The first symptoms to come to mind at the mention of multiple sclerosis (MS) are likely to be walking difficulty, vision problems, and increased fatigue. During the past 25 years, many therapies that effectively reduce these symptoms have been introduced. These therapeutic successes have enabled researchers and neurologists to focus on an aspect of MS that sometimes has been overlooked: cognitive symptoms.
|The prevalence of cognitive symptoms in patients with MS is estimated to range between 40% and 70%, with common problems including decreased processing speed, impaired memory, and decreased attention. These problems can make it difficult for a patient with MS to keep a job, thus increasing the risk of unemployment. Cognitive symptoms may reduce a patient’s ability to enjoy leisure activities, impair his or her relationships, and make it hard to perform activities of daily living. As the number of impaired cognitive domains increases, the risk of falls increases, and the likelihood of maintaining driving ability and employment decrease, said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
A current initiative is encouraging all neurologists to introduce cognitive testing into their clinical practice, said Anthony Feinstein, MD, PhD, professor of psychiatry at the University of Toronto. In November 2018, the National MS Society convened a panel of experts in cognitive dysfunction and published recommendations for screening, monitoring, and treatment. “Many patients are not getting cognitive assessments, and they should,” said Dr. Feinstein.
Patient self-report and its limitationsNeurologists can gain relevant information simply by listening to their patients. “Patients are the most valuable window into understanding cognitive impairment that we have,” said Victoria M. Leavitt, PhD, assistant professor of neuropsychology and director of the Translational Cognitive Neuroscience Laboratory at Columbia University Irving Medical Center, New York. She noticed that many of her patients were reporting problems with word substitution. These patients would say one word when they meant another, sometimes without realizing what they were doing. This problem had never been described in the literature about cognitive problems in MS until 2019, when collaborative work from the lab of James Sumowski, PhD, at the Icahn School of Medicine at Mount Sinai, New York, yielded the first paper to address this topic. “If we identify language problems early on and develop effective treatments for them, we potentially could be forestalling later-stage memory problems. But none of that would have been recognized if we hadn’t listened to exactly what patients told us.”
Nevertheless, self-report alone may be unreliable. “Metacognition [i.e., thinking about one’s own thought] is often impaired in people with MS, and so they are not often the best judges of their own cognition,” said Dr. Feinstein.
“One of the problems of measuring cognition is that self-report is very insensitive,” said Frederick W. Foley, PhD, professor of psychology at Yeshiva University, New York. When patients with MS think that their cognition is declining, “they’re much more likely to have depression and anxiety than cognitive impairment,” he said. “You really need objective measures.” But if a patient reports cognitive problems, it is appropriate to refer him or her for testing.
From comprehensive evaluations to brief screensThe standard of care for cognition in MS has not been defined clearly, according to Dr. Leavitt. “The only way that cognition is addressed generally across centers in a standardized way is through the Expanded Disability Status Scale [EDSS],” which relies on clinician impression (without formal measurement) of the patient’s cognitive status. The EDSS thus addresses cognition in a “qualitative, subjective, and cursory” way that “leaves something unaddressed,” she added.
The EDSS is “weighted very much toward pyramidal tract function” and “doesn’t do justice to cognition,” said Dr. Feinstein.
Other measures of MS disability, such as the Minimal Record of Disability in MS and the Patient-Determined Disease Steps, share the shortcomings of the EDSS. “Current measures of MS disability do a good job of measuring motor function, but are insensitive to cognitive impairments,” said Dr. Foley. “Measures of disability that have included questions on cognition in MS have not been properly validated to see if they actually measure the cognitive problems in MS.”
Computers’ role in cognitive testingThe future development of cognitive testing in MS likely will include increased computerization. Stephen Rao, PhD, director of the Schey Center for Cognitive Neuroimaging at the Cleveland Clinic, and colleagues developed a processing speed test that patients can administer to themselves using an iPad. Their test was highly correlated with the SDMT and was more sensitive than the latter test in distinguishing patients with MS from controls.
“Computers are starting to take over some of the cognitive assessments very effectively,” said Dr. Feinstein. He and his colleagues programmed a computer to administer the SDMT using voice recognition software. A proof-of-concept study showed that this technique was effective and that patients were comfortable with it.
Potential advantages of computerized cognitive tests include reduced testing time and reduced expense. “In terms of their comparison to a neuropsychologist doing a thorough evaluation, they still leave a little to be desired,” said Dr. Foley. More studies of these tests’ validity are necessary before neurologists can rely on unsupervised self-testing using tablets or computers, he added. “But I think it’s going to be the wave of the future.”
Future improvements in cognitive testingCertain aspects of cognitive testing in MS may need improvement. For example, current tests “are not very sensitive at detecting cognitive fatigue, which many patients report is like a brain fog,” said Dr. Foley. Neurologists hypothesize that cognitive fatigue is a central fatigue, and patients report that it dramatically affects their functioning. “We need to develop better tests to measure that aspect of cognition: how quickly someone fatigues when engaging in cognitive tasks.”
Also, emerging data indicate that patients with MS have deficits in social cognition: the capacity to relate well and interact smoothly with others. “Relating to another person socially is a complex cognitive event,” said Dr. Foley. “We need better tests at assessing changes in social cognition in patients with MS.”
For neurologists to monitor changes in a patient’s cognition over time, they must administer cognitive testing at regular intervals. But repeated testing entails the risk that test results will be biased by practice effects. One way to address this concern is to administer alternate forms of the test, so that a patient is exposed to different stimuli. “But we still have a way to go” in obtaining an accurate measure of cognitive function when a patient has undergone repeated testing, said Dr. Foley.
Cognitive testing generally is conducted in a quiet and undisturbed environment that promotes concentration. “That’s not a real-world environment,” said Dr. Feinstein, because noise and interruptions are common in daily life. In a series of studies, Dr. Feinstein and colleagues are introducing distractions such as automobile horns and ringing telephones while patients undergo cognitive testing. In this way, they have identified additional deficits that conventional tests do not capture. “Distractions are a useful way to go in boosting the sensitivity of some of these tests,” Dr. Feinstein added.
An increasing amount of research is focusing on cognition in MS. “It’s becoming a hot topic now. I’ve been doing this work for about 10 years, and I’ve seen a shift,” said Dr. Leavitt. “The tables are turning, and people are paying attention to cognition. Now it’s going to be up to us to put in place the proper tools for the field to address it and, ultimately, treat it.”
Dr. Freedman is the principal investigator of the 40-patient Canadian arm of the study, coined MESCAMS for Mesenchymal Stem Cells for Canadian MS Patients, which has included patients with RRMS as well as those with progressive disease. “We want to know, is tissue that isn’t completely scarred…better repaired in the presence of these cells than [when the cells are not present]? These are hard questions to answer, since no one has really shown how to measure repair,” he explained.
“We’ve thrown everything at our patients in terms of trying to measure repair–sophisticated MRI imaging on subgroups, lots of immunology, neurophysiology, and neurocognitive studies…in hopes of getting some signal [of possible repair] that can help us to move forward” in further studies if results are positive, Dr. Freedman said. “We want to know, is there a repair signal? When does it occur, and does it fade?”
MSCs have been shown in in-vitro and in-vivo preclinical studies to release anti-apoptotic, anti-oxidant, and trophic factors, all of which can provide neuroprotection. But there’s much more to learn about their potential mechanisms of action. Bruce F. Bebo, Jr., PhD, executive vice president for research at the National Multiple Sclerosis Society, said it is unlikely that MSCs travel to axons and directly repair myelin, and quite likely that the MSCs secrete factors that not only inhibit the immune response but that prompt or support the nervous system to repair itself. That, he said, is the “leading hypothesis” regarding how MSCs can be beneficial for MS. “They could prove to be a good one-punch to inhibit inflammation and at the same time promote repair,” he said.
In another closely watched phase 2 study, investigators at the Tisch Multiple Sclerosis Research Center of New York are taking a different approach to MSC therapy, creating specialized MSC-neural progenitor cells and injecting them intrathecally in an attempt to promote repair and regeneration in patients with progressive MS.
Investigators at the Center have long worked with MSC-NP cells–isolating MSCs from the bone marrow, expanding them ex-vivo in MSC growth medium, and then culturing them in neural progenitor maintenance medium—and have shown that the cells express and secrete trophic factors that mediate various aspects of neural repair. Saud A. Sadiq, MD, director and chief research scientist at the Center, has also long focused his research on MS on the cerebral spinal fluid and the intrathecal space.
“Over time we could move to a more convenient route, but for now, the intrathecal route was chosen because that’s the site of the pathology. And the central nervous system is such a protected environment, it takes away the burden of somehow having to get the cells through the blood-brain barrier,” said James A. Stark, MD, a neurologist and director of clinical trials at the International Multiple Sclerosis Management Practice, which operates alongside the Tisch MS Research Center.