Neuropathy — Symptoms, Causes & Treatment | MyMedicPlus

Peripheral neuropathy encompasses a broad spectrum of conditions characterised by structural or functional damage to the peripheral nervous system — the network of nerves outside the brain and spinal cord that transmit signals between the central nervous system and the rest of the body. Damage to peripheral nerves disrupts sensory signalling (causing pain, numbness, paraesthesia), motor function (causing weakness, wasting, and gait disturbance), and autonomic regulation (causing cardiovascular, gastrointestinal, bladder, and thermoregulatory dysfunction). Neuropathy is classified anatomically: mononeuropathy (single nerve — carpal tunnel syndrome, ulnar neuropathy, footdrop); mononeuritis multiplex or multifocal neuropathy (multiple separate nerves — vasculitis, sarcoidosis, diabetes); and polyneuropathy (diffuse symmetric involvement of multiple nerves — the most common pattern in metabolic and toxic causes, progressing in the 'length-dependent' stocking-glove pattern from the longest axons distally). Peripheral neuropathy affects approximately 2.4% of the general population, rising to 8% in adults over 55 years. Diabetic peripheral neuropathy is by far the most common identifiable cause in developed countries, ultimately affecting 50-70% of people with diabetes mellitus over their lifetime. Without intervention, peripheral neuropathy can cause permanent disability through foot ulceration, amputation, falls and fractures, intractable neuropathic pain, and autonomic failure.

The causes of peripheral neuropathy are extensive and categorised by pathological mechanism. Metabolic causes: diabetes mellitus (the most common cause in developed countries — affects 50-70% of diabetics, driven by hyperglycaemia-induced oxidative stress, aldose reductase pathway activation, and microvascular ischaemia of nerve trunks); uraemia from chronic kidney disease; hypothyroidism (causing oedema of nerve sheaths); vitamin B12 deficiency (particularly in vegans, elderly, and metformin users — causes subacute combined degeneration of the cord alongside peripheral neuropathy); thiamine (B1) deficiency (Wernicke's disease and dry beriberi, particularly in chronic alcohol users); and pyridoxine (B6) toxicity. Toxic and drug-induced: chronic heavy alcohol use (direct neurotoxin plus thiamine deficiency); chemotherapy-induced peripheral neuropathy (CIPN) — vincristine and vinca alkaloids, taxanes (paclitaxel, docetaxel), platinum compounds (cisplatin, oxaliplatin causing sensory-predominant neuropathy), bortezomib; heavy metal poisoning (arsenic, lead, thallium); amiodarone; metronidazole; linezolid. Infectious: Lyme neuroborreliosis (Borrelia burgdorferi — facial palsy, radiculopathy, European forms), HIV-associated sensory neuropathy, leprosy (Mycobacterium leprae — the most common infectious cause of peripheral neuropathy worldwide), varicella zoster virus (postherpetic neuralgia). Inflammatory/autoimmune: Guillain-Barré syndrome (GBS — acute post-infectious, post-Campylobacter AIDP); CIDP (chronic progressive or relapsing demyelinating polyneuropathy responsive to immunotherapy); vasculitic neuropathy (rheumatoid arthritis, polyarteritis nodosa, ANCA-associated vasculitis — causes mononeuritis multiplex). Hereditary: Charcot-Marie-Tooth disease (CMT — most common hereditary neuropathy affecting 1 in 2,500 — usually CMT1A from PMP22 duplication causing demyelinating neuropathy). Idiopathic or cryptogenic in approximately 30% of cases after thorough investigation.

The clinical presentation of peripheral neuropathy depends on whether sensory, motor, or autonomic fibres are predominantly affected. Sensory symptoms are the most common presenting feature of polyneuropathy — particularly the length-dependent type starting in the toes and feet and progressing proximally over months to years. Positive sensory symptoms include: burning pain (often worse at night), tingling and paraesthesia ('pins and needles'), electric shock-like sensations, and allodynia (pain evoked by normally non-painful stimuli such as light touch or bedclothes). Negative sensory symptoms include: numbness, reduced sensation to pain, temperature, light touch, and vibration; proprioceptive loss causing sensory ataxia (unsteady gait worsened in the dark, positive Romberg test, and inability to balance on one leg with eyes closed). Motor symptoms in polyneuropathy: distal lower limb weakness causing foot drop (high-stepping gait), and hand intrinsic muscle weakness causing difficulty gripping and fine motor tasks; distal wasting of the small muscles of the hands and feet; absent ankle jerks (an early and reliable sign of polyneuropathy) with progressively reduced knee reflexes as the disease advances. Autonomic neuropathy symptoms: postural (orthostatic) hypotension causing dizziness and syncope on standing; gastroparesis causing bloating, nausea, early satiety, unpredictable glycaemic control; neurogenic bladder (retention or incontinence); anhidrosis (inability to sweat) causing heat intolerance; erectile and ejaculatory dysfunction; and cardiac autonomic neuropathy (fixed tachycardia, loss of heart rate variability, risk of silent myocardial infarction and sudden cardiac death). In Guillain-Barré syndrome: rapidly ascending symmetrical weakness beginning in the legs and rising over hours to days, areflexia, and autonomic instability (blood pressure swings, arrhythmia) — a neurological emergency.

A systematic approach to neuropathy diagnosis is essential to identify treatable causes. Initial blood investigations: FBC (anaemia of B12 deficiency), HbA1c and fasting glucose (diabetes), renal function and eGFR (uraemia), liver function tests, TSH (hypothyroidism), serum B12 and folate (deficiency neuropathy), serum protein electrophoresis and immunofixation (paraprotein — MGUS, myeloma, amyloidosis), ANA and ANCA (connective tissue disease, vasculitis), anti-ganglioside antibodies (GQ1b, GM1 — GBS variants), hepatitis B and C serology, HIV serology, Borrelia serology in endemic areas, and urine heavy metal screen if toxic exposure suspected. Nerve conduction studies (NCS) and electromyography (EMG) are the cornerstone of peripheral neuropathy assessment — distinguishing: axonal neuropathy (reduced CMAP and SNAP amplitude, preserved conduction velocity — typical of diabetic, toxic, uraemic) from demyelinating neuropathy (slowed conduction velocity, prolonged F-waves and distal latencies — typical of CIDP, CMT1, GBS); identifying pattern (length-dependent polyneuropathy vs mononeuritis multiplex vs multifocal motor neuropathy); and determining chronicity (acute vs chronic denervation on needle EMG). Lumbar puncture and CSF analysis: protein elevated (above 1g/L) with normal white cell count (cytoalbuminous dissociation) is characteristic of both GBS and CIDP; oligoclonal bands in inflammatory CNS disease; CMV, VZV, EBV PCR in immunocompromised patients. Nerve biopsy (sural nerve at the ankle) reserved for vasculitic or infiltrative neuropathy (sarcoidosis, amyloid) not diagnosed by other means. Genetic testing (CMT gene panel) in young patients with symmetric motor-predominant neuropathy, high arched feet, and family history. Skin punch biopsy for intraepidermal nerve fibre density — the diagnostic standard for small-fibre neuropathy (painful neuropathy with normal NCS).

Treatment of peripheral neuropathy encompasses treating the underlying cause, managing neuropathic pain, and preventing and managing complications. Disease-specific treatment: glycaemic optimisation in diabetic neuropathy (HbA1c below 7-7.5% slows progression — DCCT trial: intensive glucose control reduced neuropathy incidence by 64% over 5 years in T1DM); intramuscular hydroxocobalamin (1mg three times weekly for 2 weeks, then monthly) for B12 deficiency neuropathy; complete alcohol cessation with thiamine supplementation for alcoholic neuropathy; IVIG (2g/kg over 2-5 days) and plasmapheresis are first-line for GBS — reducing time on ventilator and accelerating recovery (SID-GBS trial); for CIDP: IVIG (1-2g/kg every 3-4 weeks) or subcutaneous immunoglobulin (SCIG), oral corticosteroids (prednisolone 60-80mg/day tapering), or plasmapheresis; rituximab for antibody-mediated neuropathies (anti-MAG, POEMS syndrome). Neuropathic pain management (NICE CG173): duloxetine (60-120 mg daily) and pregabalin (150-600 mg/day) or gabapentin (900-3600 mg/day) are first-line treatments; amitriptyline (10-75mg nocte) is effective and low-cost but causes anticholinergic side effects; high-concentration capsaicin 8% patch (Qutenza) applied for 30-60 minutes provides 3-month relief for peripheral neuropathic pain — useful as add-on treatment; lidocaine infusions (5mg/kg IV over 60 minutes) for refractory neuropathic pain; opioids (tramadol, oxycodone) for severe refractory cases with clear benefit-risk assessment. Alpha-lipoic acid (600mg IV daily for 3 weeks, then 600mg oral) has level A evidence from the ALADIN trials for improving diabetic neuropathic symptoms. Physiotherapy: strengthening exercises for distal weakness, balance training to reduce falls, proprioceptive exercises, and ankle-foot orthoses (AFO) for footdrop. Regular podiatry and protective footwear for insensate feet in diabetic neuropathy.

Diabetic peripheral neuropathy with sensory loss is the most dangerous precursor to the diabetic foot — insensate feet do not register pain from friction, pressure, or trauma, leading to unnoticed foot ulcers that become infected and progress to osteomyelitis, Charcot neuroarthropathy (progressive neuropathic joint destruction causing deformity and instability), and gangrene requiring lower extremity amputation. Diabetic foot complications cause approximately 70,000 amputations annually in the UK alone. Falls from sensory ataxia, proprioceptive loss, and motor weakness significantly increase fracture risk — particularly hip fractures — in elderly patients with peripheral neuropathy. Autonomic neuropathy carries multiple severe complications: diabetic gastroparesis (causing bloating, vomiting, unpredictable food absorption, and dangerous hypoglycaemic episodes); urinary retention and recurrent UTIs from neurogenic bladder; silent myocardial infarction (failure to perceive ischaemic chest pain); and cardiac autonomic neuropathy (fixed resting tachycardia, impaired heart rate variability) — an independent predictor of sudden cardiac death in diabetes. Guillain-Barré syndrome progresses to respiratory failure requiring mechanical ventilation in 25-30% of patients — mortality is 3-5% even with modern intensive care. Chronic neuropathic pain causes profound impairment of sleep, mood, daily function, and quality of life — depression and anxiety are major comorbidities of chronic neuropathic pain.

Diabetic neuropathy prevention: intensive glycaemic control is the most evidence-based preventive strategy — maintaining HbA1c below 7% reduces the cumulative incidence of clinical diabetic peripheral neuropathy by 64% over 6.5 years in Type 1 diabetes (DCCT trial); similar benefits shown in Type 2 diabetes (ADVANCE, UKPDS). Additional cardiovascular risk factor control (blood pressure, lipids) provides additional neuropathy protection. Annual comprehensive diabetic foot examination (monofilament, vibration, pulse assessment) in all people with diabetes — earlier in those with established glycaemic issues. Daily foot inspection in diabetic patients: check between toes for moisture, breaks, blisters, and pressure areas; appropriate footwear (broad, soft, seamless); podiatry referral for high-risk feet (any neuropathy plus deformity, ulceration, or PAD). Metformin B12 monitoring: annual serum B12 in all patients on long-term metformin — supplement when subnormal or borderline, as metformin-induced B12 deficiency causes neuropathy indistinguishable from diabetic neuropathy. Alcohol reduction: cessation prevents further axonal injury from alcohol-related neuropathy and allows slow recovery. Chemotherapy-induced peripheral neuropathy (CIPN) mitigation: dose modification, schedule adjustment, and cryotherapy (cooling gloves and socks during taxane administration — reduces CIPN incidence 30-50%). Regular neurological assessment during all potentially neurotoxic chemotherapy courses enables timely dose modification.

Call emergency services (999/911) immediately for: rapidly progressive ascending weakness — weakness starting in the legs and moving upwards over hours to days, especially following a recent viral illness or gastrointestinal infection — Guillain-Barre syndrome (GBS) requires immediate hospital admission; some patients deteriorate to respiratory failure within days; wrist drop, foot drop, or sudden new focal neurological weakness without clear cause — acute mononeuropathy requires urgent investigation; inability to urinate or severe constipation combined with leg weakness and back pain — possible cauda equina syndrome (compressive neuropathy) — neurosurgical emergency. See your GP urgently for: new numbness or tingling in both hands and feet persisting more than 2 weeks — first-line neuropathy screen (HbA1c, B12, TSH, FBC, renal function); diabetic foot ulcer that is not healing within 2-4 weeks — multidisciplinary diabetic foot team referral; burning foot pain at night interfering with sleep in a person with diabetes — uncontrolled diabetic neuropathy requiring medication review and glycaemic optimisation. See your GP routinely for: annual foot examination and monofilament testing if you have diabetes; assessment if taking metformin for more than 5 years — B12 levels fall in long-term metformin users; new tingling, numbness, or weakness in someone on chemotherapy — dose adjustment may prevent permanent nerve damage.