What is multiple sclerosis, what causes it, and how is it treated?

Multiple Sclerosis: Definition, Causes, and Treatment

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal damage, resulting from complex interactions between genetic susceptibility and environmental factors, with Epstein-Barr virus being a key trigger. 1, 2

What is Multiple Sclerosis?

• MS is characterized by widespread focal degradation of the myelin sheath (the protective covering of nerve fibers), variable axonal and neuronal injury, and resulting disability in young adults 1, 2
• The disease typically presents in young adults (mean age 20-30 years) with symptoms developing over several days, including unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes 2
• MS affects an estimated 900,000 people in the US, with prevalence ranging from 5 to 300 per 100,000 people worldwide, increasing at higher latitudes 2
• Women are affected more frequently than men (nearly 3:1 ratio) 2
• There are two main clinical forms: relapsing-remitting MS (RRMS, affecting about 85% of cases) and primary-progressive MS (PPMS, affecting about 15% of cases) 1

What Causes Multiple Sclerosis?

• MS originates from complex interactions between genetic susceptibility, environmental factors, and immunological mechanisms 1
• The disease is initiated by unfavorable interactions between genetic and environmental risk factors that lead to activation and migration of pro-inflammatory B cells and T cells into the central nervous system 1
• Strong evidence points to Epstein-Barr virus (EBV) as a key environmental trigger 1
• Other environmental factors include:
  • Vitamin D deficiency and low sunlight exposure 1
  • Dietary factors (diets higher in saturated fat may increase risk) 1
  • Geographic location (higher incidence in regions with lower sunlight exposure) 1

Diagnosis of Multiple Sclerosis

• Diagnosis is based on the 2017 McDonald Criteria, which include a combination of:
  • Clinical signs and symptoms
  • Radiographic findings (e.g., MRI T2 lesions)
  • Laboratory findings (e.g., cerebrospinal fluid-specific oligoclonal bands) 2
• The diagnostic criteria emphasize demonstrating dissemination of lesions in both space and time 3
• MRI is a crucial diagnostic tool and should be obtained prior to initiating therapy 4
• Cerebrospinal fluid analysis may be required, especially in atypical presentations 3
• Diagnosis requires that there be no better explanation for the clinical and paraclinical abnormalities than MS 3

Treatment of Multiple Sclerosis

Disease-Modifying Therapies (DMTs)

• Nine classes of DMTs with varying mechanisms of action are available for relapsing forms of MS 2:
  • Interferons
  • Glatiramer acetate
  • Teriflunomide
  • Sphingosine 1-phosphate receptor modulators
  • Fumarates
  • Cladribine
  • Monoclonal antibodies (including natalizumab)
• These DMTs reduce clinical relapses and MRI lesions by 29-68% compared to placebo or active comparators 2, 5
• Only ocrelizumab is approved for primary progressive MS 2
• Current DMTs primarily target the inflammatory component rather than promoting remyelination 1, 6

Natalizumab as a Treatment Option

• Natalizumab is indicated as monotherapy for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 4
• The recommended dose is 300 mg intravenous infusion over one hour every four weeks 4
• Important safety consideration: Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal opportunistic viral infection 4
• Risk factors for PML include:
  • Presence of anti-JCV antibodies
  • Duration of therapy
  • Prior use of immunosuppressants 4
• Due to PML risk, natalizumab is available only through a restricted distribution program called TOUCH® Prescribing Program 4

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

• AHSCT is highly effective at stopping inflammation in the brain, as demonstrated by suppression of clinical and MRI-detected MS disease activity 3
• It can stabilize or even improve function in relapsing-remitting MS, though benefits are less clear in progressive forms 3
• AHSCT involves higher acute risk than many approved DMTs, so patient selection is crucial 3

Treatment Approach

1. Early intervention with DMTs is crucial to prevent irreversible neurological damage 2, 5
2. Selection of DMT should be based on:
   • Disease activity and severity
   • Patient characteristics and comorbidities
   • Safety profile of the medication
   • Patient preference regarding administration route 2, 5
3. Regular monitoring is essential to assess treatment response and detect adverse effects 4
4. Consider escalation to higher-efficacy treatments if breakthrough disease activity occurs 5

Challenges and Pitfalls

• MS is increasingly recognized as a neurodegenerative disease triggered by an inflammatory attack, not just an inflammatory disease 7
• Long-term disability may progress at similar rates despite variable relapse frequencies, suggesting that controlling inflammation alone may not prevent progression 8
• The safety profiles of DMTs vary significantly, with potential serious adverse effects including:
  • Infections
  • Cardiac issues (bradycardia, heart blocks)
  • Macular edema
  • Infusion/injection-site reactions
  • Secondary autoimmune adverse effects 2
• Careful monitoring for PML is essential in patients receiving natalizumab, with immediate discontinuation at the first sign or symptom suggestive of PML 4

MS remains a complex disease requiring comprehensive management of both the inflammatory and neurodegenerative components to optimize outcomes and quality of life for affected individuals.