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Virus that Causes Cervical Cancer Linked to Pediatric Epilepsy

Fitzgerald, Susan

doi: 10.1097/01.NT.0000428463.21740.b4
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For the first time, researchers found human papillomavirus 16 in brain tissue in patients with focal cortical dysplasia Type IIB, suggesting a new pathogenesis and potential therapeutic target for the common form of pediatric epilepsy.

Researchers have detected human papillomavirus (HPV16) in brain tissue from patients with a common form of pediatric epilepsy — a finding that suggests that the same virus that causes cervical cancer may also be a factor in the development of epilepsy.

The research marks the first time that HPV16 was found in the human brain, specifically in tissue excised from patients with focal cortical dysplasia Type IIB (FCDIIB), which can cause intractable seizures. The finding was published in the December 2012 edition of Annals of Neurology.

“What we have is an association between HPV16 and focal cortical dysplasia,” Peter Crino, MD, professor of neurology at Temple University and Shriners Hospitals Pediatric Research Center in Philadelphia and the paper's senior author, told Neurology Today. He cautioned, however, that the “research doesn't prove that HPV16 causes focal cortical dysplasia.”

FCDIIB is a sporadic disease characterized by malformation of the cerebral cortex early in fetal development. According to study authors, the disease is characterized by disorganized laminar architecture and enlarged dysmorphic cells called “balloon cells.” These enlarged cells activate a signaling pathway called the mammalian target of rapamycin complex (mTORC1). Anti-seizure medication and in some cases surgery are used to treat FCDIIB, which can be very debilitating.

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When HPV16 infects the cervical epithelium, it results in the formation of similarly enlarged cells, Dr. Crino explained. Moreover, HPV16 encodes for an oncoprotein called E6, which has been shown to activate the same mTORC1 signaling that is at work in focal cortical dysplasia.

There are many strains of HPV, though HPV16 is the most common cause of cervical cancer in women and it has 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 smear, or genital warts is 12.2 percent. Overall, an estimated 26.8 percent of women aged 14 to 59 in the US have been infected with HPV, though many of them are unaware of it because they have no symptoms. The researchers speculated that even in the absence of symptoms in the pregnant woman, the HPV virus may pass through the placenta.

Erle Robertson, PhD, professor of microbiology at the University of Pennsylvania, who studies tumor virology, told Neurology Today that he doubted that HPV16 is the sole cause of FCDIIB but rather that it is one of a number of factors involved in the disease.

Still, he said, the study underscores how much there remains to be learned about viruses and their role in a wide variety of diseases.

“We are dealing with a huge number of organisms and we're just beginning to understand their connection to human disease and cancer,” Dr. Robertson said.

Dr. Crino said his team plans to study brain tissue from patients with other forms of cortical dysplasia to determine whether HPV16 and related virus strains are present. Another area of potential research, he said, if to see if the mTORC1 signaling pathway, which is activated in focal cortical dysplasia, could be targeted in treatment.

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• Chen J, Tsai V, Crino PB, et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 2012;72(6):881–892.
    ©2013 American Academy of Neurology