Peripheral neuropathy: pattern and investigation

01Purpose and principlesWhat the assessment is for and the core concepts behind it.

Begin with anatomy and tempo. Length-dependent polyneuropathy starts in the longest axons, producing distal toe sensory change that ascends symmetrically and later reaches fingers; ankle reflexes fall before knees and distal weakness appears late. A focal median, ulnar, fibular or lateral cutaneous distribution suggests entrapment or injury. Multiple non-contiguous nerves affected asynchronously is mononeuritis multiplex. Root disease follows dermatomes and myotomes and can include spinal pain; plexopathy crosses several nerve and root territories. Proximal symmetrical weakness with preserved sensation suggests myopathy, while fluctuating fatigability suggests neuromuscular junction disease. Acute or subacute progression narrows the differential towards inflammatory, infectious, toxic and vasculitic causes and raises urgency.

Define fibre involvement. Large myelinated fibres carry vibration and proprioception, so loss causes unsteadiness in darkness, positive Romberg sign, impaired joint position and areflexia. Small fibres carry pain, temperature and autonomic function, producing burning, allodynia, altered sweating, postural symptoms and gastrointestinal or sexual dysfunction. Motor fibres produce wasting, fasciculation and weakness; autonomic involvement can create silent hypoglycaemia, bladder or cardiovascular risk. Examine skin and feet, trophic injury, pulses, arches, hammer toes, gait, heel and toe walking, tone, power, reflexes and mapped modalities. Check cranial nerves, upper motor neurone signs and a sensory level so peripheral symptoms do not conceal central disease.

Investigation is targeted but systematic. Establish diabetes, alcohol, nutrition, renal, thyroid, autoimmune, cancer, infection, medicine and family history. Baseline bloods commonly assess blood count, glucose, renal, liver, thyroid and B12 status, inflammatory markers and paraprotein; add folate, coeliac, HIV, hepatitis, syphilis, copper, vitamin E or B6 and autoimmune tests only when phenotype or exposure supports them. Nerve conduction and EMG confirm large-fibre physiology and demyelinating patterns but do not exclude small-fibre disease. Specialist skin biopsy or quantitative sensory and autonomic testing can support small-fibre neuropathy. Genetic testing is most useful after a hereditary phenotype and counselling, not as an indiscriminate panel. Nerve biopsy is reserved for selected vasculitic, infiltrative or amyloid questions because it causes permanent sensory loss and sampling can miss disease.

Key points

Localise before listing causes: decide whether symptoms fit length-dependent polyneuropathy, focal mononeuropathy, mononeuritis multiplex, plexopathy, radiculopathy, neuromuscular junction or myopathy.
Large-fibre loss causes vibration and joint-position impairment, sensory ataxia and reduced reflexes; small-fibre loss causes burning pain and temperature or pinprick change with preserved routine nerve conduction.
A symmetrical stocking pattern progressing slowly from toes upward suggests length-dependent axonal polyneuropathy, commonly metabolic, toxic, nutritional or idiopathic.
Painful, stepwise, asymmetric involvement of separate named nerves suggests mononeuritis multiplex and can represent treatable vasculitis, infection or infiltrative disease.
Weakness with upper motor neurone signs, a sensory level or sphincter dysfunction points to spinal cord disease, while dermatomal pain and myotomal weakness suggest radiculopathy.
Core tests commonly include FBC, renal and liver profile, glucose or HbA1c, B12, thyroid function, inflammatory markers and serum protein electrophoresis or immunoglobulins, adjusted to history.
Nerve-conduction studies and EMG classify axonal versus demyelinating, sensory versus motor and focal versus diffuse disease but can be normal in pure small-fibre neuropathy.
Ask about alcohol, chemotherapy, metronidazole, nitrofurantoin, amiodarone, excess vitamin B6, occupational toxins, bariatric surgery, vegan diet and family foot deformity.
Do not treat a neuropathic pain score alone: protect insensate feet, address falls and weakness, remove the cause where possible and select analgesia by function and adverse effects.

02Indications, selection and cautionsWhen it is useful, when urgency changes and important limitations.

Length-dependent axonal pattern

Slow symmetrical distal sensory loss, absent ankles and later distal weakness, with feet affected well before hands, suggests a dying-back polyneuropathy.

Small-fibre syndrome

Burning feet, allodynia and pinprick or temperature loss with normal strength, reflexes and routine nerve conduction can indicate selective small-fibre disease.

Demyelinating patternRed flag

Prominent weakness, diffuse areflexia and neurophysiological slowing, conduction block or temporal dispersion raises acquired or hereditary demyelinating neuropathy.

Mononeuritis multiplexRed flag

Painful acute or subacute deficits in separate individual nerves, such as foot drop followed by wrist drop, suggest vasculitic or infiltrative nerve injury.

Hereditary phenotype

Long history, family members, pes cavus, hammer toes, distal wasting and disproportionally mild sensory symptoms supports an inherited neuropathy.

Central or cauda mimicRed flag

Hyperreflexia, extensor plantar response, sensory level, new bladder dysfunction or saddle anaesthesia shifts localisation to cord or cauda equina and changes urgency.

03Method and interpretationA systematic approach to the test and its findings.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Patterned neurological examinationFirst step
Why
Map modalities, weakness and reflexes to a fibre type, nerve, root, plexus or length-dependent distribution.
Interpretation and limitations
Objective anatomy determines subsequent tests; inconsistent boundaries invite re-examination but do not by themselves establish functional symptoms.
02
Baseline neuropathy blood panel
Why
Detect common metabolic, nutritional, endocrine, organ and paraprotein causes with high clinical yield.
Interpretation and limitations
Interpret HbA1c, B12, thyroid, renal, liver, FBC, inflammatory and protein studies in context; borderline B12 may need functional markers under local practice.
03
Nerve-conduction studies and electromyography
Why
Classify large-fibre neuropathy as axonal or demyelinating and define motor, sensory, focal and chronic denervation features.
Interpretation and limitations
Normal studies do not exclude small-fibre disease, and mild slowing from cold limbs or diabetes must not be overcalled as inflammatory demyelination.
04
MRI spine or plexus imaging
Why
Investigate cord, root, cauda, plexus or infiltrative disease when examination localises beyond a distal polyneuropathy.
Interpretation and limitations
Degenerative changes are common and need anatomical concordance; urgent compression signs take precedence over elective neuropathy investigation.
05
Small-fibre and autonomic testing
Why
Confirm reduced intraepidermal nerve fibres or disordered autonomic function when routine studies are normal.
Interpretation and limitations
Specialist skin biopsy, cardiovascular autonomic testing or sensory thresholds support the phenotype but still require a cause-directed assessment.
06
Genetic testing or nerve biopsy
Why
Answer a focused inherited, vasculitic, amyloid or infiltrative question after specialist selection.
Interpretation and limitations
Testing should change counselling or treatment; biopsy morbidity and incomplete sensitivity make it inappropriate for routine symmetrical neuropathy.

04Clinical next stepsHow the result changes management or prompts escalation.

01LocaliseName the anatomical patternFirst stepNumbness, pain, weakness or imbalance could arise from peripheral nerve disease.

1Define onset, tempo, symmetry, proximal versus distal distribution, pain, autonomic symptoms and exposure or family history.
2Map pinprick, temperature, vibration, joint position, power and reflexes, while checking gait, cranial nerves and central long-tract signs.
3Classify length-dependent, focal nerve, multiple nerve, root, plexus, small-fibre, motor-predominant or demyelinating phenotype before ordering tests.
4EscalationEscalate immediately for respiratory, bulbar, sphincter, rapidly progressive motor or painful asymmetric vasculitic patterns.

02InvestigateUse a high-yield first passA stable peripheral neuropathy pattern is established without an emergency.

1Review diabetes, alcohol, diet, surgery, cancer treatment, infection, systemic autoimmunity, renal disease and a complete medicine and supplement list.
2Order core metabolic, haematological, thyroid, nutritional and paraprotein testing, adding infection or autoimmune assays only where pre-test probability supports them.
3Refer for nerve-conduction and EMG assessment when weakness, atypical distribution, progression or diagnostic uncertainty will change management.
4Use imaging, small-fibre testing, genetics or biopsy only after the remaining anatomical and causal question is explicit.

03ManageProtect function while treating causeNeuropathy is confirmed or remains the best working diagnosis.

1Remove or treat a reversible driver such as toxin, deficiency, diabetes, paraprotein or compression with relevant specialist advice.
2Assess feet, footwear, falls, gait aids, driving and occupational injury, referring to podiatry, physiotherapy or orthotics as indicated.
3Treat neuropathic pain using NICE choices and shared adverse-effect review, setting functional goals rather than promising complete numbness reversal.
4Monitor trajectory and reopen investigation for rapid progression, new asymmetry, proximal weakness, systemic features or autonomic compromise.

05Procedure and medicine safetyRelevant preparation, treatment and contraindications.

One NICE first-line option for neuropathic pain when anticholinergic and overdose risks are acceptable.

Amitriptyline for neuropathic pain

Commonly start 10 mg at night and titrate cautiously according to benefit, daytime sedation, age, cardiac risk and local formulary limits.

Dry mouth, constipation, retention, glaucoma, postural hypotension, arrhythmia, falls and toxicity in overdose can outweigh benefit, especially in frailty.

A NICE first-line neuropathic-pain option, particularly useful when painful diabetic neuropathy or comorbid depression influences choice.

Duloxetine for neuropathic pain

A common adult start is 30 mg once daily, increasing to 60 mg daily if needed and tolerated under the licensed or local regimen.

Review blood pressure, liver disease, renal impairment, nausea, sexual effects, suicidality and serotonergic interactions; taper rather than stopping abruptly.

A NICE first-line neuropathic-pain choice for selected patients when sedation and misuse risk are addressed.

Gabapentin

Start at a low divided dose and titrate gradually with renal adjustment to the lowest regimen that improves function within BNF limits.

Dizziness, somnolence, oedema, falls, respiratory depression with opioids and dependence or withdrawal require careful prescribing and gradual discontinuation.

06Risks, monitoring and follow-upComplications, safety checks and further assessment.

Document sensory boundary, reflexes, distal and proximal power, gait and autonomic symptoms over time so true progression can be distinguished from pain fluctuation.
Inspect insensate feet and footwear regularly, escalating ulceration, infection, ischaemia or a hot swollen Charcot-type foot through the appropriate urgent pathway.
Follow the identified cause with relevant measures, such as HbA1c, B12 response, paraprotein surveillance or toxin cessation, rather than repeating broad panels indiscriminately.
For neuropathic-pain medicines monitor function, sleep, sedation, falls, mood, weight, oedema, misuse and withdrawal alongside numerical pain scores.
Re-refer urgently for new bulbar or respiratory symptoms, rapidly spreading weakness, severe autonomic disturbance or painful stepwise asymmetry.

07Special situationsVariants, exceptions and circumstances that change the usual approach.

Reflexes map length

Loss of ankle jerks with preserved knees often accompanies early length-dependent neuropathy, while diffuse areflexia plus weakness raises a broader demyelinating process.

Normal conduction can hurt

Routine studies assess large myelinated fibres, so severe burning small-fibre neuropathy can coexist with normal sensory and motor conduction results.

Hands follow legs by length

In a dying-back neuropathy, sensory loss usually reaches the upper calf before fingertips become involved; early hand symptoms suggest entrapment or another pattern.

Painful asymmetry is inflammatory until assessed

Mononeuritis multiplex can represent vessel-wall destruction and irreversible axonal loss, so slow routine work-up may miss a treatment window.

A cause can be plural

Diabetes does not exclude B12 deficiency, alcohol toxicity, entrapment or CIDP; atypical progression deserves renewed localisation rather than diagnostic anchoring.

08Common pitfallsFrequent interpretation and management errors.

01
Calling any distal tingling diabetic neuropathy without mapping symmetry, reflexes, modalities and the relationship between feet and hands.
02
Using a normal nerve-conduction study to dismiss burning pain and autonomic symptoms that fit a small-fibre syndrome.
03
Ordering a vast autoimmune or genetic panel before defining phenotype and pre-test probability, creating incidental findings without answers.
04
Missing cord or cauda disease when brisk reflexes, a sensory level, sphincter symptoms or saddle change accompany apparently peripheral complaints.
05
Treating pain pharmacologically while overlooking insensate-foot injury, balance, weakness, falls and the removable toxic or nutritional cause.
06
Performing nerve biopsy for routine symmetrical neuropathy despite permanent deficit and low yield outside vasculitic, amyloid or infiltrative questions.