Part 2 · The course
Relapse & remission over time
One person's MS over 30 years: disability, relapses, MRI lesions and brain volume on one timeline. Pick a course, then press Play or step through RIS, CIS, relapses, PIRA and secondary progression.
Schematic. One illustrative person per course, not a prediction for anyone. Circled points are published medians the curve is drawn through (the Lyon cohort for relapsing and progressive onset; the British Columbia "benign" cohort). Between and beyond them the shapes are drawn, not measured. MRI dots are not to scale: real counts vary widely. Brain-volume lines are cohort means from one study (mean follow-up 7.5 years), extended as straight lines.
How the course is described: Lublin 2013
The 1996 survey gave four courses: relapsing-remitting, secondary progressive, primary progressive and progressive relapsing. The 2013 revision (published 2014) kept three core phenotypes, added clinically isolated syndrome, and added two modifiers that are reassessed at least once a year. 284,286
| Term | What it means (as published) | Example description |
|---|---|---|
| CIS | First clinical presentation of possible MS that does not yet meet dissemination in time. | "CIS, active" |
| RRMS | Relapses followed by full or partial recovery. | "RRMS, not active" |
| SPMS | Progressive worsening after a relapsing course. No clinical, imaging, immune or pathology marker shows the switch, so it is usually diagnosed in hindsight. | "SPMS, active, with progression" |
| PPMS | Progressive from onset, with no exacerbations before progression. The old "progressive relapsing" course was eliminated: an attack makes it "PP, active". | "PPMS, not active, without progression" |
| Active | Clinical relapse and/or MRI activity: a gadolinium-enhancing lesion or a new or unequivocally enlarging T2 lesion, assessed at least annually. | modifier |
| With progression | Worsening shown on clinical evaluation, assessed at least annually in progressive disease. When assessments are missing, both modifiers are "indeterminate". | modifier |
| RIS | Not an MS phenotype in 2013, because clinical evidence is lacking and MRI alone can be nonspecific. Under the 2024 McDonald criteria, RIS can meet a diagnosis of MS in certain cases. | see McDonald criteria |
| "Benign" / "malignant" | Severity labels, not phenotypes. "Benign" should only be applied in hindsight, and with caution. | not a course |
Sources: 286,325. A 2026 roadmap describes a move from these labels toward a "dynamic, biologically informed" description of the course. 464
Will a first or second attack follow?
Where the evidence disagrees
How often does RRMS become SPMS today?
Older untreated cohorts: 30–40% of people with relapsing onset and 6–10 years of disease had developed progressive MS in London, Ontario, and a JAMA paper cites 80% within two decades. A treated modern cohort (UCSF EPIC) found 18.1% at a median 16.8 years. In MSBase, initial interferon beta or glatiramer acetate went with lower conversion (5-year risk 12% vs 27%; HR 0.71). Earlier diagnosis, milder cases under newer criteria and differing SPMS definitions may explain part of the gap. The data are observational: there is no randomised long-term proof. 51,101,130,286,493
Do relapses drive long-term disability?
In natural-history data, relapses after year 2 did not change time to hard disability endpoints, although having 1 versus 3 or more attacks in the first 2 years separated time to DSS 6 by 7.6 years. Placebo-arm and pooled-trial data show residual deficits after relapses and a 31–48% higher hazard of worsening after a year with relapses. Current reading: relapses matter mostly early; PIRA dominates later. 90,235,285,287,423
What counts as PIRA?
Definitions differ in baseline (fixed or roving), confirmation period and relapse windows. Applying 18 definitions to 30,203 people in the Italian MS register, the share with PIRA ranged from 38.8% to 74.1%. A roving baseline, no relapse 90 days before or 30 days after, and 24-week confirmation predicted EDSS 6.0 best. 230,334,387
One disease on a continuum?
Confavreux and Vukusic found that disability milestones follow an age-dependent schedule whatever the first course, and treat MS as one disease. An International Advisory Committee paper argues that the move to progression reflects a partial shift from focal injury to widespread inflammation and neurodegeneration, with failing compensation and ageing. The RR/SP/PP labels stay in clinical and regulatory use while a biological description is developed. 91,264,464
"Smouldering" MS
Some authors call a diffuse, compartmentalised process, present from early disease, the "real MS", and argue that suppressing inflammatory activity alone cannot prevent disability. A 2024 consensus proposed "smouldering-associated worsening", broader than PIRA. At autopsy, smouldering plaques were found almost only in progressive MS, and iron-rim lesions grew over 3.5 years on 7 T MRI. 106,159,167,425
Brain volume and blood markers
Over a mean 7.5 years, brain volume changed by −0.51% a year in 206 people with MS against −0.27% a year in 35 healthy controls; a cut-off of −0.37% separated them best, and the values depend on software and age. Serum neurofilament light, a neuron-specific protein, rose with gadolinium-enhancing lesions (median 29.6 pg/ml without, 62.5 pg/ml with brain and spinal enhancing lesions). 115,117
Does "benign MS" exist?
About half of people "benign" at 10 years were no longer benign at 20. EDSS-based definitions miss cognitive problems, fatigue, pain and depression. The 2013 revision allows the word only in hindsight. 97,286,422
Are placebo relapse rates really falling?
Across 26 placebo-controlled RRMS trials, the placebo relapse rate fell 6.2% a year. A meta-regression of 56 trials found the trend disappeared after adjusting for older participants, longer disease and lower pre-trial relapse rates. 353,453