Approach to Polyneuropathy - Neuromedicine Resident Guide

1. DEFINITION AND EPIDEMIOLOGY

• 2-3% in individuals aged 50-60 years
• 13% in individuals aged 70-80 years

• 30% over age 80 years

• 2.4% overall US population prevalence for polyneuropathy, rising to 50% in those over 85
• Diabetes accounts for ~50% of all cases; most of the remainder are cryptogenic sensory neuropathy, and over 50% of that group has prediabetes

2. SEQUENTIAL APPROACH - THE FOUR KEY QUESTIONS

"The clinician is faced initially with several problems that can be solved sequentially... (1) establishing the existence of disease of the peripheral nervous system and differentiating it from a process of the CNS, neuromuscular junction, or muscles; (2) distinguishing which of the main topographic syndromes is being displayed; (3) determining if the problem is predominantly motor, sensory, or autonomic, or mixed, and whether myelin sheath, axon, or cell body is the target; and (4) assessing if the neuropathy is acquired or hereditary."

3. STEP 1: TOPOGRAPHIC CLASSIFICATION - WHICH SYNDROME?

• Weakness is relatively symmetrical from the outset and progresses bilaterally
• Reflexes lost in affected parts - especially ankles first
• Sensory loss most pronounced distally - feet before hands (stocking-glove)
• Autonomic features may accompany

4. STEP 2: FIBER TYPE PROFILING

A. Motor Features

• Weakness pattern: distal initially (foot drop, wrist drop), proximal in GBS/CIDP
• Wasting and fasciculations in chronic disease
• Hyporeflexia/areflexia

B. Sensory Features

• Tingling, burning, electrical pain, allodynia, lancinating pain
• Burning pain = preferential small-fiber injury

• Numbness, feeling of "walking on pebbles" or "ice-cold feet"
• Inability to sense hot bath water (thermal loss = small fiber)
• Proprioceptive loss causing sensory ataxia (large fiber)

C. Autonomic Features

• Orthostatic hypotension, syncope
• Anhidrosis or hyperhidrosis
• Erectile dysfunction, bladder dysfunction
• Gastroparesis, diarrhea (especially nocturnal)
• Fixed heart rate (diabetic autonomic neuropathy)
• Pupils: loss of Argyll Robertson-like accommodation reflexes

5. STEP 3: PATHOPHYSIOLOGIC TYPE - AXONAL vs. DEMYELINATING

Axonal Neuropathy

• Wallerian-type degeneration of the axon
• NCS: reduced amplitude of SNAP and CMAP with relatively preserved conduction velocity
• EMG: denervation (fibrillation potentials, positive sharp waves), reduced recruitment
• Loss of axons means that weakness does not appear until ~50% of axons are injured (due to collateral sprouting)
• Most systemic/metabolic/toxic neuropathies are axonal

Demyelinating Neuropathy

• Myelin sheath is the primary target (Schwann cell)
• NCS: markedly slowed conduction velocity, prolonged distal latencies, conduction block, temporal dispersion
• Hallmarks: CV < 38 m/s (upper limb) or < 26 m/s (lower limb) suggests primary demyelination
• Think: GBS/AIDP, CIDP, CMT1, paraproteinemia (IgM anti-MAG), diphtheria, leprosy

6. STEP 4: TEMPORAL PROFILE - TIME COURSE CLASSIFICATION

I. Acute Polyneuropathy (days to 4 weeks)

1. GBS (AIDP) - most common acute polyneuropathy; ascending paralysis, areflexia, albuminocytologic dissociation in CSF
2. Diphtheritic polyneuropathy - palatal palsy first, then bulbar, then limbs; demyelinating
3. Porphyric polyneuropathy (AIP) - motor > sensory; precipitated by drugs/fasting; urine porphobilinogen elevated; treat with IV hematin + glucose
4. Toxic acute polyneuropathies:

• Thallium - rapidly progressive, alopecia (hallmark), painful acral paresthesias, relative preservation of reflexes; treat with KCl
• TOCP (organophosphates) - cholinergic crisis followed by motor-predominant neuropathy
• Arsenic - GBS mimic; Mees' lines on nails, hyperpigmentation

II. Subacute Polyneuropathy (weeks to months) - Often Mononeuritis Multiplex Pattern

• Vasculitis (PAN, ANCA-associated, paraneoplastic)
• Sarcoidosis
• Lyme neuroborreliosis
• HIV neuropathy
• Diabetes (DLRPN - diabetic lumbosacral radiculoplexus neuropathy)
• Multifocal motor neuropathy (MMN) - anti-GM1 antibodies, conduction block, no sensory involvement
• MADSAM (Lewis-Sumner syndrome)

III. Early Chronic Sensorimotor Polyneuropathy (months to years - acquired)

• Paraneoplastic - carcinoma, myeloma, lymphoma (anti-Hu, anti-CV2)
• CIDP - chronic inflammatory demyelinating polyneuropathy; relapsing-remitting or progressive; albuminocytologic dissociation; responds to steroids/IVIG/PE
• Paraproteinemias - IgM (anti-MAG, distal demyelinating), IgG/IgA (POEMS, AL amyloid)
• Uremia - length-dependent axonal; improves with dialysis
• Nutritional/beriberi (thiamine deficiency) - B1, B12, B6, copper
• Diabetes - most common; distal symmetrical sensorimotor; small fiber early
• Connective tissue diseases - SLE, RA, Sjogren's (sensory neuronopathy/ganglionopathy)
• Amyloidosis - AL or hereditary (TTR); small fiber, painful, autonomic
• Leprosy - asymmetric, cool patches of anesthesia; palpable nerve thickening
• Hypothyroidism - axonal, improves with thyroid replacement

IV. Chronic Genetic Polyneuropathies (hereditary)

• Dominant mutilating sensory neuropathy (HSAN Type I)
• Congenital insensitivity to pain (HSAN Type IV)
• Riley-Day syndrome (familial dysautonomia)

• CMT1 - demyelinating, AD, PMP22 duplication (CMT1A); inverted champagne bottle legs, pes cavus, hammer toes; onset 1st-2nd decade
• CMT2 - axonal, AD; similar phenotype but milder NCS changes
• CMTX - X-linked, Cx32 mutation
• CMT3 (Dejerine-Sottas) - severe hypertrophic demyelinating; onset in infancy
• HNPP - hereditary neuropathy with liability to pressure palsies; PMP22 deletion

• Refsum disease (phytanic acid accumulation)
• Metachromatic leukodystrophy (arylsulfatase A deficiency)
• Krabbe disease (galactocerebrosidase deficiency)
• Fabry disease (alpha-galactosidase A deficiency) - small fiber neuropathy + angiokeratomas + renal/cardiac
• Tangier disease (HDL deficiency) - mononeuritis multiplex pattern
• Hereditary amyloidosis (TTR mutations - Val30Met most common)
• Porphyrias (AIP, VP, HCP)

7. ACQUIRED vs. HEREDITARY - KEY DISTINGUISHING CLUES

8. INVESTIGATIONS - SYSTEMATIC WORKUP

Tier 1 - Routine/First-line (for ALL polyneuropathies)

• Confirms peripheral localization
• Determines axonal vs. demyelinating
• Identifies focal conduction block (vasculitis, MMN)
• Identifies neuronopathy (SNAP absent with EMG showing diffuse denervation without NCS amplitude reduction)

• Fasting glucose + HbA1c (DM is #1 cause)
• CBC with differential
• Comprehensive metabolic panel (renal function, LFTs)
• Vitamin B12 level (± methylmalonic acid if borderline)
• TSH
• Serum protein electrophoresis (SPEP) + immunofixation
• ESR, CRP
• Urine protein electrophoresis (UPEP)

Tier 2 - Based on Clinical Suspicion

Tier 3 - Nerve Biopsy (selective indications)

• Vasculitic neuropathy (diagnostic and prognostic - shows epineural vessel inflammation)
• Suspected amyloid neuropathy (Congo red staining)
• Atypical CIDP not responding to treatment
• Suspected nerve tumor or infiltrative disorder
• Sural nerve is the standard biopsy site (purely sensory, recovers well)
• Pathologic patterns: axonal loss, demyelination/remyelination (onion bulbs), inflammation, amyloid deposits, vasculitis, granulomas

Skin Punch Biopsy (for small-fiber neuropathy)

• Measures intraepidermal nerve fiber density (IENFD)
• Normal NCS but abnormal biopsy = confirms small-fiber neuropathy
• Stained with anti-PGP 9.5

9. CSF ANALYSIS IN NEUROPATHY

10. SPECIFIC HIGH-YIELD NEUROPATHIES FOR RESIDENTS

Diabetic Polyneuropathy

• Most common: distal symmetrical sensorimotor polyneuropathy (DSPN) - stocking distribution, small fiber first, burning pain at night
• Also: diabetic autonomic neuropathy (gastroparesis, orthostatic hypotension, CAN), diabetic amyotrophy (DLRPN - painful proximal, asymmetric, weight loss), mononeuropathies (CN3 palsy with pupil sparing - ischemic)
• NCS: axonal; IENFD reduced on skin biopsy for small fiber

GBS (AIDP) - The Classic Acute Polyneuropathy

• Ascending flaccid paralysis with areflexia, within 4 weeks
• Albuminocytologic dissociation in CSF (protein 100-1000+ mg/dL, <10 cells)
• Brighton criteria for diagnosis
• NCS: demyelinating features (AIDP), or axonal (AMAN/AMSAN - anti-ganglioside antibodies, post-Campylobacter)
• Respiratory monitoring mandatory - admit all: VC <1L or NIF <-70 cmH2O = ICU + ventilatory support
• Treatment: IVIG (2g/kg over 2 days) or Plasma exchange (5 volumes over 10 days) - equivalent efficacy; IVIG preferred for completion
• Steroids alone: NOT beneficial (methylprednisolone + IVIG has no long-term benefit over IVIG alone)

CIDP - Chronic Counterpart

• Symmetric proximal + distal weakness and sensory loss, >8 weeks duration
• High CSF protein, NCS demyelinating
• Nerve biopsy: onion bulbs (lamellar Schwann cell processes), macrophage-mediated demyelination
• Treatment: IVIG, steroids, or plasma exchange (all equally effective)

Multifocal Motor Neuropathy (MMN)

• Pure motor, asymmetric, affecting upper > lower limbs (wrist/finger drop)
• Conduction block on NCS without sensory involvement
• Anti-GM1 IgM antibodies (in ~50%)
• Treatment: IVIG (not steroids - steroids worsen)
• Confused with ALS - the key distinction is NO UMN signs, NO sensory loss, conduction block on NCS

Vasculitic Neuropathy

• Mononeuritis multiplex pattern - stepwise, asymmetric, painful
• Underlying: PAN, ANCA vasculitis, cryoglobulinemia, paraneoplastic, connective tissue disease
• Nerve biopsy is gold standard (epineural vasculitis, axonal infarction)
• Treatment: steroids + cyclophosphamide for systemic vasculitis

11. TREATMENT PRINCIPLES

Disease-specific:

• DM: glycemic control (prevents progression), pain management (duloxetine, pregabalin, gabapentin, TCAs)
• GBS: IVIG or plasma exchange; supportive care
• CIDP: IVIG, corticosteroids, plasma exchange; maintenance therapy often needed
• Vasculitic: immunosuppression (steroids ± cyclophosphamide)
• Nutritional: replace deficient vitamins (B1, B12, B6, copper)
• Toxic: identify and remove toxin/offending drug
• Paraproteinemic: treat underlying dysproteinemia
• CMT/hereditary: genetic counseling, physiotherapy, orthoses, no cure currently; avoid drugs that worsen CMT (vincristine, amiodarone, taxanes)

Symptomatic pain management:

1. First line: duloxetine (60-120 mg/d) or pregabalin (150-600 mg/d) or gabapentin (up to 3600 mg/d)
2. Second line: TCAs (amitriptyline, nortriptyline 25-100 mg at night)
3. Third line: tramadol, opioids (with caution), topical lidocaine/capsaicin

Rehabilitation:

• Physiotherapy: balance training, strengthening
• Orthoses: ankle-foot orthosis (AFO) for foot drop
• Occupational therapy: fine motor aids
• Fall prevention strategies (critical with proprioceptive loss)

12. CLINICAL PEARLS (Exam and Bedside)

• "Dying back" axonopathy: toxins and metabolic diseases preferentially damage the most distal parts of the longest axons first - explains the stocking-glove distribution
• Onion bulb formation on nerve biopsy = repeated cycles of demyelination-remyelination = chronic demyelinating neuropathy (CIDP, CMT1)
• Palpably enlarged nerves: CMT (especially Dejerine-Sottas), CIDP, leprosy, amyloidosis, neurofibromatosis
• Areflexia with ataxia but no weakness (pure sensory ataxic neuropathy): think Sjogren's ganglionopathy, paraneoplastic anti-Hu, CANOMAD, Miller-Fisher (+ ophthalmoplegia + anti-GQ1b)
• Pure motor neuropathy: MMN (anti-GM1, conduction block), lead toxicity (radial nerve), porphyria, AMAN variant of GBS
• Autonomic neuropathy + small fiber + cardiac: think amyloid (AL or ATTR) or Fabry disease (males, angiokeratomas, renal disease)
• Painful neuropathy in young patient + family history: Fabry disease (XL), hereditary amyloidosis (AD), HSAN Type I (AD)
• Neuropathy + weight loss + night sweats: paraneoplastic workup mandatory
• Night-time deterioration of symptoms: classic for DM and CMT (stretching of nerves in recumbent position)
• Weakness does not appear in axonal neuropathy until ~50% of axons lost (collateral sprouting compensates)

• Adams and Victor's Principles of Neurology, 12th Edition - Chapter 43
• Goldman-Cecil Medicine International Edition - Chapter 388
• Localization in Clinical Neurology, 8th Edition