Hidden, Ongoing Damage in Childhood-Onset Multiple Sclerosis: What Patients and Families Need to Know

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Authors Found Their Evidence
• What Causes Smouldering Disease?
• Clinical Features: Disability and Cognition
• Imaging Markers: Seeing the Invisible
• Fluid Biomarkers: Blood and Spinal Fluid Tests
• Clinical Implications for Patients
• Limitations of the Research
• Recommendations for Patients and Families
• Frequently Asked Questions
• Source Information

Key Points

• Smouldering disease is chronic, hidden damage to the brain and spinal cord that continues even when relapses are controlled, and it may be active in children with MS before physical symptoms appear.
• In a cohort of over 16,130 individuals with MS, 40% of 558 with paediatric-onset MS who had confirmed disability accrual experienced progression independent of relapse activity (PIRA).
• Advanced MRI can detect chronic active lesions; in paediatric studies, slowly expanding lesions were found in 84–85% of participants and paramagnetic rim lesions in 71–90% of cases.
• Fluid biomarkers such as neurofilament light chain and glial fibrillary acidic protein may reflect nerve and astrocyte damage and help monitor disease activity and treatment response.
• Prompt diagnosis and high efficacy treatment before neurologic impairment is associated with a decreased likelihood of transition to a progressive course at 5 years in paediatric-onset MS.

Background: Why This Research Matters

Smouldering disease in multiple sclerosis (MS) refers to chronic, widespread damage to the central nervous system that continues even when acute inflammation is controlled. This ongoing damage drives gradual clinical worsening over time. Current therapies effectively reduce relapse rates and the number of visible lesions on MRI scans. However, many patients still experience worsening disability that is not linked to relapses.

Paediatric-onset MS (POMS) offers a unique window into early disease biology. The clinical onset of POMS happens closer to the biological start of the disease than in adult-onset MS (AOMS). This means researchers can study the earliest disease processes in children and adolescents.

Children with POMS have unique age-related features. The disease affects brain maturation processes. The central nervous system also has heightened plasticity (the ability to adapt and repair) in young people. These factors make POMS different from AOMS.

Growing evidence suggests that subclinical progressive disease biology is already active in children and adolescents with MS. This means the smouldering process may begin long before physical symptoms of progression appear. Early intervention could preserve function in these young patients.

Conventional MRI is critical for diagnosing MS. However, it lacks sensitivity for detecting subtle damage. Advanced MRI techniques can capture abnormalities in brain and spinal cord tissue that conventional imaging cannot see. These techniques include detection of chronic active lesions and measurement of global and focal brain damage.

Fluid biomarkers provide non-invasive measures of nerve injury and ongoing chronic inflammation. Two key biomarkers are neurofilament light chain and glial fibrillary acidic protein. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in POMS. The authors also describe how these tools can support treatment decisions.

How the Authors Found Their Evidence

This is a narrative review, not a systematic review. The authors searched PubMed for articles published between 1990 and April 2025. They used search terms including "adult-onset multiple sclerosis," "chronic active lesions," "confirmed disability accrual," "fluid biomarkers," "grey matter," "glial fibrillary acidic protein," "MRI," "neurofilaments," "paediatric-onset multiple sclerosis," "progression independent of relapse activity," "repair," "smouldering disease," "spinal cord," "thalamus," "treatment," and "white matter."

Each co-author performed a targeted literature search on their area of expertise. They selected the most relevant, recent, and innovative studies to support the scientific discussion. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.

Because this was not a systematic review, the authors did not report the number of records retrieved or a detailed screening process. The final reference list was generated based on originality and relevance to the broad scope of the review.

What Causes Smouldering Disease?

Smouldering MS pathology is thought to result from widespread inflammatory and degenerative processes. These processes include:

• Anterograde and retrograde axonal degeneration (damage to nerve fibres in both directions)
• Impaired neuronal metabolism and mitochondrial dysfunction (problems with energy production in nerve cells)
• Oxidative stress (damage from harmful molecules called free radicals)
• Iron accumulation
• Glutamate excitotoxicity (overstimulation of nerve cells by the chemical messenger glutamate)
• Failure of reparative and compensatory mechanisms, such as remyelination (repair of the myelin sheath) and neural plasticity

Most of our understanding of smouldering pathology comes from studies in adults with MS. To date, no pathological studies have specifically characterised smouldering mechanisms in POMS. However, these pathological processes are believed to underlie smouldering disease across all ages. They may translate at least partially to POMS, though there may be differences due to central nervous system maturation and immune responses.

Increasing evidence suggests that biological processes inside the central nervous system play a central role even in the early stages of MS. These processes are considered distinct from the mechanisms underlying MS relapses.

Several key processes may drive smouldering disease. These include:

• Microglial activation around chronic active lesions (CALs), with interactions between B cells and T cells. Microglia are immune cells in the brain and spinal cord.
• B cell activation associated with cortical demyelination (damage to the myelin in the outer layer of the brain).
• Astrocyte-driven chronic inflammation. Astrocytes are star-shaped support cells in the nervous system.
• Intrinsic neuronal metabolic deficits (problems with energy use inside nerve cells).

A network of glial, immune, and neural cells likely sustains the pathology of smouldering disease. This is reflected by the cellular composition of CALs behind an intact blood–brain barrier. The blood–brain barrier is a protective filter that controls what passes from the blood into the brain.

Chronic active lesions contain activated microglia, astrocytes, oligodendrocytes, and lymphocytes. Oligodendrocytes are cells that produce myelin. Lymphocytes are a type of white blood cell. Diffuse microglial activation and oxidative injury in the normal appearing white matter correlate with axonal damage. White matter is the tissue that contains nerve fibres connecting different brain regions.

Although microglia can be homoeostatic (helpful and balancing), they mainly promote harmful processes in MS. These harmful processes include demyelination, aberrant synaptic pruning (abnormal removal of connections between nerve cells), and excessive phagocytosis (engulfing and destroying cells).

B cells and T cells in the central nervous system and leptomeningeal chronic inflammation are also key drivers of smouldering disease. The leptomeninges are the thin layers of tissue that cover the brain and spinal cord. In the meninges, B cells can form tertiary lymphoid structures. These structures are associated with subpial cortical demyelination (damage to myelin just below the outer surface of the brain).

Even though CD8 T cells outnumber other T cells, Th17 cells have been proposed as a potentially important cell type in smouldering MS. However, targeting Th17 cells did not yield therapeutic benefits on the cumulative number of combined unique active lesions observed on brain MRI in a phase 2 trial.

Focal grey matter damage, associated with meningeal inflammation, follows a surface-in gradient. This means damage is most severe near the surface of the brain and decreases with depth. This gradient causes severe demyelination and atrophy (shrinkage).

Astrocytes activated by immune cells and microglia shift into neurotoxic states. These toxic astrocytes further impair neuronal metabolism. Mitochondrial dysfunction is seen as a key driver of neurodegeneration.

There are very limited pathological tissue samples (biopsies) or autopsy data in POMS. Because of this, it is not possible to evaluate whether age at MS onset in childhood leads to differences in the pathological features of smouldering disease.

Clinical Features: Disability and Cognition

The consequences of POMS on neurological function reflect three things: relapse-related tissue injury, repair processes including remyelination, and ongoing tissue loss driven by progressive MS pathobiological injury.

In a natural history cohort, individuals with POMS had a median age at onset of 14.5 years. They had a 50% chance of developing an expanded disability status scale (EDSS) score of 6 or higher at a median of 28.9 years after their first attack. EDSS is a scale that measures physical disability in MS, with higher scores indicating more severe disability. These individuals also had a median of 28 years to enter secondary progressive MS. In this study, most individuals with POMS were untreated or treated with low to moderate efficacy therapies. The number of relapses in the first two years was associated with worse motor outcomes.

However, the risk of progressive disability independent of relapses is not easily discerned from this data. This type of progression is called PIRA, which stands for progression independent of relapse activity. PIRA is defined as confirmed disability accrual (CDA) occurring more than 90 days following a relapse or more than 30 days before a relapse.

A more recent cohort study evaluated PIRA in over 16,130 individuals with MS. This study compared 1,383 individuals with POMS (median age at onset = 15.8 years) to 14,113 individuals with AOMS and 634 individuals with late-onset MS.

Individuals with POMS had more active disease, as measured by relapses. They appeared to have similar PIRA risk compared to AOMS. Specifically, 40% of 558 individuals with POMS who had confirmed disability accrual experienced PIRA. In comparison, 44% of 6,258 individuals with AOMS who had confirmed disability accrual experienced PIRA.

When PIRA was considered as a function of biological age at assessment, only 1.3% of individuals experienced PIRA at age 20 years. By age 30 years, 9% experienced PIRA. The rate of PIRA nearly doubled in each decade thereafter. Exposure to disease-modifying agents and longer duration of treatment reduced the likelihood of PIRA.

An extension of this work evaluated disability trajectories of 268 individuals with POMS and 3,282 individuals with AOMS. These individuals were stratified by the presence of PIRA. The rate of increase in disability was steeper in AOMS compared to POMS. Those with PIRA experienced faster accrual of disability. The impact of PIRA was greater in AOMS.

However, the absolute EDSS scores for POMS in this study were less than 2 across the years of evaluation. This is consistent with low levels of neurologic impairment. Also noteworthy is that 97% of individuals with POMS in this cohort were treated within a few months of their first attack. The majority received moderate efficacy treatments, although 62% escalated to high efficacy treatment (HET) over the observation period.

Current cohorts with POMS, particularly those reported with less than 10 years of observation, have median EDSS scores that remain very low. This indicates a very low rate of accrual of physical impairment, even if patients meet criteria for a PIRA event.

Cognitive Impairment

PIRA can occur at any age, but it is much less common while under 18 years of age. Nonetheless, at the time of diagnosis, children and adolescents have already lost some degree of brain volume relative to their non-MS peers. This finding is consistent with the concept of ongoing neurodegeneration and smouldering inflammation.

Individuals with POMS neurologically recover from relapses with fewer neurologic deficits than individuals with AOMS. Cognitive screening tests performed on POMS participants from the recent therapeutic era show little difference from similarly aged individuals without MS. Individuals with POMS also had similar academic performance as their peers without MS.

The biggest concern for smouldering inflammation among individuals with POMS is the long-term outcome of cognitive function. Among POMS individuals who underwent serial cognitive testing, a substantial subset had major cognitive declines after 10 or more years. These declines had adverse consequences for occupational attainment.

In larger samples, cognitive processing speed performance early in the disease course was similar among individuals with AOMS and POMS. However, over time, individuals with POMS showed greater impairments with increasing disease duration.

Environmental factors are also associated with cognitive reserve and structural brain outcomes in POMS. These factors include the social and economic conditions in which individuals are born and grow. Among 138 individuals with POMS with a median age at onset of 15.5 years, indicators of socioeconomic hardship were associated with greater T2-hyperintense and T1-hypointense white matter lesion volumes.

The indicators of socioeconomic hardship included public versus commercial health insurance, having parents with low educational levels, and growing up in areas of neighbourhood deprivation. Specifically, childhood neighbourhood social vulnerability index was the strongest individual predictor of total white matter lesion volume (β = 4.63, p = 0.002) and T1-hypointense lesion volume (β = 2.91, p = 0.003).

In models incorporating all childhood social determinants of health variables, public health insurance was the strongest predictor of total lesion volume (β = 2.48, p = 0.01) and T1-hypointense lesion volume (β = 1.50, p = 0.02). Public health insurance attenuated the effect of neighbourhood social vulnerability index.

Consistent with the critical role of cognitive reserve in predicting outcomes, lower baseline intelligence quotient is linked to greater grey matter volume loss and subsequent cognitive decline in POMS.

Prompt diagnosis and initiation of high efficacy treatment before the accumulation of neurologic impairment is associated with a decreased likelihood of transition to a progressive course at 5 years. Implementing cognitive rehabilitation strategies for POMS is also therapeutically important.

Imaging Markers: Seeing the Invisible

White Matter Lesions: Slowly Expanding Lesions and Paramagnetic Rim Lesions

The smouldering damage in MS manifests in multiple forms that may arise from distinct sources. One source is the downstream effects of acute inflammation. While most acute white matter lesions evolve into inactive lesions, characterised by resolution of inflammation and demyelinating processes, others develop into chronic active lesions (CALs).

Chronic active lesions are marked by persistence of inflammation in the form of a rim of activated myeloid cells at the lesion edge, without major blood–brain barrier breakdown. These lesions are often referred to as slowly expanding lesions (SELs). They are believed to gradually enlarge over time, leading to progressive myelin and axonal damage.

The detection of SELs relies on serial imaging acquisition over the course of several years, because white matter lesions expand slowly. The defining imaging criteria for SELs include both gradual and radial expansion of pre-existing T2 lesions. This distinguishes them from "new or enlarging lesions" detectable on conventional MRI, which encompass both new acute inflammatory activity near an existing lesion and chronic expansion.

Although SELs are reported more frequently in the progressive phase of MS, recent studies have identified SELs in children and adolescents with MS. One study of 19 children and adolescents with MS (median age at MRI of 14.3 years) identified SELs in 16 participants (84%). Another study of 40 children and adolescents with MS (median age at MRI of 15.6 years) identified SELs in 34 participants (85%). These findings support the underlying progressive biology as an early feature of MS pathology.

Chronic active lesions can also be detected on MRI due to the presence of iron-laden activated microglia and macrophages at the lesion edge. These are visible as a paramagnetic rim using susceptibility weighted MRI techniques. These lesions are called paramagnetic rim lesions (PRLs).

PRLs only partially overlap with SELs. They might therefore be expression of distinct pathological aspects or phases of chronic active lesions. Recent paediatric studies, with cohort sizes between 10 and 13 participants (median ages at MRI ranging from 15.0 to 16.4 years), identified PRLs in 71–90% of MS cases. PRLs accounted for less than 5% of all white matter lesions.

Thus, despite being present in most individuals with MS, PRLs constitute only a minor fraction of white matter lesions detected at any timepoint. This distinction appears even more pronounced in POMS compared to AOMS.

Both SELs and PRLs have high specificity for MS and are associated with more severe disease course. They have significant diagnostic and prognostic implications. It must be acknowledged that PRLs and SELs are difficult to correlate with other markers of disability, such as EDSS score and brain volumes. This is due to the intrinsic repair and remyelinating capacity, which results in low clinical disability, and the ongoing brain maturational processes occurring in POMS.

Despite these limitations, compared to SELs, PRLs have the advantage of being detectable at a single timepoint. This enhances their practical applicability as a prognostic biomarker. The detection of PRLs will be incorporated in the diagnostic algorithm of the 2025 revision of the MS diagnostic criteria. Their identification among individuals with POMS supports the applicability of this neuroimaging biomarker across the age span.

Normal-Appearing White Matter

Abnormalities in the normal-appearing white matter (NAWM) may contribute to clinical worsening independent of new inflammatory attacks in AOMS. Likewise, changes in white matter microstructure precede grey matter atrophy and disability in POMS.

Injury to NAWM in POMS can be demonstrated using techniques such as diffusion tensor imaging (DTI). DTI evaluates properties of the diffusion of water through tissues. In the paediatric population, diffusion becomes increasingly restricted through time. This is a direct consequence of the expected development of myelin fibre bundles.

Use of diffusion metrics, including mean diffusivity (MD) and fractional anisotropy (FA), can therefore demonstrate microstructural damage in NAWM or abnormalities in healthy myelin-related development. Other higher order diffusion methods, such as neurite orientation dispersion and density imaging (NODDI) and fixel-based analysis (FBA), offer specificity with regards to neurite orientation and fibre density. These methods may be more sensitive to identifying axonal loss.

Cross-sectional work has consistently demonstrated widespread abnormalities in NAWM in POMS. Specifically, decreases in FA and increases in mean, radial, and axial diffusivity were demonstrated in cohorts of 10, 14, and 33 paediatric MS patients. Median ages at MRI ranged from 15.1 to 16.6 years. These patients were compared to healthy children. One study noted associations of worse outcomes with longer disease duration.

Specific areas of FA decrease have been seen in the splenium of the corpus callosum, right temporal region, right and left parietal regions, and the occipital region. The corpus callosum is the bundle of nerve fibres that connects the two halves of the brain.

With regards to fibre density, children with MS (n = 18) had decreased fibre density and fibre bundle cross section in multiple areas compared to healthy children (n = 26). These areas were similar to those noted above, but also specifically in the corticospinal tracts and inferior longitudinal fasciculus. Children with myelin oligodendrocyte glycoprotein antibody-associated disease (n = 14) did not show these changes. The corticospinal tracts carry signals for movement, and the inferior longitudinal fasciculus connects visual areas to memory centres.

Similar results have been reported in a cohort of early-onset paediatric MS (onset before 12 years of age). In these patients, the main white matter tracts exhibited different susceptibility to MS-related pathology. This potentially reflects age-dependent differences in the myelin and axonal characteristics of developing white matter pathways.

Using NODDI, neurite density has been found to be low in the corpus callosum and posterior thalamic radiation. Higher NAWM density correlated with lesion volume in the cerebellar peduncle and corticospinal tract. NAWM changes are progressive, as demonstrated in a longitudinal assessment.

Grey Matter Damage

Grey matter volume abnormalities correlate with overall T2-hyperintense white matter lesion volume. This supports the hypothesis that MS not only drives neurodegeneration secondary to inflammatory demyelination but also disrupts brain development when the disease occurs during critical periods of brain development.

The thalamus seems particularly vulnerable to damage. The thalamus is a deep brain structure that relays sensory and motor signals. It shows early microstructural abnormalities and volume loss in POMS. This damage is at least partly due to disrupted thalamic connections caused by focal white matter lesions. This is indicated by strong associations with T2-hyperintense white matter lesion volume.

Recent studies have revealed a "surface-in gradient" of thalamic abnormalities. The most severe damage is near the cerebrospinal fluid (CSF) interface. This suggests the role of CSF-diffusible inflammatory or cytotoxic factors and of the choroid plexus in the onset and propagation of damage. The choroid plexus is the structure that produces cerebrospinal fluid.

Fluid Biomarkers: Blood and Spinal Fluid Tests

Serum and cerebrospinal fluid biomarkers may reflect underlying neuroinflammation and axonal damage. This supports their role in identifying smouldering disease and guiding early intervention strategies.

Two key fluid biomarkers are neurofilament light chain and glial fibrillary acidic protein. Neurofilament light chain is a protein released when nerve fibres are damaged. Glial fibrillary acidic protein is a protein released when astrocytes are damaged. Both provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation.

These biomarkers can be measured in blood (serum) and in cerebrospinal fluid. They offer a way to monitor disease activity and treatment response without requiring repeated MRI scans or invasive procedures.

Clinical Implications for Patients

This review has several important implications for patients with POMS and their families.

First, smouldering disease is an active process even in young patients. Growing evidence suggests that subclinical progressive disease biology is already active in children and adolescents with MS. This means the disease may be causing damage even when patients feel well and have no relapses.

Second, current treatments effectively reduce relapses and visible MRI lesions. However, many patients still experience progression independent of relapse activity. This highlights the need for treatments that target the smouldering processes, not just acute inflammation.

Third, advanced MRI techniques and fluid biomarkers can detect smouldering disease earlier than conventional methods. This could allow doctors to identify patients who need more aggressive treatment before significant disability accumulates.

Fourth, early intervention may preserve function. Prompt diagnosis and initiation of high efficacy treatment before the accumulation of neurologic impairment is associated with a decreased likelihood of transition to a progressive course at 5 years.

Fifth, cognitive rehabilitation strategies are important for POMS. Among POMS individuals who underwent serial cognitive testing, a substantial subset had major cognitive declines after 10 or more years. These declines had adverse consequences for occupational attainment.

Sixth, environmental factors matter. Indicators of socioeconomic hardship were associated with greater white matter lesion volumes in POMS. This suggests that social determinants of health play a role in disease outcomes.

Limitations of the Research

This review has several limitations that patients and families should understand.

First, this is a narrative review, not a systematic review. The authors did not report the number of records retrieved or a detailed screening process. This means the selection of studies may reflect the authors' perspectives and expertise.

Second, most of our understanding of smouldering pathology comes from studies in adults with MS. To date, no pathological studies have specifically characterised smouldering mechanisms in POMS. There are very limited pathological tissue samples or autopsy data in POMS. Because of this, it is not possible to evaluate whether age at MS onset in childhood leads to differences in the pathological features of smouldering disease.

Third, PRLs and SELs are difficult to correlate with other markers of disability, such as EDSS score and brain volumes. This is due to the intrinsic repair and remyelinating capacity in young patients, which results in low clinical disability, and the ongoing brain maturational processes occurring in POMS.

Fourth, the detection of SELs relies on serial imaging acquisition over the course of several years. This limits their practical applicability as a prognostic biomarker in clinical settings.

Fifth, current cohorts with POMS, particularly those reported with less than 10 years of observation, have median EDSS scores that remain very low. This indicates a very low rate of accrual of physical impairment, even if patients meet criteria for a PIRA event. Longer follow-up is needed to understand the full impact of smouldering disease.

Recommendations for Patients and Families

Based on this review, patients and families should consider the following recommendations:

1. Seek early diagnosis and treatment. Prompt diagnosis and initiation of high efficacy treatment before the accumulation of neurologic impairment is associated with a decreased likelihood of transition to a progressive course at 5 years.
2. Discuss advanced imaging with your care team. Advanced MRI techniques, including detection of chronic active lesions, can identify smouldering disease earlier than conventional imaging.
3. Ask about fluid biomarkers. Serum and cerebrospinal fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, may help monitor disease activity and treatment response.
4. Consider cognitive rehabilitation. Implementing cognitive rehabilitation strategies is therapeutically important for POMS. Among POMS individuals who underwent serial cognitive testing, a substantial subset had major cognitive declines after 10 or more years.
5. Be aware of environmental factors. Indicators of socioeconomic hardship were associated with greater white matter lesion volumes in POMS. Discuss any social or economic challenges with your care team.
6. Stay informed about treatment advances. The detection of paramagnetic rim lesions will be incorporated in the diagnostic algorithm of the 2025 revision of the MS diagnostic criteria. This supports the applicability of this neuroimaging biomarker across the age span.
7. Monitor cognitive function over time. In larger samples, cognitive processing speed performance early in the disease course was similar among individuals with AOMS and POMS. However, over time, individuals with POMS showed greater impairments with increasing disease duration.

Frequently Asked Questions

What is smouldering disease in paediatric-onset MS?

Smouldering disease is chronic, widespread damage to the brain and spinal cord that continues even when acute inflammation is controlled. It drives gradual clinical worsening over time. In children and adolescents with MS, growing evidence suggests this subclinical progressive disease biology is already active, meaning damage may occur even when patients feel well and have no relapses.

How common is progression independent of relapse activity (PIRA) in children with MS?

In a cohort of over 16,130 individuals with MS, 40% of 558 individuals with paediatric-onset MS who had confirmed disability accrual experienced PIRA. By comparison, 44% of 6,258 individuals with adult-onset MS who had confirmed disability accrual experienced PIRA. PIRA is much less common while under 18 years of age.

Can MRI detect smouldering disease before symptoms appear?

Advanced MRI techniques can capture abnormalities in brain and spinal cord tissue that conventional imaging cannot see. These include chronic active lesions, such as slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). In paediatric studies, SELs were identified in 84–85% of participants, and PRLs in 71–90% of cases, though PRLs accounted for less than 5% of all white matter lesions.

What are neurofilament light chain and glial fibrillary acidic protein?

Neurofilament light chain is a protein released when nerve fibres are damaged. Glial fibrillary acidic protein is released when astrocytes are damaged. Both can be measured in blood (serum) and cerebrospinal fluid, providing non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. They may help monitor disease activity and treatment response without repeated MRI scans or invasive procedures.

Does early treatment prevent long-term disability in paediatric-onset MS?

Prompt diagnosis and initiation of high efficacy treatment before the accumulation of neurologic impairment is associated with a decreased likelihood of transition to a progressive course at 5 years. In one cohort, 97% of individuals with paediatric-onset MS were treated within a few months of their first attack, and median EDSS scores remained very low over the observation period.

What cognitive problems can occur in paediatric-onset MS?

Among individuals with paediatric-onset MS who underwent serial cognitive testing, a substantial subset had major cognitive declines after 10 or more years, with adverse consequences for occupational attainment. Over time, individuals with paediatric-onset MS showed greater impairments with increasing disease duration compared to adult-onset MS. Cognitive rehabilitation strategies are considered therapeutically important.

Do social or economic factors affect MS outcomes in children?

In 138 individuals with paediatric-onset MS, indicators of socioeconomic hardship were associated with greater T2-hyperintense and T1-hypointense white matter lesion volumes. These indicators included public versus commercial health insurance, having parents with low educational levels, and growing up in areas of neighbourhood deprivation. Childhood neighbourhood social vulnerability index was the strongest individual predictor of total white matter lesion volume.

My child was just diagnosed with paediatric-onset MS — when should we seek a second opinion?

A second opinion can be valuable at diagnosis, when confirming the diagnosis and reviewing MRI findings, since smouldering disease may already be active in children and adolescents even without relapses. It can also help when deciding how early to start high-efficacy treatment, because prompt treatment before neurologic impairment accumulates is associated with a decreased likelihood of transition to a progressive course at 5 years. Advanced MRI markers such as paramagnetic rim lesions and slowly expanding lesions, plus fluid biomarkers, may inform that decision. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Smouldering disease in paediatric-onset multiple sclerosis

Authors: Massimo Filippi, Monica Margoni, Brenda Banwell, Tanuja Chitnis, Russell Dale, Giulia Fadda, Yael Hacohen, Lauren B. Krupp, Paolo Preziosa, E. Ann Yeh, Emmanuelle Waubant, and Maria A. Rocca

Publication: eBioMedicine, Volume 120, October 2025, Article 105921. Published online 11 September 2025.

DOI: https://doi.org/10.1016/j.ebiom.2025.105921

Copyright: © 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider. Patients should discuss their individual treatment options with their neurology team.