Elsevier

Neuroscience Letters

Volume 497, Issue 3, 27 June 2011, Pages 155-162
Neuroscience Letters

Review
Epileptogenesis after prolonged febrile seizures: Mechanisms, biomarkers and therapeutic opportunities

https://doi.org/10.1016/j.neulet.2011.02.032Get rights and content

Abstract

Epidemiological and recent prospective analyses of long febrile seizures (FS) and febrile status epilepticus (FSE) support the idea that in some children, such seizures can provoke temporal lobe epilepsy (TLE). Because of the high prevalence of these seizures, if epilepsy was to arise as their direct consequence, this would constitute a significant clinical problem. Here we discuss these issues, and describe the use of animal models of prolonged FS and of FSE to address the following questions: Are long FS epileptogenic? What governs this epileptogenesis? What are the mechanisms? Are there any predictive biomarkers of the epileptogenic process, and can these be utilized, together with information about the mechanisms of epileptogenesis, for eventual prevention of the TLE that results from long FS and FSE.

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).

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