Overview & Epidemiology

1. What is Multiple Sclerosis?

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system characterised by focal inflammatory demyelination, axonal injury and progressive neurodegeneration, expressed clinically as relapses and/or progressive accumulation of disability over decades.

• Multiple — multifocal lesions, dissemination «in space» (DIS).
• Sclerosis — the firm, glial-scar texture of the chronic plaque.
• In time — the disease relapses, remits and accrues; dissemination «in time» (DIT) is the second pillar of diagnosis.

Pathology is dominated by the classical MS plaque: a perivenular, demyelinated focus with breakdown of the blood-brain barrier, lymphocytic infiltration (T cells, B cells, macrophages), oligodendrocyte loss and reactive astrogliosis. Lesions show a strong predilection for periventricular and juxtacortical white matter, the corpus callosum, brainstem, cerebellum and spinal cord. Cortical and deep grey-matter lesions, long under-recognised, are now established correlates of cognitive decline and progression.

2. A Brief History — from Charcot to EBV

• ~1838 — Robert Carswell and Jean Cruveilhier publish the first pathological illustrations of demyelinated plaques.
• 1868 — Jean-Martin Charcot, at the Salpêtrière, gives the first systematic clinico-pathological description and names the disease «la sclérose en plaques disséminées». He defines the «Charcot triad» (nystagmus, intention tremor, scanning speech).
• 1916 — James Dawson describes «Dawson’s fingers» — perivenular demyelination radiating from the lateral ventricles.
• 1933 — Thomas Rivers produces experimental autoimmune encephalomyelitis (EAE) by repeated immunisation of monkeys with brain extract — the founding animal model of CNS autoimmunity.
• 1948 — Elvin Kabat shows oligoclonal IgG in MS CSF; intrathecal immunoglobulin synthesis becomes a hallmark.
• 1965 — Schumacher criteria — the first formal clinical diagnostic criteria.
• 1972 — Jersild describes HLA association (later refined to HLA-DR2/DRB1*15:01).
• 1981 — Ian Young uses MRI to image MS plaques in vivo — the diagnostic revolution begins.
• 1983 — Poser criteria formalise CSF + evoked-potential support for diagnosis.
• 1993 — Interferon-β-1b approved (the IFNB Multiple Sclerosis Study Group, Neurology) — the first DMT.
• 1996 — Glatiramer acetate (Copaxone) approved; the «ABC» injectables (Avonex, Betaseron, Copaxone) define the platform era.
• 2001 — First McDonald criteria integrate MRI into diagnosis (revised 2005, 2010, 2017).
• 2004 — Natalizumab approved — first monoclonal in MS; later linked to PML.
• 2010 — Fingolimod approved — the first oral DMT (S1P modulator).
• 2017 — Ocrelizumab approved — the first DMT to slow primary progressive MS (ORATORIO).
• 2022 — Bjornevik et al. (Science): in 10 million US military recruits, EBV seroconversion is associated with a 32-fold increase in MS risk — the strongest causal evidence to date.
• 2024 — Tolebrutinib BTK-inhibitor phase III readouts in progressive disease; CAR-T B-cell depletion enters early MS trials.

3. Global Epidemiology

The global MS map is published every five years by the Multiple Sclerosis International Federation (MSIF) as the Atlas of MS. The third edition (2020, Walton et al., Mult Scler 2020) raised the estimated worldwide prevalence to 35.9 per 100,000 (~2.8 million people), up from 2.3 million in 2013, reflecting both improved ascertainment and a real epidemiologic increase, particularly in women.

MS is a disease of populations of European ancestry: highest prevalence is reported in northern Europe, North America, and Australia/New Zealand, lowest in equatorial Africa and East Asia. Within high-prevalence regions a steep latitude gradient persists.

4. The Latitude Gradient

MS prevalence rises monotonically with latitude in both hemispheres — an observation first noticed by Davenport (1922) and quantified repeatedly since (Kurtzke 1975; Simpson et al., J Neurol Neurosurg Psychiatry 2011 meta-analysis). The slope is roughly:

i.e. roughly a doubling per 10° of latitude across the temperate band. Migration studies are informative: individuals migrating from a high-risk to a low-risk region before age ~15 acquire the lower risk of their adopted country (Dean & Kurtzke 1971, on Israeli immigrants), implicating an environmental exposure during childhood and adolescence. Candidate latitude-mediated factors:

• Vitamin D / UVB exposure — lower 25-OH-vitamin-D levels at high latitude correlate with higher MS risk; Mendelian randomisation supports a causal effect (Mokry et al., PLoS Med 2015).
• Epstein-Barr virus seroprevalence and age at infection — later (post-puberty) primary EBV infection (infectious mononucleosis) carries 2–4× the MS risk of asymptomatic seroconversion.
• Smoking — smoke exposure is an established environmental amplifier (gene-environment interaction with HLA-DRB1*15:01).
• Childhood obesity — recent cohorts (Munger et al.) show ~2× risk in obese adolescent girls.
• Diet & microbiome — emerging, less established.

The gradient has flattened modestly over recent decades, particularly in women, who now bear most of the rising incidence. It is widely interpreted as evidence that environmental triggers act on a genetically permissive substrate — the central insight of MS aetiology.

5. Demographics — Age, Sex, Ancestry

• Age at onset — peak incidence between 20 and 40, mean ~30. Paediatric MS (<18 yr) accounts for ~3–5% of cases; late-onset MS (>50 yr) ~5%, more often presenting with primary progressive disease.
• Sex — ~3:1 female predominance for relapsing disease; the ratio is closer to 1:1 for primary progressive MS. The female:male ratio has risen over the 20th century in most registries (the «sex-shift»), implicating environmental contributions that act preferentially on women.
• Ancestry — highest in populations of European descent. African and Asian populations have lower prevalence but a more aggressive course, with optic-spinal phenotypes and higher rates of NMOSD/MOGAD differential.
• Family history — sibling recurrence risk ratio λ_s ≈ 7–15; monozygotic twin concordance ~25–30% vs ~5% dizygotic (covered in Part IV).

6. Clinical Onset — the First Attack

The first clinical event in MS is termed a clinically isolated syndrome (CIS)when there is a single attack of CNS demyelination. The most common presentations:

Conversion from CIS to clinically definite MS is heavily MRI-driven: with any T2 lesions on initial MRI the 10-year conversion rate is ~80%; with a normal MRI it is ~20% (Fisniku et al., Brain 2008 long-term follow-up of the Queen Square cohort). McDonald 2017 criteria allow an MS diagnosis already at the first event if both DIS and DIT are present on MRI.

7. Disability Trajectory — the EDSS

The Expanded Disability Status Scale (EDSS), devised by John Kurtzke (1983), is the universal currency of MS disability:

• EDSS 0 — normal neurological examination.
• EDSS 1.0–3.5 — abnormal signs in one or more functional systems, fully ambulatory.
• EDSS 4.0–5.5 — ambulatory limits (walking distance <500 m, ~200 m).
• EDSS 6.0 — intermittent or unilateral aid (cane) for ~100 m.
• EDSS 6.5 — bilateral aids for ~20 m.
• EDSS 7.0–7.5 — wheelchair-restricted.
• EDSS 8.0–9.5 — bed-bound, dependent care.
• EDSS 10.0 — death due to MS.

Median time to landmark disability in untreated natural-history cohorts (London, Ontario; Lyon):

The annualised relapse rate (ARR) is the second key metric. In modern placebo arms ARR is ~0.3–0.5; on high-efficacy DMTs it falls below 0.1. A first-order rate ratio between two arms is reported as RR = ARR_treated/ARR_placebo. For ocrelizumab vs IFN-β-1a in OPERA-I/II, RR ≈ 0.54 (46% relative reduction; Hauser et al., NEJM 2017).

8. Burden & Cost

MS is the commonest non-traumatic cause of neurological disability in young adults in high-income countries. Lifetime medical costs in the United States exceed $4 million per patient (Adelman et al., J Med Econ 2013), dominated by DMT acquisition (~50–70% of direct costs at modern prices). Indirect costs — lost earnings, informal care — are comparable.

• Quality of life — HRQoL declines monotonically with EDSS; at EDSS ≥ 6.0 it is comparable to advanced cancer.
• Employment — ~40% of patients leave the workforce within 10 years of diagnosis (highly variable by phenotype and DMT era).
• Mortality — mean life expectancy reduced by ~7–14 years versus matched controls; cardiovascular disease and infection are leading causes.
• Cognitive impairment — clinically meaningful in ~40–65% of patients; an independent predictor of unemployment and progression.

9. Where This Course Goes