Relapses, PIRA and NEDA
What counts as a relapse
A relapse, or attack, is a new neurological symptom, or a clear worsening of an old one, that lasts at least 24 hours, comes at least 30 days after the start of the previous one, and is not explained by fever or infection. Most relapses build up over days, level off, and then improve over weeks to months.
The rules exclude two common situations. A rise in body temperature during an infection, or heat on a summer day, can bring back old symptoms for hours (Uhthoff's phenomenon, lesson 1.2). This is often called a pseudo-relapse and settles when the cause does. And everyday fluctuations in fatigue or walking are not relapses unless they meet the definition.
Recovery is often incomplete
Relapses matter beyond the weeks they last, because recovery is often partial. In an analysis of the placebo groups of clinical trials, 42 per cent of relapses left a residual increase of at least half a point on the EDSS, and 28 per cent left at least a full point. Disability that remains after incomplete recovery is called relapse-associated worsening (RAW).
Worsening without relapses
Disability can also increase without any relapse to explain it. This is called progression independent of relapse activity, or PIRA. It was long treated as the defining feature of progressive MS, but large datasets now show it throughout the disease.
When the two large trials of ocrelizumab in relapsing MS were reanalysed, most of the confirmed disability that people accumulated over two years came from PIRA, not from relapses, in both the ocrelizumab and the interferon groups. An analysis of about 200,000 EDSS assessments from more than 27,000 people in trials and observational studies found that PIRA began early, occurred in every type of MS and became the main driver of disability in the progressive phase. The same analysis shows that relapses still count. In the year after a relapse, the risk of any worsening was 31 to 48 per cent higher than after a year without one. People on placebo who started with minimal disability took a median of about 9 years to reach limited walking (EDSS 4) and about 18 years to need walking aids (EDSS 6). Treatment delayed these milestones by about three and a half and three years.
NEDA-3 for this year
Why this blurs relapsing and progressive MS
If silent worsening happens from the start, the line between relapsing and progressive MS is less a switch than a change in balance. A 2023 review by leading MS researchers proposed treating the course of MS as a continuum, shaped by how much focal inflammation, smouldering inflammation, neurodegeneration and failed repair each contribute in a given person over time, with ageing reducing the brain's resilience. The labels relapsing-remitting, secondary progressive and primary progressive remain in use because medicines are approved and trials are run according to them.
No evidence of disease activity
NEDA, no evidence of disease activity, is a way of asking whether MS is fully controlled. Its usual form, NEDA-3, requires three things over a stated period: no relapses, no confirmed disability worsening, and no new or enlarging T2 lesions or enhancing lesions on MRI. Some versions add a fourth requirement, such as limited brain volume loss.
NEDA became popular after an analysis of the natalizumab trial AFFIRM, in which 64 per cent of people on natalizumab were free of clinical activity over two years, against 39 per cent on placebo. It is hard to keep. In a Boston cohort of 219 people followed for seven years with yearly MRI, 46 per cent had NEDA after one year but only 7.9 per cent kept it for all seven years. NEDA at two years was the most useful time point: 78 per cent of people with NEDA at two years had no meaningful worsening at seven.
NEDA has limits. It depends on how often scans are done, it counts a single small lesion the same as a severe relapse, and in its usual form it does not measure thinking, fatigue or slow worsening that stays below the threshold for confirmed progression. It works better as a goal for groups and trials than as a pass or fail mark for one person.
Check yourself
What we know
- Recovery from relapses is often incomplete, and that residual disability adds up.
- Worsening without relapses (PIRA) starts early, occurs in all types of MS and causes most disability accumulation, even in relapsing MS.
- NEDA-3 is achievable in the short term on effective treatment but rarely lasts for many years.
What we don't know
- Which processes cause PIRA in a given person, and whether they differ between early and late MS.
- How best to detect PIRA early, since the EDSS changes slowly and in coarse steps.
- Whether treatments that prevent nearly all relapses also prevent most PIRA in the long run.
In the research now
Loading current research…
Key terms
- Pseudo-relapse
- A temporary return of old symptoms during fever, infection or heat. It settles when the cause does and is not a relapse.
- Uhthoff's phenomenon
- A temporary return or worsening of symptoms with heat or exercise, caused by slower conduction in demyelinated fibres. It is not a relapse.
- Lesion (plaque)
- An area of damage where myelin has been lost and the tissue scarred.
- Relapse (attack)
- New or worsening symptoms lasting at least 24 hours, without fever or infection to explain them.
- PIRA
- Progression independent of relapse activity: disability that worsens without a relapse to explain it.
- RAW
- Relapse-associated worsening: disability left behind by incomplete recovery from a relapse.
- NEDA
- No evidence of disease activity: no relapses, no new or enlarging MRI lesions and no confirmed disability worsening over a stated period. Some versions add brain atrophy or blood markers.
- EDSS
- Expanded Disability Status Scale, from 0 (normal examination) to 10, the main disability measure in trials. Its middle range depends heavily on walking.
- Confirmed disability progression
- A rise in EDSS meeting a stated threshold and still present at a check, often three or six months later. The threshold and confirmation rules vary by trial.
- Placebo
- A dummy treatment that looks like the real one, used so that trial results reflect the medicine itself.
References
- Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 2003.https://doi.org/10.1212/01.WNL.0000096175.39831.21
- Kappos L, 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 Neurol 2020.https://doi.org/10.1001/jamaneurol.2020.1568
- Lublin FD, et al. How patients with multiple sclerosis acquire disability. Brain 2022.https://doi.org/10.1093/brain/awac016
- Kuhlmann T, et al. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol 2023.https://doi.org/10.1016/S1474-4422(22)00289-7
- Havrdova E, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the AFFIRM study. Lancet Neurol 2009.https://doi.org/10.1016/S1474-4422(09)70021-3
- Rotstein DL, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol 2015.https://doi.org/10.1001/jamaneurol.2014.3537
Next module · Diagnosis
Symptoms
MS can affect almost anything the brain, spinal cord and optic nerves control. This lesson describes the common symptoms, how often they occur, and why they differ so much between people and from one day to the next.
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