Polyneuropathy is a diffuse, symmetrical disorder of multiple peripheral nerves, typically presenting with distal sensory loss, weakness, and diminished reflexes in a "stocking-glove" distribution.

Exam domain	One-glance essentials
Definition / diagnosis	Symmetric disease of multiple peripheral nerves, usually length-dependent with glove-and-stocking deficits ^[1]^[2] Classify by time course, fibre type and axonal vs demyelinating physiology ^[1]
Epidemiology / risks	Diabetes mellitus is the commonest cause; also alcohol, uraemia, hypothyroidism, B12 deficiency and drugs ^[1]^[2] Immune, paraprotein, hereditary and infectious causes are important when atypical ^[1]
Core mechanism	Axonal loss → low NCS amplitudes with relatively preserved velocity and slow recovery ^[1] Demyelination → slowed conduction/conduction block and is more often immunotherapy-responsive ^[1]^[2]
Clinical picture	Distal numbness/burning, loss of vibration/proprioception, distal weakness and areflexia ^[1]^[2] Autonomic involvement: postural hypotension, gastroparesis, bladder or erectile dysfunction ^[1]
Investigations	NCS/EMG is pivotal for axonal vs demyelinating pattern ^[1]^[2] Screen HbA1c, B12, TFT, CBC, renal/liver function, ESR/CRP and serum protein electrophoresis ^[1] Normal NCS does not exclude small-fibre neuropathy ^[1]
Management	Treat cause: glycaemic control, replace B12, stop neurotoxins or treat uraemia ^[1]^[2] Neuropathic pain: gabapentinoid, duloxetine or amitriptyline; add rehabilitation and foot care ^[1] GBS: respiratory/autonomic monitoring plus IVIg or plasma exchange, not steroids ^[3]
Complications	Foot ulcer, Charcot arthropathy, falls, contractures and chronic neuropathic pain ^[2] Autonomic neuropathy can cause silent ischaemia, arrhythmia, gastroparesis and recurrent UTI ^[2] GBS may cause respiratory failure and dysautonomia ^[3]
Prevention / follow-up	Structured diabetic foot surveillance, daily self-inspection and protective footwear ^[2]^[4] Avoid offending drugs; give pyridoxine with isoniazid when indicated ^[1]
Exam traps	Brisk reflexes, sensory level or sphincter signs suggest myelopathy, not uncomplicated polyneuropathy ^[1] *B12 deficiency may give brisk knees from myelopathy but absent ankles from neuropathy* ^[1] CIDP lasts > 8 weeks and may respond to steroids; GBS does not ^[1]^[3]

References

^[1] Senior notes: Ryan Ho Neurology.pdf (pp. 179–184, Disease of the Peripheral Nerves) ^[2] Senior notes: Ryan Ho Endocrine.pdf (pp. 97–99, Diabetic Neuropathy) ^[3] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 134–139, GBS) ^[4] Lecture slides: GC 042. Deterioration of eyesight in a diabetic patient diabetic complications [Update 2025].pdf (p. 15, Foot Care)

Polyneuropathy

Polyneuropathy ("poly" = many, "neuro" = nerve, "pathy" = disease) refers to a diffuse, symmetrical disease process affecting multiple peripheral nerves, typically in a length-dependent manner (i.e., the longest nerves are affected first, so symptoms begin distally and progress proximally — the classic "glove-and-stocking" distribution) ^[1]^[2].

Why length-dependent? The longest axons (those supplying the feet) are the most metabolically vulnerable. They have the greatest distance for axonal transport, so any systemic metabolic insult (e.g., hyperglycaemia, toxins, nutritional deficiency) hits them first. This is why polyneuropathy almost always starts in the toes/feet before the fingers/hands.

This distinguishes polyneuropathy from:

Mononeuropathy — a single nerve affected (e.g., carpal tunnel syndrome)

Mononeuritis multiplex — multiple non-contiguous individual nerves affected asymmetrically (e.g., vasculitis)

Radiculopathy — nerve root involvement (dermatomal distribution)

Plexopathy — nerve plexus involvement

Key Distinction (Exam Favourite)

Polyneuropathy = symmetrical, length-dependent, distal-first involvement of multiple peripheral nerves. If a neuropathy is asymmetrical, think mononeuritis multiplex or radiculopathy, NOT polyneuropathy.

Prevalence: Approximately 1–3% of the general population; rises to 7–8% in those aged > 55 years ^[3].
Most common cause worldwide and in Hong Kong: Diabetic polyneuropathy — affects up to 50% of patients with long-standing diabetes ^[4]^[5].
- Among T1DM → 5 to 40%; among T2DM → 1 to 20% ^[5].
Second most common cause in developed settings: Alcohol-related polyneuropathy.
In Hong Kong specifically:
- High prevalence of diabetes (> 10% of adult population) makes diabetic neuropathy the dominant cause.
- Chronic kidney disease (common in HK's ageing population) → uraemic neuropathy.
- Chemotherapy-induced polyneuropathy is increasingly relevant given rising cancer incidence.
- Vitamin B12 deficiency in elderly and vegetarian populations.
- Guillain-Barré syndrome (GBS): incidence 1–2/100,000 per year, with 20% increase in incidence with every 10-year increase in age beyond the first decade ^[2].
- CIDP: prevalence 0.9–8.9/100,000, more common in older males ^[2].

Anatomy and Function of Peripheral Nerves

Understanding the structure of a peripheral nerve is essential — it explains why some diseases cause axonal damage while others cause demyelination, and why the clinical features differ.

Layer	Structure	Function
Epineurium	Outermost connective tissue sheath	Protects the nerve trunk; contains vasa nervorum (blood supply to the nerve)
Perineurium	Surrounds each fascicle	Acts as blood-nerve barrier (analogous to BBB); maintains intrafascicular pressure
Endoneurium	Surrounds individual nerve fibres	Contains collagen, fibroblasts, capillaries
Axon	The nerve cell's conducting process	Transmits electrical impulses
Myelin sheath	Produced by Schwann cells (one Schwann cell per internode)	Insulates axons for saltatory conduction (speeds up signal transmission)
Nodes of Ranvier	Gaps between myelin segments	Site of action potential regeneration

Fibre Type	Size	Myelination	Function	Clinical Deficit When Damaged
Large myelinated (Aα)	Largest	Thick myelin	Motor function, proprioception	Weakness, areflexia, impaired proprioception/vibration
Large myelinated (Aβ)	Large	Thick myelin	Light touch, vibration, proprioception	Loss of light touch, vibration, joint position sense
Small myelinated (Aδ)	Small	Thin myelin	Sharp/fast pain, temperature, some autonomic	Loss of pinprick, temperature
Unmyelinated (C fibres)	Smallest	None	Dull/slow pain, temperature, autonomic	Burning pain, autonomic dysfunction

Why Does Fibre Type Matter?

Large, myelinated fibres → mostly negative symptoms (loss of touch/proprioception, pins-and-needles) ^[2]. Small, unmyelinated fibres → mostly positive symptoms (pain) ^[2]. This is because small fibre damage causes ectopic firing and spontaneous discharge → neuropathic pain, whereas large fibre loss simply removes sensory input.

Saltatory conduction: Action potentials "jump" between Nodes of Ranvier in myelinated fibres. This is why demyelination slows conduction velocity — the impulse can no longer jump efficiently.
Axonal transport: Proteins and organelles are synthesised in the cell body and transported down the axon via microtubules. The longest axons (to the feet) are most vulnerable to metabolic disruption — hence length-dependent polyneuropathy.
Wallerian degeneration: When an axon is severed or severely damaged, the distal segment degenerates. This is irreversible axonal loss and explains why axonal neuropathies recover more slowly (require regrowth at ~1 mm/day) than demyelinating neuropathies (which recover by remyelination).

Aetiology (Focus on Hong Kong)

The causes of polyneuropathy can be broadly categorised by the DANG THERAPIST mnemonic (or similar frameworks), but for a clinical approach, it is most useful to think in terms of:

Metabolic/Endocrine (most common)
Toxic/Drug-induced
Nutritional deficiency
Inflammatory/Immune-mediated
Infective
Hereditary
Paraneoplastic/Neoplastic
Others (e.g., critical illness, amyloidosis)

The pathological differentials for lower limb weakness include: Endocrine (Vitamin B12 deficiency resulting in neuropathy/myelopathy, diabetic neuropathy), Trauma/Toxins (neuropathy secondary to chemotherapy), Inflammatory (Guillain-Barré syndrome, vasculitic neuropathy), Autoimmune (multiple sclerosis, neuromyelitis optica), Infection, Vascular, Neoplasm, Degenerative, and Congenital causes. ^[6]

Category	Cause	Pathophysiology	HK Relevance
Metabolic	Diabetes mellitus (most common)	Chronic hyperglycaemia → polyol pathway activation (sorbitol accumulation in Schwann cells → osmotic damage) + advanced glycation end-products (AGEs) damage vasa nervorum → microvascular ischaemia + oxidative stress → axonal degeneration ± secondary demyelination	Very high — DM prevalence > 10% in HK
	Chronic kidney disease / Uraemia	Accumulation of uraemic toxins (e.g., indoxyl sulphate, p-cresyl sulphate) → direct axonal toxicity + impaired axonal transport	High — CKD common in ageing HK population
	Hypothyroidism	Mucopolysaccharide deposition in nerve → compression + metabolic dysfunction of Schwann cells	Moderate
Toxic / Drug	Alcohol	Direct neurotoxicity of ethanol + acetaldehyde on axons + associated thiamine (B1) deficiency → axonal degeneration	High — significant alcohol use in HK
	Chemotherapy (platinum agents, vincristine, taxanes, bortezomib)	Platinum → DNA cross-linking in dorsal root ganglia; Vincristine → disrupts microtubule assembly → impairs axonal transport; Taxanes → stabilise microtubules (paradoxically also impairs transport)	High — rising cancer incidence
	Isoniazid	Inhibits pyridoxal phosphokinase → depletes active vitamin B6 → impairs GABA synthesis and nerve function	Relevant — TB still endemic in HK
	Ethambutol	Optic neuritis (blurring of vision, scotoma, worsened colour discrimination); peripheral neuropathy (rare) ^[7]	As above
	Amiodarone	Lysosomal accumulation of phospholipids in Schwann cells → demyelination	Used for AF, common in cardiology
	Metronidazole	Direct axonal toxicity with prolonged use	Common antibiotic
	Heavy metals (lead, arsenic, mercury, thallium)	Lead → motor neuropathy (attacks Schwann cells); Arsenic → axonal degeneration	Occupational exposure
Nutritional	Vitamin B12 deficiency	B12 is essential for methylation of myelin basic protein and for maintaining myelin integrity → demyelination of posterior columns (SCD) + peripheral nerve axonal damage	Can occur in absence of haematological changes as neurones require higher B12 level to function ^[8]. Common in elderly, vegetarians, pernicious anaemia
	Vitamin B1 (Thiamine) deficiency	Thiamine → essential cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in Krebs cycle → energy failure in metabolically active nerve tissue → axonal degeneration	Alcoholics, malnutrition
	Vitamin B6 (Pyridoxine) — deficiency OR excess	Deficiency → impaired nerve function; Excess → sensory neuronopathy (dorsal root ganglia toxicity)	Isoniazid causes B6 depletion
	Folate deficiency	Impaired DNA synthesis → rarely isolated cause of neuropathy
	Copper deficiency	Posterior column myelopathy + peripheral neuropathy (mimics B12 deficiency)	Post-bariatric surgery, zinc excess
Inflammatory / Immune	Guillain-Barré syndrome (GBS / AIDP)	Trigger: infection (Campylobacter jejuni, Mycoplasma pneumoniae, CMV, EBV), vaccination within 4 weeks → molecular mimicry: organisms share epitopes with antigens on peripheral nerve (GQ1b, GM1) → autoantibody-mediated damage to peripheral nerve ^[2]^[9]	Sporadic, worldwide
	Chronic inflammatory demyelinating polyneuropathy (CIDP)	Autoimmune attack on peripheral nerve myelin; distinguished from GBS by protracted course (> 8 weeks), lack of association with preceding infection, more prominent sensory symptoms, and good response to steroid Tx ^[2]
	Vasculitic neuropathy	Polyarteritis nodosa: necrotising vasculitis of medium-sized arteries → vasa nervorum ischaemia → mononeuritis multiplex (up to 70%) ^[10]; also ANCA-associated vasculitis, SLE
	Paraproteinaemic neuropathy	Anti-MAG (myelin-associated glycoprotein) antibodies in IgM paraproteinaemia → demyelination
Infective	HIV	Direct HIV neurotoxicity + opportunistic infections + antiretroviral drug toxicity (e.g., didanosine, stavudine) → distal sensory polyneuropathy	Relevant in HK
	Leprosy (Hansen's disease)	Mycobacterium leprae has tropism for Schwann cells → granulomatous inflammation → nerve damage. Palpably thickened nerves ^[2]	Rare in HK but classic teaching
	Hepatitis B/C	Immune complex–mediated vasculitis (HBV-associated PAN) or cryoglobulinaemia (HCV)	HBV endemic in HK
Hereditary	Charcot-Marie-Tooth disease (CMT / HMSN)	Most common inherited neuropathy; CMT1 (demyelinating, AD) — PMP22 duplication → defective myelin; CMT2 (axonal, AD) — various gene mutations	Mostly autosomal dominant ^[2]
	Familial amyloid polyneuropathy (FAP)	Transthyretin mutations → amyloid deposition in peripheral nerves → progressive sensorimotor and autonomic neuropathy
	Hereditary neuropathy with liability to pressure palsies (HNPP)	PMP22 deletion → episodic demyelinating neuropathy at compression sites
Paraneoplastic / Neoplastic	Paraneoplastic sensory neuronopathy	Anti-Hu antibodies attack dorsal root ganglia → pure sensory neuropathy (non-length-dependent)	Associated with small cell lung CA
	Direct infiltration (lymphoma, leukaemia)	Tumour cells infiltrate peripheral nerves
	POEMS syndrome	Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes ^[1] — likely VEGF-mediated nerve damage
Other	Amyloidosis (AL type)	Amyloid fibril deposition in peripheral nerves → autonomic neuropathy, postural hypotension ^[11]
	Critical illness polyneuropathy (CIP)	Systemic inflammation (sepsis/SIRS) → microvascular damage to peripheral nerves → axonal degeneration	Critical illness polyneuropathy listed as complication of MODS in sepsis ^[12]
	Sarcoidosis	Granulomatous infiltration of peripheral nerves	Rare

HK-Specific High-Yield Causes

For Hong Kong exams, prioritise: (1) Diabetic polyneuropathy, (2) Alcohol-related, (3) Drug-induced (chemotherapy, isoniazid, ethambutol), (4) B12 deficiency, (5) GBS/CIDP, (6) CKD/uraemic neuropathy, (7) Hereditary (CMT). These cover > 90% of clinical cases you will encounter.

Pathophysiology: Axonal vs. Demyelinating — The Two Fundamental Mechanisms

This distinction is the single most important concept in polyneuropathy because it determines the electrophysiological pattern, the differential diagnosis, and often the treatability.

Mechanism: Damage to the axon itself (the "wire"). The myelin sheath is initially intact.
Pathology: Wallerian degeneration distally → the axon dies back from the distal end.
Why length-dependent? The longest axons have the most metabolic demand and are first to fail.
NCS pattern: Normal conduction velocity (myelin is intact), ↓ amplitude (fewer functioning axons) ^[1]^[2].
Clinical pattern: Early wasting is characteristic of axonal but not demyelinating neuropathies ^[2].
Recovery: Slow — requires axonal regrowth (~1 mm/day = ~1 inch/month).
Common causes: Diabetes, alcohol, uraemia, drugs/toxins, nutritional deficiency, most hereditary neuropathies.
Treatability: Majority not directly treatable → management largely by ↓ exposure to toxins and treatment of underlying disease process ^[2].

Mechanism: Damage to the Schwann cells or their myelin sheath. The axon is initially preserved.
Pathology: Segmental demyelination → loss of insulation → slowed or blocked conduction.
NCS pattern: ↓ Conduction velocity (myelin is damaged → impulse travels slowly), normal/near-normal amplitude (axons intact) ^[1]^[2]. Also: conduction block, temporal dispersion, prolonged distal latency, prolonged F-wave latency.
Recovery: Faster — remyelination can occur over weeks to months.
Common causes: GBS, CIDP, paraproteinaemic neuropathy, CMT1, anti-MAG neuropathy.
Treatability: Usually immunosuppressive treatment (e.g., IVIg, pulse steroids, plasmapheresis) — this is why distinguishing demyelinating from axonal is so clinically important ^[2].

Exam Pearl: Why Does NCS Distinction Matter?

Important because usually only demyelinating neuropathies are susceptible to treatment ^[2]. If you identify a demyelinating pattern on NCS, you must actively search for a treatable cause (GBS, CIDP, paraproteinaemia). Axonal neuropathies are generally managed by treating the underlying cause.

In practice, many chronic polyneuropathies have elements of both axonal loss and secondary demyelination (e.g., chronic diabetic neuropathy). The "primary" pathology determines the classification.

Classification

Polyneuropathy can be classified along multiple axes. This is how you systematically narrow the differential:

Time Course	Duration	Examples
Acute	Days to 4 weeks	GBS, porphyria, toxins (e.g., thallium), vasculitis
Subacute	4–8 weeks	Nutritional, drug-induced, paraneoplastic
Chronic	> 8 weeks	Diabetes, alcohol, CIDP, hereditary (CMT), uraemia
Relapsing-remitting	Fluctuating	CIDP (1/3 of cases), porphyria

Distribution	Description	Examples
Symmetric, length-dependent	Classic glove-and-stocking	Most metabolic, toxic, nutritional causes
Symmetric, non-length-dependent	Proximal + distal equally	CIDP, GBS
Asymmetric	Not fitting a single nerve territory	Mononeuritis multiplex (vasculitis, DM), multifocal motor neuropathy

Type	Clinical Features	Examples
Motor-predominant	Weakness, wasting, foot drop	GBS, CIDP, CMT, multifocal motor neuropathy, lead poisoning
Sensory-predominant	Numbness, tingling, pain	DM (early), B12 deficiency, paraneoplastic, alcohol
Sensorimotor (mixed)	Both motor and sensory	Most common pattern — DM, alcohol, CIDP, CMT
Autonomic-predominant	Postural hypotension, GI/GU dysfunction	DM autonomic neuropathy, amyloidosis, GBS (can occur)
Small fibre	Pain, temperature loss, autonomic	Early DM, amyloidosis, Fabry disease

Type	NCS Findings	Examples
Axonal	↓ Amplitude, normal/near-normal velocity	DM, alcohol, toxins, uraemia, B12 def
Demyelinating	↓ Velocity, conduction block, prolonged distal latency	GBS, CIDP, CMT1, anti-MAG
Mixed	Features of both	Chronic DM, some toxic neuropathies

Clinical Features

A. Symptoms (What the Patient Tells You)

History will reveal the diagnosis and direct our neurological examination ^[13]^[14].

Key presenting symptoms to ask about: Sensory (pain, numbness, paraesthesia, modality involved), Motor (weakness, movement disorders), Distribution, Time of onset and duration ^[2]^[15].

Symptom	Mechanism	Fibre Type
Numbness ("my feet feel dead/wooden")	Loss of sensory input from damaged sensory axons → negative symptom	Large fibre (Aβ)
Tingling / "Pins and needles" (paraesthesia)	Ectopic impulse generation from injured/regenerating nerve fibres → positive symptom	Large fibre
Burning pain	Spontaneous firing of damaged nociceptive C-fibres and Aδ fibres → positive symptom; also central sensitisation in dorsal horn	Small fibre (C, Aδ)
Lancinating / "Electric shock" pain	Ectopic discharges from demyelinated axons → ephaptic cross-talk between fibres	Mixed
Band-like tightness	Distorted sensory processing from partial denervation	Mixed
Allodynia (pain from light touch)	Aβ fibres (normally non-nociceptive) sprout into nociceptive laminae of dorsal horn after C-fibre loss → light touch now perceived as pain (central sensitisation)	Central mechanism
Loss of balance / unsteadiness (sensory ataxia)	Proprioceptive loss → brain doesn't know where limbs are in space → worse in dark (no visual compensation) → positive Romberg sign	Large fibre (Aα, Aβ)
"Walking on cotton wool"	Loss of plantar sensation → altered proprioceptive feedback	Large fibre

Distribution: Glove-and-stocking pattern — starts distally in feet, ascends proximally; hands involved later when symptoms reach mid-calf level ^[2]^[5].

Symptom	Mechanism
Difficulty tip-toeing	Distal LL weakness — ankle plantarflexion (S1–S2, tibial nerve)
Foot drop (tripping over feet, slapping gait)	Distal LL weakness — ankle dorsiflexion (L4–L5, common peroneal nerve); most characteristic early motor symptom of polyneuropathy
Difficulty with fine hand movements (buttons, keys)	Distal UL weakness — intrinsic hand muscles
Difficulty climbing stairs, standing from chair, combing hair	Proximal weakness — suggests GBS, CIDP, or myopathy rather than typical distal polyneuropathy ^[2]
Muscle cramps	Denervation → motor unit instability → involuntary contractions

Symptom	Mechanism
Postural dizziness / lightheadedness	Orthostatic hypotension due to central/peripheral sympathetic denervation ^[5]
Resting tachycardia	Impaired cardiac output control (early feature of autonomic neuropathy) ^[5]
Dry skin (anhidrosis) distally, compensatory sweating proximally	Distal hypohidrosis with compensatory proximal hyperhidrosis — sudomotor denervation ^[5]
Gastroparesis (nausea, early satiety, bloating)	Vagal autonomic neuropathy → loss of interstitial cells of Cajal coordination ^[16]
Constipation or diarrhoea (esp. nocturnal)	Painless watery nocturnal diarrhoea — enteric nervous system dysfunction ^[5]
Erectile dysfunction	Autonomic denervation of pelvic vasculature
Bladder dysfunction (incomplete emptying, overflow incontinence)	↓ Ability to sense full bladder, incomplete emptying, recurrent UTI ^[5]

Must ask about ^[2]^[6]^[15]:

Family history of similar problem → ?genetic disease (CMT, FAP)
Past medical history: Previous trauma, previous neurological diseases
Drug history: Chemotherapy, metronidazole, amiodarone → neuropathy; Alcohol abuse → neuropathy; Steroids → proximal muscle weakness (important differential)
Travel history
Other/prior neurological symptoms; other systemic symptoms
Past medical and surgical history; vaccination history; social history

B. Signs (What You Find on Examination)

Physical examination is guided by history and helps with localisation and further narrowing differential diagnosis ^[6].

Examine: Distribution and character of weakness (unilateral/bilateral, upper and/or lower limbs, proximal and/or distal, myotome/nerve distribution, UMN and/or LMN pattern); any sensory impairment (distribution, nature); cranial nerve and cerebellar signs; sphincter disturbances (anal tone, palpable bladder) ^[6].

Sign	Description	Mechanism
Wasting (muscle atrophy)	Visible loss of muscle bulk, especially in intrinsic foot muscles (extensor digitorum brevis), then hand intrinsics	Denervation → loss of trophic support → muscle fibre atrophy. Early wasting is characteristic of axonal but not demyelinating neuropathies ^[2]
Fasciculation	Irregular, non-rhythmical contraction of muscle; increased by tapping over bulk of large muscles; indicative of LMN lesion ^[15]	Spontaneous depolarisation of denervated motor units
Weakness	Typically distal > proximal; foot dorsiflexion (foot drop) often earliest motor sign	Loss of motor axons
Hypotonia / ↓ Tone	↓ Tone → LMN lesion ^[15]	Loss of lower motor neurone input to muscle spindle
Hyporeflexia / Areflexia	Diminished or absent deep tendon reflexes, ankle jerk lost first (longest reflex arc)	Interruption of the monosynaptic reflex arc (sensory afferent OR motor efferent limb)
Foot drop / Steppage gait	High-stepping gait to clear the dropped foot	Weakness of ankle dorsiflexors (tibialis anterior)

Classical Reflex Pattern in B12 Deficiency

Peripheral neuropathy classically: ↑ knee jerk (from subacute combined degeneration of cord — UMN) + ↓ ankle jerk (from peripheral neuropathy — LMN) ^[8]. This mixed UMN + LMN picture is a classic exam question. The explanation: B12 deficiency causes BOTH myelopathy (posterior + lateral column degeneration → UMN signs) AND peripheral neuropathy (→ LMN signs). The knee jerk is mediated by L3-4 (shorter nerve, less affected by PN, and the UMN lesion predominates), while the ankle jerk (S1-2, longest reflex arc) is lost due to peripheral neuropathy.

Sign	Description	Mechanism
Glove-and-stocking sensory loss	Distal symmetrical loss of sensation, ascending proximally	Length-dependent axonal degeneration
Impaired vibration sense (128 Hz tuning fork)	Lost at toes first, then ankles, then knees	Large myelinated fibre loss (dorsal column-medial lemniscal pathway)
Impaired proprioception (joint position sense)	Cannot tell direction of passive toe/finger movement	Large fibre loss → sensory ataxia
Impaired pinprick/temperature	Lost in stocking distribution	Small fibre loss (spinothalamic pathway)
Positive Romberg sign	Falls/sways with eyes closed (worse than eyes open)	Proprioceptive loss — with eyes open, vision compensates; eyes closed removes this compensation → unsteadiness
Pseudoathetosis	Slow writhing finger movements when eyes closed and arms outstretched	Severe proprioceptive loss → brain cannot track finger position
Sensory level	Horizontal level on trunk where sensation changes	More suggestive of myelopathy, but can occur in severe polyneuropathy

Sign	Mechanism
Pes cavus (high-arched foot)	Chronic denervation of intrinsic foot muscles → imbalance between long extensors/flexors and intrinsic muscles → arch elevation. Classic of hereditary neuropathy (CMT) ^[1]^[2]
Claw hand	Denervation of lumbricals/interossei → MCP hyperextension + IP flexion ^[1]^[2]
Kyphoscoliosis	Chronic paraspinal muscle denervation (hereditary neuropathies) ^[1]^[2]
Trophic ulcers (esp. plantar)	Loss of protective pain sensation → repeated unrecognised trauma → ulceration
Charcot joints (neuropathic arthropathy)	Loss of proprioception + pain → joint subjected to abnormal stresses → destruction. Charcot arthropathy is a classic complication of diabetic neuropathy ^[5]
Disuse atrophy, hair loss, brittle nails	Denervation of trophic nerve supply to skin appendages ^[2]

Palpably thickened nerves (e.g., great auricular, ulnar at elbow, common peroneal at fibular head) — found in ^[2]:

Leprosy
Acromegaly
HMSN (CMT)
CIDP
Neurofibromatosis
Amyloidosis
Refsum disease

This is a classic short-case exam finding — if you palpate thickened nerves, the differential is narrow.

Sign	Mechanism
Orthostatic hypotension (> 20 mmHg systolic drop on standing)	Sympathetic vasomotor failure → inability to vasoconstrict on standing
Resting tachycardia	Vagal denervation → unopposed sympathetic tone
Dry, cracked skin distally	Sudomotor denervation → anhidrosis
Warm foot with bounding pulses but absent sensation	Autonomic neuropathy → arteriolar vasodilation (neuropathic foot, as opposed to the cold, pulseless ischaemic foot)
Dilated, sluggish pupils	Parasympathetic pupillary denervation

The 5 Questions to Ask Yourself

Is it really polyneuropathy? (vs. myelopathy, myopathy, mononeuritis multiplex)
What is the time course? (acute → GBS; chronic → DM, CMT, CIDP)
What fibres are involved? (motor, sensory, autonomic, mixed)
Is it axonal or demyelinating? (NCS is key — determines treatability)
What is the underlying cause? (metabolic screen, autoimmune, genetic)

Special Focus: Key Aetiologies and Their Pathophysiology

Most common form of diabetic neuropathy is sensory polyneuropathy: glove-and-stocking sensory loss of all modalities or paraesthesia ^[5].

Pathophysiology (multiple interacting mechanisms):

Polyol pathway: Hyperglycaemia → aldose reductase converts glucose to sorbitol → accumulates in Schwann cells (cannot cross cell membrane) → osmotic stress → cell swelling and damage + depletes NADPH (needed for glutathione regeneration → ↑ oxidative stress)
Advanced glycation end-products (AGEs): Glucose non-enzymatically glycates proteins → AGEs cross-link extracellular matrix proteins, activate RAGE receptors → inflammation, endothelial dysfunction
Microvascular ischaemia: AGE damage to vasa nervorum → endoneurial hypoxia → axonal injury
Oxidative stress: All of the above pathways generate reactive oxygen species
Protein kinase C activation: Hyperglycaemia → diacylglycerol → PKC activation → ↑ vascular permeability, ↓ blood flow
Net result: Axonal degeneration (length-dependent) ± secondary demyelination

Screening: by symptoms and monofilament (small fibre) and tuning fork (large fibre) tests ^[5].

Pathophysiology: Dual mechanism:

Direct toxic effect of ethanol and its metabolite acetaldehyde on peripheral nerve axons
Nutritional deficiency — particularly thiamine (B1), but also B6, B12, folate, niacin — from poor dietary intake + impaired absorption + increased metabolic demand
Net result: Axonal degeneration, sensory-predominant

Definition: Acute inflammatory demyelinating polyneuropathy (AIDP) affecting nerve roots ^[1].

Trigger → Molecular mimicry: the organisms share epitopes with an antigen on peripheral nerve (GQ1b, GM1) → autoantibody-mediated damage to peripheral nerve ^[1]^[2].

Variants:

Variant	Antibody	Target	Features
AIDP (most common in West)	Various	Schwann cell/myelin	Classic ascending weakness + areflexia
AMAN (acute motor axonal neuropathy — common in Asia)	Anti-GM1, anti-GD1a	Motor axolemma	Pure motor, rapid onset, axonal pattern
AMSAN	Anti-GM1	Motor + sensory axolemma	Severe, poor prognosis
Miller Fisher	Anti-GQ1b	Oculomotor nerves, cerebellar pathways	Ophthalmoplegia, ataxia, areflexia

Similar to AIDP in terms of clinical features, CSF findings, pathology, NCS findings; distinguished by protracted course (> 8 weeks) with relapses, lack of association with preceding infection, more prominent sensory symptoms, and good response to steroid treatment ^[2].

Nerve biopsy: segmental demyelination and remyelination, "onion-bulb" appearance ^[2] — this "onion-bulb" represents repeated cycles of demyelination and remyelination, with concentric layers of Schwann cell processes accumulating around the axon.

Neuropsychiatric features: ?related to ↓ methylation of myelin proteins ^[8]:

Subacute combined degeneration of cord: affects dorsal (DC-ML) and lateral columns (CST)
- Sensory: impaired vibration/proprioception esp bilateral LL, +ve Romberg
- Motor: paraparesis ± incontinence if severe
Peripheral neuropathy
Other: depression, irritability, cognitive slowing, dementia, psychosis

Listed as a neurological complication of multiple organ dysfunction syndrome (MODS) in sepsis ^[12].

Pathophysiology: Systemic inflammatory response → cytokine-mediated microvascular damage to vasa nervorum → endoneurial oedema → axonal degeneration
Presents as difficulty weaning from ventilator + limb weakness in ICU patients
NCS: axonal pattern
Management: treat underlying sepsis; no specific treatment; slow recovery

Drug	Mechanism	Type	Prevention
Isoniazid	Depletes pyridoxine (B6) → impairs nerve function	Axonal, sensory	Vitamin B6 for those with risk factors (pregnancy, DM, renal disease) ^[7]
Ethambutol	Arabinosyltransferase inhibition; optic neuritis + peripheral neuropathy (rare) ^[7]	Axonal	Baseline visual acuity, monthly monitoring
Vincristine	Disrupts microtubule assembly → impairs axonal transport	Axonal, motor > sensory	Dose reduction
Cisplatin / Oxaliplatin	DNA damage in dorsal root ganglia → sensory neuronopathy	Axonal, sensory	Dose-dependent; magnesium supplementation
Taxanes (paclitaxel, docetaxel)	Microtubule stabilisation → impaired axonal transport	Axonal, sensory	Dose reduction
Amiodarone	Phospholipid accumulation in Schwann cells	Demyelinating	Monitor; consider alternative antiarrhythmic
Metronidazole	Direct axonal toxicity	Axonal, sensory	Avoid prolonged courses
Thalidomide	Antiangiogenic → vasa nervorum ischaemia	Axonal, sensory
Bortezomib	Proteasome inhibition → DRG neurotoxicity	Axonal, sensory	Switch to subcutaneous route
Nitrofurantoin	Direct axonal toxicity	Axonal, sensorimotor	Avoid in renal impairment

High Yield Summary

Definition: Polyneuropathy = symmetric, length-dependent disease of multiple peripheral nerves (distal → proximal, "glove-and-stocking").

Most common cause: Diabetes mellitus (HK and worldwide).

Two fundamental mechanisms: Axonal (↓ amplitude, normal velocity on NCS; slow recovery; treat underlying cause) vs. Demyelinating (↓ velocity, conduction block; treatable with immunotherapy).

Clinical features:

Sensory: numbness, tingling, burning pain (small fibre), loss of proprioception/vibration (large fibre)
Motor: distal weakness (foot drop), wasting, fasciculation, areflexia (LMN signs)
Autonomic: postural hypotension, resting tachycardia, gastroparesis, bladder dysfunction
Trophic: pes cavus, claw hand, trophic ulcers, Charcot joints
Nerve thickening: leprosy, CMT, CIDP, acromegaly, neurofibromatosis

Key teaching points:

Only demyelinating neuropathies are usually susceptible to treatment — this is why NCS is essential.
B12 deficiency → ↑ knee jerk (myelopathy/UMN) + ↓ ankle jerk (neuropathy/LMN).
GBS: molecular mimicry (GQ1b, GM1) → acute demyelinating polyneuropathy; CSF: albuminocytologic dissociation.
CIDP: distinguished from GBS by > 8 weeks duration, relapsing course, steroid-responsive.
Isoniazid neuropathy prevented by vitamin B6 supplementation.
Critical illness polyneuropathy: axonal, occurs in sepsis/MODS.

Systematic approach: Time course → Fibre type → Distribution → NCS (axonal vs demyelinating) → Targeted investigations.

Active Recall - Polyneuropathy Overview

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 11.12 — Peripheral neuropathy) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 10.2 — Disease of the Peripheral Nerves, pp. 179–184) ^[3] Epidemiological data — general medical literature ^[4] Senior notes: Ryan Ho Endocrine.pdf (p. 98 — Diabetic peripheral neuropathy) ^[5] Senior notes: Ryan Ho Endocrine.pdf (pp. 98–99 — Diabetic peripheral and autonomic neuropathy) ^[6] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (pp. 18, 20) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p. 41 — Anti-TB drug side effects) ^[8] Senior notes: Ryan Ho Haemtology.pdf (p. 29 — B12 deficiency, SCD, peripheral neuropathy) ^[9] Lecture slides: Learning_Points_All_Lectures.txt (Neurology section — GBS) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (p. 159 — PAN) ^[11] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1 — Amyloidosis, autonomic neuropathy) ^[12] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p. 36 — MODS, critical illness polyneuropathy) ^[13] Lecture slides: CFB (MED04) Central Nervous System.pdf (p. 3 — History taking) ^[14] Lecture slides: GC 094. Where is the lesion I.pdf (p. 4 — History structure) ^[15] Senior notes: Ryan Ho Fundamentals.pdf (p. 102 — Neurological examination of PNS) ^[16] Senior notes: Block A - Indigestion and 'heartburn'.pdf (p. 25 — Gastroparesis pathophysiology)

The differential diagnosis of polyneuropathy operates on two levels simultaneously:

"Is this actually polyneuropathy, or is it something else mimicking it?" — i.e., anatomical differential diagnosis (localisation).
"If it IS polyneuropathy, what is the underlying cause?" — i.e., aetiological differential diagnosis.

Both are essential. Missing the first level means you might treat a myelopathy as a neuropathy (dangerous). Missing the second means you fail to identify a treatable cause.

Level 1: Anatomical Differential Diagnosis — "Is It Really Polyneuropathy?"

The patient presents with bilateral distal weakness, sensory loss, or both. Before you commit to "polyneuropathy," you must systematically consider every anatomical level from cortex to muscle that could produce similar symptoms.

Where is the lesion (anatomical differentials)? ^[17]^[18]:

Cerebrum (primary motor cortex, corona radiata, internal capsule)
Brainstem (cerebral peduncle, anterior pons, medulla oblongata)
Extrapyramidal system
Spinal cord (anterior horn cells, cervical cord)
Nerve root
Brachial plexus
Peripheral nerve
Neuromuscular junction
Muscle
Bone and joints
Metabolic
Functional

What is the lesion (pathological differentials)? ^[17]^[18]:

Vascular (stroke, spinal cord infarction)
Infection (encephalitis, myelitis, old polio)
Neoplasm (brain tumour, Pancoast tumour with brachial plexus compression/infiltration)
Degenerative (Parkinson's disease, cervical myelopathy/radiculopathy, carpal tunnel syndrome)
Inflammatory (multiple sclerosis, myelitis, Guillain-Barré syndrome, vasculitic neuropathy)
Congenital (cerebral palsy)
Autoimmune (encephalitis, neuromyelitis optica, myasthenia gravis)
Trauma/Toxins (subdural/epidural haematoma, fracture; neuropathy secondary to chemotherapy)
Endocrine (B12 deficiency resulting in neuropathy/myelopathy, diabetic neuropathy)

Condition	Key Distinguishing Features	Why It Mimics Polyneuropathy
Myelopathy (e.g., cervical spondylotic, MS, B12 deficiency)	UMN signs: hyperreflexia, spasticity, upgoing plantars, sensory level, sphincter disturbance early ^[2]. Distal paraesthesia can precede long tract signs. Normal or ↑ tendon reflexes (vs. ↓ in polyneuropathy)	Bilateral distal paraesthesia in hands/feet can be the earliest symptom of cord compression. But the reflexes are brisk, not absent — that's the giveaway.
Mononeuritis multiplex	Involvement of entirely unrelated nerves, relative preservation of certain nerves ^[2]. Asymmetrical. Individual nerve territories identifiable.	When many nerves are affected, it can superficially look symmetrical. But careful examination reveals asymmetry and non-length-dependent pattern.
Bilateral radiculopathy / Cauda equina syndrome	Weakness and sensory loss in segmental (dermatomal) distribution ^[2]. Cauda equina: saddle anaesthesia, urinary retention with overflow incontinence, bilateral radicular pain, LMN signs ^[19].	Bilateral L5/S1 radiculopathy can cause bilateral foot drop and distal sensory loss, mimicking polyneuropathy. But the pattern follows dermatomes, not a stocking distribution.
Myopathy (e.g., polymyositis, muscular dystrophy, steroid myopathy)	Preserved reflexes (until very late), muscle tenderness, proximal weakness (difficulty standing from chair, climbing stairs, combing hair), CK markedly elevated, EMG diagnostic ^[2]. No sensory involvement.	Proximal weakness can be confused with a motor-predominant neuropathy like GBS. But myopathy has NO sensory loss and reflexes are preserved.
Myasthenia gravis	Ocular involvement common (ptosis, diplopia), fatigability present, no sensory involvement ^[2]. Fluctuating weakness that worsens with repeated use.	Generalised weakness can mimic polyneuropathy. But MG has fatigability, ocular involvement, and NO sensory loss.
Lambert-Eaton myasthenic syndrome (LEMS)	May present with distal paraesthesia and hyporeflexia in addition to weakness → RNS diagnostic ^[2]. Reflexes improve after exercise (facilitation). Associated with small cell lung cancer.	LEMS is tricky because it can have hyporeflexia AND paraesthesia — very similar to polyneuropathy. The key is that weakness improves with repeated use (opposite of MG), and repetitive nerve stimulation shows incremental response.
Motor neuron disease (ALS)	Combination of UMN + LMN signs without sensory involvement ^[20]. Fasciculation prominent. NCS: sensory and motor nerve conduction studies are NORMAL ^[20]. EMG shows denervation.	The LMN component (wasting, fasciculation, weakness) can resemble motor neuropathy. But ALS has UMN signs (brisk reflexes, upgoing plantars) AND LMN signs in the SAME limb — this mixed picture doesn't occur in polyneuropathy.
Psychogenic / Functional weakness	Fluctuating, variable symptoms not conforming to neuroanatomical principles ^[2]. Hoover sign positive. Give-way weakness. Normal reflexes, normal NCS.	Can mimic any neurological presentation. The inconsistency on examination is the clue.

Critical Exam Trap: Myelopathy vs. Polyneuropathy

The most dangerous misdiagnosis is confusing cervical myelopathy for polyneuropathy. Both can present with bilateral hand numbness and clumsiness. The key differentiator: reflexes. In polyneuropathy, reflexes are reduced or absent. In myelopathy, reflexes are brisk with UMN signs (Hoffmann's sign, upgoing plantars, clonus). A sensory level on the trunk should immediately make you think myelopathy, NOT polyneuropathy ^[2]. Miss a cord compression and the patient may become permanently paraplegic.

Level 2: Aetiological Differential Diagnosis — "What Is Causing the Polyneuropathy?"

Once you've confirmed it is polyneuropathy, the next step is determining the underlying cause. This is driven by the clinical characterisation (time course, fibre type, NCS pattern).

Differential diagnosis of peripheral neuropathy (polyneuropathy) — need to know! ^[1]:

Metabolic: DM, alcohol, B12 (sensory), hypothyroidism, uraemia, chronic liver disease
Inflammatory: GBS (AIDP) / CIDP, vasculitides
Malignancy: paraneoplastic, paraproteinaemia
Hereditary: CMT (HMSN)
Drugs: isoniazid, vincristine, cisplatin, metronidazole (sensory), colchicine (sensory)
Infective: HIV, Lyme's disease
Infiltrative: amyloidosis, sarcoidosis

High-Yield Exam List

This list from the senior notes ^[1] is the core differential for any polyneuropathy question. Memorise it. In an exam, if asked "list causes of polyneuropathy," these 7 categories with their specific examples will score full marks.

The tempo of onset is one of the most powerful discriminators:

Time Course	Duration	Key Differentials	Why This Helps
Acute (days to 4 weeks)	< 4 weeks	GBS, porphyria, toxins (arsenic, thallium), vasculitis, diphtheria, critical illness polyneuropathy	Acute onset polyneuropathy = GBS until proven otherwise. GBS reaches nadir within 4 weeks ^[21]^[22].
Subacute (4–8 weeks)	4–8 weeks	Drug-induced, nutritional (B1, B12), paraneoplastic, vasculitis	Drugs and deficiencies typically accumulate over weeks.
Chronic (> 8 weeks)	> 8 weeks	DM, alcohol, CIDP, CMT, uraemia, hypothyroidism, paraproteinaemia, amyloidosis	CIDP continues to progress or has relapses for more than 8 weeks ^[2]^[21]^[22]. Most metabolic/toxic causes are chronic.
Relapsing-remitting	Fluctuating	CIDP (1/3), porphyria, HNPP	Relapsing course should trigger consideration of CIDP and porphyria.

NCS Pattern	Key Differentials	Clinical Reasoning
Axonal (↓ amplitude, normal velocity)	DM, alcohol, drugs/toxins, B12 deficiency, uraemia, paraneoplastic, amyloidosis, critical illness, CMT2	Most common pattern. Usually metabolic/toxic aetiology. Majority not directly treatable → management by ↓ exposure to toxins and treatment of underlying disease ^[2].
Demyelinating (↓ velocity, conduction block)	GBS, CIDP, paraproteinaemia (anti-MAG), CMT1	Usually only demyelinating neuropathies are susceptible to treatment ^[2]. Actively search for treatable cause.
Mixed	Chronic DM, CIDP with secondary axonal loss	Long-standing demyelinating process → secondary axonal degeneration.

Predominant Involvement	Key Differentials	Why
Motor-predominant	GBS, CIDP, multifocal motor neuropathy, CMT, lead poisoning, porphyria, diphtheria	Motor nerves selectively targeted by anti-ganglioside antibodies (GBS) or genetic defects (CMT).
Sensory-predominant	DM (early), B12 deficiency, alcohol, paraneoplastic (anti-Hu), drugs (cisplatin, metronidazole), amyloidosis (small fibre)	Dorsal root ganglia or distal sensory terminals are the primary target.
Sensorimotor	DM (advanced), alcohol (advanced), CIDP, uraemia, CMT	Most polyneuropathies eventually affect both fibre types.
Autonomic-predominant	DM, amyloidosis, GBS (can occur), pure autonomic failure, Fabry disease	Unmyelinated autonomic fibres selectively damaged.
Small fibre (pain + temperature + autonomic)	DM (early), amyloidosis, Fabry disease, HIV, sarcoidosis, coeliac disease	Small fibres have less metabolic reserve. Standard NCS may be NORMAL (tests only large fibres). Skin biopsy for intraepidermal nerve fibre density is diagnostic.

When a patient presents with acute flaccid paralysis, the differential is particularly important and commonly examined:

Differential diagnosis of GBS ^[1]^[21]^[22]:

Category	Conditions	Key Distinguishing Feature
Other acute polyneuropathies	Vasculitis, Lyme disease, porphyria, sarcoidosis, paraneoplastic disease, critical illness, severe vitamin B1 (thiamine) deficiency, acute arsenic poisoning	Vasculitis → asymmetric; Porphyria → abdominal pain + psychiatric features + dark urine; Critical illness → ICU setting; Arsenic → GI symptoms, Mees' lines
Spinal cord disease	Spinal cord compression, acute transverse myelitis	UMN signs (brisk reflexes, upgoing plantars), sensory level, sphincter disturbance early
Motor neuron disease	Poliomyelitis, ALS, progressive spinal muscular atrophy	Polio → asymmetric, fever; ALS → mixed UMN + LMN, no sensory involvement; SMA → pure LMN, no sensory involvement
NMJ disease	Botulism, myasthenia gravis, Lambert-Eaton myasthenic syndrome	Botulism → descending paralysis (opposite to GBS), pupil involvement, food history; MG → fatigability, ocular; LEMS → incremental response on RNS
Muscle disease	Acute polymyositis	Proximal weakness, muscle tenderness, markedly ↑ CK, preserved reflexes

DDx for GBS also includes: Poliomyelitis, other causes of polyneuropathy (e.g., toxins, vasculitis, lymphomatous infiltration, critical illness polyneuropathy), NMJ disorders (e.g., MG, botulism) ^[1].

Exam Pearl: GBS vs. Transverse Myelitis vs. Myasthenia Gravis

All three can cause acute weakness. Distinguish by:

GBS: Ascending, areflexia, NO sensory level, CSF albuminocytologic dissociation
Transverse myelitis: Sensory level, UMN signs below level, sphincter disturbance early, hyperreflexia
MG: Fatigability, ocular involvement, NO sensory loss, NO reflex changes

For a patient with slowly progressive distal sensory loss ± weakness over months to years:

Cause	Key Clue on History/Exam
Diabetes mellitus	Known DM, HbA1c elevated, microvascular complications (retinopathy, nephropathy)
Alcohol	Social history, liver stigmata, macrocytosis, ↓ thiamine
B12 deficiency	Macrocytic anaemia, hypersegmented neutrophils, ↑ knee jerk + ↓ ankle jerk (SCD + PN), glossitis, early greying ^[8]^[23]
Chronic kidney disease	Known CKD, ↑ creatinine/urea, anaemia
Hypothyroidism	Fatigue, weight gain, constipation, ↑ TSH
CIDP	Relapsing course, proximal AND distal weakness, thickened nerves, responds to steroids
CMT / HMSN	Family history, pes cavus, distal wasting (inverted champagne bottle legs), onset in childhood/adolescence, mostly autosomal dominant ^[2]
Paraproteinaemia	Serum protein electrophoresis (SPE) abnormality, anti-MAG antibodies
Amyloidosis	Autonomic neuropathy, postural hypotension, organomegaly, Congo red stain salmon-pink ^[24]
Paraneoplastic	Subacute onset, non-length-dependent, known malignancy or weight loss, anti-Hu antibodies
Drug-induced	Temporal relationship to drug initiation, reversible on discontinuation

D/dx of CIDP ^[2]:

Chronic axonal neuropathy: typically affects distal muscles sparing knee reflex
Hereditary demyelinating neuropathies: uniform homogenous slowing of NCV without conduction block
Acquired demyelinating neuropathies: HIV-related, SLE, paraproteinaemia-related

Why the NCS pattern matters here: CIDP shows multifocal, non-uniform conduction slowing WITH conduction block — this non-uniformity proves it is acquired (the immune attack is patchy). Hereditary demyelinating neuropathies (CMT1) show uniform slowing WITHOUT block because every Schwann cell is genetically affected equally.

This integrates the two levels of differential diagnosis into a stepwise clinical approach:

Feature	DM	Alcohol	GBS	CIDP	CMT	B12 Deficiency	Amyloidosis
Onset	Chronic	Chronic	Acute	Chronic / relapsing	Childhood	Subacute-chronic	Chronic
Distribution	Distal, symmetric	Distal, symmetric	Proximal + distal	Proximal + distal	Distal, symmetric	Distal, symmetric	Distal, symmetric
Motor vs Sensory	Sensory > motor	Sensory > motor	Motor > sensory	Sensorimotor	Sensorimotor	Sensory ± myelopathy	Small fibre + autonomic
Autonomic	Prominent	Mild	Can occur	Mild	Rare	Rare	Prominent
NCS	Axonal	Axonal	Demyelinating	Demyelinating	Demyelinating (CMT1) or Axonal (CMT2)	Axonal	Axonal
Key clue	HbA1c, retinopathy	Liver stigmata	Post-infective, ascending	> 8 weeks, steroid-responsive	Pes cavus, FHx, inverted champagne bottle	Macrocytosis, ↑ knee jerk + ↓ ankle jerk	Postural hypotension, organomegaly, Congo red

High Yield Summary

Two-level approach: (1) Confirm it IS polyneuropathy (exclude myelopathy, myopathy, NMJ disorders, radiculopathy); (2) Identify the underlying cause.

The most dangerous mimic: Myelopathy — distinguished by brisk reflexes, UMN signs, sensory level.

Must-know aetiological differential (from senior notes): DM, alcohol, B12, hypothyroidism, uraemia, chronic liver disease, GBS/CIDP, vasculitides, paraneoplastic, paraproteinaemia, CMT, drugs (isoniazid, vincristine, cisplatin, metronidazole, colchicine), HIV, Lyme disease, amyloidosis, sarcoidosis.

NCS-based stratification: Axonal → metabolic/toxic (treat underlying cause); Demyelinating → immune-mediated or hereditary (potentially treatable with immunotherapy).

Acute weakness differential (GBS): Must distinguish from spinal cord compression (UMN signs, sensory level), botulism (descending), MG (fatigability, ocular), poliomyelitis (asymmetric, fever), acute polymyositis (proximal, ↑CK, preserved reflexes).

CIDP vs GBS: CIDP > 8 weeks, relapsing, no preceding infection, more sensory, steroid-responsive.

CIDP vs CMT: CIDP has non-uniform conduction slowing WITH conduction block; CMT has uniform slowing WITHOUT block.

Active Recall - Polyneuropathy Differential Diagnosis

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 11.12 — Peripheral neuropathy, differential diagnosis list) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 10.2 — Disease of the Peripheral Nerves, pp. 179–184) ^[8] Senior notes: Ryan Ho Haemtology.pdf (p. 29 — B12 deficiency, SCD, peripheral neuropathy) ^[17] Lecture slides: CFB_Neuro clinical skills demonstration_01.08.22_file to students.pdf (pp. 7–8) ^[18] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (pp. 18, 20) ^[19] Senior notes: Maksim Surgery Notes.pdf (p. 222–223 — Cauda equina syndrome) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1286–1291 — ALS diagnosis) ^[21] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1282–1285 — GBS differential and diagnostic criteria) ^[22] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 547–548 — GBS differential and diagnostic criteria) ^[23] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p. 18 — Pernicious anaemia) ^[24] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1 — Amyloidosis, autonomic neuropathy)

Diagnostic Criteria

Unlike conditions such as GBS or multiple sclerosis, there is no single universal set of "diagnostic criteria" for polyneuropathy as a whole. This is because polyneuropathy is a syndrome (a clinical pattern), not a single disease. The diagnostic process therefore involves:

Confirming the syndrome — demonstrating that the clinical picture is consistent with polyneuropathy (symmetric, length-dependent, LMN ± sensory pattern).
Characterising the syndrome — time course, fibre type, axonal vs. demyelinating.
Identifying the underlying aetiology — targeted investigations based on the characterisation.

However, specific subtypes of polyneuropathy DO have formal diagnostic criteria:

Required features of GBS ^[21]^[22]:

Progressive weakness of arms and legs (sometimes initially only in legs) — ranging from minimal weakness to paralysis of four limbs, trunk, bulbar and facial muscles with external ophthalmoplegia
Areflexia and hyporeflexia in weak limbs

Supportive features of GBS ^[21]^[22]:

Progression of symptoms over days to 4 weeks
Recovery starting 2–4 weeks after progression halts
Relative symmetry
Pain
No fever at onset
CN involvement especially bilateral facial nerve weakness
Mild sensory signs and symptoms
Autonomic dysfunction
Elevated protein in CSF with a normal cell count
Electrodiagnostic abnormalities consistent with GBS

Features rendering diagnosis of GBS doubtful ^[21]^[22]:

Marked persistent asymmetry of weakness
Decrement or loss of sensation below a spinal cord root level
Severe sensory signs with little or no limb weakness at onset
Bowel and bladder dysfunction at onset
Severe and persistent bowel and bladder dysfunction
Severe pulmonary dysfunction with little or no limb weakness at onset
Fever at onset
CSF pleocytosis with a white cell count > 50/mm³

Exam Pearl: Features That Make You Doubt GBS

If a patient with "ascending weakness" has a sensory level, bladder dysfunction at onset, fever at onset, or marked asymmetry, you should doubt GBS and think myelopathy, cauda equina, or poliomyelitis instead. CSF pleocytosis (WCC > 50/mm³) should raise concern for infective causes (HIV polyradiculopathy, Lyme disease, CMV) ^[21]^[22].

Dx: clinical + documented demyelination ^[2]:

NCS: multifocal conduction block, differential ↓NCV in different nerve segments
CSF: albuminocytologic dissociation
Nerve Bx: segmental demyelination and remyelination, "onion-bulb" appearance

The formal EFNS/PNS criteria require:

Clinical: Progressive or relapsing symmetrical proximal AND distal weakness + sensory dysfunction for > 8 weeks
Electrodiagnostic: At least one of — motor NCV reduction, prolonged distal motor latency, prolonged or absent F-waves, conduction block, temporal dispersion — in at least 2 nerves
Supportive: CSF protein elevation, MRI showing gadolinium enhancement/hypertrophy of nerve roots or plexus, nerve biopsy with demyelination/remyelination, clinical improvement with immunotherapy

Although not formalised as a single criteria set, the clinical-electrodiagnostic confirmation follows this framework:

Step	Requirement	Purpose
1. Clinical	Symmetric, distal-predominant sensory ± motor ± autonomic symptoms + signs (hyporeflexia, stocking sensory loss, distal weakness)	Establish the syndrome clinically
2. Electrodiagnostic	NCS/EMG confirms neuropathic pattern (not myopathic, not NMJ) and defines axonal vs. demyelinating	Confirm the clinical suspicion ^[25]. Distinguish from mimics.
3. Aetiological	Targeted blood/CSF/genetic tests identify underlying cause	Guide treatment

Neurological investigation: to confirm the clinical suspicion. What is the lesion? Caveat of PAN-investigation: false +ve or false -ve investigative findings ^[25].

Important Principle

False positive: White matter change / silent lacunar infarct. False negative: 'Normal limits' NCV, Early disease where structural changes are not obvious ^[25]. This means a normal NCS does NOT exclude polyneuropathy — particularly small fibre neuropathy, where standard NCS (which tests only large myelinated fibres) can be completely normal.

Diagnostic Algorithm

The diagnostic approach to polyneuropathy is a systematic, stepwise process. Think of it in 4 stages:

History will reveal the diagnosis and direct our neurological examination ^[13].

What to Determine	How	Why It Matters
Is it polyneuropathy?	Symmetric, distal, LMN signs, ± sensory loss in glove-and-stocking	Excludes myelopathy (UMN), myopathy (proximal, preserved reflexes), NMJ (fatigability)
Time course	Acute ( < 4w), subacute (4–8w), chronic ( > 8w), relapsing	Acute → GBS; Chronic → DM, CMT, CIDP
Fibre type	Motor, sensory, autonomic, mixed; large vs. small fibre	Narrows differential
Associated features	Systemic disease, family history, drugs, alcohol, travel	Identifies likely aetiology

Investigations for peripheral neuropathy on history/exam ^[26]:

Sensory symptoms, pain in extremities or position-dependent
Ocular-sparing
Autonomic involvement
Symmetrical distal weakness, early wasting, a-/hyporeflexia, non-dissociated sensory involvement, trophic changes, steppage gait

This is the pivotal investigation — it answers the question that determines treatment.

Stage 3: Baseline Blood Screen — Identify the Cause

Investigation Modalities: Detailed Breakdown

1. Electrodiagnostic Studies (NCS and EMG)

This is the single most important investigation in polyneuropathy. It serves three purposes:

Confirms the presence and distribution of neuropathy
Distinguishes axonal from demyelinating pathology
Excludes mimics (myopathy, NMJ disorder, radiculopathy)

Investigations for peripheral nerve lesions: Nerve conduction study, CK level, EMG ^[26].

NCS works by stimulating a nerve at one point and recording the electrical response downstream. It measures:

Parameter	What It Tells You	Normal Mechanism
Conduction velocity (CV)	Speed of signal propagation	Saltatory conduction along myelinated fibres
Distal motor latency (DML)	Time from distal stimulation to muscle response	Reflects conduction through the most distal nerve segment
Compound muscle action potential (CMAP) amplitude	Number of functioning motor axons	Each intact axon contributes to the summed electrical response
Sensory nerve action potential (SNAP) amplitude	Number of functioning sensory axons	As above for sensory fibres
F-wave latency	Conduction along the entire length of motor nerve (including proximal segments and roots)	Antidromic impulse travels to anterior horn cell, returns orthodromically
Conduction block	Focal loss of conduction across a nerve segment	Normally, all impulses propagate through

Pattern	CV	Amplitude	Other Features	Interpretation
Axonal	Normal or mildly ↓	↓ Amplitude	Early denervation on EMG	Axon itself is damaged; myelin intact
Demyelinating	↓↓ Velocity ( < 70% LLN)	Normal or mildly ↓	Conduction block, temporal dispersion, prolonged DML, prolonged F-wave latency	Myelin is damaged; axon initially intact
Uniform demyelinating	Uniformly ↓ across ALL nerves	Normal	NO conduction block	Hereditary demyelinating neuropathy (CMT1): uniform homogeneous slowing without conduction block ^[2] — because every Schwann cell is genetically identical, so the defect is uniform
Non-uniform demyelinating	Variably ↓, different segments	± ↓	Conduction block present, differential slowing	Acquired demyelinating neuropathy (GBS, CIDP): multifocal conduction block, differential ↓NCV in different nerve segments ^[2] — because the immune attack is patchy

Exam Pearl: Conduction Block

Conduction block = significant drop in CMAP amplitude between proximal and distal stimulation sites (typically > 50% drop). It means the impulse is "blocked" at a focal point — the axon is alive but the myelin at one spot is too damaged to conduct. This is the hallmark of acquired demyelinating disease and does NOT occur in hereditary demyelinating neuropathies. Finding conduction block = acquired, potentially treatable disease.

EMG involves inserting a needle electrode into muscle to assess electrical activity. It provides complementary information:

Finding	Meaning	Mechanism
Fibrillation potentials	Spontaneous activity of individual denervated muscle fibres	After denervation, muscle fibres become hypersensitive to acetylcholine and fire spontaneously
Positive sharp waves	Same significance as fibrillations	Another morphology of spontaneous denervation activity
Large, polyphasic motor unit potentials (MUPs)	Chronic denervation with reinnervation	Surviving motor neurons sprout collateral branches to reinnervate orphaned muscle fibres → larger, more complex motor units
Reduced recruitment	Fewer motor units firing for a given effort	Loss of motor axons → fewer units available
Fasciculation potentials	Spontaneous firing of a whole motor unit	Unstable motor unit from partial denervation

EMG is most useful in distinguishing myopathic causes of weakness from neuropathic causes ^[27]:

Neuropathic pattern: fibrillations, positive sharp waves, large amplitude/long duration MUPs, reduced recruitment (neurogenic pattern)
Myopathic pattern: Low amplitude, short duration, polyphasic potentials with early (full) recruitment ^[27]
ALS: Combine features of acute and chronic denervation and reinnervation. NCS: Sensory and motor nerve conduction studies are NORMAL ^[20] — this helps distinguish ALS from polyneuropathy

2. Blood Tests — The Systematic Screen

Baseline bloods: CBC, LRFT, glucose, B12/folate, TFT, ESR/CRP, autoimmune (ANA, RF, ANCA), SPE Ig ^[1].

Workup for peripheral nerve lesions: Glc/A1c, CBC, L/RFT, TFT, vit B12/B9, ESR/CRP, CXR ^[26].

Test	What You're Looking For	Interpretation
Fasting glucose / HbA1c	Diabetes mellitus	HbA1c ≥ 6.5% or FPG ≥ 7.0 mmol/L diagnostic of DM. HbA1c 5.7–6.4% = prediabetes (can still cause neuropathy)
Vitamin B12 / Holotranscobalamin	B12 deficiency	Serum holotranscobalamin = the active fraction, what we use nowadays ^[28]. Low B12 with macrocytosis and hypersegmented neutrophils is classic, but can occur without haematological changes ^[8]
Folate	Folate deficiency	Rarely sole cause of neuropathy, but may co-exist
CBC	Anaemia (macrocytic → B12/folate; normocytic → chronic disease), pancytopenia (B12, myeloma)	Macrocytic anaemia with polyneuropathy = think B12. MCV > 120 fL generally only has 2 DDx: chemotherapy or pernicious anaemia ^[23]
RFT (Cr, urea, eGFR)	Uraemic neuropathy (CKD)	Uraemic toxins cause axonal neuropathy
LFT	Chronic liver disease (alcoholic, hepatitis)	Hepatic neuropathy, or pointer to alcohol use
TFT (TSH, fT4)	Hypothyroidism	Causes mixed demyelinating/axonal neuropathy + may cause CTS
ESR / CRP	Systemic inflammation	Elevated → vasculitis, connective tissue disease, infection, malignancy
Serum protein electrophoresis (SPE) + immunoglobulins	Paraproteinaemia, myeloma	Indication for SPE: investigation of unexplained neuropathy ^[29]. Look for M-band (monoclonal spike). If paraprotein present with immunoparesis → consider myeloma ^[29]

Test	Indication	What You're Looking For
Serum free light chains + ratio	Suspected paraproteinaemia / amyloidosis	Abnormal kappa:lambda ratio → clonal plasma cell disorder
Anti-ganglioside antibodies	Suspected GBS	GQ1b antibodies: Miller-Fisher, Bickerstaff encephalitis; GM1 and GD1a antibodies: AMAN, AMSAN ^[21]^[22]
Anti-MAG antibodies	Demyelinating neuropathy with IgM paraprotein	Anti-MAG in ~50% of Waldenström-associated neuropathy → demyelinating, sensory > motor ^[30]
ANA, anti-ENA, RF, ANCA	Suspected vasculitic / connective tissue disease neuropathy	Vasculitis (ANCA), SLE (ANA, anti-dsDNA), RA (RF)
HIV serology	Risk factors for HIV	HIV can cause distal sensory polyneuropathy directly or via antiretrovirals
Lyme disease serology	Travel to endemic area, tick exposure	Lyme can cause polyradiculopathy or mononeuritis multiplex
Urine porphyrins (ALA, PBG)	Acute motor neuropathy + abdominal pain + psychiatric features	Acute intermittent porphyria
Heavy metal screen (lead, arsenic, mercury)	Occupational exposure, unusual presentation	Lead → motor neuropathy; Arsenic → sensorimotor + Mees' lines
Anti-Hu / Anti-Yo antibodies	Suspected paraneoplastic neuropathy	Paraneoplastic — anti-Hu = sensory neuronopathy (small cell lung CA) ^[2]
Genetic testing	Family history, pes cavus, young onset	CMT (PMP22 duplication for CMT1A), FAP (TTR mutation)
CXR / CT thorax	All patients with unexplained neuropathy	Sarcoidosis, lung malignancy (paraneoplastic), lymphoma

SPE Is Essential in Unexplained Polyneuropathy

Serum protein electrophoresis is indicated in the investigation of unexplained neuropathy, heavy proteinuria, or renal impairment ^[29]. Never omit SPE in your workup — paraproteinaemic neuropathies are treatable, and missing them is a preventable error. An IgM M-band with anti-MAG positivity → treat with rituximab. An IgG/IgA M-band → investigate for myeloma or POEMS.

When to perform LP: Suspected GBS, CIDP, or other inflammatory/infective causes of polyneuropathy.

CSF analysis by lumbar puncture ^[21]^[22]:

CSF Finding	GBS	CIDP	Normal	Infective Polyradiculopathy
Protein	↑ (1st week: normal; 2nd week: ~80% abnormal; 3rd–4th week: Peak)	↑	Normal ( < 0.45 g/L)	↑
Cell count	NO increase (WBC < 50 cells/μL)	Normal or mildly ↑ ( < 10)	< 5 cells/μL	↑↑ (often > 50)
Glucose	Normal	Normal	Normal	↓ if bacterial/TB
Pattern name	Cytoalbuminologic (albuminocytologic) dissociation	Albuminocytologic dissociation	—	Pleocytosis with ↑ protein

Why does protein rise in GBS? Due to increased permeability of the blood-brain barrier at the level of proximal nerve roots ^[21]^[22] — the inflammation at the nerve roots disrupts the blood-nerve barrier, allowing plasma proteins to leak into the CSF.

Timing Matters in GBS CSF

1st week: CSF protein may be normal; 2nd week: ~80% abnormal; 3rd–4th week: Peak ^[21]^[22]. A normal CSF protein in the first week does NOT exclude GBS. If clinical suspicion is high, repeat the LP in a few days or rely on the clinical and electrophysiological findings.

When: Last resort — reserved for inflammatory, infective, or infiltrative disorders where less invasive tests are inconclusive.

Site: Sural nerve (sensory nerve at the ankle) — chosen because:

It is a pure sensory nerve (no motor deficit from biopsy)
Easily accessible
Commonly affected in polyneuropathy

Key histological findings:

Finding	Condition
Segmental demyelination and remyelination, "onion-bulb" appearance	CIDP ^[2] — concentric Schwann cell layers from repeated demyelination-remyelination cycles
Necrotising vasculitis of vasa nervorum	Vasculitic neuropathy (PAN, ANCA-vasculitis)
Congo red stain, salmon-pink colour → indicative of amyloid deposition; electron microscopy showing non-branching fibrils	AL amyloidosis ^[24]
Granulomas	Sarcoidosis, leprosy
Axonal degeneration with loss of myelinated fibres	Non-specific — seen in most axonal neuropathies

When: Patient has burning pain, temperature loss, autonomic symptoms, but NCS is normal (NCS only tests large myelinated fibres).

Technique: 3mm punch biopsy from distal leg (lateral calf 10cm above lateral malleolus) ± proximal thigh.

Finding: Reduced intraepidermal nerve fibre density (IENFD) — counted using PGP9.5 immunostaining. Compared to age- and sex-matched normative data.

This is the gold standard for diagnosing small fibre neuropathy.

Investigation	Indication	Key Findings
Fat pad / rectal biopsy	Suspected amyloidosis	Congo red positive, apple-green birefringence under polarised light
Quantitative sensory testing (QST)	Small fibre assessment	Elevated thermal detection thresholds
Autonomic function tests	Suspected autonomic neuropathy	Tilt-table test (orthostatic hypotension), heart rate variability, sudomotor testing (QSART)
MRI with gadolinium (nerve roots/plexus)	CIDP, nerve root/plexus infiltration	Gadolinium enhancement of thickened nerve roots (CIDP), mass lesions
Genetic testing	Suspected hereditary neuropathy	PMP22 duplication (CMT1A), TTR mutation (FAP), connexin-32 (CMT1X)
Repetitive nerve stimulation (RNS)	If NMJ disorder suspected as mimic	Decremental response → MG; Incremental response → LEMS
Whole-body PET-CT	Paraneoplastic neuropathy, POEMS, lymphoma	Identifies occult malignancy

Clinical Scenario	First-Line Investigations	Second-Line Investigations
Chronic, symmetric, distal sensorimotor	NCS/EMG, HbA1c, B12, TFT, RFT, LFT, CBC, ESR, SPE	HIV, autoimmune panel, heavy metals, genetic test, nerve Bx
Acute ascending weakness (GBS suspected)	NCS/EMG, CSF (LP), FVC (respiratory monitoring!)	Anti-ganglioside antibodies (GM1, GQ1b) ^[21]^[22], MRI spine (exclude cord compression)
Chronic relapsing proximal + distal weakness	NCS/EMG (look for non-uniform demyelination), CSF, SPE	MRI nerve roots (enhancement), nerve Bx (onion-bulbs), trial of steroids
Burning feet, normal NCS	Skin biopsy (IENFD), QST, autonomic function tests	HbA1c, amyloid workup, Fabry enzyme assay
Neuropathy with M-band on SPE	Immunofixation, serum free light chains, anti-MAG, β2-microglobulin	Bone marrow aspirate/trephine, skeletal survey or PET-CT, fat pad biopsy for amyloid
Young patient with pes cavus + family history	NCS (uniform vs. non-uniform slowing), genetic testing	CMT gene panel

Workup order: not necessary if mild symptoms with clear cause (e.g., DM neuropathy). Systemic screen: DM (fasting glucose, HbA1c); Metabolic (CBC, L/RFT, vit B12/folate, thyroid, porphyria); Autoimmune (ESR/CRP, anti-ganglioside Ab, anti-MAG, anti-ENA, RF, ANCA); Neoplastic (SPE, CXR, CT or PET-CT, anti-Hu/anti-Yo); Infective (HIV, Lyme disease serology). LP for cell count, protein and glucose. Electrophysiological study: EMG/NCS for demyelinating vs axonal. Sural nerve biopsy (seldom done). Genetic test if FHx +ve ^[2].

High Yield Summary

No single diagnostic criteria for polyneuropathy as a syndrome — diagnosis is clinical + electrophysiological. Specific criteria exist for GBS (Asbury-Cornblath) and CIDP (EFNS/PNS).

GBS diagnostic criteria: Progressive weakness + areflexia + progression over days to 4 weeks + CSF albuminocytologic dissociation + electrodiagnostic abnormalities. Doubt GBS if: sensory level, bladder dysfunction at onset, fever, marked asymmetry, CSF pleocytosis > 50.

NCS/EMG is the pivotal investigation: Axonal (↓ amplitude, normal velocity) vs. Demyelinating (↓ velocity, conduction block). Uniform demyelination without conduction block = hereditary (CMT). Non-uniform with conduction block = acquired (GBS/CIDP) → treatable.

Baseline blood screen for ALL polyneuropathy: HbA1c, B12, TFT, CBC, L/RFT, ESR/CRP, SPE with immunoglobulins.

CSF in GBS: Albuminocytologic dissociation — ↑ protein, normal cell count. May be normal in first week.

Normal NCS does NOT exclude polyneuropathy — small fibre neuropathy requires skin biopsy for diagnosis.

SPE must be performed in all cases of unexplained polyneuropathy to exclude paraproteinaemia.

Active Recall - Polyneuropathy Diagnosis and Investigations

^[1] Senior notes: Maksim Medicine Notes.pdf (Section 11.12 — Peripheral neuropathy) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 10.2 — Disease of the Peripheral Nerves, pp. 179–184) ^[8] Senior notes: Ryan Ho Haemtology.pdf (p. 29 — B12 deficiency, SCD, peripheral neuropathy) ^[13] Lecture slides: CFB (MED04) Central Nervous System.pdf (p. 3 — History taking) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1289–1291 — ALS diagnosis, EMG, NCS) ^[21] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1282–1285 — GBS diagnostic criteria) ^[22] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 547–548 — GBS diagnostic criteria) ^[23] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p. 18 — MCV > 120) ^[24] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1 — Amyloidosis, Congo red stain) ^[25] Lecture slides: GCBA_Fundamentals_Neuro_Introduction to Neurological Investigations and Emergencies_Prof KC Teo.pdf (p. 9) ^[26] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 134 — Approach to generalised weakness table) ^[27] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1760 — EMG in myopathy vs neuropathy) ^[28] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p. 19 — Holotranscobalamin) ^[29] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 27 — SPE indications) ^[30] Senior notes: Ryan Ho Haemtology.pdf (p. 109 — Waldenström, anti-MAG neuropathy)

The management of polyneuropathy rests on three pillars:

Treat the underlying cause (disease-modifying therapy)
Symptomatic treatment (especially neuropathic pain and autonomic dysfunction)
Supportive and rehabilitative care (prevent complications, restore function)

The specific approach depends entirely on whether the neuropathy is axonal (treat the underlying cause, remove the offending agent) or demyelinating (often immunotherapy-responsive).

Management approach ^[2]:

Disease-modifying Tx: Axonal — majority not directly treatable → Mx largely by ↓ exposure to toxins and treatment of underlying disease process
Demyelinating — usually immunosuppressive Tx (e.g., IVIg, pulse steroids, plasmapheresis)
Symptomatic Tx: gabapentin and TCA for management of neuropathic pain

Pillar 1: Disease-Modifying Therapy (Treat the Cause)

A. Metabolic and Toxic Causes (Axonal Neuropathies)

This is the most common polyneuropathy you will manage. The mainstay is optimising glycaemic control — you cannot reverse existing nerve damage, but you can slow or halt progression.

Management ^[4]^[5]:

Optimise glycaemic control as mainstay
CVD risk factor control: stop smoking
Glycaemic control: aim HbA1c < 7–8%
- Prefer SGLT2i and GLP1a — these agents have additional cardiovascular and renal benefits beyond glucose lowering ^[4]
BP control (especially by ACEI/ARB) and treat hyperlipidaemia (by statins or fibrates) ^[4]
Gabapentinoids (gabapentin/pregabalin) and antidepressants (amitriptyline) for pain ^[5]

Why does glycaemic control help? By reducing chronic hyperglycaemia, you decrease the drivers of neuropathy: polyol pathway activation, AGE formation, oxidative stress, and microvascular ischaemia. The landmark DCCT/EDIC trial showed that intensive glycaemic control in T1DM reduced neuropathy incidence by ~60%. In T2DM the evidence is less dramatic but still supports glycaemic optimisation.

Intervention	Target	Mechanism of Benefit
HbA1c control	< 7% (individualized)	Reduces all pathogenic pathways (polyol, AGE, oxidative stress)
BP control (ACEI/ARB)	< 130/80 mmHg	Protects vasa nervorum; also renoprotective
Statin therapy	LDL < 1.8 mmol/L if established CVD	Reduces atherosclerotic burden → protects macrovascular supply to nerves
Smoking cessation	Complete cessation	Smoking worsens microvascular disease
Foot care programme	Annual screening + patient education	Prevents ulceration → prevents amputation

Diabetic Foot Care — High Yield

Screening by monofilament (small fibre) and tuning fork (large fibre) tests ^[5]. RFs of foot ulcer development: previous foot ulceration (most important), neuropathy (80%), foot deformity, concomitant vascular disease ^[5]. Every diabetic patient with neuropathy needs structured foot care: daily foot inspection, appropriate footwear, podiatry referral, and prompt treatment of any wound.

Intervention	Rationale
Alcohol cessation	Remove the direct neurotoxin (ethanol + acetaldehyde)
Thiamine (B1) replacement	IV thiamine initially (Pabrinex) to replete stores rapidly, then oral maintenance. Thiamine is a cofactor for pyruvate dehydrogenase — without it, nerves cannot generate ATP via aerobic metabolism
Balanced nutrition	Correct concurrent deficiencies (B6, B12, folate, niacin)
Neuropathic pain management	As per symptomatic treatment below

Why IV before oral? Alcoholics have impaired GI absorption of thiamine. Oral thiamine is absorbed via a saturable transporter, so only ~5 mg can be absorbed per dose. IV bypasses this limitation.

The principle is simple: stop the offending drug (if possible) or reduce the dose.

Drug	Action	Notes
Isoniazid	Vitamin B6 (pyridoxine) supplementation for those with risk factors (pregnancy, DM, renal disease) ^[7]. If neuropathy develops → stop isoniazid if severe, or add high-dose B6 if mild	Prevention is better than cure — always co-prescribe B6 with isoniazid in at-risk patients
Vincristine	Dose reduction or switch to less neurotoxic agent	Axonal transport disruption is dose-dependent
Cisplatin/Oxaliplatin	Dose reduction; consider magnesium supplementation for oxaliplatin	Dorsal root ganglia neurotoxicity is cumulative
Taxanes	Dose reduction	Cumulative sensory neuropathy
Amiodarone	Consider switching to alternative antiarrhythmic	Demyelinating neuropathy from phospholipid accumulation in Schwann cells
Metronidazole	Avoid prolonged courses ( > 4 weeks high dose)	Direct axonal toxicity

Treatment	Regimen	Rationale
IM hydroxocobalamin	Loading: 1 mg IM on alternate days for 2 weeks (6 doses). Maintenance: 1 mg IM every 2–3 months for life (if pernicious anaemia)	Bypasses GI absorption issues (pernicious anaemia, gastrectomy, terminal ileum disease). IM route ensures reliable delivery
Oral cyanocobalamin	1–2 mg daily if dietary deficiency only (not pernicious anaemia)	~1% of oral B12 is absorbed by passive diffusion even without intrinsic factor — but this is only sufficient if the cause is dietary, not malabsorption

Can occur in absence of haematological changes as neurones require higher B12 level to function ^[8] — this means you should treat neurological B12 deficiency even if the CBC is normal.

Key point: Neurological damage from B12 deficiency may be irreversible if treatment is delayed. The window for recovery narrows with duration of symptoms. Start treatment immediately on clinical suspicion; do not wait for confirmatory tests.

Optimise renal replacement therapy — dialysis improves but may not fully reverse neuropathy
Renal transplantation — the most effective treatment; can lead to significant improvement or resolution
Ensure adequate dialysis dose (Kt/V target ≥ 1.4 for haemodialysis)

Levothyroxine replacement — correct the hypothyroid state
Neuropathy gradually improves over months with normalisation of TSH

B. Inflammatory/Immune-Mediated Causes (Demyelinating Neuropathies)

These are the treatable polyneuropathies — the ones where correctly identifying the demyelinating pattern on NCS changes the patient's outcome.

Management has two components: specific immunotherapy and general supportive care.

Mx ^[31]:

General supportive: monitor respiratory (FVC, ABG), autonomic (BP, ECG) and bulbar function ± intubation
- Mechanical ventilation if ↑CO₂ ↓O₂, FVC < 15 mL/kg BW, inefficient cough, dysphagia, atelectasis
- General care for immobility (e.g., support stockings) and nutritional support
- Treatment of complications, e.g., respiratory failure, cardiac arrhythmia, DVT
Specific immunotherapy for moderately severe or progressive disease
- Plasma exchange: start plasmapheresis for 5 exchanges over 2 weeks
- High dose IVIg: 0.4 g/kg/day for 5 days
- Note: combination of plasmapheresis + IVIg or steroids has no benefit over either alone

Early IVIg or plasmapheresis reduces disability and duration of illness ^[9].

Why IVIg works: IVIg contains pooled polyclonal immunoglobulins from thousands of donors. It modulates the immune system by: (1) blocking Fc receptors on macrophages (reducing antibody-mediated nerve damage), (2) neutralising pathogenic autoantibodies, (3) modulating complement activation, (4) providing anti-idiotypic antibodies.

Why plasmapheresis works: It physically removes circulating autoantibodies, complement components, and immune complexes from the blood. Each exchange replaces approximately one plasma volume with albumin.

IVIg vs. Plasmapheresis — how to choose:

Factor	IVIg	Plasmapheresis
Efficacy	Equivalent	Equivalent
Ease of administration	Easier (peripheral IV)	Requires large-bore venous access + specialised equipment
Availability	More widely available	Requires apheresis unit
Contraindications	IgA deficiency (anaphylaxis risk), severe renal impairment, thromboembolic risk	Haemodynamic instability, sepsis, coagulopathy
Side effects	Headache, aseptic meningitis, thrombosis, renal impairment	Hypotension, hypocalcaemia (from citrate), line-related infection
In practice	Usually first choice in HK/most centres	Preferred if IVIg contraindicated or unavailable

Key Points for GBS Management

Corticosteroids have NO role in GBS — this is different from CIDP. Do not give steroids for GBS.
Combination of plasmapheresis + IVIg has no benefit over either alone ^[31] — do not combine.
Respiratory monitoring is paramount — GBS kills through respiratory failure. FVC must be monitored serially. Intubate if FVC < 15 mL/kg, or if declining by > 30% from baseline, or if NIF (negative inspiratory force) < -20 cmH₂O.
Autonomic instability can cause fatal arrhythmia — continuous cardiac monitoring in ICU.

Mx ^[2]:

IVIg, plasmapheresis, pulse steroids for severe/fulminant disease
Steroid + steroid-sparing agents for milder disease
Prognosis: 2/3 responds to standard therapy, majority ambulatory following treatment

Unlike GBS, corticosteroids DO work in CIDP. This is a key distinguishing feature in management.

Treatment	Regimen	Indication	Notes
IVIg	Loading: 2 g/kg over 2–5 days. Maintenance: 0.4–1 g/kg every 3–4 weeks	Severe/fulminant disease, or patient preference	Often first-line; rapid onset of action (days to weeks)
Corticosteroids	Prednisolone 1 mg/kg/day then taper, OR IV methylprednisolone pulse	Milder disease, or to reduce IVIg dependency	Effective but significant long-term side effects (osteoporosis, DM, infections, cataracts, myopathy)
Plasmapheresis	5 exchanges over 2 weeks then taper frequency	Severe/refractory, or when IVIg/steroids fail	Short-lived effect → often needs repeated courses
Steroid-sparing agents	Azathioprine, mycophenolate, cyclosporine	To reduce steroid dose in long-term maintenance	Slow onset (weeks to months); monitor for myelosuppression/hepatotoxicity
Rituximab	Anti-CD20 monoclonal antibody	Refractory CIDP not responding to above	Depletes B cells; useful in anti-MAG neuropathy

Why steroids work in CIDP but NOT GBS: This is not fully understood, but the prevailing theory relates to the different immunopathology. GBS is an acute monophasic illness driven by molecular mimicry → once the autoimmune attack is initiated, steroids cannot reverse the damage (and may even worsen outcomes by impairing axonal repair). CIDP is a chronic immune-mediated process with ongoing inflammation → steroids suppress this chronic inflammatory activity effectively.

Subtype	Treatment
IgM with anti-MAG	Rituximab (anti-CD20 depletes the B-cell clone producing anti-MAG)
POEMS syndrome	Radiation (if solitary plasmacytoma) or chemotherapy (if disseminated) — targets the underlying clonal plasma cell disorder
AL Amyloidosis	Chemotherapy (bortezomib-based regimens) ± autologous stem cell transplant
Multiple Myeloma	Treat the myeloma (chemotherapy, stem cell transplant)

Corticosteroids (prednisolone 1 mg/kg/day) ± cyclophosphamide for moderate/severe disease
Treat the underlying vasculitis (PAN, ANCA-vasculitis, SLE)
In HBV-associated PAN: antivirals (entecavir/tenofovir) + short-course steroids

Charcot-Marie-Tooth Disease (CMT/HMSN)

No disease-modifying treatment currently available
Management is entirely supportive:
- Physiotherapy and occupational therapy
- Ankle-foot orthoses (AFOs) for foot drop
- Orthopaedic surgery for severe foot deformities (pes cavus, claw toes)
- Genetic counselling for family planning
- Avoid neurotoxic drugs (vincristine absolutely contraindicated in CMT — can cause fulminant neuropathy)

Pillar 2: Symptomatic Treatment

Neuropathic pain is the most distressing symptom for many patients. It results from ectopic firing of damaged nerve fibres, central sensitisation in the dorsal horn, and disinhibition of descending pain-modulating pathways. Standard analgesics (paracetamol, NSAIDs) are largely ineffective because they target nociceptive pain, not neuropathic mechanisms.

Symptomatic Tx: gabapentin and TCA for management of neuropathic pain ^[2].

Gabapentinoids (gabapentin/pregabalin) and antidepressants (amitriptyline) for pain ^[5].

Gabapentin/pregabalin/amitriptyline for neuropathic pain ^[4].

Drug Class	Examples	Mechanism of Action	Key Side Effects	Contraindications / Cautions
Gabapentinoids	Gabapentin (start 100–300 mg TDS, max 3600 mg/day); Pregabalin (start 75 mg BD, max 600 mg/day)	Bind to α2δ subunit of voltage-gated calcium channels in dorsal horn → ↓ excitatory neurotransmitter release (glutamate, substance P) → ↓ central sensitisation	Drowsiness, dizziness, weight gain, peripheral oedema	Renal impairment (dose adjust — both are renally excreted). Caution in elderly (falls risk). Pregabalin is a controlled substance (abuse potential)
Tricyclic antidepressants	Amitriptyline (start 10–25 mg nocte, max 75–150 mg/day); Nortriptyline	Block reuptake of serotonin and noradrenaline in descending pain-inhibitory pathways → enhance endogenous pain modulation. Also block sodium channels on injured nerve fibres → ↓ ectopic firing	Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision), drowsiness, weight gain, cardiac conduction abnormalities (QT prolongation)	Contraindicated: recent MI, heart block, arrhythmias, narrow-angle glaucoma, concurrent MAOIs. Caution: elderly (anticholinergic burden, falls), prostatism
SNRIs	Duloxetine (start 30 mg daily, max 120 mg/day); Venlafaxine	Serotonin + noradrenaline reuptake inhibition → enhance descending inhibitory pathways	Nausea, insomnia, dizziness, hypertension (at high doses)	Hepatic impairment (duloxetine); uncontrolled hypertension (venlafaxine)
Topical agents	Capsaicin 8% patch; Lidocaine 5% plaster	Capsaicin: depletes substance P from C-fibre terminals → defunctionalises nociceptors. Lidocaine: blocks sodium channels locally	Capsaicin: initial burning at application site. Lidocaine: minimal systemic absorption	Capsaicin: avoid on broken skin, mucous membranes. Applied by trained personnel only
Opioids	Tramadol; tapentadol; as last resort: oxycodone	μ-opioid receptor agonism ± monoamine reuptake inhibition	Constipation, nausea, drowsiness, dependency, respiratory depression	Avoid long-term use due to tolerance, hyperalgesia, addiction. Use only as 3rd-line or for severe exacerbations

Stepwise Approach to Neuropathic Pain (Current Guidelines)

First-line: Gabapentin/pregabalin OR amitriptyline/nortriptyline OR duloxetine — choose based on patient comorbidities and side effect profile.

Second-line: Combination of two first-line agents from different classes (e.g., pregabalin + duloxetine).

Third-line: Tramadol or topical agents (capsaicin patch, lidocaine plaster).

Last resort: Strong opioids — short-term only, with clear goals and exit strategy.

In practice: amitriptyline is cheap, effective, and helps with sleep (useful since neuropathic pain is often worse at night). Start low (10 mg nocte), titrate slowly. In elderly or cardiac patients, use gabapentin instead.

Symptom	Treatment	Mechanism
Orthostatic hypotension	Non-pharmacological first: adequate hydration (2–3 L/day), increased dietary salt, compression stockings, rise slowly from bed. Pharmacological: fludrocortisone (0.1–0.3 mg daily), midodrine (α1-agonist, 5–10 mg TDS)	Fludrocortisone: mineralocorticoid → Na/water retention → ↑ plasma volume. Midodrine: direct vasoconstriction → ↑ peripheral resistance
Gastroparesis	Small frequent meals, prokinetics (metoclopramide 10 mg TDS before meals, domperidone), erythromycin (motilin agonist) at low dose	Prokinetics enhance gastric emptying by ↑ acetylcholine release (metoclopramide) or stimulating motilin receptors (erythromycin)
Bladder dysfunction	Timed voiding, intermittent self-catheterisation if large residuals, anticholinergics (oxybutynin) for overactive bladder, bethanechol for atonic bladder	Tailored to whether the problem is overactivity or retention
Erectile dysfunction	PDE5 inhibitors (sildenafil, tadalafil)	Inhibit breakdown of cGMP → sustained smooth muscle relaxation → penile erection
Nocturnal diarrhoea	Loperamide, codeine phosphate; if suspected bacterial overgrowth → empirical antibiotics (rifaximin)	Loperamide: μ-opioid agonist in gut wall → ↓ motility and secretion
Anhidrosis	Avoid overheating, humidity control	No specific pharmacological treatment

Problem	Intervention	Rationale
Foot drop	Ankle-foot orthosis (AFO)	Splints the ankle in neutral → prevents dragging toes, reduces falls
Distal weakness	Physiotherapy: strengthening exercises for preserved muscles, stretching to prevent contractures	Maintains function and prevents deformity
Falls	OT home assessment, walking aids (stick, frame), balance training	Proprioceptive loss + distal weakness = high falls risk
Hand dexterity loss	OT: adaptive devices (button hooks, large-handled utensils, modified keyboards)	Compensates for intrinsic hand muscle weakness

Domain	Interventions
Physiotherapy	Strengthening, stretching, balance training, gait retraining
Occupational therapy	Adaptive devices, workplace modifications, energy conservation
Podiatry	Nail care, callus management, custom footwear — especially in diabetic neuropathy
Pain team	Multidisciplinary pain management for refractory neuropathic pain
Psychology	Chronic pain and disability can cause depression/anxiety; CBT, counselling
DVT prophylaxis	In immobilised patients (GBS, severe polyneuropathy): LMWH + compression stockings
Nutritional support	Nasogastric feeding if bulbar dysfunction (GBS); correct nutritional deficiencies
Genetic counselling	For hereditary neuropathies (CMT, FAP, HNPP)

Because GBS is the neurological emergency you are most likely to encounter in polyneuropathy, here is a more detailed protocol:

Prognosis: mortality 2–12%, 20% permanent disability, 10% severe disability ^[31].

Aetiology	Disease-Modifying Treatment	First-Line Pain Management	Key Supportive Measures
Diabetic	Glycaemic control (HbA1c < 7%), ACEI/ARB, statin, SGLT2i/GLP1a preferred ^[4]^[5]	Gabapentin/pregabalin or amitriptyline ^[5]	Foot care programme, podiatry, annual screening
Alcoholic	Alcohol cessation + IV thiamine → oral maintenance	Amitriptyline or gabapentin	Nutritional rehabilitation, liver assessment
B12 deficiency	IM hydroxocobalamin (loading then maintenance)	If needed: gabapentin	Treat underlying cause (pernicious anaemia, diet)
Drug-induced	Stop/switch offending drug; B6 for isoniazid ^[7]	As needed	Monitor for recovery after drug cessation
Uraemic	Optimise dialysis; renal transplant if eligible	Gabapentin (dose-adjusted for renal function!)	Avoid nephrotoxins
Hypothyroid	Levothyroxine	As needed	Monitor TSH
GBS	IVIg 0.4 g/kg/day × 5 days OR plasmapheresis × 5 over 2 weeks ^[31]. No steroids	Gabapentin, opioids for severe pain	FVC monitoring, ICU if respiratory failure, DVT prophylaxis ^[31]
CIDP	IVIg, plasmapheresis, or pulse steroids ± steroid-sparing agents ^[2]	As needed	Long-term follow-up, assess for relapse
CMT	None — no disease-modifying therapy	As needed	AFOs, physiotherapy, orthopaedic surgery, genetic counselling, avoid vincristine
Vasculitic	Steroids ± cyclophosphamide	As needed	Treat underlying vasculitis
Paraneoplastic	Treat underlying malignancy	As needed	Oncology referral

High Yield Summary

Three pillars of polyneuropathy management: (1) Treat the underlying cause, (2) Symptomatic treatment (especially neuropathic pain), (3) Supportive and rehabilitative care.

Axonal neuropathies: Mostly treated by addressing the underlying cause (glycaemic control for DM, B12 replacement, stop offending drugs, dialysis for uraemia). No direct nerve repair therapy.

Demyelinating neuropathies: Often immunotherapy-responsive → IVIg, plasmapheresis, corticosteroids (CIDP only — NOT GBS).

GBS management: (1) Monitor FVC (intubate if < 15 mL/kg), (2) IVIg OR plasmapheresis (NOT both, NOT steroids), (3) DVT prophylaxis, pain management, nutrition, physiotherapy.

CIDP management: IVIg, plasmapheresis, or steroids all effective. Steroids ± steroid-sparing agents for milder/chronic disease. 2/3 respond to standard therapy.

Neuropathic pain: First-line = gabapentin/pregabalin OR amitriptyline OR duloxetine. Combine if monotherapy insufficient. Avoid long-term opioids.

Diabetic neuropathy: Glycaemic optimisation is mainstay. Foot care programme is essential. SGLT2i and GLP1a preferred oral agents.

CMT: No disease-modifying treatment. Supportive care only. Never give vincristine to CMT patients.

Active Recall - Polyneuropathy Management

^[2] Senior notes: Ryan Ho Neurology.pdf (Section 10.2 — Disease of the Peripheral Nerves, pp. 179–184) ^[4] Senior notes: Ryan Ho Endocrine.pdf (pp. 97–98 — Diabetic neuropathy management) ^[5] Senior notes: Ryan Ho Endocrine.pdf (pp. 98–99 — Diabetic peripheral neuropathy, screening, foot care) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p. 41 — Isoniazid, B6 prevention) ^[8] Senior notes: Ryan Ho Haemtology.pdf (p. 29 — B12 deficiency, neurological features without haematological changes) ^[9] Lecture slides: Learning_Points_All_Lectures.txt (Neurology section — GBS, early IVIg/plasmapheresis) ^[31] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 139 — GBS management, supportive care, immunotherapy, prognosis)

Complications of polyneuropathy arise from the loss of motor, sensory, and autonomic nerve function. The key insight is that peripheral nerves don't just transmit sensation and motor commands — they protect tissues, maintain homeostasis, and enable adaptation to the environment. When these functions fail, the consequences cascade through multiple organ systems.

The complications can be organised into:

Complications of sensory loss (the most clinically important group)
Complications of motor loss
Complications of autonomic dysfunction
Complications of acute polyneuropathy (GBS-specific)
Complications of treatment
Psychosocial complications

1. Complications of Sensory Loss

This is the single most important complication to understand. It is the leading cause of non-traumatic lower limb amputation worldwide.

Foot ulcers: 25% lifetime risk, annual risk 2%/year ^[5].

RFs of foot ulcer development ^[5]:

Previous foot ulceration (most important)
Neuropathy (80%): loss of monofilament sensation, neuropathy disability score
Foot deformity
Concomitant vascular disease

Pathophysiology of the neuropathic ulcer — why does loss of sensation cause an ulcer?

Think of it from first principles. Normal feet are protected by a feedback loop: pressure on the skin → pain signal → brain → shift weight off that spot. When sensory nerves are damaged:

Loss of protective pain sensation → Patient doesn't feel abnormal pressure, friction, or injury → repeated unrecognised microtrauma to skin
Motor neuropathy → Intrinsic foot muscle denervation → muscle imbalance → altered foot biomechanics → claw toes, prominent metatarsal heads → abnormal pressure distribution → focal high-pressure areas
Autonomic neuropathy → Loss of sweating → dry, cracked skin (portal of entry for infection) + arteriolar vasodilation → warm foot with bounding pulses (the "neuropathic foot")
Result: Painless ulcer, typically at pressure points (metatarsal heads, heel, tips of deformed toes)

Prevention of drastic consequences — foot care ^[32].

Overt complications: clinical neuropathy → symptomatic pain relief; prevention of drastic consequences — foot care ^[32].

Stage	What Happens	Management
Intact skin, neuropathy present	High-risk foot — patient cannot feel injuries	Screening by monofilament and tuning fork tests ^[5]. Patient education: daily foot inspection, appropriate footwear, no walking barefoot, podiatry referral
Neuropathic ulcer	Painless ulcer at pressure point; may have callus rim	Offloading (total contact cast or therapeutic shoe), wound debridement, infection control
Infected ulcer / Cellulitis	Erythema, warmth, purulent discharge; may be painless due to neuropathy	Broad-spectrum antibiotics (cover Gram-positives + Gram-negatives + anaerobes); deep tissue culture; vascular assessment
Osteomyelitis	Deep infection eroding into bone (often metatarsals)	Prolonged IV antibiotics (6–8 weeks); surgical debridement; MRI for diagnosis (probe-to-bone test is clinical screening)
Gangrene	Tissue necrosis — wet (infected) or dry (ischaemic)	Amputation (toe, ray, transmetatarsal, or major — below/above knee depending on vascular supply)

Neuropathic vs. Ischaemic Foot — Must Know for Exams

Feature	Neuropathic Foot	Ischaemic Foot
Temperature	Warm	Cold
Pulses	Present / bounding	Absent / diminished
Skin	Dry, cracked (anhidrosis)	Shiny, thin, hairless
Ulcer location	Plantar (pressure points)	Tips of toes, between toes, lateral border
Pain	Painless	Painful
Deformity	Claw toes, pes cavus, Charcot	None specific
ABI	Normal or falsely elevated (calcified vessels)	Low ( < 0.9)

Many diabetic feet are neuroischaemic (combination of both) — this carries the worst prognosis.

Charcot arthropathy ^[5] — a devastating complication of severe sensory neuropathy.

Pathophysiology: Loss of proprioception and pain → joint subjected to abnormal mechanical stresses without protective reflexes → repeated unrecognised micro-fractures → bone and joint destruction → collapse and deformity.

Most common site: Midfoot (tarsometatarsal joints — Lisfranc area)
Presentation: Swollen, warm, erythematous foot (often mistaken for cellulitis or gout). Often painless or only mildly painful despite severe bony destruction
Complications of Charcot: "Rocker-bottom" foot deformity → new pressure points → ulceration → infection → amputation
Diagnosis: X-ray (fragmentation, new bone, joint destruction); MRI for early Charcot (bone marrow oedema before structural changes)
Management: Immediate offloading with total contact cast until acute phase resolves (may take 3–6 months); then custom moulded footwear

Mechanism: Proprioceptive loss (large fibre) → sensory ataxia → unsteady gait especially in dark; distal motor weakness → foot drop → tripping
Consequences: Fractures (especially hip fractures in elderly → significant morbidity and mortality), soft tissue injuries, subdural haematoma
Prevention: Walking aids, AFOs for foot drop, occupational therapy home assessment (grab rails, adequate lighting, remove trip hazards), balance training

Loss of temperature and pain sensation → patients may sustain burns from hot water, radiators, or hot objects without awareness
Similarly, patients may not notice cuts, blisters, or foreign bodies in shoes

2. Complications of Motor Loss

Mechanism: Weakness of ankle dorsiflexors (tibialis anterior, L4–L5) → foot slaps the ground during walking → compensatory high-stepping (steppage) gait
Consequences: Tripping and falls, impaired mobility, difficulty with stairs, reduced independence
Management: Ankle-foot orthosis (AFO), physiotherapy for strengthening of preserved muscles

These develop from chronic imbalance between long extrinsic and short intrinsic foot/hand muscles:

Deformity	Mechanism	Consequences
Pes cavus (high arch)	Intrinsic foot muscle denervation → long extensors/flexors unopposed → arch elevation	Abnormal pressure distribution → calluses → ulceration
Claw toes	Loss of lumbricals/interossei → MCP hyperextension + IP flexion	Dorsal IP pressure from shoes → ulceration; prominent metatarsal heads → plantar ulcers
Claw hand	Loss of lumbricals/interossei in hand → MCP hyperextension + IP flexion	Loss of hand dexterity, difficulty grasping objects
Kyphoscoliosis	Paraspinal muscle denervation (in hereditary neuropathies)	Restrictive lung disease, chronic back pain

Prolonged weakness → disuse → muscle fibre atrophy beyond that caused by denervation alone
Without physiotherapy → fixed joint contractures → further immobility → vicious cycle
Prevention: Regular physiotherapy, passive range-of-motion exercises (especially important in GBS/ICU patients)

Mechanism: Motor neuropathy involving phrenic nerve (C3–C5) and intercostal nerves → diaphragmatic and intercostal muscle weakness → hypoventilation → type 2 respiratory failure
Mechanical ventilation if ↑CO₂ ↓O₂, FVC < 15 mL/kg BW, inefficient cough, dysphagia, atelectasis ^[2]^[31]
Consequences: Aspiration pneumonia, atelectasis, ventilator-associated pneumonia, prolonged ICU stay
Mortality of GBS: 2–12% ^[31] — respiratory failure is the leading cause of death

Autonomic neuropathy affects multiple organ systems simultaneously. It is most prominent in diabetic neuropathy and amyloidosis.

Diabetic autonomic neuropathy manifestations ^[5]:

System	Complication	Mechanism	Clinical Impact
Cardiovascular	Resting tachycardia (early), failure of exercise-induced ↑HR resulting in exercise intolerance ^[5]	Vagal denervation → unopposed sympathetic tone	Increased myocardial oxygen demand; exercise limitation
	Orthostatic hypotension due to central/peripheral sympathetic denervation ^[5]	Failure to vasoconstrict splanchnic/peripheral beds on standing	Syncope, falls → injuries
	Silent myocardial ischaemia	Cardiac afferent denervation → patient cannot feel angina	MI may present with heart failure or arrhythmia instead of chest pain — delayed recognition → worse outcomes
	QT prolongation	Cardiac autonomic denervation → electrical instability	Risk of sudden cardiac death (5-year mortality of symptomatic cardiac autonomic neuropathy is ~50%)
GI	Gastroparesis: N/V, early satiety, bloating, upper abdominal pain ^[5]	Vagal denervation → loss of ICC coordination → delayed gastric emptying	Erratic glycaemic control (food absorption unpredictable); malnutrition; weight loss
	Diarrhoea: painless watery nocturnal diarrhoea ^[5]	Enteric nervous system dysfunction ± bacterial overgrowth from dysmotility	Dehydration, electrolyte disturbance, social embarrassment
	Constipation	Colonic dysmotility	May alternate with diarrhoea
Genitourinary	Bladder dysfunction: ↓ability to sense full bladder, incomplete emptying, recurrent UTI, overflow incontinence ^[5]	Detrusor denervation → atonic bladder with ↑ residual volume	Recurrent UTIs (stasis → bacterial growth); hydronephrosis → CKD
	Ejaculatory dysfunction: retrograde ejaculation, erectile dysfunction ^[5]	Sympathetic denervation of internal urethral sphincter (retrograde ejaculation); parasympathetic denervation of cavernous arteries (ED)	Infertility; significant psychological impact
Sudomotor	Distal hypohidrosis with compensatory proximal hyperhidrosis ^[5]	Sympathetic sudomotor denervation (cholinergic fibres to sweat glands)	Dry, cracked feet → skin breakdown → ulceration; compensatory drenching sweating of trunk/face
	Thermoregulatory impairment and hyperthermia ^[5]	Loss of sweating → cannot dissipate heat	Heat stroke risk in hot environments (relevant in HK summers)
Pupillomotor	Impaired pupillary constriction	Parasympathetic denervation of pupillary sphincter	Poor dark adaptation; sluggish light reflex

Silent MI in Autonomic Neuropathy — A Killer Complication

Cardiac autonomic neuropathy denervates cardiac pain afferents. This means diabetic patients with autonomic neuropathy may have a heart attack without chest pain. They may present only with breathlessness, nausea, or confusion. This is why "atypical" MI presentations are so common in diabetics — and why autonomic neuropathy carries a markedly increased cardiovascular mortality.

GBS has unique complications due to its acute, potentially fulminant course:

Treatment of complications, e.g., respiratory failure, cardiac arrhythmia, DVT ^[2]^[31].

Complication	Mechanism	Management
Respiratory failure	Phrenic and intercostal nerve involvement → diaphragmatic weakness	Serial FVC monitoring; intubate early (FVC < 15 mL/kg); mechanical ventilation
Cardiac arrhythmia	Autonomic neuropathy → sympathetic/parasympathetic imbalance → sinus tachycardia, bradycardia, asystole	Continuous ECG monitoring; atropine for symptomatic bradycardia; temporary pacing if needed
Labile blood pressure	Autonomic instability → alternating hypertension and hypotension	Avoid triggers (suctioning, position changes); short-acting IV antihypertensives for crises
Deep vein thrombosis / PE	Immobility + dehydration + ICU setting	Support stockings ^[31]; LMWH prophylaxis
Aspiration pneumonia	Bulbar weakness → impaired swallow and cough	Swallow assessment; NG feeding if unsafe swallow; chest physiotherapy
Paralytic ileus	Autonomic involvement of GI tract	NPO, NG decompression, prokinetics
Urinary retention	Autonomic involvement of bladder	Indwelling catheter; trial of void when improving
Neuropathic pain	Nerve root inflammation + ectopic firing	Gabapentin, pregabalin, opioids for severe pain
ICU-acquired weakness	Prolonged immobility + critical illness myopathy ± corticosteroid exposure	Early physiotherapy; avoid unnecessary steroids
Psychological	Sudden paralysis → anxiety, depression, PTSD	Psychological support; clear communication about prognosis
Residual disability	Incomplete recovery of axonal damage	20% permanent disability, 10% severe disability ^[31]; rehabilitation programme

5. Complications of Treatment

Complication	Mechanism
Headache / aseptic meningitis	IgG entering CSF → meningeal irritation
Thromboembolism (DVT, PE, MI, stroke)	↑ serum viscosity + procoagulant factors in IVIg
Renal impairment (osmotic nephropathy)	Sucrose-containing IVIg preparations → osmotic injury to renal tubular cells
Anaphylaxis in IgA-deficient patients	Anti-IgA antibodies → type I hypersensitivity to IgA in IVIg product
Haemolytic anaemia	Anti-A or anti-B isoagglutinins in pooled IVIg

Complication	Mechanism
Osteoporosis / avascular necrosis	↓ Osteoblast activity + ↑ osteoclast activity
Steroid-induced diabetes	Gluconeogenesis ↑ + insulin resistance
Steroid myopathy (proximal weakness)	Type II muscle fibre atrophy — can confound assessment of CIDP recovery
Cushingoid features	Redistribution of fat, skin thinning, striae
Immunosuppression → infections	T-cell suppression → opportunistic infections (PJP, TB reactivation)
Cataracts	Posterior subcapsular cataract from altered lens protein metabolism

Steroid Myopathy vs. CIDP Relapse

A patient on long-term steroids for CIDP who develops new proximal weakness — is it CIDP relapse or steroid-induced myopathy? Steroid myopathy: proximal weakness WITHOUT sensory loss, normal reflexes, normal CK, EMG shows myopathic pattern. CIDP relapse: sensory + motor involvement, ↓ reflexes, NCS changes. Getting this distinction right avoids increasing steroids when you should actually be stopping them.

As covered in the management section, drugs themselves can cause or worsen neuropathy:

Isoniazid: peripheral neuropathy (numbness of fingers/toes) — prevention: Vitamin B6 for those with risk factors (pregnancy, DM, renal disease) ^[7]
Ethambutol: optic neuritis (blurring of vision, scotoma, worsened colour discrimination); peripheral neuropathy (numbness of fingers/toes) → rare ^[7]
Chemotherapy agents (vincristine, cisplatin, taxanes) — dose-dependent cumulative toxicity

Complication	Mechanism	Impact
Depression	Chronic pain, disability, loss of independence, body image changes	Prevalence 20–30% in chronic polyneuropathy; worsens pain perception (bidirectional relationship)
Anxiety	Fear of progression, falls, amputation	Avoidance behaviour → deconditioning → worsening disability
Sleep disturbance	Neuropathic pain worse at night; restless legs-like symptoms	Fatigue → reduced function → reduced quality of life
Social isolation	Mobility limitation, foot drop (embarrassment), bladder/sexual dysfunction	Withdrawal from social activities
Reduced employment	Hand dexterity loss, fatigue, pain, cognitive effects of analgesics	Financial burden, loss of identity/purpose
Relationship strain	Erectile dysfunction, dependency on carers	Marital stress, caregiver burnout

Nerve Function Lost	Complication	Worst-Case Outcome
Sensory	Neuropathic ulcers, Charcot joints, burns, falls, unrecognised injuries	Amputation (diabetic foot)
Motor	Foot drop, skeletal deformities, respiratory failure (GBS), contractures	Death (respiratory failure in GBS)
Autonomic	Orthostatic hypotension, gastroparesis, bladder dysfunction, erectile dysfunction, silent MI	Sudden cardiac death (QT prolongation, silent MI)
Treatment-related	IVIg thrombosis/renal injury, steroid myopathy/osteoporosis, drug-induced worsening	Treatment toxicity compounding disability
Psychosocial	Depression, anxiety, social isolation, employment loss	Suicide; complete loss of independence

High Yield Summary

Most important complication: Diabetic foot disease — neuropathy accounts for 80% of foot ulcer risk factors ^[5]. Previous foot ulceration is the most important risk factor ^[5]. Prevention through structured foot care programmes and patient education is essential. Prevention of drastic consequences — foot care ^[32].

Charcot arthropathy: Painless joint destruction from loss of proprioception. Often misdiagnosed as cellulitis. Midfoot most common. Offloading is key.

Autonomic complications: Cardiac autonomic neuropathy carries highest mortality (silent MI, QT prolongation → sudden death). Gastroparesis causes erratic glycaemic control. Bladder atony → recurrent UTIs → CKD.

GBS-specific: Respiratory failure is the leading cause of death (mortality 2–12% ^[31]). Serial FVC monitoring is mandatory. Also DVT, arrhythmia, aspiration.

Treatment complications: IVIg → thrombosis, renal injury, anaphylaxis in IgA deficiency. Steroids → myopathy (mimics CIDP relapse), osteoporosis, DM, infections.

Psychosocial: Depression affects 20–30% of patients with chronic polyneuropathy. Must be actively screened and managed.

Active Recall - Complications of Polyneuropathy

^[2] Senior notes: Ryan Ho Neurology.pdf (Section 10.2 — Disease of the Peripheral Nerves, pp. 179–184) ^[5] Senior notes: Ryan Ho Endocrine.pdf (pp. 98–99 — Diabetic peripheral and autonomic neuropathy, foot ulcer risk factors) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p. 41 — Isoniazid and ethambutol side effects) ^[31] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 139 — GBS management, complications, prognosis) ^[32] Lecture slides: GC 042. Deterioration of eyesight in a diabetic patient diabetic complications [Update 2025].pdf (p. 15 — Treatment of chronic complications, foot care)

High Yield Summary

Definition: Polyneuropathy = symmetric, length-dependent disease of multiple peripheral nerves (distal → proximal, "glove-and-stocking").

Most common cause: Diabetes mellitus (HK and worldwide).

Two fundamental mechanisms: Axonal (↓ amplitude, normal velocity on NCS; slow recovery; treat underlying cause) vs. Demyelinating (↓ velocity, conduction block; treatable with immunotherapy).

Clinical features:

Sensory: numbness, tingling, burning pain (small fibre), loss of proprioception/vibration (large fibre)
Motor: distal weakness (foot drop), wasting, fasciculation, areflexia (LMN signs)
Autonomic: postural hypotension, resting tachycardia, gastroparesis, bladder dysfunction
Trophic: pes cavus, claw hand, trophic ulcers, Charcot joints
Nerve thickening: leprosy, CMT, CIDP, acromegaly, neurofibromatosis

Key teaching points:

Only demyelinating neuropathies are usually susceptible to treatment — this is why NCS is essential.
B12 deficiency → ↑ knee jerk (myelopathy/UMN) + ↓ ankle jerk (neuropathy/LMN).
GBS: molecular mimicry (GQ1b, GM1) → acute demyelinating polyneuropathy; CSF: albuminocytologic dissociation.
CIDP: distinguished from GBS by > 8 weeks duration, relapsing course, steroid-responsive.
Isoniazid neuropathy prevented by vitamin B6 supplementation.
Critical illness polyneuropathy: axonal, occurs in sepsis/MODS.