Sensory Neuropathy Algorithm

Done

Safety

Red Flags — Exclude Urgent Neurological Emergencies

Sensory symptoms can herald cord compression, Guillain-Barré syndrome, or vasculitis — do not miss these.

Rapidly ascending weakness + sensory loss Legs → arms, autonomic features (HR/BP fluctuation, urinary retention) → 999 (Guillain-Barré syndrome)

Cord compression / cauda equina Bilateral leg numbness, saddle anaesthesia, urinary/bowel dysfunction, bilateral leg weakness → 999 (MRI spine same-day)

Transverse myelitis Sudden onset bilateral sensory level + weakness after infection/vaccination → 999 (urgent neurology)

Vasculitic neuropathy Mononeuritis multiplex (asymmetric, stepwise), purpuric rash, systemic illness, known RA/SLE → Same-day haematology/neurology

Acute onset ± cranial nerve involvement New facial numbness, diplopia, dysphagia with limb symptoms → 999 (stroke / MS first presentation)

Malignant neuropathy Known malignancy + new neuropathy, paraneoplastic syndrome, lymphadenopathy, weight loss → Urgent neurology + oncology

Diabetic foot with neuropathy Loss of protective sensation + ulceration, cellulitis, or Charcot foot → Same-day diabetic foot team

Subacute combined degeneration B12 deficiency + progressive posterior column signs (loss of vibration/proprioception, positive Romberg) → Urgent neurology review

Guillain-Barré syndrome progresses to respiratory failure in 25% of cases — early recognition and ITU admission saves lives. Cauda equina syndrome is an emergency with a 6-hour window for surgical decompression. Vasculitic neuropathy can cause irreversible axonal loss within days without immunosuppression. Missing diabetic neuropathic foot ulceration leads to amputation — the UK sees 135 amputations per week from diabetic foot disease (NHS England 2023).

Done

Diagnose

History — Characterise the Neuropathy Pattern

Pattern recognition drives diagnosis — distribution, onset, and quality of symptoms guide the investigation pathway.

Onset & progression

Acute (<4 weeks) → GBS, vasculitis, toxic, metabolic crisis. Subacute (4–8 weeks) → nutritional deficiency, inflammatory. Chronic (>6 months) → diabetic, hereditary, alcohol.

Distribution

Length-dependent (stocking-glove) → metabolic (DM, uraemia), toxic, alcohol. Asymmetric / patchy → mononeuritis multiplex (vasculitis, HNPP). Pure small-fibre → DM, Fabry disease.

Quality of symptoms

Burning, allodynia → small-fibre / painful peripheral neuropathy. Numbness, loss of proprioception → large-fibre. Tingling + weakness → mixed.

Causative conditions

Diabetes (commonest — 50% of T2DM at 10 years), alcohol (>21 units/week), CKD, hypothyroidism, B12 deficiency, malignancy, drugs, HIV.

Medication history

Metronidazole, isoniazid, amiodarone, vincristine, nitrofurantoin, statins, thalidomide — all cause neuropathy. Check ALL medications including OTC.

Family history

Charcot-Marie-Tooth (CMT) — pes cavus, high arch, distal wasting, slow progression. Ask about family members with similar symptoms or "unusual feet."

Occupational / toxic

Heavy metal exposure (lead, arsenic, thallium), industrial solvents, organophosphates. Occupation in agriculture, battery/paint manufacturing.

Systemic symptoms

Weight loss → malignancy, DM. Dry eyes/mouth → Sjögren's (pure sensory neuropathy). Rash, joint pain → connective tissue disease.

The distribution of sensory loss is the most diagnostically useful feature. Length-dependent stocking-glove pattern strongly suggests a metabolic or toxic cause (sensitivity >80% for diabetic neuropathy in the right context). Asymmetric mononeuritis multiplex is vasculitis until proven otherwise. Identifying and removing the causative agent (stopping a neurotoxic drug, controlling DM, replacing B12) is the single most important treatment — more than any symptomatic therapy.

Done

Diagnose

Classification — Neuropathy Type & Aetiology

Classification by fibre type and aetiology drives investigation and management.

Diabetic peripheral neuropathy

Most common cause in UK (50% at 10 years T2DM). Stocking-glove, burning, allodynia. Diagnose clinically + HbA1c. Annual foot examination mandatory (NICE NG28). Metabolic

Alcohol-related neuropathy

Predominantly painful, small-fibre early. Correlates with lifetime alcohol consumption, not current intake. B1 deficiency contributes. Toxic/nutritional

B12 deficiency neuropathy

Loss of vibration and proprioception (large-fibre), posterior column signs. Often insidious. Common in vegans, metformin users, elderly, pernicious anaemia. Nutritional

Hereditary neuropathy (CMT)

Pes cavus, distal wasting, reduced/absent reflexes, family history, very slow progression. NICE Clinical Guideline for rare neurological diseases. Refer genetics. Hereditary

CIDP / GBS

Inflammatory demyelinating. CIDP relapsing-remitting, GBS acute ascending. CSF protein elevated, NCS demyelinating pattern. Refer neurology urgently. Inflammatory

Cryptogenic / idiopathic

15–25% of peripheral neuropathy after full workup remains unexplained. Often length-dependent, small-fibre, mild. Diagnose by exclusion. Idiopathic

Uraemic neuropathy

eGFR <30 associated with polyneuropathy. Predominantly sensory, distal. Improves with dialysis. Associated restless legs. Metabolic

Drug-induced neuropathy

Identify offending drug — amiodarone (large & small fibre), metronidazole (sensory >1–2g total dose), vincristine, isoniazid (prevent with B6 50 mg OD). Toxic

Aetiological classification directly determines treatability. Diabetic neuropathy is prevented/halted by glucose control. B12 deficiency neuropathy is reversible if treated early (irreversible if >6 months established). Drug-induced neuropathy resolves on withdrawal. CIDP responds dramatically to IVIg or steroids — missing this diagnosis condemns the patient to progressive disability. Up to 25% of "cryptogenic" neuropathies on extended workup will have an identifiable cause (notably B12, pre-diabetes, or small hereditary CMT variants).

Done

Diagnose

Targeted Neurological Examination

A focused 5-minute neurological examination will confirm fibre type, distribution, and severity.

Vibration sense

128 Hz tuning fork — great toe, medial malleolus, tibial tuberosity, iliac crest. Loss at toe = distal; spreading proximally = advancing neuropathy. Compare to own sternum as reference.

Proprioception

Passive movement of great toe in IP joint. Loss = large-fibre (posterior column) involvement. If impaired → Romberg's test for balance implication.

Light touch / pinprick

Map distribution carefully — stocking-glove, asymmetric, dermatomal. Use neurotip or orange stick. Document level (toe, ankle, knee, mid-thigh).

Temperature sense

Warm/cool tuning fork or thermal testing — detects small-fibre neuropathy early (lost before vibration). Most sensitive test for early diabetic neuropathy.

Tendon reflexes

Ankle jerks absent = early neuropathy sign. Knee jerks absent = advanced. Brisk reflexes + sensory loss = upper motor neurone lesion (cord/brain) not peripheral neuropathy — re-examine.

Motor assessment

Ankle dorsiflexion, toe extension, intrinsic hand muscles (interossei). Wasting of small foot muscles. Pure sensory neuropathy — power preserved.

Autonomic features

Postural BP drop (>20 mmHg systolic on standing), dry/anhidrotic skin, fixed HR, erectile dysfunction — autonomic neuropathy (DM, amyloid, GBS).

Foot inspection

Pes cavus (CMT), Charcot foot deformity, callus over pressure points, ulceration. Monofilament test (10g) — loss = high amputation risk.

The 10g monofilament test has a sensitivity of 86% and specificity of 73% for identifying diabetic patients at high risk of foot ulceration (SIGN 116). Loss of ankle jerk is the earliest reproducible clinical sign of peripheral neuropathy and should always be tested. Brisk reflexes with sensory loss indicates cord pathology not peripheral neuropathy — this finding mandates urgent MRI spine and neurology referral, not peripheral neuropathy workup.

Done

Diagnose

Investigations — Targeted Peripheral Neuropathy Screen

Structured investigation finds a treatable cause in 50–75% of peripheral neuropathies.

First-line bloods

FBC, ESR, CRP, glucose/HbA1c, U&E (eGFR), TFTs, B12 + folate, LFTs (alcohol), serum protein electrophoresis (SPEP) — cover all common metabolic causes in one panel

B12 interpretation

Serum B12 <148 pmol/L = deficient. 148–258 pmol/L = borderline → check MMA + homocysteine (elevated = functional deficiency). Treat if neurological symptoms regardless of borderline result.

Glucose / HbA1c

HbA1c 42–47 = pre-diabetes (associated with painful small-fibre neuropathy). HbA1c ≥48 = diabetes. OGTT if HbA1c borderline. Up to 30% of "cryptogenic" neuropathy has unrecognised pre-diabetes.

SPEP / immunology

SPEP ± immunofixation — paraprotein (MGUS) in 10% of neuropathy. If paraprotein found: haematology referral. Also: ANA, ANCA, anti-Ro/La (Sjögren's), cryoglobulins if systemic features.

Nerve conduction studies

NCS / EMG — refer neurophysiology. Differentiates axonal (DM, toxic) from demyelinating (CIDP, CMT, GBS). Confirms diagnosis, guides referral. Request via neurology or direct neurophysiology.

Cerebrospinal fluid

Via neurology — if CIDP, GBS, or inflammatory neuropathy suspected. Raised protein + normal white cells (albuminocytological dissociation) = GBS/CIDP.

Genetic testing

PMP22 duplication (CMT1A) — commonest hereditary neuropathy. Via clinical genetics. Consider if young, pes cavus, family history, NCS shows demyelinating pattern.

Do NOT routinely order

MRI brain (unless UMN signs or cranial nerve involvement), heavy metals (only if occupational exposure), skin biopsy (specialist centres only for small-fibre neuropathy)

A structured first-line panel (glucose, B12, TFT, U&E, SPEP) identifies a treatable cause in 50–75% of peripheral neuropathies presenting in primary care. B12 deficiency affects 6% of adults >60 years and is easily missed when borderline — MMA is the most sensitive marker. The association between pre-diabetes and painful small-fibre neuropathy is increasingly recognised; an OGTT should be performed if fasting glucose or HbA1c is borderline. SPEP detects MGUS neuropathy in 10% of cases — this group may have IgM anti-MAG neuropathy that responds to rituximab.

Done

Refer

Referral Criteria — Neurology, Diabetology, Haematology

999 Now

Emergency GBS (ascending weakness/autonomic), cauda equina syndrome, acute cord compression, transverse myelitis, acute vasculitic neuropathy

Urgent neurology

Within 2 weeks Rapidly progressive neuropathy (>1 step decline/month), suspected CIDP, mononeuritis multiplex, cranial nerve involvement, subacute combined degeneration of cord

Routine neurology

Within 18 weeks Confirmed peripheral neuropathy with no identified cause after first-line investigation, diagnostic uncertainty, NCS required, suspected CMT, complex painful neuropathy unresponsive to treatment

Diabetic foot team

Same-day if ulcer present Neuropathic ulceration, Charcot foot (red/hot/swollen foot in DM), loss of monofilament sensation + deformity. Routine: annual diabetic foot assessment (NICE NG28)

Haematology

Within 2 weeks Paraprotein (MGUS) on SPEP, especially IgM paraprotein with demyelinating neuropathy (anti-MAG), suspected amyloid neuropathy, lymphoma/myeloma screen

Rheumatology

Within 4 weeks Suspected vasculitic neuropathy (mononeuritis multiplex + ANCA/anti-Ro positive), Sjögren's sensory neuropathy, connective tissue disease with neuropathy

Clinical genetics

Routine Suspected CMT (young patient, pes cavus, family history, demyelinating NCS), Fabry disease (young patient + small-fibre + cardiorenal features), familial amyloid

Primary care manage

Stable mild diabetic neuropathy (optimise glycaemia, start neuropathic pain agent if symptomatic), confirmed B12 deficiency (replace), alcohol-related (abstinence + thiamine + B vitamins)

CIDP is treatable — IVIg produces dramatic improvement in 65% of patients, but only if diagnosed promptly. Vasculitic neuropathy requires urgent immunosuppression to prevent irreversible axonal loss. Diabetic foot ulceration in the context of neuropathy carries a 30% 12-month amputation risk without specialist management. MGUS-associated IgM neuropathy may respond to rituximab — a diagnosis that can only be made via haematology with nerve biopsy.

Done

Treat

Pharmacological Treatment — Neuropathic Pain Ladder (NICE NG173)

Treat the underlying cause first. Add neuropathic pain agents for symptomatic relief. Do not use standard analgesics alone.

Step 1: Address Underlying Cause

B12 deficiency

Hydroxocobalamin IM

1 mg IM on alternate days × 6 doses (loading), then 1 mg IM every 3 months (maintenance). Oral 1000 mcg OD if no neurological features and adherence assured.

Diabetic neuropathy

Optimise glycaemia

Target HbA1c per NICE NG28. SGLT2i and GLP-1 RA may reduce neuropathy progression. Good glucose control reduces neuropathy risk 25–60%.

Alcohol neuropathy

Thiamine + abstinence

Thiamine 100 mg TDS oral + B-complex vitamins. Abstinence is primary treatment. Refer alcohol liaison service. Prevent Wernicke's encephalopathy.

Step 2: Neuropathic Pain — First-Line (NICE NG173)

1st lineAmitriptyline 10 mg ON — titrate by 10 mg every 2–4 weeks to 75 mg ON if tolerated. NNT 3.6. Caution: QTc prolongation, anticholinergic effects, elderly. OR Duloxetine 30 mg OD (preferred if DM) — increase to 60 mg OD after 2 weeks. NNT 5. Check LFTs if liver disease.

2nd linePregabalin 75 mg BD — titrate to 150–300 mg BD over 2–4 weeks. Schedule 3 controlled drug. NNT 7. Or Gabapentin 300 mg OD increasing to 600 mg TDS — non-controlled, cheaper. Caution: drowsiness, falls, misuse potential.

3rd lineCombination therapy — combine from different classes (e.g., amitriptyline + pregabalin). Or add tramadol 50 mg PRN (short-term only, abuse potential, Schedule 3). Refer pain clinic if inadequate control.

TopicalCapsaicin 0.075% cream TDS–QDS for localised neuropathic pain (post-herpetic, small area). Capsaicin 8% patch (Qutenza) — specialist use only, primary care managed post-herpetic neuralgia trial. Lidocaine 5% plasters for post-herpetic neuralgia.

NICE NG173 (2021) recommends amitriptyline, duloxetine, gabapentin, or pregabalin as first-line neuropathic pain treatments. Standard analgesics (paracetamol, NSAIDs, opioids) are not recommended for neuropathic pain — opioids have NNT of 4–5 with significant long-term harm. Duloxetine is preferred in diabetic neuropathy as it also improves glycaemia and has cardiovascular benefits. Pregabalin was classified as a Class C / Schedule 3 controlled drug in 2019 due to misuse and overdose concerns — prescribe cautiously. B12 replacement must use IM injections if neurological signs are present as oral absorption may be impaired via intrinsic factor deficiency.

Done

Lifestyle

Non-Pharmacological Interventions

Glycaemic optimisation (DM) Intensive glucose control reduces diabetic neuropathy incidence by 60% (T1DM, DCCT trial) and 25–35% in T2DM. HbA1c target individualised per NICE NG28. Flash/CGM technology improves time-in-range.

Alcohol cessation Alcohol-related neuropathy partially reverses with abstinence over 12 months. Refer to alcohol liaison. Combined with thiamine, approximately 50% show neurological improvement.

Foot care education Daily inspection, appropriate footwear (extra-depth, seamless), avoid barefoot walking, nail care, moisturise. Podiatry referral. Monofilament loss = high-risk foot = 3-monthly podiatry.

Exercise Aerobic exercise 150 min/week improves peripheral nerve function in DM (small-fibre density improvement on skin biopsy — 2017 RCT). Also improves balance, reducing fall risk from neuropathy.

Falls prevention Loss of proprioception and vibration sense significantly increases fall risk. Refer to falls prevention programme, home hazard assessment. Walking aids, handrails, non-slip mats. Hip protectors if high osteoporosis risk.

Dietary review Ensure B12-rich foods (meat, fish, dairy) or supplementation. Vegans need B12 supplementation throughout. Thiamine-rich diet for alcohol-related. Folate from green vegetables.

Pain education & psychology Neuropathic pain is chronic — CBT/ACT reduces pain catastrophising and improves function. Refer pain psychology if >6 months pain, significant functional impairment, or depression comorbid.

Transcutaneous electrical nerve stimulation (TENS) TENS machine for localised neuropathic pain — evidence modest but safe. Physiotherapy referral for TENS trial. Useful adjunct for post-herpetic neuralgia, painful DPN.

Exercise-induced improvement in intraepidermal nerve fibre density in diabetes is a landmark finding showing that neuropathy can be partially reversed — a paradigm shift from viewing diabetic neuropathy as purely progressive. Falls risk from neuropathy is 2× the background rate; a hip fracture in an elderly patient with neuropathy carries 30% 1-year mortality. Foot care education in high-risk neuropathic feet reduces amputation rates by 50% (NICE NG28 evidence review).

Done

Safety

Follow-Up, Monitoring & Safety-Netting

4–6 weeks

Review response to first-line neuropathic pain agent. Assess side effects — drowsiness (pregabalin/gabapentin), orthostatic hypotension (amitriptyline), nausea (duloxetine). Titrate dose if tolerated and partially effective.

3 months

B12 recheck if borderline deficiency or IM loading completed. HbA1c in diabetic neuropathy. Reassess neuropathy symptoms — LANSS score or DN4 tool. Check LFTs if on duloxetine.

6 months

Neurological re-examination — is neuropathy progressing? Repeat vibration and monofilament. Diabetic annual foot review due. Review alcohol use if alcohol-related. Update carer/family if falls risk.

Annually

Diabetic foot annual review (NICE NG28). B12 level in maintenance injection patients. Review need for ongoing neuropathic pain medication — consider stepping down if stable >6 months.

Safety-net 999

New bilateral leg weakness or ascending weakness, bladder/bowel change, new saddle anaesthesia — exclude cauda equina / GBS. Any rapidly spreading neurological deficit.

Safety-net same-day GP

Acute deterioration of neuropathy, new falls, foot ulceration or skin breakdown, signs of infection in neuropathic foot, severe pain crisis unresponsive to medications

Neurology re-referral

Progression despite treatment, new motor involvement (pure sensory neuropathy becoming motor-sensory), failure to identify aetiology, consideration of skin biopsy or ganglioside antibodies in specialist setting

Neuropathic pain medications take 4–8 weeks to reach full effect — early review prevents premature discontinuation. Progression of a pure sensory neuropathy to include motor features should always prompt urgent re-referral as this may signal CIDP or vasculitic neuropathy. Annual diabetic foot reviews are a NICE quality standard (QS177) — failure to perform is a significant clinical governance issue. B12 IM maintenance is lifelong in pernicious anaemia; stopping injections risks irreversible cord damage.