NEUROLOGY & NEUROSURGERY
Beyond Seizures
Thanks to advancements in pharmaceuticals during the last 25 years,
a variety of medications treat seizures in children. Unfortunately, a
third of those children continue having seizures anyway. “We can only
get so far with epilepsy research using non-specific approaches,” says
Amy Brooks-Kayal, MD, Chief of Pediatric Neurology. As a result, her
team’s research efforts are getting increasingly specific.
Focal cortical dysplasia, or FCD, is a malformation
of cortical development caused by a genetic
mutation that occurs in utero, leading to
disordered layers of neurons in the cerebral
cortex. It’s also a common cause of drug-resistant
epilepsy in children.
“Patients with this diagnosis often require
resection surgery for treatment of their epilepsy,”
says pediatric neurosurgeon Allyson Alexander,
MD, PhD. “Unfortunately, this surgery is invasive
and not always successful. Also, some patients are
not candidates for resection surgery due to the
location of the dysplasia in their cerebral cortex.”
Epileptologists and neurosurgeons know that
FCD leads to epilepsy, but they’re still exploring
what specific aspects of the disorder cause
seizures. That work has led to the discovery of
somatic mutations in several genes of what’s
called the mammalian target of rapamycin
pathway, or mTOR.
“This pathway regulates cell metabolism,
growth, proliferation and survival,” says Dr.
Alexander. “Now we want to understand how
genetic and histological changes in FCD lead
to a brain network that generates difficult-to-
control seizures.”
One potential clue is an abnormal bursting
pattern in some brain cells of patients with FCD,
discovered by Molly Huntsman, PhD, a researcher
with the University of Colorado’s Skaggs School
of Pharmacy, just across the Anschutz Medical
Campus from Children’s Colorado. These bursting
patterns have proven to promote seizure-like
activity in rodent and computational models.
We want to understand how the genetic and histological
changes in focal cortical dysplasia lead to a brain network
that generates difficult-to-control seizures.”
A L LY S O N A L E X A N D E R , M D, P h D
Pediatric Neurosurgeon
it very thin and putting it into an oxygenated
environment,” says Dr. Alexander. “This allows us
to keep the neurons alive and record their activity
using a micro-pipette.”
However, this approach has limitations due to the
lack of normal human brain tissue available, which
is why Dr. Alexander’s team is also developing a
mouse model for exploratory research. Based on
a previous model, it uses in-utero electroporation
to modulate the mTOR pathway in a subset of
neurons, leading to an area of disordered cortical
layers similar to that seen in patients with FCD.
Based on these findings, Dr. Alexander is using a
two-pronged approach — using resected human
brain tissue and an experimental FCD mouse
model — to further this research. She’s hoping
to determine whether neocortical pyramid cells
exhibit abnormal bursting behavior, and whether
this burst firing pattern is due to alterations in the
expressions of T-type calcium channels.
Digging deeper for targeted
treatment options
Discovering T-type calcium channels as the culprit
for FCD seizures would be good news for patients,
as the channel is a known target for ethosuximide,
an FDA-approved drug used to treat some forms
of epilepsy.
“As one part of this research, we’re taking tissue
from FCD patients resected during surgery, slicing
Triple immunofluorescent confocal microscopy demonstrates mTOR pathway
For neurology
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Once the model is up and running, Dr. Alexander
will study the bursting cells to learn whether the
T-type calcium currents play a role in the bursting
behavior. If so, her team will test whether the
T-type calcium blocker could stop these seizures.
“If we’re going to move beyond where we are today,
we have to better understand, and then specifically
target, the underlying mechanisms that cause
different types of epilepsy,” says Dr. Brooks-Kayal.
“We’re thinking beyond seizures.” ●
30 7 140+
Multidisciplinary clinics Pediatric neurosurgeons 37 140+ Active clinical
and translational
research studies
Pediatric neurologists Epilepsy surgeries annually
LEADERSHIP:
Amy Brooks-Kayal, MD
Chief, Pediatric Neurology, The Ponzio Family Chair in Pediatric Neurology
Michael Handler, MD
Chief, Pediatric Neurosurgery, The McMurry Seebaum Chair in Pediatric Neurosurgery
Sandra Friedman, MD, MPH/MSPH
Chief, Neurodevelopmental and Behavioral Pediatrics, William K. Frankenburg
Research Professorship in Developmental and Behavioral Pediatrics
upregulation in this sample of human dysplastic cortex. Neuronal cell bodies are in white;
ps6, a marker of mTOR pathway activation, is in red; and perineuronal nets are in green.
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