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Professionalism-Multiple Sclerosis
Frederik Barkhof, MD, PhD: A Slight Detour on the Way to Winning the Dystel Prize for MS Research

ARTICLE IN BRIEF

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DR. FREDERIK BARKHOF: “We were constantly trying to see new aspects of the pathology, and we still are. Particularly now we are interested in gray matter damage, which remains an under-recognized phenomenon in MS. A lot of drugs that are available suppress lesion formation, yet people still develop gray-matter atrophy. We would like to understand how that is possible.”

From an early age, Frederik Barkhof, MD, PhD, was interested in visualizing phenomenon. Here he discusses how his early interests and research interests led to his developing the classic MRI criteria for multiple sclerosis.

Frederik Barkhof, MD, PhD, could have been a dentist like his father. But the neuroradiologist who developed the eponymously named Barkhof Criteria, used with MRI findings to make an early diagnosis of multiple sclerosis (MS), took a slight detour.

Thanks to that “detour,” Dr. Barkhof has been responsible for some extraordinary advances in MS research and practice — developments that led to his receiving the John Dystel Prize for Multiple Sclerosis Research at this year's AAN Annual Meeting. The prize is sponsored by the AAN and the National MS Society.

“My father was a dentist, but for me it would have been a clear mistake,” said Dr. Barkhof, professor of neuroradiology at the department of radiology and nuclear medicine at VU University Medical Center (VUMC) in Amsterdam, the Netherlands, and at the Institutes of Neurology and Healthcare Engineering at the University College London, UK. “Since dentistry and medicine overlapped much in my first year of medical studies, I was able to move straight into my second year focusing on medicine. It's so much broader and intellectually rewarding.”

Upon receiving his MD in 1988 at VUMC, Dr. Barkhof found himself drawn to the radiological side of neurology, influenced in part by a youthful interest in photography.

“I spent a lot of time with photography when I was a kid,” he said. “I started when I was 10 or so and was in the dark room developing my own films at least twice a week. I won a prize for youths under 16 with a nature photograph, but then developed an interest in more abstract pictures.

“I've always had a good visual memory,” Dr. Barkhof continued. “And in medicine, if you have a patient with a problem, you want to see what the problem is so you can treat it. Radiology is a way to visualize what is happening.”

EARLY CAREER INFLUENCES

One of his first mentors at the university's department of neuroradiology was Professor Jacob Valk, MD, PhD, who acquired what was then a new type of technology, a magnetic resonance imaging (MRI) device.

“It was a Technicare 0.6 tesla — from a company that does not exist any more,” Dr. Barkhof recalled. “Professor Valk purchased it in 1986, and I joined him as a student a year later. Because the technique was so new, all special cases were sent to us from around the country. We were constantly researching what it was that we were seeing. In the case of MS, it was a real eye-opener, because for the first time we could see pathology findings during life. With CT you could barely see anything to do with MS, but with MRI you could see it quite well. We realized it was super sensitive to lesions in the brain and spinal cord, but then we started to notice that people with other diseases also have lesions in the brain. I was interested in differentiating the findings of MS from these other mimics.”

His approach was to systematically test and compare the many settings that can be used on an MRI device, looking at the size and location of lesions over time and how they predict clinical findings.

“MR is such a versatile technique,” he said. “You can tune the knobs in many directions: T1, T2, FLAIR, and so on. We were constantly trying to see new aspects of the pathology, and we still are. Particularly now we are interested in gray matter damage, which remains an under-recognized phenomenon in MS. A lot of drugs that are available suppress lesion formation, yet people still develop gray-matter atrophy. We would like to understand how that is possible.”

THE BARKHOF CRITERIA

His first description of what came to be known as the Barkhof Criteria for using MRI findings to predict conversion to clinically definite MS was published in November 1997 in the journal Brain. Its accuracy for both sensitivity and specificity is in the 80 percent range, he said.

“That's okay, but we'd still like to improve it,” he said. “The Barkhof Criteria are not used in isolation. They have evolved over the years. We've been optimizing them. Elements of are still in the current MS diagnostic criteria, which have just recently been revised, published in Lancet Neurology in January.”

Among the key findings of his career so far, Dr. Barkhof identified the importance of asymptomatic spinal cord lesions and infratentorial lesions, for the diagnosis and prognosis of MS; demonstrated that gadolinium enhancement increases the sensitivity of MRI and clinical assessments in detecting inflammatory activity; discovered that T1 hypointense “black holes” reflect the most destructive lesions that can serve as outcome measure for neuroprotective treatments; developed the long-interval T2-weighted subtraction MRI as a powerful outcome measure; and validated brain atrophy as outcome measure.

“In my opinion, no advance in MS research has made more of an impact on the disease than MRI, and Professor Barkhof has been at the forefront of this effort since the early stages of its development,” said Henry F. McFarland, MD, scientist emeritus at the National Institute of Neurological Disorders and Stroke, who won the Dystel Prize in 1998 and nominated Dr. Barkhof for it this year.

“His insights have greatly contributed to modern trial design and therapeutics, which is now propelling the field in important and increasingly focused directions,” wrote Jerry S. Wolinsky, MD, emeritus professor in neurology at McGovern Medical School of University of Texas.

Having led or coauthored over 900 peer-reviewed papers, half of them on MS, Dr. Barkhof has also written three books: Neuroimaging in Dementia, Clinical Applications of Functional Brain MRI, and Magnetic Resonance in Dementia.

He serves on the editorial boards of Radiology, Brain, Multiple Sclerosis Journal, Neuroradiology, and Neurology. A fellow of the Royal College of Radiology, he is the Principal Investigator of the Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) study, a large European initiative using beta-amyloid PET imaging to track the natural history of the disease and select patients for clinical trials.

His hobbies these days include bicycling, playing the piano, cooking, skiing, spending time with his three children, and enjoying electronic music — including the pioneering 1970s band, Kraftwerk.

“I saw them last time five years ago,” Dr. Barkhof said. “They did eight shows in a row in Amsterdam, and every night they did a different album. I got a ticket for one of them. But I also like experimental electronica, from artists like Brian Eno to Coil, The Orb, UNKLE, DJ Shadow, and Moodymann.”

Apparently, the Barkhof criteria for music has yet to be widely embraced.

LINK UP FOR MORE INFORMATION:

•. Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.26300. Brain 1997;120 (Pt 11):2059–69.
•. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria https://www.nejm.org/doi/full/10.1056/nejmoa1602489. Lancet Neurol 2018; 17(2):162–173.