Register-based studies on febrile seizures in Denmark

During a short period of brain development, one out of 25 children experience seizures when exposed to fever. The risk and consequences of these febrile seizures remain incompletely understood. We have conducted a number of studies within a population-based cohort of 1.6 million children born in Denmark (1977–2004). We constructed the cohort by linking registers on civil service, health, and cause of death. We followed the cohort for up to 28 years with virtually no loss to follow-up. The aetiology of febrile seizures depends on a genetic susceptibility that can be transmitted through both parents. The risk of febrile seizures increases with decreasing birth weight and gestational age at birth indicating that pre- and perinatal risk factors play a causal role. Measles, mumps, and rubella vaccination increases the risk of febrile seizures for two weeks, but the absolute risk is small even in high-risk children. Febrile seizure is associated with an increased risk of epilepsy and the risk remained high well into adulthood. The risk of epilepsy is particular high for persons with cerebral palsy, low Apgar scores, or a family history of epilepsy. The risk of schizophrenia is slightly increased among persons with a history of febrile seizures even in persons without epilepsy, but the association need not be causal and more studies are needed. Febrile seizure is a common condition with a benign outcome for the vast majority of children. Genes and environmental factors operating in early life seem to play a causal role.     

Are brief febrile seizures benign? A systematic review and narrative synthesis

Febrile seizures affect 2%–5% of U.S. children and are considered benign although associated with an increased risk of epilepsy and, rarely, with sudden unexplained death. We compared rates of mortality, neurodevelopmental disorders, and neuropathology in young children with simple and complex febrile seizures to healthy controls. We systematically reviewed studies of 3- to 72-month-old children with simple or complex febrile seizures ≤30 min. We searched studies with outcome measures on mortality, neurodevelopment, or neuropathology through July 18, 2022. Bias risk was assessed per study design. Each outcome measure was stratified by study design. PROSPERO registration is CRD42022361645. Twenty-six studies met criteria reporting mortality (11), neurodevelopment (11), and neuropathology (13), including 2665 children with febrile seizures and 1206 seizure-free controls. Study designs varied: 15 cohort, 2 cross-sectional, 3 case–control, 5 series, and 1 case report. Mortality outcomes showed stark contrasts. Six cohort studies following children after febrile seizure (n = 1348) reported no deaths, whereas four child death series and 1 case report identified 24.1% (108/449) deaths associated with simple (n = 104) and complex (n = 3) febrile seizures ≤30 min. Minor hippocampal histopathological anomalies were common in sudden deaths with or without febrile seizure history. Most electroencephalography (EEG) studies were normal. Neuroimaging studies suggested increased right hippocampal volumes. When present, neurodevelopmental problems usually preexisted febrile-seizure onset. Risk bias was medium or high in 95% (18/19) of cohort and case–control studies vs medium to low across remaining study designs. Research on outcomes after simple or brief complex febrile seizures is limited. Cohort studies suffered from inadequate sample size, bias risk, and limited follow-up durations to make valid conclusions on mortality, neurodevelopment, and neuropathology. Sudden death registries, focused on a very small percentage of all cases, strongly suggest that simple febrile seizures are associated with increased mortality. Although most children with febrile seizures have favorable outcomes, longer-term prospective studies are needed.     

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.     

The value of early postictal EEG in children with complex febrile seizures

PURPOSE: To assess the usefulness of an early postictal EEG in neurologically normal children with complex febrile seizures. METHODS: We conducted a retrospective chart review of all neurologically normal children who were hospitalized over a period of 2.5 years after complex febrile seizures, and had an EEG up to 1 week after the seizure. RESULTS: Thirty-three patients (mean age, 17.8 months) qualified for inclusion into the study. Twenty-four patients were qualified as complex cases based on one factor (prolonged in 9, repetitive in 13, and focal in 2). Nine other patients had two complex factors: in six patients, the seizures were long and repetitive; in two patients, the seizures were focal and repetitive; and in one patient, the seizures were long, focal, and repetitive. Thirteen (39%) patients experienced prior febrile seizures. All 33 patients had a normal postictal sleep EEG. Our results indicate with a 95% probability that the true rate of abnormalities in an early postictal EEG performed on otherwise normal children with complex febrile seizures is 8.6% or less. CONCLUSIONS: The yield of abnormalities of an early postictal EEG in this population is low and similar to the reported rate of abnormalities in children with simple febrile seizures. The routine practice of obtaining an early EEG in neurologically normal children with complex febrile seizures is not justified.     

A locus for febrile seizures (FEB3) maps to chromosome 2q23-24.

Febrile seizures are the most common form of childhood seizures, occurring in 2% to 5% of North American children. We report a large Utah family with 21 members affected by febrile seizures inherited as an autosomal dominant trait. All had generalized tonic-clonic seizures with onset associated with fever, consistent with the consensus febrile seizure phenotype, and none had febrile seizures beyond 6 years of age. Eighteen affected individuals had recurrent febrile seizures. Eight individuals developed afebrile seizures between ages 5 and 13 years. Afebrile seizures consisted of generalized tonic-clonic, generalized tonic, generalized atonic, simple partial, and partial complex seizure types and were associated with abnormal electroencephalographic findings in 5 individuals, all of whom were intellectually normal. We undertook linkage analysis in this family, defining the disease phenotype as febrile seizures alone. Linkage analysis in epilepsy candidate gene/loci regions failed to show evidence for linkage to febrile seizures. However, a genomewide scan and subsequent fine mapping revealed significant evidence for a new febrile seizure locus (FEB3) on chromosome 2q23-24 with linkage to the marker D2S2330 (LOD score 8.08 at theta = 0.001). Haplotype analysis defined a critical 10-cM region between markers D2S141 and D2S2345 that contains the FEB3 locus.     

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.     

The genetics of localization-related symptomatic epilepsy: risk of a family history with seizures in patients who have undergone surgery

A family history of epileptic seizures including febrile convulsions was found in 15 of 103 patients (15%) with localization related epilepsy with partial seizures with and without secondary generalization, who were operated on because of drug resistance. This rate was significantly higher than that of the cumulative incidence in the general population (4%). The localization of the brain damage did not play a role (temporal lobe resection left: 15%, right: 17%, extra-temporal lesion excision: 20%, hemispherectomy: 11%). Various family members were involved. Some patients had more than one relative with seizures. Thus, 21 relatives suffered from seizures. Eleven of them had generalized tonic-clonic seizures (one grand mal on awakening), 7 had febrile convulsions (4 complicated), and in 1 patient the grand mal seizures on awakening were preceded by absences; 1 had generalized tonic-clonic and complex partial seizures; 1 after complicated febrile seizures likewise had complex partial seizures; another mentally retarded patient suffered from generalized tonic-clonic, axial tonic and myoclonic-astatic seizures. The seizure type of 3 remote relatives was not known. The first seizure occurred in 16 family members during childhood, in 3 in adolescence and in only 1 in adulthood (1 unknown). Eight showed mental retardation of slight degree in most. It is interesting that only one-third of the patients with a family history with seizures were seizure-free after the operation; 5 still had seizures, mostly reduced in frequency, 3 had seizures and isolated auras and 2 had only isolated auras. On comparing the findings in patients with and without a family history with seizures, those with family members with epileptic seizures showed a lower rate of an intellectual deficit (7 vs 47%) and brain tumours (13 vs 44%). Our earlier findings with a different group of patients are thus confirmed: that genetics play a role in symptomatic epilepsies. Received: 9 July 1996 Received in revised form: 1 April 1997 Accepted: 23 April 1997     

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: 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.     

Epilepsy duration, febrile seizures, and cerebral glucose metabolism

PURPOSE: Studies using magnetic resonance imaging have shown that reduced hippocampal volume is associated with a history of febrile seizures, the duration of epilepsy, and the number of generalized tonic-clonic seizures. It is uncertain whether these factors have the same influence on functional as on structural measures of the integrity of the epileptogenic zone. METHODS: We used positron emission tomography (PET) with fluorine 18 2-deoxyglucose to study 91 patients with temporal lobe seizure foci localized by ictal video-EEG. PET was performed in the awake interictal resting state with ears plugged and eyes patched. We recorded surface EEG during injection (5 mCi) and the 30-min uptake period. We used a standard template to analyze PET scans. RESULTS: A significant negative relation was found between the duration of epilepsy and hippocampal glucose metabolism ipsilateral to the epileptic focus. Patients with a history of either any febrile seizures, or complex, or prolonged febrile seizures, did not have greater hypometabolism ipsilateral to the epileptic focus than did patients without a febrile seizure history. We found no effect of generalized tonic-clonic seizure history. CONCLUSIONS: Longer epilepsy duration is associated with greater hypometabolism, suggesting that epilepsy is a progressive disease.     

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.     

Childhood-onset epilepsy with and without preceding febrile seizures

OBJECTIVE: To identify characteristics in children with epilepsy that differ between those who did versus did not have a history of preceding febrile seizures. BACKGROUND: Febrile seizures precede epilepsy in 10 to 15% of children. Little is known about the specific types of epilepsy associated with febrile seizures. METHODS: In a community-based, prospectively identified cohort of children, the association between prior febrile seizures and characteristics of the children's epilepsy (seizure type, epilepsy syndrome, age at onset, underlying etiology, family history) were examined for 524 of the children who were aged > or =1 year at onset of epilepsy. RESULTS: Seventy-three (13.9%) had febrile seizures. Children with febrile seizures were more likely to have a first-degree or a second-higher-degree relative with febrile seizures and less likely to have childhood absence epilepsy and absence seizures compared with children without febrile seizures. This was especially true for simple febrile seizures. There was no specific association with localization-related forms of epilepsy. Complex, but not simple, febrile seizures were associated with younger age at onset of epilepsy. There was no evidence that focal or prolonged febrile seizures were associated with localization-related epilepsy or temporal lobe epilepsy per se. Of the three children whose initial MRIs demonstrated hippocampal atrophy, none had a history of febrile seizures. CONCLUSIONS: At the time of diagnosis, febrile seizures are not specifically related to temporal lobe epilepsy or localization-related epilepsy in general. A genetic component for febrile seizures is suggested by its positive associations with family history, especially for simple febrile seizures. Complex febrile seizures represent an underlying age-dependent susceptibility.     

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.     

Clinical and genetic analysis of a new multigenerational pedigree with GEFS+ (Generalized Epilepsy with Febrile Seizures Plus)

Febrile seizures affect 2-5% of all children younger than 6 years. A small proportion of children with febrile seizures later develop epilepsy. The syndrome of generalized epilepsy with febrile seizures plus (GEFS+) is a heterogeneous disorder characterized by febrile seizures that may persist beyond age 6 years and nonfebrile seizures. Several genes have been localized for FS by linkage analysis, and three GEFS+ genes (SCN1A, SCN1B, GABRG2) have been identified. We identified a large multigenerational family with GEFS+ in France. All affected members had FSs. Among them, seven had other types of epileptic seizures including FSs after age 6 years, nonfebrile generalized seizures, or partial seizures later in life. Genetic linkage study excluded the candidate genes and loci for FS and GEFS+, thus proving the existence of a new GEFS+ genetic locus underlying the phenotype observed in this family.     

Risk factors for complex partial seizures: a population-based case-control study

This investigation is to our knowledge the first population-based case-control study of risk factors for complex partial seizures (CPS). Included in the study were all patients with onset of complex partial seizures before age 35, who were residents of Rochester, Minnesota, at the time of diagnosis between 1935 and 1979, and who were also born in Rochester (n = 82). Two control subjects were matched to each patient, and for both patients and control subjects, the unique records-linkage system for residents of Rochester was used to obtain information about possible risk factors. A history of epilepsy or febrile seizures in the mother, febrile seizures, neonatal convulsions, cerebral palsy, head trauma, and viral encephalitis were significantly more common in patients than in control subjects (p less than 0.05). None of the prenatal or perinatal factors investigated were found to be associated with complex partial seizures, except for being small for gestational age at birth. This factor lost significance after adjustment for cerebral palsy.     

Unprovoked seizures after complex febrile convulsions

Children with complex febrile convulsions bear a higher risk of developing epilepsy than children with simple febrile convulsions. Complex febrile convulsions are defined by the presence of prolonged seizures, partial seizures and multiple seizures occurring during the same day. The aim of this study is to delineate the relative significance of each of the three criteria defining complex febrile convulsions. Fifty-seven out of 477 children (12%) admitted for febrile convulsions had complex febrile convulsions and normal neurological examination. Follow-up was available for 48 (84%) of them. Thirteen of these 48 (27%) had epilepsy at follow-up. The mean age of seizure onset among the patients with subsequent afebrile seizures was significantly lower than the rest (10.8 months versus 16.8 months). The patients with partial febrile convulsions showed a trend toward a higher risk (45%) of developing epilepsy than the patients with multiple febrile convulsions (21%).     

Complex Febrile Seizures

In the context of a prospective cohort study, we examined the associations between individual complex features of both first (n = 428) and recurrent (n = 240) febrile seizures and factors shown to predict outcome in children with febrile seizures. Thirty-five percent of first and 33% of recurrent febrile seizures had one or more complex features (focal onset, duration ≥10 min, or multiple seizures during the illness episode). There were strong correlations between focality and prolonged duration for both first and recurrent febrile seizures. A low fever at the time of the seizure was marginally associated with prolonged duration. Most factors associated with either recurrent febrile seizures or subsequent unprovoked seizures were not associated with either the initial seizure being complex or the likelihood that a recurrence would be complex. However, in children with recurrent febrile seizures, complex features tended to repeat. This factor was statistically significant and particularly striking for prolonged duration. Genetic or other constitutional factors may explain why the prolonged feature recurs. Eleven (2.5%) children had three or four risk factors for recurrent febrile seizures and a first febrile seizure that was prolonged. Eight (72.7%) of them experienced a recurrent febrile seizure that was prolonged. This very small group of children may be candidates for abortive therapy to be administered at the onset of a recurrent seizure.     

Total cerebral volume is reduced in patients with localization-related epilepsy and a history of complex febrile seizures

CONTEXT: Febrile seizures may lead to later epilepsy. They have been associated with hippocampal atrophy but their effect on total cerebral volume is unknown. OBJECTIVE: To compare total cerebral volume in patients with mesial temporal lobe epilepsy with and without a history of complex febrile seizures (CFS). DESIGN: Survey. SETTING: Epilepsy monitoring center. SUBJECTS: Forty patients with localization-related epilepsy and temporal lobe onset determined by video electroencephalogram and 20 controls. INTERVENTION: Magnetic resonance imaging measurement of cerebral volume. MAIN OUTCOME MEASURE: Total cerebral volume. RESULTS: Patients with a history of CFS had significantly reduced total cerebral volume compared with patients without CFS. In addition, male patients with CFS had significantly lower total cerebral volume than male normal controls. There was no significant difference between patients without CFS, or all patients, and controls. CONCLUSION: Complex febrile seizures may have a global effect on brain development.     

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.     

The role of EEG in febrile status epilepticus (FSE)

Febrile status epilepticus is an important neurological emergency and a risk factor for later development of epilepsy. There are guidelines recommending against the use of EEG in the evaluation of simple febrile seizures but the role in febrile status epilepticus is not well established. This article reviews the literature on the role of EEG in the evaluation of the patient with prolonged febrile seizures, summarizes the findings, and concludes with some simple recommendations based upon the existing knowledge. At least 30–40% of EEGs obtained within one week of febrile status epilepticus will contain abnormalities including focal slowing. In some series focal slowing appears to be associated with development of a spike focus in the same location. Prospective series with large numbers of patients and follow-up are required to ascertain whether such abnormalities are associated with later development of epilepsy.