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Peripheral Neuropathy

Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapter 457

Authors: Anthony A. Amato, Richard J. Barohn

Overview

Peripheral nerves contain sensory, motor, and autonomic elements. Diseases can affect the cell body of a neuron or its peripheral processes (axons or myelin sheaths). Most peripheral nerves are mixed. Nerve fibers are classified into three major types:

Fiber Type	Function	Conduction
Large myelinated	Motor + proprioception/vibration	~50 m/s
Small myelinated	Pain, temperature	Slower
Small unmyelinated	Pain, temperature, autonomic	Slowest

Pathologic classification:

Neuronopathy/ganglionopathy - cell body affected
Myelinopathy - myelin affected
Axonopathy - axon affected

General Approach: Three Main Goals

Identify where the lesion is (history, neuro exam, electrodiagnostics)
Identify the cause
Determine proper treatment

Despite extensive evaluation, ~50% of patients have no identifiable etiology - labeled cryptogenic sensory and sensorimotor polyneuropathy (CSPN).

Seven Key Questions (Table 457-1)

1. What Systems Are Involved?

Motor only → consider motor neuropathy, NMJ abnormality, or myopathy
Autonomic features (orthostatic hypotension, bowel/bladder dysfunction, heat intolerance): Autonomic dysfunction without diabetes → suspect amyloid polyneuropathy
Majority of neuropathies are predominantly sensory

2. What Is the Distribution of Weakness?

Symmetric proximal + distal → hallmark of AIDP (GBS) and CIDP
Distal > proximal (distal symmetric) → most metabolic/toxic neuropathies (diabetes, alcohol, uremia, B12 deficiency)
Asymmetric/focal weakness → mononeuropathy multiplex or radiculopathy
Pure proximal weakness → consider myopathy or NMJ disorder; rarely neuropathy (lead poisoning, porphyria)

3. What Is the Sensory Distribution?

Distal symmetric ("stocking-glove") → length-dependent axonal polyneuropathy
Asymmetric proprioception loss with vibration loss, normal strength → sensory neuronopathy/ganglionopathy (Pattern 9)
Non-length-dependent (arms affected as much as legs) → sensory neuronopathy

4. Is There Upper Motor Neuron Involvement?

Combined UMN + distal sensory neuropathy pattern → consider:

Vitamin B12 deficiency
Copper deficiency
HIV infection
Adrenomyeloneuropathy (AMN)
Hereditary spastic paraplegia

5. What Is the Temporal Pattern?

Acute (<4 weeks): GBS, porphyria, toxins (arsenic, thallium)
Subacute (4-8 weeks): GBS (ongoing), toxic/nutritional deficiency
Chronic (>8 weeks): CMT, CIDP, metabolic (diabetes, uremia), paraproteinemia
Relapsing-remitting: CIDP, porphyria, hereditary neuropathy with pressure palsies (HNPP)

6. Is There a Family History?

Suggests hereditary neuropathy (CMT, HSAN, FAP, etc.)
High-arched feet (pes cavus), hammer toes, or scoliosis suggest longstanding hereditary neuropathy

7. What Are the Medications and Toxic Exposures?

Common neurotoxic agents:

Chemotherapy: vincristine, cisplatin, paclitaxel, bortezomib
Antibiotics: metronidazole, nitrofurantoin, dapsone, isoniazid
Cardiac drugs: amiodarone, hydralazine
Vitamin B6 (pyridoxine) toxicity (>200 mg/day)
Heavy metals: arsenic, thallium, lead, mercury
Alcohol

Clinical Patterns (Table 457-2)

Pattern	Features	Key Diagnoses
1	Symmetric proximal + distal weakness + sensory loss	AIDP (GBS), CIDP
2	Symmetric distal weakness + sensory loss	CMT, metabolic, toxic, CIDP
3	Asymmetric distal weakness ± sensory loss	Mononeuropathy multiplex (vasculitis, diabetes, sarcoid)
4	Asymmetric proximal + distal weakness	Lumbosacral/brachial plexopathy, radiculopathy
5	Asymmetric distal weakness, no sensory loss	Multifocal motor neuropathy (MMN)
6	Symmetric sensory loss ± distal weakness, UMN signs	B12 deficiency, HIV, copper deficiency, AMN
7	Symmetric distal sensory loss, no weakness	CSPN, small fiber neuropathy
8	Focal midline proximal symmetric weakness	ALS, Kennedy's syndrome
9	Asymmetric proprioceptive loss, no weakness	Sensory neuronopathy (paraneoplastic, CANVAS, Sjögren's)
10	Autonomic symptoms/signs	HSAN, amyloidosis, DM, GBS, porphyria

Electrodiagnostic Studies (EDx)

Nerve conduction studies (NCS):

Demyelinating features: slow conduction velocity, prolonged distal latencies, conduction block, temporal dispersion
Axonal features: reduced amplitude of CMAP/SNAP with relatively preserved conduction velocity

EMG:

Denervation (fibrillations, positive sharp waves) = axonal damage
Chronic reinnervation (large motor units) = long-standing disease

Skin punch biopsy:

Measures intraepidermal nerve fiber (IENF) density - gold standard for small fiber neuropathy diagnosis

Sural nerve biopsy:

Reserved for atypical cases; useful for vasculitis, amyloidosis, leprosy, CIDP

Hereditary Neuropathies

Charcot-Marie-Tooth Disease (CMT)

The most common inherited neuropathy (~1:2,500). Major types:

CMT1 (Demyelinating, AD):

CMT1A - most common; duplication of PMP22 gene on 17p11.2
CMT1B - MPZ gene mutation
NCS: markedly slow conduction velocity (<38 m/s in median motor)

CMT2 (Axonal, AD):

CMT2A - most common axonal form; MFN2 (mitofusin-2) gene mutation on 1p36.2
NCS: near-normal conduction velocity but reduced amplitude

CMTX (X-linked):

Connexin 32 (Cx32/GJB1) gene mutation on Xq13.1
Males more severely affected than females

HNPP (Hereditary Neuropathy with Liability to Pressure Palsies):

Deletion of PMP22 gene (same locus as CMT1A)
Recurrent pressure palsies (peroneal nerve at fibula head, ulnar at elbow, median at wrist)
Sausage-shaped myelin swellings ("tomacula") on nerve biopsy

Clinical features of CMT (all types):

Onset in first or second decade
Pes cavus, hammer toes, thin "stork legs"
Distal weakness (foot drop, hand weakness)
Reduced/absent DTRs
Slow progression
No curative treatment - supportive (orthotics, PT, foot care)

Hereditary Sensory and Autonomic Neuropathies (HSAN)

Five types (HSAN I-V); characterized by sensory loss + autonomic dysfunction. HSAN III (Riley-Day syndrome/familial dysautonomia) involves severe autonomic failure and is caused by mutations in IKBKAP gene.

Giant Axonal Neuropathy

Autosomal recessive; GAN gene mutation (gigaxonin protein)
Large, beaded axons due to accumulation of intermediate filaments
Kinky hair is a hallmark feature
Childhood onset; CNS also involved

CANVAS (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome)

Most common cause of autosomal recessive ataxia
Sensory neuropathy/neuronopathy + cerebellar ataxia + vestibular dysfunction + dry cough
Biallelic (AAGG)n repeat expansions in RFC1 gene (second intron)
NCS: low/absent sensory responses in non-length-dependent pattern

Acquired Neuropathies

Diabetic Neuropathy

The most common cause of polyneuropathy in developed countries. Multiple patterns:

Distal symmetric sensorimotor polyneuropathy - most common (Pattern 2)
Autonomic neuropathy - postural hypotension, gastroparesis, bladder dysfunction
Diabetic amyotrophy (Bruns-Garland syndrome) - lumbosacral radiculoplexopathy; asymmetric painful proximal leg weakness
Mononeuropathy - CN III (painful, pupil-sparing), median, peroneal
Truncal neuropathy - thoracoabdominal radiculopathy with pain/dysesthesias

Management: Glycemic control slows progression. Symptomatic pain treatment (see below).

Uremic Neuropathy

Predominantly axonal distal symmetric sensorimotor polyneuropathy
Correlates with degree of renal failure
Improves (or halts) after renal transplantation or hemodialysis

Diphtheritic Neuropathy

Caused by Corynebacterium diphtheriae exotoxin
Early onset (2-4 weeks): CN palsies, palatal weakness, loss of accommodation
Late onset (5-8 weeks): Demyelinating polyneuropathy with proximal > distal weakness (similar to GBS)

Neuropathies Associated with Malignancy

Direct invasion/compression by tumor
Paraneoplastic (remote effect) - most common with small-cell lung cancer
Treatment-related (chemotherapy)
Immune compromise

Paraneoplastic Sensory Neuronopathy (Anti-Hu):

Complicates small-cell lung carcinoma
Asymmetric numbness/paresthesias → sensory ataxia
Anti-Hu antibodies (anti-neuronal nuclear antibody type 1, ANNA-1) in serum/CSF
Poor response to treatment (immunotherapy/plasma exchange usually ineffective)

Lymphoma-Associated Neuropathy

Can be due to infiltration, compression, or paraneoplastic mechanism
May improve with chemotherapy

POEMS Syndrome

Polyneuropathy, Organomegaly, Endocrinopathy, M-protein (monoclonal), Skin changes
Caused by plasma cell dyscrasia, often lambda light chain restricted
Primarily demyelinating polyneuropathy (Pattern 1 or 2)
VEGF levels are elevated and correlate with disease activity
Treatment: radiation (if solitary plasmacytoma), chemotherapy, autologous stem cell transplant

Neuropathies with Paraproteinemia

IgM with anti-MAG antibody: Predominantly distal demyelinating sensory > motor
MGUS: Usually axonal; treatment not clearly beneficial unless symptomatic CIDP-like
AL amyloidosis: Painful axonal neuropathy with autonomic features; carpal tunnel syndrome common

Familial Amyloid Polyneuropathy (FAP)

Mutations in TTR (transthyretin), apolipoprotein A1, or gelsolin genes
TTR-FAP: painful distal neuropathy + severe autonomic dysfunction + carpal tunnel syndrome; onset in 3rd-4th decade
Treatments: tafamidis, diflunisal (TTR stabilizers); patisiran (siRNA, 0.3 mg/kg IV q3 weeks), vutrisiran (25 mg SC q3 months), eplontersen (45 mg SC q4 weeks), inotersen (antisense oligonucleotide, 300 mg SC weekly)

Vasculitic Neuropathy

Mononeuropathy multiplex is the classic pattern (Pattern 3)
Caused by ischemic infarction of individual nerves
Associated with: polyarteritis nodosa, Churg-Strauss (EGPA), rheumatoid arthritis, Sjögren's, SLE, cryoglobulinemia
Diagnosis confirmed by nerve + muscle biopsy (epineural or perineurial vessel inflammation + necrosis)
Treatment: high-dose glucocorticoids ± cyclophosphamide for systemic vasculitis

Multifocal Motor Neuropathy (MMN)

Pure motor mononeuropathy multiplex, no sensory loss
Anti-GM1 IgM antibodies in ~50%
Conduction block on NCS is hallmark
Treatment: IV immunoglobulin (IVIG) is first line; subcutaneous Ig also effective
Does NOT respond to steroids or plasma exchange (may worsen)

Neuropathies in HIV Infection

Distal symmetric polyneuropathy (DSP): Most common; due to HIV itself or antiretrovirals (ddI, ddC, d4T)
AIDP/CIDP-like: Early seroconversion or later; treat like idiopathic GBS/CIDP
CMV polyradiculopathy: CD4 <50; ascending weakness + bowel/bladder dysfunction; treat with ganciclovir/foscarnet

Nutritional Neuropathies

Thiamine (B1) deficiency (beriberi): Distal axonal sensorimotor; also in alcoholism
B12 deficiency: Combined system degeneration - subacute combined degeneration of spinal cord + peripheral neuropathy
Copper deficiency: Myeloneuropathy resembling B12 deficiency; often post-gastric surgery or excess zinc intake; treat with oral copper sulfate 2 mg 1-3x/day
Neuropathy post-gastric surgery: Multi-deficiency; treat with parenteral vitamins especially thiamine

Cryptogenic (Idiopathic) Sensory Polyneuropathy (CSPN)

Diagnosis of exclusion (up to 50% of all polyneuropathies)
Onset: 6th-7th decade
Distal numbness, tingling, burning pain ("burning feet syndrome") - starts in feet
No significant weakness
10% have only small-fiber involvement
EDx: isolated SNAP amplitude reduction, or axonal sensorimotor, or normal (small-fiber only)
Treat symptoms (see below)

Entrapment Neuropathies (Mononeuropathies)

Nerve	Site	Key Features
Median (CTS)	Carpal tunnel	Tingling/pain in fingers 1-3; nocturnal symptoms; thenar wasting; Tinel's/Phalen's signs
Ulnar	Cubital tunnel (elbow)	Numbness 4th-5th fingers; hypothenar/interossei weakness; "clawing"
Radial	Spiral groove	Wrist drop; axilla compression ("Saturday night palsy")
Peroneal	Fibula head	Foot drop; sensory loss dorsum of foot; weight loss, leg crossing
Femoral	Inguinal ligament	Quad weakness, patellar reflex loss, anterior thigh numbness
Sciatic	Piriformis/gluteal region	Footdrop + hamstring weakness + sensory loss distal leg

Plexopathies

Brachial Plexopathy

Neuralgic amyotrophy (Parsonage-Turner syndrome / hereditary neuralgic amyotrophy [HNA]): Sudden severe shoulder/arm pain followed by weakness; associated with SEPT9 mutations in hereditary form
Trauma, compression, post-radiation, tumor invasion

Lumbosacral Plexopathy

Idiopathic lumbosacral plexopathy (diabetic amyotrophy): Acute severe pain → proximal leg weakness; may respond to glucocorticoids
Tumor vs. radiation: Radiation = painless, upper trunk, myokymic discharges on EMG; Tumor = painful, lower trunk involvement

Treatment of Neuropathic Pain

Drug Class	Agents	Notes
Tricyclic antidepressants	Amitriptyline, nortriptyline	First-line; also help sleep
SNRIs	Duloxetine, venlafaxine	FDA-approved for diabetic neuropathy (duloxetine)
Anticonvulsants	Gabapentin, pregabalin	First-line; pregabalin FDA-approved for DPN and fibromyalgia
Topical	Lidocaine patches, capsaicin	Adjuncts; capsaicin depletes substance P
Opioids	Tramadol, tapentadol	Second/third-line; addiction risk
Mexiletine	Oral sodium channel blocker	Used for painful neuropathy, esp. when other agents fail

Key Diagnostic Investigations

Electrodiagnostic studies (NCS + EMG) - cornerstone
Blood work: CBC, CMP, fasting glucose/HbA1c, B12, folate, TSH, ESR, CRP, serum protein electrophoresis (SPEP) + immunofixation, serum free light chains, ANA, ANCA, anti-Ro/La, cryoglobulins, HIV
Urine: 24-h urine for heavy metals (arsenic, thallium, lead, mercury)
Genetic testing: Consider if family history or young onset
Skin punch biopsy: Small-fiber neuropathy
Sural nerve biopsy: When diagnosis unclear after full workup (vasculitis, amyloid, leprosy, CIDP)
CSF analysis: Elevated protein in GBS, CIDP, CMT1; pleocytosis in HIV, CMV, Lyme
Anti-neuronal antibodies: Anti-Hu, anti-Yo, anti-CV2, anti-amphiphysin (paraneoplastic)
Anti-ganglioside antibodies: Anti-GM1 (MMN, GBS-Miller Fisher), anti-GQ1b (Miller Fisher syndrome)

Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 457: Peripheral Neuropathy, pp. 3638-3711. Authors: Anthony A. Amato, Richard J. Barohn.

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