Philadelphia researchers detect a link between cervical-cancer virus and a form of epilepsy

Peter Crino, Temple University neurologist.
Peter Crino, Temple University neurologist.
Posted: February 21, 2013

Philadelphia researchers have detected part of the virus that causes cervical cancer in a surprising place: a congenital brain malformation that causes an intractable form of epilepsy in children.

This is the first study to uncover evidence of the microbe - human papillomavirus (HPV) - in the brain. It is also the first to suggest that an infection in the fetal brain leads to the malformation, which has no known genetic or environmental cause.

Peter Crino, a neurologist in the Shriners Hospitals Pediatric Research Center at Temple University, conducted the study with colleagues at the University of Pennsylvania. It was published recently in the Annals of Neurology.

The malformation, focal cortical dysplasia, is marked by enlarged "balloon" cells that disrupt nerve signals in a brain region that governs thought and memory.

In both children and adults, the malformation is a common cause of epilepsy that does not respond to antiseizure drugs and requires brain surgery.

A link between the malformation and the virus could lead to new ways to manage or even prevent some forms of epilepsy, Crino said. Vaccines that prevent HPV infection are already available, as are drugs that might interfere in the virus' signaling pathway.

Imad Najm, director of the Cleveland Clinic epilepsy center, called the findings "exciting."

"It shows that some of these malformations may not be determined just by some congenital abnormality, but by an infection," Najm said. "Or, at least, an infection could be playing a role."

Others were skeptical.

Neurologist Lawrence Brown, an epilepsy expert at Children's Hospital of Philadelphia, said, "How do you get from a viral colonization in the cervix to a brain malformation in a fetus? It's just really hard to connect the dots."

Pathologist Richard Schlegel at Georgetown University, a coinventor of the HPV vaccine, pointed out that Crino's team found only part of the virus, not its whole genetic code. That suggests that the virus was not replicating in the brain, and thus could not be causing infection.

"Their data is good," Schlegel said, "but I find so many gaps, knowing the biology of the virus."

Forty years ago, the German virologist Harald zur Hausen faced derision when he proposed that cervical cancer, a major killer of women, was seeded by the same virus that caused ordinary skin warts.

His lab went on to prove that HPV is a family of viruses, most benign, that infect the skin or mucous membranes. The two most dangerous HPV types can induce cervical cancer, and also rare malignancies of the genitals, throat, and tongue.

Crino's team detected a cancer-promoting gene of one of those dangerous types, HPV16, in balloon cells of 50 samples of the brain malformation.

In comparison, they found no evidence of HPV in samples from 36 normal brains, plus other types of congenital brain defects and brain cancer.

The idea that a virus could reach the womb and damage a fetal brain is not far-fetched. Cytomegalovirus and rubella can do so.

But HPV had never been found in the brain or tied to a neurological disorder. So why suspect it?

The basis for Crino's hunch was similarities between the abnormal cells found in the cervix and in the brain malformation.

In both places, the cells are enlarged and contain a molecular signaling pathway, abbreviated mTOR, that is vital to cell growth and division.

Crino knew that Harvard researchers found that this signaling pathway could be thrown into overdrive by the cancer-promoting HPV gene.

Could that mechanism also damage a fetal brain?

As a test, Crino's team delivered the HPV16 gene into the brains of three fetal mice. All developed a brain malformation.

The researchers acknowledged that a "pivotal" question is how HPV could get into a fetal brain. They suggested the virus might be transmitted by an infected woman through the placental blood supply.

Schlegel called that idea "controversial."

"It will be important for another lab to replicate this study," he said. "I'm very doubtful, but time will tell."


Contact Marie McCullough at 215-854-2720 or mmccullough@phillynews.com.

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