The evolving understanding of multiple sclerosis (MS) continues to reshape our approach to its diagnosis and management. A landmark article by Giovannoni and colleagues, published in Therapeutic Advances in Neurological Disorders, introduces the concept of "smouldering MS", positing it as the fundamental driver of disease progression. Below, we distill the key insights and clinical implications.

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Understanding Smouldering MS

Smouldering MS is characterized by persistent disease activity, independent of clinical relapses or visible MRI lesions. The authors propose that this chronic, underlying pathology may be the "real MS," responsible for long-term disability and progressive neurodegeneration.

Key Features Include:

• Chronic Active Lesions: Also called "rim lesions," these slowly expanding lesions show sustained demyelination and axonal injury.
• Diffuse Inflammation: Microglial and astrocytic activation in both gray and white matter drives progressive damage.
• Cortical Demyelination: Subtle cortical damage, associated with cognitive and physical decline, is often missed on conventional MRI.
• Accelerated Brain Atrophy: Smouldering MS is linked to faster brain volume loss, a key marker of neurodegeneration.

This paradigm challenges traditional notions that focus primarily on relapsing-remitting MS (RRMS) and emphasizes the importance of identifying smouldering disease activity early.

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Diagnostic and Monitoring Challenges

Traditional MRI metrics such as gadolinium-enhancing lesions and T2 lesion count may not adequately capture smouldering MS. Instead, the authors advocate for advanced imaging techniques and biomarkers to assess:

• Chronic lesion activity: Better captured by techniques like susceptibility-weighted imaging (SWI).
• Diffuse neurodegeneration: Measured through cortical atrophy and brain volume loss.
• Microglial activation: Potentially detectable with PET imaging or other emerging modalities.

Neurologists should remain vigilant for subtle signs of progression that might not correlate with clinical relapses.

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Therapeutic Implications

Smouldering MS necessitates a paradigm shift in treatment approaches:

1. Early and Aggressive Intervention
   Delaying treatment risks missing the window to address the insidious damage associated with smouldering MS. Starting therapy early, even in clinically silent phases, may mitigate long-term disability.
2. Neuroprotective Strategies
   Therapies with potential neuroprotective effects, such as sphingosine-1-phosphate (S1P) receptor modulators (e.g., fingolimod), could play a critical role in targeting smouldering disease mechanisms.
3. Emerging Treatments
   Research into agents promoting remyelination, axonal repair, and microglial modulation is essential to address this unmet need.
4. Redefining Treatment Goals
   Beyond controlling inflammation, therapies should aim to reduce brain atrophy and slow neurodegeneration, which better reflect smouldering activity.

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Key Takeaways for Clinical Practice

• Adopt a Broader Lens: Monitor for neurodegeneration and subtle signs of progression, even in the absence of clinical relapses.
• Refine Treatment Selection: Consider therapies with neuroprotective and disease-modifying potential to address smouldering MS.
• Communicate with Patients: Educate patients about the importance of long-term, proactive management to prevent silent progression.

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For the full article, visit: Ther Adv Neurol Disord. 2022 Jan 25;15:17562864211066751.