History Of Prolonged Febrile Seizures Research Articles

Glutamatergic pathway in depressive-like behavior associated with pentylenetetrazole rat model of epilepsy with history of prolonged febrile seizures

BackgroundDepression is the most significant cause of suicide among neuropsychiatric illnesses. Major depression further affects the quality of life in an individual with epilepsy. The treatment of depression in an epileptic patient could be very challenging because of drug selection or the fact that some antiepileptic drugs are known to cause depression. It has been shown that in addition to the known involvement of the serotonergic pathway in depression, the glutamatergic system is also involved in the evolution of the disease, but this knowledge is limited. This study assessed if induction of epilepsy in rats will cause depressive-like behavior, alters the concentrations of metabotropic receptor 5 (mGluR5), glutamate transport protein (GLAST), glutamate synthase (GS) and brain derived neurotrophic factor (BDNF). Materials and methodEpilepsy was induced in rats by injecting Pentylenetetrazole at 35 mg/kg every other day. At kindle, rats were subjected to sucrose preference test (SPT) and forced swim test (FST) and decapitated 4 h later. Hippocampal tissue was collected and the BDNF concentration was measured with ELISA; mGluR5 and GS protein expression was measured using western blot while amygdala tissue was used for GLAST expression with flow cytometry. ResultsOur results showed that epilepsy leads to depressive-like behavior in rats and alters the glutamatergic system. ConclusionTherefore, we conclude that targeting the glutamate pathway may be a good strategy to alleviate depressive-like behavior associated with epilepsy.

Binding of NRSF to the HCN1 Gene Represses Expression after Seizures

Epilepsy is a devastating disorder that affects millions of people worldwide. One of the most common types of epilepsy, temporal lobe epilepsy (TLE), is associated with significant morbidity in cognitive and psychosocial dysfunction. TLE has long been correlated with a history of prolonged febrile seizures in childhood; hence, understanding the consequences of prolonged febrile seizures on TLE is of considerable clinical significance. The Baram Laboratory has consistently observed down-regulation after seizures of the hyperpolarization-activated cyclicnucleotide gated 1 (HCN1) channels that are responsible for mediating hyperpolarizationactivated (Ih) currents. In the hippocampus, these currents regulate the resting membrane potential, shape rhythmic and synchronized neuronal activity, and regulate the temporal summation of dendritic depolarization. This study targets the factors responsible for regulating the transcription of the HCN1 gene. By using chromatin immunoprecipitation (ChIP), polymerase chain reaction (PCR), and DNA electrophoresis, we show that the neuron restrictive silencer factor (NRSF) binds to the NRSE region in the first intron of the HCN1 gene. NRSF, in conjunction with its cofactors, deacetylates and methylates the chromatin, preventing transcription of the HCN1 gene. Such biochemical change may produce neuronal injury to the developing brain, promoting the onset of epilepsy.

IL-1β: an important cytokine associated with febrile seizures?

Febrile seizures (FSs) are the most common convulsions in childhood. Studies have demonstrated a significant relationship between a history of prolonged FSs during early childhood and temporal sclerosis, which is responsible for intractable mesial temporal lobe epilepsy. It has been shown that interleukin-1β (IL-1β) is intrinsically involved in the febrile response in children and in the generation of FSs. We summarize the gene polymorphisms, changes of IL-1β levels and the putative role of IL-1β in the generation of FSs. IL-1β could play a role either in enhancing or in reducing neural excitability. If the enhancing and reducing effects are balanced, an FS does not occur. When the enhancing effect plays the leading role, an FS is generated. A mild imbalance can cause simple FSs while a severe imbalance can cause complex FSs and febrile status epilepticus. Therefore, anti-IL-1β therapy may help to treat FSs.

Mesial Temporal Sclerosis in a Cohort of Children With SCN1A Gene Mutation

Mesial temporal sclerosis is uncommon in childhood but has been associated with febrile status epilepticus. SCN1A gene mutations are linked to multiple epilepsy syndromes with patients frequently presenting with prolonged febrile seizures. After observing mesial temporal sclerosis in a child with SCN1A gene mutation, we retrospectively reviewed magnetic resonance imaging (MRI) findings in all patients with SCN1A gene mutation identified between 2005 and 2010. We identified 20 patients with SCN1A mutations. Six patients had evidence of definite mesial temporal sclerosis with 2 patients having bilateral abnormalities. Another 4 patients were defined as having possible mesial temporal sclerosis. This patient group revealed that 50% had findings consistent with definite or possible mesial temporal sclerosis and many did not have a history of prolonged febrile seizures. We conclude that mesial temporal sclerosis is a common finding in children with SCN1A mutations. Many of these children will have Dravet syndrome but not all.

Long-term follow-up and outcome of children with febrile seizures

Febrile seizures (FS) precede the onset of various forms of epilepsy in 10%-15% of children. The risk of epilepsy in children with FS is 3% by the age of 7 years. Complex FS are associated with younger age at onset of epilepsy. One-third of patients with temporal lobe epilepsy have a previous history of prolonged febrile seizures. Retrospective data analysis of patients with FS treated at our Neuropediatric Unit and Outpatient Clinic in the last 20 years revealed 880 patients with FS: simple 81.1% and recurrent /complex 18.9%. Thirty-three children had subsequent non-febrile seizures. In 23 children, epilepsy occurred 1-5 years following FS: idiopathic generalized in five, partial idiopathic or cryptogenic extratemporal in seven, temporal in two, and symptomatic partial in three children. After FS, two children had epileptic encephalopathy, two had syndromes with molecular abnormalities, and one child had Fahr disease. One girl who presented for the first time with febrile status epilepticus had Sturge-Weber syndrome. Out of 23 children with epilepsy, 13 had previously had one FS episode and ten recurrent FS. Seven children had good control of epilepsy, while six children had normal intellectual development. Reviewing our 880 patients with FS revealed that 2.6% of them developed epilepsy and two of them had refractory idiopathic temporal lobe epilepsy. There was no case of hippocampal sclerosis in our children with FS and subsequent epilepsy.

Febrile seizures and mesial temporal sclerosis.

The sequence of febrile seizures followed by intractable temporal lobe epilepsy is rarely seen from a population perspective. However, several studies have shown a significant relationship between a history of prolonged febrile seizures in early childhood and mesial temporal sclerosis. The interpretation of these observations remains quite controversial. One possibility is that the early febrile seizure damages the hippocampus and is therefore a cause of mesial temporal sclerosis. Another possibility is that the child has a prolonged febrile seizure because the hippocampus was previously damaged by a prenatal or perinatal insult or by genetic predisposition. Imaging studies have shown that prolonged and focal febrile seizures can produce acute hippocampal injury that evolves to hippocampal atrophy, and that complex febrile seizures can originate in the temporal lobes in some children. Several lines of evidence now indicate that genetic predisposition is an important causal factor of febrile seizures and mesial temporal sclerosis. From recent clinical and molecular genetic studies, it appears that the relationship between febrile seizures and later epilepsy is frequently genetic, and there are several syndrome-specific genes for febrile seizures. Mesial temporal sclerosis probably has different causes. A number of retrospective studies showed that complex febrile seizures are a causative factor for the later development of mesial temporal sclerosis and temporal lobe epilepsy. However, contradictory results have come from several prospective and retrospective studies. The association between febrile seizures and temporal lobe epilepsy probably results from complex interactions between several genetic and environmental factors.

Febrile seizures and mechanisms of epileptogenesis: insights from an animal model.

Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family history, suggesting that this limbic epilepsy is a consequence of acquired rather than genetic causes. Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-->60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. However, the statistical correlation between febrile seizures and TLE does not necessarily indicate a causal relationship. For example, preexisting (genetic or acquired) 'causes' that result independently in febrile seizures and in TLE would also result in tight statistical correlation. For obvious reasons, complex febrile seizures cannot be induced in the human, and studies of their mechanisms and of their consequences on brain molecules and circuits are severely limited. Therefore, an animal model was designed to study these seizures. The model reproduces the fundamental key elements of the human condition: the age specificity, the physiological temperatures seen in fevers of children, the length of the seizures and their lack of immediate morbidity. Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. Experimental prolonged febrile seizures did not lead to death of any of the seizure-vulnerable populations in hippocampus, and the rate of neurogenesis was also unchanged. Neuronal function was altered sufficiently to promote synaptic reorganization of granule cells, and transient and long-term alterations in the expression of specific genes were observed. The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.

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.