Multiple Sclerosis, Migraine, and Nerve Pain

TL;DR. Three common neurological conditions that damage different parts of the nervous system. Multiple sclerosis is an autoimmune attack on the insulation around nerve fibres in the brain and spinal cord, producing episodes of weakness, numbness, and visual loss in young adults; the evidence that Epstein-Barr virus is a necessary cause is now very strong, and treatment has gone from nothing to more than a dozen drugs in thirty years. Migraine is not a bad headache; it is an inherited disorder of brain excitability affecting about a billion people, and the discovery of the molecule CGRP produced the first drugs designed specifically for it. Peripheral neuropathy is damage to the nerves outside the brain and spinal cord, most often from diabetes, and it produces pain that ordinary painkillers barely touch, because the problem is the alarm system rather than the tissue.

Key takeaways

• MS affects about 2.9 million people, typically diagnosed between 20 and 40, and is two to three times more common in women.
• A study of 10 million US military personnel found that Epstein-Barr virus infection raised MS risk 32-fold, and MS essentially did not occur in the EBV-negative. It is now considered a necessary though not sufficient cause.
• Migraine affects roughly 1 billion people and is among the leading causes of years lived with disability worldwide, particularly in women aged 15 to 49.
• CGRP-targeted drugs are the first preventive treatments designed for migraine rather than borrowed from other conditions.
• Medication overuse headache is a common, treatable, and frequently missed cause of daily headache, produced by the treatment itself.
• Neuropathic pain does not respond well to paracetamol, NSAIDs, or opioids. It responds to drugs that alter nerve signalling: gabapentinoids, duloxetine, and tricyclics.

Part 1: Multiple sclerosis

What it is

In short: Immune attack strips the insulation from nerve fibres at multiple sites and multiple times, which is exactly what the name describes.

Nerve fibres in the brain and spinal cord are wrapped in myelin, a fatty insulating sheath made by oligodendrocytes. Myelin lets electrical signals jump between gaps rather than travelling continuously, which makes conduction roughly 100 times faster. Multiple sclerosis is an immune attack that strips myelin in patches (plaques or lesions), scattered through the central nervous system, at different times.

That is what the name means: multiple sites, multiple times. Diagnosis (the McDonald criteria) formalises exactly this as dissemination in space and time, demonstrated by symptoms, MRI lesions, and sometimes oligoclonal bands in spinal fluid.

The history

In short: Charcot defined it in 1868 with nothing to offer, and a 2022 study of 10 million military records finally identified a necessary cause.

Descriptions go back to the fourteenth century, and the pathologist Jean Cruveilhier and then Jean-Martin Charcot in 1868 defined it, Charcot linking clinical features to the scarred plaques found at autopsy. He had no treatment to offer.

Nothing much changed for over a century. Interferon beta, the first disease-modifying drug, arrived in 1993 and reduced relapse rates by about a third. What followed was one of the fastest therapeutic expansions in neurology: glatiramer acetate, then natalizumab (2004), oral agents from 2010, and B-cell depleting antibodies from 2017, with efficacy rising from a third to two-thirds or more relapse reduction.

The causal story arrived last. In 2022, Bjornevik and colleagues analysed serum from more than 10 million US military personnel followed over two decades, and found that the risk of MS increased 32-fold after EBV infection and not after infection with other viruses, with markers of nerve damage rising only after EBV seroconversion. Almost everyone gets EBV and very few get MS, so EBV is necessary rather than sufficient, but it reframed a disease that had been unexplained for 150 years.

What actually goes wrong

In short: Inflammation strips myelin and early attacks recover, but the exposed nerve fibres degenerate, and that is what causes permanent disability.

Autoreactive T cells and B cells cross the blood-brain barrier and attack myelin. Inflammation strips the sheath, conduction slows or fails, and symptoms appear in whatever pathway was affected. Inflammation then subsides and partial remyelination occurs, which is why early relapses often recover.

Over time two things change. Remyelination becomes less effective, so recovery is incomplete. And the underlying axons, exposed and metabolically stressed, degenerate. Axonal loss, not demyelination, is what produces permanent disability, which is why current thinking favours treating hard and early rather than escalating after damage accumulates.

Why EBV? The leading hypothesis is molecular mimicry: an EBV protein (EBNA1) resembles a human central nervous system protein (GlialCAM has been implicated), so antibodies raised against the virus cross-react with myelin-associated tissue. EBV also permanently infects B cells, which is consistent with the striking efficacy of B-cell-depleting drugs.

Other risk factors and their evidence:

What it does to the body

Symptoms depend on lesion location, and the variety is the diagnostic clue:

• Optic neuritis: painful loss of vision in one eye over hours to days, often the first presentation.
• Sensory: numbness, tingling, band-like tightness, Lhermitte's sign (an electric shock down the spine on bending the neck).
• Motor: weakness, spasticity, difficulty walking.
• Cerebellar and brainstem: tremor, incoordination, vertigo, double vision, slurred speech.
• Bladder and bowel: urgency, frequency, incontinence, constipation. Extremely common and under-reported.
• Fatigue: the most commonly reported and most disabling symptom, disproportionate to physical findings.
• Cognitive: slowed processing, memory and attention difficulty, in around half of patients.
• Uhthoff's phenomenon: symptoms worsen with heat (a hot bath, exercise, fever) because demyelinated fibres conduct even less reliably at higher temperature. It is temporary and it is not a relapse.

Is it deadly?

MS reduces life expectancy by roughly 5 to 10 years, less than it used to, and most people with MS die of unrelated causes. Death, when related, comes from complications of advanced disability: infection, aspiration, and immobility. The dominant burden is disability rather than mortality, and it lands during the working and childrearing years.

Is it contagious?

No. MS is not transmissible. The EBV finding does not change that: EBV is contagious (it causes glandular fever and infects over 90 percent of adults), MS is not. Nearly everyone carries the virus and almost nobody gets MS.

Who gets it

About 2.9 million people worldwide. Prevalence rises with latitude in both hemispheres, which is one of the oldest and most robust observations in the field, and a person's risk tracks where they lived before about age 15 rather than where they live afterwards. Female-to-male ratio is roughly 2 or 3 to 1 and has risen over decades, which suggests an environmental contribution rather than a purely genetic one. Prevalence is highest in northern Europe, Canada, and the United States, and lowest in equatorial regions and among some populations regardless of latitude.

Treatment, and how it works

In short: Steroids for relapses and a dozen disease-modifying drugs, with current practice favouring high-efficacy treatment early rather than escalating after damage.

Acute relapse: high-dose corticosteroids speed recovery without changing the eventual outcome. Plasma exchange for severe steroid-resistant relapses.

Disease-modifying therapies, ordered roughly by efficacy:

Symptom management matters as much as disease modification: exercise and energy management for fatigue, baclofen and physiotherapy for spasticity, bladder management, treatment of depression, and rehabilitation.

Side effects and trade-offs: all of these suppress or modulate immunity, so infection risk, vaccination timing, and pregnancy planning are central. The general principle in current practice is that early high-efficacy treatment prevents disability better than starting low and escalating after damage occurs.

What the person can do: stop smoking (it accelerates progression), maintain vitamin D, exercise regularly (which improves fatigue, mobility, and mood, contrary to older advice to rest), keep cool in heat, and treat infections promptly since they can trigger pseudo-relapses.

What's next: remyelination therapies (attempting to rebuild myelin rather than only preventing attacks), BTK inhibitors targeting the smouldering inflammation inside the central nervous system that current drugs do not reach, and, following the EBV findings, EBV vaccines and EBV-targeted T cell therapies.

Part 2: Migraine

What it is

In short: Not a bad headache but a four-phase neurological event, of which the headache is one phase.

Migraine is a neurological disorder characterised by recurrent attacks of moderate to severe headache, typically one-sided and throbbing, worsened by movement, and accompanied by nausea and by hypersensitivity to light (photophobia), sound (phonophobia), and often smell. Untreated attacks last 4 to 72 hours.

About a third of people with migraine experience aura: transient neurological symptoms, most often visual (a shimmering zigzag arc expanding across the visual field over 20 to 30 minutes), sometimes sensory or affecting speech. Aura precedes or accompanies the headache and resolves fully.

Chronic migraine means headache on 15 or more days a month, of which 8 or more are migrainous, for over three months.

Don't be confused: a migraine is not "a bad headache." The headache is one phase of a four-phase event. The prodrome (hours to days before) brings yawning, food cravings, mood change, and neck stiffness. Then optional aura. Then the headache. Then the postdrome, a day of feeling wrung out. People who experience only the prodrome and postdrome around a mild headache still have migraine, and silent migraine (aura without headache) exists.

What actually goes wrong

In short: A wave of neuronal firing crosses the cortex at the exact speed an aura expands, and the headache comes from a nerve peptide called CGRP.

Migraine is a disorder of brain excitability rather than of blood vessels, which is a reversal of the twentieth-century view.

Aura is caused by cortical spreading depression: a slow wave of intense neuronal firing followed by suppression, moving across the cortex at about 3 mm per minute. That speed matches exactly the rate at which a visual aura expands, which is how the mechanism was inferred.

The headache involves the trigeminovascular system. Trigeminal nerve endings around the meninges become activated and release neuropeptides, above all calcitonin gene-related peptide (CGRP), causing vasodilation, inflammation, and pain signalling. Repeated activation sensitises central pain pathways, which is why chronic migraine sufferers develop allodynia, in which brushing hair or wearing glasses hurts.

The hypothalamus appears to initiate attacks, which explains the prodrome symptoms (yawning, appetite change, mood) and why so-called triggers such as chocolate craving may actually be early symptoms rather than causes.

Genetics: migraine is highly heritable and polygenic, with over 100 identified loci. Rare familial hemiplegic migraine is caused by single-gene ion channel mutations, which supports the excitability model.

Who gets it, and what it does

Roughly 1 billion people. Three times more common in women than men after puberty, with attacks frequently linked to the fall in oestrogen before menstruation. Peak prevalence is between 25 and 55, the most economically productive years, which is why migraine ranks so high in disability measures despite rarely being dangerous.

Migraine with aura carries a modest increase in ischaemic stroke risk, which becomes clinically relevant when combined with smoking and combined oral contraceptives. Guidelines generally advise against combined hormonal contraception in women with migraine with aura for this reason.

Treatment, and how it works

In short: Triptans and the newer CGRP blockers for attacks, preventives for frequent ones, and a specific trap where the painkillers themselves cause daily headache.

Acute treatment (taken during an attack, and taken early, since gastric emptying slows during an attack and delays absorption):

Preventive treatment (taken daily when attacks are frequent or disabling):

• Repurposed drugs: propranolol, amitriptyline, topiramate, candesartan, sodium valproate (with the pregnancy restrictions from Chapter 39). All were found to work by accident while being used for something else.
• CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab): monthly or quarterly injections targeting CGRP or its receptor. The first preventives designed for migraine, and generally better tolerated than the older options.
• Botulinum toxin injections for chronic migraine, on a defined injection protocol.
• Neuromodulation devices, including external trigeminal and vagus nerve stimulators.

Medication overuse headache deserves its own paragraph because it is common and reversible. Taking acute painkillers, particularly opioids, combination analgesics, or triptans, on more than about 10 to 15 days a month can convert episodic migraine into daily headache. The treatment is withdrawal of the overused drug, which makes things worse for a few weeks and then substantially better. Anyone with daily headache taking daily painkillers should be assessed for this before anything else is added.

What the person can do: keep a headache diary to identify real patterns (many suspected triggers do not survive systematic recording); protect sleep and meal regularity, since irregularity is a more reliable trigger than any specific food; manage stress, noting that attacks often come during the let-down after stress rather than during it; treat attacks early and adequately rather than waiting to see; and stay within the acute medication day limits.

Part 3: Peripheral neuropathy and nerve pain

What it is

In short: Damage to the nerves outside the brain and spinal cord, with the longest nerves failing first, so it starts in the toes.

Peripheral neuropathy is damage to nerves outside the brain and spinal cord. The commonest pattern is distal symmetric polyneuropathy: the longest nerves fail first, so symptoms begin in the toes and creep up in a "stocking" distribution, then appear in the fingertips as a "glove."

Symptoms depend on the fibres affected: numbness and loss of position sense (large fibres), burning, shooting, or electric pain and loss of temperature sensation (small fibres), and, if motor fibres are involved, weakness and wasting. Autonomic fibres cause blood pressure, sweating, bowel, and bladder disturbance.

Causes, roughly in order: diabetes (the leading cause worldwide), alcohol, vitamin B12 deficiency, chemotherapy (platinum agents, taxanes, vincristine), chronic kidney disease, hypothyroidism, HIV and its older treatments, leprosy (still a leading cause in some regions), autoimmune conditions, inherited neuropathies such as Charcot-Marie-Tooth, and a substantial proportion where no cause is found.

Focal neuropathies are different and often mechanical: carpal tunnel syndrome (median nerve compressed at the wrist), ulnar neuropathy at the elbow, and sciatica from a compressed nerve root.

What actually goes wrong

Neuropathic pain is pain caused by damage to the pain-signalling system itself, rather than by tissue injury. Damaged nerves become spontaneously active, firing without a stimulus, and the spinal cord and brain amplify the signal (central sensitisation). The consequences follow logically:

• Pain occurs with no injury to treat, which is why it feels inexplicable and is often disbelieved.
• Allodynia: normally painless stimuli hurt, so bedsheets on the feet become intolerable.
• Hyperalgesia: painful stimuli hurt far more than they should.
• Anti-inflammatories and paracetamol do little, because there is no inflammation to suppress.
• Opioids work poorly relative to their risks, and current guidance is against using them for chronic neuropathic pain.

Treatment, and how it works

In short: Treat the cause where possible, and use drugs that alter nerve signalling, because anti-inflammatories and opioids barely work on this kind of pain.

Treat the cause first where possible: glucose control in diabetes (which prevents progression better than it reverses damage), B12 replacement, stopping alcohol, adjusting chemotherapy, decompression surgery for carpal tunnel.

Drugs for the pain, all of which modify nerve signalling rather than blocking inflammation:

Typical benefit is a 30 to 50 percent reduction in pain in perhaps a third to half of patients, which is honest and modest. Combining a drug with non-drug approaches (exercise, graded activity, pain-focused psychological therapy, and treating the sleep disruption and depression that accompany chronic pain) does better than drugs alone.

Foot care in diabetic neuropathy is the highest-value intervention available, for the reasons in Chapter 18: numb feet get injured unnoticed, and unnoticed injuries become amputations.

What's next: sodium channel Nav1.7 and Nav1.8 blockers designed to silence pain neurons specifically without central side effects, with the first non-opioid drug of this class approved in 2025; better small-fibre diagnostics; and, for the underlying neuropathy, the metabolic treatments in the diabetes chapter.

Sources and notes

MS prevalence: Atlas of MS, 3rd edition (MS International Federation), approximately 2.9 million people. EBV and MS: Bjornevik et al., Science, 2022 (32-fold risk increase in a cohort of over 10 million US military personnel); molecular mimicry with GlialCAM: Lanz et al., Nature, 2022. McDonald criteria, 2017 revisions. Natalizumab and PML risk: post-marketing surveillance data. Migraine prevalence and disability ranking: Global Burden of Disease studies; approximately 1 billion people affected. Cortical spreading depression: Leão, 1944, and Hadjikhani et al., PNAS, 2001, imaging it in human aura. CGRP discovery and drug development: Goadsby and Edvinsson's work from the 1980s onward. Medication overuse headache criteria: International Classification of Headache Disorders, 3rd edition. Neuropathic pain treatment efficacy: Finnerup et al., Lancet Neurology, 2015, systematic review and NNT estimates. Diabetic neuropathy as leading cause: standard neurology references.

Open questions. Why only a tiny fraction of EBV-infected people develop MS is unknown. Whether remyelination can be induced therapeutically in humans is unresolved. The initiating event in a migraine attack, and what determines who develops chronic migraine, are not settled.

Next: the most common diseases in this book, and the ones most often dismissed. 👉