MS-001
Multiple Sclerosis · Myelin-Oligodendrocyte Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · NEURO ← RESEARCH
Myelin sheath segments
Oligodendrocyte processes
T-cell (CD4+ Th17) attack
Demyelinated lesion plaque
γ₁ floor anchor
PHASES
RX
BIOMARKERS
EEG
NPs
Core Mechanism PROVEN
Autoimmune — T + B Cells Attack Myelin
CD4+ Th17 T-cells are primary driver. CD8+ T-cells also active in lesions. B-cells contribute — this is why anti-CD20 (ocrelizumab) works so well. Attack targets myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP).
Friese et al. 2014 Nat Rev Neurosci (immunopathology) · McFarland & Martin 2007
Oligodendrocyte — 1 cell, 50 axons
One oligodendrocyte myelinates up to 50 axon segments. Each myelinated segment flanked by Nodes of Ranvier for saltatory conduction. CNS oligodendrocytes cannot remyelinate efficiently (unlike PNS Schwann cells). This is why MS lesions accumulate.
Franklin & ffrench-Constant 2008 Nat Rev Neurosci
RRMS → SPMS Disease Course
RRMS: 85% of onset. Discrete relapse + remission. McDonald criteria: MRI dissemination in space + time. SPMS: gradual progression after RRMS (50% in 10yr, 90% in 25yr). PPMS: 15% at onset, progressive from start, Ocrelizumab = only approved treatment (2017).
Polman et al. 2011 Ann Neurol (revised McDonald criteria)
Lhermitte's Sign + Uhthoff's Phenomenon
Lhermitte's: electric shock down spine on neck flexion = cervical demyelination. Uhthoff's: symptom worsening with heat/fever = conduction block in demyelinated axon worsens at higher temperature. Both pathognomonic for CNS demyelination.
Clinical signs specific to demyelination — established decades
High-Efficacy DMTs PROVEN
Ocrelizumab (Ocrevus) — Anti-CD20 FDA 2017
B-cell depleter. PROVEN for both RRMS AND PPMS. First approved PPMS treatment ever. RRMS: 46% reduction in relapse rate vs interferon (OPERA I+II). PPMS: slows confirmed disability progression. 6-monthly infusion.
Hauser et al. 2017 NEJM (OPERA I+II) · Montalban et al. 2017 NEJM (ORATORIO for PPMS)
Natalizumab (Tysabri) PROVEN
Anti-α4-integrin. Blocks T-cell entry to CNS through BBB. 68% relapse reduction. PML risk: JC virus reactivation. Annual JCV antibody monitoring required. Hold if JCV Ab titre rises.
Polman et al. 2006 NEJM (AFFIRM trial)
Alemtuzumab (Lemtrada) PROVEN
Anti-CD52. Depletes most lymphocytes. Annual short-course infusion. 49% reduction vs interferon. High efficacy with significant secondary autoimmunity risk (thyroid, ITP, nephropathy). Used for highly active RRMS.
Cohen et al. 2012 Lancet (CARE-MS II)
Moderate-Efficacy
Interferons + Glatiramer Acetate
First-generation. ~30% relapse reduction. Well-tolerated, long track record. Injectable. Now often replaced by higher-efficacy oral/infusion options for active disease. Still used for mild/moderate RRMS.
IFNB-1b Study Group 1993 · Johnson et al. 1995 (GA)
Cladribine (Mavenclad) PROVEN
Oral purine analogue. Selective lymphocyte depletion. 2 short annual courses over 2 years. ~60% relapse reduction. Long lymphocyte recovery — avoid in pregnancy.
Giovannoni et al. 2010 NEJM (CLARITY trial)
Open Pipeline
Remyelination Therapy FAILED TRIALS
Opicinumab (anti-LINGO-1), bexarotene, clemastine — all failed Phase 2/3. Remyelination works in mouse models. Human translation has failed so far. SORRY: PPMS treatment still limited to ocrelizumab with modest benefit.
SORRY: progressive MS neurodegeneration independent of inflammation not yet targetable
Established Biomarkers
MRI T2 FLAIR PROVENWhite matter lesions. Periventricular (Dawson's fingers = perpendicular to ventricles), juxtacortical, infratentorial, spinal cord. McDonald criteria require DIS (3+ regions) + DIT (active + inactive). Gold standard.
Gd-enhancing PROVENGadolinium-enhancing lesions = active BBB breakdown = acute inflammation. Confirms DIT when combined with non-enhancing. Reflects current disease activity.
CSF OCBs PROVENOligoclonal bands. IgG synthesised intrathecally. 95% sensitivity for MS. Not specific (also positive in CNS infections, neurosarcoid). Fulfils McDonald DIT criterion.
VEP latency PROVENVisual evoked potential latency increase = optic nerve demyelination. Most common MS first symptom (optic neuritis). McDonald criterion for DIS. Can detect subclinical lesions.
serum NfLMonitors treatment response. Drops with effective DMT. Tracks neurodegeneration. Research use, increasingly clinical. Kappos et al. 2019
Open Sorries
SORRY-1: PPMS treatment limited — only ocrelizumab, modest 25% slowing of confirmed disability. Most progression still occurs.
SORRY-2: Remyelination therapy has failed in every trial. Mouse → human translation failed.
SORRY-3: Progressive MS mechanism (neurodegeneration independent of inflammation?) poorly understood. DMTs that work for RRMS barely touch SPMS/PPMS.
Evoked Potentials in MS
VEP latency ↑ PROVENVisual evoked potential. P100 latency increase = optic nerve demyelination. MS first symptom most commonly. McDonald DIS criterion. Cheap and accessible.
SSEP delaySomatosensory evoked potential. Central conduction delay. Spinal cord/brainstem lesions. Supplements MRI for subclinical lesions.
MEP delayMotor evoked potential (TMS). Corticospinal tract demyelination. Central motor conduction time increase. Pyramidal symptoms correlate.
Routine EEGNon-specific in MS. Not used for diagnosis. May show focal slowing over cortical lesions. Epilepsy evaluation if seizures occur (3% MS).
Novel Patterns (8)
PROVENNP-MS-001 · Oligodendrocyte serves 50 axons — one cell death = 50 demyelinated segments · CNS cannot remyelinate efficiently unlike PNS
PROVENNP-MS-002 · Ocrelizumab: first drug proven for PPMS (2017) — changed landscape of progressive MS management · anti-CD20 B-cell mechanism unexpected
PROVENNP-MS-003 · VEP latency increase: subclinical optic neuritis detectable before visual symptoms — DIS criterion fulfilled silently
PROVENNP-MS-004 · Uhthoff's phenomenon: heat blocks conduction in demyelinated axon · explains exercise-induced temporary worsening · not relapse
PROVENNP-MS-005 · OCBs 95% sensitive for MS — IgG made inside CNS, not in blood · intrathecal synthesis confirms CNS inflammation
OPENNP-MS-006 · Serum NfL as treatment response monitor — drops within weeks of effective DMT · could enable personalised dosing
OPENNP-MS-007 · Progressive MS neurodegeneration: independent of acute inflammation? PPMS has fewer visible lesions than RRMS but more disability · mechanism gap
SORRYNP-MS-008 · Remyelination therapy failed in every trial · PPMS still largely untreatable · progressive mechanism unknown · mouse models don't translate
⚠ OPEN SORRIES · MS-001
SORRY-1 · PPMS treatment gap
Ocrelizumab is the only approved treatment for PPMS, with a modest 25% slowing of confirmed disability progression. Most PPMS patients continue to accumulate disability despite treatment. The therapeutic gap is still enormous.

SORRY-2 · Remyelination failure
Opicinumab (anti-LINGO-1), bexarotene, clemastine — all failed in Phase 2/3. The remyelination hypothesis is well-supported in mice. Human clinical translation has been a consistent failure.

SORRY-3 · Progressive MS mechanism
PPMS and SPMS show neurodegeneration that appears partly independent of the acute inflammatory attacks visible on MRI. The mechanism — whether smouldering inflammation, mitochondrial failure, or axonal transection — is not well understood and not yet targetable.
MS-001 · AUTOIMMUNE MYELIN ATTACK · OCRELIZUMAB FIRST PPMS TREATMENT · REMYELINATION STILL UNSOLVED
γ₁ = 14.134725141734693