced seizures

High affinity, gamma-aminobutyric acid (GABA) plasma membrane transporters (GATs) influence the availability of GABA, the main inhibitory neurotransmitter in the brain. Recent studies suggest a crucial role for GATs in maintaining levels of synaptic GABA in normal as well as abnormal (i.e., epileptic) adult brain. However, the role of GATs during development and specifically changes in their expression in response to developmental seizures are unknown. The present study examined GAT-1-immunolabeling in infant rats with two types of developmental seizures, one induced by corticotropin-releasing hormone (CRH) lasting about 2 h and the other by hyperthermia (a model of febrile seizures) lasting only 20 min. The number of GAT-1-immunoreactive (ir) neurons was increased in several forebrain regions 24 h after induction of seizures by CRH as compared to the control group. Increased numbers of detectable GAT-1-ir cell bodies were found in the hippocampal formation including the dentate gyrus and CA1, and in the neocortex, piriform cortex and amygdala. In contrast, hyperthermia-induced seizures did not cause significant changes in the number of detectable GAT-1-ir somata. The increase in GAT-1-ir somata in the CRH model and not in the hyperthermia model may reflect the difference in the duration of seizures. The brain regions where this increase occurs correlate with the occurrence of argyrophyllic neurons in the CRH model.

Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term

Febrile seizures (FSs) constitute the most prevalent seizure type during childhood. Whether prolonged FSs alter limbic excitability, leading to spontaneous seizures (temporal lobe epilepsy) during adulthood, has been controversial. Recent data indicate that, in the immature rat model, prolonged FSs induce transient structural changes of some hippocampal pyramidal neurons and long-term functional changes of hippocampal circuitry. However, whether these neuroanatomical and electrophysiological changes promote hippocampal excitability and lead to epilepsy has remained unknown. By using in vivo and in vitro approaches, we determined that prolonged hyperthermia-induced seizures in immature rats caused long-term enhanced susceptibility to limbic convulsants that lasted to adulthood. Thus, extensive hippocampal electroencephalographic and behavioral monitoring failed to demonstrate spontaneous seizures in adult rats that had experienced hyperthermic seizures during infancy. However, 100% of animals developed hippocampal seizures after systemic administration of a low dose of kainate, and most progressed to status epilepticus. Conversely, a minority of normothermic and hyperthermic controls had (brief) seizures, none developing status epilepticus. In vitro, spontaneous epileptiform discharges were not observed in hippocampal-entorhinal cortex slices derived from either control or experimental groups. However, Schaeffer collateral stimulation induced prolonged, self-sustaining, status epilepticus-like discharges exclusively in slices from experimental rats. These data indicate that hyperthermic seizures in the immature rat model of FSs do not cause spontaneous limbic seizures during adulthood. However, they reduce thresholds to chemical convulsants in vivo and electrical stimulation in vitro, indicating persistent enhancement of limbic excitability that may facilitate the development of epilepsy.

Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits.

Febrile (fever-induced) seizures affect 3-5% of infants and young children. Despite the high incidence of febrile seizures, their contribution to the development of epilepsy later in life has remained controversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, we determined that hyperthermia-induced seizures in the immature rat cause a selective presynaptic increase in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lasting nature of these potent alterations in synaptic communication after febrile seizures does not support the prevalent view of the 'benign' nature of early-life febrile convulsions.

The effect of GABAergic system activity on hyperthermia-induced seizures in rats

Developing rats were given GABA antagonists and agonist before electrical seizure discharges were induced by heating the brain of a rat with infra-red rays. The thresholds for the GABA antagonist groups were significantly lower than that for the control, and the threshold for the GABA agonist group was significantly higher than that for the control. These results support the hypothesis that reduced GABAergic system activity underlies febrile seizures.

Febrile seizures: an appropriate-aged model suitable for long-term studies

Seizures induced by fever are the most prevalent age-specific seizures in infants and young children. Whether they result in long-term sequelae such as neuronal loss and temporal lobe epilepsy is controversial. Prospective studies of human febrile seizures have found no adverse effects on the developing brain. However, adults with temporal lobe epilepsy and associated limbic cell loss frequently have a history of prolonged febrile seizures in early life. These critical issues may be resolved using appropriate animal models. Published models of hyperthermic seizures have used ‘adolescent’ and older rats, have yielded a low percentage of animals with actual seizures, or have suffered from a high mortality, rendering them unsuitable for long-term studies. This article describes the establishment of a model of febril seizures using the infant rat. Hyperthermia was induced by a regulated stream of midly heated air, and the seizures were determined by both behavioral and electroencephalographic (EEG) criteria. Stereotyped seizures were generated in 93.6% of 10–11-day-old rats. EEG correlates of these seizures were not evident in cortical recordings, but were clearly present in depth recordings from the amygdala and hippocampus. Prolonged febrile seizures could be induced without burns, yielding a low mortality (11%) and long-term survival. In summary, an infant rat paradigm of EEG-confirmed, hyperthermia-induced seizures which is suitable for long-term studies is described. This model should be highly valuable for studying the mechanisms and sequelae of febrile seizures.

The effect of GABA synthesis modulation in the brain on hyperthermia-induced seizures in rats

The effect of GABA synthesis modulation in the brain on hyperthermia-induced seizures in rats

Effect of hyperthermia on hippocampal synaptic transmission and CA3 kindling in developing rats

The effect of hyperthermia on excitatory synaptic transmission in the hippocampal CA1 area in response to contralateral CA3 stimuli at 23–26 days of age and the influence of hyperthermia-induced seizures (HS) on the kindling phenomenon induced by CA3 stimulation at 27–29 days of age were investigated in developing rats. When hyperthermia (43.6 ± 0.5°C) did not induced seizures in conscious unrestrained rats, transient (< 1 h) potentiation was observed in electrically evoked synaptic responses (EPSP and population spikes). When generalized seizures were induced by hyperthermia (43.3 ± 0.4°C), long-term potentiation (LTP) was observed over 24 h. The difference in time course of the potentiation depended on whether high-voltage multispikes on the EEG, which sustained for longer than 20–30 s and associated with behavioral convulsions, appeared or not. In the following kindling session, the threshold intensity required to produce afterdischarges (ADs) in the HS rats (187 ± 16 μA) was significantly lower than in the rats without HS (293 ± 41 μA). However, there was no clear difference between the development of the kindling phenomenon to repeated tetanus at the threshold intensity in the rats with and without HS. It was concluded that potentiation of synaptic responses consists of two different components, transient potentiation induced by hyperthermia alone and LTP induced by HS, and that developing rats were susceptible to kindling epilepsy at the lower AD threshold intensity when experienced HS.

The influence of blood gas changes on hyperthermia-induced seizures in developing rats

Fever induces seizures in infants with febrile convulsions or epilepsy. Hyperpnea induced by fever may contribute to the induction of these seizures. In order to examine this possibility, we evaluated the effect of changes in arterial blood gas tension on hyperthermia-induced seizures in developing rats. Electrical seizure discharges were induced by application of infra-red rays on the skull of rats under mechanical ventilation with different respiratory conditions. There was positive correlation between pCO 2 and the seizure threshold (ST) defined as a latency from the start of hyperthermia to the occurrence of seizures: ST (seconds, s) = 2.36 pCO 2 + 0.05 ( R 2 = 0.80, P<0.001). Seizure duration (SD) was longer at lower pCO 2 level: 18 (6–33) (median, range) s at pCO 2 ranging from 23 to 26 mmHg vs. 0(0–7) s at pCO 2 ranging from 35 to 57 mmHg ( P < 0.01). Hypoxia significantly increased ST: 84 (61–100) s at pO 2 ranging from 53 to 76 mmHg vs. 60 (51–72) s at pO 2 ranging from 87 to 131 mmHg ( P < 0.01). Hyperoxia prolonged SD: 27 (10–30) s at pO 2 ranging from 100 to 170 mmHg vs 9 (0–23) at pO 2 ranging from 53 to 93 mmHg ( P < 0.02). Hypocarbia caused by fever-induced hyperpnea probably contributes to the generation of fever-induced seizures.