Peripheral Neuropathy

Meet the patient

A 62-year-old with 15 years of type 2 diabetes describes two years of tingling in both feet, worse at night, now creeping up his shins. He burnt his toes in the bath without feeling it, and last month he stumbled on a step he could not feel. His ankle jerks are absent and he cannot feel a 10-gram monofilament at four sites on each foot.[1]

Two questions frame every neuropathy viva, and they are the two this whole page exists to answer. What is the pattern? — because pattern predicts the cause: distal symmetric points to diabetes, asymmetric stepwise points to vasculitis, acute ascending points to Guillain-Barre. Is there a treatable cause I am missing? — B12, hypothyroidism, a paraprotein, CIDP. The third, never far behind, is are the feet safe?[3]

What neuropathy is — and the rule that decides every stem

Pattern predicts cause. That single sentence is the discipline of the topic. Before any test, classify the neuropathy along four axes — distribution, modality, pathology and course — and the differential narrows to a short, treatable list.[3]

A peripheral nerve carries three fibre populations, and which one dies decides the symptom. Large myelinated fibres carry vibration, joint position and the reflex arc — their loss gives numbness, sensory ataxia, a positive Romberg and areflexia. Small fibres (A-delta and C) carry pain and temperature and run the autonomic end-organs — their loss gives burning pain, painless injury and autonomic failure. Motor axons give weakness, wasting and fasciculations. Most polyneuropathies are mixed; naming the predominant fibre points the work-up.[1]

The central red flag is acute, asymmetric or motor-predominant neuropathy. That triad points away from the common metabolic causes and towards Guillain-Barre syndrome, CIDP or vasculitic mononeuritis multiplex — all neurological emergencies. The chronic, symmetric, sensorimotor, distal neuropathy of a diabetic is the commonest case and the default the page is built around.[3]

The four axes — distribution, modality, pathology, course

The single most important fork is mononeuropathy (one nerve, usually compressed) versus polyneuropathy (diffuse and symmetric, usually systemic). Everything below refines the polyneuropathy.[3]

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By pathology — the electrophysiological split that drives the differential, and the single most useful step after the history. Axonal neuropathies (the commonest — diabetes, alcohol, B12, toxic) show reduced CMAP and SNAP amplitudes with near-normal conduction velocity. Demyelinating neuropathies (GBS, CIDP, CMT type 1, anti-MAG) show markedly slowed velocity under 35 m/s, prolonged distal latency, conduction block and temporal dispersion.[1]

By course — acute (days to four weeks: GBS, acute toxic), subacute (weeks to months: vasculitis, B12, paraneoplastic), chronic (years: diabetes, CMT, CIDP). The CIDP threshold is progression over more than eight weeks, which is how it parts company with GBS.[1]

How common, and who

Peripheral neuropathy affects 2 to 8 percent of the general population, rising to about 50 percent of people with diabetes after two decades of disease. The leading identifiable causes in primary care are, in order, diabetes, alcohol, B12 deficiency, drug toxicity (especially chemotherapy), chronic kidney disease and hereditary neuropathies. Charcot-Marie-Tooth, the commonest inherited neuromuscular disorder, affects about 1 in 2500. Even after a thorough work-up, 20 to 30 percent remain cryptogenic.[1]

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Risk factors for diabetic peripheral neuropathy are duration, high HbA1c, older age, hypertension, dyslipidaemia, smoking, alcohol excess, and a low BMI in type 1. In type 1 the DCCT showed intensive control cuts incident neuropathy by about 60 percent; in type 2 glucose-lowering alone is modest, and multifactorial cardiovascular risk reduction carries the weight.[2]

Why nerves fail — axonal versus demyelinating

Distinguishing axonal from demyelinating on nerve conduction is the single most useful step after the history, because it partitions the differential into treatable immune disease versus metabolic or toxic disease.[2][3]

Axonal neuropathy is the commonest pathology. The primary injury is to the axon itself; the cell body can no longer sustain the long distal process, so it undergoes distal 'dying-back' degeneration and, once transected, Wallerian degeneration. The longest axons fail first — hence length dependence (the axon to the big toe travels a metre and has the greatest metabolic demand). Nerve conduction shows low amplitudes with preserved velocity.[2]

Demyelinating neuropathy targets myelin or the Schwann cell by immune (GBS, CIDP), dysimmune (anti-MAG) or genetic (CMT1 — PMP22 duplication) mechanisms. Stripped myelin causes conduction block, slowing and temporal dispersion, with weakness out of proportion to axon loss. Velocity falls below 35 m/s, and Schwann cells can remyelinate — which is why the immune forms respond dramatically to immunotherapy.[1]

The diabetic mechanism is multifactorial — worth a viva sentence of its own. Chronic hyperglycaemia drives the polyol pathway: glucose is converted by aldose reductase to sorbitol and fructose, depleting NADPH and myo-inositol and lowering Na/K-ATPase activity. Hyperglycaemia also generates mitochondrial oxidative stress, forms advanced glycation end-products that crosslink nerve and vascular proteins, and causes microvascular ischaemia from thickened endoneurial capillaries. Together these produce the length-dependent, predominantly axonal neuropathy of diabetes.[2]

The other mechanisms worth naming. B12 deficiency impairs methylation in myelin synthesis and produces subacute combined degeneration of the dorsal columns and corticospinal tracts alongside the neuropathy. Alcohol injures nerve directly and through thiamine deficiency. Vincristine blocks microtubules and axonal transport; isoniazid competes with pyridoxine (B6) and causes a sensory neuropathy preventable with pyridoxine 25 to 50 mg daily; metronidazole causes a sensory neuropathy after prolonged courses.[1]

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Meet the neuropathy at the bedside

The symptoms follow the fibre injured. A careful sensory, motor and autonomic history, with attention to tempo and distribution, usually predicts both pathology and cause before any test.[1][3]

Sensory — positive symptoms are tingling, pins-and-needles, burning, stabbing, electric-shock or tight-band pain and allodynia (pain from bedsheets), typically glove-and-stocking and worse at night ('burning feet'). Sensory — negative symptoms are numbness and loss of feeling; large-fibre loss (vibration, proprioception) causes sensory ataxia and a positive Romberg, while small-fibre loss (pain, temperature) allows painless injuries, burns and ulcers — the patient who cannot feel the pebble in the shoe.[1]

Motor signs begin distally: weakness of ankle dorsiflexion (foot drop, tripping), intrinsic foot and hand muscles, then grip; wasting, fasciculations, clawed toes. Reflexes are lost early distally — ankle jerks go first, then knee jerks, then the arms. In hereditary CMT, chronic distal wasting gives inverted champagne-bottle ('stork leg') legs and pes cavus with hammer toes from childhood.[1]

Autonomic symptoms are prominent in diabetic and amyloid neuropathy: orthostatic hypotension (systolic drop of 20 mmHg or more), resting tachycardia, gastroparesis (early satiety, vomiting, erratic glucose), diabetic diarrhoea (often nocturnal), urinary retention, erectile dysfunction, and gustatory sweating on eating cheese or chocolate. Severe autonomic neuropathy carries a poor prognosis.[1]

The neuropathic foot is the most disabling sequel. Painless plantar ulcers appear under the metatarsal heads where repetitive unperceived pressure breaks down insensate skin. Charcot neuroarthropathy presents as a warm, swollen, erythematous, deformed foot with a rocker-bottom shape — easily mistaken for cellulitis, and an emergency for offloading. The neuropathy-ischaemia-infection triad is the classic pathway to amputation.[2]

The differential — DANG THERAPIST and four discriminators

A structured differential uses the DANG THERAPIST frame (reproduced in full at the end of the page). The four conditions below are the high-yield discriminators every viva turns on.[3]

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The classic trap: painful feet with normal nerve conduction are not 'no neuropathy' — they are small-fibre neuropathy, which routine NCS do not test. Confirm with punch skin biopsy measuring intra-epidermal nerve fibre density. Missing this dismisses a real, treatable symptom.[3]

The focused examination

The examination has one job: define the pattern and fibre type, which directs the diagnosis. Answer four questions — is the neuropathy distal symmetric, asymmetric or multifocal, acute motor, or pure sensory or autonomic?[3]

Large-fibre testing — 128-Hz tuning-fork vibration at the hallux, proprioception (toe up or down), and the 10-g Semmes-Weinstein monofilament at six foot sites per foot (hallux dorsum, the 1st, 3rd and 5th metatarsal heads, plus the heel). Inability to feel the monofilament means loss of protective sensation and predicts ulceration — the single most useful bedside test in diabetes.[1]

Small-fibre testing — pinprick and temperature distally; small-fibre neuropathy may spare reflexes and vibration, so a normal large-fibre exam does not exclude it. Motor and reflex — ankle then knee reflexes (ankle lost earliest), distal power, wasting, fasciculations, foot deformity. Gait and Romberg — sensory ataxia gives a wide-based, high-stepping gait; a positive Romberg signals proprioceptive loss.[1]

Orthostatic blood pressure — measure lying and standing for three minutes; a systolic drop of 20 mmHg or more (or diastolic 10 mmHg) within three minutes indicates autonomic failure. Inspect the neuropathic foot for callus, ulcers, deformity, Charcot changes (rocker-bottom, warmth, swelling) and palpate the pulses — a warm swollen deformed foot is acute Charcot until proven otherwise.[1]

Investigations — pattern first, then bloods, then nerve conduction

Investigation is targeted by the clinical pattern — there is no 'screen everything' panel. The goals are to confirm the neuropathy is peripheral, distinguish axonal from demyelinating, and find a treatable cause.[1][3]

First-line bloods — fasting glucose and HbA1c, vitamin B12 (plus methylmalonic acid or homocysteine if borderline, since these rise early and confirm tissue deficiency), full blood count (MCV for macrocytosis pointing to B12 or alcohol), U&E and creatinine, LFTs, TSH, folate and thiamine (if alcohol or malnutrition), and lipids.[1]

Second-line tests (when the pattern is atypical or first-line is unrevealing) — serum protein electrophoresis with immunofixation and anti-MAG antibody (paraproteinaemic neuropathy), ANA, ANCA, rheumatoid factor, complement and cryoglobulins (vasculitis), HIV, hepatitis B and C, serum copper and caeruloplasmin, serum lead, ACE (sarcoid), anti-GQ1b and anti-GM1 antibodies (GBS or multifocal motor neuropathy), and genetic testing for CMT (PMP22 duplication or deletion first, then MPZ, GJB1, MFN2 by phenotype). CSF showing cytoalbuminologic dissociation — high protein, normal cell count — points to GBS or CIDP.[1]

Nerve conduction studies with needle EMG are the key diagnostic test. They distinguish axonal from demyelinating injury and define distribution and severity.[1]

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Small-fibre testing — when symptoms suggest small-fibre neuropathy but routine NCS are normal: punch skin biopsy measuring intra-epidermal nerve fibre density (reduced below the age- and sex-adjusted fifth percentile confirms the diagnosis), quantitative sensory testing, sudomotor tests and corneal confocal microscopy. Sural nerve biopsy is reserved for suspected vasculitis or amyloid, where histology changes management.[3]

Treat the cause, the pain, the feet

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Definitive management has five strands: treat the cause, control neuropathic pain, protect the feet, manage autonomic symptoms, and provide multidisciplinary support.[1][2]

1. Treat the underlying cause — the only disease-modifying step for most. Tight glycaemic control slows diabetic neuropathy (DCCT cut incident neuropathy 60 percent in type 1; weaker in type 2). Intramuscular hydroxocobalamin (1 mg on alternate days for two weeks, then 1 mg every 2 to 3 months maintenance) can partly reverse early B12 neuropathy. Alcohol cessation and thiamine 100 mg daily halt alcoholic neuropathy. Withdraw the offending drug (switch off vincristine, reduce metronidazole, replace isoniazid-related pyridoxine). For immune neuropathies, CIDP responds to IVIg, oral prednisolone or plasma exchange.[1]

2. Neuropathic pain — first-line by class, never opioids. Start one agent, titrate to effect, combine classes on partial response. Pregabalin 150 mg a day in two divided doses, titrate every 3 to 7 days to 300 to 600 mg a day (maximum 600 mg a day; reduce in renal impairment). Gabapentin 300 mg nocte on day 1, titrate to 900 to 3600 mg a day in three divided doses (renally excreted — adjust by creatinine clearance). Duloxetine 30 mg once daily for one week, then 60 mg once daily — the preferred agent for painful diabetic neuropathy per the ADA; up to 120 mg a day. Amitriptyline 10 to 75 mg nocte. Topical lidocaine or capsaicin for focal pain.[2]

3. Foot care — prevents amputation. Daily foot inspection (use a mirror for the sole), well-fitting cushioned footwear, regular podiatry, callus debridement, moisturise dry skin (not between the toes), never walk barefoot, avoid hot water bottles, cut nails straight across, and early offloading of any ulcer with a total-contact cast or knee-high boot. Structured foot-care education is the cornerstone.[1]

4. Autonomic management. Orthostatic hypotension — withdraw aggravating drugs, increase salt (2 to 10 g a day) and fluid (2 to 3 L a day), compression stockings, then fludrocortisone 0.1 to 0.3 mg a day, midodrine 2.5 to 10 mg three times daily, or droxidopa 100 to 600 mg three times daily; raise the head of the bed. Gastroparesis — small frequent low-fat low-fibre meals, metoclopramide 5 to 10 mg before meals (beware tardive dyskinesia), domperidone or erythromycin. Erectile dysfunction — a PDE5 inhibitor (sildenafil, tadalafil).[1]

5. Multidisciplinary support — physiotherapy (strengthening, gait re-education, an ankle-foot orthosis for foot drop), occupational therapy, dietetics, the pain team, orthotics, podiatry and structured diabetes education.[1]

The subtypes that bite

Diabetic peripheral neuropathy (DPN) is the commonest form worldwide — distal symmetric, mixed sensorimotor with autonomic features, predominantly axonal. A painful small-fibre variant (burning feet, normal reflexes and normal NCS) is increasingly recognised and may precede large-fibre loss. Diabetic amyotrophy is a distinct, asymmetric, painful proximal thigh weakness with weight loss in type 2 diabetes, usually monophasic. Screen type 2 diabetes at diagnosis and type 1 from five years after, then annually (10-g monofilament, vibration, ankle reflexes).[1]

Guillain-Barre syndrome (GBS) has its own topic; in brief, an acute (under four weeks), ascending, predominantly motor demyelinating neuropathy with areflexia and cytoalbuminologic dissociation in the CSF, often post-Campylobacter. Treat with IVIg 0.4 g/kg a day for 5 days or plasma exchange; monitor respiratory function and autonomic stability. Distinguish from CIDP by tempo.[4]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic (over eight weeks), usually symmetric, proximal and distal demyelinating motor-predominant neuropathy with conduction block on NCS. Unlike GBS it is steroid-responsive. First-line is IVIg 2 g/kg over 2 to 5 days then maintenance 1 g/kg every 3 weeks, oral prednisolone or plasma exchange. Steroids are contraindicated in multifocal motor neuropathy (a CIDP mimic positive for anti-GM1).[4]

Vitamin B12 deficiency neuropathy combines neuropathy with subacute combined degeneration of the cord (dorsal columns and lateral corticospinal tracts): loss of vibration and proprioception, positive Romberg, spastic paraparesis, extensor plantars, plus a macrocytic anaemia. Risk factors: pernicious anaemia, vegan diet, metformin and proton-pump inhibitors, ileal disease, nitrous-oxide abuse. Hydroxocobalamin 1 mg IM on alternate days for two weeks, then every 2 to 3 months lifelong; partly reversible if treated early.[1]

Chemotherapy-induced peripheral neuropathy (CIPN) comes from platinum (oxaliplatin also causes an acute cold-induced throat and jaw syndrome within hours), taxanes, vincristine, bortezomib and thalidomide. A 'coasting' effect — worsening for weeks after the drug stops — is characteristic. Prevention is dose reduction; duloxetine 30 to 60 mg daily is the only agent with evidence for established CIPN pain.[2]

Charcot-Marie-Tooth disease (CMT) is the commonest inherited neuropathy. CMT1 is demyelinating from PMP22 duplication on chromosome 17p11.2 (autosomal dominant), with uniformly slow conduction from childhood, palpable nerve hypertrophy, pes cavus, hammer toes, stork legs and a family history. CMT2 is axonal; CMTX (GJB1) is X-linked and intermediate. Management is supportive only.[5]

Vasculitic neuropathy / mononeuritis multiplex is asymmetric, painful and stepwise — a classic stem is 'foot drop then wrist drop then a third-nerve palsy'. Systemic features point to polyarteritis nodosa, rheumatoid, ANCA-associated vasculitis or cryoglobulinaemia (hepatitis C). Sural nerve biopsy confirms vasculitis; treat with methylprednisolone 1 g IV daily for 3 to 5 days then oral prednisolone 1 mg/kg a day plus cyclophosphamide or rituximab. Untreated, it progresses to irreversible axonal loss within days — a true emergency.[3]

Bell palsy is an acute, unilateral, lower-motor-neuron (LMN) facial (VII) nerve palsy of presumed viral aetiology. It involves the forehead (the patient cannot wrinkle it) and the orbicularis oculi (Bell phenomenon — the eye rolls up on attempted closure). Associated features depend on the lesion site: hyperacusis (stapedius), loss of taste in the anterior two-thirds of the tongue (chorda tympani), reduced lacrimation. Examine the ear — vesicles with otalgia mean Ramsay Hunt syndrome (herpes zoster oticus), which needs urgent antivirals. Treat with prednisolone 60 mg daily for 5 days within 72 hours plus mandatory eye protection; antivirals add little. Forehead spared equals UMN (stroke), not Bell palsy.[6]

How neuropathy harms — the preventable list

• Lower-limb amputation from a preventable plantar ulcer — the neuropathy-ischaemia-infection pathway; most diabetes-related amputations are preceded by a preventable ulcer, and 10-g monofilament loss predicts it.[2]
• Acute Charcot foot misread as cellulitis or gout and treated with antibiotics instead of offloading — the joint is destroyed while the diagnosis is wrong.
• A missed treatable cause — B12, hypothyroidism, a paraprotein, CIDP — labelled 'diabetic neuropathy' and left to progress.
• Opioid dependence prescribed for neuropathic pain, where gabapentinoids, duloxetine or TCAs are the evidence-based answer.
• GBS missed as 'just numbness' before weakness develops — the window for IVIg is lost.
• Falls, fractures and burns from sensory ataxia, proprioceptive loss and insensate limbs.[3]

Prognosis, and what reverses

Prognosis depends entirely on cause and pathology. Reversible or partly reversible: B12 deficiency (if treated early), hypothyroidism, some toxic neuropathies, CIDP with immunotherapy. Arrestable (progression halts when the cause goes but the deficit persists): diabetes, alcohol, drug withdrawal. Progressive despite treatment: hereditary CMT and amyloid. Axonal neuropathies recover slowly — nerve regrows at about 1 mm a day — so recovery spans months to years if the cell body is intact. Demyelinating neuropathies (GBS, CIDP) can recover quickly through remyelination and respond to immunotherapy.[1][3]

Special populations

The elderly present with falls or imbalance rather than sensory complaint; multimorbidity and polypharmacy raise both neuropathy risk and treatment harm, so dose-reduce gabapentinoids and TCAs (falls, delirium, hyponatraemia), avoid opioids, and screen for reversible causes. In diabetes, annual foot screening (10-g monofilament, vibration, ankle reflexes) is mandatory from diagnosis in type 2 and from five years after in type 1. In pregnancy, gabapentinoids are generally avoided; carpal tunnel of pregnancy usually resolves postpartum. In renal impairment, uraemic neuropathy is partly reversible with transplantation — dose-reduce renally cleared drugs. In chemotherapy patients, baseline nerve conduction for high-risk regimens and cold avoidance for oxaliplatin. In HIV, antiretroviral toxic neuropathy and HIV-distal sensory polyneuropathy are common; distinguish from CMV polyradiculopathy.[1]

Evidence and regional deltas

Screening — the ADA recommends screening all patients with type 2 diabetes at diagnosis and type 1 from five years after, then annually, with a 10-g monofilament with or without vibration; NICE NG19 offers a similar annual foot risk review.[1]

Neuropathic pain — NICE NG193 offers amitriptyline, duloxetine, gabapentin or pregabalin first-line (chosen by comorbidity and cost), combining on partial response and avoiding opioids; the ADA specifically recommends duloxetine or pregabalin for DPN pain; the AAN lists pregabalin (Level A), duloxetine, amitriptyline, gabapentin and venlafaxine.[2]

CIDP — corticosteroids, IVIg and plasma exchange are all effective (ICE, PREDICT and Immune trials); IVIg is often first-line for motor-predominant disease, and steroids are contraindicated in multifocal motor neuropathy.[4]

Bell palsy — the Cochrane review confirms early oral corticosteroids increase good outcomes (NNT about 11); antivirals alone confer no benefit but may be added for severe palsy or Ramsay Hunt.[6]

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The mnemonic, and the mantra

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The mantra: pattern predicts cause — distal symmetric is metabolic, asymmetric is vasculitic, acute ascending is GBS; on nerve conduction axonal means low amplitude, demyelinating means slow; treat the cause, treat the pain (not with opioids), protect the feet.[1]

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Ward-round test — three stems, thirty seconds each

Stem 1 — burning feet in diabetes (answer)

A 60-year-old with type 2 diabetes of 12 years has bilateral burning feet, worse at night, and cannot feel a 10-g monofilament at four sites on each foot. Reflexes are absent at the ankle. What is the diagnosis, the next test, and the first drug for the pain? Model: This is diabetic distal symmetric polyneuropathy — the classic length-dependent, axonal pattern. Confirm with HbA1c and nerve conduction (low amplitude with near-normal velocity). The first drug for the pain is duloxetine 30 mg once daily for one week then 60 mg (the ADA-preferred agent for painful DPN), with pregabalin or amitriptyline as alternatives — not an opioid. Counsel on foot care and arrange annual screening.[1][2]

Stem 2 — foot drop then wrist drop (answer)

A 55-year-old presents with a painful right foot drop over a week, then two weeks later a painful left wrist drop, with weight loss and purpura. What is the pattern, what is the cause until proven otherwise, and what is the test? Model: The pattern is mononeuritis multiplex — asymmetric, painful, stepwise accumulation of individual nerve deficits. The cause is vasculitis until proven otherwise (polyarteritis nodosa, ANCA-associated, rheumatoid, cryoglobulinaemia). The test is an urgent sural nerve biopsy with a contralateral muscle biopsy, then high-dose corticosteroids plus cyclophosphamide or rituximab — untreated, it progresses to irreversible axonal loss within days.[3]

Stem 3 — numbness with a positive Romberg and macrocytosis (answer)

A 65-year-old vegan on metformin has six months of numbness in the feet, a positive Romberg, loss of vibration at the hallux, brisk knee jerks and extensor plantars, and an MCV of 108 fL. What single diagnosis ties this together, and what is the treatment? Model: This is vitamin B12 deficiency causing subacute combined degeneration of the cord plus peripheral neuropathy — dorsal column loss (vibration, proprioception, positive Romberg) with corticospinal tract signs (brisk knees, extensor plantars) and a macrocytic anaemia. The metformin and the vegan diet are the clues. Confirm with serum B12 plus methylmalonic acid, and treat with hydroxocobalamin 1 mg IM on alternate days for two weeks, then every 2 to 3 months lifelong — partly reversible if caught early.[1]

References

1. [1]Selvarajah D, Kar D, Khunti K, et al. Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention Lancet Diabetes Endocrinol, 2019.PMID 31624024
2. [2]Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy Nat Rev Endocrinol, 2021.PMID 34050323
3. [3]Watson JC, Dyck PJB. Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management Mayo Clin Proc, 2015.PMID 26141332
4. [4]Lehmann HC, Burke D, Kuwabara S, et al. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment J Neurol Neurosurg Psychiatry, 2019.PMID 30992333
5. [5]Berciano J, García A, Gallardo E, et al. Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review J Neurol, 2017.PMID 28364294
6. [6]Madhok VB, Gagyor I, Daly F, et al. Corticosteroids for Bell's palsy (idiopathic facial paralysis) Cochrane Database Syst Rev, 2016.PMID 27428352