#183: Silent progression in MS. Can we really detect it early?

Can we detect gradual MS progression before it becomes obvious?

In this episode, I look at what current research can — and cannot — tell us about subtle worsening without an obvious relapse.

The key distinction is important: noticing a change, detecting a trend, confirming progression and understanding its biological cause are four different steps.

We look at why a single clinic visit cannot prove irreversible progression, what the EDSS may miss, and how patient-reported outcomes and self-administered tests could help identify meaningful changes earlier.

I also discuss what MRI, OCT, neurofilament light chain (NfL), GFAP and newer approaches such as BrainAGE can add — and why none of them currently functions as a stand-alone "progression detector".

In this episode

• Why gradual worsening can occur without an obvious relapse
• Why one abnormal measurement does not prove progression
• What the EDSS may miss
• How patient-reported outcomes and self-administered tests can add important information
• The difference between PIRA and smouldering MS
• Why "independent of a recognised relapse" does not necessarily mean "independent of inflammation"
• What MRI, OCT, NfL and GFAP can — and cannot — tell us
• Why different biomarkers may give different answers
• Why repeated measurements over time matter more than one snapshot
• What people with MS can realistically observe in everyday life without constantly monitoring themselves

Read the full article

Silent progression in MS: Can we really detect it early?
👉 https://ms-perspektive.de/en/183-silent-progression/

Infographic: four steps towards confirming progression

Research papers behind this episode

Voigt I, Ziemssen T.
Detecting progressing events in multiple sclerosis clinics in real-time is possible: No.
Multiple Sclerosis Journal. 2026;32(6):570–572.
https://doi.org/10.1177/13524585251409547
Key role in this episode: Why earlier detection is not the same as real-time confirmation of irreversible progression.

Reinders EM, Masot-Llima A, Otero-Romero S, et al.
Assessing progression independent of relapse activity in multiple sclerosis using a patient-reported disability measure and self-administered neuroperformance outcomes.
Annals of Neurology. 2026;100:525–546.
https://doi.org/10.1002/ana.78275
Key role: Evidence from 9,088 people with MS showing that patient-reported and self-administered measures can capture clinically meaningful change, while only partly overlapping with EDSS-based PIRA.

Bsteh G, Dal-Bianco A, Krajnc N, Berger T.
Biomarkers of progression independent of relapse activity—Can we actually measure it yet?
International Journal of Molecular Sciences. 2025;26:4704.
https://doi.org/10.3390/ijms26104704
Key role: Overview of EDSS, functional testing, MRI, OCT, NfL, GFAP and multimodal approaches, including the important distinction between predicting future PIRA and measuring ongoing progression.

Ciccarelli O, Barkhof F, Calabrese M, et al., MAGNIMS Study Group.
Using the progression independent of relapse activity framework to unveil the pathobiological foundations of multiple sclerosis.
Neurology. 2024;103:e209444.
https://doi.org/10.1212/WNL.0000000000209444
Key role: Why PIRA is a useful clinical framework but not a single biological process, and why PIRMA is difficult to establish in routine care.

Pawlitzki M, Kirschner P, Masanneck L, et al.
Brain age gap in multiple sclerosis: associated with disability but independent of serum biomarkers.
Therapeutic Advances in Neurological Disorders. 2026;19:1–13.
https://doi.org/10.1177/17562864261458516
Key role: An example of why different biomarkers may capture different aspects of MS rather than providing one universal measure of progression.

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(9):1132–1140.
https://doi.org/10.1001/jamaneurol.2020.1568
Key role: Historical context for why relapse-independent disability accumulation became such an important topic in relapsing MS.

See you soon and try to make the best out of your life,
Nele

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