Multiple Sclerosis (MS) is characterized by the immune system mistakenly attacking the central nervous system (CNS). Traditionally, MS understanding focused on acute relapses—sudden episodes of new or worsening neurological symptoms—followed by remission. However, this model fails to account for the steady decline in function many patients experience over time, even when relapses are controlled. The newer concept of “smoldering MS” describes a continuous, underlying process of damage that often goes unnoticed, representing a persistent driver of long-term disability.
Defining Smoldering MS
Smoldering Multiple Sclerosis (SMS) refers to a chronic, low-grade inflammatory and neurodegenerative process occurring within the CNS, operating largely independent of acute relapses. An international consensus defines SMS as an umbrella term for chronic pathobiological processes in the CNS, beyond acute focal inflammation, leading to clinical worsening. This underlying activity is a major contributor to the gradual accumulation of physical and cognitive disability, often called progression independent of relapse activity.
The concept of SMS represents a paradigm shift in how MS progression is viewed. Traditional MS management focuses on suppressing the acute inflammation that causes relapses and new lesions visible on standard magnetic resonance imaging (MRI). SMS, in contrast, highlights continuous, non-acute damage that occurs even when the disease appears stable by conventional measures. This persistent process is the main driver of brain volume loss, or atrophy, which correlates strongly with long-term functional decline.
The Pathological Mechanisms
The biological engine of smoldering MS involves specialized immune cells resident within the CNS operating in a state of chronic activation. The primary cellular drivers are microglia, the brain’s resident immune cells, and astrocytes, a type of glial cell. In smoldering lesions, microglia often remain persistently activated at the edges of old lesions, failing to switch off after the initial inflammatory event. This chronic activation leads to a harmful state where these cells continuously cause damage.
This persistent inflammation is often described as “compartmentalized,” meaning it is trapped within the CNS, behind the protective blood-brain barrier. The chronic activity of microglia and astrocytes contributes to demyelination and neuroaxonal damage. Specific areas like the meninges, the membranes covering the brain, can harbor clusters of immune cells that contribute to localized neuroinflammation. This compartmentalization may shield the smoldering process from many current disease-modifying therapies that primarily target immune cells circulating in the bloodstream.
Detection and Diagnostic Markers
Because smoldering MS activity is chronic and low-grade, it is often missed by standard clinical observation and routine MRI scans. Specialized imaging techniques are necessary to visualize this ongoing damage. One significant marker is the Paramagnetic Rim Lesion (PRL), a type of chronic active lesion seen on iron-sensitive MRI sequences. These lesions appear with a dark outer rim, indicating the presence of iron-laden immune cells, primarily activated microglia, that are actively expanding the lesion over time.
Another key indicator of SMS activity is brain volume loss, or atrophy, particularly in the deep gray matter. This atrophy is a direct consequence of the long-term neurodegeneration driven by the smoldering process. Researchers are also investigating emerging non-MRI techniques, such as Positron Emission Tomography (PET) scans, which can directly image activated microglia, and spinal fluid biomarkers that correlate with CNS damage. The presence of multiple PRLs correlates with a greater likelihood of a more aggressive, progressive form of MS, underscoring their importance as a diagnostic marker for SMS.
Implications for Disease Progression and Treatment
Recognizing smoldering MS is fundamentally changing the understanding of how disability accumulates. This chronic, underlying process is strongly linked to the progressive forms of MS, including Secondary Progressive MS (SPMS) and Primary Progressive MS (PPMS). The gradual worsening of physical and cognitive function, even without visible relapses, is a direct consequence of the damage driven by SMS.
Current disease-modifying therapies (DMTs) are highly effective at preventing acute relapses and new inflammatory lesions, but they often fail to halt the long-term accumulation of disability because they do not adequately address the smoldering process. The future of MS treatment is shifting toward developing next-generation therapies designed to penetrate the CNS compartment. Researchers are focusing on compounds, such as Bruton’s tyrosine kinase (BTK) inhibitors, that can target and modulate the chronic activation of microglia and astrocytes, aiming to stop the neurodegeneration at its source.