Peripheral neuropathy - acquired
Description
- Characterise before you investigate. Four questions settle the differential:
- 1. Pattern - symmetric length-dependent | mononeuritis multiplex | radiculoplexus | non-length-dependent (ganglionopathy)
- 2. Fibre type - motor | large-fibre sensory | small-fibre | autonomic
- 3. Physiology - axonal vs demyelinating (NCS decides)
- 4. Tempo - acute (<4 wk) | subacute | chronic (>8 wk)
Pattern -> cause
| Pattern | Think |
|---|---|
| Distal symmetric, length-dependent ("glove and stocking") | Diabetes, alcohol, CKD, B12, drugs, idiopathic. Legs before arms; arms involved once legs affected to the knee |
| Mononeuritis multiplex | Vasculitis, diabetes, leprosy, sarcoid, amyloid, HNPP, HIV, malignancy |
| Demyelinating, proximal + distal | GBS, CIDP, anti-MAG, CMT1, HNPP |
| Sensory ganglionopathy (non-length-dependent, ataxic, arms early) | Paraneoplastic (anti-Hu, SCLC), Sjogren's, cisplatin, B6 toxicity |
| Pure motor | GBS, multifocal motor neuropathy, lead, porphyria, dapsone, CMT (HMSN), MND (not a neuropathy) |
| Small fibre | Diabetes/prediabetes, amyloid, HIV, Sjogren's, Fabry, sodium channel variants, idiopathic |
| Autonomic-predominant | Amyloid, diabetes, paraneoplastic, GBS, porphyria, HIV |
| Painful, rapidly progressive, asymmetric | Vasculitis - a medical emergency |
Large vs small fibre
- Large - vibration, proprioception, reflexes, motor. Sensory ataxia, Romberg positive, pseudoathetosis
- Small - pinprick, temperature, burning/dysaesthetic pain, autonomic. NCS are NORMAL - a normal NCS does not exclude neuropathy
Epidemiology
- Prevalence ~2-3% overall, ~8% over 55
- Diabetes is the commonest cause in the developed world; distal symmetric polyneuropathy the commonest pattern
- ~50% of people with diabetes develop it; 20-30% of those have neuropathic pain
- Leprosy is the commonest cause worldwide
- ~25-30% remain idiopathic ("cryptogenic sensory polyneuropathy") after full work-up - most are older, and a substantial fraction have impaired glucose tolerance
Aetiopathogenesis
Metabolic and endocrine
- Diabetes mellitus (and impaired glucose tolerance - causes small-fibre neuropathy before diabetes is diagnosed)
- Chronic kidney disease (uraemic), hypothyroidism, acromegaly, critical illness polyneuropathy
Toxic
- Alcohol - direct toxicity + thiamine deficiency; painful, small and large fibre
- Drugs: isoniazid (give pyridoxine 25 mg with it), vincristine, cisplatin/oxaliplatin, taxanes, bortezomib, thalidomide, nitrofurantoin, metronidazole, linezolid, amiodarone, phenytoin, dapsone, checkpoint inhibitors, nucleoside analogues, excess pyridoxine (B6) itself
- Heavy metals - lead (motor, wrist drop), arsenic (Mees lines), thallium, mercury; organophosphates, n-hexane
Nutritional
- B12 (also SACD), B1 (thiamine), B6 (both deficiency and excess), B3 (pellagra), vitamin E, copper, folate
- Post-bariatric surgery, malabsorption, nitrous oxide abuse (functional B12 deficiency, normal B12 level - check MMA/homocysteine)
Inflammatory / immune
- GBS, CIDP and variants
- Vasculitis - PAN, EGPA, GPA, rheumatoid vasculitis, cryoglobulinaemia, non-systemic vasculitic neuropathy
- Connective tissue disease - Sjogren's (ganglionopathy, small fibre), SLE, RA, scleroderma
- Sarcoidosis; coeliac disease
Infective
- HIV (disease and drugs), leprosy, hepatitis B and C (via cryoglobulins), Lyme disease, syphilis, diphtheria, HTLV-1, Chagas
Neoplastic and paraproteinaemic
- Paraneoplastic sensory neuronopathy (anti-Hu, small cell lung cancer), anti-CV2/CRMP5
- MGUS, myeloma, POEMS (osteosclerotic myeloma, inc VEGF), Waldenstrom/anti-MAG, AL amyloidosis
- Direct infiltration - neurolymphomatosis, leptomeningeal disease
- Chemotherapy-induced peripheral neuropathy - dose-dependent, stocking-glove, often permanent
Other
- Amyloidosis - AL (acquired) and hereditary ATTR; painful small fibre + autonomic + carpal tunnel + cardiac
- Porphyria (acute motor neuropathy + abdominal pain + psychiatric features + hyponatraemia)
- Hereditary (see hereditary neuropathy), HNPP
- Idiopathic
Diagnosis
Examination
- Distribution and gradient - map the sensory level up the leg, then check the hands
- Symmetric loss to the knees with early hand involvement suggests a non-length-dependent process
- Reflexes - absent ankle jerks first; generalised areflexia suggests demyelination
- Motor: distal wasting (EDB, intrinsic hand muscles), foot drop, pes cavus (= long-standing/hereditary)
- Sensory ataxia: Romberg, pseudoathetosis, high-stepping stamping gait
- Autonomic: postural BP, resting tachycardia, anhidrosis, gastroparesis, bladder
- Feet: ulcers, callus, Charcot joint, deformity, pulses, nail changes
- Palpable thickened nerves (ulnar, greater auricular, common peroneal) - leprosy, CMT1, amyloid, HNPP, acromegaly
- Skin: purpura and livedo (vasculitis), Mees lines, alopecia (thallium), rash
First-tier investigations - in everyone
- FBE, UEC, LFT, HbA1c (and a 2-hour OGTT if HbA1c normal), TSH, B12 (+ MMA/homocysteine), folate
- SPEP + immunofixation + serum free light chains - never omit; a paraprotein changes everything
- ESR/CRP
- NCS/EMG - the single most informative test
- Axonal: reduced amplitudes, relatively preserved velocities
- Demyelinating: slowed velocity, prolonged distal latency, conduction block, temporal dispersion, prolonged F-waves
- Demyelinating = a short, treatable list. Axonal = a long, mostly metabolic list
Second-tier - guided by the pattern
- Vasculitis/mononeuritis multiplex: ANCA, ANA/ENA, RF, cryoglobulins, complement, hepatitis B/C, HIV -> nerve (sural) + muscle biopsy
- Demyelinating: CSF (protein, cells, oligoclonal bands), anti-MAG, nodal/paranodal antibodies, genetic testing for CMT
- Ganglionopathy/subacute sensory: paraneoplastic antibody panel, CT chest/abdomen/pelvis +/- PET, anti-Ro/La
- Amyloid: serum free light chains + fat pad/nerve biopsy with Congo red, echocardiogram, TTR genetic testing
- Small fibre with normal NCS: skin punch biopsy for intraepidermal nerve fibre density, quantitative sensory testing, autonomic testing
- Copper, vitamin E, heavy metals, porphobilinogen (urine, during an attack), lead
- MRI plexus/roots; nerve ultrasound
Red flags demanding urgent work-up
- Rapid progression over days-weeks (GBS, vasculitis, porphyria, diphtheria)
- Asymmetry / mononeuritis multiplex with systemic features -> vasculitis: biopsy and treat within days
- Prominent autonomic failure -> amyloid, paraneoplastic, GBS
- Weight loss, constitutional symptoms -> malignancy, vasculitis
- Motor > sensory, proximal involvement -> CIDP, MMN, porphyria - all treatable
Management
A. Treat the cause - the only thing that changes the trajectory
- Diabetes: tight glycaemic control prevents and slows neuropathy in type 1; the effect in type 2 is far smaller - so also treat BP, lipids, smoking, weight
- Alcohol: abstinence + parenteral thiamine before glucose + broad B-group replacement
- B12: hydroxocobalamin IM; treat the nitrous oxide use, not just the level
- Drug-induced: stop or substitute; some (platins) show "coasting" - worsening for weeks after stopping
- CKD: dialysis adequacy; transplantation improves it
- Hypothyroidism, coeliac disease, sarcoidosis: treat the disease
- Vasculitic neuropathy: high-dose corticosteroid + cyclophosphamide or rituximab, urgently - axons lost are not recovered
- CIDP/GBS/MMN: IVIg, steroids or plasma exchange as appropriate (MMN: IVIg - steroids and PLEX can worsen it)
- AL amyloid: treat the plasma cell clone. ATTR: tafamidis, patisiran/vutrisiran, eplontersen
- Paraneoplastic: treat the tumour; immunotherapy has limited benefit once neurons are lost
- Leprosy: multidrug therapy + steroid for reactions
B. Neuropathic pain - four equal first-line agents
| Agent | Notes |
|---|---|
| Amitriptyline | Start 10-25 mg nocte. Anticholinergic - avoid in the elderly, glaucoma, urinary retention, cardiac disease |
| Duloxetine | 30-60 mg daily. Good evidence in diabetic neuropathy; nausea, BP |
| Pregabalin | 75 mg BD, titrate. Renally cleared - reduce in CKD. Sedation, oedema, weight gain |
| Gabapentin | Slower titration, TDS dosing, same cautions |
- Choose by comorbidity and adverse effect profile, not by hierarchy - efficacy is broadly equivalent (OPTION-DM)
- Titrate to the maximum tolerated dose before declaring failure; if partial response, combination therapy is better than switching
- Set expectations: a 30-50% reduction in pain is a success. Complete relief is not the goal
- Second-line: nortriptyline, venlafaxine, topical capsaicin 8% patch, topical lidocaine, carbamazepine/oxcarbazepine
- Avoid opioids - poor long-term efficacy, dependence, hyperalgesia; tramadol and tapentadol only short-term and reluctantly
- Gabapentinoid misuse and diversion are real - screen, and be cautious with concurrent opioids (respiratory depression)
- Non-pharmacological: exercise, CBT, pain psychology, sleep, TENS; spinal cord stimulation for refractory painful diabetic neuropathy
C. Prevent the complications that cause the disability
- Daily foot inspection, professional podiatry, appropriate footwear, treat callus - insensate feet ulcerate; ulcers amputate
- Annual monofilament and vibration screening in diabetes
- Falls prevention, home OT assessment, walking aids
- Ankle-foot orthosis for foot drop
- Burns and pressure injury education
- Driving assessment where proprioception or foot power is impaired
D. Autonomic neuropathy
- Postural hypotension: stop culprit drugs, salt/fluid, compression, head-up tilt; fludrocortisone, midodrine
- Gastroparesis: small low-fat low-fibre meals, metoclopramide short-term, erythromycin
- Bladder: timed voiding, intermittent catheterisation
- Erectile dysfunction: PDE5 inhibitor
- Silent myocardial ischaemia - a low threshold for cardiac investigation
Associations
- Diabetes - and impaired glucose tolerance, metabolic syndrome, obesity
- Alcohol use disorder - with thiamine deficiency, cerebellar degeneration
- Chronic kidney disease, especially dialysis
- Monoclonal gammopathy - MGUS, myeloma, POEMS, Waldenstrom, AL amyloid
- Vasculitis and connective tissue disease - PAN, EGPA, GPA, RA, SLE, Sjogren's
- Malignancy - small cell lung cancer (anti-Hu), lymphoma; and its treatments
- HIV, hepatitis B and C, leprosy, Lyme disease
- Coeliac disease, inflammatory bowel disease, bariatric surgery
- Sarcoidosis, hypothyroidism, acromegaly
- Charcot neuroarthropathy, foot ulceration and amputation - the endpoint of untreated insensate feet
- Restless legs syndrome; depression and sleep disturbance from neuropathic pain
Natural history & complications
- Depends entirely on the cause and on how much is axonal
- Demyelinating and inflammatory - potentially fully reversible if treated early
- Axonal - regeneration at ~1 mm/day and only from surviving axons; recovery is slow, partial and length-limited
- Ganglionopathy - dorsal root ganglion neurons do not regenerate; usually permanent
- Diabetic distal symmetric polyneuropathy is progressive and largely irreversible - the goal is prevention of ulceration, not reversal
- Painful diabetic neuropathy may burn out as fibres are lost - less pain with more numbness is not improvement
- Chemotherapy-induced neuropathy: platinum agents "coast" (worsen for weeks after the last dose); partial recovery over 1-2 years, often incomplete
- Vasculitic neuropathy: stepwise accumulation; deficits fixed once axons are lost - early immunosuppression is the whole prognosis
- Idiopathic sensory polyneuropathy: slowly progressive, rarely disabling, does not shorten life
Complications
- Foot ulceration, osteomyelitis, Charcot joint, amputation
- Falls, fractures, loss of independence
- Chronic neuropathic pain, sleep disturbance, depression, opioid dependence
- Autonomic failure - syncope, silent ischaemia, gastroparesis, sudden death (in amyloid and diabetes)
Monitor
- Annual foot examination in diabetes and any sensory neuropathy
- Objective strength, gait and disability measures if immunotherapy is used
- Re-investigate if the pattern changes - a new asymmetry or motor progression means a second diagnosis
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