Treatment of Inflammatory Myelitis and Optic Neuritis With Early vs Rescue Plasma Exchange (TIMELY-PLEX)

Study Population and Setting The proposal will recruit participants presenting to participating sites with severe ON or severe TM to two separate sub-trials. The detailed inclusion and exclusion criteria for each sub-trial are listed below: Optic Neuritis Sub-Trial: Inclusion criteria: * ≥18 years of age * MRI orbits demonstrating evidence of new T2 hyperintensity and/or post-gadolinium contrast enhancement of the optic nerve(s) and meeting the clinical criteria for Optic Neuritis * Visual acuity 20/200 or worse * Within 14 days of onset of visual symptoms * Able to initiate PLEX within 72h of the first dose of HDCS (if randomized to the "Early PLEX" treatment arm) * Able to sign and date informed consent form * Willingness to comply with all study procedures and availability for the duration of the study Exclusion criteria: * Evidence of prior episode of optic neuritis in the affected eye (by history or ophthalmological evaluation) * Ophthalmological comorbidity that would significantly affect best corrected visual acuity or visual fields * Pregnancy * Presence of any contraindication to receiving HDCS or PLEX, including, but not limited to, hemodynamic instability, significant bleeding/coagulopathy, or sepsis. * Any medical condition that, in the opinion of the investigator, may interfere with the patient's participation in the trial, pose any added risk for the patient, or confound the assessment of the patient (including but not limited to concurrent neurological disease and/or medical comorbidity) * Treatment with any investigational agent within 6 months of baseline or five half-lives of the investigational agent (whichever is longer) * Ongoing/prior treatment with immune-modulating/immunosuppressive therapy including: * Mycophenolate mofetil, azathioprine, methotrexate, fingolimod, siponimod, ponesimod, ozanimod, tocilizumab, satralizumab, eculizumab or ravulizumab within 3 months of randomization * Anti-CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) or anti-CD19 (inebilizumab) therapy within 6 months of randomization * Intravenous or subcutaneous immune globulin within 3 months of randomization * Plasma exchange within 3 months of randomization * Interferon-beta, glatiramer acetate, fumarates (dimethyl fumarate, monomethyl fumarate, diroximel fumarate) within 1 month of randomization * Teriflunomide use within prior 24 months * Systemic corticosteroid therapy (intravenous or oral; excluding inhaled or topical corticosteroids) within 1 month of randomization * Any previous treatment with alemtuzumab, cladribine, mitoxantrone or cyclophosphamide * Previous treatment with any immune-modulating or immunosuppressive therapy not mentioned above within 6 months of randomization or five-half-lives (whichever is longer) Transverse Myelitis Sub-Trial: Inclusion criteria: * ≥18 years of age * Diagnosis of Transverse Myelitis (defined based on modified criteria adapted from the 2002 Transverse Myelitis Consortium Working Group; ALL are required) * Development of sensory, motor and/or autonomic symptomatology attributable to spinal cord dysfunction * Onset of symptoms to nadir \>12 hours * Exclusion of extra-axial compressive etiology by neuroimaging * Demonstration of inflammation within the spinal cord by presence of intramedullary T2 lesion (post-gadolinium enhancing OR non-enhancing) on MRI * Expanded Disability Status Scale \[EDSS\] ≥3.0 (excluding visual and cerebral functional systems) * EDSS Pyramidal Functional System Score ≥ 2 * Within 14 days of onset of motor symptoms * Able to initiate PLEX within 48h of the first dose of HDCS (if randomized to the "Early PLEX" treatment arm) * Able to sign and date informed consent form * Willingness to comply with all study procedures and availability for the duration of the study Exclusion criteria: * Pre-existing ambulatory, motor, sensory, or bowel/bladder disability of any cause that could confound trial assessments * Fulfillment of possible, probable or definite spinal cord infarction diagnosis per proposed diagnostic criteria (Zalewski et al. JAMA Neurology 2018) * History of radiation to the spine * Pregnancy * High clinical suspicion for infectious etiology of myelitis (e.g., fever, rash or other findings) * Presence of any contraindication to receiving HDCS or PLEX, including, but not limited to, hemodynamic instability, significant bleeding/coagulopathy, or sepsis. * Any medical condition that, in the opinion of the investigator, may interfere with the patient's participation in the trial, pose any added risk for the patient, or confound the assessment of the patient (including but not limited to concurrent neurological disease and/or medical comorbidity) * Treatment with any investigational agent within 24 weeks of baseline or five half-lives of the investigational agent (whichever is longer) * Ongoing/prior treatment with immune-modulating/immunosuppressive therapy including: Mycophenolate mofetil, azathioprine, methotrexate, fingolimod, siponimod, ponesimod, ozanimod, tocilizumab, satralizumab, eculizumab or ravulizumab within 3 months of randomization * Anti-CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) or anti-CD19 (inebilizumab) therapy within 6 months of randomization * Intravenous or subcutaneous immune globulin within 3 months of randomization * Plasma exchange within 3 months of randomization * Interferon-beta, glatiramer acetate, fumarates (dimethyl fumarate, monomethyl fumarate, diroximel fumarate) within 1 month of randomization * Teriflunomide use within prior 24 months * Systemic corticosteroid therapy (intravenous or oral; excluding inhaled or topical corticosteroids) within 1 month of randomization * Any previous treatment with alemtuzumab, cladribine, mitoxantrone or cyclophosphamide * Previous treatment with any immune-modulating or immunosuppressive therapy not mentioned above within 6 months of randomization or five-half-lives (whichever is longer)