Peripheral Neuropathy¶
Chapter 457 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 457
Key Clinical Points¶
- Approximately 50% of patients with generalized symmetric peripheral neuropathy have no identifiable etiology (idiopathic or cryptogenic).
- Symmetric proximal and distal weakness with sensory loss is the hallmark of inflammatory demyelinating polyneuropathy (GBS and CIDP).
- CMT1 is the most common hereditary neuropathy, characterized by motor conduction velocities <38 m/s and onion bulb formation on biopsy.
- Small-fiber neuropathy: suspected if pain/temperature are lost while vibratory/position sense and muscle strength are preserved with normal NCS.
- Vitamin B12 deficiency is a primary cause of combined system degeneration (CNS involvement + neuropathy).
- Nerve biopsy is rarely performed; primarily indicated for suspected amyloid neuropathy or vasculitis.
- Skin biopsy can diagnose small-fiber neuropathy by measuring the density of small unmyelinated fibers.
- Autonomic dysfunction without diabetes should trigger suspicion for amyloid polyneuropathy.
- CSF pleocytosis in GBS/CIDP suggests non-inflammatory causes like HIV, Lyme, sarcoidosis, or lymphomatous infiltration.
- Distinction between axonopathy and myelinopathy is critical: Axonopathy shows low-amplitude potentials; Myelinopathy shows slow conduction velocities and prolonged latencies.
DEFINITION & CLASSIFICATION¶
• Nerve Composition: Mixed fibers including sensory, motor, and autonomic. • Fiber Classifications: ◦ Large myelinated: Motor axons (typically ~50 m/s) and large-diameter sensory fibers (proprioception, vibration). ◦ Small myelinated & unmyelinated: Sensory fibers (pain, temperature) and autonomic nerves. • Pathology Classification: ◦ Neuronopathy/Ganglionopathy: Affecting the cell body. ◦ Myelinopathy: Affecting the myelin sheath. ◦ Axonopathy: Affecting the axon.
General Approach¶
• Primary Goals: (1) Identify lesion location, (2) identify cause, (3) determine treatment. ◦ Clinical Evaluation: Includes history, physical exam, and electrodiagnostic (EDx) studies. ◦ Idiopathic/Cryptogenic: ~50% of cases have no identifiable etiology; typically predominantly sensory polyneuropathy.
EPIDEMIOLOGY¶
• Idiopathic Cases: Approximately 50% of generalized symmetric peripheral neuropathies. • Hereditary: CMT is the most common form of hereditary neuropathy. • Acquired: Diabetes mellitus is a common cause of acquired neuropathy. • Sensory Predominance: The majority of neuropathies are predominantly sensory.
ETIOLOGY & PATHOPHYSIOLOGY¶
• General Causes: Hereditary factors, metabolic disorders, drugs, toxins, infections, autoimmune diseases, and paraneoplastic syndromes. • Axonopathy Characteristics: ◦ Low-amplitude potentials. ◦ Relatively preserved distal latencies, conduction velocities, and late potentials. ◦ Fibrillations on needle EMG. • Segmental Demyelination Characteristics: ◦ Slow conduction velocities. ◦ Prolonged distal latencies and late potentials. ◦ Relatively preserved amplitudes. ◦ Absence of fibrillations on needle EMG. ◦ Indicators of acquired demyelinating neuropathy: Nonuniform slowing, conduction block, or temporal dispersion.
Hereditary Neuropathies¶
• Charcot-Marie-Tooth (CMT): A syndrome of genetically distinct disorders. ◦ CMT1: Inherited demyelinating sensorimotor neuropathies. → Most cases have motor NCVs between 20 and 25 m/s. ◦ CMT2: Axonal sensory neuropathies. → Defined by motor conduction velocities in the arms slowed to 38 m/s. ◦ Inheritance: Mostly autosomal dominant (AD). ◦ Management: No medical therapies; physical/occupational therapy and bracing (e.g., AFOs) are used. ◦ Key Genetic Variants (Table 4): ◦ CMT1A: AD, 17p11.2, PMP22 (usually duplication). ◦ CMT1B: AD, 1q21-23, MPZ. ◦ CMT2B: AD, 3q13-q22, RAB7. ◦ CMT2P: AD and AR, 9q31.3-34.2, LRSAM1. ◦ Other variants include mutations in NEFL, MFN2, LMNA, etc.
Acquired Neuropathies¶
• Metabolic/Systemic: Diabetes mellitus (common), Amyloidosis (consider in small-fiber cases). ◦ Inflammatory/Autoimmune: Vasculitis, Sjögren's syndrome, SLE. ◦ Infectious: HIV, Lyme disease, leprosy, hepatitis B, C, or E. ◦ Toxic: Medications (vincristine, cisplatin), alcohol, heavy metals (arsenic, lead, thallium). ◦ Paraneoplastic: Various syndromes associated with malignancy.
CLINICAL FEATURES¶
• Symptoms: Numbness, altered sensation to touch (hyperpathia or allodynia), spontaneous sensations (tingling, burning, aching). ◦ Pain Types: → Protopathic: Burning, dull, poorly localized (polymodal C nociceptor fibers). → Epicritic: Sharp and lancinating (A-delta fibers). • Small-Fiber Neuropathy Indicators: → Loss of pain/temperature perception. → Preservation of vibratory/position sense, muscle strength, and deep tendon reflexes. → Normal Nerve Conduction Studies (NCS). → Common causes: Diabetes mellitus or glucose intolerance. • Sensory Neuronopathy/Ganglionopathy Indicators: → Severe proprioceptive loss + vibration loss + normal strength. → Asymmetric or affects arms more than legs (non-length-dependent). • Laboratory Evaluation for Generalized Symmetric Polyneuropathy: ◦ CBC, basic chemistries (electrolytes, renal/hepatic function). ◦ Fasting blood glucose (FBS), HbA1c, thyroid function. ◦ B12, folate, ESR, RF, ANA. ◦ SPEP, immunoelectrophoresis/immunofixation, and free light chains (serum/urine) for amyloid suspicion. ◦ Skeletal survey if M-spikes are present. ◦ Oral glucose tolerance test (even if FBS/HbA1c normal) for painful sensory neuropathies.
History & Physical Examination¶
• Seven Key Questions (Table 1): 1. Systems involved: Motor, sensory, autonomic, or combinations. 2. Distribution of weakness: Only distal vs. proximal and distal; Focal/asymmetric vs. symmetric. 3. Nature of sensory involvement: Temperature loss/burning/stabbing (small fiber) vs. Vibratory/proprioceptive loss (large fiber). 4. Upper motor neuron (UMN) involvement: With or without sensory loss. 5. Temporal evolution: Acute (days to 4 weeks), Subacute (4–8 weeks), Chronic (>8 weeks); Monophasic, progressive, or relapsing-remitting. 6. Hereditary evidence: Family history; Lack of sensory symptoms despite sensory signs. 7. Associated conditions: Cancer, DM, autoimmune disease, infection, medications, preceding events/toxins.
DIFFERENTIAL DIAGNOSIS¶
• Pattern 1: Inflammatory demyelinating polyneuropathy (GBS and CIDP). • Pattern 2: CSPN, DM, metabolic disorders, drugs, toxins, familial (HSAN), CMT, amyloidosis, CANVAS, SORD. • Pattern 3: Multifocal CIDP, vasculitis, cryoglobulinemia, amyloidosis, sarcoid, infectious (leprosy, Lyme, Hep B/C/E, HIV, CMV), HNPP, tumor infiltration; or mononeuropathy/plexopathy/radiculopathy. • Pattern 4: Polyradiculopathy or plexopathy due to DM, meningeal carcinomatosis/lymphomatosis, sarcoid, amyloid, hereditary plexopathy (HNPP, HNA), idiopathic. • Pattern 5: Motor neuron disease (with UMN) or progressive muscular atrophy, juvenile monomelic amyotrophy, multifocal motor neuropathy, multifocal acquired motor axonopathy (without UMN). • Pattern 6: Vitamin B12, E, and copper deficiency; chronic liver disease; hereditary leukodystrophies; HSP-plus. • Pattern 7: SMA (proximal/distal) or hereditary motor neuropathy (distal SMA) or atypical CMT. • Pattern 8: ALS (neck extensor), ALS/PLS, isolated bulbar ALS, Kennedy's syndrome, bulbar presentation GBS. • Pattern 9: Sensory neuronopathy (ganglionopathy): Cancer, CANVAS, Sjögren's, Idiopathic, Cisplatin, Vitamin B6 toxicity, HIV-related. • Pattern 10: Hereditary sensory and autonomic neuropathy, Amyloidosis, DM, GBS, Idiopathic pandysautonomia, Porphyria, HIV-related, Vincristine/chemotherapy.
DIAGNOSTIC APPROACH¶
- Electrodiagnostic (EDx) Study: • Consists of Nerve Conduction Studies (NCS) and needle electromyography (EMG). • Purpose: Confirm mononeuropathy, multiple mononeuropathy, radiculopathy, plexopathy, or polyneuropathy. • Differentiation: Distinguish sensory vs. motor/autonomic involvement; axonopathy vs. myelinopathy. • Axonopathy Indicators: Low-amplitude potentials, preserved distal latencies/conduction velocities, fibrillations on needle EMG. • Myelinopathy Indicators: Slow conduction velocities, prolonged distal latencies/late potentials, presence of conduction block or temporal dispersion.
- Autonomic Studies: • Used for small myelinated (A-delta) or unmyelinated (C) fiber involvement. • Tests: Heart rate response to deep breathing; heart rate and blood pressure response to Valsalva maneuver and tilt-table testing; quantitative sudomotor axon reflex testing. • Indicated when: Patient has pure small-fiber neuropathy or autonomic neuropathy where routine NCS are normal.
- Laboratory Screening: • Standard panel: CBC, chemistry, glucose (FBS/HbA1c), thyroid, B12, folate, ESR, RF, ANA, SPEP/immunofixation, free light chains. • Specific tests: Oral glucose tolerance test for painful sensory neuropathies; heavy metal screen only if exposure suspected or specific features present (e.g., thallium).
- Biopsy: • Nerve biopsy: Rarely performed; primary indications are suspicion of amyloid neuropathy or vasculitis. • Skin biopsy: Used to diagnose small-fiber neuropathy by measuring density of small unmyelinated fibers.
Flowchart: Approach to Evaluation¶
- Initial Screening: History and examination compatible with neuropathy? → No → Evaluate other disorder or reassurance. → Yes → Proceed to EDx.
- Mononeuropathy Path: → If Axonal → Determine if systemic disorder present → Treatment for specific diagnosis. → If Demyelinating with focal conduction block → Consider multifocal CIDP → If tests negative, consider treatment for CIDP.
- Polyneuropathy Path: → If Axonopathy → Determine if Subacute (months) or Chronic (years). → Subacute/Chronic: Review history for systemic disease/infection; treat specific diagnosis. → If Demyelinating → Assess conduction velocity characteristics. → Uniform slowing, chronic → Test for paraneoplastic; if negative, review family history/genetics → Treatment for CIDP. → Nonuniform slowing, conduction block → If acute: GBS → IVIg or plasmapheresis + supportive care (respiratory).
- Mononeuropathy Multiplex: → If Axonal → Consider vasculitis/multifocal process → Possible nerve biopsy. → If Demyelinating with focal conduction block → Consider multifocal CIDP.
MANAGEMENT & TREATMENT¶
- Pain Management (Table 6): • First-Line: ◦ Lidoderm 5% patch: Apply to painful area; up to 3 patches qd. ◦ Tricyclic antidepressants (amitriptyline, nortriptyline): PO; 10–100 mg qhs. ◦ Gabapentin: PO; 300–1200 mg tid. ◦ Pregabalin: PO; 50–100 mg tid. ◦ Duloxetine: PO; 30–60 mg qd. • Second-Line: ◦ Carbamazepine: PO; 200–400 mg q 6–8 h. ◦ Phenytoin: PO; 200–400 mg qhs. ◦ Venlafaxine: PO; 37.5–150 mg/d. • Third-Line: ◦ Mexiletine: PO; 200–300 mg tid.
- Acute Demyelinating (GBS): → IVIg or plasmapheresis → Supportive care including respiratory assistance.
Toxic Neuropathies (Table 7 & 8)¶
• Vinca alkaloids: Axonal degeneration; symmetric S-M, large/small fiber PN; autonomic symptoms common. • Cisplatin: Predominant large-fiber sensory neuronopathy; sensory ataxia. • Taxanes: Symmetric, predominantly sensory PN; large-fiber modalities affected more than small-fiber. • Cytarabine: GBS-like syndrome; pure sensory neuropathy; brachial plexopathy. • Bortezomib: Length-dependent, sensory, predominantly small-fiber PN. • Misonidazole: Painful paresthesias and loss of large/small-fiber sensory modalities. • Chloroquine/Hydroxychloroquine: Loss of large/small-fiber; may have superimposed myopathy. • Colchicine: Numbness, paresthesias, loss of large-fiber; potential for myopathy. • Thalidomide: Axonal degeneration of dorsal root ganglia. • Dapsone: Distal weakness (may progress to proximal) or paresthesias/numbness. • Nitrofurantoin: Numbness, painful paresthesias, severe weakness (GBS-like). • Isoniazid: Dysesthesias and sensory ataxia; impaired large-fiber modalities. • Antinucleosides: Dysesthesia and sensory ataxia. • Lithium: Numbness with loss of large-fiber modalities.
COMPLICATIONS & PROGNOSIS¶
• GBS/CIDP: Acute GBS requires monitoring for respiratory failure; CIDP is a chronic condition requiring long-term management. • Toxicity: Certain drugs (e.g., Vincristine, Cisplatin) cause significant axonal degeneration and may require discontinuation or dose adjustment.
SPECIAL POPULATIONS¶
• Pediatric/Genetic: CMT patients require early identification for physical therapy and orthotics. • Cancer Patients: Paraneoplastic syndromes and chemotherapy-induced toxic neuropathies (e.g., Vincristine, Cisplatin) must be differentiated from primary neurological disorders.
KEY PEARLS & HIGH-YIELD POINTS¶
• Rule of Thumb: If it's symmetric and demyelinating → GBS/CIDP. If it's asymmetric or involves specific nerve roots → Radiculopathy/Plexopathy. • Small Fiber Alert: Pain/temp loss + normal NCS = Small-fiber neuropathy (think DM, Amyloid). • Autonomic Clue: Autonomic dysfunction without DM → suspect Amyloid. • EDx Distinction: Axonopathy (Low amplitude) vs. Myelinopathy (Slow conduction/Block).
Reference Tables¶
TABLE 457-1 Approach to Neuropathic Disorders: Seven Key Questions 1. What systems are involved? 2. What is the…¶
Harrison's 22e, p.3596
-
- What systems are involved?
• Motor, sensory, autonomic, or combinations
2. What is the distribution of weakness?
• Only distal versus proximal and distal
• Focal/asymmetric versus symmetric
3. What is the nature of the sensory involvement?
• Temperature loss or burning or stabbing pain (e.g., small fiber)
• Vibratory or proprioceptive loss (e.g., large fiber)
4. Is there evidence of upper motor neuron involvement?
• Without sensory loss
• With sensory loss
5. What is the temporal evolution?
• Acute (days to 4 weeks)
• Subacute (4–8 weeks)
• Chronic (>8 weeks)
• Monophasic, progressive, or relapsing-remitting
6. Is there evidence for a hereditary neuropathy?
• Family history of neuropathy
• Lack of sensory symptoms despite sensory signs
7. Are there any associated medical conditions?
• Cancer, diabetes mellitus, connective tissue disease or other autoimmune
diseases, infection (e.g., HIV, Lyme disease, leprosy)
• Medications including over-the-counter drugs that may cause a toxic
neuropathy
• Preceding events, drugs, toxins
- What systems are involved?
TABLE 457-2 Patterns of Neuropathic Disorders
- Pattern 1: Symmetric proximal and distal weakness with sensory loss
- Consider: inflammatory demyelinating polyneuropathy (GBS and CIDP)
- Pattern 2: Symmetric distal sensory loss with or without distal weakness
- Consider: cryptogenic or idiopathic sensory polyneuropathy (CSPN), diabetes
mellitus and other metabolic disorders, drugs, toxins, familial (HSAN), CMT,
amyloidosis, CANVAS, SORD neuropathy, and others - Pattern 3: Asymmetric distal weakness with sensory loss
- With involvement of multiple nerves
- Consider: multifocal CIDP, vasculitis, cryoglobulinemia, amyloidosis,
sarcoid, infectious (leprosy, Lyme, hepatitis B, C, or E, HIV, CMV), HNPP,
tumor infiltration - With involvement of single nerves/regions
- Consider: may be any of the above but also could be compressive
mononeuropathy, plexopathy, or radiculopathy - Pattern 4: Asymmetric proximal and distal weakness with sensory loss
- Consider: polyradiculopathy or plexopathy due to diabetes mellitus, meningeal
carcinomatosis or lymphomatosis, sarcoid, amyloid, hereditary plexopathy
(HNPP, HNA), idiopathic - Pattern 5: Asymmetric distal weakness without sensory loss
- With upper motor neuron findings
- Consider: motor neuron disease
- Without upper motor neuron findings
- Consider: progressive muscular atrophy, juvenile monomelic amyotrophy
(Hirayama’s disease), multifocal motor neuropathy, multifocal acquired
motor axonopathy - Pattern 6: Symmetric sensory loss and distal areflexia with upper motor neuron
findings - Consider: vitamin B , vitamin E, and copper deficiency with combined system
12
degeneration with peripheral neuropathy, chronic liver disease, hereditary
leukodystrophies (e.g., adrenomyeloneuropathy), HSP-plus - Pattern 7: Symmetric weakness without sensory loss
- With proximal and distal weakness
- Consider: SMA
- With distal weakness
- Consider: hereditary motor neuropathy (“distal” SMA) or atypical CMT
- Pattern 8: Focal midline proximal symmetric weakness
- Neck extensor weakness
- Consider: ALS
- Bulbar weakness
- Consider: ALS/PLS, isolated bulbar ALS (IBALS), Kennedy’s syndrome
(X-linked, bulbospinal SMA), bulbar presentation GBS - Diaphragm weakness (SOB)
- Consider: ALS
- Pattern 9: Asymmetric proprioceptive sensory loss without weakness
- Consider causes of a sensory neuronopathy (ganglionopathy):
- Cancer (paraneoplastic)
CANVAS - Sjögren’s syndrome
- Idiopathic sensory neuronopathy (possible GBS variant)
- Cisplatin and other chemotherapeutic agents
- Vitamin B toxicity
- 6
HIV-related sensory neuronopathy - Pattern 10: Autonomic symptoms and signs
- Consider neuropathies associated with prominent autonomic dysfunction:
- Hereditary sensory and autonomic neuropathy
- Amyloidosis (familial and acquired)
- Diabetes mellitus
- GBS
- Idiopathic pandysautonomia (may be a variant of GBS)
- Porphyria
- HIV-related autonomic neuropathy
- Vincristine and other chemotherapeutic agents
TABLE 457-3 Electrophysiologic Features: Axonal Degeneration versus Segmental Demyelination¶
Harrison's 22e, p.3597
| AXONAL DEGENERATION | SEGMENTAL DEMYELINATION |
|
|---|---|---|
| Motor Nerve Conduction Studies | ||
| CMAP amplitude | Decreased | Normal (except with CB or distal dispersion) |
| Distal latency | Normal | Prolonged |
| Conduction velocity | Normal | Slow |
| Conduction block | Absent | Present |
| Temporal dispersion | Absent | Present |
| F wave | Normal or absent | Prolonged or absent |
| H reflex | Normal or absent | Prolonged or absent |
| Sensory Nerve Conduction Studies |
Table 457-2). In particular, if this loss is asymmetric or affects the arms more than the legs, this pattern suggests a…¶
Harrison's 22e, p.3597
| Decreased | ||
|---|---|---|
| Normal | ||
| Normal | ||
| Needle EMG | ||
| Spontaneous activity | ||
| Fibrillations | Present | Absent |
| Fasciculations | Present | Absent |
| Motor unit potentials | ||
| Recruitment | Decreased | Decreased |
| Morphology | Long duration, large amplitude, polyphasic (if there is reinnervation) |
Normal |
TABLE 457-4 Classification of Charcot-Marie-Tooth Disease and Related Neuropathies¶
Harrison's 22e, p.3599
| NAME | INHERITANCE | GENE LOCATION | GENE |
|---|---|---|---|
| CMT1 | |||
| CMT1A | AD | 17p11.2 | PMP22 (usually duplication of gene) |
| CMT1B | AD | 1q21-23 | MPZ |
| CMT1C | AD | 16p13.1-p12.3 | LITAF |
| CMT1D | AD | 10q21.1-22.1 | ERG2 |
| CMT1E (with deafness) | AD | 17p11.2 | PMP22 gene (usually point mutations) |
| CMT1F | AD | 8p13-21 | NEFL |
| CMT1G | AD | 8q21 | PMP22 |
| AD | 17p11.2 1q21-23 |
||
| CMT dominant-intermediate (CMTDI) | |||
| CMT-DIA | AD | 10q24.1-25.1 | ? |
| CMT-DIB | AD | 19.p12-13.2 | DNM2 |
| CMT-DIC | AD | 1p35 | YARS |
| CMT-DID CMT-DIE CMT-DIF CMT-DIG |
AD AD AD AD |
1q22 14q32.33 3q26 8p31 |
MPZ IFN-2 GNB4 NEFL |
| AR AR AR AR |
8q21.1 6q23 1p36 12q24 |
||
| CMT2 | |||
| CMT2A2 (allelic to HMSN VI with optic atrophy) | AD | 1p36.2 | MFN2 |
| CMT2B | AD | 3q13-q22 | RAB7 |
| CMT2B1 (allelic to LGMD 1B) | AR | 1q21.2 | LMNA |
| CMT2B2 | AR | 19q13 | PNKP |
| CMT2C (allelic to scapuloperoneal neuropathy) | AD | 12q23-24 | TRPV4 |
| CMT2D (allelic to distal SMA5) CMT2DD |
AD AD |
7p14 1p13 |
GARS1 ATP1A1 |
| CMT2E (allelic to CMT1F) CMT2EE |
AD AD |
8p21 2p23 |
NEFL MPV17 |
| CMT2F | AD | 7q11-q21 | HSPB1 |
| CMT2G (allelic to CMT2P) | AD | 9q31.3-34.2 | LRSAM1 |
| CMT2I (allelic to CMT1B) | AD | 1q22 | MPZ |
| CMT2J | AD | 1q22 | MPZ |
| CMT2H, CMT2K (allelic to CMT4A) | AD | 8q13-q21 | GDAP1 |
| CMT2L (allelic to distal hereditary motor neuropathy type 2) |
AD | 12q24 | HSPB8 |
| CMT2M | AD | 16q22 | DNM2 |
| CMT2N | AD | 16q22.1 | AARS |
| CMT2O | AD | 14q32.31 | DYNC1H1 |
| CMT2P | AD and AR | 9q31.3-34.2 | LRSAM1 |
| CMT2P-Okinawa (allelic to HSMN2P) | AD | 3q13-q14 | TFG |
| CMT2Q CMT2RCMT2S CMT2T CMT2U CMT2V CMT2W CMT2X CMT2Y CMT2Z |
AD AD AD ADAD AD AD AD AD AD |
10p14 4q 11q13.3 3q25.2 12q13 17q11 5q31 15q21.1 9p13 22q12 |
DHTKD1 TRIM2 IGHMBP2 MME MARS1 NAGLU HARS1 SPB11 VCP MORC2 |
TABLE 457-5 Rare Hereditary Neuropathies Hereditary Disorders of Lipid Metabolism Metachromatic leukodystrophy Krabbe’s…¶
Harrison's 22e, p.3602
- Hereditary Disorders of Lipid Metabolism
- Metachromatic leukodystrophy
- Krabbe’s disease (globoid cell leukodystrophy)
- Fabry’s disease
- Adrenoleukodystrophy/adrenomyeloneuropathy
- Refsum’s disease
- Tangier disease
- Cerebrotendinous xanthomatosis
- Hereditary Ataxias with Neuropathy
- CANVAS (cerebellar ataxia, neuropathy, and vestibular areflexia syndrome)
Friedreich’s ataxia - Vitamin E deficiency
- Spinocerebellar ataxia
- Abetalipoproteinemia (Bassen-Kornzweig disease)
- Disorders of Defective DNA Repair
- CANVAS
Ataxia-telangiectasia - Cockayne’s syndrome
- Giant Axonal Neuropathy
- Porphyria
- Acute intermittent porphyria (AIP)
- Hereditary coproporphyria (HCP)
- Variegate porphyria (VP)
- Familial Amyloid Polyneuropathy (FAP)
- Transthyretin-related
- Gelsolin-related
- Apolipoprotein A1-related
TABLE 457-6 Treatment of Painful Sensory Neuropathies THERAPY First-Line Lidoderm 5% patch Tricyclic antidepressants…¶
Harrison's 22e, p.3604
| THERAPY | ROUTE | DOSE | SIDE EFFECTS |
|---|---|---|---|
| First-Line | |||
| Lidoderm 5% patch | Apply to painful area | Up to 3 patches qd | Skin irritation |
| Tricyclic antidepressants (e.g., amitriptyline, nortriptyline) |
PO | 10–100 mg qhs | Cognitive changes, sedation, dry eyes and mouth, urinary retention, constipation |
| Gabapentin | PO | 300–1200 mg tid | Cognitive changes, sedation, peripheral edema |
| Pregabalin | PO | 50–100 mg tid | Cognitive changes, sedation, peripheral edema |
| Duloxetine | PO | 30–60 mg qd | Cognitive changes, sedation, dry eyes, diaphoresis, nausea, diarrhea, constipation |
| Second-Line | |||
| PO | 200–400 mg q 6–8 h | ||
| PO | 200–400 mg qhs | ||
| PO | 37.5–150 mg/d | ||
| PO | 50 mg qid | ||
| Third-Line | |||
| Mexiletine | PO | 200–300 mg tid | Arrhythmias |
| Other Agents | |||
| Apply cutaneously | qid | ||
| Apply cutaneously | qid |
TABLE 457-7 Toxic Neuropathies Secondary to Chemotherapy DRUG Vinca alkaloids (vincristine, vinblastine, vindesine…¶
Harrison's 22e, p.3608
| DRUG | MECHANISM OF NEUROTOXICITY |
CLINICAL FEATURES | NERVE HISTOPATHOLOGY | EMG/NCS |
|---|---|---|---|---|
| Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine) |
Interfere with axonal microtubule assembly; impairs axonal transport |
Symmetric, S-M, large-/small- fiber PN; autonomic symptoms common; infrequent cranial neuropathies |
Axonal degeneration of myelinated and unmyelinated fibers; regenerating clusters, minimal segmental demyelination |
Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception |
| Preferential damage to dorsal root ganglia: ? binds to and cross-links DNA ? inhibits protein synthesis ? impairs axonal transport |
Predominant large-fiber sensory neuronopathy; sensory ataxia |
Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination |
||
| Taxanes (paclitaxel, docetaxel) |
Promotes axonal microtubule assembly; interferes with axonal transport |
Symmetric, predominantly sensory PN; large-fiber modalities affected more than small-fiber |
Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination |
Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception |
| Unknown;? inhibition of neurotrophic growth factor binding;? neuronal lysosomal storage |
Symmetric, length-dependent, sensory-predominant PN |
None described | ||
| Unknown;? immunomodulating effects |
Subacute, S-M PN with diffuse proximal and distal weakness; areflexia; increased CSF protein |
Loss of large and small myelinated fibers with primary demyelination and secondary axonal degeneration; occasional epi- and endoneurial inflammatory cell infiltrates |
||
| Cytarabine (ARA-C) | Unknown;? selective Schwann cell toxicity;? immunomodulating effects |
GBS-like syndrome; pure sensory neuropathy; brachial plexopathy |
Loss of myelinated nerve fibers; axonal degeneration; segmental demyelination; no inflammation |
Axonal, demyelinating, or mixed S-M PN; denervation on EMG |
| Unknown;? selective dorsal root ganglia toxicity |
Length-dependent, sensory- predominant PN; autonomic neuropathy |
None described | ||
| Bortezomib (Velcade) | Unknown | Length-dependent, sensory, predominantly small-fiber PN |
Not reported | Abnormalities consistent with an axonal sensory neuropathy with early small-fiber involvement (abnormal autonomic studies) |
TABLE 457-8 Toxic Neuropathies DRUG Misonidazole¶
Harrison's 22e, p.3609
| DRUG | MECHANISM OF NEUROTOXICITY |
CLINICAL FEATURES | NERVE HISTOPATHOLOGY | EMG/NCS |
|---|---|---|---|---|
| Misonidazole | Unknown | Painful paresthesias and loss of large- and small-fiber sensory modalities and sometimes distal weakness in length-dependent pattern |
Axonal degeneration of large, myelinated fibers; axonal swellings; segmental demyelination |
Low-amplitude or unobtainable SNAPs with normal or only slightly reduced CMAP amplitudes |
| Unknown | Painful paresthesias and loss of large- and small-fiber sensory modalities and sometimes distal weakness in length-dependent pattern |
Axonal degeneration | ||
| Chloroquine and hydroxychloroquine |
Amphiphilic properties may lead to drug-lipid complexes that are indigestible and result in accumulation of autophagic vacuoles |
Loss of large- and small-fiber sensory modalities and distal weakness in length-dependent pattern; superimposed myopathy may lead to proximal weakness |
Axonal degeneration with autophagic vacuoles in nerves as well as muscle fibers |
Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; distal denervation on EMG; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy |
| Amphiphilic properties may lead to drug-lipid complexes that are indigestible and result in accumulation of autophagic vacuoles |
Paresthesias and pain with loss of large- and small-fiber sensory modalities and distal weakness in length-dependent pattern; superimposed myopathy may lead to proximal weakness |
Axonal degeneration and segmental demyelination with myeloid inclusions in nerves and muscle fibers |
||
| Colchicine | Inhibits polymerization of tubulin in microtubules and impairs axoplasmic flow |
Numbness and paresthesias with loss of large-fiber modalities in a length- dependent fashion; superimposed myopathy may lead to proximal in addition to distal weakness |
Nerve biopsy demonstrates axonal degeneration; muscle biopsy reveals fibers with vacuoles |
Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy |
| Binds to microtubules and impairs axoplasmic flow |
Sensory loss, tingling, muscle weakness, and diminished muscle stretch reflexes in length-dependent pattern; autonomic neuropathy |
Axonal degeneration | ||
| Thalidomide | Unknown | Numbness, tingling, and burning pain and weakness in a length-dependent pattern |
Axonal degeneration; autopsy studies reveal degeneration of dorsal root ganglia |
Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes |
| Accumulation of neurofilaments and impaired axoplasmic flow |
Numbness, tingling, and burning pain in a length-dependent pattern |
Axonal degeneration with accumulation of neurofilaments in the axons |
||
| Dapsone | Unknown | Distal weakness that may progress to proximal muscles; sensory loss |
Axonal degeneration and segmental demyelination |
Low-amplitude or unobtainable CMAPs with normal or reduced SNAP amplitudes |
| Unknown | Paresthesias and numbness in a length-dependent pattern |
Unknown | ||
| Nitrofurantoin | Unknown | Numbness, painful paresthesias, and severe weakness that may resemble GBS |
Axonal degeneration; autopsy studies reveal degeneration of dorsal root ganglia and anterior horn cells |
Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes |
| Unknown | Dysesthesias and sensory ataxia; impaired large-fiber sensory modalities on examination |
Marked loss of sensory axons and cell bodies in dorsal root ganglia |
||
| Isoniazid | Inhibits pyridoxal phosphokinase leading to pyridoxine deficiency |
Dysesthesias and sensory ataxia; impaired large-fiber sensory modalities on examination |
Marked loss of sensory axons and cell bodies in dorsal root ganglia and degeneration of the dorsal columns |
Reduced amplitudes or absent SNAPs and, to a lesser extent, CMAPs |
| Unknown | Numbness with loss of large-fiber modalities on examination |
Axonal degeneration | ||
| Antinucleosides | Unknown | Dysesthesia and sensory ataxia; impaired large-fiber sensory modalities on examination |
Axonal degeneration | Reduced amplitudes or absent SNAPs |
| Unknown | Numbness with loss of large-fiber modalities on examination |
Axonal degeneration and segmental demyelination |
||
| Lithium | Unknown | Numbness with loss of large-fiber modalities on examination |
Axonal degeneration | Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes |
TABLE 457-9 Causes of Radiculopathy • Herniated nucleus pulposus • Degenerative joint disease • Rheumatoid arthritis •…¶
Harrison's 22e, p.3614
- • Herniated nucleus pulposus
• Degenerative joint disease
• Rheumatoid arthritis
• Trauma
• Vertebral body compression fracture
• Pott’s disease (tuberculosis)
• Compression by extradural mass (e.g., meningioma, metastatic tumor,
hematoma, abscess)
• Primary nerve tumor (e.g., neurofibroma, schwannoma, neurinoma)
• Carcinomatous meningitis
• Perineurial spread of tumor (e.g., prostate cancer)
• Acute inflammatory demyelinating polyradiculopathy
• Chronic inflammatory demyelinating polyradiculopathy
• Sarcoidosis
• Amyloidoma
• Diabetic radiculopathy
• Infection (Lyme disease, herpes zoster, HIV, cytomegalovirus, syphilis,
schistosomiasis, Strongyloides)
• Arachnoiditis (e.g., postsurgical)
• Radiation
TABLE 457-10 Lumbosacral Plexopathies: Etiologies • Retroperitoneal hematoma • Psoas abscess • Malignant neoplasm •…¶
Harrison's 22e, p.3616
- • Retroperitoneal hematoma
• Psoas abscess
• Malignant neoplasm
• Benign neoplasm
• Radiation
• Amyloid
• Diabetic radiculoplexus neuropathy
• Idiopathic radiculoplexus neuropathy
• Sarcoidosis
• Aortic occlusion/surgery
• Lithotomy positioning
• Hip arthroplasty
• Pelvic fracture
• Obstetric injury