"Your MRI is stable." It is the sentence everyone with relapsing-remitting MS hopes to hear, and it usually ends the visit on a good note. And yet the walk from the car takes longer than it did last year. The stairs need a rail. Buttons take two tries. Both things can be true at once, and the reason is worth understanding, because it changes what you should ask for at your next appointment.
Two ways MS causes disability
Disability in multiple sclerosis accumulates in two different ways, and they come from different biology.
The familiar way is a relapse: an attack of new inflammation, a step down in function, partial or complete recovery, and sometimes a new level to live at. Relapses come from new lesions, the kind an MRI shows as an enhancing spot. Neurologists call the disability they leave behind relapse-associated worsening.
The less familiar way is a slope: slow, steady worsening with no attack near it, often with no new lesion on the scan, confirmed when it is still there months later. This is progression independent of relapse activity, or PIRA. It comes mostly from ongoing injury to nerve fibers that have already lost their myelin, from smoldering inflammation inside older lesions, and from the nervous system gradually losing its ability to compensate. Some researchers call the same thing silent progression or smoldering MS.
Both patterns can happen in the same person. The steps are easy to notice and easy to date. The slope is neither, which is why it went underappreciated for so long.
Visual guide
Steps or a slope
- Steps: A relapse, partial recovery, and a new level. Dated by the attack and often visible on MRI.
- Slope: Gradual worsening with no relapse near it, confirmed months later. Often nothing new on the scan.
- Schematic: The two patterns are drawn separately to show the difference, not to scale.
How much is which: what the trials showed
The surprise came when researchers went back through large clinical trials and sorted every episode of confirmed worsening by whether a relapse had happened near it.
| Study | Who | What was found |
|---|---|---|
| Pooled OPERA I and II trials (Kappos et al., 2020) | 1,656 people with relapsing MS, followed for 96 weeks | PIRA accounted for 78% of confirmed disability accumulation in the interferon arm and 88% in the ocrelizumab arm. Relapse-associated worsening explained about 18%. The authors' conclusion: "Most disability accumulation in RMS is not associated with overt relapses." |
| Novartis-Oxford MS data pool (Lublin et al., 2022) | More than 27,000 people across all types of MS, about 200,000 disability assessments | PIRA started early, occurred in every type of MS including relapsing-remitting, and became the main driver of disability in the progressive phase. In adult relapsing-remitting MS, PIRA events were more frequent than relapse-related ones |
Two things follow from those numbers. First, PIRA is not a feature of progressive MS alone. It is happening, quietly, inside relapsing MS, and from early on. Second, a follow-up plan built entirely around relapses and new lesions is monitoring the smaller of the two processes.
Why a stable MRI can miss it
A routine monitoring MRI answers a specific question: has new inflammation appeared since the last scan? It does that by counting new or enlarging T2 lesions and looking for enhancement. Our guide to understanding your MS brain MRI explains what each of those findings means. What the scan does not do is measure how well the nerve fibers inside old lesions, and the brain's connections generally, are holding up.
PIRA, meanwhile, was defined in the trials as a confirmed worsening on measures of function: the EDSS disability scale, a timed 25-foot walk, or a nine-hole peg test, with no relapse within the confirmation window and with the baseline reset after any relapse. None of those three instruments is a lesion count.
| What a routine MRI reports | What the slope reflects |
|---|---|
| New or enlarging lesions | Ongoing injury inside lesions that already exist |
| Enhancing lesions (active inflammation now) | Slow loss of nerve fibers and their connections, without a new spot |
| Overall lesion load | Loss of the reserve the nervous system uses to compensate |
| "Stable" when none of the above changed | Worsening that only shows on a measure of function |
That is why "stable" and "worse than last year" can both be accurate. They are answers to different questions.
How progression is actually measured
Progression is measured, not guessed, and the measures are simple. Each takes minutes, and each turns "I think I am slower" into a number that can be compared a year later.
- Timed 25-foot walk. How long it takes to walk 25 feet as quickly and safely as you can. A meaningful change is a 20% slowing, confirmed on a later visit.
- Nine-hole peg test. How long it takes to place nine pegs in nine holes and remove them, one hand at a time. It tracks the fine hand function that buttons, typing, and cooking depend on.
- EDSS. The Expanded Disability Status Scale, the standard score a neurologist assigns from the examination, weighted toward walking.
- Cognitive screening. A short timed test of processing speed, because thinking speed can slip along the same slope as walking.
- Blood and imaging markers of ongoing injury. A neurofilament light chain blood test read as an age-adjusted z-score, and brain volume measurements across scans, add information about how much damage is ongoing. They support the functional measures; they do not replace them.
A change on any of these is treated as real only when it is still present three to six months later. That confirmation step is what separates progression from a bad week, a hot day, or an infection.
Visual guide
Turning an impression into a number
- Timed walk: Twenty-five feet, timed, at each visit.
- Peg test: Nine pegs in and out, one hand at a time.
- Confirmed later: A change counts when it is still there months afterwards.
What it changes
Ask for your function to be measured, not only your scan read. If your visits record lesion status but not a timed walk or a peg test, PIRA cannot be detected by design. Asking for those measures is a reasonable request, and it costs a few minutes.
Treat function as the target. Physical therapy, strength and balance work, and treatment of spasticity aim at the very things the slope takes away, walking and stamina and hand use. They are not a consolation prize. In progressive disease they are among the interventions with the best evidence for keeping people mobile, and the same logic applies when the slope appears inside relapsing MS.
Confirmed progression on a stable MRI is a legitimate reason to revisit treatment. In the pooled OPERA analysis, the higher-efficacy therapy reduced relapse-associated worsening by more (hazard ratio 0.47) than it reduced PIRA (hazard ratio 0.78). Suppressing new inflammation addresses the steps more than the slope, which is one reason PIRA is the focus of so much current research and of clinical trials aimed at the smoldering inflammation inside the brain. It is also why a confirmed slope is worth a conversation about whether the current disease-modifying therapy is the right one. The conversation is individual, and the decision belongs to you and your neurologist.
Two different questions
At your next visit, notice that these are two different questions:
- "Any new lesions?" answers whether new inflammation has appeared. It has a scan.
- "Am I worse than a year ago?" answers whether function is holding. It needs its own measurement.
A good MS follow-up asks both. If only the first is being asked, the second is worth raising yourself.
When to see an MS specialist
See an MS specialist if walking, stamina, balance, or hand function has slowly worsened over months while your scans have been reported as stable, if you have noticed it and been told it is nothing because the MRI is unchanged, or if you want your function measured so that next year's visit has something to compare against. At our Multiple Sclerosis Clinic, Dr. Ntranos, a fellowship-trained MS specialist, reviews your MRI with you, measures function at each visit, and works through the treatment options honestly, including trials. Visits are 60 minutes, usually the same or next day, in Beverly Hills, West Los Angeles, or by video anywhere in California. You can request a visit and send your records ahead.
Frequently asked questions
References
- Kappos L, Wolinsky JS, Giovannoni G, et al. Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurology, 2020;77:1132-1140.
- Lublin FD, Häring DA, Ganjgahi H, et al. How patients with multiple sclerosis acquire disability. Brain, 2022;145:3147-3161.
- Cree BAC, Hollenbach JA, Bove R, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Annals of Neurology, 2019;85:653-666.
- Benkert P, Meier S, Schaedelin S, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. The Lancet Neurology, 2022;21:246-257.
- National Institute of Neurological Disorders and Stroke. Multiple sclerosis.