Key Facts

MS is a chronic immune-mediated demyelinating disease of the CNS. Early diagnosis and initiation of disease-modifying therapy can significantly reduce relapse rate and delay disability accumulation. The approach to MS has been revolutionised by highly effective DMTs.

Epidemiology

UK prevalence ~130 per 100,000 (~130,000 people affected). Incidence ~7 per 100,000 per year. F:M 3:1. Mean age of onset 20-40 years. Higher prevalence with increasing distance from the equator (vitamin D hypothesis). Scotland has one of the highest prevalences globally. Genetic susceptibility: HLA-DRB1*15:01; concordance in monozygotic twins ~25-30%.

Aetiology

Multifactorial: genetic susceptibility (HLA-DRB1*15:01) + environmental triggers including EBV infection (virtually 100% of MS patients are EBV seropositive), low vitamin D, smoking, adolescent obesity. EBV is increasingly considered a necessary (but not sufficient) cause of MS.

Pathophysiology

Autoimmune-mediated inflammation targets CNS myelin and oligodendrocytes. Autoreactive T cells (CD4+ Th1/Th17 and CD8+) cross the blood-brain barrier → release pro-inflammatory cytokines → recruit macrophages/microglia → demyelination. B cells play a critical role (basis for anti-CD20 therapies). Early disease: focal inflammation and demyelination (plaques) with potential for remyelination (relapsing-remitting course). Progressive disease: diffuse neurodegeneration, axonal loss, brain atrophy, compartmentalised inflammation. Lesion distribution: periventricular white matter, optic nerves, brainstem, cerebellum, spinal cord.

Common Presentations

• Optic neuritis: unilateral painful visual loss (pain on eye movement); relative afferent pupillary defect (RAPD); colour desaturation; 50% of ON patients develop MS
• Transverse myelitis: sensory level, limb weakness/spasticity, bladder dysfunction; Lhermitte sign (electric shock down spine on neck flexion)
• Brainstem/cerebellar: diplopia (INO — internuclear ophthalmoplegia), vertigo, ataxia, nystagmus, trigeminal neuralgia (young patient)
• Sensory: paraesthesiae, numbness, band-like sensations
• Motor: spasticity, weakness, fatigue

MS Subtypes

• RRMS (85%): episodes of neurological dysfunction (relapses) followed by partial/complete recovery; relapses last days-weeks
• SPMS: follows RRMS; progressive disability accumulation ± superimposed relapses
• PPMS (10-15%): progressive disability from onset without distinct relapses; older onset, equal sex ratio, spinal cord predominant

Red Flags

• Rapidly progressive course (consider NMO, ADEM, CNS lymphoma)
• Bilateral optic neuritis simultaneously (NMO rather than MS)
• Longitudinally extensive transverse myelitis (≥3 segments — NMO)
• Peripheral nervous system involvement (NOT MS — consider NMO, CIDP)

MRI

• MRI brain + spine with gadolinium: essential; demonstrates DIS and DIT
  • T2/FLAIR: hyperintense white matter lesions in periventricular (Dawson fingers), juxtacortical, infratentorial, and spinal cord locations
  • Gadolinium enhancement: active (new) lesions enhance for ~4-6 weeks
  • DIS: ≥1 T2 lesion in ≥2 of 4 typical areas
  • DIT: simultaneous enhancing and non-enhancing lesions on single scan, OR new T2/enhancing lesion on follow-up MRI

CSF

• Lumbar puncture: oligoclonal bands (OCBs) in CSF but not matched in serum — present in >95% of MS; can substitute for DIT in McDonald criteria
• Mildly raised lymphocytes, raised IgG index

Bloods

• AQP4 and MOG antibodies: exclude NMOSD/MOGAD
• B12, folate: exclude deficiency
• HIV, syphilis serology: exclude mimics
• ANA, dsDNA, ACE: exclude SLE, sarcoidosis
• NMO-IgG (AQP4-Ab): essential to exclude NMO

Other

• Visual evoked potentials (VEPs): delayed P100 latency in optic neuritis (even subclinical)
• OCT (optical coherence tomography): retinal nerve fibre layer thinning — marker of axonal loss

Acute Relapse

• IV methylprednisolone 1 g daily × 3-5 days (oral methylprednisolone 500 mg daily × 5 days if IV not possible)
• Shortens relapse duration but does NOT affect long-term disability
• Plasma exchange for severe relapses refractory to steroids

Disease-Modifying Therapies (NICE NG220)

RRMS — Moderate efficacy (first-line):

• Dimethyl fumarate 240 mg BD (DEFINE/CONFIRM trials); side effects: flushing, GI, lymphopenia (PML risk if prolonged lymphopenia)
• Teriflunomide 14 mg OD (TEMSO trial); teratogenic — Pregnancy Prevention Programme
• Interferon-β (Avonex, Rebif, Betaferon); flu-like symptoms, injection site reactions
• Glatiramer acetate 20 mg daily or 40 mg TIW SC

RRMS — High efficacy (escalation or first-line for active disease):

• Natalizumab 300 mg IV monthly (AFFIRM trial); anti-α4-integrin; risk of PML (JC virus — check JCV antibody index; PML risk ~1 in 250 if JCV+ >2 years)
• Ocrelizumab 600 mg IV 6-monthly (OPERA I/II trials); anti-CD20; also licensed for PPMS (ORATORIO trial)
• Alemtuzumab IV (CARE-MS I/II); anti-CD52; highly effective but risk of secondary autoimmunity (thyroid 30%, ITP 1-2%, Goodpasture — requires 4-year monitoring)
• Cladribine 3.5 mg/kg total over 2 years (CLARITY trial)
• Ofatumumab 20 mg SC monthly (ASCLEPIOS trials); anti-CD20

PPMS:

• Ocrelizumab (ORATORIO trial) — only DMT with evidence in PPMS; reduces disability progression

SPMS:

• Siponimod 2 mg OD (EXPAND trial) — for active SPMS

Symptom Management

• Spasticity: baclofen 5-100 mg/day, gabapentin, tizanidine, Sativex (nabiximols — NICE)
• Fatigue: amantadine 100 mg BD, CBT, exercise
• Neuropathic pain: amitriptyline 10-75 mg ON, gabapentin 300-3600 mg/day, pregabalin
• Bladder: intermittent self-catheterisation, oxybutynin 2.5-5 mg BD-TDS, mirabegron
• Depression: SSRIs

Referral Criteria

• All suspected MS: neurology (seen within 6 weeks — NICE NG220)
• DMT initiation and monitoring by MS specialist
• MDT: MS nurse, physiotherapy, occupational therapy, continence, psychology

Highly variable. RRMS: ~50% convert to SPMS within 15-20 years (less with modern DMTs). Life expectancy reduced by ~7-10 years. PPMS has worse prognosis (progressive from onset). Poor prognostic factors: male sex, older onset, motor/cerebellar presentation, incomplete relapse recovery, high lesion load, brain atrophy. Good prognosis: young onset, sensory/optic neuritis presentation, female, low lesion load. Modern DMTs have significantly improved outcomes — early high-efficacy treatment may change the natural history.

McDonald Criteria 2017 (Simplified)

MS Subtypes Comparison