20.5 — Multiple Sclerosis

In 1990 there was no treatment for multiple sclerosis at all.

Today there are more than twenty licensed disease-modifying therapies, and the most effective reduce relapse rates by around 70 to 80 percent.

A person diagnosed today and treated early has a substantially different outlook from someone diagnosed thirty years ago — and the change is one of the clearest in modern neurology.

What it is

An immune-mediated disease in which the immune system attacks myelin in the central nervous system (Chapter 11.1).

Demyelination slows or blocks conduction, so the affected pathway fails — and which pathway determines the symptom.

Plaques of demyelination occur in multiple places at multiple times, which is where the name comes from and which is also the diagnostic criterion: dissemination in space and in time.

And axonal loss occurs from the start, which is what produces the progressive disability rather than the relapses — a point that took decades to appreciate.

Who gets it

Around 2.8 million people worldwide. Two to three times commoner in women, and typically diagnosed between 20 and 40.

And the geographic pattern is striking: incidence rises with distance from the equator, in both hemispheres.

Migration studies found that moving before around age 15 confers the risk of the destination, and moving later retains the risk of origin — which points to an environmental exposure acting in childhood.

The candidates:

Vitamin D and sunlight — consistent with the latitude gradient, and supported by genetic evidence linking vitamin D pathways to risk. Trials of supplementation have not clearly reduced risk, so the honest position is a strong association without established causation.

Epstein–Barr virus, and this is the strongest finding.

A 2022 study following ten million US military personnel found that EBV infection increased MS risk 32-fold, and that MS essentially never occurred in people who had never been infected (Chapter 13.6).

It is now considered a necessary but not sufficient cause, and it has made an EBV vaccine a serious research priority.

Smoking — increases risk and accelerates progression, and it is the clearest modifiable factor.

Obesity in adolescence.

Genetics — around 200 identified variants, mostly immune-related, with HLA-DRB1*15:01 the strongest. Risk in a sibling is around 3 percent against 0.1 percent in the population — familial, and not inherited in any simple sense.

The symptoms

And their variety follows directly from the fact that any central pathway can be affected.

Optic neuritis — a common first presentation. Painful loss of vision in one eye, with pain on eye movement, developing over days. Colour vision is affected disproportionately, and most recover substantially over weeks to months.

Sensory symptoms — numbness, tingling, and a band-like sensation around the trunk.

Motor symptoms — weakness, spasticity, and increased reflexes (Chapter 11.3).

Cerebellar — clumsiness, intention tremor, unsteady gait, scanning speech (Chapter 11.4).

Brainstem — double vision, vertigo, facial numbness, and trigeminal neuralgia in a young person, which should raise the question (Chapter 11.7).

Bladder — urgency, frequency and incomplete emptying, affecting the majority and consistently under-asked-about.

Fatigue — the commonest symptom and the most disabling, reported by around 80 percent, and frequently the reason someone cannot work despite minimal physical disability. It is not ordinary tiredness and it is not proportional to exertion.

Cognitive — processing speed and memory, affecting around half, often mildly.

Depression — commoner than in comparable chronic conditions.

And two signs worth knowing:

Lhermitte's sign — an electric-shock sensation running down the spine on neck flexion. Not specific to MS and characteristic.

Uhthoff's phenomenon — symptoms worsening with heat, from a hot bath, exercise or fever. Demyelinated axons conduct marginally, and raised temperature tips them into failure. It is temporary and reverses on cooling, and it is not a relapse — which matters, because people frequently think they are deteriorating.

The patterns

Relapsing-remitting — around 85 percent at onset.

Discrete relapses — new or worsening symptoms lasting over 24 hours in the absence of fever or infection — with recovery, complete or partial, between.

Secondary progressive — after 10 to 20 years, many transition to steady progression with fewer relapses. Modern treatment appears to be delaying or reducing this transition, though the long-term data is still accumulating.

Primary progressive — around 10 to 15 percent. Progressive from the outset, typically older at onset, more often affecting the spinal cord, and historically the hardest to treat.

Clinically isolated syndrome — a first episode. Treating at this stage delays conversion to definite MS.

Radiologically isolated syndrome — typical lesions found incidentally on a scan done for something else, with no symptoms. An increasingly common situation, and one where the right action is genuinely uncertain.

Diagnosis

The McDonald criteria — dissemination in space and time, demonstrated clinically or on MRI.

MRI — characteristic lesions in specific locations. Gadolinium enhancement indicates active inflammation, because the blood–brain barrier is broken there (Chapter 11.10) — and it distinguishes new lesions from old.

Cerebrospinal fluid — oligoclonal bands, present in over 90 percent, indicating antibody production within the central nervous system.

And the criteria have been progressively relaxed so that diagnosis can be made earlier, sometimes after a single episode with supporting MRI — which matters because early treatment produces better long-term outcomes.

Treatment

Relapses — high-dose steroids for 3 to 5 days. They speed recovery and do not change the eventual extent of it, which is worth knowing, because people frequently assume steroids determine the outcome.

Disease-modifying therapies, and this is where the change has been.

Moderate efficacy: interferon-beta and glatiramer acetate — the original drugs from the 1990s, well tolerated, reducing relapses by around 30 percent. Oral agents including teriflunomide and dimethyl fumarate.

High efficacy: natalizumab, ocrelizumab, alemtuzumab, cladribine, and the S1P modulators.

Reducing relapses by 70 to 80 percent, and reducing disability accumulation.

And a genuine strategic debate: escalation versus early high-efficacy treatment.

The traditional approach started with a safer moderate drug and escalated on failure. The emerging evidence supports starting with a high-efficacy drug in those with active disease, because the damage prevented in the first years is not recoverable.

Risks matter and differ by drug. Natalizumab carries a risk of progressive multifocal leukoencephalopathy — a severe brain infection — in people carrying the JC virus, which is why JC antibody status is monitored. Alemtuzumab carries a substantial risk of secondary autoimmune disease, particularly thyroid. The B-cell depleting drugs increase infection risk and reduce vaccine responses.

Progressive MS — historically untreatable, and ocrelizumab has shown benefit in primary progressive disease, which was the first drug to do so. Siponimod in secondary progressive. The effects are modest and they are real.

Symptomatic treatment, which affects daily life more than anything else:

Fatigue — exercise has the best evidence, which is counter-intuitive and consistent. Also sleep, treating depression, and amantadine or modafinil with modest evidence.

Spasticity — physiotherapy, baclofen, tizanidine, botulinum toxin, and cannabinoid spray, which has licensed evidence for spasticity specifically.

Bladder — anticholinergics, intermittent self-catheterisation, botulinum toxin (Chapter 10.5).

Pain — neuropathic agents (Chapter 11.13).

Depression — treated actively.

And rehabilitation, which is the intervention with the largest effect on function.

Living with it

And the outlook deserves stating plainly, because the assumption on diagnosis is frequently far worse than the reality.

Most people with MS do not end up in a wheelchair.

Life expectancy is reduced by around 5 to 10 years, and the gap is narrowing.

Around a third have a benign course with minimal disability after 15 years.

And modern cohorts are doing substantially better than the historical figures that still circulate, because those figures describe people treated before any effective drug existed.

What helps:

Stopping smoking — it accelerates progression measurably.

Exercise — for fatigue, mood, strength and probably progression.

Vitamin D — commonly supplemented, with the honest note that trial evidence for altering the disease course is not strong.

Managing heat — cooling strategies for Uhthoff's phenomenon.

Vaccination — important, and live vaccines are avoided on immunosuppressive treatment.

Pregnancy — relapse rates fall substantially during pregnancy, particularly the third trimester, and rise in the three months afterwards. MS does not reduce fertility and does not affect the pregnancy adversely. Medication needs planning in advance.

And the psychological impact of a diagnosis in a young adult is substantial — an unpredictable condition with a variable course, at the point in life when careers and relationships are being established. Support at diagnosis matters as much as the drug choice.

What the next page fixes

Chapter 20.6 covers the remaining neurological conditions worth knowing — motor neurone disease, neuropathy, and the ones people are most likely to encounter.