What is the current theory on the pathophysiology of Multiple Sclerosis (MS) and its treatment?

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Current Pathophysiology and Treatment of Multiple Sclerosis

Pathophysiology

Multiple sclerosis results from unfavorable interactions between genetic susceptibility and environmental factors (particularly Epstein-Barr virus) that trigger activation and migration of pro-inflammatory B cells and T cells into the CNS, leading to focal demyelination, axonal injury, and progressive neurodegeneration that begins early in the disease course. 1, 2

Dual Pathological Mechanisms

The current understanding recognizes MS as having two interconnected pathological processes:

  • Inflammatory component: Autoimmune-mediated demyelination characterized by multiple focal lesions in cerebral white and grey matter, driven by myelin-specific CD4+ and CD8+ T cells that enter the CNS and initiate inflammatory responses 1, 3

  • Neurodegenerative component: Irreversible demyelination, axonal transection, and neuronal loss that occurs early in the disease and continues throughout, serving as the main driver of irreversible disability 1

Immunological Mechanisms

The disease involves complex immune dysregulation:

  • Pro-inflammatory T helper 1 (Th1) and Th17 cells produce cytokines that drive inflammation 4, 5
  • B cells contribute through antibody production and antigen presentation 1
  • CD8+ T lymphocytes play a larger role than previously recognized 4
  • Oligodendrocyte death, axonal loss, and ion channel dysfunction contribute to neurodegeneration 6

Key Environmental Trigger

  • Epstein-Barr virus (EBV) is now recognized as a key environmental trigger that leads to immune dysregulation in genetically susceptible individuals 2
  • Vitamin D deficiency and low sunlight exposure are associated with increased MS risk 2

Treatment Approaches

Disease-Modifying Therapies (DMTs)

Nine classes of DMTs are available for relapsing-remitting MS and secondary progressive MS with activity, reducing annual relapse rates by 29-68% compared to placebo, though they primarily target inflammation rather than promoting remyelination or neuroprotection. 2, 3

The available DMT classes include:

  • Interferons: Modulate immune responses 3
  • Glatiramer acetate: Acts by modifying immune processes through induction of glatiramer-specific suppressor T-cells in the periphery 7
  • Teriflunomide: Inhibits pyrimidine synthesis 3
  • Sphingosine 1-phosphate receptor modulators: Prevent lymphocyte egress from lymph nodes 3
  • Fumarates: Activate Nrf2 pathway with anti-inflammatory effects 3
  • Cladribine: Selectively depletes lymphocytes 3
  • Monoclonal antibodies (3 types): Target specific immune cells or molecules 3

Primary Progressive MS

  • Ocrelizumab is the only DMT approved specifically for primary progressive MS 3

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

AHSCT represents an emerging treatment that eradicates disease-associated immune components through high-dose chemotherapy, followed by immune system reconstitution that leads to long-term suppression of inflammatory activity. 1

Mechanisms of AHSCT include:

  • Ablation of the haematolymphoid system followed by deep immune reconstitution over 6 months to 2 years 1
  • Increase in regulatory T cells (FoxP3+ Tregs) and reduced Th17 responses 1
  • Reduction in switched memory B cells and renewal of T cell receptor repertoire 1
  • Decreased T cell reactivity to MS autoantigens in CD4+ effector memory cells 1
  • Patient selection has evolved to favor relapsing-remitting MS rather than progressive forms, improving safety outcomes 1

Symptomatic Management

For specific symptoms:

  • Spasticity: Baclofen or gabapentin as first-line; tizanidine or dantrolene as second-line; benzodiazepines as third-line, combined with physiotherapy 5
  • Urinary incontinence: Anticholinergics (oxybutynin), tricyclic antidepressants (amitriptyline), or intermittent self-catheterization 5
  • Bowel dysfunction: Stool softeners and high-fiber diet 5

Treatment Monitoring

  • Brain MRI should be performed annually (or every 3-4 months for patients at risk of serious treatment-related adverse events) using contrast-enhanced T1 sequences to detect acute inflammation and T2 sequences to assess new or enlarging lesions 1
  • Brain volume changes can measure tissue damage but pseudoatrophy (excessive volume decrease in first 6-12 months of treatment due to resolution of inflammation) must be distinguished from true neurodegeneration 1

Critical Treatment Gaps

Current DMTs primarily target the inflammatory component and have limited effectiveness on neurodegeneration, with no approved therapies that promote remyelination or provide neuroprotection. 2, 6

Common adverse effects of DMTs include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune conditions such as thyroid disease 3

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Multiple Sclerosis Pathogenesis and Risk Factors

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

4
Research

Immunopathogenesis of multiple sclerosis.

Annals of Indian Academy of Neurology, 2009

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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