MS Relapse vs Pseudo-Relapse After Infection: COVID-19 Shows Divergent Risk Pattern

Infections are known to trigger symptom worsening in multiple sclerosis (MS), but distinguishing between true relapses and pseudo-relapses—transient deteriorations due to systemic stress—remains critical to guiding appropriate treatment. New data from the North American Research Committee on Multiple Sclerosis (NARCOMS), the largest self-report registry of people with MS in the United States, brings much-needed granularity to this clinical gray zone—especially as the field reassesses COVID-19’s role in MS disease activity.

Published in Neurology: Clinical Practice in August 2025, the analysis draws on spring 2023 survey responses from 2,927 NARCOMS participants. The study classified respondents by recent infection status—COVID-19, non-COVID infections, both, or uninfected—and compared reported relapses and pseudo-relapses in the preceding six months. Pseudo-relapses were specifically defined for respondents as symptom flares driven by infection or systemic illness without new CNS inflammation.

The analysis found that:

• A non-COVID infection was associated with a 39 percent increased likelihood of relapse (adjusted odds ratio [aOR] 1.39, confidence interval 1.04 to1.87).
• In contrast, a recent COVID-19 infection was associated with a 55 percent decrease in relapse odds (aOR 0.45, confidence interval 0.23–0.87).
• All infection types increased pseudo-relapse risk compared to uninfected controls:
• COVID alone: aOR 1.80 (confidence interval 1.32–2.45) 
•  Non-COVID: aOR 1.78 (confidence interval 1.44–2.20) 
•  COVID + non-COVID: aOR 3.04 (confidence interval 2.24–4.12)

Despite these associations, most reported relapses were not treated with corticosteroids, raising the possibility that many were misclassified pseudo-relapses. This distinction matters; treating pseudo-relapse with high-dose steroids or modifying disease-modifying therapy (DMT) may lead to overtreatment without benefit.

Symptom Clues to Distinguish Pseudo-Relapse

Pseudo-relapses were most often marked by fatigue (80.5 percent), leg/foot weakness (55.9 percent), coordination issues (48.2 percent), and difficulty walking (46.7 percent). Two infection-specific patterns emerged:

• Bladder symptoms were more common with non-COVID infections, likely reflecting the high prevalence of urinary tract infections.
• Chewing and swallowing difficulties were more frequent with COVID, potentially tied to the virus’s respiratory tropism and known MS-related dysphagia risk.

Limitations to Consider

While the NARCOMS dataset offers a robust sample size and longitudinal scope, its reliance on self-reported data introduces several caveats. Relapse and pseudo-relapse events were not clinically confirmed, raising the risk of misclassification—particularly in cases where corticosteroids weren’t used. The analysis also lacks granular details on timing and severity of infections, prior disease activity, and vaccination status, all of which can factor into relapse risk. Finally, the absence of neuroimaging or biomarker data limits insights into inflammatory mechanisms underlying symptom worsening. These considerations underscore the need for prospective, clinician-verified studies to validate and expand on these findings.

Clinical Implications

These findings suggest that:

• Clinical assessment is key before treating infection-linked worsening as a relapse. Careful history and symptom context remain vital.
• COVID-19 infections may provoke pseudo-relapse without immune reactivation, especially in vaccinated individuals.
• Using symptom profiles (e.g., bladder vs bulbar signs) can help guide clinical reasoning in infection-associated flares.

The unexpectedly lower relapse rate with COVID-19 contradicts the general assumption that viral infections uniformly heighten relapse risk in MS. The authors suggest that widespread vaccination, lower infection severity, or different immunologic pathways could explain the divergence. These findings reinforce the importance of having infection-free controls in any analysis of post-infectious neurologic worsening.

This study also strengthens the case for pseudo-relapse as a distinct and prevalent clinical entity—one that underscores the need for more precise diagnostic tools and structured management pathways. Recognizing pseudo-relapse as a frequent, clinically distinct entity in MS may help prevent overtreatment and reduce patient uncertainty, particularly in the era of post-viral symptom surveillance.

Reference

Salter A, Lancia S, Sharma M, Cutter GR, Fox RJ, Marrie RA. Infection, relapses, and pseudo-relapses in individuals with multiple sclerosis. Neurol Clin Pract. 2025;15(4):e200493. doi:10.1212/CPJ.0000000000200493