Febrile seizures

Pathogenesis and pathophysiology
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By Renée Shellhaas MD MS, Carol S Camfield MD, and Peter Camfield MD

The pathophysiology of febrile seizures is incompletely understood. The role of activation of the cytokine network is presently being studied. There appears to be increased susceptibility to febrile seizures associated with specific variants of inflammation-associated genes, especially interleukin alleles (Tsai et al 2002; Virta et al 2002; Kanemoto et al 2003; Kira et al 2005; 2010; Serdaroglu et al 2009; Chou et al 2010; Emsley et al 2014), whereas others might be protective (Ishizaki et al 2009). 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 (Wu et al 2012).

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 (Matsuo et al 2006), and interleukin-1β may promote hyperthermia-induced seizures in young rats (Fukuda et al 2009). 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 (Choi et al 2011). However, other studies found no significant role of interleukin-1β, interleukin-1α, or interleukin-1Ra in the pathogenesis of febrile seizures (Haspolat et al 2005; Tomoum et al 2007).

Animal models have demonstrated hyperthermia-induced changes in expression of hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN) (Brewster et al 2002). Mutant HCN2 channels, resulting in increased currents (ie, hyperpolarity) that could increase neuronal excitability have been identified among some patients with febrile seizures and/or GEFS+ (Dibbens et al 2010). 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+ (Egri et al 2012). In a patch-clamp recording study of cortical pyramidal cells in rat brain slices, L-type calcium channels were recently 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 (Radzicki et al 2013).

An autosomal dominantly inherited abnormality 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 (Kang et al 2006). Similar mutations may also result in reduced GABAa receptor expression, which could decrease GABAergic inhibition (Todd et al 2014). These findings have translated to the identification of higher risk populations. For example, a GABRG2 polymorphism has been associated with simple febrile seizures in a cohort of 100 Egyptian children (Salam et al 2012).

A case-control study of children in India showed decreased serum zinc levels in patients with simple febrile seizures (Ganesh and Janakiraman 2008), 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 (Mollah et al 2008). 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 8 case-control studies has also demonstrated deficiencies in iron (Idro 2010). Low selenium levels have been found in 2 case control studies among children with febrile seizures compared to controls (Mahyar 2010; Akbayram et al 2012).

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 (Suga et al 2000). Immaturity of thermoregulatory mechanisms (McCaughran and Schechter 1982) and a limited capacity to increase cellular energy metabolism at elevated temperatures have also been suggested as contributory factors (Holtzman et al 1981). Lastly, animal studies have demonstrated enhanced neuronal excitability during normal brain maturation (Jenssen and Sanchez 2002), which may explain the age-related susceptibility of children to febrile seizures.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
References cited
Contributors