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[February 27, 2017]

Lack of Oxygen, Not Excessive Stimulation, Cause for Half of Seizure-Related Brain Damage in Epilepsy

 

Brooklyn, NY – Neuronal degeneration is the most severe long-term consequence of repetitive seizures in patients with epilepsy, which until now was thought to be primarily caused by excitotoxicity, or over-stimulation of the neurons. New findings indicate hypoxia, or lack of oxygen, due to abnormal blood flow may be to blame for as much as half the neuronal death caused by the condition.

A new study published in the journal Scientific Reports describes researchers’ investigation into the true culprit for seizure-related neuronal degeneration in epilepsy. Stephen Macknik, PhD, and Susana Martinez-Conde, PhD, both professors of ophthalmology, neurology, and physiology and pharmacology at SUNY Downstate Medical Center, were co-authors in the study.

Advanced imaging enabled researchers to detect a cascade of abnormal capillary vasodynamics, which indicate that even though blood can be observed flowing into the hippocampus—a part of the brain that suffers damage from seizures—an unusually high number of microscopic vascular spasms block flow to some of the delicate brain tissue. This cumulative damage over a lifetime of seizures could contribute to severe cognitive decline or even death in patients with epilepsy. The study also discovered that microscopic spasms in capillaries occur, albeit with lower frequency, during normal brain function, too, suggesting that one problem caused by epilepsy is that seizures drive these vasospasms to abnormal levels.

The study delved further into the mechanism of the vasospasms and found that tiny cells on capillaries, called mural cells, are precisely associated with the points of the vasospasms in the vessels. This contributes to the growing literature that suggests that capillaries are not simply passive tubes through which blood cells flow to irrigate tissue, but rather they may actively contribute to the control of local blood flow directly.

“Our findings have the potential to transform current understanding of neural degeneration in epilepsy (a wide-reaching and often intractable condition, affecting 50 million people worldwide),” writes Dr. Macknik, “as well as its potential treatment. They moreover resolve a historical controversy about the causes and mechanisms of epilepsy, dating back to observations in the 18th century.”

In the study, researchers examined the brain function of animals with epilepsy to distinguish between neuronal death caused by excitotoxicity versus hypoxia. Helped by the recent development of fiber-optic-bundle-coupled laser-scanning confocal fluorescence imaging (Confocal Laser Endomicroscopy—CLE), which allowed the scientists to image blood flow more deeply in the brain than ever before, the researchers were able to look more closely at the microvascular dynamics around the hippocampus, which is thought to be a critical region of seizure genesis in patients.

Researchers were able to conclude hypoxia was the cause for approximately half the neuronal death through a novel stereological analysis, which was able to identify neuronal death happening in close proximity to hypoxic blood vessels. Since excitotoxic neuronal death is not related to blood flow, the authors concluded that the nearby hypoxia may be to blame. Their hypothesis was borne out by a comparison to similar neuronal death in epileptic animals versus healthy ones.

The authors believe their findings suggest a potential value in treatment of epilepsy with blood flow regulating drugs to reduce the amount of seizure-related neurodegeneration.

The article in Scientific Reports is titled, “Abnormal Capillary Vasodynamics Contribute to Ictal Neurodegeneration in Epilepsy.” [Leal-Campanario, R. et al. Abnormal Capillary Vasodynamics Contribute to Ictal Neurodegeneration in Epilepsy. Sci. Rep. 7, 43276; doi: 10.1038/srep43276 (2017)]. The article is available at: http://www.nature.com/articles/srep43276.
 
The project was funded by a Research Initiative Award from the American Epilepsy Society and the Arizona Biomedical Research Commission to S.L.M., as well as a challenge grant from Research to Prevent Blindness Inc. to the Department of Ophthalmology at SUNY Downstate, the New York State Empire Innovation Program, and further grants from the National Science Foundation (0726113, 0852636, and 1523614), the Barrow Neurological Foundation, Mrs. Marian Rochelle, Mrs. Grace Welton, Dignity Health SEED awards, the Research Preventing Blindness Foundation, and Empire Innovator Scholar (New York State) funds to S.L.M and S.M.-C. This work was also supported by the Office of the Assistant Secretary of Defense for Health Affairs under Award No.W81XWH-15-1-0138. The content is solely the responsibility of the authors and does not necessarily reflect the views of funding sources.

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SUNY Downstate Medical Center, founded in 1860, was the first medical school in the United States to bring teaching out of the lecture hall and to the patient’s bedside. A center of innovation and excellence in research and clinical service delivery, SUNY Downstate Medical Center comprises a College of Medicine, College of Nursing, College of Health Related Professions, a School of Graduate Studies, a School of Public Health, University Hospital of Brooklyn, and a multifaceted biotechnology initiative including the Downstate Biotechnology Incubator and BioBAT for early-stage and more mature companies, respectively.

SUNY Downstate ranks twelfth nationally in the number of alumni who are on the faculty of American medical schools. More physicians practicing in New York City have graduated from SUNY Downstate than from any other medical school. For more information, visit www.downstate.edu.

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