What is the best approach for a 19-year-old male patient with a history of Relapsing-Remitting Multiple Sclerosis (RRMS) on Dimethylfumarate (Dimethyl fumarate) for 3 years, presenting with new complaints of pain and discomfort in the right hand, and a new small non-enhancing T2 lesion on MRI brain?

Management Approach for RRMS Patient with New Non-Enhancing Lesion on Dimethyl Fumarate

This patient requires escalation to a high-efficacy disease-modifying therapy immediately, as the new T2 lesion represents treatment failure on dimethyl fumarate despite 3 years of therapy. 1

Critical Assessment of Current Disease Activity

The presence of a new T2 lesion, even without gadolinium enhancement, definitively indicates ongoing MS disease activity and treatment failure. 2 The lack of enhancement does not diminish the significance of this finding—non-enhancing lesions still represent active MS disease, as enhancement occurs only during acute inflammatory phases lasting weeks, and small new lesions frequently fail to enhance but still count as disease progression. 2

Key Clinical Considerations:

• The right hand pain with prolonged writing for 7 days may represent a subtle clinical relapse correlating with the new MRI lesion, even though the patient remains "functionally preserved" 3
• New or enlarging T2 lesions on MRI while on treatment meet criteria for breakthrough disease activity requiring treatment escalation 1
• The 3-year duration on dimethyl fumarate with documented radiographic progression indicates this moderate-efficacy DMT is insufficient for this patient's disease activity 4, 5

Immediate Management Algorithm

Step 1: Confirm Disease Activity with Gadolinium-Enhanced MRI

Repeat the brain MRI with gadolinium enhancement immediately to determine if the new lesion shows active inflammation. 6 This is critical because:

• Enhancement occurs in almost all new lesions during serial scans of RRMS patients 6
• Gadolinium enhancement increases conspicuousness of small new lesions and confirms their sometimes equivocal appearance on T2-weighted scans 6
• The timing matters—scanning should start at least 5 minutes after gadolinium injection, as most lesions display maximum enhancement 5-30 minutes post-injection 6

Step 2: Escalate to High-Efficacy Disease-Modifying Therapy

Switch immediately to a high-efficacy DMT (natalizumab, ocrelizumab, alemtuzumab, or cladribine) rather than continuing dimethyl fumarate or switching to another moderate-efficacy agent. 1 The rationale:

• High-efficacy agents should be considered for patients who have failed standard or high-efficacy DMT for ≥6 months 7
• This patient has been on dimethyl fumarate for 3 years with documented breakthrough disease 1
• Delaying escalation risks irreversible disability accumulation 1

Preferred high-efficacy options in order of consideration:

1. Ocrelizumab - approved for RRMS with proven efficacy and favorable safety profile 7
2. Natalizumab - particularly if JC virus antibody-negative, as escalation therapy for breakthrough disease 7
3. Alemtuzumab - lymphocyte-depleting monoclonal antibody for highly active MS 1, 7

Step 3: Pre-Treatment Screening Before DMT Switch

Complete the following baseline assessments before initiating high-efficacy DMT: 1

• Brain and spinal cord MRI with T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences
• JC virus antibody testing (critical if considering natalizumab) 1
• Complete blood count, liver function tests
• Viral profiles (hepatitis B/C, HIV, varicella zoster)
• Cognitive baseline using Symbol Digit Modalities Test (SDMT) 1

Ongoing Monitoring Protocol

MRI Surveillance Schedule:

• Every 3-6 months for the first year after switching to high-efficacy DMT to assess treatment response 2, 1
• Every 6 months during the second year given documented disease activity 2
• Annually thereafter if disease remains stable on the new treatment 1
• Use consistent MRI protocols with the same scanner, T2-weighted sequences, and gadolinium enhancement to allow accurate comparison 6

Clinical Monitoring:

• Clinical assessments every 6 months minimum measuring disability and recording relapses 1
• Cognitive assessment every 6 months using validated tools 1
• Do not rely on imaging alone—parallel clinical assessments are essential 1

Critical Pitfalls to Avoid

• Do not delay treatment escalation due to lack of gadolinium enhancement on the initial scan—non-enhancing lesions still represent disease progression 2
• Do not continue dimethyl fumarate hoping for stabilization—this represents clear treatment failure requiring immediate escalation 1
• Do not underestimate the significance of small lesions—they invariably indicate ongoing disease activity 2
• Do not use inconsistent MRI protocols between follow-up scans, as this makes accurate comparison impossible 6, 1
• Do not unnecessarily prolong DMT withdrawal during the transition, as this increases relapse risk 1

Addressing the Right Hand Symptoms

The right hand pain and discomfort with prolonged writing likely represents a subtle clinical manifestation of the new lesion rather than a separate issue. 3 This symptom pattern—developing over 7 days with new MRI findings—is consistent with an MS relapse, even without overt functional impairment. 3, 8

• Consider a short course of high-dose corticosteroids (methylprednisolone 1000 mg IV daily for 3-5 days) if symptoms are bothersome or progressing 8
• Implement physical and occupational therapy immediately to address hand function and prevent secondary complications 1
• Monitor closely for symptom progression that would indicate a more significant relapse requiring aggressive treatment 3

If High-Efficacy DMT Also Fails

If new clinical relapses or new/enlarging T2 lesions occur despite high-efficacy DMT treatment, consider autologous hematopoietic stem cell transplantation (AHSCT) for aggressive relapsing-remitting MS refractory to high-efficacy disease-modifying therapies. 1, 7