20.6 — Neuropathy and the Nerve Diseases

Nerves are the longest cells in the body. A single motor neuron running from the lower spine to the muscles of the foot is around a metre long, and it has to keep that entire length supplied from a cell body no bigger than any other.

Which is why the longest nerves fail first, and why almost every nerve disease starts in the feet.

That single fact explains most of what follows.

Peripheral neuropathy

Damage to the nerves outside the brain and spinal cord (Chapter 11.12).

The classic pattern is length-dependent: symptoms begin in the toes, spread up the feet, reach the ankles and shins, and only then do the fingertips start — producing the "glove and stocking" distribution. The hands begin at roughly the point the leg symptoms reach the knees, because that is where the arm nerves become the next longest in the body.

What it feels like:

Sensory — numbness, tingling, burning, and a sensation of walking on cotton wool or pebbles. Frequently worse at night.

And the loss of position sense matters more than people expect — balance depends on knowing where your feet are, and losing that makes people unsteady, particularly in the dark or with eyes closed.

Motor — weakness, usually later, starting with the small muscles of the foot and producing a high-arched foot or clawed toes over years.

Autonomic — dizziness on standing, sweating changes, bowel and bladder disturbance, erectile dysfunction.

The causes

Diabetes is the commonest by a wide margin, affecting around half of people with diabetes eventually (Chapter 18.7).

And it is the most consequential, because a foot that cannot feel damage is a foot that gets damaged — which is why diabetic foot checks exist and why they are worth taking seriously.

Alcohol — both directly toxic and through thiamine deficiency.

Vitamin B12 deficiency (Chapter 7.1). And this one is worth flagging: it can also affect the spinal cord, producing a combination of neuropathy and cord signs, and it is fully preventable and partly reversible if caught early.

And a specific trap: metformin lowers B12 over years, so someone with diabetes on long-term metformin who develops neuropathy may have two causes, one of which is treatable.

Drugs — chemotherapy agents in particular, some antibiotics, and isoniazid, which is why it is given with pyridoxine (Chapter 17.8).

Kidney disease, hypothyroidism, and liver disease.

Vitamin B6 in excess — unusual in that both deficiency and excess cause neuropathy, and high-dose supplements are the usual route.

Immune-mediated — including chronic inflammatory demyelinating polyneuropathy, which is important because it is treatable with immunotherapy and is otherwise mistaken for an untreatable neuropathy.

Inherited — Charcot-Marie-Tooth disease, the commonest inherited neurological condition, presenting with high arches, clawed toes and thin lower legs, often noticed in the teens.

Infection — HIV, hepatitis C, leprosy, and Lyme disease.

And around a quarter have no identified cause after investigation, which is worth saying because people are frequently told this means the workup was inadequate.

What to do about it

Treat the cause where there is one, which is the part that gets skipped. Glucose control, stopping alcohol, replacing B12, stopping the offending drug.

Nerves regenerate at roughly a millimetre a day, so recovery, where it happens, is slow — months for the feet.

For the pain, and neuropathic pain does not respond to ordinary painkillers, which is a frequent source of frustration:

First line: amitriptyline, duloxetine, gabapentin or pregabalin.

They work by damping abnormal nerve signalling rather than by blocking inflammation, which is why paracetamol and ibuprofen do so little.

Topical capsaicin or lidocaine for localised areas.

And a realistic expectation: a good response is around a 30 to 50 percent reduction in pain, not abolition. Saying that up front prevents a cycle of disappointment and escalating doses.

Foot care, which prevents more harm than any drug: daily inspection, well-fitting shoes, checking inside shoes before putting them on, professional nail care, and never walking barefoot. This is the intervention that prevents amputations.

Carpal tunnel syndrome

The commonest nerve compression, and one of the more satisfying conditions in medicine because the fix works.

The median nerve passes through a tunnel at the wrist bounded by bone and a tough ligament (Chapter 5.5). Swelling in a space that cannot expand compresses the nerve.

Symptoms: tingling and numbness in the thumb, index, middle and half the ring finger. Characteristically worse at night, waking people, who shake the hand for relief. Later, weakness and wasting of the thumb muscles.

And the sparing of the little finger is the useful sign, because that finger is supplied by a different nerve.

Commoner in pregnancy, hypothyroidism, diabetes, rheumatoid arthritis and obesity, and often with none of these.

Treatment: wrist splints worn at night, which work for a substantial proportion; steroid injection; and surgical release, which is a small operation with high success rates. Persistent numbness and thumb wasting means it should not be left, because established nerve damage recovers poorly.

Other common compressions: the ulnar nerve at the elbow, causing little-finger symptoms; and the peroneal nerve at the knee, causing foot drop, classically after prolonged leg crossing or a plaster cast.

Bell's palsy

Sudden weakness of one side of the face, developing over hours to a day.

And the single most important thing about it is how to distinguish it from a stroke, because that distinction is made at the bedside and it changes everything.

In Bell's palsy the forehead is affected — the person cannot raise that eyebrow or wrinkle that side of the forehead.

In a stroke the forehead is spared, because the forehead muscles receive input from both sides of the brain, so one hemisphere failing leaves them working (Chapter 11.7).

So: forehead not moving points to the nerve; forehead moving with the lower face drooping points to the brain, and that is an emergency.

Also in Bell's palsy: pain behind the ear, sounds seeming uncomfortably loud on that side, altered taste, and a dry or watering eye.

Cause: most likely reactivation of herpes simplex virus causing swelling of the nerve within its bony canal.

Treatment: prednisolone started within 72 hours improves recovery meaningfully, which is why it is time-critical. Antivirals may add a small benefit in severe cases.

And eye care is essential and frequently under-emphasised — an eye that will not close dries out and can ulcerate. Lubricating drops by day, ointment and taping the eye closed at night.

Outlook: around 70 percent recover completely without treatment, and more with it. Most improvement occurs within three weeks.

Ramsay Hunt syndrome — the same weakness with a painful vesicular rash in or around the ear, caused by shingles. Worse outlook, and it needs antivirals as well as steroids, so the rash is worth looking for.

Guillain-Barré syndrome

Ascending weakness developing over days, usually one to three weeks after an infection.

The immune response to the infection cross-reacts with nerve myelin (Chapter 13.6) — molecular mimicry.

Typically starts with numbness and weakness in the feet and ascends, with loss of reflexes as an early and useful sign.

And it is a medical emergency for one reason: it can paralyse the breathing muscles.

Which is why respiratory function is measured repeatedly, and why people are admitted even when they look reasonably well. Around 20 to 30 percent need ventilation.

Treatment: intravenous immunoglobulin or plasma exchange, both effective, with steroids notably ineffective here. Supportive care, and prevention of the complications of immobility.

Outlook: most recover substantially, though it takes months and a minority are left with lasting weakness. Mortality is around 3 to 5 percent, mostly from respiratory and autonomic complications.

Myasthenia gravis

Weakness that worsens with use and improves with rest — which is the whole picture in one sentence, and it is unusual enough to be nearly diagnostic.

Antibodies block the acetylcholine receptor at the neuromuscular junction (Chapter 6.2), so each successive nerve impulse produces less muscle response.

Presentation: drooping eyelids and double vision in most, often first, worse at the end of the day. Then difficulty chewing partway through a meal, slurred speech that worsens as a person talks, and weakness of the neck and limbs.

Myasthenic crisis — weakness of breathing or swallowing. An emergency requiring ventilatory support.

Diagnosis: antibody tests, nerve stimulation studies, and a CT of the chest, because the thymus gland is involved — around 10 percent have a thymoma and many more have thymic abnormality (Chapter 13.2).

Treatment: pyridostigmine, which blocks acetylcholine breakdown and so increases what is available at the junction; immunosuppression with steroids and steroid-sparing agents; thymectomy, which improves outcomes even without a tumour in selected patients; and immunoglobulin or plasma exchange for crises.

And a safety point worth carrying: several common drugs worsen myasthenia markedly — certain antibiotics, particularly aminoglycosides and some quinolones, magnesium, and beta blockers. Anyone with myasthenia should have this checked before any new prescription.

Outlook is good with treatment, and most people live normal lives — which was not true before immunosuppression.

Motor neurone disease

And this is the hardest condition on the page, so it is worth being straightforward about it.

Progressive degeneration of the motor neurons — both the upper ones in the brain and the lower ones in the spinal cord (Chapter 11.3).

Sensation, and usually intellect, are preserved, which is what makes it the condition it is.

Presentation varies: weakness beginning in one hand or one leg; or bulbar onset with slurred speech and swallowing difficulty, which carries a worse outlook.

The combination of upper and lower motor neuron signs in the same limb is the characteristic finding — brisk reflexes with wasting and twitching, which do not usually occur together.

Around 10 percent are familial, with C9orf72 the commonest gene, which is shared with frontotemporal dementia — and around 15 percent have some degree of cognitive change.

Treatment: riluzole extends survival by a few months; edaravone in some countries; and tofersen for the specific SOD1 genetic form, which is the first treatment targeting a genetic cause in this disease.

And the interventions that matter most are supportive: non-invasive ventilation at night, which improves both survival and quality of life more than any drug; feeding support; communication aids; and specialist multidisciplinary care, which measurably improves outcomes.

Median survival is around 3 years from symptom onset, with wide variation — some people live decades, as Stephen Hawking did for over 50 years.

And research is more active than it has been, with genetic therapies the most promising direction, since they are the first approach targeting a cause rather than the consequences.

What the next page fixes

Chapter 20.7 covers depression — the commonest condition in this Part, the most treatable, and the one most likely to go untreated.