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In the Clinic: Alice Lam, MD, PhD: On the Hunt for a Non-Invasive Toolbox for Diagnosing Epilepsy

Hurley, Dan

doi: 10.1097/01.NT.0000521902.81399.b2
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Alice Lam, MD, PhD, recipient of the Susan B. Spencer Clinical Research Training Fellowship, is seeking to develop a non-invasive “neurophysiological toolbox” for diagnosing epilepsy in Alzheimer's disease. Here, she discusses her pathway to the research.

BOSTON—After completing her undergraduate degree at the University of Chicago in just three years, Alice Lam spent a year working in an electrophysiology laboratory, eight years in a dual MD-PhD program at the University of Michigan, a year interning at St. Joseph Mercy Ann Arbor Hospital, three years as a neurology resident at Massachusetts General Hospital and Brigham and Women's Hospital, and two more years as an epilepsy fellow at Massachusetts General Hospital.

“That's a total of 18 years from the time I started college,” she said with a smile, “and there's still so much I have yet to learn!” Now in her first year as an instructor and epileptologist at Massachusetts General Hospital, she added, “It feels like another beginning.”

In April, at the AAN meeting here, Dr. Lam was awarded the Susan B. Spencer Clinical Research Training Fellowship, co-sponsored by the AAN, the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation. For her research project, she is seeking to develop a non-invasive “neurophysiological toolbox” for diagnosing epilepsy in Alzheimer's disease.

“One of the big questions in the field is whether seizures and seizure-like activity contribute to the cognitive impairments of Alzheimer's, and whether they accelerate that process,” she said. “The problem is that it's been difficult to study, because seizures occurring in the mesial temporal lobe tend not to show up on scalp electroencephalograms [EEGs].”

In a study published in Nature Medicine in May, Dr. Lam and colleagues reported the first intracranial electrode recordings in two patients with Alzheimer's disease without a history of seizures. Recording directly from the mesial temporal lobes, they detected abundant epileptiform spiking occurring during sleep in both patients. One patient had several subclinical seizures during sleep. The vast majority of these abnormalities were not visible on the scalp EEG. “The scalp EEG is our standard clinical test for detecting epileptiform activity in Alzheimer's disease,” she said, “but our current methods of interpreting the scalp EEG may be giving us a very incomplete picture of what is actually going on in Alzheimer's disease.”

To get at this issue, Dr. Lam has been developing computational approaches to detect the activity being missed on visual interpretation of the scalp EEG. In a study published in the journal Brain last October, she and colleagues identified 25 mesial temporal lobe seizures in 10 patients that were not detected by routine clinical interpretation of scalp EEGs.

Using computational analyses of those same scalp EEGs to ferret out occult signal patterns, they correctly identified scalp-negative seizures in 40 percent of patients, and correctly identified the side of seizure onset for each seizure detected. Their method had a false alarm rate of 0.31 per day, and a positive predictive value of 75 percent.

Dr. Lam called the study a proof of principle. “We need to scale it up before we can say this is powerful enough to be used in clinical practice,” she said. If the method does prove capable of consistently identifying otherwise hidden seizures, however, “it will allow us to get at questions about the natural history and prevalence of seizures in Alzheimer's disease,” she said. “Then we can ask if treatment of these seizures would slow progression of Alzheimer's. We're at the very beginning.”

For Dr. Lam's family, the beginning was in Vietnam, which her parents left in the early 1960s to pursue university scholarships in Canada.

“My grandfather was a very forward-thinking guy,” she said. “He told his daughters, including my mother, ‘I want you to go out and get an education and not be dependent on a husband to support you.’”

Upon completing their studies, Dr. Lam's mother and father settled in Chicago, where her father was a physicist at Argonne National Laboratory. After the war in Vietnam ended, Dr. Lam's grandparents joined them in Chicago. Her grandfather, a poet, eventually developed Alzheimer's disease.

“Watching how it progressed, how it affected our family, how my parents had to make decisions, made me understand how devastating a disease it really is,” Dr. Lam said.

While still in high school, she was accepted into a program at Argonne that encouraged students to learn electronics. “I built a little photo detector that they actually used in a synchrotron,” she said. “It was really fun work, and when I started college, I thought I wanted to be a physicist.”

But after deciding that medicine was better suited to her outgoing nature, she received her bachelor's degree in biology and then took a year to work in the electrophysiology laboratory of Dorothy Hanck, PhD, at the University of Chicago.

“I felt so at home there,” she said. “It reminded me of the physics stuff I had been doing in high school.”

Given a copy of a textbook, Ion Channels of Excitable Membranes, by Bertil Hille, she read it while commuting back and forth from her home. “I found it exciting that these little proteins that sit in your cell membrane regulate the ions that come in and out, like mechanical doors opening and closing. I thought that was the coolest thing ever. It was during that year that I knew I would want to do science as part of my medical career.”

As part of her neuroscience doctoral studies, Dr. Lam trained in the laboratory of Edward L. Stuenkel, PhD, professor of molecular and integrative physiology at the University of Michigan.“Ed was an amazing mentor,” she said. “He taught me formally and informally how to be a scientist.”

Her mentor now at MGH is Sydney S. Cash, MD, PhD, who was senior author of her paper last year in Brain. “He's a great role model for me as a physician-scientist,” she said. “As a mentor, he's given me the support and freedom I need to explore my scientific ideas.”

Whether or not her research shows, as she hopes, that treating seizures in people with Alzheimer's can slow that disease's progression, there is little doubt she has already succeeded in honoring the memory of a certain forward-thinking poet from Vietnam who believed in the education of women.

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LINK UP FOR MORE INFORMATION:

•. Lam AD, Zepeda R, Cole AJ, Cash SS. Widespread changes in network activity allow non-invasive detection of mesial temporal lobe seizures https://academic.oup.com/brain/article-abstract/139/10/2679/2196656/Widespread-changes-in-network-activity-allow-non?redirectedFrom=fulltext. Brain 2016; 139 (Pt 10): 2679–2693. Epub 2016 Jul 29.
•. Lam AD, Deck G, Goldman A, et al Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease https://http://www.nature.com/nm/journal/v23/n6/full/nm.4330.html. Nat Med 2017; 23(6): 678–680.
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