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Possible epilepsy trigger point identified

Stanford researchers find defect that sets off common childhood seizures

A brain-circuit defect that triggers the most common form of childhood epilepsy has been identified by Stanford University School of Medicine researchers.

The researchers showed for the first time how defective signaling between two key brain areas -- the cerebral cortex and the thalamus -- can produce in mice the brief loss of consciousness and brain oscillations that characterize so-called absence seizures in children, according to a study published Aug. 21 online in Nature Neuroscience.

Young patients can spontaneously experience these seizures up to hundreds of times per day. The new findings could lead to a better understanding of how ordinary, waking, sensory experiences can ignite seizures, said the study's senior author, John Huguenard, a professor of neurology, neurological sciences and molecular and cellular physiology.

Epilepsy, a pattern of recurrent seizures, affects about one in 26 people over their lifetime, according to Huguenard. Absence, or petit-mal, seizures -- the form that epilepsy usually takes among children ages 6-15 -- feature a sudden loss of consciousness lasting 15 seconds or less.

These seizures can be so subtle that they aren't noticed, or are mistaken for lack of attention. The patient remains still for several seconds, as if frozen in place. Usually, a person who experiences an absence seizure has no memory of the episode.

"It's like pushing a pause button," Huguenard said.

Inside the brain, however, things more resemble an electrical storm than a freeze-frame, according to the researchers.

During an absence seizure the brain's electrical signals spontaneously go into rhythmic oscillations, beginning in the neighborhood of the cortex and thalamus. Exactly where or how this pattern is initiated has been a source of controversy, said the study's lead author, Jeanne Paz, a postdoctoral researcher in Huguenard's lab.

The cortex assesses sensory information, draws conclusions, makes decisions and directs action. To keep from being constantly bombarded by distracting sensory information from other parts of the body and the outside world, the cortex sends a steady stream of signals down to the thalamus, which act like an executive assistant.

The thalamus sifts through sensory inputs from the eyes, ears and skin, and translating their insistent patter into messages relayed up to the cortex, the researchers said.

These upward- and downward-bound signals would soon lead to out-of-control excitement, similar to a microphone being placed too close to a speaker. But an inhibitory nerve tract monitors the signals and dampens activity, keeping the system well modulated, researchers said.

But the Stanford team discovered that in bio-engineered mice a protein in the inhibitory cells that is critical to turning them on is missing. Mice affected with the missing protein are prone to the petit-mal seizures, they said.

When the researchers selectively turned on and off the stimulating signals from the cortex or thalamus nerves, something strange happened. While one nerve tract did turn off the signals as expected, the other, which comes from the thalamus, continued to fire signals.

This forced the cells from the thalamus nerve tract into overdrive, which caused the dampening cells to become overactive. They silenced all signaling from the thalamus to the cortex -- a key first step in a seizure, the researchers said.

But the shutdown was transitory. When the signaling stopped, the dampening cells ceased their output. The thalamus nerve-tract cells resumed a strong volley of signaling that overloaded the system again.

These oscillations of alternating quiet and exuberant periods repeated over the course of 10 or 15 seconds, constituting a seizure, researchers said.

The importance of this defect in humans is not yet known, Huguenard said. Most individuals who suffer from these seizures appear to have "normal" nerve cells and circuits indistinguishable from those of non-epileptics. But researchers now have an experimental system to study why ordinary everyday experiences can trigger these seizures.

Behavioral experiments are under way in Huguenard's lab to see what can trip off a similar circuit malfunction in normal mice. The resulting observations may someday help patients control their own exposures to minimize seizures, Huguenard said.

Sue Dremann

Comments

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Posted by question
a resident of Another Palo Alto neighborhood
on Aug 23, 2011 at 8:22 pm

I don't want to undermine the significance of this remarkable achievement, but...

My first test in college biochemistry had an organic chemistry question on it. I thought the answer was obvious and having been something of a whiz in organic chem, I was a little stunned that I missed it. When I asked about it, the TA deadpanned: Yes, that reaction is correct, but it's not what happens in the human body.

Oh.

Just because these researchers can reproduce the symptomology in the mice does not mean that's what is happening to produce that symptomology in the human disease. I just find this approach a bit too circular. In children with absence seizures, the ketogenic diet can be curative - does anything comparable happen in some of these mice models if given the same conditions?


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Posted by Kim
a resident of Adobe-Meadow
on Aug 24, 2011 at 12:54 pm

This is very interesting. My 11 year old daughter started having seizures last April. We were told she has benign Rolandic Epilepsy. We have never seen her have the twitching of the face, drooling, silent stare. We have witnessed about 10 Tonic Clonic seizures. They begin with in 15 minutes after she falls asleep. During the beginning of the summer her seizures were coming more frequently. Her doctor in Oakland thought it might be a good ides to start her on medication because they were coming so regularly. We decided to wait and make a lifestyle change. We started making sure she was in bed no later then 10:00. She has not had a seizure since. It has been a little over a month. This is all very new to us I would appreciate any input...


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Posted by E springer
a resident of another community
on Aug 24, 2011 at 9:11 pm

My daughter has absence siezures that we first noticed at 18 months. The sensory overload makes complete sense. She is 6 and we homeschool bc the more she concentrates the worse they get. She would be totally lost in a classroom setting. She also takes meds.


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Posted by marie
a resident of another community
on Aug 27, 2011 at 10:46 am

My son was recently diagnosed with epilepsy. He has absence seizures, but they seem to be controlled well with Keppra. No one talked to me about the possibility of putting him on a ketogenic diet, and I haven't seen anything about it in the literature I've found.

One of the most puzzling things about my youngest son's seizures is that they result in expressive aphasia and he is unable to remember how to swallow a pill (he will have a seizure approximately 6 hours after missing a dose of Keppra). His older brother had a grand mal seizure a little over a year ago. Immediately following that seizure he was unable to speak. He underwent emergency surgery to remove a tumor on the right temporal lobe of the brain. My younger son's seizures originate in the temporal lobe, but fortunately he has no tumor.

I appreciate the additional avenue to pursue. I'm also hoping that the family history of "growing out of epilepsy" holds true.


Like this comment
Posted by A Senior
a resident of Another Palo Alto neighborhood
on Aug 27, 2011 at 12:38 pm

This research seems to concentrate mainly on childhood epilepsy which is most important. However, epilepsy can first manifest itself in the old which can be very troubling to an otherwise healthy senior.


Sorry, but further commenting on this topic has been closed.

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