Brain plasticity promotes worsening of epileptic seizures, study finds | message center


The researchers focused on a common type called absence seizures, in which all behavior usually stops for less than a minute. People with such seizures appear as if they are staring or dreaming. You also experience a brief loss of consciousness; after that they don’t know what happened. While these seizures are less dramatic than those that cause convulsions or collapse, they still impact the lives of epilepsy sufferers and can be dangerous, for example, if someone has an absence seizure while crossing a street.

Children and adults with certain types of epilepsy can experience hundreds of absence seizures every day. Although it can be treated with medication, about 30% of patients with childhood absence epilepsy still have seizures despite taking medication.

“We don’t have disease-modifying treatments for most forms of epilepsy,” Knowles said. “We can give drugs that temporarily stop seizures, but that doesn’t address what’s structurally happening in the brain.”

To understand how seizures alter the brain, the researchers studied rodents with absence seizures. As with some types of human absence epilepsy, animals develop seizures early in life that gradually worsen over time.

In the brains of rats with absence epilepsy, the researchers examined changes in myelin-forming cells, the so-called oligodendrocytes. At the end of the seizure onset period – 4.5 months later – the animals had more and a greater density of new or dividing oligodendrocyte progenitor cells and more mature oligodendrocytes compared to before the onset of seizures.

This finding corresponded with the presence of a thicker myelin coating on the nerve fibers – and more nerve fibers with myelin – in the brain region where seizures occur. However, there was no change in myelination in brain regions where seizures are uncommon. In addition, control animals without seizures did not show these changes.

To see if disrupting seizure-induced myelination could block seizure development, the researchers genetically engineered mice to advance their understanding of absence epilepsy. The scientists modified an important receptor in mouse oligodendrocyte progenitor cells that is required for adaptive myelination. Using genetic engineering, the researchers were able to selectively remove the TrkB receptor from the oligodendrocyte progenitor cells in these mice from the expected onset of seizures. When TrkB was deleted, the mice still had some seizures, but the number of seizures was fewer and they did not become more frequent.

The researchers also used a drug that blocks aspects of oligodendrocyte progenitor cell maturation and administered the drug a week after the mice began to have seizures. The finding was similar to that seen in genetically engineered mice: the seizures still occurred, but they didn’t get worse or more frequent.

The class of drugs used in the study, HDAC inhibitors, includes some FDA-approved drugs. The scientists hope to study whether such drugs could improve outcomes, particularly in children newly diagnosed with a severe form of epilepsy.

“Much more needs to be done to explore the molecular mechanisms that link pathological patterns of neuronal activity to maladaptive myelination and to explore the potential of HDAC inhibition for severe and refractory epilepsy,” said Knowles.

The other Stanford authors on the study are life science researchers Haojun Xu, Ankita Batra, Lijun Ni, and Sydney Talmi; student Tristan Saucedo; medical student Lydia Tam; and former research associates Caroline Soane, Eleanor Frost, Danielle Fraga, and Katlin Villar.

The authors include members of Stanford Bio-X, the Stanford Maternal and Child Health Research Institute, the Stanford Wu Tsai Neurosciences Institute, the Stanford Institute for Stem Cell Biology and Regenerative Medicine, and the Stanford Cancer Institute.

The research was funded by the National Institute of Neurological Disorders and Stroke (Grants R01NS092597, K12NS098482, K08NS119800, R01NS034774, and R01NS117150), an NIH Director’s Pioneer Award (Grant DP1NS111132), the Robert J. and Helen C. Kleberg Foundation, Stanford Maternal, and the Child Health Research Institute, Stanford Bio-X, Cancer Research UK, the American Epilepsy Society, the CURE Epilepsy Foundation and the Child Neurology Foundation.

Monje is on the Scientific Advisory Board of Cygnal Therapeutics. The authors have no other competing interests.


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