Multiple sclerosis is both an inflammatory and a degenerative disease, though the degenerative side has historically received far less attention. The condition begins with immune-driven attacks on the protective myelin coating of nerve fibers in the brain and spinal cord, but underlying those attacks, nerve cells and their long extensions (axons) steadily deteriorate. This neurodegeneration is now recognized as the main driver of the irreversible disability that most people with MS eventually face.1PubMed. Multiple sclerosis: an immune or neurodegenerative disorder? Whether the inflammation causes the degeneration, or whether something within the brain itself sets both processes in motion, remains one of the most actively debated questions in neurology.
The Degenerative Process Behind the Relapses
For decades, MS was understood almost entirely through its inflammatory episodes: the immune system mistakenly attacks myelin, a flare-up occurs, and then things partially or fully recover. That framing is accurate as far as it goes, but it hides a parallel process that begins surprisingly early. When immune cells strip myelin from axons, some of those axons are physically cut in the process. This axonal transection is not a rare accident; pathology studies find it throughout MS brain tissue and show that it correlates with how much inflammation is present.2PubMed. Axonal pathology in multiple sclerosis: relationship to neurologic disability Once an axon is severed, it does not regrow. The nerve cell it belongs to may survive for a while, but the connection it maintained is permanently lost.
Several mechanisms pile on top of each other to damage axons. Inflammatory chemicals released during an immune attack can be directly toxic. The loss of myelin itself deprives axons of metabolic support they depend on. Stripped axons must work much harder to conduct electrical signals, which disrupts their internal balance of sodium and calcium ions. When calcium floods in, it triggers a cascade that damages the cell’s energy-producing machinery, the mitochondria, and can ultimately destroy the axon.3PubMed. Pathogenesis of axonal and neuronal damage in multiple sclerosis This energy failure is not just a side effect of inflammation; it becomes a self-sustaining problem. Even in areas where active inflammation has quieted down, chronically demyelinated axons continue to degenerate because they cannot meet their own energy demands.4PubMed Central. Mitochondrial Dysfunction and Multiple Sclerosis
Research into the mitochondrial side of this problem has shown that demyelinated nerve fibers have measurably deficient respiratory chains, meaning their mitochondria produce less of the cellular fuel (ATP) that axons need to maintain ion balance. Reduced ATP output leads to calcium overload, which in turn damages more mitochondria. That vicious cycle is one of the clearest explanations for why disability in MS keeps worsening even when new inflammatory lesions are not forming.5PubMed. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Disability That Accumulates Without Relapses
If you follow MS closely, you may have heard the term PIRA, which stands for progression independent of relapse activity. It refers to the slow worsening of disability that happens in the background, outside of and between identifiable relapses. PIRA has become a major focus of MS research because it appears to capture the degenerative component of the disease in a way that counting relapses alone does not.6PubMed Central. Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis
The concept matters practically because it changes how clinicians and patients think about disease control. Someone whose relapses are well controlled by medication may still be accumulating disability if the neurodegenerative side of MS is active. Early PIRA, occurring within the first five years of disease onset, has been flagged as a particularly ominous sign, associated with worse long-term outcomes.7PubMed. Development of early progression independent of relapse activity significantly impacts on disability accumulation in patients with multiple sclerosis The trouble is that PIRA is hard to measure cleanly. Researchers are still debating exactly how to define it and how to distinguish it from very subtle relapse-related damage that was not clinically obvious.8PubMed Central. Biomarkers of Progression Independent of Relapse Activity-Can We Actually Measure It Yet? Still, the recognition that MS can worsen silently has shifted the field’s understanding of the disease away from a purely relapse-centric model.
Brain Shrinkage Starts Earlier Than Most People Realize
One of the more sobering findings in MS research is that measurable brain tissue loss begins very early, sometimes even before a formal MS diagnosis is made. Studies of people with a clinically isolated syndrome (CIS), meaning a first neurological episode suggestive of MS, have found that grey matter volume is already reduced compared to healthy individuals at that early stage.9PubMed. Clinical impact of early brain atrophy in clinically isolated syndromes That grey matter loss within the first year after a CIS predicted who would go on to develop full MS.
A 30-year follow-up study put this in stark terms: the amount of brain atrophy that occurred within the first five years after a first episode predicted whether someone would develop secondary progressive MS or die from MS-related causes decades later. Specifically, one millimeter of atrophy in a particular brain region within the first five years was associated with nearly a sixfold increase in the odds of progressive MS or MS-related death by 30 years.10Journal of Neurology, Neurosurgery & Psychiatry. Linear brain atrophy measures in multiple sclerosis and clinically isolated syndromes: a 30-year follow-up The brain, in other words, is losing tissue from very early on, and that loss has consequences that play out over a lifetime.
The spinal cord tells a similar story. People who eventually converted from relapsing-remitting MS to secondary progressive MS showed faster spinal cord shrinkage at least four years before that transition was clinically apparent. Each one percent increase in the annual rate of cord atrophy was linked to a 69 percent shorter time to silent progression and a 53 percent shorter time to formal conversion to progressive disease.11PubMed Central. Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis These imaging findings reinforce that degeneration is not something that only starts late in MS; it runs alongside the disease from early on, and MRI-based measures of tissue loss may offer an earlier warning than clinical assessments alone.12PubMed. Measurement of brain and spinal cord atrophy by magnetic resonance imaging as a tool to monitor multiple sclerosis
Smoldering Inflammation and Slow-Burning Lesions
The classic MS lesion, visible as a bright spot on an MRI, forms during an acute inflammatory attack and then often stabilizes. But a subset of lesions does not stabilize. These chronic active lesions have a rim of activated immune cells, particularly iron-laden microglia and macrophages, that slowly expand outward over months and years, chewing through surrounding tissue in a process researchers call smoldering neuroinflammation.13PubMed Central. Chronic active lesions in multiple sclerosis: classification, terminology, and clinical significance These lesions are detectable on advanced MRI and have been linked to a more aggressive disease course.
What makes smoldering inflammation particularly troublesome is that it is largely trapped inside the central nervous system, behind the blood-brain barrier. Most current MS medications work by suppressing or redirecting the peripheral immune system, which means they have limited reach against immune activity that is already established within the brain itself. Smoldering lesions are therefore considered relatively resistant to existing therapies, and they represent a key frontier for drug development.
Beyond white matter lesions, the outer layer of the brain, the cortex, also takes damage. Pathology studies have found cortical demyelination, neuronal loss, and inflammation in the meninges (the membranes surrounding the brain) even in the early stages of MS.14PubMed. Meningeal inflammation and cortical demyelination in acute multiple sclerosis In progressive MS, meningeal inflammation is strongly tied to neuronal loss in the underlying cortex. Microglia, the brain’s resident immune cells, initially appear to protect neurons by stripping away damaged connections, but over time they lose this protective function and contribute to cell death instead.15PubMed Central. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration This shift from protective to destructive microglia behavior is one of the reasons progressive MS is so difficult to treat.
Blood Biomarkers That Track Degeneration
One practical consequence of viewing MS as a degenerative disease is the search for blood tests that can track neurodegeneration in real time, rather than waiting for disability to show up on a clinical exam. Two protein biomarkers have emerged as especially promising: neurofilament light chain (NfL), which spills into the blood when axons are damaged, and glial fibrillary acidic protein (GFAP), which is released when astrocytes, a type of support cell in the brain, are activated or injured.16PubMed Central. Protein biomarkers in multiple sclerosis
These two markers appear to capture different facets of the disease. In a study comparing them, higher baseline NfL levels predicted faster loss of white matter volume over time, while higher baseline GFAP levels predicted faster loss of grey matter volume. GFAP was the stronger predictor of future PIRA: each doubling of baseline GFAP concentration was associated with roughly a fourfold increased risk of progression independent of relapse activity, compared to about a twofold risk for an equivalent doubling of NfL.17JAMA Neurology. Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis The fact that GFAP, a marker of astrocyte pathology, outperformed a direct marker of axonal damage in predicting silent progression hints that the glial cell environment in the brain may drive degeneration at least as much as axonal injury itself.
How MS Compares to Other Neurodegenerative Diseases
MS is fundamentally different from conditions like Alzheimer’s and Parkinson’s disease, but the degenerative processes involved share more common ground than you might expect. All three involve mitochondrial injury, oxidative stress, and the eventual death of neurons and their connections. Reactive oxygen and nitrogen species are major culprits in damaging mitochondria across these conditions.18PubMed. Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease Inflammation is present in all of them too, though it plays a more central and earlier role in MS than in Alzheimer’s, where it tends to amplify damage already initiated by protein aggregates.
The overlap extends to other features: inappropriate protein aggregation, genetic susceptibility factors, and biochemical pathways leading to cell death appear across MS, Parkinson’s, ALS, and Alzheimer’s.19PubMed. Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases This shared biology has practical implications. Neuroprotective strategies being tested in Alzheimer’s or Parkinson’s, such as drugs that shore up mitochondrial function or reduce oxidative stress, could in principle be relevant to MS as well. Researchers have noted that progressive MS in particular behaves as an “immune-initiated neurodegenerative condition,” distinct from the relapse-dominated early phase of the disease.20Cell Press. Neuron That framing puts progressive MS squarely in the neurodegenerative disease category, even if its origins are immunological.
Why Current Treatments Struggle With the Degenerative Side
The more than 20 disease-modifying therapies approved for MS are, overwhelmingly, anti-inflammatory drugs that work by calming or reshaping the peripheral immune system. They are effective at reducing relapses and slowing the formation of new lesions. But because they primarily target immune activity outside the brain, their effect on the compartmentalized, smoldering neurodegeneration within the central nervous system may be limited. Almost all major clinical trials have excluded patients over age 55, which means the evidence base for treating the later, more degenerative phase of MS is thin.21PubMed Central. De-escalating and discontinuing disease-modifying therapies in multiple sclerosis
This gap has spurred interest in therapies that tackle degeneration more directly. Remyelination therapies aim to restore the protective myelin coating around damaged axons, which could both restore lost function and prevent further axonal breakdown.22PubMed Central. Remyelination Therapy in Multiple Sclerosis Other experimental approaches include neuroprotective agents that target mitochondrial health, drugs that modulate microglia to keep them in a protective rather than destructive state, and combination strategies that pair anti-inflammatory treatment with neurorepair.23PubMed. New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis None of these has yet become a standard-of-care therapy, but their development reflects a field-wide acknowledgment that controlling inflammation alone is not enough.
Aging, Brain Reserve, and Why MS Gets Harder Over Time
Age complicates MS in ways that go beyond simple disease duration. Most people are diagnosed with the relapsing-remitting form in their twenties or thirties. As they age, the disease is more likely to transition to a progressive course. This is not just because damage has accumulated; aging itself changes the immune system in ways that favor the degenerative side of MS. Younger immune responses tend to be driven by adaptive immune cells like T cells and B cells, which are the main targets of current therapies. As the immune system ages, innate immune cells like microglia and astrocytes play a larger role, and these are the cells most implicated in smoldering neuroinflammation and progression.24PubMed Central. Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration
There is also growing evidence that MS accelerates the biological aging process itself. Studies measuring age-related biomarkers, such as telomere length and DNA methylation patterns, suggest that people with MS are biologically older than their chronological age would predict.25PubMed Central. Biological aging in multiple sclerosis This opens up the question of whether anti-aging therapies, sometimes called senolytics or senotherapies, could slow progression by targeting age-related cellular dysfunction rather than the immune system directly. That line of research is still in its early stages, but it reflects how deeply the degenerative biology of MS is entwined with aging itself.
On the other end of the age spectrum, children and adolescents who develop MS face a unique challenge. Their brains are still developing, and MS-related tissue loss occurs alongside normal processes of brain maturation like grey matter pruning. A study of pediatric MS patients found that higher cognitive reserve, as reflected by IQ scores, appeared to offer some protection, potentially by promoting healthier remodeling of the brain’s grey matter during this critical window.26PubMed. Dynamic gray matter volume changes in pediatric multiple sclerosis: A 3.5 year MRI study The concept of brain reserve, the idea that a larger or more richly connected brain can absorb more damage before symptoms appear, applies across MS generally. People with greater reserve may tolerate more tissue loss before their function noticeably declines, which is one reason two people with similar-looking MRI scans can have very different levels of disability.
The Inside-Out Hypothesis
The traditional story of MS goes “outside-in”: the immune system in the body (outside) mistakenly attacks the brain and spinal cord (inside). But a competing idea, sometimes called the “inside-out” hypothesis, proposes that the process may start within the brain itself. Under this model, something goes wrong inside the central nervous system first, perhaps a metabolic failure, a viral trigger within brain cells, or an overactivation of the complement system, a set of immune proteins that normally helps prune synapses during development. This internal disturbance then signals the peripheral immune system, which launches the inflammatory attacks that clinicians recognize as relapses.27PubMed Central. An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases
If the inside-out model turns out to be correct, or at least partly correct, it would reframe MS as a neurodegenerative disease with secondary inflammation rather than the other way around. Evidence supporting this view includes findings of local complement production by brain-resident cells and the discovery of intracellular complement functions that operate without any involvement of the peripheral immune system. The truth is likely not an either-or answer. Both processes may operate simultaneously, with their relative contributions shifting as the disease evolves from its early relapsing phase to its later progressive phase. For patients and clinicians, the practical takeaway is the same either way: treating the inflammatory side of MS is necessary but not sufficient, and finding ways to protect and repair the nervous system directly is where much of the unmet need lies.