Preventing autism after infant seizures

Early seizures may disrupt circuit formation in babies' brains, leading to autism. But new research suggests that an existing drug can reverse this.

This is the third post in a series about new approaches for seizures and epilepsy. Read the first and second posts.

We already know that there’s some kind of connection between epilepsy and autism: Children who have seizures as newborns not uncommonly develop autism, and studies indicate that about 40 percent of patients with autism also have epilepsy. New research at Boston Children’s Hospital finds a reason for the link, and suggests a way to break it — using an existing drug that’s already been given safely to children.

In the online journal PLoS ONE, Frances Jensen, MD, in the Department of Neurology and the F.M. Kirby Neurobiology Center at Boston Children’s, and lab members Delia Talos, PhD, Hongyu Sun, MD, PhD, and Xiangping Zhou, MD, PhD, showed in a rat model that early-life seizures not only lead to epilepsy later in life, but also produce autistic-like behaviors.

Drilling deeper, they showed that early seizures hyper-activate a group of signaling molecules collectively known as the mTOR pathway. This increased signaling – above and beyond the normal surge that happens early in life – disrupts the normal balance of connections (synapses) in the rats’ developing brains. The rats go on to develop epilepsy and altered social behavior, and Jensen believes something parallel happens in humans.

But here’s what’s exciting. They did other experiments where they gave the rats the drug rapamycin, which disables the mTOR pathway, before and after seizures. The mice did not show abnormal synapse or circuit development, and were less likely to have seizures later in life. Autistic-like symptoms appeared less often.

“Our findings show one of probably many pathways that are involved in the overlap between epilepsy and autism,” says Jensen. “Importantly, it’s one that is already a therapeutic target and one where treatment can reverse the later outcome.”

Rapamycin is already used to treat a variety of diseases that involve the mTOR pathway, from cancer to a genetic disorder called tuberous sclerosis complex (TSC) that often includes epilepsy and autism. Boston Children’s is currently conducting a clinical trial of a rapamycin-like drug called Afinitor in children with TSC.

“Our study suggests that even without tuberous sclerosis, seizures are inducing the mTOR pathway, and might on their own be contributing to the development of autism,” says Jensen.

Targeting early seizures may also help spare children from later cognitive problems. Last December, Jensen and colleagues published another study showing that early seizures cause rats’ brains to have an excess of excitable synapses that couldn’t reconfigure in response to life experience, affecting the animals’ ability to learn. These problems were reversed with a drug called NBQX, which blocks receptors associated with excitation.

Jensen’s findings carry echoes of research we reported last week by Tobias Loddenkemper, MD, showing that children with developmental delay and/or autism sometimes have seizure-like brain activity at night that shows up only on sleep EEGs. Indeed, the two may be comparing notes in the future.

“The fields of epilepsy and autism may inform each other about new treatment targets,” Jensen says.

For more on the epilepsy-autism connection, see this feature published last year in Nature Medicine. And read more about the emerging view of autism as a disorder of brain connectivity, exemplified by two conditions associated with autism: TSC and Rett syndrome.