Peripheral nerve

What it normally does

• A nerve fibre has two parts that fail separately. The axon is the conducting wire. The myelin is insulation, made by Schwann cells that each wrap one segment of one axon, with bare gaps between them (nodes of Ranvier) where the sodium channels are packed. The impulse jumps node to node (saltatory conduction), so a large myelinated fibre conducts at about 40 to 70 m/s while a bare unmyelinated fibre manages about 1 m/s. Strip the myelin and the impulse must crawl along the membrane, or stop altogether (conduction block); cut or starve the axon and the wire is simply gone, and the muscle and skin it supplied are denervated.

  the two failure modes look different at the bedside and on nerve conduction studies: demyelination slows conduction and abolishes reflexes early with the muscle bulk still intact, while axonal loss gives wasting, fasciculation and small (low-amplitude) sensory and motor responses. Myelin can be rebuilt in weeks once the attack or the pressure stops; a severed axon has to be regrown from the injury site along its whole remaining course at roughly a millimetre a day, which is months.

• The axon builds almost none of its own protein. Mitochondria, channels and structural protein are made in the cell body (anterior horn cell for motor, dorsal root ganglion for sensory) and shipped down the axon by motor proteins running on microtubules (axonal transport), fast anterograde transport moving at a few hundred millimetres a day. The axon running from an L5 dorsal root ganglion to the tip of the great toe is close to a metre long. Its oxygen and glucose come from small vessels in and along the nerve (vasa nervorum); these anastomose along its length, but there are watershed zones with little reserve once many small vessels are diseased at once.

  anything that raises the metabolic cost or cuts the supply — hyperglycaemia, alcohol, B12 deficiency, chemotherapy, uraemia — kills the far end of the longest axons first and works backwards (dying-back axonopathy). That is why toxic and metabolic neuropathies are symmetrical and begin at the toes, and why the level has usually climbed to around the knees before the fingertips are involved: the fingertip sits about the same distance from its cell body as the knee does from a lumbar ganglion. That is the stocking-then-glove pattern, and a neuropathy that reaches the hands while the feet are barely affected is not length-dependent and needs a different explanation.

• Not all fibres are the same size, and size decides both what they carry and whether a machine can see them. Large myelinated fibres carry motor output to muscle, vibration, joint position sense and light touch, and they are the afferent limb of the tendon reflexes. Thinly myelinated and unmyelinated fibres carry pain, temperature, and the postganglionic sympathetic output that drives sweating and vascular tone. Nerve conduction studies only record from the large myelinated fibres.

  you can predict the syndrome from the fibre. Small-fibre damage gives burning pain, loss of pinprick and temperature, dry skin from lost sweating and postural dizziness, with normal reflexes and normal nerve conduction studies. Large-fibre damage gives absent ankle jerks, lost vibration, a sensory ataxia with a positive Romberg sign, and abnormal conduction studies. A normal nerve conduction study does not exclude a neuropathy.

• The nerve is a cable in three sheaths — endoneurium around each fibre, perineurium around each bundle, epineurium around the whole trunk — and the perineurium carries the blood-nerve barrier and holds a resting endoneurial pressure inside. At several points the cable runs through a fixed tunnel or lies against bone with no padding: the median nerve under the flexor retinaculum at the wrist, the ulnar nerve behind the medial epicondyle and in the cubital tunnel just beyond it, the common fibular nerve wrapping the neck of the fibula. External pressure there first compresses the endoneurial venules and causes local ischaemia and focal demyelination; sustained pressure then kills axons, which regrow only from the injury site at roughly 1 mm per day.

  entrapment produces sensory loss confined to the territory of one nerve, although the accompanying ache often radiates proximally up the limb and that does not exclude it; symptoms are intermittent at first and worse in the position that narrows the tunnel; conduction studies show slowing localised across the tunnel; and prognosis follows the pathology — demyelinating compression recovers in weeks once the pressure is off, axonal loss takes months and may never fully come back, so a wasted thenar eminence is a reason to act, not to wait.

What goes wrong

• Diabetic distal symmetrical polyneuropathy← from “The axon builds almost none of its own protein…”

  Chronic hyperglycaemia loads the nerve in several ways at once: excess glucose is shunted through the polyol pathway, consuming NADPH and with it the capacity to regenerate glutathione, proteins are glycated (advanced glycation end products), mitochondria leak reactive oxygen species, and the vasa nervorum thicken and narrow so the nerve is also mildly ischaemic. The axon with the highest metabolic bill and the longest supply line fails first, and the damage marches proximally from the toes. Small fibres commonly go before large ones, so burning feet and lost pinprick can precede any loss of vibration or reflexes. Sympathetic fibres to the sweat glands die with them, leaving dry cracked skin, and the same disease has already damaged the arteries and the healing response — insensate foot plus poor skin plus poor perfusion is how a small stone in a shoe becomes an ulcer, then osteomyelitis, then an amputation.

  Length-dependent, symmetrical, sensory-predominant, starts at the toes, ankle jerk goes first. Painless ulcer at a pressure point means protective sensation is gone. Screen every diabetic foot with a 10 g monofilament and a 128 Hz tuning fork; if the neuropathy is not length-dependent, is asymmetrical, or is mostly motor, stop blaming the diabetes and look for another cause.

  You would find: Symmetrical numbness and burning in both feet, worse at night, creeping up over months; absent ankle jerks; loss of vibration at the great toe with a 128 Hz tuning fork; failure to feel a 10 g monofilament at the plantar pressure points; dry hairless skin and a painless ulcer under the first metatarsal head. About 1.3 million Australians are living with diagnosed diabetes and roughly a third to a half will develop neuropathy. Diabetes is around three to four times more common in Aboriginal and Torres Strait Islander people, who carry a far higher burden of diabetes-related foot disease and lower limb amputation, especially in remote communities — which is why the annual foot check with a monofilament, and access to podiatry and offloading, is core care and not an optional extra.

• Guillain-Barre syndrome← from “A nerve fibre has two parts that fail separate…”

  One to three weeks after an infection — classically Campylobacter jejuni gastroenteritis, also CMV, EBV, Mycoplasma, and the respiratory viruses — the immune system makes antibody against a bacterial surface sugar that happens to resemble a ganglioside on peripheral nerve (molecular mimicry). In the demyelinating form (AIDP, the common form in Australia) antibody and complement mark the Schwann cell surface and macrophages strip the myelin, most heavily at the roots and terminals where the blood-nerve barrier is weakest. Demyelinated segments conduct slowly or not at all (conduction block), and because the large fibres go first, reflexes disappear early while the muscle is still bulky and sensation is only mildly disturbed. The attack is not selective about which nerves: the phrenic nerves weaken the diaphragm, the lower cranial nerves impair swallowing, and autonomic fibres produce swinging blood pressure and arrhythmia. The Campylobacter-associated axonal variant (acute motor axonal neuropathy, anti-GM1 and anti-GD1a antibodies) attacks the nodal axolemma rather than the myelin: if the attack is aborted before the axon degenerates the nodal block reverses and recovery can be quick, but once axons are actually lost recovery is slow and often incomplete.

  Ascending weakness plus early areflexia after a diarrhoeal illness. Trend the FVC and the bedside cough, not the pulse oximeter. Treat with intravenous immunoglobulin or plasma exchange — corticosteroids do not work here.

  You would find: Symmetrical weakness ascending from the legs over days to about two weeks, areflexia out of proportion to any sensory loss, back and limb pain, and often bilateral facial weakness. Progression stops by four weeks — anything still worsening after that is not classic Guillain-Barre. Lumbar puncture after about a week shows a high protein with a normal cell count (albuminocytological dissociation); protein is often still normal in the first few days, and a raised cell count should make you think HIV seroconversion, Lyme disease or malignant infiltration. Nerve conduction studies show conduction block and prolonged or absent F waves. The measurement that matters is serial forced vital capacity, not the oxygen saturation: an FVC falling towards about 20 mL/kg, a weak cough and a rising respiratory rate mean impending ventilatory failure, and desaturation is a late and dangerous sign. Incidence in Australia is roughly 1 to 2 per 100 000 per year.

• Entrapment neuropathy — carpal tunnel and its cousins← from “The nerve is a cable in three sheaths — endone…”

  A nerve running through a rigid tunnel has nowhere to go when the tunnel narrows or its contents swell. Pressure in the carpal tunnel rises, the endoneurial venules are compressed, the nerve becomes ischaemic and the myelin under the compression point breaks down. Early on this is intermittent and reversible, which is why symptoms come at night when the wrist is held flexed for hours and fluid redistributes. If the pressure persists, axons die, and then you get wasting and fixed sensory loss. Anything that swells the tunnel or makes the nerve more vulnerable stacks the odds: pregnancy, hypothyroidism, obesity, rheumatoid arthritis, repetitive forceful wrist use, and diabetes — a nerve already sick from metabolic injury is compressed more easily.

  One nerve's territory, not a stocking. Symptoms at night, in the position that shuts the tunnel. Central palm sparing points to the median nerve at the wrist rather than higher; preserved inversion points to the common fibular nerve rather than the L5 root. Wasting means axons are dying — that is a surgical referral, not a splint.

  You would find: Carpal tunnel: night pain and numbness in the hand relieved by shaking it out (flick sign), numbness of the thumb, index, middle and radial half of the ring finger with the central palm spared — because the palmar cutaneous branch leaves the median nerve before the tunnel — and, late, a wasted thenar eminence with weak thumb abduction. Tinel and Phalen tests support it but are neither sensitive nor specific; nerve conduction studies localise the slowing across the wrist. Common fibular nerve at the fibular neck: foot drop after habitual leg crossing, a plaster cast or rapid weight loss, with numbness over the dorsum of the foot and weak eversion but preserved ankle inversion, which is what separates it from an L5 root lesion. Ulnar nerve at the elbow: numb little finger and ulnar half of the ring finger, wasted first dorsal interosseous, worse with elbow flexion. Carpal tunnel syndrome affects a few percent of adults, more women than men, and its release is one of the most commonly performed hand operations in Australia.

• Neuropathic pain from a damaged nerve← from “Not all fibres are the same size, and size dec…”

  A damaged small fibre does not just fall silent — it becomes a faulty transmitter. The injured axon and its regenerating sprouts accumulate extra voltage-gated sodium channels in the membrane, lowering the threshold until they fire without any stimulus at all (ectopic discharge). Injured sensory neurons also up-regulate the alpha-2-delta-1 subunit of voltage-gated calcium channels and traffic it to their central terminals, so each impulse arriving in the dorsal horn releases more glutamate and substance P. The dorsal horn amplifies the barrage (central sensitisation), large touch fibres get recruited into the pain pathway, and descending noradrenergic inhibition from the brainstem is overwhelmed. The result is pain generated inside the nervous system in a body part that has lost sensation.

  Burning pain in numb skin, worse at night. Neuropathic pain answers to antidepressants that raise noradrenaline in the dorsal horn and to gabapentinoids, not to NSAIDs; opioids work poorly and are not first line. Trial one drug at a time against a stated goal and stop it if it fails. Every drug we have treats the symptom — none repairs the nerve.

  You would find: Burning, electric-shock or lancinating pain in numb skin, worse at night, with pain from light touch (allodynia) and an exaggerated response to pinprick (hyperalgesia). The distribution follows the nerve, not a joint or a muscle. The paradox — a foot that is numb and yet agonising — is the giveaway that this is neuropathic and will respond poorly to paracetamol or an anti-inflammatory.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.