What treatment approach is recommended for a patient with multiple sclerosis (MS) and recent magnetic resonance imaging (MRI) findings showing four lesions, two on the left side (0.3cm subcortical and 0.6cm periventricular) and two on the right side (0.3cm subcortical and 0.6cm periventricular), with no enhancement with gadolinium (Gad) and a history of migraines?

Treatment Approach for MS with Non-Enhancing Lesions

This patient requires immediate initiation of disease-modifying therapy (DMT) given the clear evidence of radiological disease progression with two new lesions appearing over approximately 2.5 years, despite the absence of gadolinium enhancement. The lack of enhancement does not indicate disease inactivity—it simply means these lesions are not in an acute inflammatory phase at the time of imaging 1.

Key Clinical Interpretation

Understanding Non-Enhancing Lesions

• Non-enhancing lesions on T2-weighted sequences still represent active MS disease, as enhancement occurs primarily during acute inflammatory phases lasting only weeks 1
• The appearance of two new lesions (right-sided 0.3cm subcortical and 0.6cm periventricular) between May 2023 and October 2025 demonstrates ongoing disease activity 1
• In relapsing-remitting MS, only a small percentage of new lesions fail to enhance, and these are invariably small—but they still count as disease progression 1

Prognostic Significance

• The presence of multiple new lesions over time predicts worse long-term disability outcomes, even when asymptomatic 2
• Patients with frequent new lesions (median 11 over 6 months) showed definite EDSS deterioration at 5-year follow-up, while those with minimal activity (median 0 lesions) remained stable 2
• This patient's pattern of bilateral periventricular and subcortical lesions with documented progression fulfills radiological criteria for active MS requiring treatment 1

Recommended Treatment Algorithm

Immediate Actions

1. Initiate disease-modifying therapy without delay 3

   • Glatiramer acetate has demonstrated 34-35% reduction in relapse rates and 35-45% reduction in new/enlarging T2 lesions in clinical trials 3
   • Alternative DMTs (interferons, oral agents, or higher-efficacy therapies) should be considered based on disease severity and patient factors 3

2. Address the migraine history separately 4, 5, 6

   • Migraine occurs more frequently in MS patients than the general population 6
   • Worsening migraine can be an initial MS manifestation, particularly with periaqueductal grey matter involvement 5
   • Unresponsiveness to standard migraine prophylaxis in the presence of active demyelinating lesions should raise suspicion for MS-related headache 4

Monitoring Protocol

Establish a structured MRI surveillance schedule:

• First follow-up MRI at 3-6 months after initiating DMT to assess treatment response 7
• Subsequent MRIs every 6 months for the first 1-2 years given documented disease activity 7
• Use consistent MRI protocols with T2-weighted sequences and gadolinium enhancement to allow accurate comparison 1
• Monthly MRI monitoring may be considered if participating in treatment trials or if disease activity remains high 8

Clinical monitoring requirements:

• Neurological examinations every 3 months with EDSS scoring 1
• Document any new relapses or neurological symptoms immediately 1
• Never rely on MRI findings alone—clinical assessments must parallel imaging 1, 9

Critical Pitfalls to Avoid

Common Errors in Management

1. Delaying treatment due to lack of gadolinium enhancement 1

   • Enhancement indicates acute inflammation but its absence does not exclude active disease
   • New T2 lesions represent disease progression regardless of enhancement status

2. Attributing all symptoms to migraine 4, 5, 6

   • MS can present with worsening migraine symptoms
   • Failure to respond to migraine prophylaxis should prompt MS evaluation
   • Both conditions require separate but coordinated management

3. Inconsistent MRI protocols between scans 1, 7

   • Use identical slice thickness (5mm recommended), matrix (256x256), and sequences 1
   • Maintain same timing post-gadolinium injection (at least 5 minutes) 1
   • Store images for direct comparison by experienced neuroradiologists 1

4. Underestimating the significance of small lesions 1

   • Even 0.3cm lesions represent clinically relevant disease activity
   • Bilateral distribution and periventricular location are characteristic of MS
   • Accumulation of lesions over time predicts disability progression 2

Treatment Expectations

Short-Term Goals (6-12 months)

• Reduction in new lesion formation by 35-45% with effective DMT 3
• Stabilization of existing lesions without enlargement 3
• Prevention of clinical relapses with 34% relative risk reduction 3

Long-Term Monitoring (Beyond 1 year)

• Transition to annual MRI if disease remains stable on treatment 7
• Continue clinical assessments every 6 months minimum 1
• Adjust treatment intensity if breakthrough disease activity occurs (new lesions, relapses, or progression) 3