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Where Seizures Freeze

At GW, bridges between the clinic and the bench may revolutionize epilepsy care

By Amy Maxmen

When Carrie Morgan* turned 10 years old, she learned she had a seizure disorder. For the next 28 years, she would try to calm the intense and sudden attacks with every anticonvulsant in the book. Nothing worked; the seizures grew more frequent. By 2000, she was suffering as many as 10 seizures per day. “My life was so restricted,” Morgan recalls. “I went from neurologist to neurologist, and they would just give up on me.” Then, Morgan met Samuel Potolicchio, M.D., the director of the Neurophysiology Center at the George Washington University Hospital (GW Hospital). He told her that by surgically removing a portion of her temporal lobe, the region of the brain where the seizures originated, he might be able to put an end to her attacks.

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Taking out a piece of the damaged brain is a scary proposition, but not as scary as a life with uncontrolled seizures. Before committing to the surgery, however, the team needed to determine which side of Morgan’s brain dominated her verbal memory recall. Potolicchio and Anthony Caputy, M.D., professor and chair of the Department of Neurosurgery, had to confirm which sides of the brain had good or poor memory recall. More importantly, however, they needed to confirm that the side opposite of where the seizures were focused had good recall. To do that they performed the WADA test, named after Canadian neurologist Juhn Atsushi Wada, to determine the language and memory dominance between the hemispheres of the brain.

The team anesthetized the right side of Morgan’s brain, and they asked her what Dr. Potolicchio held in his hand. “A pen,” she correctly answered. When he anesthetized the left side, Morgan recalls, “I couldn’t say what he was holding. I understood, but I just couldn’t say it.” Immediately, Potolicchio told her she an excellent candidate for the procedure, and that her WADA test results confirmed that she was quite safe in terms of her memory. Shortly after her 38th birthday in 2001, Caputy performed surgery. She has not experienced a seizure since then, moreover she no longer takes medications to control her seizures, allowing her to fulfill her dream of graduating from college and becoming a medical technician. “I now have a new lease on life,” she says.

One-third of people with epilepsy cannot control their seizures with ordinary anti-epileptic drugs. Like Morgan in her teenage and young adult years, people with untreatable epilepsy are often barred from normal activities like swimming or driving because they frequently lose control of their bodies. Unlike her, a subset of these patients are not able to be treated through surgery. Neurologists and neuroscientists at George Washington University (GW) find this outcome terribly troubling. The Epilepsy Center at GW Hospital has long helped those patients, and now it aims to do even better by translating cutting-edge science into patient care. For example, GW recently installed state-of-the-art equipment to monitor brain activity, which will help doctors pinpoint the origin of seizures so that they can tailor treatment to the individual. What’s more, collaborations between clinicians and researchers focused on the brain across the GW campus promise to usher in a wave of new and personalized seizure treatments in the years to come.

“My vision for the center is to be at the forefront of utilizing the most advanced technology for the care of individuals with epilepsy, to be at the forefront of research, and to be a leader in epilepsy education,” says Mohamad Koubeissi, M.D., a neurologist directing the center. “Luckily,” he adds, “these objectives are interwoven.” Indeed, translational research requires an ever-flowing partnership between the scientists at the bedside and the bench.

A PLANNED ATTACK

Koubeissi’s interdisciplinary attack resonates among his colleagues at GW, as does his sense of urgency. “Only frequent dialogue between clinicians and basic scientists can make inroads into the big problems that have prevented cures for epilepsy thus far,” says Anthony LaMantia, Ph.D., director of the GW Institute for Neuroscience (GWIN).

Methods to intervene with epilepsy have stalled in part because the brain is such a complicated organ to observe and manipulate. However, new technology that can image and monitor brain activities, and improved tools for analyzing the genes that reveal a risk of epilepsy and drug toxicity, may foster the next wave of advances. To this end, the center’s new system for monitoring the electrical activity in patients’ brains does not require patients to remain in their beds with wires connecting sensors on their scalps to computers at their bedsides. Now, the sensors wirelessly communicate with a hospital computer, meaning patients may be monitored more comfortably for longer periods. With this additional electroencephalogram (EEG) data, neurologists can more accurately predict where seizures arise in a person’s brain, and whether that person may be amenable to surgery or another investigational option.

People who are not safe candidates for surgery may soon seek solace at GW too. GW has been exploring memory loss for several years with other researchers on campus, including GW’s Department of Psychology in the Columbian College of Arts and Sciences. Koubeissi is investigating a couple of procedures that may avoid memory loss. One involves short-circuiting the seizure-generating section of the brain by snipping connections between it and neighboring regions. The second procedure is to electrically stimulate the malfunctioning area in order to get its signaling back on track. Through clinical trials to test these procedures at the GW Epilepsy Center, patients with no viable options would be offered the opportunity to try something new. “Following the textbook, we currently tell these patients, I’m sorry, there’s nothing we can do; you will live with your seizures,” Koubeissi says. “In the future, we want to explain that we’ve done everything in the textbook, but there may be procedures we can offer that might help you without interfering with your memory.”

Matthew Colonnese, Judy Liu, Mohamad Koubeissi
Partners without boarders. Matthew Colonnese, Ph.D.; Judy Liu, M.D., Ph.D.; and Mohamad Koubeissi, M.D., form an information exchange that moves data from clinic to lab as well as lab to clinic.
BACK IN THE LAB

For many years GW and the Department of Neurosurgery has been a leader in the exploration into procedures using electrical pulses, called deep brain stimulation. Continuing in that tradition, Koubeissi is investigating his own techniques into the procedure. In preparation for the trials he hopes to soon lead, Koubeissi is refining new methods of delivering electrical pulses using rats with epilepsy. He studies them in his laboratory in GW’s Institute for Neuroscience. “People talk about moving findings from the lab to the clinic, but it works both ways,” Koubeissi says. “It’s clinic to lab, lab to clinic. It’s this type of dynamic relationship that we want to foster at GW.”

Judy Liu, M.D., Ph.D., assistant professor of pediatrics at the GW-affiliated Children’s National Medical Center (Children’s National) and member of its Center for Neuroscience Research, operates in a similar manner. She focuses on the neurological disorder lissencephaly, in which a person’s brain cells do not migrate to the correct spot during early childhood. By age 10, children begin suffering from seizures and mental disabilities. Various mutated genes underlie the disorder, and Liu learns how these genes affect neuronal migration by altering them in mice, and analyzing the downstream changes in proteins that occur. “If we can figure out which proteins become dysregulated in the mice,” Liu says, “we can think about trying to alter proteins in patients in order to counteract seizures.”

Liu’s laboratory work also focuses on samples from patients, which ensures that what she discovers in mice is applicable to humans. Liu collaborates with neurologists at Children’s National. Weekly, she and the neurologists gather to discuss difficult cases, including any children who might go to surgery to ameliorate their epilepsy. When surgeries are performed, Liu, or a member of her laboratory, heads to the operating room to learn more about the patient and to observe exactly which part of the brain the neurosurgeons remove. They then cart the extracted tissue back to Liu’s laboratory for analysis. “We usually find that the tissue is more prone to [electrical] excitation, and we examine which genes are on and off compared to normal brain tissue,” Liu explains. “Next, we recapitulate those changes in mice so that we can understand the problems those genes cause.” Soon, Liu hopes to collaborate with neurologists at the Epilepsy Center to examine adult brain tissue.

Neurologists at the Epilepsy Center already converse with GW’s neuroscientists on a regular basis. Recently, Koubeissi helped Matthew Colonnese, Ph.D., an assistant professor at the GWIN, understand patterns he saw in an EEG from a rat brain. Colonnese studies the erroneous brain development that occurs in the genetic disorder Fragile X syndrome. In humans, the disorder is a common cause of epilepsy and mental disability, but parents often do not detect that their child has the disorder until they are at least 2 years old. If scientists could pinpoint when neurons begin to misfire during a baby’s development, Colonnese suspects they might develop a way to intervene before the problem becomes irreversible. To learn when the problems begin, Colonnese experiments with rats, engineered by an outside firm to bear a similar genetic mutation, observing them as they develop Fragile X syndrome. He has already had promising results: Before the rats showed any behavioral signs of having Fragile X syndrome, Colonnese noticed that some of their EEGs looked different from the EEGs of normal rats. “I saw crazy activity patterns, and so I asked Mohamad [Koubeissi] to look at the graph,” says Colonnese. “He pointed to a spike followed by a wave of activity and described the type of seizure it was.” Although the baby rats’ muscles were not seizing up, the rats were enduring the first neurological components of seizures.

BRIDGE BUILDERS

Translating findings from the laboratory to the clinic begins with interdisciplinary collaborations like these. To facilitate those interactions, clinical and neuroscience departments host seminars, and the Epilepsy Center hosts a monthly series of lectures by epilepsy experts from around the world. In addition, GW researchers can conduct their brain-related experiments in a well-stocked core facility located at the GWIN (see sidebar). Henry Kaminski, M.D., the chair of GW’s Department of Neurology, trusts that basic findings will move to the clinic at GW because the heads of each component actively push for translation. “I meet with scientists and clinicians in other departments spontaneously because I want to promote this type of interaction,” Kaminski says.

Kaminski suggested expanding the Epilepsy Center in 2011 for several reasons. First, he knew that top neurologists and neurosurgeons at the center recognized the importance of research in finding new treatments, and therefore, that they might interact with neuroscientists like LaMantia elsewhere on the GW campus. Second, Kaminski and GW Hospital’s clinical partners appreciated an unmet need for the Epilepsy Center in the greater Washington, D.C., area. “GW is among the few places that patients with difficult cases can go,” says Kaminski.

“We have the opportunity to establish a continuity between pediatric neurology at Children’s National and adult neurology at GW,” says Vittorio Gallo, Ph.D., professor of pediatrics and of pharmacology and physiology at GW, and the Wolf-Pack Chair in Neuroscience and director of the Center for Neuroscience Research at Children’s National.

The collaborative work between Colonnese, Koubeissi, and Liu, adds Gallo, is a prime example of how investigators can find colleagues whose research interests interface with their own. That exchange, adds Gallo, goes both ways. Normally, he says, research flows from basic science questions to translational research and ultimately ends up as clinical applications. “What we are able to do in this setting is reverse that pipeline. Physicians are able to find partnerships to study mechanisms that are at the basis of therapeutic applications by working together with investigators who are using animal models of disease.”

One of the greatest medical challenges of the 21st century is finding cures for brain disorders. Neurological problems have been nearly impossible to solve because the brain is difficult to study and difficult to treat. Despite these hurdles, the army of clinicians and researchers across GW are well positioned to make a serious dent in the toll that seizures take on patients. On their side are modern medical and scientific tools, the push to interact across sectors, and raw drive. “As a doctor, I got tired of telling patients and their parents, we don’t know why these seizures happen and we can’t tailor our therapy to you or to your child,” Liu says. “That’s why a lot of us are back in the lab, so that five to 10 years down the road we can target therapy to specific patients.”

*The name has been changed to protect the patient’s identity.

Core Strength

Collaborative research is engineered into the Institute for Neuroscience. At the institute’s Biomarker Discovery and Analysis Core Facility, researchers from the Neurology Department as well as myriad other centers across the GW campus gather in search of molecular biology services, tools, and expertise. There, researchers can have the DNA within their samples analyzed with high-throughput polymerase chain reaction platforms, microarrays, and in situ hybridization. Alternatively, they may visit the core facilities to conduct experiments that involve fluorescence microscopy; transgenic animals, plants, and bacteria; or embryonic stem cells from mice. This consolidation of resources saves money for individual laboratories on campus because they do not need to purchase their own equipment from scratch. In addition, it allows investigators to pursue questions outside their laboratory’s—and often their department’s—reach. Finally, it offers investigators from disparate realms a place to collaborate. “You can’t force people to do things together, but you can provide opportunities that enable people with a variety of interests to cooperate,” says Anthony LaMantia, Ph.D., director of the GW Institute for Neuroscience.

Much of the work conducted at the core facility applies directly to biomedical issues. For example, Thomas Maynard, Ph.D., director of the facility, uses tools at the core to analyze changes in gene expression that result in seizures, learning disabilities, and other symptoms of DiGeorge syndrome. Scientists know that the syndrome is caused by a DNA deletion in a part of the human genome called 22q11.2; however, they do not yet understand how this defect disrupts protein networks to cause neurological problems. Maynard’s findings unexpectedly aided Irene Zohn, Ph.D., of Children’s National Medical Center, when she visited the core facility to learn which genes and proteins caused neurological defects in malformed mice embryos. Maynard and Zohn realized that a protein from Maynard’s experiment on DiGeorge syndrome, the nutrient retinoic acid (or vitamin A), also went awry in Zohn’s embryos.


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