Fever, Febrile Seizures and Epileptogenesis

Jasper's Basic Mechanisms of the Epilepsies
Fever, febrile seizures and epileptogenesis

Cline M. Dub
Shawn McClelland
ManKin Choy
Amy L. Brewster
Yoav Noam
Tallie Z. Baram
Departments of Anatomy/Neurobiology, Pediatrics and Neurology, University of California Irvine, Irvine,
CA USA, 92697-4475
Summary
Febrile seizures (FS) are the most common types of seizures in children around the world, yet
remarkably little is known about the mechanisms generating these seizures. In addition, long duration
or focal FS are associated with increased probability of temporal lobe epilepsy (TLE), but it remains
unclear as to whether this relationship is causal. A specific major clinical enigma has centered on
whether FS themselves can provoke TLE in individuals without genetic or structural predisposition.
In addition, the mechanisms of FS-related epileptogenesis require elucidation. Individuals with TLE
and a history of FS have been found to often have a specific pattern of cell loss within the
hippocampus, known as mesial temporal sclerosis (MTS). However, if FS cause MTS, or if the cell
loss is secondary to the TLE has also been enigmatic.
We created and characterized an immature rodent model of FS, which has been useful in defining
how fever leads to FS, and if FS lead to epilepsy. Using this rat model, we established that long
duration FS cause TLE, and FS duration governed the severity of epilepsy. Epileptogenesis was
accompanied, perhaps causally, by ion channel dysfunction and inflammatory changes. Because FS
are a prevalent antecedent of TLE, studying the epileptogenesis that follows them provides powerful
insights, and may lead to potential therapies for epilepsy.
1Introduction
Febrile seizures (FS) are the most common type of convulsions in infants and young children,
occurring in 26% of children.1,2 They are defined as seizures arising during fever, not caused
by an infection of the central nervous system. However their definition does not exclude
children with pre-existing neurological deficits, a fact that might confound studies on the
outcome of these seizures. Although there is limited evidence for adverse outcomes of simple
(defined as short, with no focal motor phenomena) FS on the immature brain, complex FS,
particularly long duration FS or febrile status epilepticus (defined as seizures lasting more than
30 minutes) have been associated with subsequent limbic epilepsy as indicated from both
prospective and retrospective studies as well as from recent data in animal models.314 Some
investigators have suspected that long FS might result in cognitive defects in a subset of
children.1517 Understanding the basic mechanisms of FS, and the potential epileptogenesis
that follows them, requires animal models which enable the investigator a direct examination
of causal mechanisms for the generation and consequences of these seizures. The mechanisms
by which fever leads to FS, the outcome of FS measured as the risk of epilepsy, the properties
of FS associated with limbic epilepsy, and the mechanisms of epileptogenesis are discussed in
the following paragraphs.
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2How does fever cause seizures?

Genetic susceptibility to FS
FS occur sporadically and also run in families, suggesting a contribution of genetic background
to their onset.18 In immature rodents, including mice and rats of many different strains, all the
animals developed hyperthermia-induced seizures indicating that genetic susceptibility is not
necessarily required for their generation. 12,1921 Conversely, the fact that seizure-temperature
thresholds (a measure of excitability),22,23 vary among mouse strains with differing genetic
make-up, suggests the involvement of genotype in these seizures. Recently, increased
susceptibility to FS has been found to result from mutations of several genes, including sodium
channels,2426 GABAA receptors,2730 and hyperpolarization-activated cyclic nucleotide-gated
(HCN) channels.31 Other single gene mutations, such as in the interleukin gene promoter, might
predispose individuals to FS.32 In addition several genes might interact to promote the
occurrence of these seizures in a more complex manner.
Increased brain temperature as a mechanism of FS
Temperature influences neuronal properties.33 The functions of specific ions channels (e.g.,
transient receptor potential vanilloid, 1 and 4) are regulated by brain temperature in the
physiological and fever ranges.34,35 Therefore, elevating brain temperature should increase
neuronal firing culminating in a seizure. Notably hyperthermia induced by hot baths36 or
overdose on hyperthermia-inducing medications (anticholinergic),37 can provoke seizures in
children, indicating that increased temperature in itself can generate seizures. However the
exact mechanisms by which increased temperature might lead to the generation of FS are not
fully elucidated.
Fever mediators lead to seizures
Fever not only increases brain temperature but also involves release of inflammatory mediators,
particularly cytokines38,39 such as interleukin-1 (IL-1) within the brain. IL-1 contributes
to neuronal hyperexcitability long term, in part by increasing ceramide-induced Src-family of
tyrosine kinase function.40 Acute changes of brain excitability might derive from the enhanced
calcium influx through glutamate receptors.41 In addition, IL-1 exacerbates convulsantinduced seizures.42,43 The involvement of endogenous IL-1 in the generation of FS was
supported by the increased threshold temperature required to elicit experimental FS in mice
lacking the Interleukin-1 receptor type 122 (Figure 1). Interestingly higher levels of this
cytokine have been detected in individuals with FS with a mutation in the IL-1 gene
promoter32 - although the significance of this finding has been debated.44 It is intriguing that
fever of specific infectious etiologies, and specifically human herpes virus 6, might influence
the probability of generation of FS.45,46 Whether this virus, compared with other pathogens,
leads to higher levels of cytokines in the childs brain has not been studied.
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Figure 1. Mice lacking the IL-1 receptor type 1 (IL-1RI /) are more resistant to the generation
of experimental FS, compared to wild-type controls of a similar genetic background (129/Sv)
Threshold temperatures for the onset of these seizures were significantly higher in IL-1RI / mice (42.4 0.3C, n = 26) compared
with wild-types (41.3 0.2 C, n = 21). (Reprinted with permission from,22 Wiley Interscience).
Hyperthermia-induced hyperventilation and alkalosis

Hyperthermia-induced hyperventilation and the consequent alkalosis have been suggested as
important mechanisms for the generation of FS. Brain alkalosis has been shown to promote
neuronal excitability47,48 and may contribute to seizure pathophysiology in models with a long
delay from hyperthermia to seizure onset.49 However it should be noted that severe alkalosis
that is found during prolonged crying, and that can exist for weeks in babies with pyloric
stenosis, has not been correlated with a higher incidence of seizures (fever-induced or
otherwise).
3Do febrile seizures cause epilepsy?

There is little evidence for an enduring adverse impact of short FS on the developing
brain.4,50,51 However, prolonged or focal FS have been associated with the development of
limbic (temporal lobe) epilepsy.3,6,7,52 What is the neurobiological basis of this statistical
correlation? Do long FS cause temporal lobe epilepsy (TLE)? Are FS a marker of pre-existing
pathology? Is there a common denominator or cause that independently leads to FS and TLE,
or that alters the probability that FS would result in TLE?
A causal relationship between long duration FS and the development of TLE is difficult to
demonstrate or refute in humans, because of the diverse genetic make-up of children or other
uncontrolled pre-existing factors. Single gene (e.g., ion channel, see above) mutations, or a
combination of multiple susceptibility genes, might predispose certain individuals to FS or to
the development of epilepsy following FS.25,27,28,31 In addition, the previous history of a child
might render him/her more vulnerable to FS or their pro-epileptic or cognitive consequences.
Controlling for these genetic and environmental/acquired factors is very difficult.
Therefore, to facilitate investigation of these seizures and their consequences, several animal
models of prolonged FS11,14,1921,49,53,54 have been developed. In recent years, these models
have led to fundamental discoveries about the mechanisms of these seizures, their effects on
neuronal excitability, and their relationship to epilepsy.8,12,5559 We have devised and
characterized a model of FS in infant rats and mice. Because fever cannot be reliably induced
in suckling rodents,60 we employed hyperthermia. Core and brain temperatures were raised to
the range of 39.5 to 41.5C, for 30 minutes or ~60 minutes (recreating febrile status epilepticus)
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in 1011 days old rats,12,21 an age when hippocampal development approximates to that of
human infants.61 In this model, core body measurements provide an adequate approximation
of brain threshold temperature for experimental FS.62 As described above, hyperthermia and
fever utilize common mechanisms to elicit the seizures because hyperthermia leads to the
release of cytokines.
Using this model, we determined if long duration FS, induced at the stage of hippocampal
development that corresponds to that of human infants,61 leads to the development of limbic
epilepsy. We demonstrated that experimental FS cause spontaneous recurrent seizures in a
significant proportion of animals (35%) later in life.57 These later seizures, resulting from an
early 20 minute FS, consisted of sudden freezing and typical limbic automatisms (stage 1)63
that were coupled with polyspike/sharp-wave trains with increasing amplitude and slowing
frequency on EEG. In addition, interictal epileptiform discharges were recorded in 88.2% of
the experimental FS group. Interictal activity was never detected in normothermic control rats
nor in hyperthermic control rats (animals that sustained hyperthermia with no seizures).57
Because, as described above, predisposing factors, both genetic and acquired, have largely
been excluded in this model, these studies directly supported a causal relationship of long FS
and the development of TLE, and set the stage for investigating the mechanisms by which these
seizures promote epileptogenesis.
4Which FS cause epilepsy?
FS occur in 26% of children,2,64,65 and are prolonged in ~15% of this group.1,6668 As

mentioned above, a key issue about FS has involved the clinical question of whether long
duration FS cause epilepsy, and if so, why the process takes place only in some individuals.
To address this question, we tested the hypothesis that seizure duration was a key parameter
that governs epileptogenesis, as suggested from clinical studies.4,7 We found that experimental
FS lasting ~20 minutes resulted in limbic epilepsy in ~35% of rats.57 In contrast, when we
increased the duration of seizures to ~60 minutes, we found that ~45% of rats developed limbic
epilepsy13. Importantly, whereas the spontaneous seizures that resulted from FS lasting ~20
minutes were mild (Racine63 stage 1; duration average ~8 sec), the duration of seizures
constituting the limbic epilepsy provoked by febrile status epilepticus (FSE; 60 minute FS)
was much longer: 137 seconds on average (Figure 2). The behavioral manifestations of the
epileptic seizures was also more pronounced and included head bobbing, alternating or bilateral
clonus, rearing and falling (Racine stages 25).63 The interictal activity recorded from cortical
and hippocampal electrodes varied according to the duration of the inciting FS. Interictal
activity was found in 84% of rats sustaining a ~60 minute inciting FS, and individual interictal
activity bouts were significantly longer and more robust than that after a ~20 minute
seizure13. However the presence and the duration of the interictal events did not predict the
development of epilepsy. Thus, using an animal model enabled us to define the duration of FS
as an important predictor of the severity of the TLE that develops after FS. This finding, in line
with suggestive clinical literature,6972 carries enormous implication for the clinical
management of FS.
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Figure 2. Examples of typical spontaneous electrographic seizures recorded from hippocampal and
cortical bipolar electrodes in adult rats that had experienced (A) a 20 minute or (B) a 60 minute
experimental FS
In the 60 minute epilepsy model, spontaneous seizures commenced first in the hippocampus and propagated to the cortex (Figure
2B) where epileptiform cortical discharges were apparent. In epilepsy generated by a 20 minute FS (Figure 2A) the epileptic
seizure propagation to the cortex consisted of suppression. Note the duration of seizures was significantly longer after a 60 minute
FS compared to a 20 minute FS (Mean: 137 and 8 seconds, respectively; median durations, 91 and 7 seconds, respectively). Arrows
point to onset and end of epileptiform discharges. Calibration: 1 sec. (Reprinted with permission from13 Society for Neuroscience).
5How do FS cause epilepsy?

The mechanisms by which long FS might contribute to the development of TLE are not fully
resolved. Here we review several mechanisms that have been implicated in epileptogenesis,
and discuss their role in the epileptogenic process that follows long experimental FS.
Inflammation and cell loss
As mentioned above, the inflammatory cytokine IL-1 contributes to the generation of
experimental (and probably human) FS. However whether or not IL-1 contributes to the
epileptogenic process that is triggered by FS has remained unclear. We found that IL-1
expression was induced in reactive astrocytes for at least 24 hours after a ~60 minute FS and
returned to basal levels within 72 hours.13 Interestingly, when FS-sustaining rats that became
epileptic were compared to those in which the inciting FS did not lead to spontaneous seizures,
hippocampal IL-1 levels were higher only in rats that developed epilepsy compared to the
controls13.
Cytokines and other inflammatory mediators have been shown to contribute to neuronal injury
and death.7375 In the mature brain, limbic seizures lead to the loss of vulnerable hippocampal
cell populations7679 and this loss is considered by many to be required for
epileptogenesis76,78,79. In the FS model described above, a model that has been adopted by
several other groups, appreciable neuronal death has not been found.13,54,57,80 The seizures
did provoke neuronal injury in the same cell distribution experiencing cell damage in human
mesial temporal sclerosis (MTS); yet, the involved neurons did not seem to die.21 Neurogenesis
was also not detected after these seizures, and mossy fiber sprouting was minimal.14,54,80,81
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Therefore, such structural alterations are unlikely to account for the epileptogenic process that
follows long FS.
Role of changes in the expression of gene sets, including ion channels, in FS-induced
epileptogenesis
The likely mechanisms of epileptogenesis that follow experimental (and perhaps human) long
duration FS involve profound and persistent molecular changes in hippocampal neurons that
induce alterations of their intrinsic excitability and network properties. Numerous molecular
changes have been described after experimental FS (reviewed in 82) and many are as yet not
known. Lasting changes in the expression of specific genes such ion channels and
endocannabinoid receptors have been explored to date. For example, experimental long
duration FS led to altered expression of ion channels conducting Ih, a hyperpolarizationtriggered cationic current that contributes to the maintenance of neuronal membrane potential,
subthreshold oscillations, and dendritic integration.8385 This change in Ih promoted
frequency-dependent rebound depolarization in response to hyperpolarizing input; this
rebound depolarization was augmented after the seizures.8,55 At the molecular level, these
changes were a result of long-lasting reduction in the expression of the HCN1 isoform, leading
to an increased HCN2/HCN1 ratio and augmented heteromerization of these two
isoforms.86,87 Remarkably, reduction of HCN1 expression has since emerged as a fairly
general principle in a number of models of acquired TLE.8892 HCN1 channel expression was
found altered in a subset of resected hippocampi from patients with TLE and MTS, often with
a history of early life seizures.93 As mentioned above, mutations in HCN channel genes have
recently been discovered in individuals with epilepsy,31 further supporting the role of these
channels in the epileptogenic process. The precise mechanisms by which alterations in HCN
channels and Ih contribute to human epileptogenesis are not fully understood.
An additional mechanism by which long FS may promote hyperexcitability involves an

increase of a short-term plasticity phenomenon known as depolarization-induced suppression
of inhibition (DSI).56 DSI is mediated by cannabinoid receptors (CB1).94,95 Following
experimental FS, increased release of endocannabinoids upon post-synaptic depolarization of
hippocampal pyramidal cells led to an enhancement of the number of presynaptic cannabinoid
type 1 receptors, promoting an increased retrograde inhibition of GABA release, that resulted
in a reduction of inhibition in the hippocampal circuit.9,56
Activation of specific transcription factors by seizures, including experimental FS, has been
recently found,96 suggesting that rather than changes in single genes (even those governing
important properties of the neuron), a coordinated change in the expression of gene clusters
may be an important mechanism in the transformation of normal neurons and neuronal
circuits into epileptic ones. One can only speculate that, in addition to the mechanisms
described above, many other alterations in gene expression will be found - after experimental
and human prolonged FS - that will contribute to the epileptogenic process.
6Relationship between Febrile Seizures, Mesial Temporal Sclerosis and

Temporal Lobe Epilepsy
The absence of cell loss in rats that became epileptic following long duration FS and FSE raises
questions regarding the causal relationship of cell loss to epileptogenesis in children sustaining
these seizures. One of the structural hallmarks in patients with mesial TLE with a history of
long duration FS is a specific pattern of cell loss in hippocampus, i.e MTS. It has been widely
hypothesized that FS cause MTS, and that the development of TLE is a consequence of
MTS.69,71,97 An alternative view is also supported by clinical data: MTS results from the
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recurrent seizures in individuals with TLE after FS.98100 The absence of cell loss in epileptic
rats in our model is more consistent with the latter view.
In addition, increased T2 relaxation time seen on MRI was reported in children with FSE and
interpreted as indicating MTS.69,71,97 In our animal model we found abnormally elevated T2
relaxation times in the hippocampus in a subpopulation of FS-experiencing rats13,17 (Figure
3). These T2 changes on MRI were not associated with increased water content (Dub,
unpublished observations) and not accompanied by neuronal loss in the hippocampus. These
data suggest that acute MRI changes after long FS should be interpreted with caution.
Interestingly, the MRI changes observed in the hippocampus of a subset of rats following long
duration FS were predictive of hippocampal dysfunction manifesting as cognitive defects.17
Figure 3.
(A) Examples of T2-weighted images obtained one month after a 60 minute FS: T2 signal (arrows) increased in hippocampus of
a subset of rats that experienced long FS (right panels) compared with control rats (left panels). Absolute T2 relaxation time values
(ms) were calculated on a pixel-by-pixel basis from the T2 weighted images and T2 maps were generated. FS rats segregated into
two groups: one group with hippocampal T2 relaxation time values significantly higher compared to the mean of the control and
a second group with similar T2 values to those of controls (Reprinted with permission from13 Society for Neuroscience). (B)
Examples of 3D reconstruction of the hippocampi of two rats that sustained FS: pixels with significantly higher hippocampal T2
values compared to the values found in controls are noted in orange.
7Future directions
FS are common and important and we have only a partial understanding of their generation
and consequences. Whereas short (simple) FS are benign, more work is needed to tease out
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the neurobiological basis of the consequences of long duration FS and FSE -- both cognitive
changes as well as epileptogenesis.
Among the key remaining goals in this field is the development of early and effective
biomarkers that will define which child with long duration FS is at risk for epilepsy or cognitive
sequelae. Such surrogate markers of the disease process that culminate in the development of
TLE and/or cognitive deficits should provide powerful tools for testing potential interventions
aimed at stopping or reversing the epileptogenesis.
An additional important goal is the elucidation of the complex mechanisms underlying
epileptogenesis that follows long FS. Current data suggest that persistent changes in the
expression and function of gene sets that regulate neuronal and network activity (including
cytokines and ions channels) might be involved. Identifying the key genes that contribute to
the development of these sequelae, and delineating the mechanisms (e.g. epigenetic) that
regulate these genes, may provide molecular targets for the development of novel preventive
and therapeutic strategies for preventing the development of TLE after long duration FS.96
Acknowledgments
The authors thank Mrs. Barbara Cartwright for excellent editorial help. Supported by NIH grant R37 NS35439 and
NS35439-S1 (ARRA).
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