Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS

Objective: Intrathecal Immunoglobulin M synthesis (IgM _{Intrathecal Fraction (IF)} ⁺) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgM _IF ⁺ is associated with spinal cord manifestation and higher neuroaxonal damage in early MS. Methods: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgG _IF ⁺ (vs IgG _IF ⁻) or IgM _IF ⁺ (vs IgM _IF ⁻) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgG _IF and IgM _IF (>0% vs 0%, respectively): (1) OCGB ⁻/IgG _IF ⁻/IgM _IF ⁻; (2) OCGB ⁺/IgG _IF ⁻/IgM _IF ⁻; (3) OCGB ⁺/IgG _IF ⁺/IgM _IF ⁻; and (4) OCGB ⁺/IgG _IF ⁺/IgM _IF ⁺. Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters. Results: Patients with a spinal syndrome had a 8.36-fold higher odds of IgM _IF ⁺ (95%CI 3.03–23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02–1.90; p = 0.037) and CE lesion (OR 2.73; 1.22–6.09; p = 0.014) was associated with an increased risk of IgM _IF ⁺ (but not of IgG _IF ⁺); this was not the case for cerebral lesions. OCGB ⁺/IgG _IF ⁺/IgM _IF ⁺ category patients showed highest sNfL levels (estimate:1.80; 0.55–3.06; p < 0.01). Interpretation: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022.