<p>Outcome measures for relapsing multiple sclerosis (MS) can be used to assess and follow disease activity and progression over time, but they have limitations. Our featured experts discuss current and new or emerging outcome measures, such as clinical assessments, magnetic resonance imaging (MRI) biomarkers, and fluid biomarkers, that may contribute to advances in relapsing MS treatment and improve patient outcomes.</p>

MRI is very useful for assessing how people are doing over time. It is certainly good for looking at lesion numbers and lesion activity, as well as for determining if there are new enhancing lesions. We are still learning how to use fluid biomarkers, and the use of brain volume changes is still in its infancy. Perhaps we will learn more as these techniques improve. Some newer metrics, such as central vein sign and paramagnetic rim lesions, have a high specificity for MS but are not routinely used at most centers, partly due to licensing issues.

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While MRI is valuable, the neurological examination is key, both at diagnosis and at follow-up. Spinal fluid is also useful at the time of diagnosis, although not everyone needs a spinal tap. There is debate over how often these should be performed. Spinal taps do not help very much with follow-up, and there are not any real spinal fluid metrics that I find useful.

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We are also just starting to explore how optical coherence tomography (OCT) can help us longitudinally. There are data suggesting that OCT provides complementary information that allows us to see brain volume changes over time, which could be helpful. Another beneficial metric is a periodic cognitive battery, which can identify changes in cognition that are not often picked up during routine neurological or other standardized examinations and can even differentiate between age-related cognitive changes and those caused by MS. This is especially important because the average age of the MS population has risen; more than half of patients with MS are 50 years of age or older.

We have gotten good at controlling relapses and MS lesions with the current generations of therapies. One of the most humbling experiences for me is when I tell a patient, “Great news. I looked at your MRI, and it is stable. Everything looks great.” And then they ask, “Well, why am I getting worse?” It is clear that patients with relapsing MS do get worse throughout the course of their disease. This is most evident when you quiet down relapses and other disease-related factors.

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Some tests that we run include the Timed 25-Foot Walk (T25FW) test and other components of the Multiple Sclerosis Functional Composite (MSFC) such as the 9-Hole Peg Test (9HPT), along with the Symbol Digit Modalities Test (SDMT). We also follow MRI scans and OCT over time.

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Despite the availability of these tests and biomarkers, it is still difficult to identify worsening in the short-term. However, if you have a patient with relapsing MS who reports that they are getting worse, and you look back at their T25FW, you can usually see small changes over the long-term.

Within a clinic, we have a limited amount of time to work with patients with relapsing MS. Because we are not seeing many relapses in our patients, much of our evaluations are geared toward eliciting symptoms of subtle worsening and progression independent of relapse activity (PIRA) measures. We want to identify progression as early as possible, particularly if we have therapies that target this process. We do not want to wait until patients are using canes, walkers, or wheelchairs; we want to know if they are having issues as early as possible, for the purpose of early intervention.

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A semiquantitative evaluation of ambulation is key for detecting progression. For example, I ask my patients, “Is your walking unlimited, or do you have restrictions? Could you walk a mile or 2 but not much more than that?” Or I ask, “How many minutes can you walk?” To help obtain some sort of measure of time that you can track from visit to visit, we also perform the T25FW in the clinic. If you are seeing somebody who has a worsening T25FW, PIRA could be a concern.

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Moreover, we ask patients about their use of assistive devices, which will differ within the home vs outside the home. We ask, “What do you use within your house? Do you have to hold onto walls or the furniture? Are you having falls or near falls? When and how often do you use a cane?” If you can get patients to quantify their abilities for you in this way, it can show you whether their weakness or gait is worse. Finally, although ambulation and balance are key components of progression, you certainly also want to inquire about cognition and upper-extremity function.

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Overall, we really want to try to detect PIRA early. And, for me, a large component of that is quantifying, over time, the patient’s ambulation on neurological examination, along with their performance on functional tests, to see if there is a persistent trend.