Peripheral Neuropathy — Common Causes and Approach to the Patient

Peripheral Neuropathy — Common Causes and Approach to the Patient Definition and classification

Peripheral neuropathy is a disorder of peripheral nerves — motor, sensory and/or autonomic — producing weakness, sensory disturbance or autonomic failure.

Prevalence is 11% in people aged 55 and over; the commonest single risk factor is diabetes mellitus (44% of cases), followed by alcoholism, non-alcoholic liver disease and malignancy.

Classify by pattern of nerve involvement: mononeuropathy (a major nerve trunk), mononeuritis multiplex (multiple mononeuropathies), symmetrical polyneuropathy (terminal branches of multiple nerves, bilateral and similar in distribution), radiculopathy (nerve roots) and polyradiculoneuropathy.

Also classify by time course (acute <4 weeks, subacute, chronic >8 weeks), fibre type (large fibre vs small fibre) and pathology (axonal vs demyelinating) — these four axes together generate the differential diagnosis.

Diabetes mellitus — the commonest cause. Lifetime prevalence of diabetic neuropathy reaches 50%; prevalence rises with age (8.4% at 20–34 years to 42.4% at ≥65 years), and age is an independent risk factor. Neuropathic pain occurs in 13.3% of people with diabetes, 8.7% with impaired glucose tolerance, 4.2% with impaired fasting glucose and 1.2% of controls — so prediabetes also causes neuropathy.

Alcohol and non-alcoholic liver disease.

Nutritional: vitamin B12 deficiency (poor B12 status is associated with worse sensory and motor peripheral nerve function in older adults), thiamine, pyridoxine (both deficiency and excess), vitamin E, folate.

Malignancy and paraproteinaemia: multiple myeloma, MGUS, AL amyloidosis, POEMS syndrome, anti-Hu paraneoplastic neuronopathy, lymphoma.

Drugs and toxins: vincristine, cisplatin, taxanes, bortezomib, thalidomide, isoniazid, metronidazole, nitrofurantoin, amiodarone, phenytoin, linezolid; lead, arsenic, thallium, organophosphates.

Infections: leprosy (the commonest treatable cause of neuropathy in India), HIV, hepatitis B and C, syphilis, diphtheria, herpes zoster.

Endocrine and metabolic: hypothyroidism, chronic kidney disease/uraemia, acromegaly.

Immune-mediated: Guillain–Barré syndrome (acute), CIDP, multifocal motor neuropathy with conduction block, vasculitic neuropathy (polyarteritis nodosa, rheumatoid, Sjögren's, ANCA-associated), sarcoidosis.

Hereditary: Charcot–Marie–Tooth disease (HMSN) and hereditary transthyretin amyloidosis — the latter frequently mislabelled as idiopathic in older patients.

Entrapment: carpal tunnel syndrome, ulnar neuropathy at the elbow, common peroneal palsy at the fibular head. Pressure neuropathy is not diabetes-specific but occurs more commonly in diabetes.

Idiopathic (chronic idiopathic axonal polyneuropathy) in 25–30% after complete evaluation.

History: tempo of onset, distribution and symmetry, positive versus negative symptoms, family history, occupational and toxin exposure, alcohol, a complete drug history, systemic symptoms, diabetes or prediabetes, and diet.

Positive sensory symptoms: burning, tingling, pins and needles, electric shocks, allodynia (pain from a non-painful stimulus) and hyperalgesia. Negative symptoms: reduced sensation, numbness, a "dead" feeling. Pain from small-fibre neuropathy is superficial and burning, worse at night and interferes with sleep; pain from large-fibre neuropathy is deep and less sharp. Patients describe walking "barefoot on hot charcoal".

Distal symmetrical polyneuropathy is the commonest pattern — length-dependent, starting at the toes and ascending, in a "glove and stocking" distribution, with sensory symptoms reaching the knees before the fingers are affected.

Examination: pin prick, light touch, temperature, vibration (128 Hz tuning fork) and joint position sense; muscle strength testing and inspection for wasting; reflexes; gait and Romberg's test. Inspect the feet for ulcers, deformity and Charcot arthropathy; palpate peripheral nerves for thickening (leprosy, CMT); check postural blood pressure for autonomic involvement.

Red flags for urgent referral: rapid progression, marked asymmetry, prominent motor involvement, autonomic failure, or an associated systemic illness — these suggest GBS, vasculitis or malignancy.

Extensive testing is not necessary in a patient with mild symptoms and a known underlying diagnosis such as diabetes or alcohol excess.

In patients with no clear aetiology, electrodiagnostic testing (NCS/EMG) should be the initial diagnostic study — it distinguishes axonal from demyelinating physiology, identifies polyradiculopathy, plexopathy and mononeuritis multiplex, and separates hereditary from acquired demyelinating patterns (Rutkove algorithm).

First-line laboratory tests, directed by the electrodiagnostic result: full blood count, ESR, TSH, blood glucose and glycated haemoglobin, serum and urine protein electrophoresis with immunofixation, vitamin B12, antinuclear antibody, rheumatoid factor, heavy metals and HIV. Add renal and liver function.

Second-line, if the above are negative: urinary heavy metals and porphyrins, Sjögren's antibodies, Lyme serology, anti-Hu antibody, and — in patients with borderline-normal serum B12 — methylmalonic acid and homocysteine. For demyelinating patterns: lumbar puncture (albuminocytological dissociation), anti-GM1 and anti-MAG antibodies, hepatitis B and C serology.

Specialised tests: skin biopsy for intraepidermal nerve fibre density in small-fibre neuropathy, corneal confocal microscopy as a non-invasive measure of small-fibre loss, autonomic function testing (sympathetic skin response, tilt table, R–R interval, Valsalva), genetic testing for CMT and TTR, and sural nerve biopsy reserved for suspected vasculitis or amyloidosis.

Treatment should address the underlying disease process and alleviate symptoms. Avoidance of toxins such as alcohol or drugs is the most important step.

Disease-directed therapy: glycaemic control (more effective in type 1 than type 2 diabetes), lipid and blood pressure control, withdrawal of the offending drug, B12 replacement, thyroxine, dialysis, multidrug therapy for leprosy, and immunotherapy for CIDP (corticosteroids, IVIG, plasma exchange) or vasculitis.

Symptomatic pain relief — see Question 8. In painful neuropathies, tricyclic antidepressants and gabapentin are effective, with SNRIs and pregabalin preferred in older adults.

Function and falls: physiotherapy assessment is important in patients with weakness; ankle–foot orthoses, splints and walking-assistance devices improve function. Diabetic neuropathy substantially increases the risk of falls — use a structured programme such as STEADI, with balance and gait training. Care plans should focus not only on pain relief but on improving mobility and maintaining independence and quality of life.

Proper foot and nail care is important in reducing the risk of foot ulcers — daily inspection, appropriate footwear, podiatry review and prompt treatment of minor injury.