Numbness, Tingling

Numbness and tingling (paresthesia) are abnormal sensations resulting from dysfunction or irritation of peripheral nerves, nerve roots, or central sensory pathways, often indicating neuropathy, compression, or ischemia.

Paraesthesia and numbness are sensory disturbances — abnormal perceptions arising from dysfunction anywhere along the somatosensory pathway, from peripheral nerve endings all the way up to the parietal cortex.

Let's break the words down from their roots:

Paraesthesia (Greek: para- = abnormal, aisthesis = sensation): an abnormal spontaneous sensation — classically described as "pins-and-needles," "tingling," "pricking," or "burning." These are positive symptoms, meaning the nervous system is generating signals that shouldn't be there (irritation/ectopic firing of sensory neurones) ^[1]^[2].
Numbness (hypoaesthesia/anaesthesia): a negative symptom — reduced or absent sensation ("loss of feeling," "deadness"). This implies conduction block or destruction of sensory neurones — the signal simply isn't getting through ^[2]^[3].

Related terminology you must distinguish ^[1]:

Term	Definition	Mechanism
Paraesthesia	Abnormal spontaneous sensation (tingling, pricking, pins-and-needles)	Ectopic firing of intact but irritated sensory axons
Dysaesthesia	Unpleasant abnormal sensation (burning, electric-like)	Pathological processing of afferent signals; often neuropathic
Hyperaesthesia	Increased sensitivity to stimulation	Peripheral or central sensitisation
Hypoaesthesia	Decreased sensitivity to stimulation	Partial conduction block / reduced axon number
Anaesthesia	Complete loss of sensation	Complete conduction block / axon destruction
Allodynia	Pain from a normally non-painful stimulus	Central sensitisation (Aβ fibres activating pain pathways)
Hypalgesia	Decreased pain response to normally painful stimulus	Loss of nociceptive fibre function

The clinical distinction between positive (paraesthesia) and negative (numbness) sensory symptoms is crucial — positive symptoms suggest irritation of neurones (they're firing when they shouldn't), while negative symptoms suggest loss of function (neurones are dead or blocked). Both can coexist. ^[2]^[3]

Key Concept

Sensory disturbance may take place in the form of negative symptoms (numbness): 'loss of feeling', 'deadness', or positive symptoms (paraesthesia): 'pins-and-needles', 'burning-like' ^[2]^[3]. When a patient says "my hand is numb," always clarify — do they mean they can't feel things (negative), or do they have tingling/pins-and-needles (positive)? The two have different localisation implications.

Epidemiology and Risk Factors

These are best understood by the underlying cause:

Risk Factor	Conditions Predisposed
Diabetes mellitus	Diabetic peripheral neuropathy (most common), mononeuropathy, CTS
Alcohol excess	Nutritional / toxic peripheral neuropathy
Advancing age	Cervical spondylosis, CTS, diabetic neuropathy, CKD
Female sex	CTS (hormonal influence on carpal tunnel contents)
Obesity	CTS, diabetic neuropathy, metabolic syndrome
Pregnancy	CTS (fluid retention → carpal tunnel swelling)
B12/folate deficiency	Subacute combined degeneration, megaloblastic neuropathy
Hypothyroidism	CTS, peripheral neuropathy
Rheumatoid arthritis	CTS, ulnar neuropathy, entrapment neuropathies
CKD / uraemia	Uraemic neuropathy
Neurotoxic drugs	Drug-induced neuropathy (chemotherapy, statins, metronidazole, amiodarone)
Repetitive strain / occupation	Entrapment neuropathies
Hypertension, smoking, dyslipidaemia	Stroke/TIA, peripheral vascular disease
Family history of neuropathy	Charcot-Marie-Tooth, hereditary neuropathies
Immunocompromise (HIV, etc.)	HIV neuropathy, opportunistic infections

Anatomy and Physiology of the Somatosensory System

To understand numbness and tingling, you must understand the somatosensory pathway from first principles. A lesion at any level produces a characteristic pattern — and that pattern is what lets you localise the problem.

Sensory information begins at specialised receptors in the skin, joints, muscles and viscera:

Mechanoreceptors (touch, vibration, proprioception): Meissner's corpuscles (light touch), Pacinian corpuscles (vibration/pressure), Merkel discs (sustained touch), Ruffini endings (stretch), muscle spindles & Golgi tendon organs (proprioception)
Thermoreceptors: free nerve endings detecting temperature
Nociceptors: free nerve endings detecting pain (mechanical, thermal, chemical)

These receptors transduce stimuli into electrical signals carried by different fibre types:

Fibre Type	Myelination	Diameter	Speed	Modality
Aα	Heavily myelinated	12–20 μm	70–120 m/s	Proprioception
Aβ	Myelinated	6–12 μm	30–70 m/s	Touch, vibration
Aδ	Thinly myelinated	1–5 μm	5–30 m/s	Sharp/fast pain, temperature
C	Unmyelinated	0.2–1.5 μm	0.5–2 m/s	Dull/burning pain, temperature, itch

Why does numbness often progress from distal to proximal?

This is the "length-dependent" pattern. The longest axons (going to the toes) are most vulnerable to metabolic or toxic insults because: (1) they have the highest metabolic demand for axonal transport, (2) they have the greatest surface area exposed to toxins, and (3) the furthest point from the cell body receives the least trophic support. This is why diabetic neuropathy and most toxic neuropathies produce a "glove-and-stocking" distribution — feet before hands, distal before proximal.

The Two Main Ascending Sensory Pathways

The somatosensory system can be disrupted at any level ^[2]^[3]:

Each level produces a characteristic pattern of sensory loss:

Lesion Level	Pattern	Key Features
Single peripheral nerve	Mononeuropathy distribution	Follows named nerve territory (e.g., median nerve → lateral 3.5 digits)
Multiple peripheral nerves	Mononeuritis multiplex	Asymmetric, multiple named nerves
Length-dependent neuropathy	Glove-and-stocking	Symmetric, distal > proximal, feet before hands
Nerve root (radiculopathy)	Dermatomal	Follows a dermatome (e.g., C6 → lateral forearm and thumb)
Spinal cord	Sensory level on trunk	All modalities below the level; may be dissociated (e.g., central cord → "cape-like" pain/temperature loss)
Brainstem	Crossed pattern	Ipsilateral face + contralateral body (lateral medullary/Wallenberg)
Thalamus	Contralateral hemibody	ALL modalities lost on entire contralateral face, arm, trunk, leg
Parietal cortex	Contralateral cortical	Discriminatory loss (two-point, stereognosis), sensory inattention, minimal pain/temperature loss

Etiology (Focus on Hong Kong)

The causes of numbness and tingling are best organised by the anatomical level of the lesion. Below is a comprehensive classification with pathophysiology. In Hong Kong, the bolded causes are most commonly encountered in clinical practice.

A. Peripheral Nerve Causes (Most Common Overall)

1. Peripheral Neuropathy (Generalised)

2. Entrapment Neuropathies (Mononeuropathy)

Classification

Numbness and tingling can be classified in several clinically useful ways:

Type	Implication
Positive (tingling, pins-and-needles, burning)	Nerve irritation / ectopic discharge
Negative (numbness, deadness)	Nerve conduction block / axon loss

Pattern	Differential
Sudden onset (seconds–minutes)	Stroke/TIA, acute limb ischaemia, trauma
Acute (hours–days)	GBS, transverse myelitis, acute radiculopathy
Subacute (days–weeks)	Inflammatory neuropathy, MS, B12 deficiency
Chronic progressive (weeks–months)	DM neuropathy, CKD, drug-induced, hereditary, tumour
Intermittent/episodic	Migraine aura, TIA, hyperventilation, CTS (nocturnal)

Distribution	Anatomical Localisation
Single nerve territory	Mononeuropathy (entrapment, trauma)
Multiple discrete nerve territories	Mononeuritis multiplex (vasculitis, DM)
Glove-and-stocking	Length-dependent polyneuropathy
Dermatomal	Radiculopathy (nerve root)
Sensory level on trunk	Spinal cord lesion
Hemibody	Thalamic or cortical (contralateral)
Perioral + acral	Hypocalcaemia / hyperventilation
Non-anatomical / bizarre	Functional / psychogenic

Modalities Lost	Pathway Involved
Pain + temperature	Spinothalamic tract (small fibres: Aδ, C)
Vibration + proprioception + discriminatory touch	Dorsal column-medial lemniscus (large fibres: Aα, Aβ)
All modalities	Complete nerve/cord/thalamic lesion

Clinical Features

A. Symptoms (with Pathophysiological Basis)

The history is the single most important tool in evaluating numbness/tingling ^[4]. You must systematically characterise the sensory disturbance:

"History of diabetes, migraine, cancer, spinal problems, injury, possible bites, fever/sweating and other symptoms. Take a travel and diet history, incl. nutrition and alcohol. Gather a drug history, particularly cancer therapy, interferon, colchicine, thalidomide, statins, alcohol or any illicit drugs." ^[4]

"Check the patient's occupational history, e.g. exposure to lead, and psychiatric history, esp. anxiety states." ^[4]

History Domain	What to Ask	Why
DM	Duration, HbA1c, complications	Diabetic neuropathy risk correlates with duration + control
Drug history	Cytotoxic agents, interferon, colchicine, thalidomide, statins, metronidazole, amiodarone, isoniazid, alcohol, OTC medications	Neurotoxic drugs are a common and reversible cause ^[4]
Alcohol	Quantity, duration	Direct toxicity + nutritional deficiency
Diet / nutrition	Vegan/vegetarian, malabsorption	B12/folate deficiency
Cancer history	Type, treatments received	Paraneoplastic neuropathy, chemotherapy toxicity, spinal metastases
Spinal problems	Previous back/neck pain, trauma, surgery	Radiculopathy, myelopathy
Travel history	Endemic areas	Lyme disease, leprosy, tropical infections
Occupational history	Exposure to lead, heavy metals, vibrating tools	Heavy metal neuropathy, vibration-induced neuropathy ^[4]
Psychiatric history	Anxiety states	Hyperventilation, conversion disorder ^[4]
Family history	Neuropathy, similar symptoms	Charcot-Marie-Tooth, hereditary neuropathies

Take a detailed drug history

"Take a detailed drug history including the above, alcohol and OTC medications" ^[4]. Drug-induced neuropathy is one of the most commonly missed causes of numbness and tingling. Always ask specifically about chemotherapy, statins (very commonly prescribed), and alcohol. Missing this is a common medical student pitfall.

B. Signs (with Pathophysiological Basis)

"General health and nutritional status. Focused neurological especially sensory, motor function, reflexes. Look for 'glove and stocking' distribution, muscle wasting e.g. thenar eminence. Peripheral vasculature." ^[4]

Test each modality systematically and map the distribution:

Modality	How to Test	Pathway	Localisation Value
Light touch	Cotton wool	Dorsal columns (fine touch) + STT (crude touch)	Screening; identifies area of deficit
Pin-prick (pain)	Neurotip	Spinothalamic tract (Aδ fibres)	Small fibre function
Temperature	Cold tuning fork or thermal rollers	Spinothalamic tract (Aδ/C fibres)	Small fibre function
Vibration	128 Hz tuning fork on bony prominence	Dorsal columns (Aβ fibres)	Large fibre function; often first lost in polyneuropathy
Proprioception	Passive joint position sense	Dorsal columns (Aα fibres)	Large fibre function
Two-point discrimination	Callipers	Dorsal columns / cortical processing	Cortical sensory function
Stereognosis	Object identification by touch	Parietal cortex	Cortical sensory function

Key patterns to look for:

Glove-and-stocking distribution: polyneuropathy ^[4]
Dermatomal: radiculopathy
Sensory level on trunk: spinal cord lesion (test with pin-prick ascending from below)
Dissociated sensory loss (one modality lost, others preserved): specific tract lesion (e.g., syringomyelia → loss of pain/temperature with preserved touch over the "cape" area)
Saddle anaesthesia: cauda equina syndrome — test the perianal dermatomes (S2–S4)

Finding	Interpretation
Absent ankle jerk	S1 root, peripheral neuropathy (earliest reflex lost in length-dependent neuropathy — because the S1 reflex arc is the longest)
↑Knee jerk + ↓ankle jerk	Subacute combined degeneration of the cord (B12 deficiency) — UMN lesion at cord level causing ↑knee jerk, PLUS peripheral neuropathy causing ↓ankle jerk ^[7]
Generalised areflexia	GBS, severe polyneuropathy
Hyperreflexia + upgoing plantars	UMN lesion — myelopathy, stroke
Inverted reflexes (e.g., inverted supinator)	Cervical myelopathy — LMN at the level of the lesion, UMN below ^[6]

To tie everything together, here are the fundamental mechanisms by which numbness and tingling occur:

Mechanism	Examples	Positive or Negative?
Demyelination (focal or diffuse loss of myelin sheath)	CTS, GBS, CIDP, MS, B12 deficiency	Both (early = positive from ectopic conduction; late = negative from conduction block)
Axonal degeneration (death of the axon itself)	DM neuropathy, toxic/drug neuropathy, uraemia	Usually negative (numbness), but early regenerating sprouts may fire ectopically → positive
Nerve compression (mechanical pressure)	Radiculopathy, entrapment neuropathy, tumour	Both (compression initially irritates → tingling; sustained → conduction block → numbness)
Ischaemia (inadequate blood supply to nerve)	PVD, vasculitis, acute limb ischaemia	Both (early ischaemia → paraesthesia; prolonged → numbness/paralysis)
Inflammation (immune-mediated attack on nerve or CNS)	GBS, MS, transverse myelitis, vasculitic neuropathy	Both
Metabolic/toxic (derangement of neuronal biochemistry)	Hyperglycaemia (polyol pathway), uraemic toxins, drugs	Predominantly negative but burning/dysaesthesia common
Ion channel dysfunction (altered neuronal excitability)	Hypocalcaemia, ciguatera toxin, channelopathies	Predominantly positive (spontaneous firing)
Central pathway disruption (CNS lesion)	Stroke, tumour, demyelination	Depends on level; thalamic/cortical lesions often negative

Murtagh's Diagnostic Strategy Summary for Paraesthesia and Numbness

This is the framework from the lecture slides ^[4]. Treat every item below as high yield:

Key Investigations (Overview)

Key investigations from lecture slides ^[4]:

Imaging e.g. spine, carotid vessels, CT or MRI, angiography
Specific blood tests for infection
Lumbar puncture (CSF protein, oligoclonal IgG, etc.) — for suspected GBS, MS, CNS infection

Diagnostic Tips from Lecture Slides

"In many cases of peripheral neuropathy or a sensory symptoms, the diagnosis is not only elusive but may not be identified" ^[4]. This is an honest reality of clinical medicine — not every case of numbness/tingling gets a neat label. Up to 30% of peripheral neuropathies remain idiopathic even after extensive workup. The key is to exclude serious and treatable causes first.

High Yield Summary

Paraesthesia = positive sensory symptom (nerve irritation/ectopic firing); Numbness = negative sensory symptom (conduction block/axon loss)
Probability diagnoses: DM neuropathy, nutritional neuropathy (alcohol/B12/folate), hyperventilation/anxiety, nerve root pressure (sciatica/cervical spondylosis), CTS, neurotoxic drugs
Serious disorders not to miss: CVA/TIA, PVD, GBS, infections (HIV, Lyme, leprosy), CKD/uraemia, spinal cord tumours/trauma, marine toxins
Pitfalls: migraine with focal signs, MS/transverse myelitis, hypocalcaemia
Distribution is king for localisation: glove-and-stocking = polyneuropathy; dermatomal = radiculopathy; hemibody = central; perioral + acral = hypocalcaemia/hyperventilation; non-anatomical = functional
Length-dependent pattern (distal → proximal) occurs because longest axons are most vulnerable to metabolic/toxic insults
Key examination: sensory modalities, motor function, reflexes, look for glove-and-stocking, thenar wasting, peripheral vasculature
↑Knee jerk + ↓ankle jerk = subacute combined degeneration (B12 deficiency) — UMN at cord + LMN peripherally
First-line investigations: urinalysis, blood sugar, FBE, ESR/CRP; then consider calcium, B12/folate, LFTs, U&E, TFTs, KFTs, nerve conduction studies
Always take a thorough drug history — neurotoxic drugs are a common and reversible cause

Active Recall - Numbness and Tingling (Part 1)

Differential Diagnosis of Numbness and Tingling

The differential diagnosis of numbness and tingling is vast because sensory disturbance can originate from a lesion at any level of the somatosensory pathway — from the peripheral receptor all the way to the parietal cortex. The clinical approach, therefore, is not to memorise an endless list, but to use the pattern of sensory loss to localise the lesion first, and then generate a focused differential based on that localisation.

Think of it as a two-step process:

Where is the lesion? (anatomical diagnosis — pattern recognition)
What is the lesion? (pathological diagnosis — informed by tempo, risk factors, associated features)

This is the fundamental principle of neurological diagnosis ^[2]^[3].

The Murtagh Framework — Structured Differential

The lecture slides organise the differential by clinical probability, which is the approach you should use in the exam and on the ward ^[4]:

Diagnosis	Key Distinguishing Features	Why It Causes Numbness/Tingling
Diabetic peripheral neuropathy	Bilateral, symmetric, glove-and-stocking; chronic/insidious; known DM or undiagnosed DM discovered on screening	Hyperglycaemia → polyol pathway/AGEs/microvascular disease → length-dependent axonal degeneration, longest fibres first ^[5]
Nutritional peripheral neuropathy esp. alcohol, B12, folate	Glove-and-stocking; history of alcohol excess, poor diet, vegetarian/vegan, gastrectomy; may have macrocytic anaemia, glossitis	Alcohol = direct neurotoxicity + thiamine/B12 malabsorption; B12 = ↓methylation of myelin proteins → demyelination of peripheral nerves ± spinal cord (subacute combined degeneration) ^[7]
Hyperventilation with anxiety	Perioral + acral (fingertips); episodic; clear anxiety/stress trigger; often young patient; associated sighing, chest tightness, light-headedness	Respiratory alkalosis → ↓ionised Ca²⁺ → neuronal hyperexcitability → spontaneous depolarisation of sensory nerves ^[4]^[14]
Nerve root pressure e.g. sciatica, cervical spondylosis	Dermatomal distribution; associated radicular pain; aggravated by Valsalva/neck movements; ± weakness/hyporeflexia in the myotome	Mechanical compression of nerve root → focal demyelination and axonal injury → both positive (tingling, pain) and negative (numbness) symptoms in that dermatome ^[6]^[13]
Nerve entrapment esp. carpal tunnel syndrome	Single nerve territory (e.g., lateral 3.5 digits for CTS); nocturnal symptoms; specific provocative tests positive (Phalen's, Tinel's); risk factors (female, DM, hypothyroid, pregnancy, RA)	↑Pressure in confined anatomical space → focal compression of nerve → demyelination (early, reversible) → axonal loss (late, irreversible) ^[6]^[9]
Neurotoxic drugs	Glove-and-stocking; temporal relationship to drug initiation/dose escalation; improves with drug withdrawal	Direct axonal toxicity or impairment of mitochondrial function/axonal transport; majority are distal axonopathies ^[4]^[12]

Exam Tip — The 'Big 6' Probability Diagnoses

If you're asked "What are the common causes of numbness/tingling?" in an exam, these six are the answer. In Hong Kong, diabetic neuropathy is by far the most common, followed by CTS, cervical spondylosis, and drug-induced neuropathy (especially in oncology patients on chemotherapy). Hyperventilation is the most common cause of acute episodic perioral paraesthesia in the Emergency Department.

These are the "can't-miss" diagnoses — conditions where delayed diagnosis leads to permanent disability or death:

Category	Diagnosis	Distinguishing Features	Mechanism
Vascular	CVA/TIA	Sudden onset (seconds–minutes); typically negative rather than positive ^[2]^[3]; hemibody or focal distribution following vascular territory; associated motor deficit, dysphasia, visual loss	Acute ischaemia or haemorrhage → neuronal death in somatosensory cortex, thalamus, or brainstem → sudden contralateral sensory loss
	Peripheral vascular disease	Unilateral limb; associated with rest pain, claudication, colour/temperature changes, absent pulses; risk factors (smoking, DM, HTN)	Chronic ischaemia of vasa nervorum → nerve ischaemia; in acute limb ischaemia, paraesthesia is among the earliest of the 6Ps (nerves > muscles > skin > bone sensitivity to ischaemia) ^[10]
Infection	AIDS	Risk factors for HIV; may have constitutional symptoms; distal symmetric polyneuropathy	Direct HIV neurotoxicity + antiretroviral drug toxicity → distal axonal degeneration
	Lyme disease	Travel to endemic areas; tick bite history; erythema migrans rash; cranial neuropathy (especially facial nerve)	Borrelia burgdorferi → immune-mediated radiculitis, cranial neuritis, peripheral neuropathy
	Leprosy	Travel/residence in endemic areas; thickened palpable nerves; anaesthetic skin patches; skin lesions	Mycobacterium leprae has tropism for Schwann cells → granulomatous inflammation of peripheral nerves → patchy sensory loss
	Some viral infections	Recent viral illness; may be post-infectious (GBS-like)	Post-infectious molecular mimicry or direct viral neurotropism
Tumour/cancer	Disseminated malignancy	Weight loss, anorexia, known malignancy history; may have paraneoplastic syndrome	Paraneoplastic neuropathy (anti-Hu, anti-CV2 antibodies → immune attack on DRG); direct nerve infiltration; or compression by metastatic disease
	Cerebral/spinal cord tumours	Progressive; focal neurological signs; headache/raised ICP features; spinal cord lesion → sensory level	Mass effect compressing neural pathways; or infiltration destroying sensory neurones
Other	CKF: uraemia	Known CKD; elevated creatinine/urea; glove-and-stocking neuropathy; ± other uraemic symptoms (fatigue, pruritus, nausea)	Accumulation of uraemic "middle molecules" → axonal degeneration; improves with dialysis ^[8]
	Guillain-Barré syndrome	Acute onset (days); ascending weakness predominates but paraesthesia often precedes; areflexia; may rapidly progress to respiratory failure; preceding infection (Campylobacter, CMV)	Post-infectious molecular mimicry → autoimmune attack on peripheral nerve myelin → acute inflammatory demyelinating polyradiculoneuropathy → conduction block
	Trauma to spinal cord	Clear history of trauma; sensory level on trunk; UMN signs below level	Direct mechanical disruption of ascending sensory tracts
	Marine fish toxins e.g. toadfish, Ciguatera	Recent ingestion of reef fish (relevant in HK); perioral/extremity paraesthesia; pathognomonic reversal of hot/cold sensation	Ciguatoxin activates voltage-gated Na⁺ channels at resting potential → persistent neuronal depolarisation → paraesthesia; cold allodynia due to preferential effect on thermosensitive fibres

Red Flag — Acute Limb Ischaemia

In the context of unilateral limb numbness/tingling, always assess the peripheral pulses. Acute limb ischaemia presents with paraesthesia as one of the earliest symptoms because nerves are the most metabolically sensitive tissue (sensitivity to ischaemia: nerves > muscles > skin > bone) ^[10]. Missing this diagnosis can lead to limb loss within 6 hours. The 6Ps mnemonic: Pain, Paraesthesia, Pallor, Pulselessness, Perishingly cold, Paralysis ^[10].

These are the conditions that frequently catch clinicians off-guard:

Diagnosis	Why It's Missed	Key Distinguishing Features
Migraine variant with focal signs	Paraesthesia without headache confuses clinicians; may mimic TIA	Spreading tingling or paraesthesia followed by numbness, evolving over 20–30 min over one half of body ^[2]^[3]; slow "march" of symptoms across body parts (due to cortical spreading depression — a wave of depolarisation sweeping across cortex); may occur without headache in older patients (up to 42%) ^[3]^[11]
Multiple sclerosis/transverse myelitis	Young patient; initial episode may be subtle; episodic nature confuses	Ascending from one or both lower limbs to a distinct level on trunk over hours to days ^[2]^[3]; may have Lhermitte's sign; optic neuritis (40–70% have paraesthesia as associated symptom) ^[15]; relapsing-remitting course; Uhthoff's phenomenon (heat worsens symptoms)
Hypocalcaemia	Attributed to "just anxiety" when it's actually a metabolic problem	Perioral + acral paraesthesia; may have Trousseau's sign (carpal spasm with BP cuff inflation) and Chvostek's sign (facial twitching on tapping parotid); causes include hypoparathyroidism, vitamin D deficiency, post-thyroidectomy, pancreatitis
Chronic inflammatory polyneuropathy (CIDP)	Slowly progressive; confused with other chronic neuropathies	Progressive or relapsing-remitting weakness + sensory loss > 8 weeks; proximal and distal; areflexia; elevated CSF protein; demyelinating pattern on NCS
Charcot-Marie-Tooth syndrome	Slowly progressive since childhood; patient may not present until adulthood	Pes cavus, hammer toes, "inverted champagne bottle" legs, high-stepping gait; family history; very slowly progressive
Amyloidosis	Rare; not considered in differential	Painful small-fibre neuropathy (burning dysaesthesia); may have systemic features (macroglossia, periorbital purpura, nephrotic syndrome, cardiomyopathy)
Heavy metal toxicity e.g. lead	Occupational exposure not asked about	Lead → predominantly motor neuropathy (wrist drop/foot drop) but can have sensory symptoms; arsenic/thallium → painful sensory neuropathy with GI symptoms

Migraine Aura vs Stroke/TIA — How to Distinguish

This is a classic exam question. The key difference is tempo of onset:

Migraine aura: positive symptoms (tingling) spread slowly over 20–30 minutes, often "marching" from one body part to another (e.g., hand → arm → face). This reflects the slow propagation of cortical spreading depression across the somatosensory cortex (~3 mm/min). Positive symptoms (tingling) typically precede negative symptoms (numbness) ^[2]^[3].
Stroke/TIA: occurs more rapidly (seconds to minutes, maximal at onset); typically negative rather than positive (numbness rather than tingling) ^[2]^[3]. Follows a vascular territory.

These are common conditions that "masquerade" as other diagnoses — always screen for them:

Masquerade	How It Causes Numbness/Tingling	How to Screen
Diabetes	Peripheral neuropathy (most common cause of chronic paraesthesia)	Blood sugar, HbA1c, urinalysis
Drugs e.g. cytotoxic agents, interferon	Direct neurotoxicity → axonal degeneration	Detailed drug history (including OTC, herbal, alcohol) ^[4]
Anaemia: pernicious anaemia	B12 deficiency → demyelination of peripheral nerves + dorsal columns/CST (subacute combined degeneration) ^[7]	FBE (macrocytic anaemia), serum B12, anti-IF antibodies
Thyroid/other endocrine: hypothyroid?	Myxoedematous infiltration of peripheral nerves; also predisposes to CTS	TFTs
Spinal dysfunction	Radiculopathy or myelopathy from spondylosis, disc herniation, or spinal stenosis	Spinal examination, MRI spine

This is the most clinically useful way to generate a focused differential ^[2]^[3]^[6]:

Distribution	Localisation	Top Differentials
Glove-and-stocking (bilateral, symmetric, distal > proximal)	Peripheral polyneuropathy	DM, alcohol, B12/folate, drugs, uraemia, hypothyroid, CIDP, CMT, amyloidosis
Single peripheral nerve territory	Mononeuropathy	CTS (median), cubital tunnel (ulnar), meralgia paraesthetica (LFCN), peroneal palsy
Multiple individual nerve territories (asymmetric)	Mononeuritis multiplex	Vasculitis (PAN, RA, SLE), DM (diabetic amyotrophy), sarcoidosis, leprosy
Dermatomal	Radiculopathy	Cervical/lumbar disc herniation, spondylosis, herpes zoster, tumour, infection
Bilateral dermatomal with sensory level	Spinal cord lesion	MS/transverse myelitis, cervical myelopathy, tumour, B12 deficiency (SCD), trauma, epidural abscess
Unilateral hemibody	Contralateral thalamus or cortex	Stroke/TIA, tumour, migraine aura, MS plaque
Crossed (ipsilateral face + contralateral body)	Brainstem (lateral medullary)	Stroke (Wallenberg syndrome), tumour, demyelination
Perioral + acral (bilateral fingertips)	Metabolic / systemic	Hypocalcaemia, hyperventilation, hypoglycaemia ^[5]
Non-anatomical / bizarre	Functional / psychogenic	Conversion disorder, anxiety; diagnosis of exclusion ^[2]^[3]^[4]

Differential Diagnosis of Specific High-Yield Presentations

This is an extremely common clinical scenario. The differential depends on which part of the hand is affected:

Distribution	Likely Nerve/Level	Top Differentials
Lateral 3.5 digits (palmar), thenar wasting	Median nerve at wrist	CTS ^[4]^[9]
Medial 1.5 digits, intrinsic muscle wasting	Ulnar nerve at elbow or wrist	Cubital tunnel syndrome, Guyon canal syndrome ^[9]
All digits + forearm + neck pain aggravated by neck movement	Cervical nerve root	Cervical radiculopathy (C6/C7) ^[13]
All digits bilaterally, glove distribution	Polyneuropathy	DM, B12, drugs, alcohol
Whole hand + UMN signs in legs	Cervical spinal cord	Cervical myelopathy ^[6]
Medial forearm + medial 1.5 digits + lower trunk weakness	Lower brachial plexus (C8-T1)	Thoracic outlet syndrome (neurological type) ^[6]; Pancoast tumour

The DDx for CTS specifically includes ^[9]:

Cervical spondylosis (esp. C6/7): neck pain, symptoms exacerbated by neck movement (not wrist position)
Pronator teres syndrome: forearm motor involvement, palmar sensation affected (palmar cutaneous branch involved — unlike CTS where it is spared because it branches proximal to the retinaculum)
Thoracic outlet syndrome: lower trunk distribution (C8-T1), not pure median territory
Peripheral neuropathy: bilateral and symmetric, not confined to median nerve territory

Distribution	Localisation	Top Differentials
Lateral thigh only	Lateral femoral cutaneous nerve	Meralgia paraesthetica (compression under inguinal ligament — obesity, pregnancy, tight clothing)
Posterior leg to foot + back pain	L5-S1 nerve root	Sciatica (disc herniation) ^[4]^[9]
Lateral leg + dorsum of foot + foot drop	Common peroneal nerve	Peroneal nerve palsy (compression at fibular head — leg crossing, plaster cast, weight loss)
Both feet, stocking distribution	Polyneuropathy	DM, alcohol, B12, drugs, uraemia
Both legs with sensory level on trunk	Spinal cord	MS, transverse myelitis, cord compression (tumour, epidural abscess), B12 deficiency
Bilateral saddle area + bladder/bowel dysfunction	Cauda equina (below L2)	Disc herniation (L4/5, L5/S1), tumour, infection — SURGICAL EMERGENCY ^[6]

Distribution	Localisation	Top Differentials
Unilateral face (trigeminal distribution)	Trigeminal nerve or nucleus	Trigeminal neuropathy (tumour, MS plaque in pons, herpes zoster)
Perioral (bilateral)	Metabolic	Hypocalcaemia, hyperventilation, hypoglycaemia ^[4]^[5]
Unilateral face + contralateral body	Lateral medulla (Wallenberg)	Posterior circulation stroke ^[2]^[3]
Unilateral face + ipsilateral body	Contralateral pons or above	Pontine/thalamic/cortical stroke ^[2]^[3]

Feature	Peripheral Neuropathy	Radiculopathy	Myelopathy	Stroke/TIA
Distribution	Glove-and-stocking	Dermatomal	Sensory level on trunk	Vascular territory (hemibody)
Onset	Gradual (weeks–months)	Subacute (days–weeks)	Variable	Sudden (sec–min)
Motor signs	LMN (distal weakness, wasting)	LMN (segmental)	UMN below level, LMN at level	UMN (contralateral)
Reflexes	↓ or absent (esp ankle jerk)	↓ in affected segment	↑ below level, ↓ at level	↑ (contralateral)
Positive vs negative	Both (burning + numbness)	Both (pain + numbness)	Usually negative	Typically negative ^[2]^[3]
Bladder/bowel	Late/absent	Only if cauda equina	Common	Only if bilateral/brainstem

This summary from the senior notes is extremely high yield:

Temporal Pattern	Likely Diagnosis	Pathophysiological Explanation
Spreading tingling/paraesthesia followed by numbness, evolving over 20–30 min over one half of body	Migraine aura	Cortical spreading depression (CSD): a wave of neuronal depolarisation followed by suppression propagates across the cortex at ~3 mm/min; the slow "march" produces the characteristic gradual spread ^[2]^[3]^[11]
Rapid onset (seconds–minutes), typically negative	Stroke or TIA	Sudden vascular occlusion → immediate neuronal ischaemia → acute loss of function; negative because neurones are dying/non-functioning, not irritated ^[2]^[3]
Ascending from one or both lower limbs to a distinct level on trunk over hours to days	Inflammatory cord lesion (transverse myelitis, MS)	Inflammatory demyelination spreads within the spinal cord; the ascending pattern reflects progressive involvement of adjacent tracts over time ^[2]^[3]
Bizarre, not conforming to known anatomical pattern	Psychogenic (functional neurological disorder)	No structural lesion; the distribution does not map onto any dermatome, peripheral nerve, or CNS pathway ^[2]^[3]

High Yield Summary — Differential Diagnosis

Localise first, then differentiate: distribution pattern is the single most powerful tool — glove-and-stocking (polyneuropathy), dermatomal (radiculopathy), sensory level (cord), hemibody (central), perioral + acral (metabolic), non-anatomical (functional)
Tempo matters: sudden = vascular (stroke/TIA); slow march over 20–30 min = migraine; ascending over hours–days = cord inflammation; chronic progressive = metabolic/toxic neuropathy
Probability diagnoses: DM neuropathy, nutritional (alcohol/B12/folate), hyperventilation, nerve root pressure, CTS, neurotoxic drugs
Must not miss: CVA/TIA, PVD/acute limb ischaemia, GBS (can kill via respiratory failure), spinal cord compression, cauda equina syndrome (surgical emergency), infections (HIV, Lyme)
Often missed: migraine with aura, MS/transverse myelitis, hypocalcaemia, CIDP
Stroke vs migraine: stroke is rapid and typically negative; migraine aura spreads slowly over 20–30 min with positive symptoms preceding negative
Always take a drug history — neurotoxic drugs are common and reversible
Always check peripheral pulses — acute limb ischaemia presents with paraesthesia as the earliest symptom (nerves most sensitive to ischaemia)

Active Recall - Differential Diagnosis of Numbness and Tingling

References

^[2] Senior notes: Ryan Ho Fundamentals.pdf (Sensory Disturbances, p.320–321) ^[3] Senior notes: Ryan Ho Neurology.pdf (Sensory Disturbances, p.71–72; D/dx and Characteristic Presentations, p.72; Where is the Lesion, p.45; Cervical Spondylosis, p.172; Toxic Neuropathies, p.187; Migraine Aura, p.62) ^[4] Lecture slides: murtagh merge.pdf (Paraesthesia and numbness, p.75–77) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Hypoglycaemia clinical features, p.94) ^[6] Senior notes: maxim.md (Cervical myelopathy, Radiculopathy, Cauda equina syndrome, p.464–465; TOS/CTS, p.502–503) ^[7] Senior notes: Ryan Ho Haemtology.pdf (B12/folate deficiency and pernicious anaemia, p.29) ^[8] Senior notes: Ryan Ho Urogenital.pdf (CKD clinical manifestations, p.99) ^[9] Senior notes: maxim.md (CTS differential diagnosis and clinical features, p.500–503) ^[10] Senior notes: Ryan Ho Cardiology.pdf (Acute limb ischaemia 6Ps, p.209) ^[11] Senior notes: Ryan Ho Neurology.pdf (Migraine aura, p.62) ^[12] Senior notes: Ryan Ho Neurology.pdf (Toxic neuropathies, p.187) ^[13] Senior notes: Ryan Ho Neurology.pdf (Cervical radiculopathy, p.172) ^[14] Senior notes: Ryan Ho Respiratory.pdf (Psychogenic hyperventilation features, p.20) ^[15] Senior notes: Ryan Ho Opthalmology.pdf (Optic neuritis associated symptoms, p.92)

Diagnostic Criteria for Specific Conditions Causing Numbness/Tingling

While there are no "diagnostic criteria" for numbness per se, several of the underlying conditions have formal criteria. Here are the most exam-relevant ones:

GBS does not have a single "criterion set" but rather a constellation of supportive features ^[3]:

Feature	Expected Finding	Why
Clinical	Progressive, symmetrical ascending weakness + distal paraesthesia + hypo-/areflexia (> 90%)	Autoimmune demyelination of peripheral nerves → conduction block (motor > sensory) ^[17]
CSF	↑protein without pleocytosis (albuminocytologic dissociation)	Inflammation at nerve roots causes protein leak into CSF, but inflammatory cells are mostly in nerve, not CSF ^[17]^[18]
NCS	Demyelinating pattern (↑distal latency, ↓conduction velocity, conduction block, temporal dispersion) OR axonal pattern depending on variant	Confirms peripheral nerve pathology and distinguishes from myelopathy ^[17]
Temporal	Onset to nadir within 4 weeks; should NOT progress beyond 8 weeks (if so → consider CIDP)	CIDP defined by progression > 8 weeks ^[17]

Key exclusion: should NOT have new-onset UMN signs or sensory level (these point to spinal cord disease instead) ^[17].

Investigation Modalities — Detailed

These should be ordered for every patient presenting with new, persistent, or unexplained numbness/tingling. They screen for the common "masquerade" causes:

Investigation	What It Tests	Key Findings & Interpretation	Why Order It
Urinalysis	Glucose, protein	Glycosuria → undiagnosed DM; proteinuria → CKD/diabetic nephropathy	Screens for the single most common cause (DM) and its renal complications ^[4]
Blood sugar (fasting glucose ± HbA1c)	Glycaemic status	Fasting glucose ≥ 7.0 mmol/L or HbA1c ≥ 6.5% = DM; 5.7–6.4% = pre-diabetes	DM is the most common cause of peripheral neuropathy. Every 1% ↑HbA1c → 26% ↑risk of PAD ^[4]^[5]
FBE (Full Blood Examination / CBC)	Haemoglobin, MCV, WCC, platelets	Macrocytic anaemia (MCV > 100 fL, typically > 115 fL in megaloblastic) → B12/folate deficiency; pancytopenia → marrow infiltration (malignancy) or megaloblastic anaemia	Screens for B12/folate deficiency (the second most common nutritional cause); hypersegmented neutrophils on PBS are pathognomonic ^[7]
ESR/CRP	Inflammatory markers	↑ → vasculitis, infection, malignancy, autoimmune disease	Non-specific but raises suspicion for serious underlying systemic disease requiring further workup ^[4]

Investigation	What It Tests	Key Findings & Interpretation	When to Order
Serum calcium (total + ionised)	Ca²⁺ homeostasis	↓Ionised Ca²⁺ → neuronal hyperexcitability → perioral/acral paraesthesia. Causes: hypoparathyroidism, vitamin D deficiency, post-thyroidectomy, renal failure, respiratory alkalosis	Perioral + acral paraesthesia (especially episodic), Trousseau/Chvostek signs, post-thyroidectomy, CKD ^[4]
B12 and folate	Vitamin levels	Serum B12 < 200 pg/mL = deficient; 200–300 = borderline (check metabolites); RBC folate < 150 ng/mL = prolonged deficiency ^[7]	Macrocytic anaemia, glove-and-stocking neuropathy, suspected SCD, vegetarian/vegan diet, gastrectomy, elderly
LFTs (γGT)	Liver function, alcohol marker	↑γGT → chronic alcohol use (even without overt liver disease); deranged ALT/AST → hepatic cause	Suspected alcoholic neuropathy; γGT is the most sensitive marker of chronic alcohol consumption ^[4]
U&E (urea and electrolytes)	Renal function, electrolytes	↑Urea, ↑creatinine → CKD → uraemic neuropathy; ↑K⁺ → hyperkalaemia can itself cause paraesthesia and muscle weakness ^[4]^[16]	All patients with neuropathy (CKD is common and treatable)
TFTs	Thyroid function	↑TSH + ↓fT4 → hypothyroidism → peripheral neuropathy + predisposition to CTS	Unexplained neuropathy, CTS, clinical features of hypothyroidism ^[4]
KFTs (renal function tests)	eGFR, creatinine	↓eGFR → CKD staging → uraemic neuropathy suspected if eGFR < 15–20 mL/min	Suspected uraemic neuropathy ^[4]
Nerve conduction studies (NCS)	Peripheral nerve function	See detailed section below	Confirming neuropathy, distinguishing axonal vs demyelinating, localising entrapment, pre-surgical assessment ^[4]^[3]

B12 Deficiency — When Serum Level Is Borderline

If serum B12 is 200–300 pg/mL (borderline), check metabolites for confirmation ^[7]:

Methylmalonic acid (MMA): elevated in B12 deficiency (B12 is a cofactor for methylmalonyl-CoA mutase)
Homocysteine: elevated in both B12 and folate deficiency (both are cofactors for methionine synthase)
B12 deficiency: ↑MMA + ↑homocysteine
Folate deficiency: normal MMA + ↑homocysteine

This distinction matters because subacute combined degeneration of the cord is confined to B12 deficiency and does NOT occur in folate deficiency ^[7].

Tier 3: According to Clinical Findings (Refer) [4]

These are specialist-level investigations ordered when the clinical picture and first/second-line tests point to a specific diagnosis:

NCS/EMG are the cornerstone of peripheral neuropathy workup. They help answer two critical questions ^[3]:

Is there a neuropathy? (confirms what the clinical exam suggests)
What type of neuropathy? (demyelinating vs axonal → dramatically narrows the differential)

Principles of NCS ^[3]:

Percutaneous electrical stimulation of a peripheral nerve → record the generated impulse at a distant point
Measures: conduction velocity (speed of impulse), distal latency (time to reach distal recording site), amplitude (number of functioning axons), F-wave latency (proximal nerve function)

NCS Parameter	Demyelinating Pattern	Axonal Pattern	Why
Conduction velocity	↓↓ (slowed)	Normal or mildly ↓	Demyelination strips insulation → saltatory conduction fails → impulse must crawl along bare axon → slow. Axonal loss preserves surviving myelin → velocity OK in remaining fibres
Distal motor latency	↑↑ (prolonged)	Normal or mildly ↑	Same reason — takes longer for impulse to reach distal point
Amplitude (CMAP/SNAP)	May be normal early; ↓ if secondary axonal loss	↓↓ (reduced)	Amplitude reflects number of functioning axons. In axonal disease, axons die → fewer fibres → lower amplitude. In demyelination, axons initially survive
Conduction block	Present	Absent	Block occurs when impulse fails to propagate past a focal demyelinated segment — pathognomonic of acquired demyelination
Temporal dispersion	Present	Absent	Different fibres conduct at different speeds through a demyelinated segment → compound action potential spreads out
F-wave latency	↑↑ (prolonged)	Normal	F-wave tests proximal nerve segment (motor neurone → nerve root); prolonged in proximal demyelination (e.g., GBS)

Clinical significance of the distinction:

Demyelinating Neuropathy	Axonal Neuropathy
GBS (AIDP variant), CIDP, anti-MAG neuropathy, Charcot-Marie-Tooth type 1, paraproteinaemic neuropathy	DM, alcohol, drugs/toxins, uraemia, B12 deficiency, Charcot-Marie-Tooth type 2, vasculitic neuropathy

What NCS is NOT useful for ^[3]:

It cannot identify the aetiology of a neuropathy (it tells you the pattern, not the cause)
It does not assess CNS function (so it is useless for cervical myelopathy)
It should not be used to "exclude" neuropathy when the clinical picture is clear (clinical findings should suffice) ^[3]

EMG complements NCS by assessing muscle electrical activity:

Fibrillation potentials and positive sharp waves at rest → denervation (axonal loss)
Chronic neurogenic changes (large-amplitude, long-duration MUAPs) → reinnervation after chronic denervation
Useful for distinguishing neuropathy from myopathy (myopathic pattern: small, short, polyphasic MUAPs)

Modality	When to Use	Key Findings
MRI spine	Suspected radiculopathy, myelopathy, cord compression, cauda equina	Disc herniation: posterior/posterolateral disc protrusion compressing nerve root or cord. Myelopathy: cord signal change (↑T2 = oedema/gliosis). Tumour: enhancing mass. MS/transverse myelitis: ↑T2 cord lesion ± Gd enhancement. NMOSD: longitudinally extensive transverse myelitis ≥ 3 segments ^[19]^[20]
MRI brain (with contrast)	Suspected stroke, MS, brain tumour, brainstem lesion	MS: periventricular ↑T2 lesions, Dawson's fingers, Gd-enhancing acute plaques ^[19]. Stroke: DWI restriction in acute ischaemia (< 48h sensitivity 86–100% on MRI vs 48% on CT) ^[21]. Tumour: enhancing mass ± surrounding oedema
CT brain (non-contrast)	Acute stroke (first-line to exclude haemorrhage)	Haemorrhagic stroke: hyperdense (white) lesion. Ischaemic stroke: early signs include dense MCA sign, loss of insular ribbon, subtle hypodensity with loss of grey-white junction; sensitivity only 48% on day 1 ^[21]. Tumour: mass with surrounding oedema ± enhancement
X-ray spine	Spondylosis, fractures, deformity	Loss of lordosis, reduced disc height, osteophytes, spondylolisthesis. Pavlov ratio < 0.8: suggests cervical spinal stenosis ^[6]
Carotid Doppler USS	Suspected TIA/stroke with carotid territory symptoms	Carotid artery stenosis (degree of narrowing), plaque morphology
CT/MR angiography	Suspected PVD, acute limb ischaemia	Site and severity of arterial occlusion/stenosis
CXR	Screening for malignancy, Pancoast tumour (lower brachial plexus compression), sarcoidosis	Apical mass (Pancoast → C8-T1 symptoms), hilar lymphadenopathy (sarcoidosis), cervical rib (thoracic outlet syndrome) ^[6]

CT vs MRI in Acute Stroke

For acute stroke, non-contrast CT brain is the first-line investigation — not to diagnose ischaemic stroke (sensitivity is only ~48% on day 1 ^[21]) but to exclude haemorrhage (which is a contraindication to thrombolysis). MRI with DWI is far more sensitive (86–100%) for acute ischaemic infarction, but CT is faster and more widely available in the emergency setting.

LP is indicated when you suspect CNS inflammatory, infective, or infiltrative disease:

Condition	CSF Findings	Why
GBS	↑Protein without pleocytosis (albuminocytologic dissociation); may be normal in first week, abnormal in ~80% by week 2 ^[17]	Inflammation at nerve roots causes protein exudation into CSF, but the autoimmune attack targets myelin/axons in the PNS, not generating a cellular response in the CSF
MS	Oligoclonal bands (OCBs) with ↑IgG; lymphocytic pleocytosis in acute relapse ^[19]	OCBs represent intrathecal IgG synthesis by clonally expanded B cells — evidence of chronic CNS immune activation
NMOSD	CSF pleocytosis (monocyte/lymphocyte, occasionally neutrophil); no oligoclonal bands (helps distinguish from MS) ^[20]	More intense acute inflammation than MS but without the chronic intrathecal IgG synthesis
CNS infection	Depends on organism: bacterial (↑WCC with neutrophils, ↓glucose, ↑protein), TB/fungal (↑WCC with lymphocytes, ↓glucose, ↑protein), viral (↑WCC with lymphocytes, normal glucose, mildly ↑protein) ^[18]	Different organisms elicit different immune responses and have different effects on glucose metabolism (bacteria consume glucose)
Carcinomatous meningitis	Lymphocytosis, ↑protein, ↓glucose; malignant cells on cytology	Tumour cells infiltrate meninges, consume glucose, cause protein exudation

Test	Condition Screened
HIV serology	HIV-associated distal symmetric polyneuropathy
Lyme serology (anti-Borrelia antibodies)	Lyme neuroborreliosis
Syphilis serology (RPR/VDRL, FTA-ABS)	Neurosyphilis (tabes dorsalis — dorsal column degeneration → proprioceptive loss)
Hepatitis B/C	Cryoglobulinaemic vasculitic neuropathy (HCV), PAN-associated neuropathy (HBV)

Investigation	Indication	Key Findings
Serum protein electrophoresis (SPEP) / Urine protein electrophoresis (UPEP)	Suspected paraproteinaemic neuropathy, amyloidosis, myeloma	Monoclonal band → MGUS, myeloma, Waldenström's; associated with anti-MAG neuropathy (IgM paraprotein) or AL amyloidosis
Anti-ganglioside antibodies	Suspected GBS variants	Anti-GQ1b (specific for Miller Fisher syndrome), anti-GD1a/GM1 (AMAN variant) ^[17]
Anti-AQP4 (NMO-IgG)	Suspected NMOSD	100% specific, 72% sensitive ^[20]
Autoantibody panel (ANA, anti-dsDNA, ANCA, RF, anti-CCP)	Suspected connective tissue disease / vasculitis causing neuropathy	+ve ANA/anti-dsDNA → SLE; +ve ANCA → vasculitis; +ve RF/anti-CCP → RA ^[22]
Anti-intrinsic factor / Anti-parietal cell antibodies	Suspected pernicious anaemia	Anti-IF: insensitive (~50–70%) but specific; Anti-parietal cell: sensitive (~85–90%) but non-specific ^[7]
Nerve biopsy (commonly sural nerve)	Mononeuritis multiplex, asymmetric polyneuropathy, nerve thickening of unknown cause	Vasculitis (vessel wall inflammation + fibrinoid necrosis), amyloid deposits (Congo red staining with apple-green birefringence), granulomas (leprosy, sarcoidosis), demyelination patterns (onion bulb = CIDP/CMT1) ^[18]
Genetic testing	Suspected hereditary neuropathy (CMT)	CMT1A: PMP22 duplication (most common); CMT1B: MPZ mutation; CMTX: GJB1 mutation
Skin biopsy (intraepidermal nerve fibre density)	Suspected small fibre neuropathy (when NCS is normal because NCS only tests large fibres)	↓Intraepidermal nerve fibre density confirms small fibre neuropathy — important for painful neuropathies where NCS may be completely normal

When NCS Is Normal But the Patient Clearly Has Neuropathy

NCS tests large myelinated fibres (Aα, Aβ). If a patient has burning pain, dysaesthesia, and autonomic dysfunction but normal NCS, consider small fibre neuropathy (Aδ and C fibres). This is diagnosed by skin biopsy showing ↓intraepidermal nerve fibre density, or by quantitative sensory testing (QST) and sudomotor function testing. Common causes: DM (often the earliest manifestation), amyloidosis, Fabry disease, sarcoidosis.

Suspected Localisation	Key Investigations	What You Expect to Find
Polyneuropathy (glove-and-stocking)	Glucose/HbA1c, FBE, B12/folate, U&E, TFTs, LFTs/γGT, ESR/CRP → NCS/EMG → SPEP → nerve biopsy if needed	Axonal vs demyelinating pattern on NCS → guides further workup
Entrapment neuropathy (single nerve)	Clinical diagnosis ± NCS (focal slowing/conduction block at entrapment site)	Focal demyelination at carpal tunnel (CTS), cubital tunnel (ulnar neuropathy)
Radiculopathy (dermatomal)	MRI spine (corresponding level); NCS may show denervation in specific myotome on EMG	Disc herniation, foraminal stenosis, osteophyte compressing nerve root
Myelopathy (sensory level)	Urgent MRI whole spine; B12/folate; consider LP (MS, infection)	Cord compression, ↑T2 signal (oedema/demyelination), enhancing lesion
Central lesion (hemibody)	Urgent CT brain (exclude haemorrhage) → MRI brain (if ischaemic stroke suspected or subacute)	DWI restriction (acute ischaemic stroke), ↑T2 lesions (MS), enhancing mass (tumour)
Vascular (unilateral limb + absent pulses)	Handheld Doppler, formal Doppler USS, CT/MR angiography	Arterial occlusion, stenosis, absent flow
Metabolic (perioral + acral)	Ionised Ca²⁺, VBG/ABG (pH, pCO₂), glucose	↓Ionised Ca²⁺, respiratory alkalosis (↓pCO₂), ↓glucose

"Intermittent perioral paraesthesia indicates hypocalcaemia associated with hyperventilation" ^[4]. This is the single most important diagnostic tip from the lecture slides. In practice, check an ABG/VBG: if you find respiratory alkalosis (↓pCO₂, ↑pH) with normal total calcium, the reduced ionised Ca²⁺ is secondary to alkalosis, and the treatment is reassurance + rebreathing (not calcium replacement).

"In many cases of peripheral neuropathy or a sensory symptoms, the diagnosis is not only elusive but may not be identified" ^[4]. Up to 30% of chronic peripheral neuropathies remain idiopathic after full workup. This is an honest clinical reality — do not over-investigate a stable, mild, non-progressive neuropathy once serious causes have been excluded.

"Take a detailed drug history including the above, alcohol and OTC medications" ^[4]. Sometimes the most important "investigation" is simply asking the patient what they are taking. Drug-induced neuropathy is common and reversible if the offending agent is stopped.

High Yield Summary — Diagnosis

Numbness/tingling has no single diagnostic criteria — the approach is to localise the lesion clinically, then confirm with targeted investigations
First-line investigations for all patients: urinalysis, blood sugar, FBE, ESR/CRP ^[4]
Second-line: serum calcium, B12/folate, LFTs (γGT), U&E, TFTs, KFTs, nerve conduction studies ^[4]
Third-line (specialist): imaging (MRI spine/brain, CT, angiography), LP (CSF protein, OCBs), specific blood tests for infection, nerve biopsy ^[4]
NCS is the cornerstone for neuropathy workup: distinguishes demyelinating (↓velocity, ↑latency, conduction block) from axonal (↓amplitude) — this distinction dramatically narrows the differential ^[3]
NCS does NOT assess CNS function — it is useless for myelopathy; use MRI instead ^[3]
Normal NCS does not exclude CTS ^[9] or small fibre neuropathy (use skin biopsy for the latter)
GBS CSF: ↑protein without pleocytosis (albuminocytologic dissociation); may be normal in week 1 ^[17]
MS MRI: dissemination in space (≥ 2/4 regions) + dissemination in time (enhancing + non-enhancing lesions); OCBs can substitute for DIT ^[19]
CT brain in acute stroke: first-line to exclude haemorrhage, NOT to diagnose ischaemic stroke (sensitivity only 48% day 1) ^[21]

Active Recall - Diagnostic Criteria, Algorithm and Investigations

Emergency Management

These are the time-critical conditions where delayed treatment causes irreversible harm. You must recognise and act fast.

Cause-Directed Management of Common Conditions

This is the most common cause ^[4] and warrants the most detailed discussion:

Principles: The cornerstone is glycaemic control — this is both preventative and therapeutic. There is no drug that reverses established diabetic neuropathy; you can only slow progression and manage symptoms.

Strategy	Details	Mechanism / Rationale
Glycaemic control	Target HbA1c < 7% (individualise for elderly/comorbid); prefer SGLT2 inhibitors and GLP-1 receptor agonists ^[5]	Every 1% ↑HbA1c → 26% ↑risk of PAD. Tight control ↓microvascular complications (UKPDS, DCCT trials). SGLT2i and GLP1a have additional cardiovascular and renal benefits
CVD risk factor control	BP control (target < 130/80), lipid control (statin), smoking cessation	Diabetic neuropathy shares risk factors with macrovascular disease; vasa nervorum ischaemia contributes to neuropathy
Foot care	Daily inspection, appropriate footwear, podiatry, annual monofilament testing	Loss of protective sensation → unnoticed injuries → ulceration → Charcot joint → amputation. Prevention is everything
Neuropathic pain Mx	See below (gabapentin/pregabalin, duloxetine, amitriptyline) ^[5]	Symptomatic — does NOT reverse the underlying neuropathy
Avoid nephrotoxic OHAs	Metformin contraindicated if eGFR < 30; dose-adjust if 30–45	CKD progression exacerbates uraemic neuropathy on top of diabetic neuropathy

B12 replacement ^[7]:

Aspect	Details
Route	Parenteral (IM) if impaired absorption (pernicious anaemia, gastrectomy, terminal ileum disease); oral if dietary deficiency (vegans)
IM regimen	1000 μg IM weekly until normalised → then 1000 μg IM every 1–2 months
Oral regimen	1000 μg PO daily — even in malabsorption, very high oral doses can work via non-IF-dependent passive diffusion (~1% of oral dose is absorbed passively)
Duration	Lifelong if underlying condition is irreversible (pernicious anaemia, gastrectomy); otherwise until deficiency corrected
Urgency	Urgent replacement indicated if severe anaemia or neuropsychiatric symptoms — risk of irreversible neurological deficits if delayed
Monitoring	Reticulocyte count peaks day 5–10; Hb rises ~1 g/dL/week. Watch for ↓K⁺ (rapid haematopoiesis consumes K⁺) and Fe depletion (increased erythropoiesis)
Neurological recovery	Sensory neuropathy takes 6–12 months to correct; some deficits may not improve ^[7]. This is why early treatment is critical

Folate replacement ^[7]:

Oral: 1–5 mg/day — sufficient even if malabsorption
Critical rule: If B12 status is unknown, always give B12 alongside folate — use of folate alone in the presence of B12 deficiency may worsen neurological deficit despite partially masking haematological deficits (mechanism unclear but well-documented) ^[7]

Never Give Folate Alone Without Checking B12 Status

This is a classic exam point and a real clinical danger. Folate alone in B12 deficiency may worsen neurological deficit while correcting the macrocytic anaemia — giving a false sense of security from the improving blood count while the spinal cord degenerates. Always check B12 before or alongside folate replacement ^[7].

Alcoholic neuropathy:

Alcohol cessation (most important)
Thiamine replacement (IV Pabrinex in acute setting, then oral thiamine)
B12/folate replacement if deficient
Balanced nutrition

Acuity	Treatment	Mechanism
Acute symptomatic (tetany, severe paraesthesia)	IV calcium gluconate 10% (10 mL over 10 min, then infusion)	Directly raises ionised Ca²⁺ → stabilises neuronal membranes → stops spontaneous firing
Chronic	Oral calcium + vitamin D (alfacalcidol/calcitriol)	Restores calcium homeostasis
Hyperventilation-induced	Reassurance, slow breathing, rebreathing into cupped hands or paper bag	Raises pCO₂ → corrects respiratory alkalosis → ↑ionised Ca²⁺. Total calcium is normal — NO calcium replacement needed

This follows a stepwise approach from conservative to surgical ^[9]:

Stage	Treatment	Details
Conservative (first-line for mild-moderate)	Night-time wrist splint (in neutral position) ^[9]	Prevents wrist flexion during sleep → ↓carpal tunnel pressure → ↓median nerve compression. The nerve recovers if compression is intermittent
	Physiotherapy, lifestyle modification	Activity modification (ergonomic keyboards, rest breaks), weight loss
Pharmacological	Local steroid injection (into carpal tunnel) ^[9]	Reduces synovial inflammation/swelling → ↓pressure on nerve. Provides temporary relief (weeks to months). Pyridoxine (vitamin B6) also used but evidence is weak
Surgical	Carpal tunnel release (division of flexor retinaculum) ^[9]	Definitive: opens up the tunnel by cutting the transverse carpal ligament → permanent pressure relief. Can be open or endoscopic

Surgical indications ^[9]:

CTS unresponsive to conservative treatment for 6 weeks
Associated sensory / motor deficit (thenar wasting = late sign = urgent)
Axonal loss on NCS (indicates irreversible nerve damage is occurring)

Specific surgical complications ^[9]:

Persistent CTS symptoms (inadequate release)
Nerve injury: palmar cutaneous branch of median nerve
Vascular injury: superficial palmar arch

Severity	Treatment
Mild (pain, paraesthesia only)	Conservative: analgesia (NSAIDs, neuropathic pain agents), physiotherapy, cervical collar for acute flare, activity modification
Moderate (persistent pain despite conservative Mx)	Cervical epidural steroid injection, nerve root block
Severe (progressive motor deficit, myelopathic signs, failed conservative Mx)	Surgical decompression ± stabilisation (anterior cervical discectomy and fusion, or posterior laminectomy) ^[6]

Symptomatic Management of Neuropathic Pain

Many causes of numbness/tingling are associated with neuropathic pain (burning, tingling, electric-like). Even when the underlying cause is addressed, neuropathic pain often requires dedicated pharmacological management. The character of neuropathic pain is described as tingling, pricking, needle-like, numbness, electric-like, burning and it is less opioid-responsive ^[1].

Neuropathic pain responds to antidepressants and anticonvulsants ^[1]:

Line	Drug Class	Examples	Mechanism	Key Points
1st line	Gabapentinoids	Gabapentin (300–3600 mg/day in 3 divided doses), Pregabalin (75–600 mg/day in 2 divided doses)	Bind α₂δ subunit of voltage-gated Ca²⁺ channels → ↓presynaptic Ca²⁺ influx → ↓excitatory neurotransmitter release (glutamate, substance P) → ↓neuronal hyperexcitability	Pregabalin has more predictable pharmacokinetics (linear absorption) than gabapentin. S/E: drowsiness, dizziness, peripheral oedema, weight gain. Dose-reduce in renal impairment
1st line	SNRIs	Duloxetine (30–120 mg/day)	Inhibits reuptake of serotonin AND noradrenaline → enhances descending inhibitory pain pathways from brainstem → ↓pain signal transmission in dorsal horn	Preferred over TCAs in elderly/cardiac patients (better S/E profile). S/E: nausea, dry mouth, constipation. C/I: hepatic impairment, concomitant MAOIs
1st line	TCAs	Amitriptyline (10–75 mg nocte), Nortriptyline	Inhibits reuptake of serotonin + noradrenaline (same as SNRIs) PLUS blocks Na⁺ channels and NMDA receptors → multiple analgesic mechanisms	Excellent for neuropathic pain + insomnia (sedating). Start low, go slow. S/E: anticholinergic (dry mouth, constipation, urinary retention, blurred vision), sedation, cardiac arrhythmia. C/I: recent MI, heart block, urinary retention, narrow-angle glaucoma
2nd line	Combination	Gabapentinoid + SNRI or TCA	Synergistic — target different mechanisms	If monotherapy fails, combine drugs from different classes rather than switching between same class
2nd line	Topical	Capsaicin 8% patch, lidocaine 5% patch	Capsaicin depletes substance P from sensory nerve terminals; lidocaine blocks Na⁺ channels locally	For localised neuropathic pain. Few systemic S/E
3rd line	Opioids	Tramadol (weak opioid + SNRI-like action); strong opioids (morphine, oxycodone) as last resort	μ-opioid receptor agonism → ↓pain perception; tramadol also inhibits NA/5-HT reuptake	Use with caution — neuropathic pain is less opioid-responsive ^[1]. Risk of dependence. Tramadol preferred over strong opioids
3rd line	Anticonvulsants	Carbamazepine (specifically for trigeminal neuralgia)	Blocks voltage-gated Na⁺ channels → stabilises hyperexcitable neurones	Carbamazepine is first-line for trigeminal neuralgia specifically (not general neuropathic pain). S/E: hyponatraemia, aplastic anaemia, Stevens-Johnson syndrome. Monitor FBE and Na⁺

Why Standard Analgesics Don't Work Well for Neuropathic Pain

Neuropathic pain arises from ectopic firing of damaged neurones and central sensitisation, not from ongoing tissue damage. This is why:

Paracetamol: works on COX in the CNS for nociceptive pain → minimal effect on ectopic neuronal firing
NSAIDs: work on peripheral COX/prostaglandin pathway → irrelevant to neuropathic mechanisms
Opioids: work on μ-receptors → somewhat effective but the descending inhibitory pathways are already dysfunctional in neuropathic states → less opioid-responsive ^[1]

Instead, gabapentinoids (↓Ca²⁺ channel activity), antidepressants (↑descending inhibition), and Na⁺ channel blockers (stabilise ectopic firing) target the actual pathophysiology.

Modality	Details	Evidence
Physiotherapy	Desensitisation techniques, graded motor imagery, TENS	Moderate evidence for chronic neuropathic pain
Psychological	CBT for pain management, mindfulness-based stress reduction	Good evidence for chronic pain syndromes
Neurostimulation	Spinal cord stimulation (implanted), transcutaneous electrical nerve stimulation (TENS)	Reserved for refractory pain; spinal cord stimulation has good evidence for FBSS, CRPS
Acupuncture	Various protocols	Limited evidence; may offer modest benefit

Cause	Key Management	Emergency?
Diabetic neuropathy	Glycaemic control (HbA1c < 7%), CVD risk factor control, foot care, neuropathic pain Mx	No
B12 deficiency	IM B12 (if malabsorption) or high-dose oral B12; lifelong if irreversible cause	Urgent if neuropsychiatric Sx
Folate deficiency	Oral folate 1–5 mg/day; ALWAYS co-administer B12 if B12 status unknown	No
Alcoholic neuropathy	Alcohol cessation, thiamine/B12/folate replacement, nutrition	No
Drug-induced	Withdraw offending agent; symptomatic Mx	No
Uraemic	Optimise dialysis; renal transplant for definitive cure	No
Hypothyroid	Levothyroxine replacement	No
Hypocalcaemia	IV calcium gluconate (acute); oral Ca + Vit D (chronic); rebreathing (if hyperventilation)	Acute if tetany
CTS	Night splint → steroid injection → surgical release if failed or motor deficit	No
Cubital tunnel	Elbow splint → anterior transposition if failed	No
Cervical radiculopathy	Conservative (analgesia, physio, collar) → epidural injection → surgery if progressive	No (unless myelopathy)
Cervical myelopathy	Surgical decompression + stabilisation	Semi-urgent
Cauda equina	Urgent MRI → surgical decompression < 48h	YES
Acute limb ischaemia	Heparin → embolectomy/thrombolysis within 6h	YES
Stroke / TIA	CT → thrombolysis (< 4.5h) / thrombectomy (< 6h) → aspirin → secondary prevention	YES
GBS	ICU monitoring → plasma exchange OR IVIg (NOT steroids)	YES if respiratory
MS	Acute: IV methylprednisolone; Chronic: DMTs	Acute relapse: urgent
NMOSD	Acute: IV steroids/PE/IVIg; Prophylaxis: rituximab/AZA/MMF. Do NOT use MS-specific agents	Acute relapse: urgent
Hyperventilation	Reassurance, slow breathing, treat underlying anxiety (CBT, SSRIs)	No
Functional	Positive diagnosis, education, physiotherapy, CBT	No

High Yield Summary — Management

Management is cause-directed — there is no "treatment for numbness"; identify and treat the underlying cause
Emergencies requiring immediate action: acute limb ischaemia (heparin + revascularisation < 6h), stroke (CT → thrombolysis < 4.5h), cauda equina (MRI → decompression < 48h), GBS with respiratory failure (ICU + PE or IVIg), cord compression (MRI → steroids → surgery/RT)
Diabetic neuropathy: glycaemic control is the cornerstone; no drug reverses established neuropathy
B12 replacement: IM if malabsorption, oral if dietary; lifelong if irreversible cause; never give folate alone without checking B12 — may worsen neurological deficit
Drug-induced neuropathy: withdraw offending agent — always take a detailed drug history
CTS: conservative (night-time wrist splint) → injection → carpal tunnel release if failed or motor deficit/axonal loss
GBS: plasma exchange OR IVIg — NOT steroids (steroids alone are ineffective)
NMOSD: do NOT use MS-specific agents (may be harmful); use rituximab/AZA/MMF for prophylaxis
Neuropathic pain: first-line = gabapentin/pregabalin, duloxetine, amitriptyline; standard analgesics (paracetamol, NSAIDs) are largely ineffective because the mechanism is ectopic neuronal firing, not nociceptive
Hyperventilation: reassurance + slow breathing; do NOT give IV calcium (the total calcium is normal — it's the ionised fraction that's transiently low due to alkalosis)

Active Recall - Management of Numbness and Tingling

A. Complications of Sensory Loss Itself

These complications arise directly from the loss of protective sensation, regardless of the underlying cause. They are most commonly seen in diabetic neuropathy (the most common cause of chronic numbness in Hong Kong ^[4]) but apply to any condition causing significant sensory loss.

B. Complications of Specific Underlying Conditions

Diabetic neuropathy (70–90% of diabetic patients eventually) ^[5] has its own cascade of complications:

Complication	Mechanism	Clinical Consequence
Neuropathic foot ulcer	Loss of protective sensation + motor neuropathy (claw toes) + autonomic neuropathy (dry skin, ↑blood flow) + often co-existing PVD	Chronic non-healing ulcer → osteomyelitis → amputation
Charcot neuroarthropathy	Repeated microtrauma + autonomic dysregulation (see above)	Joint destruction, deformity, rocker-bottom foot
Diabetic amyotrophy (proximal diabetic neuropathy)	Likely ischaemic infarction of lumbosacral plexus → asymmetric proximal weakness + paraesthesia ^[5]	Acute severe proximal LL weakness and wasting; 60% good functional recovery in 12–24 months but mild residual weakness may remain ^[5]
Autonomic neuropathy	Damage to autonomic fibres → cardiovascular, GI, genitourinary, sudomotor dysfunction	Postural hypotension, resting tachycardia, gastroparesis, erectile dysfunction, neurogenic bladder, anhidrosis
Acute diabetic mononeuropathy	Likely ischaemic infarction of single peripheral nerve → acute onset, usually transient ^[5]	CN III palsy (typically pupil-sparing), CN VI palsy, median nerve, common peroneal nerve

2. Complications of Acute Limb Ischaemia

When numbness/tingling is due to acute limb ischaemia, the complications are severe and time-critical ^[10]^[25]^[26]:

If CTS is left untreated ^[9]:

Complication	Mechanism	Clinical Feature
Thenar muscle atrophy	Chronic axonal loss in the motor branch of the median nerve → denervation of abductor pollicis brevis, opponens pollicis, flexor pollicis brevis	Thenar muscle wasting, weakness of thumb abduction and opposition; loss of pinch grip strength. This is often irreversible once established
Permanent sensory loss	Progressive axonal degeneration (beyond the initial demyelination) → permanent loss of sensory axons	Persistent numbness in the lateral 3.5 digits; impaired fine touch discrimination
Functional disability	Loss of opposition + sensory loss in thumb, index, middle fingers	Difficulty with buttons, keys, writing, gripping objects — significant impact on ADLs

Complications of carpal tunnel release surgery ^[9]:

Persistent CTS symptoms (inadequate release of the flexor retinaculum)
Nerve injury: palmar cutaneous branch of median nerve (numbness over thenar eminence)
Vascular injury: superficial palmar arch

When numbness/tingling is due to spinal cord pathology:

Complication	Mechanism
Progressive motor deficit	Untreated cord compression → progressive UMN weakness below the level; may become irreversible
Bladder/bowel dysfunction	Loss of sacral parasympathetic (S2–S4) autonomic control → neurogenic bladder (retention ± overflow incontinence), faecal incontinence
Chronic neuropathic pain	Central sensitisation from cord damage → "central pain syndrome" (burning, dysaesthetic pain below the level of lesion)
Pressure ulcers	Loss of sensation + immobility → sustained pressure over bony prominences → tissue ischaemia → skin breakdown
DVT/PE	Immobility + loss of muscle pump function in paralysed limbs → venous stasis → thrombosis
Autonomic dysreflexia (if lesion above T6)	Noxious stimulus below the level → massive uninhibited sympathetic discharge → severe hypertension, bradycardia, headache, flushing — a medical emergency

GBS, while presenting with paraesthesia + ascending weakness, has major systemic complications ^[17]:

Complication	Mechanism	Incidence
Respiratory failure	Ascending weakness involves respiratory muscles (diaphragm, intercostals) → inability to ventilate → hypercapnic respiratory failure	20% require ventilation
Autonomic dysfunction	Autoimmune attack on autonomic nerve fibres → tachycardia, fluctuating BP, urinary retention, ileus, cardiac arrhythmia	> 2/3 of patients
DVT/PE	Immobility from paralysis → venous stasis	Significant risk
Nosocomial infection	Prolonged ICU stay, mechanical ventilation → ventilator-associated pneumonia, UTI, line infections	Common
Chronic pain	Neuropathic pain persists beyond acute phase in many patients	> 2/3 initially; may persist
Residual disability	Incomplete nerve recovery → permanent weakness, sensory loss, fatigue	20% permanent disability, 10% severe disability ^[17]

Numbness is a recognised complication of many surgical procedures due to iatrogenic nerve injury:

Surgery	Nerve at Risk	Resulting Numbness
Varicose vein surgery	Saphenous nerve; sural nerve	Numbness along medial calf (saphenous); numbness in posterolateral leg and lateral foot (sural) ^[29]
Mastectomy / axillary dissection	Intercostobrachial nerve	Numbness and paraesthesia on inner upper arm ^[30]
Carpal tunnel release	Palmar cutaneous branch of median nerve	Numbness over thenar eminence ^[9]
Thyroidectomy	Superior/recurrent laryngeal nerve; parathyroids (hypocalcaemia)	Voice changes; perioral numbness (hypocalcaemia) ^[27]^[28]

Complication Category	Examples	Key Mechanism
Direct consequences of sensory loss	Trophic changes, painless burns, Charcot joint, neuropathic ulcer, falls from sensory ataxia	Loss of protective sensation → unperceived injury → cumulative tissue damage
Vascular/ischaemic	Compartment syndrome, rhabdomyolysis, reperfusion injury, AKI, arrhythmia	Ischaemia → cell death → reperfusion → toxic metabolite release
Diabetic complications	Neuropathic ulcer → osteomyelitis → amputation; Charcot foot; autonomic neuropathy	Multifactorial: sensory + motor + autonomic + vascular neuropathy
Post-surgical	Nerve injury (saphenous, sural, intercostobrachial), hypocalcaemia (thyroidectomy)	Iatrogenic nerve transection/traction; parathyroid damage
GBS-specific	Respiratory failure, autonomic dysfunction, DVT/PE, residual disability	Autoimmune demyelination of motor + autonomic + sensory nerves
Psychological	Depression, anxiety, insomnia, social isolation, loss of independence	Chronic pain + functional disability

High Yield Summary — Complications

Numbness is not benign — loss of protective sensation leads to painless burns, neuropathic ulcers, Charcot joints, and falls from sensory ataxia
Neuropathic foot ulceration is the most devastating complication of diabetic neuropathy and the leading cause of non-traumatic amputation — prevention through annual monofilament screening and foot care is essential
Charcot joint: progressive painless joint destruction due to ↓proprioception + ↓pain → repeated microtrauma; hallmark = mismatch between severe radiological destruction and minimal pain
Trophic changes (cold blue extremities, hair loss, brittle nails) are due to loss of autonomic innervation — they precede ulceration ^[2]
Compartment syndrome: earliest = pain out of proportion; most sensitive = pain on passive stretch; numbness in the web space of toes = deep peroneal nerve compression in anterior compartment. Pulses can be present. Treatment = emergent fasciotomy ^[10]^[26]
Rhabdomyolysis: K⁺ → arrhythmia; myoglobin → AKI. Treat with aggressive hydration + IV bicarbonate + mannitol ± dialysis ^[10]
Post-thyroidectomy hypocalcaemia: most common complication; perioral numbness is earliest symptom; severe cases → laryngospasm. CATS GO NUMB mnemonic ^[27]^[28]
GBS complications: 20% need ventilation; > 2/3 have autonomic dysfunction; 20% permanent disability ^[17]
Iatrogenic nerve injury is a recognised complication of many surgeries (varicose vein, mastectomy, CTS release) — always counsel patients pre-operatively

Active Recall - Complications of Numbness and Tingling

High Yield Summary

Paraesthesia = positive sensory symptom (nerve irritation/ectopic firing); Numbness = negative sensory symptom (conduction block/axon loss)
Probability diagnoses: DM neuropathy, nutritional neuropathy (alcohol/B12/folate), hyperventilation/anxiety, nerve root pressure (sciatica/cervical spondylosis), CTS, neurotoxic drugs
Serious disorders not to miss: CVA/TIA, PVD, GBS, infections (HIV, Lyme, leprosy), CKD/uraemia, spinal cord tumours/trauma, marine toxins
Pitfalls: migraine with focal signs, MS/transverse myelitis, hypocalcaemia
Distribution is king for localisation: glove-and-stocking = polyneuropathy; dermatomal = radiculopathy; hemibody = central; perioral + acral = hypocalcaemia/hyperventilation; non-anatomical = functional
Length-dependent pattern (distal → proximal) occurs because longest axons are most vulnerable to metabolic/toxic insults
Key examination: sensory modalities, motor function, reflexes, look for glove-and-stocking, thenar wasting, peripheral vasculature
↑Knee jerk + ↓ankle jerk = subacute combined degeneration (B12 deficiency) — UMN at cord + LMN peripherally
First-line investigations: urinalysis, blood sugar, FBE, ESR/CRP; then consider calcium, B12/folate, LFTs, U&E, TFTs, KFTs, nerve conduction studies
Always take a thorough drug history — neurotoxic drugs are a common and reversible cause

High Yield Summary — Differential Diagnosis

Localise first, then differentiate: distribution pattern is the single most powerful tool — glove-and-stocking (polyneuropathy), dermatomal (radiculopathy), sensory level (cord), hemibody (central), perioral + acral (metabolic), non-anatomical (functional)
Tempo matters: sudden = vascular (stroke/TIA); slow march over 20–30 min = migraine; ascending over hours–days = cord inflammation; chronic progressive = metabolic/toxic neuropathy
Probability diagnoses: DM neuropathy, nutritional (alcohol/B12/folate), hyperventilation, nerve root pressure, CTS, neurotoxic drugs
Must not miss: CVA/TIA, PVD/acute limb ischaemia, GBS (can kill via respiratory failure), spinal cord compression, cauda equina syndrome (surgical emergency), infections (HIV, Lyme)
Often missed: migraine with aura, MS/transverse myelitis, hypocalcaemia, CIDP
Stroke vs migraine: stroke is rapid and typically negative; migraine aura spreads slowly over 20–30 min with positive symptoms preceding negative
Always take a drug history — neurotoxic drugs are common and reversible
Always check peripheral pulses — acute limb ischaemia presents with paraesthesia as the earliest symptom (nerves most sensitive to ischaemia)

High Yield Summary — Diagnosis

Numbness/tingling has no single diagnostic criteria — the approach is to localise the lesion clinically, then confirm with targeted investigations
First-line investigations for all patients: urinalysis, blood sugar, FBE, ESR/CRP ^[4]
Second-line: serum calcium, B12/folate, LFTs (γGT), U&E, TFTs, KFTs, nerve conduction studies ^[4]
Third-line (specialist): imaging (MRI spine/brain, CT, angiography), LP (CSF protein, OCBs), specific blood tests for infection, nerve biopsy ^[4]
NCS is the cornerstone for neuropathy workup: distinguishes demyelinating (↓velocity, ↑latency, conduction block) from axonal (↓amplitude) — this distinction dramatically narrows the differential ^[3]
NCS does NOT assess CNS function — it is useless for myelopathy; use MRI instead ^[3]
Normal NCS does not exclude CTS ^[9] or small fibre neuropathy (use skin biopsy for the latter)
GBS CSF: ↑protein without pleocytosis (albuminocytologic dissociation); may be normal in week 1 ^[17]
MS MRI: dissemination in space (≥ 2/4 regions) + dissemination in time (enhancing + non-enhancing lesions); OCBs can substitute for DIT ^[19]
CT brain in acute stroke: first-line to exclude haemorrhage, NOT to diagnose ischaemic stroke (sensitivity only 48% day 1) ^[21]

High Yield Summary — Management

Management is cause-directed — there is no "treatment for numbness"; identify and treat the underlying cause
Emergencies requiring immediate action: acute limb ischaemia (heparin + revascularisation < 6h), stroke (CT → thrombolysis < 4.5h), cauda equina (MRI → decompression < 48h), GBS with respiratory failure (ICU + PE or IVIg), cord compression (MRI → steroids → surgery/RT)
Diabetic neuropathy: glycaemic control is the cornerstone; no drug reverses established neuropathy
B12 replacement: IM if malabsorption, oral if dietary; lifelong if irreversible cause; never give folate alone without checking B12 — may worsen neurological deficit
Drug-induced neuropathy: withdraw offending agent — always take a detailed drug history
CTS: conservative (night-time wrist splint) → injection → carpal tunnel release if failed or motor deficit/axonal loss
GBS: plasma exchange OR IVIg — NOT steroids (steroids alone are ineffective)
NMOSD: do NOT use MS-specific agents (may be harmful); use rituximab/AZA/MMF for prophylaxis
Neuropathic pain: first-line = gabapentin/pregabalin, duloxetine, amitriptyline; standard analgesics (paracetamol, NSAIDs) are largely ineffective because the mechanism is ectopic neuronal firing, not nociceptive
Hyperventilation: reassurance + slow breathing; do NOT give IV calcium (the total calcium is normal — it's the ionised fraction that's transiently low due to alkalosis)

High Yield Summary — Complications

Numbness is not benign — loss of protective sensation leads to painless burns, neuropathic ulcers, Charcot joints, and falls from sensory ataxia
Neuropathic foot ulceration is the most devastating complication of diabetic neuropathy and the leading cause of non-traumatic amputation — prevention through annual monofilament screening and foot care is essential
Charcot joint: progressive painless joint destruction due to ↓proprioception + ↓pain → repeated microtrauma; hallmark = mismatch between severe radiological destruction and minimal pain
Trophic changes (cold blue extremities, hair loss, brittle nails) are due to loss of autonomic innervation — they precede ulceration ^[2]
Compartment syndrome: earliest = pain out of proportion; most sensitive = pain on passive stretch; numbness in the web space of toes = deep peroneal nerve compression in anterior compartment. Pulses can be present. Treatment = emergent fasciotomy ^[10]^[26]
Rhabdomyolysis: K⁺ → arrhythmia; myoglobin → AKI. Treat with aggressive hydration + IV bicarbonate + mannitol ± dialysis ^[10]
Post-thyroidectomy hypocalcaemia: most common complication; perioral numbness is earliest symptom; severe cases → laryngospasm. CATS GO NUMB mnemonic ^[27]^[28]
GBS complications: 20% need ventilation; > 2/3 have autonomic dysfunction; 20% permanent disability ^[17]
Iatrogenic nerve injury is a recognised complication of many surgeries (varicose vein, mastectomy, CTS release) — always counsel patients pre-operatively

Numbness, Tingling

Definition and Terminology

Epidemiology and Risk Factors

Epidemiology

Risk Factors

Anatomy and Physiology of the Somatosensory System

Peripheral Sensory Receptors

The Two Main Ascending Sensory Pathways

1. Dorsal Column–Medial Lemniscal (DC-ML) Pathway

2. Spinothalamic Tract (STT)

Key Anatomical Levels for Localisation

Etiology (Focus on Hong Kong)

A. Peripheral Nerve Causes (Most Common Overall)

1. Peripheral Neuropathy (Generalised)

a) Diabetic Peripheral Neuropathy — Most common cause worldwide and in Hong Kong [4]

b) Nutritional Peripheral Neuropathy — Especially alcohol and B12/folate deficiency [4]

c) Neurotoxic Drugs [4]

d) Uraemic Neuropathy (CKD/Uraemia) [4][8]

e) Other Metabolic/Endocrine

f) Inflammatory/Autoimmune Neuropathy

g) Infective

h) Hereditary

i) Other

2. Entrapment Neuropathies (Mononeuropathy)

a) Carpal Tunnel Syndrome (CTS) — Most common entrapment neuropathy [4][6]

b) Cubital Tunnel Syndrome (Ulnar neuropathy at elbow) [6]

c) Thoracic Outlet Syndrome (TOS) [6]

d) Other entrapments

B. Nerve Root Causes (Radiculopathy)

C. Spinal Cord Causes

D. Brainstem Causes

E. Central (Brain) Causes

F. Vascular Causes

G. Psychiatric/Functional

H. Other Rare/Important Causes

Classification

By Symptom Type

By Temporal Pattern

By Distribution (Most Clinically Useful for Localisation)

By Modality Affected

Clinical Features

A. Symptoms (with Pathophysiological Basis)

1. Nature of the Sensory Disturbance

2. Distribution

3. Onset and Temporal Pattern

4. Associated Neurological Symptoms

5. Associated General Symptoms

6. Relevant History to Gather

B. Signs (with Pathophysiological Basis)

1. General Inspection

2. Sensory Examination

3. Motor Examination (Always Examine Alongside Sensory)

4. Reflexes

5. Special Tests

6. Peripheral Vascular Examination

Pathophysiological Mechanisms of Numbness/Tingling — Summary

Murtagh's Diagnostic Strategy Summary for Paraesthesia and Numbness

Probability Diagnosis [4]

Serious Disorders Not to Be Missed [4]

Pitfalls (Often Missed) [4]

Masquerades Checklist [4]

Is the Patient Trying to Tell Me Something? [4]

Key Investigations (Overview)

First Line [4]

Consider [4]

According to Clinical Findings (Refer) [4]

Active Recall - Numbness and Tingling (Part 1)

References

Differential Diagnosis of Numbness and Tingling

The Murtagh Framework — Structured Differential

Probability Diagnosis (common, think of first) [4]

Serious Disorders Not to Be Missed [4]

Pitfalls (Often Missed) [4]

Masquerades Checklist [4]

Psychogenic / Functional [4]

Differential by Distribution Pattern — A Practical Localisation Framework

Differential by Temporal Profile

Differential Diagnosis of Specific High-Yield Presentations

1. Numbness/Tingling in the Hand

2. Numbness/Tingling in the Leg