In a three year prospective study in Britain and Ireland, blood samples of 205 children (2-35 months of age) hospitalized with fever and convulsions and/or suspected encephalitis were tested for primary HHV-6 and -7 infections and reported from Royal Free and University College Medical School, London, UK. Of 156 children aged 2-23 months with primary infection coinciding with the acute illness, 26 (17%) tested positive for HHV (11 children with HHV-6; 13 HHV-7; and 2 with both viruses). All were febrile, 25 had convulsions (status epilepticus in 18), half had a rash, and 11 required ventilation. CSF from 21 patients was negative for HHV DNA, and only 2 had >5 white cells. Primary infection was defined by a) seronegative or low antibody titer in the acute sample containing viral DNA; and b) seroconversion to low avidity IgG antibody and rising titer >4 fold to the virus between acute and early convalescent sera, or low or high avidity IgG antibody between acute and late convalescent sera and viral DNA in the acute sample. The number of cases of HHV was much higher than that expected by chance (p<0.001), and HHV-6 and -7 were equally important causes of encephalopathy or convulsions, especially status epilepticus. Children at 1 year receiving MMR or other vaccine and developing fever and convulsion should be tested for HHV infection to avoid misdiagnosis of vaccine reaction. [1]

COMMENT. This prospective study shows that primary infection with HHV-6 or -7 is responsible for encephalopathy and/or severe convulsions with fever in 17% of children <2 years of age (median age 1 year) who require hospitalization. Primary HHV infection is not associated with the rash of exanthem subitum in one half the cases. CSF does not show evidence of direct viral involvement of the CNS, and the severe convulsions with fever could be classified as “complex febrile seizures.” In the US, infection with HHV-6 accounts for one-third of all first-time febrile seizures in children <2 years old (Ped Neur Briefs 2004; 18:59) [2]. An elevated cytokine response independent of the severity of infection may be a factor in the mechanism of febrile seizures (Kawada et al, 2003). [3]

Cytokines and febrile seizures. The height of the fever (not rate of rise) is the important determinant of a threshold to febrile seizures [4]. Other FS causative factors related to infection include 1) an abnormal immune state and allergic response to infection; 2) genetic susceptibility; 3) a neurotropic toxin (eg. Shigella) or virus (eg. HHV-6 or -7, influenza A); 4) encephalopathy; and 5) an elevated cytokine response. Proinflammatory cytokines (interleukin-lB [IL-1B]) act as pyrogens, and fever induces IL-1B synthesis in brain microglia, leading to enhanced neuronal excitability and decreased seizure threshold. Dube C and colleagues (University of CA at Irvine) have shown that IL-1B receptor-deficient mice are resistant to experimental FS [5]. This resistance was independent of genetics and due to lack of IL-1B signaling; high IL-1B doses induced seizures only in IL-1B receptor-expressing mice. The authors conclude that endogenous IL-1B contributes to FS, and potentially contributes to hippocampal epilepsy. Further investigation of viral and cytokine-related factors in the cause of simple and complex febrile seizures is indicated.