Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Febrile seizures are common and typically have a benign outcome. The genetic basis and pathogenesis of this syndrome are under intense investigation. Evidence-based guidelines suggest minimal investigations are needed for diagnosis, and most children require neither intermittent nor long-term treatment. This clinical article includes summaries from the results of the multicenter study on the consequences of febrile status epilepticus (FEBSTAT).
• Febrile seizures are the most common seizure type, affecting 3% to 4% of all children.
• Although many affected children have recurrent febrile seizures, the risk of subsequent epilepsy is very small.
• The American Academy of Pediatrics offers guidelines for the evaluation and management of children with febrile seizures.
Febrile seizures (febrile convulsions) are the most common convulsive events in human experience. They were recognized as distinct from other seizures in the mid-19th century, and at that time treatment was redirected to the underlying causes of fever rather than the symptom of a seizure. With the introduction of the thermometer at the end of the 1800s, fever was understood to be the primary factor producing the convulsion. Until the early 20th century, infantile convulsions were thought to be severe and often fatal, and few effective treatments were available. Sentinel studies in the 1940s by Lennox and Livingston investigated risk factors for recurrence and later epilepsy (115; 111).
In the 1970s two population-based studies formed the foundation of the current view of febrile seizures (191; 50): they are common, many recur, developmental outcome is not altered, and few children later develop epilepsy. In 2008 and 2011, updated evidence-based practice parameters were published by the American Academy of Pediatrics Committee on Quality Improvement, Subcommittee on Febrile Seizures. This, along with the original 1996 publication, and a consensus statement by the International League Against Epilepsy (28), reflects the current evidence for diagnosis, and treatment recommendations for febrile seizures (05; 06).
Studies conducted in the United States and Denmark reported that about 3% to 4% of all children will have at least 1 febrile seizure (132; 201). However, febrile seizures may be more common in other countries. For example a longitudinal study of 54,233 children in Korea reported a prevalence of 11.19% (37). Although the seizures are associated with fever (greater than 38°C by rectal or tympanic membrane measurement), those provoked by central nervous system (CNS) infection are excluded. The peak age for febrile seizures is about 2 years of age with a range between about 6 months and 5 years (04; 37).
Febrile seizures can be subdivided into “simple” (generalized tonic-clonic semiology, duration less than 15 minutes, and without recurrence within the following 24 hours) or “complex” (focal, duration more than 15 minutes, or occurring in a cluster of 2 or more convulsions within 24 hours). Febrile seizures are generally thought to be benign, and only 2% to 6% of affected children will later develop epilepsy (132; 45). The risk of epilepsy following a simple febrile seizure is about 2%, and following a complex febrile seizure, it is still only 5% to 10%. Therefore, febrile seizures can be viewed as a syndrome of acute symptomatic seizures rather than as a true epilepsy syndrome (52).
In many cases, febrile seizure in a child is the first clear symptom of illness. Most febrile seizures are brief, less than 15 minutes in duration, and appear to be generalized in semiology; brief, generalized seizures are referred to as simple febrile seizures. Seizures that are focal in onset, have a prolonged duration, or are recurrent within 24 hours are deemed “complex.” The first febrile seizure is “complex” in approximately 25% of cases. In the National Collaborative Perinatal Project study of 55,000 infants, 1706 experienced a first febrile seizure and were followed to 7 years of age. Twenty-eight percent of the initial febrile seizures were “complex”: 4% focal, 8% prolonged greater than 15 minutes, and 16% with recurrence within 24 hours. A Todd paresis (transient focal post-ictal weakness) occurred in 0.4% (50). In another prospective cohort study of first febrile seizures, 35% of 428 children had 1 or more features of a complex febrile seizure (14). A retrospective study from Singapore reported similar findings (110).
There is a bimodal distribution of febrile seizure duration: most are brief (82% lasting a mean of 3.8 minutes), whereas the remaining 18% constitute a seemingly separate population whose seizures last a mean of 39.8 minutes (77). Prolonged febrile seizures are relatively uncommon, but concern about subsequent development of mesial temporal sclerosis and epilepsy prompted a multicenter study, referred to as the FEBSTAT study, to evaluate the phenomenology and imaging findings in 199 affected children (median age 16 months; interquartile range 12 to 24 months). These children had a median status epilepticus duration of 70 minutes. The majority of the episodes of febrile status epilepticus were focal at onset (68%) and nearly all (98%) were convulsive seizures (80). Prolonged postictal unconsciousness (greater than 30 minutes), although rare, has been associated with febrile seizures that are focal or last longer than 5 minutes (142).
Two important risks are associated with febrile seizures and are key for counseling patients and their families: recurrent febrile seizures and later epilepsy (57).
Recurrent febrile seizures occur in about 30% to 40% of children, usually within a year of the first seizure (57; 14; 110; 147). Young age at onset and family history of febrile seizures are the strongest predictors of another seizure (16; 147). Additional predictors of recurrence include a shorter duration of illness before the first febrile seizure and a lower temperature at the time of the seizure (17; 106).
The earlier the age of onset, the greater the risk of recurrence. Children with a first febrile seizure before 1 year of age have a 50% chance of recurrence, compared with 20% if the first seizure is after 3 years of age (196).
A family history of febrile seizures is consistently associated with recurrence (20; 192; 147). However, a family history of afebrile seizures has not consistently demonstrated this relationship (50; 17; 138). Compared to simple febrile seizures, complex febrile seizures are not more frequently associated with recurrence (50; 195; 14). However, children with prolonged complex febrile seizures are more likely to have another prolonged seizure, in the event of recurrence (14), and children with recurrent febrile seizures are more likely to have an afebrile seizure within a year (37).
Risk factors can be combined to provide a useful prediction scheme. In a sample of 428 children who presented to an urban emergency room with a first febrile seizure, 32% had another febrile seizure within 2 years. The recurrence risk for those with none of the 4 risk factors (age less than 18 months, family history of febrile seizures, low temperature at the time of the seizure, and short duration of illness) was 4%; with 1 factor it rose to 23%, with 2 factors 32%, with 3 factors 62%, and with all 4 factors 76% (15).
Only 2% to 5% of children with a first febrile convulsion subsequently develop epilepsy (132; 196; 08; 146; 02; 45). Risk factors for later epilepsy include (1) an abnormal neurologic or developmental status prior to the first febrile seizure, (2) a family history of afebrile seizures, (3) a complex febrile seizure, and (4) a low-grade fever (38 to 39°C) during the first febrile seizure (02). Sixty percent of children with a first febrile seizure have none of these risk factors and a subsequent risk of epilepsy of only 0.9%. About 2% of children with 1 risk factor (34% of children with febrile seizures) and 10% of those with 2 or more risk factors (6% of children with febrile seizures) will develop epilepsy (50; 08). The cumulative risk of epilepsy has been found to increase with the number of febrile seizures (188; 45). In a large population-based cohort study in Demark, the 30-year cumulative incidence of epilepsy was 2.2% at birth, 6.4% after the first febrile seizure, 10.8% after the second, and 15.8% after the third (45). Notably, this study did not distinguish between simple versus complex febrile seizures.
The risk of epilepsy in children with seizures in the setting of fever after 5 years of age is unclear. A prospective study reported that 14% of 64 neurodevelopmentally normal children with late onset febrile seizures (mean age of 8) went on to develop epilepsy (62). However, other work has not shown increased risk of epilepsy for children with later-onset febrile seizures (ages 5 to 10) (205).
In an animal model, female rats who were exposed to febrile seizures as immature animals appeared to have higher risk for seizures in adulthood than males (41). This observation has not been reported in humans.
When epilepsy does develop, the seizures can be of virtually any type, although the highest association is with generalized, rather than focal seizures (154; 25).
Approximately 15% of children with epilepsy have 1 or more preceding febrile seizures, regardless of the cause of the epilepsy (25). A history of febrile seizures was reported in 10% of 200 patients with treatment-resistant epilepsy, compared with 2.5% of 200 age-matched children with well-controlled epilepsy (odds ratio 4.33, 95% confidence interval 1.59 – 11.79) (186). These observations suggest that the tendency for febrile seizures plays an important role in a person’s seizure threshold. However, there is no evidence that 1 or multiple febrile seizures actually cause epilepsy.
There is also no evidence that a brief febrile convulsion damages the human brain. The National Collaborative Perinatal Project study included 431 sibling pairs discordant for febrile seizures (50). Psychometric testing at 7 years of age included the Wechsler Intelligence Scale for Children as a measure of overall intelligence and the Wide Range Achievement Test as a measure of academic achievement. For those known to be neurotypical before the first febrile seizure, there was no difference in intelligence or school achievement between sibling pairs, even among the 27 with febrile status epilepticus (seizures longer than 30 minutes).
Chang and colleagues conducted another study utilizing a prospective, population-based, case-control method to assess the learning, spatial, and sequential working memory of 87 school-aged children with a previous febrile seizure and 87 randomly selected age-matched control subjects (33). The febrile seizure group performed significantly and consistently better than control subjects on mnemonic capacity and had more flexible mental processing abilities than their age-matched controls. A mouse model of febrile seizures suggested that this improved function could be related to enhanced structural plasticity. It was reported that experimentally-induced febrile seizures could increase large mossy fiber terminal density of dentate granule cells and result in improved performance on cognitive tasks (180). A case-control study of children of low socioeconomic status (159 with first febrile seizure, 141 healthy controls) also demonstrated no significant differences in cognition, motor skills, or adaptive behavior within 1 year of a febrile seizure (109).
Although there were some statistically different results of motor and cognitive functioning measured 1 year after febrile status epilepticus versus 1 year after a simple febrile seizure, no clinically meaningful difference was reported by the FEBSTAT study team (206). Long-term follow-up into adolescence and young adulthood confirms these studies’ encouraging findings. A population-based Danish study of 507 18- to 20-year-old men with histories of febrile seizures, but not of epilepsy, who presented for obligatory evaluation by the military draft board demonstrated no difference in intelligence testing results compared to 17,769 men without history of febrile seizures (136). Additionally, a Finnish study followed a random birth cohort of 900 children and found that academic and social accomplishments measured at 12 and 18 years of age were no different for those who experienced febrile seizures than for those who did not (174). However, another large Danish cohort study reported an increase in attention deficit hyperactivity disorder among people with a history of febrile seizures (19), and smaller studies have shown an association of febrile seizures with neurodevelopmental disorders (134; 21).
Starting with the sentinel work of Murray Falconer, an important connection has been drawn between prolonged febrile seizures, mesial temporal sclerosis, and intractable temporal lobe epilepsy. Studies have shown acute vasogenic edema in the hippocampus following febrile status epilepticus, which resolves over 3 to 5 days (163), as well as markers of oxidative stress after febrile seizures (67). The cause and effect relationship has been a source of intense controversy. It has been suggested that “2 hits” are required for this sequence of events–the first an initial injury or malformation of the temporal lobe and the second a vulnerability factor (possibly genetic) unique to the child that allows the febrile seizure to occur.
Fortunately, the sequence of a prolonged febrile seizure, mesial temporal sclerosis, and intractable temporal lobe epilepsy is uncommon, occurring in not more than 1 of 75,000 children (25). Although in retrospect, patients with intractable epilepsy due to cortical malformations in addition to mesial temporal sclerosis are likely to have experienced febrile seizures in early childhood (53), no prospective studies document a normal MRI and then a prolonged febrile seizure followed by unilateral hippocampal swelling, mesial temporal sclerosis, and intractable temporal lobe epilepsy.
Among 199 children with febrile status epilepticus, in the FEBSTAT study, 22 (11.5%) had abnormal hippocampal T2 signal on acute brain MRI, and many had coexisting temporal lobe abnormalities (eg, hippocampal malrotation) (172). After 1 year, 10 of the 14 children available for follow-up MRI had developed hippocampal sclerosis, whereas only 1 of the 116 subjects with normal hippocampal signal immediately after febrile status epilepticus went on to develop abnormal signal on follow-up MRI (113). These children are being followed to evaluate whether these MRI findings are predictors of later development of epilepsy. Hippocampal malrotation was found in higher prevalence in people with a history of febrile status epilepticus (8.8%) versus normal controls (2.1%), but this finding is of unclear pathological or clinical significance, especially because the suspected abnormality was unilateral and had no relationship to the side affected with T2 changes (32).
A 3-year-old boy with a 2-day history of rhinorrhea presented to the emergency department via ambulance following a witnessed convulsion lasting 3 minutes. His mother described him having lost consciousness, falling to the ground, and “shaking all over.” He was somnolent for about 20 minutes following the event. Of note, there is a family history of febrile seizures in his father and paternal grandfather.
Clinically, the child was sitting in bed, mildly uncomfortable with a fever of 40°C via rectal thermometer. He was tachycardic to 105 beats per minute. He had rhinorrhea and a mildly erythematous oropharynx. The remainder of his general and neurologic examinations were normal. Specifically, he had no meningeal or focal neurologic signs.
He was given a dose of acetaminophen, and 30 minutes later he was able to tolerate a popsicle without any difficulty and was seen playing with his toy cars. No laboratory testing or imaging was performed.
This is a fictitious, albeit typical, case of a first simple febrile seizure.
Three features interact to produce a febrile seizure: immature brain, fever, and genetic predisposition.
Febrile seizures rarely occur before 6 months of age or after 5 years of age, so there is a clear relationship with brain maturation. However, the nature of this maturation process is unclear and could be related to increasing myelination, normal “dying back” of excessive neurons, and/or increasing synaptic complexity.
Causes of fever vary and remain the “everyday illnesses of childhood” including: upper respiratory tract infection or pharyngitis, otitis media, pneumonia, gastroenteritis, roseola infantum, and noninfectious illness (50; 114). Vaccines against Haemophilus influenzae, varicella, pneumococcus, and meningococcus are now in widespread use and have greatly changed the background of infectious pediatric illness. Although no published reports document the impact of those vaccines on the incidence of infections inciting febrile seizures, studies have demonstrated protection against febrile seizures among children who received the rotavirus vaccine (149; 171).
There is an increasing body of literature regarding viral pathogens in pediatric patients, and confirmed viral infections are far more commonly associated with febrile seizures than bacterial illnesses (Millichap and Millichap 2008). There have been multiple reports associating influenza A with febrile seizures (39; 70; 58; 144; 71). In addition to influenza, enterovirus is also a common association with febrile seizures (69). A study in Turkey found that adenovirus was the most commonly detected virus in children with febrile seizures, followed by influenza A and B (31). In a prospective cohort study that included 225 children with febrile seizures, coronaviruses had the highest relative risk for febrile seizures compared to other respiratory viral infections, followed by influenza A and B (76). Another study found that human coronavirus HKU1 was associated with a higher rate of febrile seizures than respiratory syncytial virus, parainfluenza virus type 1, or adenovirus (108). There has been a case report of the SARS-CoV-2 virus associated with febrile status epilepticus in a 2-year-old child (34). Human herpes virus type 6 (HHV6) is another documented pathogen associated with febrile seizures (126). HHV6 causes infant roseola, a common infection of infants and toddlers that is usually associated with fevers of 103°F or higher.
Febrile seizures after immunizations. As many as 1 in 10 febrile seizures occur within 14 days of immunization administration (55). Children with febrile seizures associated with vaccines, compared with those whose febrile seizures are independent of vaccines, have identical (good) outcomes (178; 181; 43). The excellent safety profile of typically administered childhood vaccines has been reviewed (118). Yet, parents indicate significant concern about febrile seizures. In one study, parents expressed willingness to have children receive more injections and even lower disease protection in order to reduce the possibility of vaccine-associated febrile seizures (212). These concerns, particularly regarding coadministered vaccines, must be balanced against the benefits of avoiding vaccine-preventable illness through fully immunizing children, as well as decreased numbers of office visits associated with vaccine administration (160). Suggested approaches for discussions with vaccine-hesitant families are provided by the American Academy of Pediatrics (48).
Febrile seizures occurring soon after immunization with whole cell diphtheria-pertussis-tetanus and measles vaccines should not be regarded as a direct adverse effect of the vaccine (86). Such seizures are believed to be triggered by vaccine-induced fever. Their clinical course is identical to other febrile seizures (85), with no increased risk for subsequent afebrile seizures or abnormal neurologic development (12; 178).
The frequency of febrile seizures after diphtheria-pertussis-tetanus or measles vaccination is 6 to 9 and 24 to 25 per 100,000 children vaccinated, respectively. Newer acellular pertussis vaccines rarely induce a febrile reaction, and fewer febrile seizures may result from this immunization (112). However, vaccines are often given in combination, and a study of combined DTaP-IPV-Hib did demonstrate an increased risk for febrile seizures on the day of the first and second doses of these immunizations. Affected children had no increased risk for epilepsy (178). Coadministration of influenza vaccine with pneumococcal conjugate and DTaP is also associated with slightly increased risk of febrile seizures; compared with administration of these vaccines on separate days, the absolute excess risk was 30 febrile seizures per 100,000 children vaccinated (46).
The incidence of febrile seizures following measles, mumps, and rubella (MMR) combined vaccines demonstrates mixed data. Previous studies suggested an increased risk of febrile seizures, up to 70 per 100,000 MMR combined vaccines (91; 201). Evidence suggests there may be specific genetic vulnerability to febrile seizures after MMR vaccine (54). Vaccination with MMR combined with varicella vaccine (MMRV) appears to increase the risk of febrile seizures, compared to administration of MMR with a separate varicella immunization (103; 116). The magnitude of this increased risk depends on the child’s age (higher incidence of febrile seizures among 16- to 23-month-old children compared with 12- to 15-month old children after measles-containing vaccines) (157). However, only 1 additional febrile seizure is expected to occur for every 2300 to 2600 children, aged 12 to 23 months, vaccinated with MMRV, when compared with separate MMR and varicella vaccine administration (40). The excess risk is not described for older children, who are typically scheduled to receive their second vaccine at 48 months of age. Despite this, many pediatricians feel uncomfortable prescribing the MMRV preparation, due to their concern about febrile seizures (143). Importantly, a large cohort study from Australia demonstrated no increase in febrile seizures following MMRV at 18 months of age, despite this being the peak age of febrile seizures (117).
The 13-valent pneumococcal conjugate vaccine (PCV13) has also been associated with a slightly increased risk of febrile seizures (attributable risk of 0.33 to 5.16 per 100,000 doses by week of age), though this risk is transient and low compared to the overall risk in this age group (11). In the same study, the authors did not find an increased risk of febrile seizures following the inactivated influenza vaccine.
Of critical importance for clinicians and families to understand is the fact that vaccines are not the cause of severe epilepsy syndromes. Several studies have demonstrated that children who develop epilepsy after a routine vaccination, even when the initial seizure is associated with fever, most often have a genetic epilepsy syndrome. For example, such children have been reported to have Dravet syndrome or genetic epilepsy with febrile seizures plus (both due to SCN1A gene mutations), PCDH19 gene mutations, neuronal migration disorders, and other identifiable childhood epilepsy syndromes (194). These cases, although sometimes severe, should not dissuade parents or pediatricians from following vaccination guidelines.
Genetics. Although the mode of inheritance is complex, genetic factors are clearly important. These factors may be either causative or protective against febrile seizures. Monozygotic twins have high concordance as compared with dizygotic twins (62% vs. 16%) (47), who have the same rate as their siblings. Autosomal recessive inheritance is unlikely, as an excess of parents are affected, and the risk to siblings is approximately 25% (50). The mode of inheritance is more likely polygenic or autosomal dominant with reduced penetrance (07; 189). Multiple chromosome linkage sites have been associated with febrile seizures (Audenaert 2006; 129) suggesting locus heterogeneity. In addition, multiple genes have been identified as causal for epilepsy syndromes that include febrile seizures (207; Audenaert 2006; 129; 22). This includes the unique syndrome of genetic (previously named “generalized”) epilepsy with febrile seizures plus (GEFS+), which is caused in most cases by an autosomal dominant variant (variable penetrance) in cerebral voltage-gated sodium channels subunits (SCN1B, SCN1A, and SCN2A) or a variant in the gamma 2 subunit of the GABAA receptor (18). Although GEFS+ includes seizure types other than febrile seizures, study of this syndrome may give insight into the biology of age-limited temperature-dependent seizure susceptibility.
Pathophysiology. The pathophysiology of febrile seizures is incompletely understood. The role of activation of the cytokine network continues to be studied. There appears to be increased susceptibility to febrile seizures associated with specific variants of inflammation-associated genes, especially interleukin alleles (187; 203; 95; 102; 101; 165; 38; 51; 35), whereas others might be protective (90). In their meta-analysis, Wu and colleagues suggested that these associations are complex, with certain interleukin alleles associated with febrile seizures among Asian populations, but not among those studied in Europe (208). Using the FEBSTAT ancillary study, in a comparison of 17 control children with fever and 33 with febrile status epilepticus, a lower ratio of IL-1RA/IL-6 was strongly predictive of the development of hippocampal hyperintensity in patients following febrile status epilepticus (60).
Transforming growth factor beta (TGFB) has become an area of investigation and may play a role in patients with febrile seizures (168). TGFB controls cellular differentiation and proliferation and has a role in the inflammatory response in rats with induced seizures (09; 152). It was found that certain genotypes and haplotypes of TFGB genes were overrepresented in patients with febrile seizures, perhaps leading to a predisposition in these individuals (168).
It is possible that circulating toxins and immune reaction products modulate neuronal excitability. One study showed that in the presence of viral RNA, the leukocytes of children who had febrile seizures produced significantly more interleukin-1β than did those of healthy controls (122), and interleukin-1β may promote hyperthermia-induced seizures in young rats (59). A study of 41 children with febrile seizures demonstrated a 4-fold increase in interleukin-1β, 1.8-fold increase in interleukin-1α, and 2.8-fold increase in interleukin-10 compared to control subjects with fever and no seizure (36). However, other studies found no significant role of interleukin-1β, interleukin-1α, or interleukin-1Ra in the pathogenesis of febrile seizures (75; 185).
Basic science research suggests possible mechanisms by which fever induces seizures. In rat pups, fever causes hyperventilation and a respiratory alkalosis. This results in a change in the cortical pH, which increases neuronal excitability, thereby inducing seizures (162). The same authors reported that respiratory alkalosis also occurs in children with febrile seizures (compared with metabolic acidosis in children with febrile gastroenteritis who did not experience febrile seizures) (161). A cross-sectional observational study of 45 children with febrile seizures identified that 91% of these children had hypocapnia after febrile seizures, though only 20% had alkalosis (158).
Animal models have demonstrated hyperthermia-induced changes in expression of hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN) (23). Abnormal HCN2 channels that cause increased currents (ie, hyperpolarity) and could thereby increase neuronal excitability have been identified among some patients with febrile seizures or GEFS+ (44). Temperature-dependent changes in sodium channel function, resulting in excitability, have also been identified in in vitro studies of voltage-gated sodium channels carrying a mutation associated with GEFS+ (49). In a patch-clamp recording study of cortical pyramidal cells in rat brain slices, L-type calcium channels were found to be active at hyperpolarized potentials and drove intrinsic firing as the temperature rose, which suggests these channels may also play a role in febrile seizure pathophysiology (153).
An autosomal dominantly inherited variant in the gamma-2 subunit of GABAA receptors (also known as GABRG2) has been associated in vitro with decreased receptor trafficking and endocytosis in the setting of fever–a property that is not seen with the wild-type receptors (97). Similar mutations may also result in reduced GABAA receptor expression, which could decrease GABAergic inhibition (184). These findings have translated to the identification of higher risk populations. For example, loss-of-function GABRG2 variants have been reported in families with febrile seizures, with or without associated epilepsy (22).
Case-control studies of children in India have shown decreased serum zinc levels in patients with febrile seizures (61; 10), whereas a controlled study in Bangladesh found depressed zinc levels in both serum and cerebrospinal fluid among children with febrile seizures compared to febrile controls without seizures (127). Zinc is an important modulator in the GABA synthesis pathway. Both of these findings raise the possibility of reduced inhibition from GABAA receptors in the setting of fever, resulting in febrile seizures. A meta-analysis of 17 case-control studies has also demonstrated deficiencies in iron among children with febrile seizures (107). A prospective case-control study performed in Greece demonstrated lower plasma ferritin levels in patients with febrile seizures than those without, with average ferritin levels of 30 versus 89, respectively (145), and similar results were reported in a study of Turkish children (105). Low selenium levels have been found in 2 case control studies among children with febrile seizures compared to controls (119; 01).
In the case of HHV-6, it is postulated that direct viral invasion of the brain, when combined with fever, causes the initial febrile seizure and that the virus might be reactivated by fever during subsequent illnesses, causing recurrent febrile seizures (176). Immaturity of thermoregulatory mechanisms (123) and a limited capacity to increase cellular energy metabolism at elevated temperatures have also been suggested as contributory factors (87). Lastly, animal studies have demonstrated enhanced neuronal excitability during normal brain maturation (92), which may explain the age-related susceptibility of children to febrile seizures.
By 7 years of age, 3% to 4% of children have 1 or more febrile seizures (50; 197) in the United States, South America, and Western Europe. However, the incidence varies in other parts of the world (Finland 6.9%, India 5% to 10%, Japan 8.8%, Korea 11%, Guam 14%, and Brazil with just 0.7%). Febrile seizures are slightly more common in boys and in black (4.2%) versus white (3.5%) North American children (50).
Risk factors for a first febrile convulsion have been studied in comparison with age-matched febrile and afebrile controls (20). The risk of a first febrile seizure is about 30% if a child has 2 or more of the following independent risk factors: (1) a first- or second-degree relative with febrile seizures, (2) delayed neonatal discharge of greater than 28 days of age, (3) parental report of slow development, and (4) day care attendance. Age younger than 18 months at the time of a child’s first febrile seizure and family history of febrile seizures were confirmed as risk factors for recurrence in a Greek study (147). Children with these 2 risk factors as well as low-grade fever at time of seizure or history of prematurity are also at increased risk for febrile status epilepticus (170). It may be reasonable to offer anticipatory guidance (familiarization with febrile seizures, first aid, and types of management) to families at high risk.
For 7 years after a first “simple” febrile seizure, children have the same health care utilization as age-matched febrile and afebrile controls, except for a minor increase in referrals to ear, nose, and throat services shortly after the febrile seizure (64). Children with febrile seizures do not seem to be more vulnerable to illness. In addition, their parents apparently are not compelled by concern about the child’s health to excessively consult a physician.
As fever is an essential element for the genesis of febrile seizures, it seems intuitively correct that antipyretic medications would prevent the first or recurrent febrile convulsions. However, several studies have shown that appropriate, rigorous use of antipyretic medication does not prevent febrile seizures during subsequent fever episodes, as summarized by Offringa and Newton’s 2012 Cochrane Review and as confirmed in a meta-analysis (155). The American Academy of Pediatrics Practice Guideline advises against the use of antipyretics for this purpose (05; 140). Though there is no evidence to support the efficacy of antipyretics to prevent febrile seizure recurrence during subsequent fever episodes, there is weak evidence for a role of acetaminophen to prevent febrile seizures within the same fever episode (74). A randomized controlled trial in Japan of 423 patients with febrile seizures showed that within the same fever episode, the febrile seizure recurrence rate after receiving acetaminophen was significantly lower (9.1% vs. 23.5%; p< 0.001) (128).
Dutch investigators followed a group of children who experienced a first febrile seizure (193). Those with more frequent fever episodes during the following 6 months had more recurrent febrile seizures than those with fewer fevers (odds ratio 1.8). Another Dutch study demonstrated a linear relationship between the number of febrile illnesses and the risk of febrile seizures for children in their second and third year of life, but this was not true for those less than 12 months old (204). The association between the number of fevers and the risk of febrile seizures was higher for those with recurrent febrile seizures. Gordon and colleagues demonstrated that children presenting with febrile seizures have higher temperatures than those presenting with febrile illness alone (65). However, we are unaware of any study that proves that efforts to reduce bouts of febrile illness result in fewer febrile seizures.
Although medications to treat symptoms of uncomplicated upper respiratory infections are not recommended for children, many parents do administer these agents. Because there is some (though mixed) evidence that antihistamines and xanthines (eg, theophylline) may be associated with longer duration of febrile seizures (209; 177; 179), the most recent Japanese guideline recommends against the use of these medications in children with a history of febrile seizures (131). Notably, though, a recent cross-sectional study found no difference in febrile seizure duration with antihistamine use (42).
Interestingly, two independent studies from Japan and China found that exclusive breastfeeding up to 6 months of age was an independent protector against febrile seizures (125; 151). The means by which breastfeeding is protective against febrile seizures is unknown.
Because febrile seizures are usually brief, the diagnosis must be made from the history. Frequent diagnostic errors include rigors due to fever, febrile myoclonus, breath-holding, and syncope triggered by illness (175). Other provoking causes for febrile seizures must also be excluded, especially a CNS infection. A single-center, retrospective analysis of 333 children in Japan presenting with complex febrile seizures showed that none of these children had bacterial meningitis or encephalitis, including those who presented with febrile status epilepticus (defined in the study as seizure longer than 30 minutes or multiple seizures without return to baseline by 30 minutes) (73). Seven children with febrile status epilepticus were diagnosed with viral encephalitis or meningitis, and none of the patients with complex febrile seizures had encephalitis or meningitis. About 15% of children with meningitis will have seizures, but virtually none are neurologically normal shortly after the seizure (63). There are constitutional symptoms such as headache and signs such as nuchal rigidity in older children with meningitis. Any child with meningeal signs or symptoms who presents with a fever and a seizure should have a lumbar puncture. However, children under 1 year of age may not have such obvious signs of meningeal irritation. For children aged 6 to 12 months who present with a seizure and fever, a lumbar puncture should be considered, especially if the child has not received Haemophilus influenzae type B or Streptococcus pneumoniae vaccinations (06). In addition, if the child previously has been treated with antibiotics, the clinician should be aware that the signs and symptoms of CNS infection may become masked, and lumbar puncture should be strongly considered.
The entity of a provoked, afebrile seizure associated with infection has also been described (110). The age group of the patients described by Lee and Ong was similar to children with febrile seizures, and there was a high prevalence of family history of febrile seizures. Children with this disorder frequently had febrile seizures on other occasions. The seizures occurred in children who were afebrile (temperature lower than 37.8° C), had definite signs or symptoms of illness, and normal metabolic and CSF findings with no other cause for seizures. Nearly 25% of the 125 children had more than 1 recurrent seizure within the next 24 hours. The risk for subsequent unprovoked afebrile seizures in children with afebrile, mild, infection-related seizures at 5 years was 5.7%, which was higher than the 1.6% risk in children with simple febrile seizures. The “afebrile-febrile seizure” scenario was also noted in a study of 39 children from Seattle, Washington and in 2 studies of benign afebrile convulsions after mild gastroenteritis (211; 199; 96); both had a similar profile and excellent psychomotor development and medical outcome. Compared to febrile seizures, these illness-related seizures appear to be associated more frequently with gastroenteritis. The benign course of childhood development, and low risk of relapse or epilepsy after gastroenteritis-associated seizures, was confirmed in a large, retrospective study (198).
The initial workup of a febrile seizure should include a thorough history from a reliable witness and a careful pediatric and neurologic examination (57). If the cause of fever can be identified and if the child has no disturbance of consciousness, it is usually not necessary to obtain further laboratory evaluation (04; 06). Implementation of evidence-based protocols for evaluation and management of children with febrile seizures can decrease the rate of hospital admission and of unnecessary testing (24). Without standard protocols, however, many centers report lack of adherence to published guidelines (159; 169).
Measurements of serum electrolytes (particularly sodium), glucose, blood urea nitrogen, calcium, and phosphorus levels should be reserved for children for whom there is a reasonable suspicion that the results will be abnormal (83). These tests are not recommended if their sole purpose is to identify the cause of a simple febrile seizure (06). Despite this recommendation, laboratory studies are frequently done. One study showed that 74% of children have a complete blood count (CBC), and 59% have electrolytes measured (30). It should be noted children who present with a febrile seizure often have a serum sodium less than 135 µmol/L. Studies have reported no difference in serum sodium levels between children with initial single simple and recurrent (within 24 hours) brief febrile seizures (183; 120). Another study showed that routine laboratory tests results, including CBC, blood sugar levels, calcium levels, sodium levels, blood creatinine, blood urea nitrogen, and urinalysis, are virtually always normal in patients with febrile seizures (210). Rates of bacteremia are low, 2% (167), as are other serious bacterial illnesses. Therefore, blood cultures and complete blood count are not routinely necessary.
A retrospective study of all cases of first simple febrile seizure presenting to an American tertiary care emergency department from 1995 to 2006 demonstrated a cerebrospinal fluid pleocytosis in 10 (3.8%; 95% confidence interval: 1.9% to 6.9%) of the 260 infants who underwent a lumbar puncture, with no pathogens isolated on bacterial culture. No patient in this study who was initially diagnosed with a first simple febrile seizure went on to develop bacterial meningitis (100). The same group analyzed the yield of lumbar puncture among 340 children with their first complex febrile seizure (99). Fourteen of the 340 patients had a CSF pleocytosis, and 3 had acute bacterial meningitis. These patients had additional signs and symptoms, which raised suspicion for meningitis. In another study, among 136 children with febrile status epilepticus who had a nontraumatic lumbar puncture (less than 1000 red blood cells/mm3), 96% had less than or equal to 3 white blood cells/mm3 (56). In a study of 205 emergency department visits for a first simple febrile seizure in infants aged 6 to 11 months, none of the patients had bacterial meningitis (66). A single-center, retrospective analysis of 333 children in Japan presenting with complex febrile seizures as well as febrile status epilepticus (seizure longer than 30 minutes or no return to baseline between multiple seizures) showed that none of these children had bacterial meningitis or encephalitis (73). Seven children with febrile status epilepticus were diagnosed with viral encephalitis or meningitis, and none of the patients with complex febrile seizures had encephalitis or meningitis.
However, these studies apply only to populations with high rates of vaccination against Haemophilus influenzae type B and Streptoccocus pneumoniae.
Neuroimaging should not be performed in the routine evaluation of a child with a first simple febrile seizure (06). A head CT or brain MRI should be performed only when an underlying structural lesion is suspected (04; 84). Even in complex febrile seizures, in most cases, neither an emergent head CT nor MRI is necessary (68; 182; 78). CT scans, in particular, should be avoided due to the increased susceptibility to radiation effects in young children (150). Associated brain abnormalities do not alter the clinical management of the febrile seizure, and the recommendation remains that brain MRI is unnecessary in children with a simple febrile seizure (78). Of course, neuroimaging might be considered when the child has significant focal neurologic or developmental abnormalities, neurocutaneous lesions, or abnormal head size.
An EEG should not be routinely performed in the evaluation of a neurologically healthy child with a first simple febrile seizure, either at the time of presentation or within the following month (06). An updated Cochrane Review concluded that there are no high-quality studies to support or refute the role of EEG, or the timing of EEG, after complex febrile seizures (166). Abnormalities (most often focal slowing) are reported to occur in 45% of EEGs recorded for research purposes in the first 3 days after febrile status epilepticus (135). Additional work has suggested associations between epileptiform abnormalities after complex febrile seizures and risk of recurrence or of later epilepsy (93; 72; 29). Yet, the predictive value of an abnormal EEG is not perfect in this population, and there are no clinically indicated preventative treatments for those deemed at risk.
Febrile seizures are usually brief and self-limited. When the seizure occurs, the child should be placed in a prone position or on his/her side on a protected surface, observed carefully, and brought to an emergency facility if the seizure lasts longer than 5 minutes (130). In most cases, a feverish child is taken to a medical facility after the seizure has ended. If the convulsion is prolonged, however, the child's airway should be kept clear, oxygenation maintained, and intravenous or rectal anticonvulsants such as diazepam, midazolam, or lorazepam given to halt the seizure. Febrile status epilepticus is often underdiagnosed and undertreated (80; 13) and is unlikely to remit spontaneously (164). Parents, emergency medical responders, and clinicians should have a low threshold for using rescue medications for children with prolonged febrile seizures.
Parents should be counseled that family routines will be disrupted for several weeks, but that normal life will continue and their child will do well. The only serious sequelae appear to be parental anxiety and subsequent labeling of the child as “vulnerable.” An Iranian study demonstrated that 39% of mothers thought their child was dying during their first febrile seizure and 95% were concerned that the seizure would impact their children’s health in the future (104). Often parents worry about the potential association of febrile seizures and sudden infant death. Vestergaard and colleagues compared the risk of sudden infant death syndrome in 9977 siblings of children with a febrile seizure and 20,177 siblings who never had febrile seizures (200). These data did not support a shared susceptibility hypothesis.
A population-based Danish study demonstrated that the mortality rate for children with simple febrile seizures was not different from the general population (202). Although there was a slightly increased risk of death among children with complex febrile seizures (lasting longer than 15 minutes or recurring within 24 hours), the result was not statistically significant when children with preexisting neurologic conditions were excluded. In the FEBSTAT study, the 2 children who died (of 119 included children) had premorbid developmental delays (173).
Several studies have documented the magnitude of parental anxiety and improvement with education, understanding, and reassurance (193; 88; 89; 94). Parent information sheets can be accessed on the internet (03).
There does not seem to be any compelling reason to treat children with daily prophylactic medication after 1 or more febrile seizures (04; 05; 141). The potential side effects of drugs outweigh the benefits. Prophylactic daily therapy with phenobarbital or valproate may reduce the recurrence of febrile seizures. Daily administration of phenobarbital at a dosage sufficient to achieve a blood level of 15 µg/mL can effectively reduce the risk of a recurrent febrile seizure (27; 57). However, metaanalyses of phenobarbital for prevention of febrile seizures suggest that it cannot be recommended (139; 141). Valproate has a similar effect (121). However, concerns about reports of fatal hepatitis in children younger than 2 years, or of pancreatitis, although rare, make valproate an inadvisable choice. Daily carbamazepine or phenytoin is ineffective for prevention of febrile seizures.
Intermittent treatment with anticonvulsant medication during illness is not generally recommended. For success, there must be excellent compliance and few caretakers. A dose of 0.2 mg/kg per dose of oral diazepam has been shown to be ineffective (190). A mild reduction in recurrence risk is seen with 0.3 mg/kg per dose, but at this dose about one third of children will have significant side effects of somnolence or ataxia (156; 26). A Greek study randomized children with a first simple febrile seizure to intermittent prophylaxis with rectal diazepam or no prophylaxis during subsequent febrile illnesses (148). In the 3-year follow-up, there were no significant side effects from the 0.33 mg/kg per dose diazepam, and the risk of febrile seizure recurrence was reduced (85% recurrence in high-risk children in the control group vs. 38% in the highest risk children randomized to diazepam). There was no difference in recurrence rate between children randomized to oral diazepam versus clobazam for intermittent febrile seizure prophylaxis in a small study from India, but there were fewer reported side effects in the clobazam group (98). It has been estimated that 14 children with a first febrile seizure would have to be treated with intermittent oral diazepam to prevent 1 recurrent febrile seizure.
Per the FEBSTAT study, prolonged febrile seizures rarely stop spontaneously (164). A total of 199 children were studied as part of an observational prospective study if they had a seizure lasting greater than 30 minutes. Shorter time from seizure onset to proper treatment was related to shorter seizure overall duration. Risk factors for febrile status epilepticus include a younger age at onset, lower temperature, impaired regulation of seizure duration, previous febrile status epilepticus, and any brain MRI abnormality (81; 79). Febrile status epilepticus should be treated in the same manner (eg, the same medications and doses) as afebrile status epilepticus. The children’s families should also be taught to administer a rescue medication in the case of a recurrent febrile seizure.
The use of a rescue medication during a prolonged seizure may reduce subsequent seizures during the same febrile illness (82). Nasal midazolam shows promise because of its ease of delivery, although more study is needed in the range of febrile seizures. Rectal diazepam gel also is effective, but it is an expensive home management tool and should be reserved for children at risk for status epilepticus (137).
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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