Three features interact to bring on 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. 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 “every day illnesses of childhood” including: upper respiratory tract infection or pharyngitis (38%), otitis media (23%), pneumonia (15%), gastroenteritis (7%), roseola infantum (5%), and noninfectious illness (12%) (Nelson and Ellenberg 1978; Lewis et al 1979). Vaccines against Haemophilus influenzae, varicella, pneumococcus, and meningococcus are now in widespread use and have greatly changed the background of infectious pediatric illness; however, no published studies document the impact of these vaccines on the incidence of infections inciting febrile seizures.
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 (Chung and Wong 2007; Hara et al 2007; Frobert et al 2011; Ozkan et al 2011; Harder et al 2012), and an influenza vaccine was associated with an increased risk of febrile seizures in Australia (Kelly et al 2010). Human corona virus HKU1 has been associated with a higher rate of febrile seizures than respiratory syncytial virus, parainfluenza virus type 1, or adenovirus (Lau et al 2006). Human herpes virus type 6 (HHV6) is another documented pathogen associated with febrile seizures (Suga et al 2000; Laina et al 2010; Epstein et al 2012). HHV6 causes infant roseola, a common infection of infants and toddlers that is usually associated with fevers of 103°F or higher.
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 (Hirtz et al 1983). Such seizures are believed to be triggered by fever induced by the vaccine. Their subsequent clinical course is identical to other febrile seizures (Hirtz and Nelson 1983), with no increased risk for subsequent afebrile seizures or abnormal neurologic development (Barlow et al 2001; Sun et al 2012). 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 (Le Saux et al 2003). 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 (Sun et al 2012).
The incidence rate may be higher, up to 70 per 100,000 with measles, mumps, rubella (MMR) combined vaccines (Jacobsen et al 2009; Vestergaard and Christensen 2009). Recent evidence suggests there may be specific genetic vulnerability to febrile seizures after MMR vaccine (Feenstra et al 2014). 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 (Klein et al 2010). The magnitude of this increase 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) (Rowhani-Rahbar et al 2013). 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 (Committee on Infectious Diseases 2011). 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 (O’Leary et al 2012).
Children with febrile seizures associated with vaccines, compared with those whose febrile seizures are independent of vaccines, have identical (good) outcomes (Sun et al 2012; Tartof et al 2014). The safety profile of typically-administered childhood vaccines has recently been reviewed (Maglione et al 2014).
Importantly, 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 (Verbeek et al 2014). These cases, although sometimes severe, should not dissuade parents or pediatricians from following vaccination guidelines.
Basic science research suggests a possible mechanism 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 (Schuchmann et al 2006). The same authors recently 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) (Schuchmann et al 2011).
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%) (Eckhaus et al 2013), 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% (Nelson and Ellenberg 1978). The mode of inheritance is more likely polygenic or autosomal dominant with reduced penetrance (Annegers et al 1982; Tsuboi and Endo 1991). Multiple chromosome linkage sites have been associated with febrile seizures (Audenaert 2006; Nakayama and Arinami 2006) suggesting locus heterogeneity. In addition, multiple genes have been identified as causal for epilepsy syndromes that include febrile seizures (Winawer and Hesdorffer 2004; Audenaert 2006; Nakayama and Arinami 2006). 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 defect in cerebral voltage-gated sodium channels subunits (SCN1B, SCN1A, and SCN2A) or a defect in the gamma 2 subunit of the GABAA receptor (Berkovic and Scheffer 1998). Although GEFS+ includes seizure types other than febrile seizures, it may give insight into the biology of age-limited temperature-dependent seizure susceptibility.