Dodging the long-term cognitive effects of early-life seizures

Seizures seem to strengthen and “lock in” synapses too soon, leaving no room for development. (Image: Ice synapses, Joe Flintham/Flickr)

It’s well known that babies who have seizures soon after birth have roughly a 50-50 chance of developing long-term intellectual and memory deficits and cognitive disorders like autism. But until now, it wasn’t understood why these deficits occur, much less how to prevent them from happening.

In the December 14 Journal of Neuroscience, researchers at Children’s Hospital Boston, led by neurologist-neuroscientist Frances Jensen, detail in a rat model how early-life seizures affect brain development at the cellular and molecular level. But more to the point, they show that it might be possible to ward off these effects with drug treatment soon after the seizure – using a drug called NBQX or similar drugs that are already approved by the FDA.

Jenson was particularly interested in what seizures do to synapses, the connections between neurons that are rapidly developing in the infant brain.

Her previous work has shown repeatedly that newborns’ brains are different from everyone else’s.

Examining slices of brain tissue from the hippocampus, an area important in learning and memory, Jensen’s team found that after a seizure, newborn rats had a diminished pool of “silent” or inactive synapses, which should predominate soon after birth. Instead, an excessive number of synapses had been converted to an excitable form by acquiring more so-called AMPA receptors.

An excitatory brain state and strengthening of synaptic connections are normal and necessary for cognitive development. But here’s the thing: Jensen’s team found that seizures exaggerated excitation and synaptic strengthening too soon in development, to the point where synapses lost their “plasticity,” or their ability to adapt to information from the environment — what learning is all about.

Frances Jensen

“Seizures have ‘fixed’ the synapses so they have much less potential to respond to experience,” Jensen says. “Epilepsy seems to be co-opting normal synaptic plasticity mechanisms.”

As a result, the rats’ brain tissue showed diminished long-term potentiation (LTP), a widely accepted molecular proxy for learning that looks at electrical responses to stimulation of neurons as a measure of synapses’ ability to change their strength. “When we try to induce LTP in brain slices from animals that have had epilepsy, it can’t be done,” Jensen says. “There’s no more ‘flex’ in the synapses.”

All these effects were evident within 2-3 days after the seizure – but amazingly, it looks like they can be undone. When Jensen’s team gave the rats NBQX, which blocks AMPA receptors, inactive synapses and LTP were preserved, even when NBQX was given as late as 48 hours after the seizure. And the protective effects lasted into adulthood.

Since drugs similar to NBQX are already FDA-approved for other indications, Jensen believes these results might eventually lead to a clinical trial in newborns who have had seizures.

“Because we can reverse the strengthening of synapses, we might be able to modify the disease after the fact, which is one step in the right direction toward thinking about potential strategies for cures,” she says. “Epilepsy has many mechanisms and potential therapeutic targets, but this is one that may be important in undoing the cognitive effects that epilepsy may have.”

  • Darshan Singh

    Have the clinical trials ended? If so, is this drug used for treatment of epileptic children? My daughter who is 2.5 months old now, was born with Epileptic Encepalopathy. We are looking for some form of cure for her so she can develop normally and her infant brain doesn’t get damaged. This treatment seems to be a promising one. We are willing to do anything for our daughter’s health and betterment. Please help!!

    • nansona

      Dr. Jensen has left Boston Children’s Hospital and we’re not sure if the work has continued anywhere. The Epilepsy Center at Boston Children’s told me:
      “The FDA did approve a medication for seizures that has this effect, known as perampanel. This is an antagonist of the glutamatergic AMPA receptor (the class of compounds studied and discussed in this post). While the approval is for patients ages 12 and older, there has been some use of this in younger patients. The actual ability to preserve neurodevelopment, however, remains unknown. Your neurologist will be able to advise you regarding your specific case.”
      Hope this helps! –Nancy Fliesler, editor

      • Darshan Singh

        Thank you so much! I will check with the Neurologist here and see if we can give our daughter the same medication Perampanel. Do you know if the Epilepsy Center in Boston has any other break through treatments or any research studies going on for infants with seizure disorders? Can my daughter be a part of those studies or treatments if any? Thank you very much!

        • nansona

          We can’t really comment medically on a blog, but here is our web page for people looking for second opinions – http://www.childrenshospital.org/patient-resources/second-opinion-program. And if you would like to contact the Epilepsy Center at Boston Children’s, that # is 1-617-355-7970. All the best to you and your daughter!

          • Darshan Singh

            Thank you! I will check out the options you’ve mentioned. Appreciate your help.

  • Darshan Singh

    Hi Rohit, sorry for my tardy reply. Somehow I didn’t get notified about your post till yesterday. So very late. Anyway, to answer your question, we haven’t made much progress on this. We are trying everything we can right now for our daughter. Here’s my email address darshansinghr at y a h o o.com. Shoot me an email and we can chat more in detail.