NeurologyTier 1Disease (DEADMAN)

Multiple sclerosis

Description

Immune-mediated demyelination + axonal loss of the CNS, disseminated in space and time
Peripheral nervous system is never involved - that is a defining negative

Phenotypes

	%	Features
RRMS	~85% at onset	Discrete relapses with full or partial recovery; no progression between
SPMS	Most RRMS eventually	Progressive disability accrual after an initial relapsing course, +/- superimposed relapses
PPMS	10-15%	Progressive from onset; older (~40s), M=F, spinal cord predominant

Each classified as active/not active (relapse or new/enhancing MRI lesion) and progressing/not progressing - this drives PBS eligibility, not just description
CIS - a first demyelinating episode not yet meeting criteria
RIS - incidental MRI lesions, no clinical event; ~1/3 develop clinical MS within 5 years
PIRA (progression independent of relapse activity) - disability accrues without relapses even in "RRMS"; the reason relapse-free is not disease-free

Common presentations

Optic neuritis - subacute monocular loss, pain on eye movement, colour desaturation, RAPD, normal disc in 2/3 (retrobulbar)
Transverse myelitis - partial, sensory level, bladder involvement; MS cord lesions are short, <2 vertebral segments, dorsolateral
Brainstem - INO (bilateral INO in a young person = MS), diplopia, vertigo, trigeminal neuralgia
Cerebellar - ataxia, intention tremor, scanning speech
The classic triad of cerebellar + pyramidal + dorsal column signs in one patient
Lhermitte sign - electric shock down the spine on neck flexion (dorsal column)
Uhthoff phenomenon - transient worsening with heat/exercise. This is a pseudorelapse, not a relapse

Epidemiology

~33,000 Australians; prevalence ~130/100,000 and rising
Strong latitude gradient - Tasmania roughly 3x Queensland
F>M ~3:1 (and the ratio is increasing); onset 20-40
PPMS: older onset (~40s), M=F
Second commonest cause of neurological disability in young adults after trauma

Aetiopathogenesis

Risk factors - the exam list

EBV infection is close to necessary - MS is essentially absent in EBV-seronegative people; seroconversion raises risk ~32-fold
Low vitamin D / low UV exposure - explains the latitude gradient
Smoking - risk and faster progression
Adolescent obesity
*HLA-DRB1\15:01** - the strongest genetic risk allele; >200 other loci of small effect
Sibling risk ~2-5%, monozygotic twin ~25-30% - polygenic, not Mendelian
Adult female sex

Mechanism

Autoreactive CD4 Th1/Th17 cells cross the blood-brain barrier -> perivenular inflammatory plaques with macrophages, CD8 T cells and B cells
B cell role explains why anti-CD20 therapies work so well - antigen presentation and cytokine production, not just antibody
Plaques: periventricular, juxtacortical, infratentorial, spinal cord, optic nerve; demyelination -> conduction block/slowing
Remyelination is incomplete -> axonal transection accumulates -> progressive phase
Compartmentalised inflammation behind an intact blood-brain barrier (meningeal follicles, microglia) drives progression - which is why peripherally acting drugs work less well in SPMS/PPMS

Diagnosis

Two attacks + two lesions = clinical diagnosis. Otherwise use MRI/CSF to fill the gaps
A relapse = new/worsening neurological symptoms lasting >24 h, >=30 days from the last, in the absence of fever or infection

McDonald criteria - 2024 revisions (current)

Dissemination in space - >=1 T2 lesion in >=2 of five locations:
- Periventricular (Dawson's fingers, perpendicular to the ventricles) | Juxtacortical/cortical | Infratentorial | Spinal cord | Optic nerve
- *The optic nerve is new - it is now a fifth topography*
Dissemination in time - a new lesion on follow-up MRI, OR simultaneous enhancing and non-enhancing lesions, OR a CSF surrogate
CSF: oligoclonal bands OR kappa free light chains can substitute for dissemination in time
- *Kappa FLC is new and equivalent in sensitivity/specificity to OCB* - cheaper, automated, less operator-dependent
Central vein sign and paramagnetic rim lesions on susceptibility-weighted MRI now add specificity where diagnostic certainty is low
Net effect: earlier diagnosis, a single unified framework across relapsing and progressive courses and all ages, and diagnosis possible in selected RIS
PPMS: 1 year of progression + 2 of (>=1 periventricular/juxtacortical/infratentorial T2 lesion; >=2 cord lesions; positive CSF)

Investigations

MRI brain and whole spine, with gadolinium - T2/FLAIR hyperintense lesions; enhancing = active within ~4-6 weeks
CSF - OCB (present in >85-95%, unmatched in serum) or kappa FLC; mild lymphocytosis (<50); cells >50 or protein >1 g/L argues against MS
Visual evoked potentials - delayed P100 with preserved amplitude; reveals a clinically silent optic nerve lesion
OCT - retinal nerve fibre layer thinning
Always exclude the mimics before committing to lifelong therapy:
- AQP4 (NMOSD) and MOG antibodies - mandatory in optic neuritis (especially bilateral or severe), longitudinally extensive myelitis, area postrema syndrome
- B12, TSH, ANA/ENA, ACE (neurosarcoid), ESR/CRP, HIV, syphilis, HTLV-1, Lyme serology, anti-phospholipid
- Consider CADASIL, Susac syndrome, vasculitis, ADEM, small vessel disease, Behcet, Whipple

MS vs NMOSD vs MOGAD - the key discrimination

	MS	NMOSD (AQP4)	MOGAD
Optic neuritis	Unilateral, mild-moderate	Severe, often bilateral, posterior/chiasmal	Bilateral, anterior with disc oedema, very steroid-responsive
Myelitis	Short (<2 segments), dorsolateral	Longitudinally extensive (>=3 segments), central	Longitudinally extensive, conus
Other	Brainstem, cerebral	Area postrema (intractable hiccups/vomiting)	ADEM-like, cortical encephalitis, seizures
OCB	Present >85%	Usually absent	Usually absent
Treatment	MS DMTs	MS DMTs make it WORSE - use rituximab/eculizumab/satralizumab/inebilizumab	Steroid, IVIg, tocilizumab, rituximab

*Giving interferon, fingolimod or natalizumab to NMOSD causes severe relapses - test the antibodies first*

Management

A. Acute relapse

Confirm it is a relapse, not a pseudorelapse - exclude infection (urine and chest first), fever, heat, metabolic upset
Only treat if functionally disabling - mild sensory relapses need no steroid
IV methylprednisolone 1 g daily for 3-5 days (high-dose oral methylprednisolone is equivalent and appropriate)
- Speeds recovery; does not change the final degree of recovery or long-term disability**
Plasma exchange if severe and steroid-refractory - start within days
Rehabilitation input from the outset

B. Disease-modifying therapy - the central decision

Start early. The current standard is early high-efficacy therapy, not the old escalation ladder starting with injectables
- The window of maximal inflammatory activity is the first few years; disability prevented is disability never accrued
Choose by disease activity, patient factors (pregnancy plans, JCV status, comorbidity, monitoring burden) and PBS criteria

Tier	Agents	Key issues
High efficacy	Ocrelizumab, ofatumumab (anti-CD20); natalizumab; alemtuzumab; cladribine	See toxicity below
Moderate	S1P modulators - fingolimod, siponimod, ozanimod, ponesimod; dimethyl fumarate	Oral, convenient
Lower	Interferon beta, glatiramer acetate, teriflunomide	Safest in pregnancy planning; now rarely first choice

PPMS: ocrelizumab is the only agent with proven benefit - most effect in younger patients with active inflammatory (enhancing) lesions
SPMS: siponimod for active SPMS; tolebrutinib (BTK inhibitor) approved in the EU for non-relapsing SPMS - rejected by the FDA over hepatotoxicity, and not available in Australia. Know it as the first agent aimed at progression without relapses

### Toxicity and monitoring - the examinable part

Drug	Watch for
Natalizumab	PML - highest risk of any DMT. Stratify by JCV antibody index, duration >2 yr, prior immunosuppression. Check JCV serology 6-monthly. Rebound disease on cessation
Fingolimod / S1P modulators	First-dose bradycardia and heart block (observe 6 h), macular oedema, lymphopenia, VZV - check immunity and vaccinate first, hepatotoxicity, PML (rare), rebound on stopping
Dimethyl fumarate	Lymphopenia -> PML, flushing, GI upset
Ocrelizumab / ofatumumab	Infusion reactions, hypogammaglobulinaemia, infection, screen HBV (reactivation), delayed neutropenia; blunted vaccine response - vaccinate before starting
Alemtuzumab	Secondary autoimmunity - thyroid ~40%, ITP, anti-GBM disease. Monthly FBE, UEC and urinalysis + thyroid function for 4 years after the last dose. Listeria, infusion reactions, stroke/dissection
Cladribine	Lymphopenia, herpes zoster, malignancy signal; short courses in years 1 and 2
Teriflunomide	Hepatotoxicity, alopecia, teratogenic - long half-life, needs cholestyramine washout

### Pregnancy

*Contraindicated before/during pregnancy: teriflunomide (accelerated elimination required), fingolimod and other S1P modulators, cladribine (contraception for 6 months after a course)*
Relapse rate falls in the third trimester and rises in the first 3-6 months postpartum
Glatiramer and interferon beta may be continued; anti-CD20 given before conception gives cover through pregnancy; natalizumab continued in highly active disease with a plan for the third trimester
Breastfeeding is not contraindicated and may be protective; vitamin D supplementation throughout

C. Symptomatic management - where quality of life is won

Problem	Treatment
Spasticity	Physiotherapy + stretching, baclofen, tizanidine, botulinum toxin, intrathecal baclofen; treat the trigger - infection, constipation, pressure area
Fatigue (the commonest symptom)	Exercise, sleep and mood optimisation, energy conservation; amantadine, modafinil
Bladder	Post-void residual first. Antimuscarinic/mirabegron for storage; intermittent self-catheterisation for retention; botulinum toxin
Walking	Fampridine (4-aminopyridine) in selected responders; lowers seizure threshold
Neuropathic pain / trigeminal neuralgia	Carbamazepine, amitriptyline, duloxetine, pregabalin, gabapentin
Tremor / ataxia	Poorly responsive; OT, weighting, rarely thalamic DBS
Depression, cognition	Screen actively; SSRI, neuropsychology
Sexual dysfunction, bowel, pressure care	Address explicitly - patients rarely raise these

D. General

Vitamin D supplementation, smoking cessation, exercise, weight and vascular risk management - all modify progression
Vaccinate BEFORE starting immunotherapy (live vaccines contraindicated afterwards); annual influenza, COVID, pneumococcal, VZV
MS nurse specialist, MS Australia, employment and driving advice
Monitor with annual MRI and clinical review - target NEDA (no relapses, no MRI activity, no disability progression); serum neurofilament light is emerging as a monitoring biomarker

Associations

Other autoimmune disease - thyroid disease, type 1 diabetes, coeliac disease, IBD, psoriasis, uveitis
*HLA-DRB1\15:01**; family history
EBV seropositivity (essentially universal), low vitamin D, smoking, adolescent obesity
Trigeminal neuralgia - TN in 2-5% of MS; MS in 2-4% of TN. Bilateral or young-onset TN = MS until excluded
Depression (~50% lifetime) and suicide risk above the general population
Osteoporosis - immobility + steroids
NMOSD and MOGAD - not MS, but the differential that must always be excluded
Cognitive impairment - information processing speed, present early and under-recognised

Natural history & complications

Highly variable. RRMS -> SPMS in a substantial proportion, though modern DMTs appear to delay this
PIRA is the dominant driver of long-term disability - relapse suppression alone does not stop progression
Median time to needing a walking aid (EDSS 6) historically ~20-25 years; substantially longer in the treated era
Life expectancy reduced by ~5-10 years; most deaths from complications (infection, aspiration, immobility) rather than MS itself

Predictors of a worse course

Male sex, older age at onset, multifocal onset
Onset with motor, cerebellar, brainstem or bladder symptoms (better: isolated sensory or optic neuritis)
>=2 gadolinium-enhancing lesions, or >9 T2 lesions at baseline; spinal cord and infratentorial lesions
High burden of multimodal evoked potential abnormality; thin peripapillary retinal nerve fibre layer on OCT
High early relapse rate, incomplete recovery from the first relapse, short interval to the second
Smoking, low vitamin D, obesity, comorbid vascular disease
Progressive course from onset (PPMS)

Complications

Spasticity and contracture, pressure injury
Neurogenic bladder -> recurrent UTI, hydronephrosis
Aspiration pneumonia, falls, osteoporotic fracture
Cognitive impairment and unemployment (most people with MS leave the workforce far earlier than the disability alone suggests)
Depression, carer strain

Monitor

Annual neurological review + MRI; relapse count; EDSS
DMT-specific monitoring as above; JCV serology; vaccination status
Bladder residuals, bone density, mood, cognition, vitamin D

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