Challenging Perspectives on Early Signs of Progression in RMS Video

Dr Edward Fox:

Hello. I'm Dr. Edward Fox, Director of the MS clinic of Central Texas at Central Texas Neurology Consultants, and also clinical assistant professor of neurology at the University of Texas Dell Medical School in Austin, Texas.

Today, Dr Ralph Benedict and I will discuss why early signs of progression are important to discuss with patients.

We will also talk about what clinicians should look for to identify early signs of progression in relapsing MS patients and discuss several practical insights on how progression can be assessed.

Dr Ralph Benedict:

Thank you for the kind introduction, Dr Fox.

I'm Ralph Benedict. I'm a professor of neurology and psychiatry at the University at Buffalo, and I've been working in the MS area for the past 20 or 25 years. I'm a clinical neuropsychologist, which means that much of my research has been informed by my clinical experience with patients. And I have focused quite a bit on the effects of MS on mental status and how it changes over time with the progression of the disease.

Despite the high global prevalence of multiple sclerosis and its recognition as a leading cause of nontraumatic disability in adults, the diagnosis of various subtypes of MS continues to be a challenge in many cases Identifying the transition of relapsing-remitting MS to active secondary-progressive MS remains a key clinical challenge

Dr Fox:

Right, and recognizing this, we want to discuss the rationale as to WHY we should spotlight early signs of progression in relapsing MS?

Multiple sclerosis, MS, is a chronic, inflammatory and neurodegenerative disease with a highly variable clinical course.

Dr Fox:

And there is an overlapping clinical course in relapsing and progressive phases of MS.

For clinicians, diagnosing the transition within RMS from a relapsing-remitting phase to a progressive phase is challenging for several reasons.

The decline in patients' abilities over time, both physically and cognitively, may be so gradual that it is unnoticed by the patient or physician.

And disability progression may be confounded by worsening as a result of relapses with up to 30% of patients experiencing relapses after progression has begun.

Dr Fox:

The term silent progression has been used to describe the insidious decline that accrues in many patients who meet criteria for relapsing-remitting MS but who are not yet recognized as having secondary progressive MS in the clinic.

And importantly, this underlying process occurs earlier than is clinically recognized, emphasizing the importance of proactively looking for signs of progression.

Dr Fox:

Based on a recent study of actively treated patients who were followed up to 10 years, data showed that out of 138 individuals who experienced disability worsening, roughly 67% or two out of three patients, were still considered by their physicians to have a relapsing-remitting disease course.

Dr Fox:

In this study, clinically meaningful worsening was defined as:

A 20% increase in the Timed 25-Foot Walk averaged over 2 runs

A 20% increase in the 9-Hole Peg Test for each arm

An increase in the reliable change index for the Paced Auditory Serial Addition Test A 4-point worsening in the Symbol Digit Modalities Test

And an increase in EDSS based on each patient's baseline EDSS scores.

Dr Benedict:

Adding to what Dr Fox just said, pathophysiologically, the underlying neurodegenerative processes of the CNS are already present in the relapsing phase of MS and as MS progresses

While patients are in this gradual transitioning from inflammatory-driven disease to a stage predominated by neurodegeneration, the compensatory mechanisms that mask declining brain and cognitive reserve may obscure early clinical manifestations of progressive disease

Diffuse tissue loss and brain atrophy may be the principal driver of disability during progressive disease

Dr Benedict:

Lack of awareness about the transition to SPMS is common among patients, as 43% of patients reported unawareness in a recent qualitative survey of patients

Patients may only become aware when these compensatory mechanisms are exhausted

Dr Fox:

Thanks for sharing, Dr Benedict.

I'd also add that in my experience, I've seen individuals with MS compensate for changes by just changing their activities of daily living subtly. They may decide that they don't want to go to movie theaters because of the difficulty in going up or down stairs in dim light, and want to see movies at home; or they have changed their workspace environment so they don't have to walk as far. There are many subtle ways that patients will decide to have themselves have less impairment by simply just getting rid of the tasks they do on a daily basis that cause them the most problems.

Dr Fox:

The CNS has a finite capacity to compensate for neurodegeneration, which supports the urgency to recognize progression early and to intervene before compensatory processes are exhausted.

Dr Benedict:

Right, well said -

Consequently, it's uncertain whether classification of patients into relapsing-remitting MS and active SPMS is meaningful—rather, patients could be considered to gradually transition from a stage where inflammation is prominent toward a stage where neurodegeneration is more prominent

So what does it all mean for clinical practice and what can clinicians act on? WHAT are signs of progression among patients with relapsing MS?

Dr Fox:

Well...A study found that early changes in Expanded Disability Status Scale, or EDSS, score within the first 2 years of MS diagnosis was the most predictive of clinical progression at 6 and 12 years. Patients in this particular study had a median baseline EDSS score of 2.0 and displayed a 0.5- to 1-point change in EDSS scores within 2 years.

Early increases in EDSS scores may be considered valuable in predicting long-term clinical progression, and measuring disability progression by EDSS scores has been validated in many trials. However, the EDSS is nonlinear, and patients with scores of less than 3 are less likely to show year-to-year changes than patients with higher EDSS scores, obscuring recognition of an underlying neurodegenerative process labeled as silent progression.

Dr Fox:

Another point to note is that EDSS scores are typically perceived as problems with ambulation.

Beyond problems with ambulation, there is a great heterogeneity of clinical course, symptoms and response to therapy associated with different immunopathological phenotypes. They can evolve differently between patients over time and involve several physical domains.

A US National Health and Wellness Survey was developed to gain insight into the characteristics of individuals with SPMS and their perceived burden of illness compared to individuals with RRMS. Patients across the MS spectrum most commonly reported difficulty with balancing or walking and muscle spasms. Less-recognized physical domains may include changes in urinary incontinence or urgency, stiffness, constipation, sexual dysfunction, and tremor.

Dr Fox:

I typically see these physical manifestations occur in groupings. A patient may bring up one specific problem, and then on further questioning, be seen to have a number of problems that go together. And because of that, I can generally rule out the possibility that it doesn't have to do with MS and is an unrelated problem. Once you hear of a myriad of problems occurring simultaneously, it's generally much more evident that the cause is neurodegeneration.

So it is crucial to discuss all physical changes, even if they are subtle and gradual, with patients to identify progression in RMS as early as possible.

Dr Fox:

To note, multidimensional tests can be more sensitive than EDSS alone.

Data from the Multiple Sclerosis Outcome Assessments Consortium, or MSOAC, included almost 13,000 (n=12,776) patients, from 14 clinical trials.

This study validated the clinical value of a multidimensional battery of tests that included tests for:

Short-distance walking to measure ambulation, the Timed 25-Foot Walk Test

The 9-Hole Peg Test to measure dexterity and upper extremity motor function Low-Contrast Letter Acuity Test to measure visual acuity

And the Symbol Digit Modalities Test, SDMT, to measure cognitive processing speed and sustained attention, one of the most widely used tests to determine cognitive processing speed.

This combination of tests was found to be more sensitive in measuring progression than EDSS scores.

Dr Benedict:

You bring a good point in the component of cognitive processing speed as a part of a multidimensional test

Cognitive impairment can be present at early clinical stages of MS and typically occurs between the ages of 20 to 40 years of age

It can significantly impair quality of life due to its profound impact on many aspects of a patient's daily life, including the inability to drive, work, and maintain social relationships

Dr Benedict:

Though about 15% of patients are unemployed due to physical restrictions, a majority of patients are unemployed at 10 years after the onset of the disease due to cognitive impairment

Clinic-based cross-sectional studies on MS-related cognitive impairment provide estimates ranging between 54% and 65%, whereas large-scale, community-based surveys show prevalence estimates of 43% to 46%

It is a major cause of disability in MS patients and is often underdiagnosed

Therefore, it is important to include cognitive evaluation of MS patients in clinical routine care since deficits may be present early on

Dr Benedict:

In an example study, the prevalence of cognitive impairment was assessed across domains including information processing speed, executive function, visuospatial memory, and verbal memory

Nearly half of the patients with RRMS showed impairment and nearly 80% of patients with SPMS exhibited some form of cognitive impairment across these domains

Assessing cognitive impairments through validated tests may help uncover signs of progression to reduce the impacts of cognitive decline over time

Dr Benedict:

Whole brain atrophy is mainly driven by neuroaxonal loss in grey matter

Greater brain atrophy develops in patients with worsening disability than those who are clinically stable, can be present at early clinical stages of the disease, and is associated with cognitive impairment

Dr Benedict:

For reference, annual brain volume loss occurs at a rate of about 0.1% to 0.3% in healthy individuals

Dr Benedict:

In the MS-EPIC dataset that was mentioned earlier, analyses found that baseline brain atrophy was associated with both an increased risk of long-term disability and silent progression

Measurement of whole brain atrophy with MRI might serve as a surrogate marker to identify patients with insidiously progressive ongoing disability and should be possible to measure reliably in a single patient with annual follow up

Dr Benedict:

In studies of grey matter regions, the cortex and the thalamus were found to be affected by volume loss more extensively than other regions

This is important. The extent of cortical and thalamic volume loss correlates with disability and cognitive impairment

Dr Benedict:

The rate of cortical atrophy occurs 1.8 times faster in progressive MS patients compared to relapsing-remitting MS patients x

Dr Benedict:

Further, thalamic atrophy was correlated with impaired performance on the Symbol Digit Modalities Test, or SDMT, as well as the Brief Visuospatial Memory Test, or BVMT

Dr Fox:

Thanks for covering all of that, Dr. Benedict. As we get into the final portion of our discussion today, I think it's important to discuss how we can currently identify early signs of progression.

We can both agree that physical and cognitive disability progression should be detected as early as possible. The question is how do we do that and are we equipped to do so?

Dr Benedict?

Dr Benedict:

Sure.

We discussed today that progression may be occurring earlier than one thinks. So it's prudent to act as soon as there are suspicions or subtle signs of cognitive impairment.

Physician to patient dialogue is one mechanism, to understand this - to assess memory, concentration, and attention that affect patient's daily lives. This is important to gauge in the clinical interaction.

In addition, there are ways to monitor performance-based metrics to assess cognition at baseline and to follow changes in these metrics and individual patients.

To test for memory, we use tests such as the BVMT, which I mentioned earlier, and the California verbal learning test, which measures verbal memory. The BVMT involves the memorization of visual figures that are presented for 10 seconds. Patients are asked to render these from memory and they are given several attempts to assess the accrual of information or learning over time. For the verbal memory test, the California verbal learning test, A simple word list is read to the patient and they are asked to recall as many as possible after the end of the list, there are five learning trials and again, we are looking for the accrual information or learning over time.

Dr Benedict:

For cognitive processing speed, the test is actually quite simple, and this is the Symbol Digit Modalities Test or SDMT that we mentioned earlier. This is a matrix of symbols paired with numbers presented at the top of a page and below only the symbols appear. And the patient's task is to simply state which number goes with each of those symbols as rapidly as possible. They only do the test for 90 seconds and it's quite easy to score. And it's a very good metric of visual, cognitive processing speed.

The task is to correlate these cognitive changes with any evidence of change on MRI. These measures are strongly correlated with brain atrophy, particularly gray matter atrophy.

Dr Benedict:

In conversation, I like to ask questions, like, thinking back to a year ago, were there things you could do then that you can't do now?

And I ask them to reflect on a time where they may have been forgetful or had difficulty finding the right word in the conversation?

I ask them if they have had any difficulties at work, poor performance reviews, needing extra time to complete tasks. I ask them if they've been missing work due to MS symptoms or other problems. I ask them if they've been feeling overwhelmed due to cognitive or physical disability, fatigue, difficulty concentrating and the like.

Dr Benedict:

Objective measures including MRI for brain atrophy and spinal cord atrophy may be the most promising biomarkers for monitoring neurodegeneration, and annual clinical assessment is recommended

There is still an unmet need for more precise and unambiguous measures for progression that allow for timely identification, but a lot can be done today

Anything to add, Dr Fox?

Dr Fox:

From a patient's perspective, they may be reluctant to report a change in symptoms due to fear of progression and implications regarding changes in treatment regimen.

Some allied health professionals have described their role around transition and diagnosis as “planting a seed” for the patient to consider progression of symptoms, such as prompting them to reflect on the reduction in their ability to perform normal activities of daily living.

We briefly talked about the value of incorporating multidimensional tests to detect changes in MS beyond ambulation. Regularly assessing these objective tests can uncover signs of sustained progression over 3 to 6 months, and a lot can be done in everyday practice to detect progression on the individual patient level.

In my practice, I will ask the patient how they're doing compared to a year before. I'll try to link it to a holiday around that same time, because it's easier for them to recall whether they were doing the same activities of daily living and whether it's harder for them lately to do things that they were doing without difficulty the previous year. I have to be very open-ended in this question and I have to ask them about home life, work, and other interactions to be able to get the full spectrum of answers.

Dr Fox:

The questions I like to ask to assess physical health include talking about changes since their last visit.

Have you noticed any change in physical function? For example, bladder issues, bowel issues, visual disturbance.

Do you have more difficulty balancing or walking since your last visit?

Have you been able to perform day-to-day tasks, such as household chores, since your last visit?

What time do you go to bed, and what time do you get up? Any problems getting to sleep or staying asleep? Do you feel refreshed after sleep?

Are these difficulties only apparent to you, or are family members, friends, or coworkers also noting any new or worsening deficits or difficulties?

Dr Fox:

To sum it all up, I hope that in today's program we were able to emphasize the importance of detecting early signs of disability progression in relapsing MS.

Underlying neurodegenerative processes, silent progression, can occur earlier than is generally recognized. So it's important to initiate a dialogue with patients and actively seek signs and symptoms of progression during clinical visits.

Also, continued communication with patients, caregivers and other allied health professionals is essential to understand disease progression and to monitor treatment effect and adjust care plans accordingly. As MS transitions from relapsing-remitting MS to progressing RMS, treatment goals may change for each patient to slow down disability progression across physical and cognitive domains.

Previously, delays in recognizing progression may have been partly attributed to limited treatment options; however, the treatment landscape has since evolved and conversations can be much more optimistic, further underscoring the importance of detecting progression early and providing the best care for patients.