ReviewEpileptogenesis after prolonged febrile seizures: Mechanisms, biomarkers and therapeutic opportunities
Highlights
► Febrile seizure (FS) duration is an important parameter for epileptogenesis. ► T2 MRI indicates no acute cell loss after FS; sclerosis may be a result of epilepsy. ► Inflammation is important; IL-1B levels are up only in rats that develop epilepsy. ► Coordinate expression changes in sets of genes contribute to epileptogenesis. ► Biomarkers and identification of epileptogenic mechanisms are crucial for treatment.
Introduction
Febrile seizures (FS) are defined as seizures taking place during fever, but which are not a result of an invasive infection of the central nervous system. These seizures occur in infants and young children, with a median age of 11–18 months [42], [88], [107], [112]. Fever-related seizures are very rare in normal adults, so that the ability of fever to generate seizures is generally considered a characteristic of the developing brain. In addition, the reason that FS are the most common of all childhood seizures may derive from the fact that infants and children sustain >6 febrile episodes per year, so that fever is more common than other potential seizure-provoking insults such as trauma or hyponatremia.
FS, both short and long, may occur in both normal children and those with a predisposition to the seizures and to the development of epilepsy, such as ion channel mutations or cortical dysplasia. However, studies indicate that even identical twins may diverge in the presence of long FS and the development of temporal lobe epilepsy (TLE), suggesting that the occurrence of FSE in itself might be epileptogenic in the non-predisposed brain [60]. However, whereas twin studies provide a valuable tool, it is difficult to control clinical studies for host-brain variability. Therefore, discovering if long FS or FSE are sufficient to provoke epilepsy requires controlled experimental models. Here we focus on the following points:
- A.
Are prolonged FS and febrile status epilepticus (FSE) epileptogenic?
- B.
What is the role of predisposing elements of the host brain, such as gene mutations, cortical dysplasia, in FS-induced epileptogenesis?
- C.
What parameters of the FS themselves (duration, severity) govern the development of epilepsy?
- D.
How does epilepsy arise after FS? Several mechanisms (cell loss, inflammation and altered patterns of gene expression) have been implicated in epileptogenesis.
- E.
Are there predictive biomarkers of epileptogenesis?
- F.
What therapeutic strategies can be used for preventing and/or reversing FS-induced epileptogenesis?
For each of these points, we briefly describe available information from clinical studies, followed by contributions of experimental approaches.
Section snippets
Are prolonged FS and FSE epileptogenic?
FS lasting less than 10 or 15 min [2], [14], [89] have not been associated with subsequent epilepsy or cognitive deficits in prospective or retrospective studies [11], [121], [122]. However, the consequences of long FS, one of the forms of complex FS, are controversial [2], [12]. Retrospective studies have linked a history of long FS and subsequent TLE [26], [50], [54], [116]. Prospective studies generally failed to implicate long FS as causing TLE (see [106], for review), although careful
What is the role of predisposing elements of the host brain (gene mutations, cortical dysplasia) on epileptogenesis?
A large body of literature has addressed the potential genetic basis of FS [13], [35], [46], [55], [75], [128], and the hypothesis that characteristics of the brain of the child who has a long FS govern if the child will develop epilepsy. FS run in families [15], [16] but are also more common in children in day-care centers [17], and their generation is likely a result of both genetic and environmental causes that vary in each individual [13], [25], [47]. In several clear instances, specific
What parameters of the FS themselves (duration, severity) govern the development of epilepsy?
In children, simple FS are defined as short (<10 or 15 min), and without focal features. The vast majority of epidemiological studies suggest that these FS are not associated with epileptogenesis [2], [11], [89]. Complex FS are defined as seizures that are long (>10–15 min), or with focal features (e.g., involvement of one side of the body), or recur within 24 h of the first episode [2], [88] or within the same febrile illness [23]. In addition FSE is generally defined as FS longer than 30 min [93]
Is epileptogenesis associated with cell loss?
One of the structural hallmarks in patients with mesial TLE and a history of long FS is a specific pattern of cell loss in hippocampus, i.e. mesial temporal sclerosis (MTS), and a reorganization of the remaining circuit [34], [59], [79], [85], [114]. These changes are considered by many to be required for epileptogenesis [7], [91], [108]. The nature of the relationship between cell loss and epileptogenesis in humans after long FS remains unclear. It has been widely hypothesized that FS cause
Predictive biomarkers of epileptogenesis
If FS lead to TLE, this process arises only in a subset of children. Defining predictive biomarkers to identify the individuals experiencing long FS and/or FSE that are risk for epilepsy is critical and should provide a powerful tool for testing of potential interventions. MRI changes and EEG activity alterations could constitute excellent biomarkers because they can be quantified and repeated.
Early MRI changes, specifically, increased T2 signal arising within days after long FS in children,
What therapeutic strategies can be used for preventing and/or reversing FS-induced epileptogenesis?
The evidence summarized here indicates that long FS and FSE may provoke epilepsy. In addition, the duration of the FSE seems to be an important determinant of the development of subsequent limbic epilepsy in the non-predisposed brain (Fig. 1). These findings suggest that preventing long FS should be a therapeutic goal. In addition, because it is clinically not feasible to abort all long FS and FSE, identification of children at risk for epileptogenesis should lead to preventive measures. At the
Acknowledgments
The authors thank Mrs. Barbara Cartwright for excellent editorial help. Supported by NIH grant R37NS35439, T32NS045540, and NS35439-S1 (ARRA).
References (131)
- et al.
Human herpesvirus-6 infection in children with first febrile seizures
J. Pediatr.
(1995) - et al.
A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome
Am. J. Hum. Genet.
(2008) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy
Neuroscience
(1985)- et al.
Effects of seizures on developmental processes in the immature brain
Lancet Neurol.
(2006) - et al.
Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures
Neurobiol. Dis.
(2005) - et al.
Repetitive febrile seizures in rat pups cause long-lasting deficits in synaptic plasticity and NR2A tyrosine phosphorylation
Neurobiol. Dis.
(2005) - et al.
Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures
Neuron
(2003) - et al.
Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy
Brain Res.
(1989) - et al.
Fever, febrile seizures and epilepsy
Trends Neurosci.
(2007) - et al.
Febrile seizures: mechanisms and relationship to epilepsy
Brain Dev.
(2009)
Cognitive dysfunction after experimental febrile seizures
Exp. Neurol.
Longitudinal EEG and clinical study of children with febrile convulsions
Electroencephalogr. Clin. Neurophysiol.
Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus
Am. J. Hum. Genet.
Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat
Neuroscience
Short- and long-term limbic abnormalities after experimental febrile seizures
Neurobiol. Dis.
Interleukin-1beta levels in serum and cerebrospinal fluid of children with febrile seizures
Pediatr. Neurol.
Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy
Neuroscience
Long-term behavioral outcome after early-life hyperthermia-induced seizures
Epilepsy Behav.
h channel-dependent deficit of theta oscillation resonance and phase shift in temporal lobe epilepsy
Neurobiol. Dis.
Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities
J. Biol. Chem.
Hippocampal neuron damage in human epilepsy: Meyer's hypothesis revisited
Prog. Brain Res.
Comorbidity between epilepsy and depression: role of hippocampal interleukin-1beta
Neurobiol. Dis.
Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy
Prog. Brain
Febrile seizures: characterization of double-stranded RNA-induced gene expression
Pediatr. Neurol.
The interleukin-1 system: receptors, ligands, and ICE in the brain and their involvement in the fever response, Ann
N. Y. Acad. Sci.
Factors prognostic of unprovoked seizures after febrile convulsions
N. Engl. J. Med.
A novel GABRG2 mutation associated with febrile seizures
Neurology
An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability
J. Neurosci.
Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures
Hippocampus
Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus
J. Neurosci.
Unprovoked seizures in children with febrile seizures: short-term outcome
Neurology
Complex febrile seizures
Epilepsia
Risk factors for a first febrile seizure: a matched case–control study
Epilepsia
Predictors of recurrent febrile seizures: a prospective cohort study
Arch. Pediatr. Adolesc. Med.
Childhood-onset epilepsy with and without preceding febrile seizures
Neurology
Febrile seizures: genetics and relationship to other epilepsy syndromes
Curr. Opin. Neurol.
Which child will have a febrile seizure?
Am. J. Dis. Child.
Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy
Neurology
Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors
Brain Pathol.
Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [gamma 2(R43Q)] found in human epilepsy
Proc. Natl. Acad. Sci. U. S. A.
Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner
J. Neurosci.
Febrile seizures
Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat
J. Physiol.
Risk of febrile seizures in childhood in relation to prenatal maternal cigarette smoking and alcohol intake
Am. J. Epidemiol.
Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study
Neurology
Febrile seizures impair memory and cAMP response-element binding protein activation
Ann. Neurol.
Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits
Nat. Med.
Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability
Nat. Med.
Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures
J. Neurosci.
Developmental hyperthermic seizures alter adult hippocampal benzodiazepine binding and morphology
Epilepsia
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- 1
These two authors have contributed equally to this work.