Unpacking MS Progression - Part 2

From Tidy Definitions to Lived Experience: Making Sense of MS Progression in the Clinic.

A few words of gratitude

My clinic schedule changed a couple of months ago, and Mondays have become my longest days. I wear many hats as a clinician, researcher, educator, and clinic director and I used to think I’d prefer to ease into the week, using Mondays to get organized amid all those (sometimes competing) responsibilities. But this new rhythm has turned out to be a gift. Though fast and furious, Mondays now leave me with a full heart and words of wisdom from my patients that stay with me all week.

This week, I saw one of the very first patients I met after moving from France to Texas 13 years ago. Together, we’ve been through it all: the good years when her MS was stable and she was thriving in her career; then the storms—the real one, when Hurricane Harvey destroyed her home in 2017, and the metaphorical ones that followed as her MS progressed until she could no longer walk well on her own. But then came spring again: she reinvented her life, found joy where she was instead of looking in the rearview mirror, and began to thrive once more, differently, but fully.

As I left the clinic tonight, she texted to thank me for encouraging her and for the hug we shared. But the truth is, I’m the one who leaves inspired, strengthened by the grit, grace, and resilience of my patients.

To those of you who sometimes wonder if your life matters or if you’re making a difference: you are. The strength and wisdom you share with us carry us through and help us care for others more deeply. You are a gift. Thank you for letting us walk through the storms—and the springs—of life with you.

MS progression in practice

Last week, we dove into the history of MS clinical descriptors, the language we use to define “progression” and how it came to shape the MS world (especially the world of clinical trials). We sorted through the acronyms and categories that look tidy on paper. But as any clinician or person living with MS knows, the real story is never that neat.
People with MS are not a collection of symptoms or scores. They are whole persons, with histories and circumstances that can’t be captured by any acronym.

Let me introduce you to Rima.

Rima is 48 and has lived with MS for 22 years. She was diagnosed at a time when treatment options were scarce and daily injections were the norm. She still remembers feeling like a human pincushion, faithfully giving herself shots that too often failed to prevent new relapses. When oral medications arrived, she switched, hopeful, but the disease still simmered. Finally, six years ago, she moved to a B-cell therapy, and since then, things have been calmer: no relapses, no new lesions, quiet MRIs year after year.

She built a full life through it all. A demanding career as a paralegal, two teenagers, a marriage that weathered every storm. She’s vegan, disciplined, and walks daily. Her life, she says, has been good; busy, yes, but deeply meaningful.

Then, slowly, things began to change.

At first, it was subtle: searching for words, struggling to stay organized. Then came moments she couldn’t ignore, forgetting how to do tasks that once felt effortless. She told herself it was stress, grief maybe, after losing her sister to cancer, a loss that left a void she still feels every day. But time passed, and things didn’t improve. They worsened.

This year, for the first time in her 15 years at the firm, she was called into her director’s office. A conversation about performance. A conversation she never imagined she’d have.

As she told me this story, tears streamed down her face. Her husband sat beside her, gentle but worried. He’d noticed it too—the forgetfulness, the frustration, the anxiety that now wraps around her nights. She can’t sleep, wakes drenched in sweat, and often starts her days with pounding headaches.

And yet, when I examine her, the findings are subtle, almost deceptively so. She walks unassisted. There’s just a trace of imbalance if you look closely. But not much else.

This is the reality of MS care, the part that doesn’t fit on a spreadsheet. Symptoms that can’t be captured by scales. Lives that can’t be distilled into labels. And that’s where the real practice of medicine happens: in the spaces between definitions.

A Framework to Understand MS Progression in Practice

Situations like Rima’s are not rare. Making sense of them, so that we can truly help and make sound treatment decisions, isn’t always straightforward. Over the years, I’ve come to rely on a simple three-step process that brings structure and clarity to the complexity of MS progression.

Step 1: Listen

Identifying progression in a clinical trial dataset takes a good statistician and a powerful computer. Identifying it in the real world takes time and active listening.

Patients rarely come to clinic with tidy datasets in their pockets (though I hope neurodigital biomarkers will get us there soon). They come with stories. And those stories hold more information than any lab result or MRI scan.

I like to let my patients speak first, unfiltered, in their own words. Then I ask questions to deepen my understanding:
“Are there things you could do last year that you can’t do now?”
“What hobbies or activities have you had to give up?”
“Have coworkers, friends, or family noticed any changes?”

Listening is our first responsibility. Objective data is essential, of course: a detailed exam can uncover subtle worsening, and bedside tools like the Symbol Digit Modalities Test (SDMT) can reveal meaningful cognitive changes over time. But it all begins with listening.

Step 2: See the Whole Picture

When someone with MS experiences worsening, it doesn’t always mean that MS is to blame. This nuance is often lost in the world of clinical trials, where every change is assumed to be disease-driven. In reality, MS doesn’t exist in a vacuum.

Take Rima. Are we certain her cognitive difficulties are due to MS alone? Her story reminds us how many threads are intertwined in a person’s health:

• Grief and depression can cloud concentration and memory.

• A strict vegan diet, if not carefully supplemented, can lead to vitamin B12 deficiency, which itself causes cognitive impairment.

• At 48, perimenopause could be contributing to memory lapses, poor sleep, and hot flashes.

• And sleep apnea, present in up to half of people with MS, can cause non-restorative sleep, morning headaches, and brain fog.

Before attributing worsening to MS, we must take inventory of all possible contributors. This process takes time, curiosity, and compassion. But how many of us have seen someone with “progressive MS” suddenly improve after a hip replacement or successful treatment of another condition? Context matters.

Step 3: Understand What’s Driving It

As we discussed last week, true MS progression can occur in two main contexts:

• Relapse-Associated Worsening (RAW): progression linked to new inflammatory activity

• Progression Independent of Relapse or MRI Activity (PIRA or PIRMA): progression that unfolds quietly, without visible inflammation

These reflect distinct biological processes, and understanding which one is at play guides treatment.

Relapse-associated worsening stems from focal inflammation in the central nervous system. In the real world, though, it isn’t always obvious. A patient might not have a dramatic relapse but could show subtle stepwise changes alongside new MRI lesions. That’s why my first task is always to assess for evidence of disease activity, both clinically and radiologically. In my clinic, I also use serum biomarkers to detect inflammatory activity and guide whether escalation to a higher-efficacy DMT is warranted.

If progression persists despite optimized therapy and no evidence of disease activity, we begin to suspect other mechanisms, most notably microglial activation, the slow, smoldering process thought to drive neurodegeneration.

Emerging imaging and blood biomarkers may soon help us recognize this form of progression more precisely, but they haven’t yet made their way into routine care. That’s about to shift. As BTK inhibitors, drugs that act on both B cells and microglia, enter the field, understanding these underlying mechanisms will become essential in daily practice.

And that’s where we’ll go next week: exploring the innovations on the horizon that may finally help us address progression more effectively and more thoughtfully than ever before.