Key Facts

Diabetic neuropathy is the commonest microvascular complication of diabetes. It is the leading cause of non-traumatic amputation in the UK. Prevention through glycaemic control and early detection through annual screening are the most important interventions.

Epidemiology

Prevalence: ~50% of diabetic patients have some form of neuropathy; ~25% have painful neuropathy. Risk increases with duration of diabetes, poor glycaemic control, and presence of other microvascular complications. Both T1DM and T2DM affected.

Aetiology

• Hyperglycaemia is the primary driver; duration of exposure correlates with risk
• Other risk factors: dyslipidaemia, hypertension, smoking, obesity, genetic susceptibility
• Metabolic syndrome components independently contribute

Pathophysiology

Multiple interconnected pathways driven by chronic hyperglycaemia:

• Polyol pathway: glucose → sorbitol (aldose reductase) → osmotic damage to Schwann cells
• Advanced glycation end-products (AGEs): protein glycation → oxidative stress → endothelial damage
• PKC activation: vascular dysfunction, reduced endoneurial blood flow
• Hexosamine pathway: altered gene expression
• Oxidative/nitrosative stress: mitochondrial dysfunction, DNA damage
• Microvascular disease: endoneurial hypoxia from vasa nervorum disease
• Result: progressive axonal degeneration (dying-back pattern) and segmental demyelination

Distal Symmetric Polyneuropathy (DSPN — ~75%)

• Gradual onset; sensory > motor; glove-and-stocking distribution
• Numbness, tingling, burning pain (worse at night), impaired vibration/proprioception
• Absent ankle jerks; loss of 10g monofilament sensation
• May be asymptomatic — hence importance of annual screening
• Risk of painless injuries → neuropathic ulceration → Charcot foot

Painful Diabetic Neuropathy

• Burning, lancinating, shooting pain; allodynia; hyperalgesia
• Worse at night; disrupts sleep
• May occur paradoxically with improvement in glycaemic control ("insulin neuritis" or treatment-induced neuropathy)

Autonomic Neuropathy

• Cardiovascular: resting tachycardia, orthostatic hypotension, exercise intolerance, silent MI
• GI: gastroparesis (nausea, vomiting, early satiety), constipation, diarrhoea (often nocturnal)
• GU: erectile dysfunction, neurogenic bladder
• Sudomotor: gustatory sweating, anhidrosis (feet)

Other Forms

• Diabetic amyotrophy (proximal motor neuropathy): painful wasting of thigh muscles; often asymmetric; weight loss; usually self-limiting over 12-18 months
• Cranial mononeuropathy: CN III palsy (pupil-sparing — distinguishes from compressive cause); CN VI, VII
• Mononeuritis multiplex: painful; multiple named nerves affected sequentially

Red Flags

• Loss of protective sensation → high amputation risk
• Autonomic neuropathy with silent MI risk
• Rapid asymmetric weakness (exclude other causes)
• Charcot foot (hot, swollen, painless joint destruction)

Bedside

• 10g monofilament testing: annual diabetic foot screening (NICE NG19)
• Vibration perception (128 Hz tuning fork): reduced at great toe
• Ankle reflexes: absent in DSPN
• Ipswich Touch Test: simple screening alternative to monofilament

Bloods

• HbA1c: current glycaemic control
• B12: metformin-induced deficiency (check in all diabetic patients on metformin with neuropathy)
• U&Es: renal function (concurrent diabetic nephropathy)
• TFTs: coexistent hypothyroidism
• SPEP: exclude paraprotein

Neurophysiology

• NCS: axonal sensorimotor polyneuropathy; reduced SNAP/CMAP amplitudes distally with relatively preserved conduction velocities
• Not routinely required for typical DSPN but useful if diagnostic uncertainty

Autonomic Testing

• Lying/standing BP: orthostatic hypotension (>20 mmHg systolic drop)
• Heart rate variability: reduced R-R interval variation (Valsalva, deep breathing)
• Gastric emptying study: if gastroparesis suspected

Foot Assessment

• Annual comprehensive foot exam (NICE NG19): risk stratification for ulceration/amputation

Prevention (Most Important)

• Optimise glycaemic control: target HbA1c individualised (NICE NG28); tight control reduces neuropathy by ~60% in T1DM (DCCT/EDIC) and significantly in T2DM (UKPDS)
• Cardiovascular risk management: BP control, lipids, smoking cessation

Painful Diabetic Neuropathy (NICE CG173)

• First-line: amitriptyline 10-75 mg ON, duloxetine 60-120 mg OD, gabapentin 300-3600 mg/day, or pregabalin 150-600 mg/day
• Duloxetine has specific evidence for painful diabetic neuropathy (NICE preferred in T2DM with concurrent depression)
• Combination therapy: if monotherapy inadequate
• Topical: capsaicin 0.075% cream for localised pain
• Specialist referral: pain clinic for refractory cases; consider tramadol as rescue

Autonomic Neuropathy

• Orthostatic hypotension: fludrocortisone 100-300 μg OD, midodrine 2.5-10 mg TDS; compression stockings; slow positional changes
• Gastroparesis: domperidone 10 mg TDS (short-term), metoclopramide 10 mg TDS (short-term; avoid long-term — tardive dyskinesia); dietary modification (small frequent meals)
• Erectile dysfunction: PDE5 inhibitors (sildenafil 25-100 mg)

Diabetic Foot Care (NICE NG19)

• Annual risk assessment and foot exam
• Podiatry: nail care, callus management, footwear advice
• Patient education: daily foot checks, appropriate footwear
• Prompt treatment of foot ulcers (MDT — diabetic foot team)

Referral Criteria

• Diabetic foot team: any ulceration, Charcot foot, ischaemia
• Neurology: atypical features, diagnostic uncertainty
• Pain clinic: refractory neuropathic pain

DSPN is generally slowly progressive. Tight glycaemic control slows but does not reverse established neuropathy. Painful neuropathy may spontaneously improve in some patients (but nerve damage progresses). Diabetic foot ulceration: lifetime risk ~25%; 5-year mortality after diabetic amputation ~50% (comparable to many cancers). Autonomic neuropathy: associated with increased cardiovascular mortality (silent MI, sudden death — 5-year mortality ~25-50% if symptomatic cardiac autonomic neuropathy).

Types of Diabetic Neuropathy

Key Trials