Peripheral Neuropathy

Definition and Overview

• Large myelinated fibers - conduct rapidly (~50 m/s); carry proprioception, vibration, and motor signals
• Small myelinated fibers - carry pain and temperature
• Small unmyelinated fibers - carry pain, temperature, and autonomic signals

• Axonopathy - axon degeneration (most common)
• Myelinopathy - myelin/Schwann cell pathology
• Neuronopathy/ganglionopathy - cell body destruction

Clinical Approach: Seven Key Questions (Harrison's)

1. What systems are involved? (sensory, motor, autonomic, or combination)
2. What is the distribution of weakness? (proximal vs. distal, symmetric vs. asymmetric)
3. What is the nature of the sensory involvement? (large vs. small fiber symptoms)
4. Is there evidence of upper motor neuron involvement?
5. What is the time course? (acute, subacute, chronic, relapsing-remitting)
6. Is there a family history?
7. What is the pattern of involvement? (mononeuropathy, mononeuropathy multiplex, polyneuropathy)

"Despite an extensive evaluation, in approximately half of patients, no etiology is ever found; these patients typically have a predominately sensory polyneuropathy and have been labeled as having idiopathic or cryptogenic sensory and sensorimotor polyneuropathy (CSPN)." - Harrison's Principles of Internal Medicine 22E

Pattern Recognition (Clinical Patterns)

Etiology and Common Causes

Metabolic/Systemic

• Diabetes mellitus - the most common cause; up to 80% of patients with >15 years of disease show evidence of neuropathy (Robbins). Manifests as distal symmetric sensorimotor polyneuropathy (most common form), autonomic neuropathy, and lumbosacral radiculopathy (diabetic amyotrophy).
• Uremia (chronic kidney disease)
• Hypothyroidism
• Liver disease

Nutritional Deficiencies

• Vitamin B1 (thiamine) - alcoholic neuropathy
• Vitamin B12 - combined system degeneration
• Vitamin B6 (pyridoxine)
• Vitamin E, copper

Toxic/Drug-Induced

• Alcohol - axonal sensorimotor neuropathy, stocking-glove distribution, painful paresthesias, loss of ankle reflexes (Goldman-Cecil)
• Chemotherapy agents - taxanes, platinum compounds
• Isoniazid (INH) - causes B6 deficiency neuropathy
• Amiodarone, dapsone, metronidazole, thalidomide

Immune-Mediated

• Guillain-Barré Syndrome (GBS) - acute demyelinating, ascending weakness, triggered by infection (Campylobacter jejuni, EBV, CMV, HIV, Zika, SARS-CoV-2). Immune-mediated cross-reactivity against nerve sheath antigens.
• CIDP - chronic, relapsing-remitting, mixed sensorimotor; associated with paraproteinemias and HIV.
• Vasculitis, cryoglobulinemia, sarcoidosis

Infectious

• Leprosy (most common worldwide cause)
• Lyme disease, HIV, hepatitis B/C/E, CMV

Hereditary

• Charcot-Marie-Tooth (CMT) disease - most common inherited peripheral neuropathy
• Hereditary neuropathy with liability to pressure palsy (HNPP)
• Familial amyloid polyneuropathy

Neoplastic/Paraneoplastic

• Paraneoplastic sensory neuronopathy (anti-Hu antibodies, lung cancer)
• Direct tumor infiltration
• MGUS-associated neuropathy (~5% of sensorimotor neuropathy of unknown cause)

Pathology: Axonal vs. Demyelinating

Electrodiagnostic Studies (EDx)

• Confirm mononeuropathy vs. polyneuropathy vs. mononeuropathy multiplex
• Distinguish axonal from demyelinating pathology
• Identify pure sensory vs. motor vs. sensorimotor involvement
• Guide biopsy if needed

Laboratory Workup

• Fasting glucose/HbA1c (diabetes)
• CBC, ESR
• Vitamin B12, folate
• Thyroid function (TSH)
• Serum protein electrophoresis (SPEP) + immunofixation (MGUS)
• Renal and liver function
• Urinalysis

• Anti-Hu, anti-Yo (paraneoplastic)
• Anti-ganglioside antibodies (GBS subtypes - anti-GM1, anti-GQ1b)
• VGCC, VGKC antibodies
• Genetic testing (CMT panel)
• Nerve biopsy (vasculitis, amyloid, leprosy)

Treatment

Symptomatic Pain Management

• Gabapentin - first-line for neuropathic pain
• Pregabalin - comparable efficacy
• Tricyclic antidepressants (TCAs) - amitriptyline, nortriptyline
• SNRIs - duloxetine (FDA-approved for diabetic neuropathy)
• Topical lidocaine, capsaicin
• Opioids - reserved for refractory cases

Specific Entities at a Glance

Alcoholic Neuropathy

Diabetic Neuropathy

GBS

CMT (Hereditary)

• Harrison's Principles of Internal Medicine 22E, Chapter 457 (Amato & Barohn)
• Robbins & Kumar Basic Pathology, Chapter 20 - Disorders of Peripheral Nerves
• Goldman-Cecil Medicine - Alcoholic Peripheral Neuropathy, Chapter 388

📘 PERIPHERAL NEUROPATHY

Harrison's Chapter 457 — Study Notes

1. INTRODUCTION

• Peripheral nerves = sensory + motor + autonomic elements
• Disease can affect: cell body, axon, or myelin sheath
• Nerve fiber classes:
  • Large myelinated → motor axons, proprioception, vibration (~50 m/s)
  • Small myelinated → pain, temperature
  • Small unmyelinated → pain, temperature, autonomic
• Classification by structure primarily affected:
  • Axonopathy → axon
  • Myelinopathy → myelin (Schwann cell)
  • Neuronopathy/Ganglionopathy → nerve cell body

2. GENERAL APPROACH (Three Main Goals)

1. Identify the lesion location
2. Identify the cause
3. Determine treatment

Key: ~50% of cases have no etiology found despite full workup → labeled Cryptogenic Sensory and Sensorimotor Polyneuropathy (CSPN)

3. SEVEN KEY QUESTIONS (Table 457-1)

Q1. What systems are involved?

• Sensory only → most neuropathies
• Motor only (no sensory/autonomic) → consider motor neuropathy, NMJ disorder, or myopathy
• Autonomic features: orthostatic hypotension without compensatory HR rise, heat intolerance, bowel/bladder/sexual dysfunction
  • Autonomic dysfunction without diabetes → think amyloid polyneuropathy

Q2. Distribution of weakness?

• Symmetric proximal + distal → hallmark of acquired immune demyelinating polyneuropathy (GBS/CIDP)
• Distal only → length-dependent; typical of metabolic/toxic neuropathies
• Asymmetric/focal → mononeuropathy, vasculitis, compression

Q3. Nature of sensory involvement?

• Large fiber involvement: loss of proprioception, vibration → sensory ataxia (Romberg positive)
• Small fiber involvement: loss of pain and temperature; dysesthesias, burning
• Asymmetric proprioceptive loss with preserved strength → sensory neuronopathy/ganglionopathy

Q4. Evidence of upper motor neuron (UMN) involvement?

• Distal sensory neuropathy + UMN signs → combined system degeneration
• Most common cause: Vitamin B12 deficiency
• Others: copper deficiency, HIV, hepatic disease, adrenomyeloneuropathy (AMN), hereditary spastic paraplegia

Q5. Temporal evolution?

• Acute (days to 4 weeks) → GBS, porphyria, vasculitis, toxins
• Subacute (4–8 weeks) → nutritional deficiency, paraneoplastic
• Chronic (>8 weeks) → CMT, CIDP, diabetes, CSPN
• Relapsing-remitting → CIDP, porphyria, hereditary neuropathy with liability to pressure palsies (HNPP)

Q6. Hereditary neuropathy?

• Family history of foot deformity (pes cavus), hammer toes, scoliosis → hereditary
• Examine parents and siblings
• Very slow NCVs in relatives even without symptoms → CMT1

Q7. Associated medical conditions?

• Diabetes, renal failure, hypothyroidism, malignancy, HIV, alcohol use, medications → all common causes

4. CLINICAL PATTERNS (Table 457-2)

5. ELECTRODIAGNOSTIC STUDIES (Table 457-3)

What EDx tells you:

• Type: mononeuropathy, mononeuropathy multiplex, radiculopathy, plexopathy, polyneuropathy
• Fiber involved: sensory, motor, autonomic, or mixed
• Pathology: axonal degeneration vs segmental demyelination

Axonal vs Demyelinating:

6. LABORATORY EVALUATION

Tier 1 (All patients):

• Fasting glucose / HbA1c (diabetes)
• CBC, CMP (renal, liver)
• TSH (hypothyroid)
• Vitamin B12
• SPEP + immunofixation (MGUS, myeloma)
• ESR
• Urinalysis

Tier 2 (Guided by pattern):

• Anti-Hu, anti-Yo → paraneoplastic
• Anti-GM1, anti-GQ1b → GBS variants
• ANA, ANCA, anti-SSA/SSB → connective tissue / Sjögren's
• Cryoglobulins, hepatitis B/C/E serology
• HIV
• Urine porphyrins (ALA, PBG)
• Genetic testing (CMT panel: PMP22, MFN2, MPZ, etc.)
• Nerve biopsy → vasculitis, amyloid, leprosy, CIDP

7. HEREDITARY NEUROPATHIES

Charcot-Marie-Tooth (CMT) Disease

CMT1 (Demyelinating, AD)

• Most common: CMT1A → duplication of PMP22 gene (17p11.2)
• NCV markedly slowed (typically <38 m/s)
• Clinical: distal weakness + wasting, pes cavus, hammer toes, absent reflexes, stocking-glove sensory loss; onset 1st–2nd decade
• CMT1B → mutation in MPZ (myelin protein zero)

CMT2 (Axonal, AD)

• NCS: mildly slowed or normal velocity; reduced CMAP/SNAP amplitudes
• Most common: MFN2 mutation (~20–30% of CMT2) → impairs mitochondrial fusion

CMT4 (Demyelinating, AR)

• Autosomal recessive; typically more severe

HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)

• Deletion of PMP22 (opposite of CMT1A duplication)
• Repeated focal neuropathies with mild trauma (crossing legs, prolonged pressure)
• Tomaculous myelin sheaths on nerve biopsy

HSAN (Hereditary Sensory and Autonomic Neuropathies)

• Predominantly sensory and autonomic; pain and temperature most affected
• Risk of painless ulcers/Charcot joints (HSAN-I, HSAN-II)

Porphyria

• Three forms with neuropathy: AIP, HCP, VP
• Attacks precipitated by: P450-metabolized drugs, hormonal changes (pregnancy, menstrual cycle), dietary restriction
• Presentation: abdominal pain → psychosis/seizures → ascending weakness mimicking GBS
• Dysautonomia common (tachycardia, hypertension, pupillary dilation)
• Urine: brown; elevated ALA + porphobilinogen
• Treatment: IV glucose (10–20 g/h); if no improvement in 24h → IV hematin 2–5 mg/kg/day × 3–14 days; Givosiran (siRNA) 2.5 mg/kg SC monthly for recurrent AIP

8. ACQUIRED NEUROPATHIES

Diabetic Neuropathy

• Most common cause; present in up to 80% with >15 years of disease
• Forms:
  1. Distal symmetric sensorimotor polyneuropathy (DSPN) - most common; sensory > motor; axonal + demyelinating features; strict glycemic control is best treatment
  2. Autonomic neuropathy - orthostatic hypotension, gastroparesis, bowel/bladder/sexual dysfunction
  3. Lumbosacral radiculopathy (Diabetic amyotrophy) - asymmetric pain + weakness + atrophy, starts in one lower limb

Neuropathy with Monoclonal Gammopathy (MGUS)

• ~5% of sensorimotor neuropathy of unknown cause have monoclonal gammopathy
• IgM MGUS → typically demyelinating; anti-MAG antibodies common
• IgG/IgA MGUS → typically axonal

Vasculitic Neuropathy

• Pattern 3: asymmetric, multifocal neuropathy (mononeuropathy multiplex)
• Associated with PAN, rheumatoid arthritis, Wegener's, SLE, cryoglobulinemia
• Nerve biopsy: epineural vessel inflammation + axonal degeneration
• Treatment: immunosuppression (glucocorticoids ± cyclophosphamide)

Amyloid Neuropathy

• Primary (AL): axonal sensorimotor + prominent autonomic; carpal tunnel syndrome
• Familial (transthyretin - TTR): small fiber sensory + autonomic; Val30Met mutation most common
• Autonomic dysfunction without diabetes → think amyloid
• Nerve biopsy: Congo red positive deposits

Sarcoid Neuropathy

• Can produce mononeuropathy, mononeuropathy multiplex, or polyradiculopathy
• Facial neuropathy common

Leprosy (Most Common Worldwide)

• Caused by Mycobacterium leprae
• Tuberculoid form: single or few hypopigmented anesthetic skin patches; thickened peripheral nerves
• Lepromatous form: diffuse symmetric neuropathy
• Treatment: dapsone + rifampin + clofazimine × 2 years
• Reversal reaction → exacerbation during treatment (upregulation of cellular immunity) → treat with high-dose glucocorticoids
• Erythema nodosum leprosum (ENL) → treat with glucocorticoids or thalidomide

Lyme Disease

• Borrelia burgdorferi; second/third stage neurologic involvement
• Facial neuropathy (bilateral in ~50%); polyradiculoneuropathy; mononeuropathy multiplex
• EDx: primary axonopathy; nerve biopsy: axonal degeneration + perivascular inflammation
• Treatment: antibiotics

HIV Neuropathy

• ~20% of HIV-infected individuals develop neuropathy
• Types: distal symmetric polyneuropathy (most common), mononeuropathy multiplex, inflammatory demyelinating polyneuropathy, CMV polyradiculopathy

Diphtheritic Neuropathy

• Corynebacterium diphtheriae toxin
• 3–4 weeks post-infection: palatal/throat numbness, dysphagia, blurred vision (impaired accommodation)
• 2–3 months: generalized polyneuropathy with ventilatory failure possible
• Treatment: antitoxin + antibiotics within 48 h

COVID-19

• GBS reported in acute COVID-19 (causal relationship not firmly established)
• Increased GBS risk with adenovirus-vector vaccines; not with mRNA vaccines

9. TOXIC NEUROPATHIES

10. MONONEUROPATHIES

Carpal Tunnel Syndrome (Median Nerve at Wrist)

• Most common mononeuropathy
• Paresthesias in first 3.5 digits; nocturnal symptoms; Phalen's/Tinel's sign
• Causes: pregnancy, hypothyroidism, amyloidosis, rheumatoid arthritis, diabetes
• Treatment: wrist splint, steroid injection, surgical decompression

Ulnar Neuropathy (Elbow)

• Weakness/wasting of intrinsic hand muscles; sensory loss in 4th/5th digits
• Elbow the most common site of compression

Peroneal Neuropathy (Fibular Head)

• Foot drop (ankle dorsiflexion + eversion + toe extension weakness)
• Sensory loss: anterolateral distal leg + dorsum of foot
• Distinguish from L5 radiculopathy (ankle inversion also weak in L5; spared in peroneal)
• Management: weight loss, avoid leg crossing, ankle brace, knee pad; most resolve spontaneously

Sciatic Neuropathy

• Complicates hip arthroplasty, pelvic procedures, trauma
• Weakness: all ankle/toe motions + knee flexion; spares hip abduction/extension
• Peroneal subdivision usually disproportionately affected → can mimic peroneal neuropathy

11. NEUROPATHIC PAIN MANAGEMENT

12. QUICK RECALL - HIGH-YIELD FACTS

• Most common cause of peripheral neuropathy → Diabetes mellitus
• Most common worldwide → Leprosy
• Most common inherited → CMT (CMT1A = PMP22 duplication)
• HNPP → PMP22 deletion (opposite of CMT1A)
• ~50% of cases → no etiology found (CSPN)
• Autonomic dysfunction without diabetes → think amyloid
• GBS risk → adenovirus-vector vaccines (not mRNA vaccines)
• INH neuropathy prevention → pyridoxine 100 mg/d
• Coasting effect → antiretroviral neuropathy worsens 2–3 weeks after stopping drug
• Porphyria treatment → IV glucose first; then hematin; givosiran for recurrent AIP
• Reversal reaction in leprosy → high-dose glucocorticoids