Peripheral Neuropathy

Aka: Peripheral Neuropathy, Neuropathy

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II. Epidemiology

  1. Prevalence: 1-7% in general U.S. population (increased over age 50 years)

III. Pathophysiology: Injury affects one of four components

  1. See Neuron
  2. Neuronal or Axonal Neuropathy
    1. Affects cell body or axon of nerve
    2. See Symmetric Peripheral Neuropathy (Polyneuropathy)
    3. See Asymmetric Peripheral Neuropathy (Mononeuropathy)
    4. See Peripheral Nerve Injury
    5. Diabetes Mellitus
    6. Collagen vascular disease Vasculitis
    7. Thyroid disease
    8. Vitamin Deficiency (e.g. Vitamin B12 Deficiency)
    9. Hereditary Neuropathy
  3. Demyelinating Neuropathy (Myelinopathy)
    1. Affects myelin swan cell sheath around axon
    2. Symmetric Peripheral Neuropathy (Polyneuropathy)
      1. Consider hereditary Neuropathy
    3. Asymmetric Peripheral Neuropathy (Mononeuropathy)
      1. Acute Demyelinating Neuropathy (e.g. Guillain Barre Syndrome)
      2. Chronic Inflammatory Demyelinating Polyneuropathy
  4. Infiltrative Neuropathy: Affects supporting tissue
    1. Appears similar to demyelinating Neuropathy
    2. Sarcoidosis
    3. Myelomatosis
    4. Amyloidosis
  5. Ischemic Neuropathy: Affects nerve vascular supply
    1. Diabetes Mellitus
    2. Collagen vascular disease

IV. Pathophysiology: Nerve Fiber Size

  1. Large Nerves
    1. Carry motor and sensory, as well as proprioception and vibration sense
  2. Small Nerves
    1. Carry pain and Temperature, as well as Autonomic System signals

V. History

  1. What is the distribution of nerve involvement?
    1. Symmetric: Polyneuropathy
      1. Usually due to systemic or hereditary condition
      2. Idiopathic in 20% of cases
    2. Asymmetric: Mononeuropathy
      1. Usually due to nerve compression or inflammation
      2. Mononeuropathy: Isolated to a single nerve
      3. Mononeuropathy Multiplex: >1 discrete nerve
  2. Is the deficit sensory, motor or sensorimotor?
    1. Most neuropathies affect both sensory and motor
    2. Pure motor or sensory seen in distal Mononeuropathy
    3. Is motor more than sensory involvement?
      1. Amyotrophic Lateral Sclerosis
      2. Poliomyelitis or other chronic infectious cause
      3. Hereditary sensorimotor Neuropathy
      4. Toxin exposure
    4. Is sensory more than motor involvement?
      1. Toxin exposure
      2. Vitamin B12 Deficiency
      3. Hereditary sensory Neuropathy
      4. Systemic condition
        1. Diabetes Mellitus
        2. Uremia
        3. Myelomatosis
        4. Dysproteinemia
  3. Are Cranial Nerves Involved (e.g. speech, Swallowing, facial, Tongue or neck weakness)?
    1. Diabetes Mellitus
    2. Guillain Barre Syndrome
    3. HIV Infection
    4. Lyme Disease
    5. Diphtheria
    6. Sarcoidosis
    7. Tumor invasion of Meninges or skull base
  4. Is there Autonomic Dysfunction (Orthostasis, Gastroparesis, Erectile Dysfunction, bowel or Bladder changes)?
    1. Amyloidosis
    2. Diabetes Mellitus
    3. Lymphoma
    4. Paraneoplastic syndromes
    5. Porphyria
    6. Heavy Metal Toxicity (e.g. thallium, Arsenic, Mercury Poisoning)
  5. Are upper extremities predominately affected?
    1. Amyloidosis (hereditary type II amyloid Neuropathy)
    2. Diabetes Mellitus
    3. Familial Motor Sensory Neuropathy
    4. Guillain Barre Syndrome
    5. Lead Toxicity
    6. Porphyria
    7. Vitamin B12 Deficiency
  6. When was the onset of symptoms?
    1. Acute over hours or days
      1. Consider Trauma, ischemia, Vasculitis
      2. Motor Neuropathy most common
        1. See Acute Motor Weakness Causes
        2. Acute motor loss is risk for Respiratory Failure (e.g. Guillain Barre Syndrome)
        3. Requires urgent evaluation
      3. Sensory Neuropathy: Herpes Zoster
    2. Subacute over days to weeks
    3. Chronic over months to years
      1. Accounts for most cases of Neuropathy
      2. Consider Medication Causes of Neuropathy, and metabolic disorders
  7. Other related history
    1. Infectious Disease Risks
      1. HIV Infection risks
      2. Lyme Disease risks
    2. Medications
      1. See Medication Causes of Neuropathy
      2. Also review herbal use
    3. Family History
      1. Neurologic disorders (familial Neuropathy) or skeletal deformity
    4. Exposures
      1. Travel History
      2. Work exposure (e.g. Heavy Metal exposure)
      3. Recent Immunizations (e.g. Guillain Barre Syndrome associations)
    5. Past Medical History
      1. Diabetes Mellitus
      2. Vitamin Deficiency risks (e.g. Vitamin B12 Deficiency)
      3. Connective Tissue Disorders, Rheumatologic Disorders or Vasculitis (e.g. Rheumatoid Arthritis, Sarcoidosis)
    6. New bowel and Bladder dysfunction (e.g. Incontinence, retention)
      1. Associated with central Neuropathy causes (e.g. Cauda Equina Syndrome)

VI. Exam

  1. Perform thorough evaluation, including cardiopulmonary exam and skin exam
  2. Complete Neurologic Exam (see specific signs below)
    1. See Neurologic Exam
    2. See Sensory Exam
    3. See Motor Exam
    4. See Deep Tendon Reflex

VII. Signs: Sensory

  1. Specific Sensory Exam features
    1. Evaluate for common compression neuropathies (e.g. sciatic nerve, lateral femoral cutaneous, Median Nerve)
    2. Identify affected Dermatome(s) including over the trunk, comparing to the opposite side
    3. Include vibratory Sensation (128 Hz tuning fork) and monofilament (10-g)
  2. Pathognomonic neuropathic findings
    1. Allodynia (pain from non-painful stimulus - such as light touch)
    2. Hyperalgesia (excessive pain from a painful stimulus)
  3. Demyelinating or infiltrative Neuropathy
    1. Loss of vibration sense
    2. Loss of joint position sense
    3. Loss of tactile discrimination
  4. Axonal Neuropathy
    1. Sensory modes affected equivalently
    2. Neuropathy begins distally and moves proximally
    3. Injured Nerve Cell body cannot pump to axon end
    4. Results in stocking-and-glove distribution
    5. Long axons (e.g. legs) lose distal function first
      1. First: Sensory loss begins in feet
      2. Next: Deficit progresses proximally to knees
      3. Next: Hands begin to lose Sensation
      4. Face is rarely affected (generally short axons)

VIII. Signs: Motor

  1. Specific Motor Exam features
    1. Stand-Squat-Stand with arms flexed forward in front
      1. Identifies subtle proximal Muscle Weakness
    2. Unilateral heal raise (arms against wall for support)
      1. Identifies subtle calf weakness
  2. Demyelinating or infiltrative Neuropathy
    1. Early loss of Deep Tendon Reflexes
    2. Sensory often affected more than motor function
  3. Axonal Neuropathy
    1. Initial: Damage to anterior horn cell at spinal cord
      1. Weakness
      2. Muscle wasting
      3. Muscle Fasciculations
    2. Later
      1. Deep Tendon Reflex loss in chronic Neuropathy
      2. Demyelination may occur secondary to axonal loss
        1. Differentiate from primary demyelination as above
    3. Motor loss follows same pattern as for sensory loss
      1. Distal affected before proximal involvement

IX. Causes

  1. See Medication Causes of Neuropathy
  2. See Symmetric Peripheral Neuropathy (Polyneuropathy)
  3. See Asymmetric Peripheral Neuropathy (Mononeuropathy)
  4. Most common causes
    1. Idiopathic in >25% of cases
    2. Diabetes Mellitus (25-50% of diabetic patients)
    3. Alcoholic Neuropathy
    4. Nerve compression or injury
    5. Toxin exposure
    6. Hereditary Neuropathy causes
    7. Nutritional Deficiency (e.g. Vitamin B12 Deficiency)
  5. Painful Neuropathy causes
    1. Alcoholic Neuropathy
    2. Amyloidosis
    3. Chemotherapy
      1. See Medication Causes of Neuropathy
    4. Diabetic Neuropathy (25-50% of diabetic patients)
    5. Porphyria
  6. Neuropathy with autonomic findings
    1. All painful neuropathies also cause autonomic features
    2. Paraneoplastic syndrome
    3. Heavy Metal Toxicity
    4. Vitamin B12 Deficiency

X. Differential Diagnosis: Central Neuropathy

  1. Central Neuropathy causes
    1. Myelopathy
    2. Spinal Cord Syndromes (e.g. syringmyelia, Trauma, Tabes Dorsalis)
    3. Upper Motor Neuron or Central Nervous System disorder
    4. Cerebrovascular Accident
  2. Findings that may distinguish central Neuropathy (from Peripheral Neuropathy)
    1. Bilateral sensory deficits with multiple Dermatomes affected
    2. Motor deficits are often bilateral (below the level of the lesion)
    3. Upper Motor Neuron Deficit (spasticity, hyperreflexia, Clonus)
    4. Bowel and Bladder dysfunction may be present (e.g. Cauda Equina Syndrome)
    5. Loss of Sensation rather than the altered Sensation of Peripheral Neuropathy (hyperesthesia, Paresthesia)

XI. Labs: Initial

  1. Complete Blood Count (CBC)
  2. Comprehensive metabolic panel (includes Electrolytes, Liver Function Tests, Renal Function tests)
  3. Erythrocyte Sedimentation Rate or C-Reactive Protein (C-RP)
  4. Fasting Blood Glucose (or Hemoglobin A1C)
  5. Thyroid Stimulating Hormone
  6. Serum Vitamin B12

XII. Labs: Axonal Neuropathy Suspected

  1. First-line
    1. Hemoglobin A1C
    2. HIV Test
    3. Lyme Antibody test
    4. Rapid Plasma Reagin (RPR) or VDRL
    5. Antinuclear Antibody (ANA)
    6. P-ANCA and C-ANCA
  2. Second-line (if first-line tests negative or suggest additional specific testing)
    1. Serum Protein Electrophoresis (SPEP)
    2. Urine Protein Electrophoresis (UPEP)
    3. Urine 24 hour collection for Heavy Metals and porphyria
    4. Paraneoplastic syndrome testing

XIII. Diagnostics

  1. Indications
    1. Testing indicated if persistent symptoms or unclear etiology
    2. Distinguishes axonal and demyelinating types of Peripheral Neuropathy
  2. General
    1. EMG and NCS used in combination
    2. Differentiate axonal from myelin-infiltrative cause
    3. See Nerve Conduction Velocity for Interpretation
  3. Nerve and Muscle Transmission
    1. Indications
      1. Nondiagnostic workup for persistent Neuropathy
      2. Demyelinating condition suspected
      3. Acute asymmetric, motor or Autonomic Neuropathy
    2. Needle Electromyography (EMG)
    3. Nerve Conduction Studies (Nerve Conduction Velocity, NCS)
  4. Nerve biopsy
    1. Vasculitis
    2. Amyloidosis
    3. Sarcoidosis
    4. Leukodystrophy
    5. Chronic Inflammatory demyelinating Neuropathy
  5. Additional studies (not commonly indicated)
    1. MRI Brain
    2. Lumbar Puncture

XIV. Evaluation

  1. Obtain initial labs above
  2. Treat specific evident causes (e.g. Diabetic Neuropathy)
  3. If symptoms persist, obtain diagnostic studies above
  4. Type of Neuropathy based on EMG
    1. Axonal
      1. Consider second-line and third-line lab testing as listed above
    2. Demyelinating
      1. Uniform: Hereditary Neuropathy
      2. Nonuniform
        1. Acute: Guillain-Barre Syndrome
        2. Subacute or Chronic: Chronic Inflammatory Demyelinating Polyneuropathy

XV. Precautions: Red Flags

  1. Progressive ascending weakness (risk of Respiratory Failure, e.g. Guillain Barre Syndrome)
  2. Central Nervous System Lesion Symptoms
    1. Altered speech or Swallowing
    2. Ataxia or Double Vision
    3. Hemiparesis or Hemiplegia
    4. Altered bowel or Bladder function (new retention or Incontinence)
    5. Cranial Nerve Deficit

XVI. Management

  1. Neurology Consultation indications
    1. Nondiagnostic Neuropathy evaluation
    2. Acute or subacute, severe or progressive Neuropathy
    3. Polyneuropathy or multifocal Neuropathy
    4. Pure motor Neuropathy
    5. Autonomic Neuropathy
  2. General Measures
    1. Neuropathic pain tends to be worse at night (when less distracted or trying to initiate sleep)
    2. Consider physical therapy
    3. Weight loss
    4. Eliminate provocative activities (e.g. Compression Neuropathy, poor footwear)
    5. Non-specific measures
      1. Warm soaks
      2. Moisturizing rubs
      3. Desensitizing massage
  3. First-line medications: Tricyclic Antidepressants (NNT 3-4)
    1. Desipramine
    2. Amitriptyline or Nortriptyline
      1. Start at 10-30 mg at bedtime
      2. Goal dose 75-100 mg nightly
  4. Second-line medications: SNRI (NNT 6-7)
    1. Duloxetine (Cymbalta)
      1. Goal dose 60 mg daily
    2. Venlafaxine
  5. Third-line medications (NNT 7-8)
    1. Gabapentin (Neurontin)
      1. Goal dose 1800-3600 daily divided three times daily
    2. Pregabalin (Lyrica)
      1. Goal dose 300-600 mg daily divided twice daily
  6. Additional measures
    1. Consider combining medications listed above
    2. Lidocaine Patch
  7. Other medications (typically started by neurology)
    1. Lamotrigine
    2. Topomax
    3. Carbamazepine

XVII. References

  1. Della-Giustina (2024) Crit Dec Emerg Med 38(10): 27-34
  2. Gallagher in Marx (2002) Rosen's Emergency Med, p. 1506
  3. Pryse-Phillips in Noble (2001) Primary Care, p. 1579
  4. Azhary (2010) Am Fam Physician 81(7): 887-92 [PubMed]
  5. Castelli (2020) Am Fam Physician 102(12): 732-9 [PubMed]
  6. Finnerup (2015) Lancet Neurol 14(2): 162–73 [PubMed]
  7. Hughes (2002) BMJ 324(7335): 466-9 [PubMed]

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