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The role of neuroimaging in the investigation of patients with single seizures, febrile seizures, or refractory partial seizures.

Seizures are a symptom of an underlying brain disorder. The accurate identification of the nature of the disease generating the seizures facilitates treatment and can prevent further brain damage. The understanding of the physiopathology underlying the seizures has been greatly enhanced by the possibility to examine these patients with advanced forms of neuroimaging. Among different forms of investigation, neuroimaging techniques play a major role in diagnosis and decision-making in the care of patients with epilepsy. We review the contributions of current methods of imaging in the investigation of patients with single seizures, febrile seizures or refractory seizures, assessing the practical aspects, benefits, and operational costs of various neuroimaging techniques. The focus is on MRI, which is the imaging modality of choice for outpatient investigation. We also assessed the benefits from CT scans, which remain the first option for emergency seizure assessment. The aim was to evaluate how the structural, functional and metabolic information provided by modern techniques of neuroimaging decreases the need for additional investigation and speeds the management of these epileptic disorders. This makes it possible to accurately define the location and the nature of the epileptogenic lesions related to seizures.

Brain↗

Febrile seizures.

Febrile seizures are the most common form of childhood seizures, occurring in 2 to 5% of children in the United States. Most febrile seizures are considered simple, although those with focal onset, prolonged duration, or that occur more than once within the same febrile illness are considered complex. Risk factors for a first febrile seizure, recurrence of febrile seizures, and development of future epilepsy are identifiable and varied. Children with febrile seizures encounter little risk of mortality and morbidity and have no association with any detectable brain damage. Recurrence is possible, but only a small minority will go on to develop epilepsy. Although antiepileptic drugs can prevent recurrent febrile seizures, they do not alter the risk of subsequent epilepsy. This has led to a changing view of how we approach the treatment of these common and largely benign seizures. This chapter will review the current understanding of the prognosis and management of febrile seizures.

Analgesics, Non-Narcotic↗

Controversies in febrile seizures.

Febrile seizures are benign, self limiting, common neurological problems encountered in children between 3 months and 5 years. Controversies exist regarding its definition and it is important to distinguish between the terms febrile seizures and convulsions with fever. In the vast majority, febrile seizures occur within the first 24 hours of illness, and an encephalitic process should be considered if it occurs later, especially with exanthema. The temperature threshold varies in the same child and from one child to another. Febrile seizures are classified as simple and complex and debate continues regarding the usage of these terms and their prognostic value. Practice parameters are suggested regarding the performance of lumbar puncture in a child with first febrile seizure, but they should be used as guidelines and the decision depends on the experience and judgement of the physician. EEG is of limited value and not a guide to treatment or prognosis and neuroimaging not recommended. The predictors of recurrent febrile seizures include younger age, lower threshold of temperature, onset within one hour of fever and positive family history. Whether the syndrome of mesial temporal sclerosis beginning with prolonged febrile seizure has a causal relationship with pre existing brain disease is a matter of debate. There are effective therapies to prevent febrile seizures but the potential side effects of drugs outweigh their benefit. Intermittent prophylaxis during fever may be effective but long term prognosis is not influenced by the treatment applied in early childhood. A practical approach to a child with febrile seizure is suggested.

Analgesics, Non-Narcotic↗

Prevention and management of febrile seizures.

Febrile seizures are the most common seizures in childhood and, like all seizures, can be frightening to witness. Therefore, it is not surprising that febrile seizures have been the focus of intense research with an extensive literature describing various preventative measures. In addition, there is also an extensive and sophisticated epidemiological literature delineating the natural history of this disorder in American and British children. For simple febrile seizures, the most common form of this disorder, the epidemiological studies demonstrate a generally benign natural history, making it unlikely that any preventative measure could improve the long term outcome for most children. Children with simple febrile seizures have a slight increased risk of epilepsy, but there are no studies that demonstrate that phenobarbital or other therapy can alter this risk. Daily therapy with phenobarbital or valproic acid can reduce the number of subsequent simple febrile seizures. However, as a recent Practice Parameter from the American Academy of Paediatrics concludes, the risk of adverse effects from daily therapy appears to outweigh the benefit of preventing the short term recurrence of simple febrile seizures. It is possible that in some families, where the occurrence of an additional simple febrile seizure would be particularly distressing, the routine use of oral diazepam during febrile illnesses might be appropriate.

Anticonvulsants↗

Preventive treatment for recurrent febrile seizures.

Febrile seizures are the most common convulsive events in childhood occurring in 2-5 % of children. 20-30% of these children will have a recurrence during a subsequent febrile infection. Even though the outcome of febrile seizures is benign, the possibility of recurrences keeps most families in fear for years after the first seizure event. Each febrile infection the child experiences increases the risk of recurrence, and there is a positive correlation between the height of the temperature during an infectious disease and the occurrence of febrile seizures. However, prophylactic use of antipyretics does not decrease the recurrence rate. Intermittent use of diazepam during febrile episodes prevents febrile seizures only in selected child populations. The continuous use of antiepileptic drugs is no longer warranted because their side-effects outweigh their benefits. The number of febrile episodes is the only risk factor that can be influenced by preventive measures. The time being, we can reassure parents on the benign nature of febrile seizures.

Analgesics, Non-Narcotic↗

Febrile seizures in patients with complex partial seizures.

Febrile seizures occurred in 14 of 155 (9%) out-patients with complex partial seizures. Twelve patients had prolonged or recurrent febrile seizures, convulsive status epilepticus or a transient postictal neurological deficit. Febrile seizures were associated with perinatal abnormalities, an earlier onset of epilepsy and with a poor seizure control. Recurrent febrile seizures or those with complicating features are associated with an unfavourable therapeutic outcome in adult patients with complex partial seizures.

Adult↗

Interleukin-1alpha, interleukin-1beta, and interleukin-1Ra polymorphisms in febrile seizures.

Febrile seizures are the most common form of childhood seizures. The exact mechanism promoting convulsions during a common febrile illness remains unknown, but it is accepted that genetic influences are likely to account for at least some of the cases. Previous studies reported high interleukin-1beta levels in the cerebrospinal fluid of patients with febrile seizures. Recently, an association between a regulatory polymorphism in the genes encoding interleukin-1beta and interleukin-1Ra and febrile seizures was reported. In this study, we attempted to confirm these findings. We analyzed the cytokine gene polymorphisms of interleukin-1beta, interleukin-1alpha, and interleukin-1Ra of 73 children with febrile seizure and 152 healthy controls. The distribution of interleukin-1beta -511, interleukin-1alpha -889, and interleukin-1Ra genotypes and alleles did not differ significantly between cases and controls. Our data suggest that the studied gene polymorphisms of interleukin-1beta, interleukin-1alpha, and interleukin-1Ra do not have a significant role in the pathogenesis of febrile seizures.

Case-Control Studies↗

Febrile Seizures.

Febrile seizures should not be treated with continuous or intermittent antiepileptic medication. Parents should be given a comprehensive explanation as to the nature of this benign disorder and potential strategies to terminate prolonged seizures or clusters of seizures. Patients with complex febrile seizures (ie, those that are prolonged, focal, recur within the same day or those which affect children with pre-existing neurologic abnormalities) should be encouraged to use rectal diazepam at the time of recurrent seizures. Chronic daily prophylaxis should be considered only in highly selected cases. There is no definitive way to distinguish the small subset of children with febrile seizures that are at an increased risk for the development of complex partial epilepsy with mesial temporal sclerosis. Complex febrile seizures, particularly focal and prolonged seizures beyond 15 minutes duration are at somewhat higher risk as demonstrated by family studies, magnetic resonance imaging (MRI) studies, and retrospective analysis of intractable complex partial epilepsy.

Journal Article↗

Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures.

Febrile seizures can be the first sign of epilepsy. In a recent study, patients with temporal lobe epilepsy were reported to carry the interleukin-1beta allele 2 at position -511 more often than healthy control subjects. Because pro-inflammatory cytokines, such as interleukin-1, are well-known inducers of fever and therefore could play an important part in the pathogenesis of febrile seizures, we have, in this study, analyzed the cytokine gene polymorphism of interleukin-1beta at position -511 in children with febrile seizures and control subjects. We found a statistically significant increase in the frequency and the carriage of interleukin-1beta (-511) allele 2 in children with febrile seizures (n = 35) compared with healthy blood donors (n = 400) (P = 0.03 and P = 0.05, respectively). In previous studies, this allele has been connected to increased in vitro production of interleukin-1. Children with febrile seizures may therefore have an increased pro-inflammatory reaction during fever. This pro-inflammatory reaction may also predispose some children to the development of epilepsy.

Alleles↗

Variation in clinical practice in the management of febrile seizures.

Febrile seizures are a common problem facing those who provide health care to children. Wide variation in physician management of the simple febrile seizure has been reported. Recent published data have helped to clarify some of the diagnostic and therapeutic issues confronting the physician managing a child with this entity. In order to assess the current management of the child with a first simple febrile seizure, a questionnaire was sent to 584 physicians who care for children. Twenty-five percent of the respondents reported that they would use anticonvulsant therapy in a manner that has been shown to be ineffective. The responses showed that wide variation still exists in the management of febrile seizures.

Anticonvulsants↗

Febrile seizures.

Febrile seizures are commonly seen in emergency departments that treat children. Risk factors for initial and recurrent febrile seizures and epilepsy have been identified. Controversy still exists over the need for performing a lumbar puncture as part of the initial evaluation. Most children with a febrile seizure and meningitis present with an abnormal level of consciousness or have obvious meningeal signs. Emphasis should be placed on looking for a source of fever and reassuring and educating the caretakers.

Child↗

The natural history of febrile seizures.

Febrile seizures are a common occurrence in early childhood and most children who experience them do well. This article reviews the clinical characteristics of febrile seizures, and summarizes the relevant clinical and laboratory research. The natural history of febrile seizures, the recurrence rate, and frequency of later epilepsy or intellectual handicap is presented, and controversies in evaluation and treatment are discussed.

Animals↗

Molecular genetics of febrile seizures.

Febrile seizures (FSs) represent the most common form of childhood seizures, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Six susceptibility FS loci have been identified on chromosomes 8q13-q21 (FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18p11 (FEB6). Furthermore, mutations in the voltage-gated sodium channel alpha-1, alpha-2 and beta-1 subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor gamma-2 subunit gene (GABRG2) have been identified in families with a clinical subset of seizures termed "generalized epilepsy with febrile seizure plus (GEFS+)". However, the causative genes have not been identified in most patients with FSs or GEFS+. Common forms of FSs are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies in FSs have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility genes have emerged. To find a true association, larger sample size and newer methodologic refinements are recommended.

Genetic Linkage↗

Molecular genetics of febrile seizures.

Febrile seizures are the most common form of convulsion, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. In large families, the febrile seizure (FS) susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2 (chromosome 19p13.3) have been mapped. A clinical subset of FS, termed generalized epilepsy with febrile seizures plus (GEFS+), was reported. In GEFS+ families, a mutation in the voltage-gated sodium channel beta1 subunit gene (SCN1B) at chromosome 19q13.1 and two mutations of the same alpha1 subunit gene (SCN1A) at chromosome 2q24 were identified. These loci are linked to febrile convulsions in large families. We conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families using nonparametric allele-sharing methods, and found a new FS susceptibility locus, FEB4 (chromosome 5q14-q15). In contrast to the FEB1, FEB2, and GEFS+ genetic loci, linkage to FEB4 was suggested in nuclear FS families, indicating that FEB4 may be the most common linkage locus in FS families.

Age Factors↗

Management of febrile seizures.

Febrile seizures are seizures associated with fever of extracranial origin. The preventive and long-term management aspects of febrile seizures are briefly discussed in this article.

Anticonvulsants↗

Pedigree analysis in families with febrile seizures.

Febrile seizures are the most common form of seizures, occurring in an estimated 2-5% of North American children. We carried out a systematic pedigree study of febrile seizure probands. Forty of 52 probands (77%) in a referral population selected for increased severity had more than one case per family: one family had 10 cases, one family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fit the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. Because the cases were selected for increased severity, this represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies. Simulated lod scores showed adequate power for a linkage study in the absence of heterogeneity. Individual families had simulated average lod scores as high as 2.1. However, with potential heterogeneity, assuming only 70% of families share the same disease locus, average lod scores were marginal, and a high density map of marker loci and additional families would be required to document linkage.

Databases, Factual↗

Febrile seizures.

Febrile seizures are the most common convulsive disorder in children. The definition, epidemiology, genetics, clinical features, evaluation and management are reviewed. The importance of evaluating the very young child with febrile seizure for an underlying CNS infection is reviewed. The current standard of treatment is discussed. The importance of recognizing and alleviating parental anxiety is discussed.

Anxiety↗