 also been linked to cancers of the mouth and throat. There are two vaccines — Gardasil and Cervarix — that protect against HPV16 and a federal advisory committee on immunizations recommends routine vaccination for girls, ages 11 to 12.
Dr. Crino was struck by the fact that FCDIIB and cervical dysplasia had some similar features and decided to test a hunch.
“Based on cytopathic and cell signaling similarities between cervical dysplasia and FCDIIB, we hypothesized that HPV16 E6 DNA, mRNA, and protein are present in human FCDIIB brain specimens and could serve as a pathogenic agent in FCDIIB,” his team wrote in their published article.
Using the same standard molecular techniques that are used to detect the HPV16 E6 protein in cervical disease, Dr. Crino and his team set about to test the hypothesis.
They first analyzed FCDIIB brain tissue samples from 50 patients and found that the F6 oncoprotein was present in balloon cells of all 50 samples, but not in regions without the enlarged cells. Their controls consisted of 36 brain tissue samples from patients who did not have FCDIIB. None of the 36 samples tested positive for the HPV16 E6 protein.
The researchers next tested the samples for the DNA and mRNA of HPV16 E6, comparing FCDIIB samples to tissue samples from healthy controls as well as tissue from controls who had other types of brain malformation and epilepsy. Again, the samples from patients with FCDIIB showed genetic evidence of HPV16 E6, while the control samples did not.
The researchers also tested their hypothesis using mice. When they delivered the E6 protein into the brains of fetal mice, the mice developed focal cortical malformations that occurred in conjunction with enhanced mTORC1 signaling.
“Although further investigation is warranted to understand how FCDIIB causes epilepsy, our findings suggest a new pathogenesis for FCDIIB based on localized central nervous system HPV16 infection during fetal brain development that accounts for many of the known features of FCDIIB, including sporadic occurrence, enhanced mTORC1 signaling, and altered brain cytoarchitecture,” the researchers wrote. “Our study is the first to provide an association between HPV16 infection and a neurological disorder and the first to detect HPV16 in human brain.”
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“The study is very intriguing,” said Delia Talos, MD, assistant professor of neurology at New York University, who does epilepsy research but was not involved with this study. “No one has ever suggested this before.”
She said that while “it is very tempting to say that this terrible disease could be prevented,” more work is needed to confirm the findings and understand the possible clinical implications.
Other researchers told Neurology Today they were impressed by the design of the study and the strength of the results. Leon Epstein, MD, the Derry A. and Donald L. Shoemaker professor of pediatric neurology at Northwestern University, said the paper was “very persuasive” and an example of the insight that can result when scientists think creatively across disciplines.
He said the researchers “asked a totally testable question: Was the HPV16 E6 oncoprotein present in FCDIIB tissue? The answer was yes, and specifically the protein was localized in balloon cells.”
“I think this is a very important study if the role of HPV in the pathogenesis of focal cortical dysplasia is confirmed by future studies,” said Dr. Epstein, whose research specialty is neurovirology. He said “it is possible that the HPV vaccines currently used to prevent cervical cancer might also result in fewer children born with focal cortical dysplasia and associated epilepsy.”
Dr. Crino and his team noted in their paper that “one pivotal unresolved issue is the mode of HPV16 transmission in FCDIIB.”
“Because it is believed that FCDIIB forms during embryonic brain development, a possibility is transplacental HPV16 infection of progenitor cells in the developing brain,” they wrote.
They noted that the transplacental transmission rate of HPV among women with either known HPV infection, an abnormal PAP s