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.     

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.     

Febrile seizures and mesial temporal sclerosis

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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 associated with influenza A

To clarify the clinical impact of influenza A on the development of febrile seizures (FS), consecutive FS patients brought to our hospital between October 2003 and September 2004 were prospectively surveyed. Patients infected with influenza A (influenza A patients) and those uninfected with influenza (non-influenza patients) were compared with regard to clinical characteristics of FS. Influenza infection was determined by rapid antigen test and/or serologically. Associations of influenza A with atypical findings of FS, including partial seizures, prolonged seizures, multiple seizures during the same illness, and 30-min or longer prolonged postictal impairment of consciousness (PPIC), were analyzed by multiple logistic regression. A total of 215 patients (47 influenza A and 168 non-influenza patients) were enrolled in the study. Age was significantly higher in the influenza A group (39.85+/-22.16 months vs. 27.51+/-17.14 months, P<0.001). Of 42 patients aged 48 months or older, which corresponded to the 80th percentile for age, 15 (35.7%) were influenza A patients, with a significantly higher incidence of such patients than in the subgroup of patients aged 47 months or younger (32/173, 18.5%) (P=0.015). On multiple logistic regression analysis, influenza A was independently associated with PPIC (odds ratio: 4.44, 95% confidence interval: 1.52-12.95, P=0.006), but not with other atypical findings. The positive association of influenza A with PPIC suggests that influenza may affect state of consciousness at the same time that it induces seizures with fever.     

Febrile seizures and later intellectual performance

The relationship of febrile seizures to later intellectual and academic performance was examined in a sibling-control study. Amont 431 sibling pairs tested at the age of 7 years, the mean full scale IQ on the Vechsler Intelligence Scales for Children was not different for children who had febrile seizures as compared with siblings who were seizure-free. Neither recurrent seizures nor those lasting 30 minutes or longer were associated with IQ deficit. Poor academic achievement, defined as Wide Range Achievement Test performance more than one grade level below school placement in children with IQs of 90 or above, was equally frequent in index cases and control patients. Febrile seizures were not associated with a decrement in IQ or early academic performance, as judged by comparison of affected children with their siblings.     

Febrile seizures - treatment and outcome

Assessment of treatment strategies in febrile seizures should be based on short- and long-term outcomes, with and without acute, intermittent, or chronic medical intervention, as well as short- and long-term side effects. Febrile seizures are a benign condition with a normal neurological, motor, intellectual, and cognitive long-term outcome and have a low risk of later epilepsy in most cases. Even many complex febrile seizures have a benign outcome. Prophylaxis may or may not reduce the recurrence rate, but does not appear to improve the long-term outcome as compared to acute treatment of seizures in progress. All agree that chronic prophylaxis with anti-epileptic agents is justified only in highly selected cases, if at all. Treatment with benzodiazepines during febrile episodes appears to effectively reduce the recurrence rate, provided adequate doses are given and compliance problems minimized. A selective approach to intermittent diazepam prophylaxis seems rational, as the recurrence risk and response to treatment are highly variable. An attractive alternative is acute treatment at seizure onset with rectal diazepam in solution given by the parents at home in order to prevent prolonged recurrent seizures. This regimen has the potential of moving the first line of anti-convulsant defence close to the child. It appears to be effective, inexpensive, feasible even for non-professionals, has few side effects and is well accepted by the parents. A reasonable policy would be to treat simple febrile seizures solely with acute rectal diazepam in solution and reserve intermittent diazepam prophylaxis for selected cases including those with multiple or prolonged recurrences, several risk factors for recurrent febrile seizures and other special situations.     

Febrile seizures and risk of schizophrenia

BACKGROUND: Febrile seizure is a benign condition for most children, but experiments in animals and neuroimaging studies in humans suggest that some febrile seizures may damage the hippocampus, a brain area of possible importance in schizophrenia. METHODS: A population-based cohort of all children born in Denmark between January 1977 and December 1986 was followed until December 2001 by using data from nationwide registries. RESULTS: We followed 558,958 persons including 16,429 with a history of febrile seizures for 2.8 million person-years and identified 952 persons who were diagnosed with schizophrenia. A history of febrile seizures was associated with a 44% increased risk of schizophrenia [relative risk (RR)=1.44; 95% confidence interval (CI), 1.07-1.95] after adjusting for confounding factors. The association between febrile seizures and schizophrenia remained virtually unchanged when restricting the analyses to people with no history of epilepsy. A history of both febrile seizures and epilepsy was associated with a 204% increased risk of schizophrenia (RR=3.04; 95% CI, 1.36-6.79) as compared with people with no such history. CONCLUSIONS: We found a slightly increased risk of schizophrenia among persons with a history of febrile seizures. The association may be due to a damaging effect of prolonged febrile seizures on the developing brain, shared etiological factors, or confounding by unmeasured factors.     

Febrile seizures: treatment and prognosis

Recent epidemiologic data indicate that the vast majority of children with febrile seizures have a normal longterm outcome. A precise knowledge of the short- and long-term outcome with or without treatment, and short- and long-term side effects is an important prerequisite for assessing the various treatment strategies. We focus on the impact of short-term or prophylactic treatment on the short- and long-term outcome of various types of febrile seizures. There is universal agreement that daily prophylaxis with antiepileptic agents should never be used routinely in simple febrile seizures, but only in highly selected cases, if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may not reduce the recurrence rate, but it does not appear to improve the long-term outcome as compared with short-term seizure control. The treatment may be used to reduce the recurrence rate for a small arbitrarily defined group with multiple simple febrile seizures, complex febrile seizures, especially focal, prolonged or both, febrile status, and when parental anxiety is severe. However, there is no evidence that treatment of simple febrile seizures can prevent the rare cases of later epilepsy, and many children with complex febrile seizures have a benign long-term outcome, even without treatment. Many prefer a "wait and see" policy. An attractive alternative is to treat new febrile seizures with rectal DZP in solution at seizure onset, given by the parents at home to prevent febrile status. Newer, less well documented short-term strategies include nasal, oral, or rectal administration of other benzodiazepines. Short-term seizure control of febrile status and careful parental counseling are the two most important targets of treatment.     

Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+)

Aim. To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Methods. Selected literature review. Results. Febrile seizures are the most common convulsive event in humans, occurring in 2–6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long‐term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14–16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ～3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually “come to grips” with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. “Rescue” benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage‐gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Conclusions. Febrile seizures may distress parents but rarely have any long‐term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling.     

Febrile seizures: recent developments and unanswered questions

Background

Febrile seizures (FS) are typically observed in infants and children affecting 2–5 % of the pediatric population and are the commonest seizures in childhood.

Objectives

The present review summarizes epidemiology, etiology, clinical picture, and diagnostic procedures as well as the therapeutic options and the different courses this disorder may take.

Method

An extensive review of literature is performed, while views and aspects towards the pathogenesis of FS are stated. Risk factors for multiple recurrences of FS and for subsequent epilepsy are analyzed. Questions regarding the treatment and follow-up of children with FS are answered.

Results

Whereas the frequency of epilepsy following simple FS is estimated to be 1.0–2.2 % of patients, and thus does not differ from the risk of normal population, complicated FS are associated with an increased risk of subsequent epilepsy in 4.1–6.0 %. Febrile status epilepticus with focal symptoms may result in approximately 5 % of cases in complex partial epilepsy. Furthermore, multiple recurrences increase the risk for generalized epilepsy (>4 %). The immediate management of FS, intermittent prophylaxis, and the effectiveness of the treatment in combination with antipyretics are presented in detail.

Conclusion

FS can cause a great anxiety and even panic to parents and to the whole family. Parents should be educated about the benign condition and the good prognosis. Although much information has been gained, much remains to be learned.     

Febrile seizures: Mechanisms and relationship to epilepsy

Studies of febrile seizures have been driven by two major enigmas: first, how these most common of human seizures are generated by fever has not been known. Second, epidemiological studies have linked prolonged febrile seizures with the development of temporal lobe epilepsy, yet whether long or recurrent febrile seizures cause temporal lobe epilepsy has remained unresolved. To investigate these questions, a model of prolonged (complex) febrile seizures was developed in immature rats and mice, permitting mechanistic examination of the potential causal relationships of fever and seizures, and of febrile seizures and limbic epilepsy. Although the model relied on hyperthermia, it was discovered that the hyperthermia-induced secretion of endogenous fever mediators including interleukin-1β, which contributed to the generation of these ‘febrile’ seizures. In addition, prolonged experimental febrile seizures provoked epilepsy in a third of the animals. Investigations of the mechanisms of this epileptogenesis demonstrated that expression of specific ion (HCN) channels and of endocannabinoid signaling, may be involved. These may provide novel drug targets for intervention in the epileptogenic process.     

Febrile seizures. From molecular biology to clinical practice

Febrile seizures occur between the age of 3 months and 5 years with a temperature of 38 degrees C or higher, and are either simple or complex. Eight gene loci have been identified to be associated with certain cases of autosomal dominant familial febrile seizures, and 12 genes have been associated with some of the familial epilepsy syndromes that can start with febrile seizures. The mutations and the protein products are known for only some of these 20 genes. The risk of recurrence of convulsions in a further febrile illness is on average 30%, and of developing epilepsy is on average 6%, but both vary depending on the presence and number of risk factors in any given patient. The immediate treatment of a febrile convulsion is intravenous or rectal diazepam, but febrile status epilepticus requires intravenous Phenobarbital and possibly other medications. Long-term antiepileptic drugs are not recommended in most patients with febrile seizures. However, exceptions should be considered on an individual basis in patients with complex febrile seizures with multiple risk factors for development of later epilepsy.     

Febrile seizures impair memory and cAMP response-element binding protein activation

The long-term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated-air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early-life FS, however, showed long-term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long-term memory but spared short-term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding (CREB) protein in the hippocampus was significantly lower in nine-FS-group rats than in controls. Furthermore, rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-FS-group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long-term cognitive consequences of even brief frequently repetitive FS during early brain development.     

Febrile seizures are a syndrome of secondarily generalized hippocampal epilepsy

Aim The objective of this study was to examine in detail the semiology of febrile seizures, particularly to look for features that might suggest focality. In prolonged febrile seizures there is acute evidence of hippocampal involvement. Retrospective data relates mesial temporal sclerosis to such early prolonged febrile seizures. Animal models of prolonged seizures causing hippocampal damage show limbic seizures at low dose of the precipitants. Method A detailed history of the early ictal phase of 10 children with typical febrile seizures and of the behavioural components of 10 children with high fever was taken by two independent observers and a consensus reached. Results There were seven males and three females aged 1 year to 2y 8mo (mean age 1y 11mo). In seven of the 10 children with febrile seizures there was an early phase of the attack compatible with focal origin and in four of these there were clear mesial temporal features. No such features were seen in the children with fever alone. Interpretation We conclude that the majority of febrile seizures have evidence of focal origin and many appear to arise in the hippocampus.     

Febrile seizures in southern Chinese children: incidence and recurrence

This study investigates the incidence, recurrence, and risk factors of febrile seizures in southern Chinese children. A retrospective study of a 5-year period (March 1998 through February 2003) was conducted for all children admitted with first febrile seizure to a university teaching hospital of Hong Kong, serving a population of 31,700 under 6 years. A total of 565 Chinese children (329 males, 236 females) were identified with mean age of 2.1 +/- 1.1 years. The annual incidence was 0.35%. Among them 16% (91/565) had complex febrile seizures. Family history of febrile and afebrile seizures was present in 17.5% and 2.7% respectively. The mean follow-up period was 2.33 +/- 1.69 years. Altogether 103 children (18%) had recurrence, and the cumulative rates by 1, 2, and 3 years were 12.7%, 18.7%, and 20.5% respectively. Three significant factors were identified for higher risk of recurrence: early age of onset, family history of febrile seizure, and complex febrile seizure. The incidence of first febrile seizure in Chinese children is low compared with the Western world and relatively similar to mainland China. Recurrence is also lower despite similarities in the predictive factors. Further epidemiologic and genetic studies will be necessary to confirm and explain this interethnic variation.     

Febrile seizures in a South Indian district: incidence and associations

One thousand four hundred and three children participated in a home-based survey of psychiatric disorders in 8- to 12- year-old children in Calicut District, Kerala, India. One thousand one hundred and ninety-two consecutive children underwent neurological and psychometric assessments. The projected number of children with a history of febrile seizures was 120 giving a lifetime incidence of 10.1%. Recurrent febrile seizures predominated and these were strongly associated with a history of perinatal adversity. Febrile seizures were independently associated with indices of infective illness and mothers' education. Epilepsy developed in 2.7% of children with febrile seizures, but no evidence was found that febrile seizures had adverse intellectual or behavioural sequelae.     

Febrile seizures: an epidemiological and outcome study of 482 cases

Introduction

Febrile seizures (FSs) are the most common type of seizures seen in children. After the first FS, 3 to 12?% of children develop epilepsy, and 30?% of these patients present with recurrent FS. The purpose of this study was to describe the epidemiological aspects of FS in order to better define the long-term outcomes in children with first FS and to identify the risk factors associated with the recurrence of FS as well as the development of epilepsy.

Methods

A retrospective study of 482 children with FS was conducted from January of 2004 to December of 2009 in the pediatric department of Hedi Chaker University Hospital in Sfax, Tunisia. The medical records for each patient were first collected and then analyzed at a later time.

Results

The study included 482 children. Simple FSs were found in 55.2?% of children, and complex FSs were observed in 44.8?%. The mean duration for follow-up examinations was 2?years and 4?months, and ranged from 1 to 5?years. No deaths or permanent neurological deficits due to FSs were observed, and only six children (1?%) developed epilepsy. A total of 57 children (11.7?%) developed recurrent seizures. Our findings suggest that a family history of FS, young age at onset, and a low degree of fever were predictive of recurrent FSs.

Conclusion

Children with FSs encounter a minor risk of mortality and morbidity. While recurrent seizures are observed in these children, only a minority of these patients develop epilepsy.