Fever, genes, and epilepsy

About 13% of patients with epilepsy have a history of febrile seizures (FS). Studies of familial forms suggest a genetic component to the epidemiological link. Indeed, in certain monogenic forms of FS, for which several loci have been reported, some patients develop epilepsy with a higher risk than in the general population. Patients with generalised epilepsy with febrile seizures plus (GEFS+) can have typical and isolated FS, FS lasting more beyond age 6 years, and subsequent afebrile (typically generalised) seizures. Mutations associated with GEFS+ were identified in genes for subunits of the voltage-gated sodium channel and the gamma2 subunit of the ligand-gated GABAA receptor. Screening for these genes in patients with severe myoclonic epilepsy in infancy showed de novo mutations of the alpha1 subunit of the voltage-gated sodium channel. Antecedent FS are commonly observed in temporal-lobe epilepsy (TLE). In sporadic mesial TLE-characterised by the sequence of complex FS in childhood, hippocampal sclerosis, and refractory temporal-lobe seizures-association studies suggested the role of several susceptibility genes. Work on some large pedigrees also suggests that FS and temporal-lobe seizures may have a common genetic basis, whether hippocampus sclerosis is present or not. The molecular defects identified in the genetic associations of FS and epileptic seizures are very attractive models to aid our understanding of epileptogenesis and susceptibility to seizure-provoking factors, especially fever.     

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence

BackgroundA history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy.MethodsInformation on the history of seizures was obtained by a questionnaire from twin pairs in the Mid-Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes.ResultsHistories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group.ConclusionA twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities.     

Genetic approach to the pathogeneses of epilepsy]

Recently, genetic causes have been identified in certain epilepsy syndromes in which the phenotypes are similar to common idiopathic epilepsies. Interestingly, almost all such genetic abnormalities were detected in genes encoding ion channels expressed in the brain. Thus such epilepsy syndromes are disorders of ion channels, i.e., "channelopathies". The list of ion channel abnormalities that are associated with childhood epilepsy is expanding and includes the followings. Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor, a ligand-gated ion channel, were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two KCNQ K+-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na+-channel and GABA(A) receptor, a ligand-gated ion channel, were also identified as underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus or generalized epilepsy with febrile seizures plus, benign familial neonatal infantile seizures and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene can result in different epilepsy phenotypes. Abnormalities of Na+-channel alpha1 subunit were also associated with severe myoclonic epilepsy in infancy. Epilepsy syndromes mentioned above, except for severe myoclonic epilepsy in infancy, were familial epilepsy syndromes showing dominant inheritance with high penetrance while common idiopathic epilepsies do not show obvious inheritance. However, the similarities in symptomatology between such familial epilepsies and common idiopathic epilepsy may provide us with clues to the genetics of common idiopathic epilepsies.     

Genetics of epilepsy]

Epilepsy is a common neurological disease and encompasses a variety of disorders with paroxysms. Although there is a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remain poorly understood. The identification of genes responsible for human epilepsy was first documented in progressive myoclonic epilepsy (EPM) because of their clear inheritance and phenotypic presentation. EPM is characterized by frequent myoclonic jerks and cumulative neurological deterioration and includes MERRF, a mitochondrial disease and DRPLA, a triplet disorder. The genes responsible for EPM seem to participate in the maintenance of cell viability. Genetic defects have been recently identified also for some familial epilepsy in which the phenotypes are similar to common idiopathic epilepsies. Defects of neuronal nicotinic acetylcholine receptor, a ligand-gated ion channel, caused nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations in the voltage-gated Na(+)-channel alpha 1, 2 and beta 1 and the GABAA receptor gamma 2 subunit genes were found as a cause of dominant epilepsy with febrile seizures plus, a clinical subset of febrile seizures. Abnormalities of Na(+)-channel alpha 1 subunit were also associated with severe myoclonic epilepsy in infancy. Other genes encoding ion channels expressed in the brain were also found to be associated with other familial epilepsy. This line of evidence suggests the involvement of channels expressed in the brain in the pathogenesis of certain idiopathic epilepsy, albeit there are a few exceptions that abnormalities of non-channel molecules have been found to be associated with idiopathic epilepsy.     

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.     

Progress in searching for the febrile seizure susceptibility genes

Febrile seizures (FS) represent the most common form of childhood seizures. They affect 2–5% of infants in the Caucasian population and are even more common in the Japanese population, affecting 6–9% of infants. Some familial FS are associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical FS (FS+) and afebrile seizures. A significant genetic component exists for susceptibility to FS and GEFS+: extensive genetic studies have shown that at least nine loci are responsible for FS. Furthermore, mutations in the voltage-gated sodium channel subunit genes (SCN1A, SCN2A and SCN1B) and the GABA_A receptor subunit genes (GABRG2 and GABRD) have been identified in GEFS+. However, the causative genes have not been identified in most patients with FS or GEFS+. Common forms of FS are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies on FS have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility gene has emerged. Herein, we review the genetic data reported in FS, including the linkage analysis, association studies, and genetic abnormalities found in the FS-related disorders such as GEFS+ and severe myoclonic epilepsy in infancy.     

Clinical evaluation of the patients with epilepsy following febrile convulsions

We studied clinical, EEG and developmental features of 46 epileptic children following febrile convulsions. Incidence of developing epilepsy was 9.9 percent. Eleven patients (group G) out of 46 had generalized epileptic seizures, and 34 patients (group P) had partial seizures. Febrile convulsions of early onset, partial seizures and postictal neurological symptoms were more striking in group P (p less than 0.05), whereas febrile convulsions of late onset and prolonged seizures were slightly dominant in group G. And EEG abnormalities were more frequent in group P (p less than 0.05). Group P patients had significant number of risk factors (complex features of febrile convulsions) than group G patients (p less than 0.01). The interval between the last febrile convulsion and subsequent epileptic seizures was shorter in group G (p less than 0.01). Although subsequent epileptic seizures were well controlled in the both groups (91% in group G and 82% in group P), intractable seizures were recognized in 9% of group P patients. The patients who had risk factors of prolonged seizures, postictal neurological symptoms and early onset manifested poor controlled epileptic seizures (p less than 0.01). Motor or mental deficits were more frequently associated with group P: in some patients they had been observed before the onset of febrile convulsions. These results suggest that pathogenesis of epilepsy following febrile convulsions may be different among various seizure types of subsequent epilepsy. And the risk factors during febrile convulsions may be related to the prognosis of subsequent epileptic seizures as well as the incidence of developing epilepsy.     

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 mortality and morbidity of febrile seizures

Approaches to the treatment and investigation of febrile seizures have changed since the main reference studies on outcomes were conducted in the 1960s and 1970s. We have, therefore, conducted a systematic review of literature from the past 15 years to see whether outcomes have also changed. We found that simple febrile seizures do not carry a risk of death, but there is a very small risk of death after complex febrile seizures (CFSs), particularly febrile status epilepticus. There is no evidence that SUDEP (sudden unexpected death in epilepsy) occurs in association with febrile seizures. The risk of later epilepsy after a febrile seizure lies between 2.0% and 7.5%, and the risk of developing epilepsy after CFSs is estimated at around 10-20%. There is no evidence of any risk of hippocampal or mesial temporal sclerosis (HS/MTS) in association with simple febrile seizures. Serial imaging has shown that HS/MTS develops in 0-25% of patients over time after prolonged febrile seizures; the range in prevalence reflects selection bias in different studies. The overall risk of HS/MTS associated with CFSs is around 3%. Approximately 40% of patients with medically refractory temporal lobe epilepsy and HS/MTS on neuroimaging have a history of febrile seizures.     

Fieberkrämpfe

Febrile seizures are the most common seizure type in man and may be classified as simple or complex. The overall recurrence rate is 30–35%. Predictors of recurrence include a family history of febrile seizures, age at onset of less than 18 months, and a relatively low body temperature at the time of the seizure. The risk of subsequent epilepsy is only slightly elevated in children with simple febrile seizures. Factors that increase epilepsy risk are complex febrile seizures, abnormal neurological development, and a family history of epilepsy. While older studies did not report increased mortality in children with frebrile seizures, a recent large population-based study found increased mortality during the first 2 years after a febrile seizure in children with complex febrile seizures, seizure onset in the first year of life as well as seizures triggered by a body temperature of less than 39°C. Semiology and prognosis of febrile seizures are heterogeneous. Simple febrile seizures have a good prognosis with diagnostic and therapeutic procedures being uniform at the international level. Children with complex febrile seizures have a poorer prognosis, concerning both risk of epilepsy and mortality within the first 2 years after the first febrile seizure. In these children, decisions concerning diagnostic work-up and medical management are based on the risk profile of the individual patient.     

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.     

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.     

Posterior fossa malformations and epilepsy

The association between posterior fossa malformations and epilepsy is rarely reported in the literature. We describe 54 cases with posterior fossa malformations, according to embryogenesis classification, divided into two groups on the basis of presence or absence of epilepsy. Epilepsy occurred in 22 cases (40.7%) and was not related to the type of posterior fossa malformation or to supratentorial cerebral lesions associated with the malformation. Familial antecedents for epilepsy and/or febrile convulsions influenced the presence of epilepsy in patients with posterior fossa malformations (P < .01). Epilepsy was mainly partial (77.3%); benign partial/generalized epilepsies and febrile convulsions occurred in 27.3% of cases. Seizures disappeared for 2 or more years at the end of follow-up in 36.4% of patients. Good epilepsy prognosis was not related to the age at onset of seizures, familial antecedents for epilepsy and/or febrile convulsions, supratentorial associated lesions, or age of patients at the last observation. Profound mental retardation prevailed in patients with epilepsy (P < .01), as did pathologic electroencephalograms (EEG) (P < .0001), with paroxysmal abnormalities (P < .001) and asymmetry (P < .01). In our 54 cases of posterior fossa malformation, we identified two risk factors for epilepsy: familial antecedents for epilepsy and/or febrile convulsions and the involvement of the cerebellum in the malformation.     

Familial genetic predisposition, epilepsy localization and antecedent febrile seizures

PURPOSE: The magnitude of genetic influence in epilepsy may vary in relation to epilepsy classification and localization and factors such as antecedent febrile seizures. We assessed this genetic influence in a large epilepsy population. METHODS: Patients with established epilepsy diagnosis evaluated in the Vanderbilt Epilepsy Program were systematically questioned about family history of epilepsy and febrile seizures, prior febrile seizures and other risk factors for epilepsy. RESULTS: A total of 1994 patients with epilepsy and reliable family history were identified. Patients with prior febrile seizures (FS) were more likely to have a family history of febrile seizures than those without prior FS (p<0.000001) and also had a greater proportion of relatives with febrile seizures. The groups did not differ with respect to family history of epilepsy. Patients with generalized epilepsy were more likely to have first and second degree relatives with epilepsy than those with partial epilepsy (40.2% versus 31.2%, p=0.001), and also had a greater proportion of affected first degree relatives (p<0.000001). The proportion of first degree relatives affected with epilepsy was higher than local published prevalence, for both groups. CONCLUSION: Susceptibility for febrile seizures with subsequent epilepsy may be genetically distinct from susceptibility for afebrile seizures alone. Although family history of epilepsy was more likely with generalized epilepsy, a familial tendency was considerable in partial epilepsy.     

A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1

Benign familial infantile seizures (BFIS) is a dominant idiopathic epilepsy with partial and secondarily generalized seizures with age of onsetr between 3 and 12 months. Here we describe a four-generation family with some characteristic features of BFIS but with unusual clinical signs, in eight affected members with an unusual clinical phenotype. Onset was consistently between 14 and 20 months of age with clusters of complex-partial or generalized tonic-clonic seizures and a high rate of febrile seizures, which have not been described for BFIS previously. All affected members showed multifocal interictal epileptiform discharges in the EEG. The known loci for benign familial neonatal/infantile seizures (BFNS/BFNIS), generalized epilepsy with febrile seizures plus (GEFS+) and the BFIS locus on chromosome 19q were excluded. Further genetic analysis showed suggestive linkage to the major BFIS locus on chromosome 16 between markers D16S690 and D16S3136. This ;;BFIS-like' syndrome may enlarge the phenotypic spectrum of diseases linked to the chromosome 16 region.     

Fever and fever-related epilepsies

Febrile seizures are a common emergency faced by general pediatricians. They are mostly self-limiting, isolated events with no sequelae in later life. A minority are more complex. In the acute stage, there are a small number of underlying etiologies that are important to recognize in order to determine the prognosis accurately and to optimize management. There has been a long-standing debate about the relationship of early febrile seizures to the later development of epilepsy. It is now clear that this risk differs for simple and complex febrile seizures: complex febrile seizures may herald the presentation of a number of epilepsy syndromes of which febrile and illness-related seizures are part of the phenotype. This review examines the existing knowledge on febrile seizures and the various clinical phenotypes to which they are linked.     

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.     

The role of genetics and ethnicity in epilepsy management

Recent exciting developments in epilepsy genetics have led to significant insights into the mechanisms underlying seizure disorders. Success in epilepsy genetics research to date has resulted from identification of genes responsible for rare monogenic disorders, the majority encoding either voltage- or ligand-gated ion channels. For some conditions, such as benign familial neonatal seizures, an understanding of the underlying genetics is helpful in predicting prognosis. However, for other disorders, such as autosomal dominant nocturnal frontal lobe epilepsy, phenotypic severity is determined by factors other than the major dominant nicotinic subunit mutation found in some families. Further complexity arises when single-gene mutations give rise to heterogeneous phenotypes, as typically occur with generalized epilepsy with febrile seizures plus. Another area of increasing genetic endeavour, pharmacogenetics will allow tailoring of antiepileptic medication for each patient. Pharmacogenetics explores genetic polymorphisms in genes coding for drug-metabolizing enzymes, receptors and transporters. Polymorphisms have been identified that result in marked ethnic and interindividual differences in response to treatment. With further understanding of the impact of these differences, pharmacogenetic screening is likely to guide the management of epilepsy in the future.     

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.