Smoldering neuroinflammation is a slow, continuous inflammatory process inside the brain and spinal cord that causes ongoing damage even when a person with multiple sclerosis appears clinically stable. Unlike the dramatic flare-ups of relapsing MS, where immune cells breach the blood-brain barrier and cause visible attacks, smoldering inflammation is quieter. It operates behind a sealed blood-brain barrier, driven by immune cells already trapped inside the central nervous system, steadily destroying nerve fibers and expanding old lesions over months and years.
The concept has reshaped how neurologists think about MS progression. It explains why many people continue to accumulate disability between relapses, or even without relapses at all, and why current treatments that work by blocking immune cells from entering the brain often fail to stop long-term worsening.
How It Differs From Relapsing Inflammation
In relapsing MS, the immune system launches episodic, high-intensity attacks. White blood cells cross the blood-brain barrier, creating well-defined areas of damage that light up on MRI scans. These attacks cause relapses, symptoms flare and then partially or fully resolve, and the barrier reseals. Most MS drugs target this process by preventing immune cells from getting into the brain in the first place.
Smoldering neuroinflammation works differently in almost every way. The inflammation is low-grade and chronic rather than episodic. It doesn’t require the blood-brain barrier to break open because the immune cells driving it are already inside the central nervous system. The damage it causes is diffuse and cumulative rather than concentrated in distinct lesion spots. And because it doesn’t produce the kind of barrier disruption that shows up as bright enhancement on standard MRI, it can be nearly invisible on routine scans.
What Drives It Inside the Brain
The central players are microglia, the brain’s resident immune cells. In healthy tissue, microglia patrol for threats and help maintain neural connections. In smoldering MS, they become chronically activated, losing their normal housekeeping functions and shifting into a destructive state. These activated microglia cluster at the edges of old lesions, where they continue to break down the protective myelin coating around nerve fibers. They also release toxic molecules, including reactive oxygen species and inflammatory signaling proteins, that damage surrounding neurons.
Research using single-cell analysis of brain tissue from people with progressive MS has shown that these microglia look fundamentally different from their healthy counterparts. They ramp up proteins involved in inflammation and tissue destruction while shutting down the markers associated with their normal protective role. Once locked into this activated state, they can sustain damage indefinitely.
Clusters of immune cells, including B cells, also accumulate in the membranes surrounding the brain. The density of these immune cell clusters in the brain’s outer lining correlates with the number of chronically active lesions in the underlying white matter. This suggests the inflammation becomes self-sustaining: immune cells compartmentalized within the central nervous system continue to drive damage without needing reinforcements from the bloodstream.
Slowly Expanding Lesions
The hallmark of smoldering neuroinflammation on imaging is the slowly expanding lesion. These are old MS plaques that never fully quiet down. At their edges, a rim of iron-laden activated microglia and macrophages continues to chew outward into healthy tissue, gradually enlarging the lesion over years. On specialized MRI sequences, this rim of iron-containing cells appears as a dark ring, known as a paramagnetic rim lesion.
Paramagnetic rim lesions are emerging as one of the most specific imaging markers for smoldering activity. They are far more common in progressive MS than in the relapsing form, and their presence is associated with ongoing axonal destruction and disability accumulation. Standard MRI sequences used in routine clinical care don’t always detect them, which is part of why smoldering inflammation went unrecognized for so long. Specialized phase-sensitive imaging can reveal these dark rings, though debate continues about whether all smoldering lesions produce a visible rim.
Damage Beyond Visible Lesions
One of the most important insights about smoldering neuroinflammation is that damage extends far beyond the lesions themselves. Brain tissue that looks normal on standard MRI, referred to as normal-appearing white and gray matter, shows widespread abnormalities when examined more closely.
Brain atrophy begins early in MS and accelerates as smoldering processes take hold. On imaging, this appears as widening of the grooves on the brain’s surface and enlargement of the fluid-filled ventricles inside the brain. Ventricular enlargement, in particular, reflects white matter loss and distinguishes MS-related atrophy from normal aging. Cortical thinning tends to become apparent later in the disease.
The nerve fibers most vulnerable to this process are the smallest-diameter axons, likely because they have lower energy reserves and are more susceptible to the toxic byproducts of chronic inflammation. When myelin blisters and separates from the nerve fiber it protects, the gap disrupts energy delivery to the axon, which can trigger a “dying back” degeneration that spreads along connected nerve tracts. This mechanism means that a smoldering lesion in one brain region can cause nerve fiber loss in distant, seemingly unaffected areas.
Symptoms That Don’t Look Like Relapses
Smoldering neuroinflammation doesn’t typically announce itself with the sudden vision loss or limb weakness of a classic relapse. Instead, it drives a gradual worsening that can be difficult for both patients and clinicians to pin down. Neurologists now call this progression independent of relapse activity, or PIRA, and it accounts for at least half of all disability accumulation even in people with the relapsing form of MS. Roughly 5% of people with relapsing MS experience PIRA in any given year.
The symptoms most closely tied to this slow-burn inflammation are often invisible to others. Fatigue affects 60 to 80% of people newly diagnosed with MS and can precede diagnosis as part of an early prodrome. It manifests as a combination of physical and mental exhaustion, reduced motivation, and a persistent need to rest that interferes with daily activities. Cognitive impairment, pain, and depression are also common. These “hidden disabilities” can be present even in people whose disease appears inactive on standard monitoring, meaning they may not be receiving treatment that addresses the underlying smoldering process.
Fatigue, in particular, is prevalent even in people who are not experiencing inflammatory relapses. This is clinically significant because it suggests ongoing smoldering activity in patients who might otherwise be considered stable.
Blood Markers Under Investigation
Two blood proteins are gaining traction as potential windows into smoldering activity. Neurofilament light chain is a structural protein released when nerve fibers are damaged, and its blood levels reflect the rate of ongoing neurodegeneration. Glial fibrillary acidic protein is released by activated support cells in the brain called astrocytes, making it more of a marker for the inflammatory glial response itself. Higher levels of both proteins are associated with faster progression to an MS diagnosis after a first neurological episode, with neurofilament light chain showing a 36% increased risk and glial fibrillary acidic protein showing a 12% increased risk per unit increase.
Neither marker is specific enough to diagnose smoldering inflammation on its own, but together with paramagnetic rim lesions on MRI, they are building toward a more complete picture of what’s happening inside the brain between relapses.
Why Current Treatments Fall Short
Most approved MS therapies work by intercepting immune cells in the bloodstream or preventing them from crossing the blood-brain barrier. This approach is effective against relapses but does little to address inflammation that is already compartmentalized inside the central nervous system. The immune cells driving smoldering lesions are behind the barrier, out of reach.
This is why a class of drugs called BTK inhibitors has generated significant interest. BTK is an enzyme involved in the activation of both B cells and microglia. Tolebrutinib, the most advanced of these compounds, is designed to cross the blood-brain barrier and act directly on the immune cells fueling smoldering inflammation from within the brain. In the HERCULES trial, it was tested in people with nonrelapsing secondary progressive MS, a population with no previously approved treatment options who continue to worsen despite the absence of relapses. A separate ongoing trial, PERSEUS, is evaluating whether similar benefits extend to primary progressive MS.
Safety remains a concern. In clinical trials, about 4% of people taking tolebrutinib developed elevated liver enzymes, compared to 1.6% on placebo. This will shape how the drug is monitored if it reaches routine clinical use. Still, the ability to target inflammation behind the blood-brain barrier represents a fundamental shift in how progressive MS might be treated, moving beyond blocking immune cell entry to quieting the smoldering process itself.