What is the initial treatment approach for patients with Multiple Sclerosis (MS) and significant nerve pathology?

Initial Treatment Approach for Multiple Sclerosis with Nerve Pathology

Initiate high-efficacy disease-modifying therapies (DMTs) immediately at diagnosis for relapsing-remitting MS, prioritizing ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine as first-line agents rather than using a traditional escalation strategy. 1, 2

Disease Classification and Baseline Assessment

Before initiating treatment, establish the MS subtype through specific diagnostic steps:

• Obtain brain MRI with gadolinium-enhanced T1 and T2/FLAIR sequences to quantify focal inflammatory lesions, total lesion burden, and active gadolinium enhancement 1, 2
• Document EDSS score, disease duration, relapse frequency, and completeness of recovery from prior relapses to stratify disease severity 1, 2
• Identify aggressive disease markers including ≥2 relapses per year, incomplete recovery from relapses, high frequency of new MRI lesions, and rapid onset of disability 1, 2

Treatment Strategy for Relapsing-Remitting MS

The evidence strongly favors abandoning the traditional stepped escalation approach:

• Start with high-efficacy DMTs immediately rather than moderate-efficacy agents, as early aggressive treatment yields superior long-term outcomes with 68% achieving no evidence of disease activity (NEDA) at year 1 versus only 36% with moderate-efficacy DMTs 3
• The first treatment choice is the most critical determinant of outcome, with odds ratio of 3.9 for achieving NEDA with high-efficacy versus moderate-efficacy first-line therapy 3
• Preferred first-line agents include ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine based on current guideline recommendations 1, 2

The 2025 ECTRIMS-EBMT consensus explicitly recommends early escalation and induction strategies over traditional stepped approaches 4, 1. This represents a paradigm shift supported by real-world evidence demonstrating that delayed initiation of high-efficacy therapy results in worse long-term disability outcomes 3, 5.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

For highly active disease refractory to initial high-efficacy DMT:

• Consider AHSCT after failure of the first high-efficacy DMT in patients with aggressive disease features, as this represents the most effective escalation therapy with 87% progression-free survival at 10 years 2
• Optimal AHSCT candidates are age <45 years, disease duration <10 years, EDSS <4.0, and high focal inflammation on MRI 4, 1, 2
• AHSCT may be considered as first-line therapy only for rapidly evolving, severe, treatment-naive MS with poor prognosis, ideally within clinical trials 4, 6

Treatment for Progressive Forms

The approach differs substantially for progressive MS:

• For primary progressive MS (PPMS), initiate ocrelizumab as the only FDA-approved specific therapy, though efficacy is limited to slowing disability progression 1, 7
• For secondary progressive MS (SPMS), consider AHSCT only in young patients (<45 years) with early SPMS of short duration and documented active inflammatory disease on both clinical and radiological grounds 4, 1, 6
• AHSCT is not indicated for advanced progressive MS without active inflammation 4, 1

MRI Monitoring Protocol

Establish a structured surveillance schedule:

• Perform brain MRI at least annually for stable patients 1, 2
• Increase MRI frequency to every 3-4 months for high-risk patients, including those with highly active disease, recent treatment changes, or those receiving natalizumab (due to progressive multifocal leukoencephalopathy risk) 4, 1, 2
• Include T2/FLAIR sequences for new or enlarging lesions and gadolinium-enhanced T1 sequences for active inflammatory lesions 1, 2
• Be aware of pseudoatrophy effect within the first 6-12 months of treatment, where excessive brain volume decrease from resolution of inflammation should not be mistaken for disease progression 6

Age-Specific Treatment Modifications

Treatment decisions should account for patient age and disease duration:

• For patients <45 years with disease duration <10 years, continue aggressive DMT even if clinically stable, particularly if there is history of highly active disease before stabilization 1, 2
• For patients >55 years with stable disease and duration >20 years, consider discontinuing DMT, as infection risks and other adverse effects may outweigh benefits of continued immunosuppression 1, 2

Critical Pitfalls to Avoid

• Do not delay high-efficacy DMT initiation while attempting moderate-efficacy agents first, as the first treatment choice has the greatest impact on long-term outcomes 3, 5
• Do not consider AHSCT for patients >55 years or those with advanced progressive disease without active inflammation, as these patients are not appropriate candidates 1, 2
• Do not mistake pseudoatrophy on early MRI follow-up for treatment failure, as this represents resolution of inflammation rather than disease progression 6

Immediate Post-Treatment Rehabilitation

For patients receiving AHSCT:

• Begin intensive rehabilitation immediately after AHSCT using a phased approach including pre-habilitation, early mobilization, intensive outpatient rehabilitation, and maintenance rehabilitation to exploit neuroplasticity during complete inflammatory suppression 2, 6