Multiple Sclerosis

Matching Medicine to the MS Patient

UConn Health researchers have discovered why drugs for an aggressive form of multiple sclerosis work in the lab but fail in real patients: Each primary progressive multiple sclerosis patient has uniquely defective stem cells, perhaps making the debilitating illness a prime candidate for precision medicine.

By Kim Krieger

Illustration by Katie Carey

illustration of stylized silhouettes holding their perfectly matched medication


At first, Christine Derwitsch thought she was just really out of shape. She and her husband had gone out for a hike. They went hiking often, but this time, by the summit of the first hill she had to sit down. Her legs were so heavy.

She laughed it off, saying she’d been spending too much time sitting at a desk. But over the next few months, walking became harder and harder. And gradually, Derwitsch realized something was wrong.

“I went on Facebook, and I looked at what I’d been able to do before — hiking, my sister’s wedding — and I couldn’t do that anymore. I thought, ‘This isn’t right.’”

It took her almost a year, but 29-year-old Derwitsch was finally referred to a neurologist at UConn Health, who diagnosed her with primary progressive multiple sclerosis (PPMS). It was a relief to finally understand what was happening to her legs, but the news wasn’t good; there were very few treatment options available.

Most cases of multiple sclerosis have a pattern of illness and then remission: symptoms flare up, then go away, then flare up again. There are effective drugs that help patients extend the periods of remission, and someone diagnosed with MS in his or her 20s may live comfortably for decades.

But PPMS is a different story.

“It’s a harder diagnosis to make because there are no attacks,” says Dr. Matthew Tremblay, Derwitsch’s neurologist at UConn Health, who specializes in treating MS.

And the same thing that makes PPMS harder to diagnose makes it harder to treat.

Most drugs for MS are designed to prevent relapses by suppressing the immune system. But PPMS patients don’t have relapses. To help them, a drug would need to help them regrow myelin, the insulation around our nerves that people with multiple sclerosis can’t reliably repair. Doctors seeking this kind of drug for PPMS keep chasing a mirage.

It’s like you bring in the National Guard to stop a riot, and [instead] they all sit down and start having lunch.

For PPMS, many researchers look for possible treatments among medications that have already been approved for other illnesses. That way they can go right from lab to patient if they show promise. And so far many medications have shown promise — in the lab. But no matter how well a compound works in the lab, it never seems to help many people in the clinic. It’s a conundrum that frustrates both doctors and patients.

But researchers at UConn Health now think they know why the drugs coming out of labs are duds. And they have an idea of how to fix it.

In a new study, UConn Health neuroscientist Stephen Crocker and his colleagues collected blood cells from patients with PPMS, as well as the patients’ siblings or spouses. Then in the lab, they “reprogrammed” the cells and turned them into neuroprogenitor stem cells.

Stem cells can turn into any type of cell in the body; neuroprogenitor stem cells are found only in the brain and specialize in turning into new brain and nerve tissue, such as the oligodendrocyte cells that re-myelinate nerves. These neuroprogenitor stem cells are known to protect the brain from injury, but this recent study was the first to ask whether these stem cells from someone with PPMS had the same ability to protect the brain as those from someone without the disease.


Christine Derwitsch

While primary progressive multiple sclerosis is harder to treat than typical MS, UConn Health researchers have found why drugs that work in the lab fail on real patients with PPMS, like Christine Derwitsch (pictured). Photo: Tina Encarnacion


To explore this question, the researchers first tried adding the stem cells to brain tissues in animals with damage similar to PPMS. Stem cells from the healthy relatives and spouses started repairing the damaged areas. But the PPMS stem cells didn’t do anything.

“It’s like you bring in the National Guard to stop a riot, and [instead] they all sit down and start having lunch,” Crocker says.

Crocker and his colleagues then tested how these stem cells were different by growing them in dishes in the lab. They collected the soup that the cells grew in, called conditioning media, and tested how this affected other cells grown in it afterward. The stem cells had left behind chemicals and proteins in the conditioned media, little messages that tell other cells that come later what they need to do.

Oligodendrocyte cells grown to maturity in media conditioned by healthy stem cells matured into nice, big oligodendrocytes with no problems. But the cells added to dishes conditioned by PPMS stem cells didn’t mature at all. Something about the neural stem cells from PPMS patients was messing up the young oligodendrocytes, leading them astray.

So members of Crocker’s research team next tested some drug candidates for PPMS and added them to the young oligodendrocytes. The drugs absolutely helped the young oligodendrocytes mature when they were growing in media conditioned by stem cells from healthy people. But the same drugs didn’t help the young oligodendrocytes when they were grown in media conditioned by diseased stem cells. In those cases, the cells responded differently every time.

As Tolstoy might have said, healthy stem cells are all alike, but stem cells with PPMS are all unhealthy in their own way. It might appear to be the same disease from the symptoms, but each patient’s PPMS seems to be caused by a different problem with that specific patient’s cells.

But that means that doctors may be able to screen drugs for brain repair on a patient-by-patient basis, Crocker says. He and his colleagues published their findings in the Feb. 1 issue of Experimental Neurology.

Tremblay has begun collaborating with Crocker as they plan the next steps to this research, looking to recruit patients for future studies.

And in the lab they’ve already found that some drugs that have been dismissed as ineffective when tested using more typical techniques may have the potential to work very well for certain PPMS patients — patients like Derwitsch.

Derwitsch hasn’t participated in the study yet, but it’s exactly patients like her who could benefit from this personalized approach.

In the meantime, she is staying mobile and positive. She credits Tremblay for getting her insurance to cover her treatment — he actually got on the phone with her insurance company, she says.

“Dr. Tremblay has so much knowledge about MS, but also a dedication and passion. Every time I have a question, he has an answer.”

The Power of MRI

A UConn Health physician is seen reviewing an MRI brain scan.

A UConn Health physician is seen reviewing an MRI brain scan. At UConn Health, doctors are pioneering ways to use MRI technology to diagnose and monitor a range of conditions affecting many parts of the body Photo: Peter Morenus


Magnetic resonance imaging (MRI) has come a long way since the technique was first used in the U.S. in the late 1970s. UConn Health is now taking this powerful, non-invasive imaging tool to the next level.

UConn Health physicians in a variety of specialties are using the technology — which captures images of the inside of the body using a large magnet rather than radiation — in new ways to detect and monitor illnesses.

Prostate Cancer

Dr. Peter Albertsen, chief of UConn Health’s Division of Urology, currently follows 100 patients with localized prostate cancer, which is slow-growing, using advanced multiple-parametric MRI imaging. The technology has now replaced ultrasound as the imaging method of choice for prostate cancer. The technique yields multiple imaging sequences of the prostate, providing information about the anatomy, cellular density measurement, and vascular supply.

There is growing evidence to support the idea that the best treatment plan for low-grade prostate cancer is “watchful waiting” to monitor its progression, instead of immediate surgery or radiation. Albertsen’s practice of active surveillance, and not intervention, for localized prostate cancer was reinforced by a recent long-term study published in September in the New England Journal of Medicine, on which Albertsen served as a consultant.

The technology is extraordinarily helpful, allowing us to avoid invasive biopsy testing and associated risks of bleeding and infection.

Liver Disease

UConn Health is the first in Greater Hartford to use MRI to measure the stiffness of patients’ livers to reveal disease without the need for biopsy. Its MR elastography technique involves placing a paddle on a patient’s skin over the liver during MRI to create vibrations and measure the velocity of the radio waves penetrating the organ. This can indicate a stiffer liver and help diagnose fibrosis, cirrhosis, a fatty liver, or inflammation associated with hepatitis. The initiative is led by Dr. Marco Molina, radiologist in the Department of Diagnostic Imaging and Therapeutics.

“The technology is extraordinarily helpful, allowing us to avoid invasive biopsy testing and associated risks of bleeding and infection,” Molina says. “Plus, with the obesity epidemic, patients developing nonalcoholic steatohepatitis (NASH), or fatty liver, can receive earlier diagnosis and take action to reverse their disease’s progression with diet and exercise.”

Breast Cancer

The new Women’s Center at UConn Health has opened its state-of-the-art Beekley Imaging Center, featuring advanced breast cancer screening. Dr. Alex Merkulov, associate professor of radiology and section head of women’s imaging, and his team are conducting research to test the effectiveness of using an abbreviated, five-minute MRI scan to confirm or rule out a breast cancer diagnosis. Typically, an MRI test takes 20 minutes, but researchers are seeing that a briefer MRI scan of just a few minutes can help provide a definitive answer to whether an abnormal breast growth is cancer or not — and potentially help women avoid the biopsy process.

Arthritis

The UConn Musculoskeletal Institute is now researching the use of MRI to assess and map the strength, weakness, and underlying makeup of a patient’s cartilage, especially for those with arthritis. The tool can allow orthopedic experts to identify any thinning or loss of cartilage in the body, which signifies moderate to late-stage disease. In early stages of arthritis, MRI can help pinpoint early morphological and subtle biochemical changes in cartilage.

Neurological Disorders

In neuroradiology, UConn Health is using the power of MRI to differentiate brain tumors, to detect strokes, to assess dementia, to diagnose multiple sclerosis, to evaluate traumatic brain injury, to find the source of epilepsy, and to guide brain surgery. In March 2017, leading neuroradiologist Dr. Leo Wolansky joins UConn Health to advance its research and chair the Department of Diagnostic Imaging and Therapeutics. Wolansky’s neuroimaging research has focused on enhancing understanding of MRI and its contrast agents, especially for multiple sclerosis and brain tumors. He also specializes in the hybrid imaging modality PET-MRI.

“Thanks to the power and advancement of MRI, doctors can see early evidence of disease and seize the opportunity to intervene and improve their patients’ health,” Molina says.

New Neurology Chair Sees UConn’s Possibilities

UConn Health Exterior, Farmington CT


Dr. L. John Greenfield looks forward to helping push UConn Health’s Department of Neurology to the next level as its new chair.

Greenfield, a nationally known epilepsy expert, came to UConn Health in early September from the University of Arkansas for Medical Sciences College of Medicine, where he also served as chair of neurology. He will also serve as the academic chair of neurology at Hartford Hospital.

“I see a lot of possibilities at UConn,” Greenfield says.

These include goals of establishing an epilepsy monitoring unit, developing a high-density electroencephalography (EEG) facility, and continuing to expand the stroke, neuromuscular, MS, and movement disorders programs.

Because we’re training the next generation of neurologists, we’re focused on … doing research and developing new treatments.

Greenfield’s arrival as UConn Health’s third epilepsy specialist puts the department at a “critical mass for moving things to the next level,” he says.

Previously, UConn Health has relied on Hartford Hospital for inpatient monitoring of epilepsy patients to determine if they are candidates for epilepsy surgery. Greenfield hopes UConn can establish its own unit for the initial phase of the process. He plans for continued and expanded collaboration with neurologists at Hartford Hospital in epilepsy and other areas. Neurologists at UConn and Hartford Hospital already work closely together in training neurology resident physicians and fellows.

UConn Health is also developing a high-density EEG facility, which would be a resource for the region, he says. Traditional EEGs monitor brainwaves using 15-20 electrodes. A high-density EEG involves a special cap with more than 250 contact points, providing more detailed information on where seizures are coming from, along with other potential uses.

The department also plans to hire more doctors to support its successful movement disorders, neuromuscular, MS, and stroke programs, according to Greenfield, while continuing to provide top-quality care in more “bread and butter” neurological disorders, such as chronic headaches.

“The fact that we’re accessible, very highly trained and patient focused, and an academic medical center gives us an edge against our competitors,” Greenfield says. “Because we’re training the next generation of neurologists, we’re focused on not only using the latest techniques and information so we can teach them, and also doing research and developing new treatments.”