---

Case History and Clinical Examination in Peripheral Neuropathy

---

Diagnostic Approach Overview

1. Is this truly a peripheral nervous system disease, or a CNS/neuromuscular junction/muscle disorder?
2. What is the topographic pattern (polyneuropathy, mononeuropathy, radiculopathy, plexopathy)?
3. Is the process motor, sensory, autonomic, or mixed - and is it axonal or demyelinating?
4. Is the neuropathy acquired or hereditary?

---

---

PART I: CASE HISTORY

A. Chief Complaint and Onset

• Onset: sudden vs. gradual
• Duration and progression: acute (days-4 weeks), subacute (4-8 weeks), chronic (>8 weeks)
• Course: monophasic, progressive, relapsing-remitting
• Distribution: feet first? Both feet simultaneously? One limb? Multiple sites?

A chronic, slowly progressive symmetrical sensory-predominant course starting in the feet is the classic pattern of a length-dependent polyneuropathy (e.g., diabetic, toxic, idiopathic).

An acute onset (days to 4 weeks) of ascending weakness with areflexia strongly suggests Guillain-Barré syndrome (GBS).

An asymmetric, multifocal or episodic onset suggests mononeuropathy multiplex (vasculitis, diabetes, sarcoid, leprosy).

---

B. The 7 Key Questions from History (Harrison's)

Question 1: What Systems Are Involved?

• Motor: weakness, foot drop, difficulty with grip, trips/falls
• Sensory: numbness, tingling, burning, "pins and needles," pain, loss of balance in the dark
• Autonomic: fainting, orthostatic dizziness, heat intolerance, anhidrosis, bowel/bladder/sexual dysfunction

• Pure motor involvement without sensory symptoms → consider motor neuron disease (ALS), myopathy, or neuromuscular junction disorder (myasthenia gravis, Lambert-Eaton) rather than polyneuropathy
• Prominent autonomic dysfunction without diabetes → strongly suggests amyloid polyneuropathy or hereditary sensory and autonomic neuropathy (HSAN)
• Sensory-only with normal strength → small-fiber neuropathy (DM, glucose intolerance, amyloid) or sensory neuronopathy/ganglionopathy (paraneoplastic, Sjögren's)

---

Question 2: What Is the Distribution of Weakness?

• Distal-only weakness: typical axonal polyneuropathy (DM, toxic, idiopathic)
• Proximal AND distal symmetric weakness: hallmark of acquired immune demyelinating polyneuropathies - GBS (acute) and CIDP (chronic); this pattern cannot be overemphasized as it identifies a treatable disorder
• Asymmetric/multifocal weakness: radiculopathy, plexopathy, compressive mononeuropathy, or mononeuropathy multiplex (vasculitis, leprosy, diabetes)
• Unilateral extremity weakness without sensory symptoms: consider ALS (motor neuron disease) vs. multifocal motor neuropathy (MMN) - the latter is treatable with IVIg

• Proximal-predominant weakness without sensory loss → myopathy or NMJ disorder, not polyneuropathy
• Neck extensor/bulbar weakness → ALS, isolated bulbar GBS, Kennedy's syndrome

---

Question 3: What Is the Nature of Sensory Involvement?

• Pain, burning, temperature loss, allodynia = small-fiber (C and A-delta fibers) involvement → DM, glucose intolerance, amyloid, HIV, Fabry's disease
• Vibration and proprioception loss (with normal pain/temperature) = large-fiber involvement → vitamin B12 deficiency, CIDP, hereditary neuropathy (CMT)
• Severe proprioceptive loss with imbalance, positive Romberg, pseudoathetosis = sensory neuronopathy/ganglionopathy → paraneoplastic (anti-Hu), Sjögren's syndrome, cisplatin toxicity, vitamin B6 toxicity, CANVAS syndrome

• Loss of vibration/proprioception with hyperreflexia and UMN signs → posterior column + corticospinal lesion (subacute combined degeneration from B12 deficiency, MS, cervical myelopathy) - NOT peripheral neuropathy alone
• Pain and temperature loss with preserved vibration/proprioception = dorsal horn or spinothalamic tract lesion (syringomyelia, Brown-Séquard) rather than peripheral neuropathy

---

Question 4: Is There Upper Motor Neuron Involvement?

• Peripheral neuropathy produces lower motor neuron signs: weakness, wasting, hyporeflexia/areflexia, sensory loss
• If UMN + LMN signs coexist: suspect ALS (UMN + LMN), vitamin B12 deficiency (combined system degeneration), adrenomyeloneuropathy, or hereditary spastic paraplegia with neuropathy (HSP-plus)
• UMN signs alone with no sensory loss → motor neuron disease (ALS, PLS), NOT peripheral neuropathy

---

Question 5: What Is the Temporal Evolution?

• Hyperacute onset (hours-1 day) of profound weakness → consider acute ischemic neuropathy, porphyria, or critical illness polyneuropathy
• Very slow insidious course over decades, often with pes cavus and no sensory symptoms → hereditary neuropathy (CMT) rather than acquired

---

Question 6: Is There Evidence of a Hereditary Neuropathy?

• Family history of neuropathy, gait difficulty, foot deformity, inability to run since childhood
• Pes cavus (high arched feet) and hammer toes (especially if present since childhood)
• Lack of sensory symptoms despite sensory signs on examination (highly characteristic of CMT - patients adapt to slow fiber loss)
• Scoliosis, kyphoscoliosis

• CMT: onset in childhood/teens, slowly progressive, family members similarly affected, no sensory complaints despite objective loss
• Porphyria (acute intermittent): episodic attacks of neuropathy with abdominal pain, psychiatric symptoms, urine that turns red/dark on standing
• Fabry's disease: X-linked, burning/lancinating pain in hands and feet in males since childhood, angiokeratomas around umbilicus and scrotum, premature cardiovascular disease
• Familial amyloid polyneuropathy: autonomic + sensory neuropathy, family history, carpal tunnel syndrome, cardiomyopathy

---

Question 7: Are There Associated Medical Conditions?

• Diabetes mellitus (most common cause, ~50% of polyneuropathies)
• Prediabetes/metabolic syndrome (accounts for many "idiopathic" neuropathies)
• Hypothyroidism, uraemia, liver disease, vitamin deficiencies (B1, B6, B12, folate, vitamin E)

• Known cancer (especially lung, breast, lymphoma) → paraneoplastic neuropathy (anti-Hu antibodies); may precede tumour diagnosis
• Multiple myeloma, POEMS syndrome → paraproteinemic neuropathy

• Rheumatoid arthritis, lupus, Sjögren's, vasculitis, sarcoidosis
• Sjögren's → sensory neuronopathy (ganglionopathy) or painful sensory neuropathy

• HIV (distal painful sensory neuropathy, most common neurological complication)
• Leprosy (most common treatable neuropathy worldwide; thickened cutaneous nerves)
• Lyme disease (mononeuropathy multiplex, cranial nerve palsies)
• Hepatitis B/C (cryoglobulinemia → vasculitic mononeuropathy multiplex)
• CMV, EBV (GBS trigger, polyradiculopathy in immunocompromised)

• Drugs: chemotherapy (vincristine, cisplatin, paclitaxel), isoniazid, metronidazole, nitrofurantoin, phenytoin, thalidomide, amiodarone, colchicine
• Alcohol (direct toxic + nutritional B1 deficiency)
• Heavy metals: lead (motor-predominant), arsenic (painful sensory), thallium (alopecia + neuropathy)
• Industrial solvents: n-hexane, methyl n-butyl ketone

• If a clear toxic/drug cause identified → acquired toxic neuropathy (remove agent, observe for recovery)
• If DM present and neuropathy is distal, symmetrical, sensory-predominant → likely diabetic polyneuropathy, but UMN signs or rapid course mandate exclusion of other causes

---

C. Additional History Points

---

PART II: CLINICAL EXAMINATION

A. General Inspection

• Pes cavus (high arched foot) + hammer toes → hereditary neuropathy (CMT)
• Foot drop gait (steppage gait) → distal motor neuropathy
• Wide-based ataxic gait → severe proprioceptive loss (sensory ataxia) - do the patient's symptoms worsen in the dark? This distinguishes sensory from cerebellar ataxia
• Fasciculations in muscle → suggests motor neuron disease rather than pure peripheral neuropathy
• Skin: leprosy patches (hypopigmented, anaesthetic), angiokeratomas (Fabry's), xanthomas (hyperlipidaemia)
• Thickened nerves: leprosy, CMT, amyloid, Refsum's disease - palpate greater auricular, ulnar at elbow, common peroneal at fibular head

---

B. Motor Examination

• Wasting: distal > proximal distribution in polyneuropathy; "inverted champagne bottle" legs (below-knee atrophy) in CMT
• Fasciculations: ALS > peripheral neuropathy

• Test distal muscles first: ankle dorsiflexors (tibialis anterior), intrinsic foot/hand muscles, extensor hallucis longus
• Then proximal: hip flexors, shoulder abductors
• Predominantly distal weakness = axonal polyneuropathy
• Proximal + distal weakness = demyelinating polyneuropathy (GBS, CIDP) - this is a key differential finding
• Asymmetric or multifocal weakness = mononeuropathy multiplex (vasculitis), radiculopathy, plexopathy

• Proximal-predominant weakness without sensory loss → myopathy (check CK, EMG)
• Global weakness with fatigability (worse with repetition, worse in afternoon) → NMJ disorder (myasthenia gravis)
• UMN signs (spasticity, clonus, extensor plantar) with weakness → central/combined lesion, not pure PNS

---

C. Sensory Examination

• Vibration (128 Hz tuning fork): start at great toe; if absent, move to medial malleolus, tibial tuberosity, anterior iliac spine (to define the level)
• Joint position sense (proprioception): small passive movements of great toe; if impaired, confirm pseudoathetosis with eyes closed
• Light touch (cotton wool or 10g monofilament)
• Two-point discrimination

• Pin-prick (sterile pin or neurological pin): compare left vs right, proximal vs distal
• Temperature (warm/cold test tubes or Tip-Therm)

• Falls/sway only with eyes closed = sensory ataxia (posterior column or large-fiber neuropathy)
• Falls with eyes open also = cerebellar ataxia or vestibular disorder

---

D. Reflexes

• Absent or reduced ankle jerks = peripheral neuropathy (almost universal finding); absent throughout = more widespread neuropathy
• Loss in an asymmetric or patchy pattern = mononeuropathy multiplex, radiculopathy
• Preserved or brisk reflexes in the presence of weakness or sensory loss = question whether lesion is truly peripheral; if UMN signs coexist → combined system disease (B12), ALS, or structural cord lesion

• Hyperreflexia/clonus/Babinski = UMN lesion (cord or brain), NOT peripheral neuropathy
• Selective loss of knee jerks with preserved ankle jerks = L3/L4 radiculopathy rather than peripheral neuropathy

---

E. Autonomic Examination

• Blood pressure lying and standing: orthostatic hypotension (fall ≥20 mmHg systolic) without reflex tachycardia = autonomic neuropathy (DM, amyloid, GBS, HSAN)
• Skin: anhidrosis, trophic changes in feet, vasomotor changes (cold/cyanotic feet)
• Pupils: Argyll Robertson pupils or Horner's syndrome in autonomic neuropathy
• Bladder and bowel: palpate for distended bladder; rectal tone

• Orthostatic hypotension with appropriate tachycardia = hypovolaemia or autonomic failure from a non-neurological cause
• Absent sweating over trunk with preserved limb sweating = central autonomic lesion, not peripheral

---

F. Cranial Nerve Examination

• Facial diplegia (bilateral VII) = GBS (occurs in >50% of cases), Lyme disease, sarcoidosis
• Ophthalmoplegia (III, IV, VI) + ataxia + areflexia = Miller Fisher syndrome (GBS variant, anti-GQ1b antibodies)
• Bilateral lower cranial nerve palsies (IX, X, XII: dysphagia, dysarthria) = GBS, ALS, myasthenia gravis
• Trigeminal sensory neuropathy = Sjögren's syndrome, paraneoplastic
• Hearing loss with neuropathy = Refsum's disease (also has retinitis pigmentosa + ataxia), CMT-X

---

G. Special Tests on Examination

• Tinel's sign (wrist, elbow): focal entrapment neuropathies (carpal tunnel, cubital tunnel)
• Phalen's test: carpal tunnel syndrome
• Straight leg raise: lumbosacral radiculopathy (rules out polyneuropathy at that level)
• Nerve palpation: thickened, palpable nerves at ulnar at elbow, common peroneal at fibular head = CMT, leprosy, amyloid
• Tandem gait, heel-toe walking: discloses subtle proximal weakness or ataxia
• Pseudoathetosis: slow writhing movements of outstretched fingers with eyes closed = severe proprioceptive loss

---

Summary: Key Differentiating Features at a Glance

---

Topographic Patterns and Their Differential Diagnosis (Adams & Victor + Harrison's)

---

References

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 457: "Peripheral Neuropathy," pp. 3638-3645
• Adams and Victor's Principles of Neurology, 12th Ed., Chapter 43: "Approach to the Patient with Peripheral Neuropathy," pp. 1295-1298
• Goldman-Cecil Medicine, Chapter: "Peripheral Neuropathy," pp. 4073+