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Measuring the effect

of MS on the mind

 

BY ERIK GREB

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.


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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.

Dr. Mark Gudesblatt

Dr. Anthony Feinstein

Patient self-report and its limitations

Neurologists 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.

Dr. Victoria Leavitt

“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 screens

The 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.

Dr. Frederick Foley

credit: Louise A. Koenig/MDedge News

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.”

When it comes to a detailed neuropsychological assessment, consensus supports using the Minimal Assessment of Cognitive Function in MS (MACFIMS), said Dr. Feinstein. The MACFIMS is “a battery of tests that takes about 90 minutes in a healthy person and probably longer in someone with MS who is impaired,” he added. The battery assesses processing speed, visual and verbal memory, verbal fluency, executive function, and visuospatial abilities.

The MACFIMS “has been advocated as the Cadillac of cognitive function assessment,” said Dr. Gudesblatt. But accessing the test, repeating it, and obtaining insurance coverage for it may be problematic. Dr. Gudesblatt and colleagues found that the NeuroTrax computerized cognitive battery was 86% as sensitive as MACFIMS and identified problems that MACFIMS did not perceive, such as reduced processing speed. Validated computerized tests can add significantly to cognitive examination.

The Brief International Cognitive Assessment in MS (BICAMS) battery comprises three of the tests included in MACFIMS: the California Verbal Learning Test, the Brief Visual Memory Test and the Symbol Digit Modalities Test (SDMT). The BICAMS can be administered in 20 minutes. “If you have a little bit of time and not a lot of money and want to test more patients, you can give the BICAMS test assessment,” said Dr. Foley. The abbreviated MACFIMS and the BICAMS are good at screening, but are not thorough assessments, he added.

Use of the BICAMS may not be widespread among neurologists, however. Because of the test’s length and because it may not be reimbursable, “few people do it outside of research studies,” said Dr. Gudesblatt.

If a neurologist had to administer one screening test that is sensitive to cognitive impairments in MS, he or she likely would choose the SDMT, said Dr. Foley. The test largely measures cognitive processing speed, which is the most prevalent cognitive impairment among patients with MS and may underlie other cognitive impairments. To complete the test, which takes 90 seconds, a patient must match numbers with given geometric figures. The SDMT is the single best screening test for cognitive impairments in MS, Dr. Foley added.

Although the SDMT primarily measures processing speed, poor performance on the test could result from other problems such as memory, language, or oculomotor dysfunction, said Dr. Leavitt. “It’s the most sensitive of all of our measures because it incorporates all of those different things. But that means that each patient who does poorly on it does so for a different reason.”

“In the real world, neurologists aren’t going to do a MACFIMS,” said Dr. Feinstein. “If you can get a BICAMS done, that’s great, but even that is asking a lot of neurologists. If there is only time for a single test, then consensus suggests this should be the SDMT. Obviously, it’s not going to give you the range of cognitive deficits, but it’s an important clue as to whether cognition is impacted or impaired.”

Although batteries such as BICAMS and MACFIMS have been validated for use in MS, none of the tests included in these batteries were developed to measure cognition in people with MS, said Dr. Leavitt. The exception is the Paced Auditory Serial Addition Test, which many patients consider intolerable. Instead, they were developed for detecting much more severe impairment, such as that seen in the context of dementia, traumatic brain injury, and stroke.

“These are quite blunt instruments,” said Dr. Leavitt. “Some of them have high sensitivity in MS. But what that means is that these measures are good at distinguishing between a person with MS and a person without MS. To my thinking, we need to do better than that. We need to be able to measure and track subtle changes in cognition, with an aim of ultimately localizing neural substrates to serve as treatment targets.”

Computers’ role in cognitive testing

The 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 testing

Certain 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.

Suggested Reading

Brandstadter R et al. Word-finding difficulty is a prevalent disease-related deficit in early multiple sclerosis. Mult Scler. 2019 Nov 19. doi: 10.1177/1352458519881760.

Golan D et al. Validity of a multidomain computerized cognitive assessment battery for patients with multiple sclerosis. Mult Scler Relat Disord. 2019;30:154-62.

Kalb R et al. Recommendations for cognitive screening and management in multiple sclerosis care. Review Mult Scler. 2018;24(13):1665-80.

Rao SM et al. Processing speed test: Validation of a self-administered, iPad-based tool for screening cognitive dysfunction in a clinic setting. Mult Scler. 2017;23(14):1929-37.