Volumetric magnetic resonance imaging differences between complex febrile seizure and recurrent simple febrile seizure.

PURPOSE: We investigated the volumetric differences in cortical and subcortical structures between patients with complex febrile seizure (FS) and recurrent simple FS. We aimed to identify the brain morphological patterns of children with complex FS. METHODS: Twenty-five patients with complex FS and age- and sex-matched 25 patients with recurrent simple FS with structural magnetic resonance imaging (MRI) scans were studied. Cortical volumetric analysis was performed using a voxel-based morphometry method with the CAT12 toolbox within SPM12. FSL-FIRST was used to obtain volume measures of subcortical deep grey matter structures (amygdala, caudate nucleus, thalamus, nucleus accumbens, putamen, globus pallidus, and hippocampus). The volumetric asymmetry index (AI) and laterality index (LI) were calculated for each subcortical structure. RESULTS: Compared with recurrent simple FS, complex FS demonstrated lower volume in the left putamen (p = .003) and right nucleus accumbens (p = .001). Additionally, patients with complex FS presented a higher magnitude of AI of the nucleus accumbens (p < .001) compared with recurrent simple FS. CONCLUSIONS: The findings indicate that volumetric analysis may be a useful marker for the detection of FS-induced changes that reflect microstructural alterations. This study is the first to report on alterations in the putamen and nucleus accumbens in FS.

Fangjing decoction relieves febrile seizures-induced hippocampal neuron apoptosis in rats via regulating the Akt/mTOR pathway.

Background: Fangjing decoction is a Traditional Chinese Medicine that exhibits anticonvulsive effects in treating febrile seizures (FS). Its action mechanism and the regulation on Akt/mammalian target of rapamycin (mTOR) pathway were revealed in the present study.Methods: FS model was established in Sprague-Dawley rats with or without Fangjing decoction treatment. On day 5, following initiation of drug treatment, seizures were monitored. Hippocampal neuron apoptosis was assessed using terminal dUTP nick end-labeling method. The levels of Bax, protein kinase B (Akt), phospho-Akt (p-Akt), mTOR, and p-mTOR proteins were analyzed using Western blotting. The content of hippocampal γ-aminobutyric acid (GABA) was measured by using ELISA assay.Results: Compared with the control group (n=8), Fangjing decoction effectively prolonged the latency but shortened the duration of FS in rats (n=8). Concomitantly, the apoptosis of hippocampal neurons, as well as Bax protein levels were also decreased in FS rats which were treated with Fangjing decoction. In addition, the Akt/mTOR signaling was found to be activated in rat hippocampus following FS, as evidenced by increased p-Akt and p-mTOR, while Fangjing decoction could inhibit the activation of Akt/mTOR signaling. Furthermore, the low GABA content in rat hippocampus following FS was significantly elevated by Fangjing decoction treatment. More importantly, SC79, a specific activator for Akt, apparently attenuated the protective effects of Fangjing decoction on FS rats.Conclusion: These results suggest that Fangjing decoction protects the hippocampal neurons from apoptosis by inactivating Akt/mTOR pathway, which may contribute to mitigating FS-induced brain injury.

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants.

Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.

Zinc supplementation prolongs the latency of hyperthermia-induced febrile seizures in rats.

Some studies have shown a relationship between febrile seizures and zinc levels. The lowest dose zinc supplementation in pentylenetetrazole seizure model has a protective effect. But, zinc pretreatment has no effect in maximal electroshock model. However, it is unclear how zinc supplementation affects hyperthermia-induced febrile seizures. The aim of the present study was to investigate the effects of zinc supplementation on febrile seizures in male Sprague-Dawley rats. The rats were randomly assigned to four groups. Zinc supplementation was commenced 5 days prior to febrile seizure induction by placing the animals in a water bath at 45°C. We measured the rectal temperature and determined the febrile seizure latency, duration, and stage. In the zinc-supplemented group, both the seizure latency and the rectal temperature triggering seizure initiation were significantly higher than in the other groups. We suggest that zinc supplementation can positively modulate febrile seizure pathogenesis in rats.

Prenatal undernutrition increases the febrile response to lipopolysaccharides in adulthood in male rats.

It has been reported that prenatal undernutrition affects the development of the peripheral immune system. In this study, the effects of prenatal undernutrition on the febrile response and hypothalamic innate immune system were evaluated in male rats. Pregnant rats were divided into normally nourished (NN) and undernourished groups (UN). The febrile and anorectic responses to lipopolysaccharides (LPS) were evaluated in the offspring of NN and UN dams. The hypothalamic expression levels of pro-inflammatory cytokines, toll-like receptor 4 (TLR4), and neuropeptide Y (NPY) were also evaluated. The UN rats exhibited significantly lighter body weights than the NN rats at birth; however, their mean body weight was the same as that of the NN rats by postnatal day 10. In adulthood, the UN rats exhibited significantly stronger febrile responses than the NN rats, and the anorectic responses of the UN rats also tended to be stronger than those of the NN rats. On the other hand, no differences in hypothalamic interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, TLR4, or NPY mRNA expression were detected between the NN and UN rats. These results suggest that prenatal undernutrition has long-lasting effects on the febrile response to LPS. However, the precise mechanism underlying these effects and their pathophysiological significance remain unclear.

Postnatal interleukin-1ß enhances adulthood seizure susceptibility and neuronal cell death after prolonged experimental febrile seizures in infantile rats.

Febrile seizures (FS) are recognized as an antecedent to the development of temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), but it is unclear whether prolonged FS are a direct cause of TLE-HS. Here, we used a rat model of infantile FS to study the effects of inflammatory cytokines on seizure susceptibility and neuronal death in adults. Prolonged hyperthermia-induced seizures (pHS) were induced in male Lewis rats at post natal day (P) 10. Cytokines were administered twice intranasally, once immediately after pHS and once the following day. The effects of intranasal interleukin (IL)-1ß or tumor necrosis factor (TNF) α were tested in rats undergoing a single episode of pHS (P10) and in rats undergoing repeated pHS (P10 and P12). Seizure susceptibility was tested at P70-73 by quantifying the seizure onset time (SOT) after kainic acid administration, and neuronal cell injury and gliosis in adulthood. SOT significantly reduced in rats receiving IL-1ß together with repeated pHS, whereas no significant effects were seen in rats receiving IL-1ß after a single pHS episode, or in rats receiving TNFα. Hippocampal neuronal cell loss was observed in the CA3 region of rats receiving IL-1ß together with repeated pHS; however, there was no significant change in gliosis among each group. Our results are consistent with the hypothesis that excessive production of IL-1ß after repeated prolonged FS can enhance adult seizure susceptibility and neuronal cell death, and might contribute to the development of TLE-HS.

Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures.

Febrile seizures are associated with increased brain temperature and are often resistant to treatments with antiepileptic drugs, such as carbamazepine and phenytoin, which are sodium channel blockers. Although they are clearly correlated with the hyperthermic condition, the precise cellular mechanisms of febrile seizures remain unclear. We performed patch-clamp recordings from pyramidal cells in acute rat brain slices at temperatures up to 40°C and found that, at ≥37°C, L-type calcium channels are active at unexpectedly hyperpolarized potentials and drive intrinsic firing, which is also supported by a temperature-dependent, gadolinium-sensitive sodium conductance. Pharmacological data, RT-PCR, and the current persistence in Cav1.3 knock-out mice suggested a critical contribution of Cav1.2 subunits to the temperature-dependent intrinsic firing, which was blocked by nimodipine. Because intrinsic firing may play a critical role in febrile seizures, we tested the effect of nimodipine in an in vivo model of febrile seizures and found that this drug dramatically reduces both the incidence and duration of febrile seizures in rat pups, suggesting new possibilities of intervention for this important pathological condition.

GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.

Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

Serum zinc levels are low in children with simple febrile seizures compared with those in children with epileptic seizures and controls.

AIM: To investigate serum zinc levels in children with simple febrile and epileptic seizures and compare them with controls. METHODS: A prospective, case-control study was conducted between July 2009 and September 2010 in Kanchi Kamakoti CHILDS Trust Hospital, Chennai. Sixty-seven children (22 with epileptic seizures, 23 with simple febrile seizures and 22 controls) were enrolled. Serum zinc level was estimated using atomic absorption spectrometry. RESULTS: Mean (SD) serum zinc level in children with epileptic seizures, simple febrile seizures and controls were 969·8 (177·3), 638·1 (206·8) and 939·9 (258·4) ug/L, respectively (p<0·05). CONCLUSION: Serum zinc levels are lower in children with febrile seizures than in those with epileptic seizures and normal children. Zinc supplementation of children at risk of febrile seizures requires further study.

Infant febrile seizures: changes in declarative memory as revealed by event-related potentials.

OBJECTIVE: According to a widespread opinion the vast majority of infant febrile seizures (IFS) are harmless. However, IFS are often associated with hippocampal sclerosis, which should lead to deficient episodic memory with spared context-free semantic memories. Although IFS represent the most common convulsive disorder in children, these consequences are rarely examined. METHODS: We measured the hippocampal volume of 17 IFS children (7-9 years old) and an age-matched control group on the basis of MR images. Furthermore, we examined episodic and semantic memory performance with standardized neuropsychological tests. Two processes underlying recognition memory, namely familiarity and recollection, were assessed by means of event-related potentials (ERP). RESULTS: The IFS children did not show a decreased hippocampus volume. Intelligence, working memory, semantic and episodic memory were intact. However, ERP indices of recognition memory subprocesses revealed deficits in recollection-based remembering that presumably relies on the integrity of the hippocampus, whereas familiarity-based remembering seemed to be intact. CONCLUSIONS: Although hippocampus volume remains unaffected, IFS seems to induce functional changes in the MTL memory network, characterized by a compensation of recollection by familiarity-based remembering. SIGNIFICANCE: This study significantly adds to the debate on the consequences of IFS by differentiating the impact on memory processing.

N-methyl-D-aspartate, hyperpolarization-activated cation current (Ih) and gamma-aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampus.

Febrile seizures are the most common types of seizure in children, and are generally considered to be benign. However, febrile seizures in children with dysgenesis have been associated with the development of temporal lobe epilepsy. We have previously shown in a rat model of dysgenesis (cortical freeze lesion) and hyperthermia-induced seizures that 86% of these animals developed recurrent seizures in adulthood. The cellular changes underlying the increased risk of epileptogenesis in this model are not known. Using whole cell patch-clamp recordings from CA1 hippocampal pyramidal cells, we found a more pronounced increase in excitability in rats with both hyperthermic seizures and dysgenesis than in rats with hyperthermic seizures alone or dysgenesis alone. The change was found to be secondary to an increase in N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs). Inversely, hyperpolarization-activated cation current was more pronounced in naïve rats with hyperthermic seizures than in rats with dysgenesis and hyperthermic seizures or with dysgenesis alone. The increase in GABAA-mediated inhibition observed was comparable in rats with or without dysgenesis after hyperthermic seizures, whereas no changes were observed in rats with dysgenesis alone. Our work indicates that in this two-hit model, changes in NMDA receptor-mediated EPSCs may facilitate epileptogenesis following febrile seizures. Changes in the hyperpolarization-activated cation currents may represent a protective reaction and act by damping the NMDA receptor-mediated hyperexcitability, rather than converting inhibition into excitation. These findings provide a new hypothesis of cellular changes following hyperthermic seizures in predisposed individuals, and may help in the design of therapeutic strategies to prevent epileptogenesis following prolonged febrile seizures.

Short- and long-term limbic abnormalities after experimental febrile seizures.

Experimental febrile seizures (FS) are known to promote hyperexcitability of the limbic system and increase the risk for eventual temporal lobe epilepsy (TLE). Early markers of accompanying microstructural and metabolic changes may be provided by in vivo serial MRI. FS were induced in 9-day old rats by hyperthermia. Quantitative multimodal MRI was applied 24 h and 8 weeks later, in rats with FS and age-matched controls, and comprised hippocampal volumetry and proton spectroscopy, and cerebral T2 relaxometry and diffusion tensor imaging (DTI). At 9 weeks histology was performed. Hippocampal T2 relaxation time elevations appeared to be transient. DTI abnormalities detected in the amygdala persisted up to 8 weeks. Hippocampal volumes were not affected. Histology showed increased fiber density and anisotropy in the hippocampus, and reduced neuronal surface area in the amygdala. Quantitative serial MRI is able to detect transient, and most importantly, long-term FS-induced changes that reflect microstructural alterations.

MRI volumetry of the thalamus in temporal, extratemporal, and idiopathic generalized epilepsy.

OBJECTIVE: To examine the specificity of thalamic atrophy in epilepsy. METHODS: Thalamic volume measurements were carried out using high-resolution MRI in 40 patients with pharmacologically intractable temporal lobe epilepsy (TLE), 16 patients with extratemporal lobe epilepsy (ETE), and 17 with idiopathic generalized epilepsy (IGE). Thalamic volumes of patients were compared with those of 21 neurologically normal control subjects. Volumes were correlated with duration of epilepsy. The effect of prolonged febrile seizures and generalized seizures on thalamic volumes was examined. RESULTS: Compared with normal control subjects, patients with TLE had a reduction in thalamic volume ipsilateral to the seizure focus. Thalamic volumes in patients with ETE and IGE were not significantly different from those of normal control subjects. In TLE patients, thalamic volumes ipsilateral to the seizure focus were negatively correlated with duration of epilepsy. Patients with a history of prolonged febrile seizures had more severe thalamic atrophy ipsilateral to the seizure focus than those without febrile seizures. CONCLUSIONS: Thalamic atrophy ipsilateral to the seizure focus is found in TLE but not in other forms of focal epilepsy or IGE. In TLE, thalamic atrophy is correlated with duration of disease. Patients with a history of prolonged febrile seizures had smaller thalamic volumes ipsilateral to the seizure focus than those without.

Volumetric measurements of subcortical nuclei in patients with temporal lobe epilepsy.

OBJECTIVE: To determine the volumes of subcortical nuclei in patients with chronic epilepsy. BACKGROUND: Animal and human data suggest a crucial role for subcortical structures in the modulation of seizure activity, mostly as seizure-suppressing relays. Although cortical epileptogenic foci can vary in localization and extent, it nevertheless appears that these structures subsequently influence seizure propagation in a universal fashion. There is, however, little knowledge about the size of implicated subcortical structures in patients with epilepsy. METHOD: Using high-resolution MRI, the volumes of selected subcortical nuclei, such as the thalamus, caudate nucleus, putamen, and pallidum, were measured in both hemispheres of 27 patients with temporal lobe epilepsy. Fourteen healthy volunteers served as controls. Statistical analysis was done for both normalized volumes (by total brain volume) and unnormalized volumes. RESULTS: Overall, the patient group had smaller thalamic and striatal volumes in both hemispheres, mostly ipsilateral to the epileptic focus. No significant correlations were noted between volume measurements and age, age at onset, duration of epilepsy, or total seizure frequency, including frequency of generalized seizures. The putamen and thalamus seemed to be affected predominantly in patients with a history of febrile convulsions, whereas patients without febrile convulsions had smaller caudate nuclei bilaterally. CONCLUSIONS: Volumetric measurements of subcortical nuclei reveal atrophy of distinct subcortical nuclei in the patient group, predominantly ipsilateral to the focus. This finding probably reflects persistent abnormalities and not secondary change. In addition, the structural differences between patients with and patients without previous febrile convulsions suggest that these conditions may have different causes.

Hyperthermic seizures: an animal model for hot-water epilepsy.

Freely ambulant wistar adult rats of both sexes when exposed to a hot water jet on the head (50 degrees C - 55 degrees C) for a period of 8-10 minutes, manifested seizure activity similar to the ones noted in 'hot-water epilepsy' (HWE) in humans. Depth electrode recording from the hippocampus revealed seizure discharges during the ictus lasting from 34 seconds to three minutes, followed by low voltage indeterminate activity and a quiescent resting phase. Seizure initiation was noted to be critically dependent on the rectal temperature of 41.5 degrees C and regional hippocampal temperature of 37 degrees C. There appeared to be no clear evidence for kindling phenomenon. Intervention of hyperthermia by cooling the body after the ictus prevented subsequent occurrence of spontaneous seizures. Pathological study of the brain revealed ischaemic changes in specific topographic areas like Sommer's sector in hippocampus, layer 4 and 5 neurons of the cerebral cortex and reticular neurons in the brain stem- a pathological feature reminiscent of the human epileptic brain. Seizure initiation by hyperthermic stimulation with hot water poured over the head, the progression and the EEG recording the seizure activity in these rats appears to resemble the HWE in human subjects and could thus serve as the first animal model for this form of "reflex' epilepsy. This has given new insight into the understanding of human HWE. Our preliminary observations in humans has suggested that HWE is a type of hyperthermic seizure similar to febrile convulsion but differs from it with respect to stimulus and rate of rise in temperature in a susceptible individual.