Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from relapsing disease to a progressive phase have not yet been firmly established, a reality that continues to frustrate both patients and clinicians alike (Cree et al., 2021). This uncertainty has made secondary progressive multiple sclerosis particularly challenging to diagnose, study, and treat. Many patients notice subtle changes long before formal classification occurs, while clinicians must rely on patterns of disability progression rather than a single defining test. This gap has driven growing interest in new theories of disease mechanisms in secondary progressive multiple sclerosis, as researchers seek to better understand what truly drives progression once relapses become less prominent.
The secondary progressive refers to a phase of multiple sclerosis (MS) in which disability worsens gradually over time, often independent of overt inflammatory relapses (Cree et al., 2021). Unlike relapsing remitting MS, where disease onset is marked by discrete attacks followed by recovery, secondary progressive multiple sclerosis reflects a shift in the underlying disease course. Understanding why this shift occurs, and how it differs from primary progressive MS, is central to improving long-term outcomes.
Rethinking Progression Beyond Relapses
For many years, progression in multiple sclerosis was viewed primarily as the cumulative consequence of inflammatory relapses. While inflammation remains important, it has become increasingly clear that progressive MS cannot be explained by relapse activity alone. In secondary progressive MS, disability progression often continues despite minimal or absent relapses, a phenomenon now described as progression independent of relapse activity. This concept has prompted a reassessment of long-held assumptions about how and where disease activity persists.
Clinical tools such as the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite allow clinicians to document confirmed disability progression and disability worsening over time, but they do not explain why progression occurs (Cree et al., 2021). As a result, attention has shifted toward biological processes that unfold quietly within the central nervous system, even when conventional measures suggest low disease activity.
Chronic Active Lesions and Compartmentalized Inflammation
One of the most influential emerging concepts in progressive MS research involves chronic active lesions. These lesions differ from the acute inflammatory plaques typical of relapsing disease. Rather than resolving, they expand slowly over time and are characterized by persistent microglial activation at their margins. Pathological and imaging studies suggest that chronic active lesions contribute directly to ongoing tissue injury, brain atrophy, and spinal cord damage in progressive disease (Dal-Bianco et al., 2024).
Importantly, this inflammatory activity appears compartmentalized behind a relatively intact blood–brain barrier, which may explain why many disease modifying therapies have limited impact on progression once secondary progressive MS has developed (Mahad et al., 2015). Recognition of this mechanism has reshaped how researchers think about monitoring disease progression and identifying progression earlier, even in patients without obvious relapses.
Neurodegeneration, Energy Failure, and Axonal Vulnerability
Another major theory centers on neurodegeneration driven by metabolic stress rather than direct immune attack. Chronically demyelinated axons require increased energy to maintain function, making them particularly vulnerable to mitochondrial dysfunction and oxidative stress. Over time, this energy imbalance can lead to axonal loss, contributing to confirmed disability accumulation and poorer long-term clinical outcomes (Mahad et al., 2015; Peixoto de Barcelos et al., 2019; Delic et al., 2025).
This framework helps explain why progression may continue despite effective suppression of relapsing MS activity. It also sheds light on the gradual emergence of cognitive impairment and subtle motor decline, changes that reflect cumulative injury rather than new inflammatory events. Measures such as the pyramidal functional system score and the Multiple Sclerosis Severity Score are increasingly used to capture these aspects of disease evolution (Cree et al., 2021).
The Role of the Meninges and B-Cell–Driven Pathology
Research has also highlighted the importance of immune activity within the meninges. In some patients with secondary progressive MS, immune cells form organized aggregates resembling lymphoid tissue. These meningeal infiltrates are strongly associated with cortical demyelination and more aggressive disability progression (Magliozzi et al., 2007). Their presence may help explain why progressive forms of MS behave differently from relapsing disease and why certain patients face an increased risk of rapid decline.
These findings have influenced growing interest in therapies targeting B cells and have implications for predicting disease progression, particularly in patients with a long history of relapsing remitting multiple sclerosis (Ransohoff, 2023).
Implications for Treatment and Research
Improved understanding of underlying disease progression has important consequences for both clinical practice and research. Clinical trials in progressive MS increasingly emphasize progression-related endpoints rather than relapse reduction alone. Concepts such as confirmed disability progression and longitudinal measurement of MS disease activity are now central to trial design and interpretation (Brieva et al., 2025).
These insights have also informed decisions around treatment continuation, discontinuation, and assessment of treatment efficacy, particularly when disease modifying therapies reduce relapse frequency without meaningfully altering long-term progression (Oh et al., 2019; Bagnato et al., 2025). At the same time, evidence that delaying MS progression has been observed in some contexts suggests that early intervention, careful monitoring, and timely treatment adjustments may still influence long-term outcomes (Cree et al., 2021).
What This Means for Patients and Clinicians
For patients, these evolving theories help explain why symptoms may worsen even when MRI scans show little new activity. For clinicians, they underscore the importance of longitudinal assessment, integrating imaging, functional measures, and patient-reported changes. Identifying disease progression early, rather than waiting for obvious disability accumulation, remains a major goal (Ransohoff et al., 2023).
As a specialized neurological health clinic, this evolving understanding informs how Clinique Neuro-Outaouais considers emerging therapies. As research continues, the hope is that clearer biological markers will allow more precise classification, better prediction of MS progression, and ultimately improved care for those living with this chronic autoimmune disorder.
References
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