ARTICLE IN BRIEF
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.
SIMILARITIES WITH CERVICAL DYSPLASIA
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