TABLE 3.

Criteria for causality and strength of evidence linking HHV-6A/B to febrile seizures and status epilepticus

Disease causation criterion	Evidencea
HHV-6A/B nucleic acid is present in diseased tissue, in most cases, in higher abundance than in nondiseased tissue (by qPCR or other means).	Viral DNA is present in CSF (9, 82, 83) and in brain (87).
The amount of HHV-6A/B nucleic acid in diseased tissue or blood, and/or antibody levels, correlates with the severity of the disease.	Higher levels of viral nucleic acid are present in blood at the time of seizures (8, 9, 14, 19, 82, 83, 97–103).
HHV-6A/B nucleic acid is demonstrated in cells relevant to disease pathology.	Brain biopsies/autopsies are typically not performed in febrile seizures, even following status epilepticus. However, HHV-6A/B can infect adult neurons (230, 232), adult astrocytes (109, 230, 231), and microglial cells (30, 229, 230).
HHV-6A/B mRNA (by RT-PCR or other means) and antigens by immunohistochemistry are present in diseased tissue.	Brain biopsies/autopsies are typically not performed in febrile seizures, even following status epilepticus.
Exposure to and then presence of the viruses and their gene products in affected tissue precede the development of the disease (temporal relationship).	95% of humans are infected with HHV-6B in early childhood. The number of humans infected with HHV-6A, and the typical age of primary infection, is less clear.
Infectious agents other than HHV-6A/B are not detected in diseased tissue in a substantial number of cases.	Negative evidence: Other agents capable of inducing seizures sometimes are found along with HHV-6B (113).
There are cellular or humoral immune responses to HHV-6A/B in diseased tissue and/or in blood, and these responses correlate with the severity of the disease.	In animal models, HHV-6A infection generates activated CD4+ and CD8+ T cells and B cells and proinflammatory cytokines (68). Primary HHV-6B infection and reactivated HHV-6B infection (each defined by blood nucleic acid and antibody studies) have been detected in 20% and 10% of children with FSE (14, 82, 90, 103, 105, 106). HHV-6B DNA has been found in the CSF of some children with FSE (8).
HHV-6A/B affect cellular function in diseased tissue in a manner known to cause or augment the disease pathology (in vitro or in vivo studies).	Positive evidence:  Infection of astrocytes or oligodendrocytes results in the production of proinflammatory cytokines, and chemokines (32, 33, 63, 69–71, 76–79)  … as well as mediators of neuronal hyperexcitability (32, 79, 80) …  … and autoantibodies against glutamic acid decarboxylase (81).
	Negative evidence: HHV-6B nucleic acid or antibodies have not been found in FS (112).
Specific antiviral therapy both reduces viral load in diseased tissue or blood and is followed by clinical improvement.	No evidence yet.

^aAll evidence cited is positive evidence in support of the assertion unless specifically identified as negative evidence.