Numbness and paraesthesia

Numbness is reduced or absent sensation. Paraesthesia is an abnormal sensation (tingling, pins and needles, burning) occurring spontaneously or on stimulation. Most cases are due to peripheral neuropathy or focal nerve entrapment, but stroke, demyelination, cord disease and metabolic disturbance must be considered first when onset is sudden or the distribution is unusual.

Clinical relevance. The distribution of symptoms localises the lesion; the speed of onset and the associated weakness decide urgency.

Anatomy and localisation.

• Glove and stocking distribution: length dependent polyneuropathy.
• Single nerve territory: mononeuropathy (carpal tunnel: thumb, index, middle and half the ring finger; ulnar: little finger and half the ring finger; lateral cutaneous nerve of the thigh: lateral thigh).
• Dermatomal band with radiating pain: radiculopathy.
• Hemisensory loss with face, arm and leg: thalamus, internal capsule or cortex.
• Sensory level on the trunk: spinal cord.
• Crossed face and body loss: lateral medullary lesion.
• Perioral and distal limb tingling: hypocalcaemia, hyperventilation.
• Cape distribution of loss of pain and temperature: syringomyelia.

Mechanisms. Axonal degeneration, demyelination, nerve compression and ischaemia, dorsal root ganglion injury, central lesion, metabolic and ionic disturbance, and abnormal excitability of sensory fibres.

Temporal patterns. Sudden (stroke, transient ischaemic attack, migraine aura, hypocalcaemia, hyperventilation), subacute (inflammatory neuropathy, vasculitis, toxic, B12 deficiency), and chronic (diabetes, alcohol, hereditary, uraemia).

History. Describe the sensation, distribution, onset, progression, and whether it affects both sides symmetrically.

Ask about:

• Pain, weakness, balance problems and falls, night symptoms, wrist or elbow posture effects, and neck or back pain.
• Bladder and bowel symptoms, and autonomic features (postural dizziness, sweating, erectile dysfunction).
• Visual change, speech disturbance, headache, perioral tingling, palpitations and anxiety.
• Recent infection or vaccination, and weight loss.

Background.

• Diabetes (duration, glycaemic control), alcohol intake, and diet (vegetarian, vegan, bariatric surgery, malabsorption).
• Thyroid disease, kidney or liver disease, HIV, hepatitis B and C, and syphilis.
• Cancer and chemotherapy, autoimmune disease, monoclonal gammopathy, and amyloidosis.
• Family history of neuropathy or foot deformity, occupation and repetitive movements, and toxin or heavy metal exposure.

Drug history. Isoniazid (without pyridoxine), metronidazole and nitrofurantoin (prolonged use), linezolid, dapsone, ethambutol, antiretrovirals (stavudine, didanosine, zalcitabine), amiodarone, phenytoin, platinum agents, taxanes, vincristine, bortezomib, thalidomide, statins, disulfiram, nitrous oxide, and excess pyridoxine (over 50 mg daily).

Examination.

• Light touch, pinprick, temperature, vibration (128 Hz tuning fork) and joint position at the toes and fingers, monofilament testing in the foot, two point discrimination, and the extent of any level.
• Power, bulk, tone, reflexes (absent ankle jerks in length dependent neuropathy), plantar responses, Romberg test, gait.
• Tinel sign (percussion at the carpal tunnel or ulnar groove), Phalen test, Spurling test, straight leg raise, Lhermitte sign.
• Cranial nerves, face sensation, visual fields, and speech.
• Skin: ulcers, trophic changes, hair loss, nail changes, hypopigmented anaesthetic patches (leprosy), thickened nerves, rash.
• Thyroid, signs of liver disease, pallor, glossitis, blood pressure and lying and standing readings, pulse, cardiac murmur, and signs of vasculitis (livedo, purpura, nailfold infarcts).

Red flags

• Sudden onset in a vascular pattern (face, arm and leg), or with speech, visual or motor symptoms
• Ascending numbness with weakness and reduced reflexes over days
• Sensory level, bladder or bowel dysfunction, or saddle anaesthesia
• Rapid progression over weeks, severe asymmetric or painful neuropathy (vasculitis)
• Weight loss, cancer, fever, or night sweats
• Perioral numbness with carpopedal spasm or tetany
• Neurological deficit after neck manipulation
• Painless wounds, burns or foot ulcers

Special groups. Pregnancy: carpal tunnel syndrome and meralgia paraesthetica are common; pre-eclampsia with neurological features. Older adults: B12 deficiency, diabetes, and cervical myelopathy are common. Region specific: leprosy (hypopigmented anaesthetic patches, thickened nerves), HIV neuropathy, konzo and tropical neuropathy, and diabetes in all settings.

Length dependent and generalised polyneuropathy

• Diabetic neuropathy, impaired glucose tolerance
• Vitamin B12, folate, thiamine, pyridoxine deficiency or excess, copper deficiency
• Alcohol related neuropathy
• Hypothyroidism, uraemia, liver disease, amyloidosis
• Drug and toxin induced neuropathy (isoniazid, metronidazole, nitrofurantoin, linezolid, dapsone, stavudine and didanosine, amiodarone, phenytoin, platinum agents, taxanes, vincristine, bortezomib, thalidomide, nitrous oxide), heavy metals (arsenic, lead, thallium, mercury)
• Infective: HIV, leprosy, syphilis, hepatitis B and C, Lyme disease, diphtheria
• Paraproteinaemic (IgM monoclonal gammopathy, myeloma, POEMS syndrome), paraneoplastic neuropathy
• Inflammatory: Guillain Barré syndrome, chronic inflammatory demyelinating polyneuropathy, vasculitic neuropathy and mononeuritis multiplex, Sjogren syndrome, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis
• Hereditary: Charcot Marie Tooth disease, hereditary neuropathy with pressure palsies, Fabry disease, hereditary amyloidosis, porphyria
• Small fibre neuropathy (burning pain with normal conduction studies)
• Critical illness polyneuropathy

Focal peripheral causes

• Carpal tunnel syndrome, cubital tunnel syndrome, radial nerve palsy, meralgia paraesthetica, common peroneal nerve palsy, tarsal tunnel syndrome, thoracic outlet syndrome, Morton neuroma
• Cervical or lumbar radiculopathy, nerve root avulsion
• Brachial and lumbosacral plexopathy, neuralgic amyotrophy

Spinal cord and brainstem

• Cervical spondylotic myelopathy, cord compression, syringomyelia
• Multiple sclerosis, transverse myelitis, neuromyelitis optica, subacute combined degeneration, tabes dorsalis
• Lateral medullary syndrome, dorsal column lesions

Cerebral

• Transient ischaemic attack and stroke (thalamic, parietal, lacunar), cerebral venous thrombosis
• Migraine aura, focal seizure with sensory onset
• Brain tumour, abscess, demyelination

Metabolic and other

• Hypocalcaemia, hypomagnesaemia, hypokalaemia, hyperkalaemia, hyperventilation syndrome, panic attack
• Ciguatera, tetrodotoxin and shellfish toxin poisoning
• Reduced circulation: peripheral arterial disease, Raynaud phenomenon, compartment syndrome
• Postural pressure (positional paraesthesia), functional sensory loss

Reasoning. Decide whether the distribution is central, spinal, root, plexus, nerve or length dependent, and whether there is weakness. Rule out stroke and cord compression first when onset is sudden or a level is present. Then test for treatable systemic causes of neuropathy.

First line for suspected neuropathy:

• fasting glucose and HbA1c (diabetes: HbA1c 48 mmol/mol or more; impaired glucose regulation 42 to 47 mmol/mol)
• full blood count and film (macrocytosis)
• vitamin B12 (under 200 ng/L or 148 pmol/L indicates deficiency; 200 to 300 ng/L is borderline and needs methylmalonic acid or homocysteine)
• folate
• urea, electrolytes, creatinine, calcium, magnesium
• liver function
• thyroid stimulating hormone
• ESR and C reactive protein
• serum protein electrophoresis with immunofixation and free light chains
• HIV test
• hepatitis B and C and syphilis serology

Further tests by suspicion

• Antinuclear antibody, anti-Ro and anti-La, ANCA, rheumatoid factor, complement, cryoglobulins, angiotensin converting enzyme.
• Heavy metals (blood, urine), urinary porphyrins during attacks, thiamine and pyridoxine levels, copper and caeruloplasmin.
• Paraneoplastic antibodies (anti-Hu, anti-CV2) and CT chest, abdomen and pelvis.
• Nerve conduction studies and electromyography: confirm and classify neuropathy (axonal or demyelinating), carpal tunnel and other entrapments, radiculopathy and plexopathy. Normal studies do not exclude small fibre neuropathy.
• Skin biopsy for intraepidermal nerve fibre density in suspected small fibre neuropathy; nerve and skin biopsy for vasculitis, leprosy (slit skin smear and biopsy) and amyloidosis.
• Genetic testing for hereditary neuropathy, Fabry disease and amyloidosis after counselling.
• Cerebrospinal fluid for Guillain Barré syndrome, chronic inflammatory demyelinating polyneuropathy and infection (after imaging when raised pressure is possible).
• MRI brain or spine for central, root or cord patterns, and for any sensory level or myelopathic signs.
• Carotid imaging and echocardiography in suspected embolic transient ischaemic attack.
• Ionised calcium, magnesium and arterial or venous blood gas (alkalosis with low ionised calcium) in perioral numbness.

Limitations. Reference ranges for vitamin B12 are imprecise, and neuropathy can occur with normal levels. About a fifth of neuropathies remain idiopathic after investigation. Nerve conduction studies may be normal in early or small fibre disease.

Exclude emergencies. Sudden vascular pattern numbness: treat as a transient ischaemic attack or stroke with immediate stroke team contact. Sensory level or bladder dysfunction: emergency spinal imaging. Ascending weakness with sensory symptoms: respiratory monitoring and treatment of Guillain Barré syndrome (intravenous immunoglobulin 0.4 g/kg daily for 5 days).

Treat the cause

• Diabetes: glycaemic control (avoid rapid intensification that can cause treatment induced neuropathy), foot care and annual foot examination.
• Vitamin B12 deficiency with neurological signs: hydroxocobalamin 1 mg IM on alternate days until no further improvement (up to 3 weeks), then 1 mg every 2 months; oral cyanocobalamin 1 mg daily when deficiency is dietary without neurological signs; never give folic acid alone first.
• Alcohol: abstinence, thiamine 100 mg orally three times daily (500 mg IV every 8 hours for 3 days when Wernicke encephalopathy is possible), and nutrition.
• Hypothyroidism: levothyroxine 1.6 micrograms/kg orally daily (start at 25 to 50 micrograms in older adults and in heart disease).
• Drug induced neuropathy: stop or reduce the culprit drug when possible. Isoniazid: pyridoxine 10 mg daily prophylaxis, and 50 to 100 mg daily if neuropathy has developed.
• Hypocalcaemia with tetany: calcium gluconate 10 percent 10 mL IV over 10 minutes with ECG monitoring, then an infusion and treatment of the cause.
• Hyperventilation: reassurance, breathing retraining and anxiety treatment.
• Chronic inflammatory demyelinating polyneuropathy: intravenous immunoglobulin 2 g/kg over 2 to 5 days, or prednisolone 1 mg/kg daily (maximum 60 to 80 mg), under specialist care. Vasculitic neuropathy: prednisolone 1 mg/kg daily with cyclophosphamide or rituximab by specialists.
• Leprosy: multibacillary disease takes rifampicin 600 mg once monthly (supervised), clofazimine 300 mg once monthly (supervised) and 50 mg daily, and dapsone 100 mg daily for 12 months. Paucibacillary disease takes the same three drugs at the same doses for 6 months. Doses are reduced in children.
• Prednisolone 40 mg daily with gradual reduction for nerve function impairment and reactions. Specialist care and nerve function monitoring.
• HIV neuropathy: antiretroviral therapy review (avoid stavudine and didanosine).
• Monoclonal gammopathy, myeloma, amyloidosis and POEMS: haematology referral.

Carpal tunnel syndrome. Neutral wrist splint at night for 6 to 8 weeks; local corticosteroid injection (methylprednisolone 40 mg into the carpal tunnel) for temporary relief; surgical release for persistent symptoms, weakness, wasting or severe findings on nerve conduction studies. In pregnancy, splinting alone is usual because symptoms often settle after delivery.

Other entrapments. Avoid sustained elbow flexion (ulnar), avoid leg crossing (peroneal), weight loss and loose clothing (meralgia paraesthetica), and specialist referral for persistent or severe symptoms or motor loss.

Radiculopathy.

• Analgesia: paracetamol 1 g every 6 hours, maximum 4 g in 24 hours.
• Ibuprofen 400 mg three times daily with food, maximum 2.4 g daily, avoiding use in renal impairment, heart failure or peptic ulcer.
• Early activity and physiotherapy.
• Referral for progressive weakness or severe pain.

Painful neuropathy (when numbness or paraesthesia is painful). First choices are one of the following.

• Amitriptyline 10 mg orally at night, increased by 10 mg every week to 25 to 75 mg (avoid in cardiac conduction disease, glaucoma, urinary retention; ECG and sedation monitoring in older adults).
• Duloxetine 30 mg orally daily for 1 week, then 60 mg daily (maximum 120 mg daily). Avoid when creatinine clearance is under 30 mL/min or in hepatic impairment; monitor blood pressure and sodium.
• Gabapentin 300 mg orally at night, increased every 3 to 7 days to a usual 1.8 to 3.6 g daily in 3 divided doses. Adjust: creatinine clearance 30 to 59 mL/min 400 to 1,400 mg daily in 2 doses; 15 to 29 mL/min 200 to 700 mg once daily; under 15 mL/min 100 to 300 mg once daily.
• Pregabalin 75 mg orally twice daily, increased after 1 week to 150 mg twice daily; maximum 300 mg twice daily (600 mg daily). Warnings: sedation, dizziness, oedema, misuse.
• Pregabalin renal dosing: creatinine clearance 30 to 59 mL/min, 75 to 300 mg daily in 2 or 3 doses; 15 to 29 mL/min, 25 to 150 mg daily in 1 or 2 doses; under 15 mL/min, 25 to 75 mg once daily.
• Topical capsaicin 8 percent patch applied to the painful area for 30 to 60 minutes every 3 months for focal pain (specialist), or lidocaine 5 percent plaster for localised pain.
• Opioids and tramadol are not first line; tramadol 50 mg orally at night, increased to a maximum of 400 mg daily, may be used briefly when other drugs fail (seizure risk, serotonin syndrome, dependence).

Review response and tolerability at 2 to 4 weeks; stop a drug that has not helped after adequate dose and time and change to the next.

Supportive care. Foot protection for insensate feet (daily inspection, well fitting shoes, podiatry), falls prevention, heat and injury avoidance, physiotherapy and balance training, occupational therapy.

Monitoring. Symptom and pain scores, neurological examination, vitamin levels after replacement (B12 at 3 months), glucose control and HbA1c every 3 months in diabetes, sodium and renal function on gabapentinoids and duloxetine, liver function on antituberculous and antileprosy drugs.

Referral and escalation. Immediate: suspected stroke, cord compression, Guillain Barré syndrome. Urgent neurology within 2 weeks: rapidly progressive, asymmetric, painful or severe neuropathy, suspected vasculitis, and mononeuritis multiplex. Neurology and neurosurgery for myelopathy or radiculopathy with weakness. Endocrinology and podiatry for diabetic neuropathy. Dermatology and infectious disease for leprosy. Haematology for paraproteinaemic neuropathy.

Admission criteria. Acute stroke or transient ischaemic attack with high risk features, Guillain Barré syndrome, spinal cord compression, vasculitic neuropathy with rapid progression, severe hypocalcaemia, or unsafe self care.

Discharge and safety netting. Return for new weakness, difficulty walking, loss of bladder or bowel control, speech or visual change, chest pain or palpitations, or spreading numbness. Follow up in 2 to 4 weeks, with foot care advice and instructions on avoiding injury to numb areas.