II. Epidemiology
- Prevalence: 1-7% in general U.S. population (increased over age 50 years)
III. Pathophysiology: Injury affects one of four components
- See Neuron
-
Neuronal or Axonal Neuropathy
- Affects cell body or axon of nerve
- See Symmetric Peripheral Neuropathy (Polyneuropathy)
- See Asymmetric Peripheral Neuropathy (Mononeuropathy)
- See Peripheral Nerve Injury
- Diabetes Mellitus
- Collagen vascular disease Vasculitis
- Thyroid disease
- Vitamin Deficiency (e.g. Vitamin B12 Deficiency)
- Hereditary Neuropathy
- Demyelinating Neuropathy (Myelinopathy)
- Affects myelin swan cell sheath around axon
- Symmetric Peripheral Neuropathy (Polyneuropathy)
- Consider hereditary Neuropathy
- Asymmetric Peripheral Neuropathy (Mononeuropathy)
- Acute Demyelinating Neuropathy (e.g. Guillain Barre Syndrome)
- Chronic Inflammatory Demyelinating Polyneuropathy
- Infiltrative Neuropathy: Affects supporting tissue
- Appears similar to demyelinating Neuropathy
- Sarcoidosis
- Myelomatosis
- Amyloidosis
- Ischemic Neuropathy: Affects nerve vascular supply
- Diabetes Mellitus
- Collagen vascular disease
IV. Pathophysiology: Nerve Fiber Size
- Large Nerves
- Carry motor and sensory, as well as proprioception and vibration sense
- Small Nerves
- Carry pain and Temperature, as well as Autonomic System signals
V. History
- What is the distribution of nerve involvement?
- Symmetric: Polyneuropathy
- Usually due to systemic or hereditary condition
- Idiopathic in 20% of cases
- Asymmetric: Mononeuropathy
- Usually due to nerve compression or inflammation
- Mononeuropathy: Isolated to a single nerve
- Mononeuropathy Multiplex: >1 discrete nerve
- Symmetric: Polyneuropathy
- Is the deficit sensory, motor or sensorimotor?
- Most neuropathies affect both sensory and motor
- Pure motor or sensory seen in distal Mononeuropathy
- Is motor more than sensory involvement?
- Amyotrophic Lateral Sclerosis
- Poliomyelitis or other chronic infectious cause
- Hereditary sensorimotor Neuropathy
- Toxin exposure
- Is sensory more than motor involvement?
- Toxin exposure
- Vitamin B12 Deficiency
- Hereditary sensory Neuropathy
- Systemic condition
- Diabetes Mellitus
- Uremia
- Myelomatosis
- Dysproteinemia
- Are Cranial Nerves Involved (e.g. speech, Swallowing, facial, Tongue or neck weakness)?
- Diabetes Mellitus
- Guillain Barre Syndrome
- HIV Infection
- Lyme Disease
- Diphtheria
- Sarcoidosis
- Tumor invasion of Meninges or skull base
- Is there Autonomic Dysfunction (Orthostasis, Gastroparesis, Erectile Dysfunction, bowel or Bladder changes)?
- Amyloidosis
- Diabetes Mellitus
- Lymphoma
- Paraneoplastic syndromes
- Porphyria
- Heavy Metal Toxicity (e.g. thallium, Arsenic, Mercury Poisoning)
- Are upper extremities predominately affected?
- Amyloidosis (hereditary type II amyloid Neuropathy)
- Diabetes Mellitus
- Familial Motor Sensory Neuropathy
- Guillain Barre Syndrome
- Lead Toxicity
- Porphyria
- Vitamin B12 Deficiency
- When was the onset of symptoms?
- Acute over hours or days
- Consider Trauma, ischemia, Vasculitis
- Motor Neuropathy most common
- See Acute Motor Weakness Causes
- Acute motor loss is risk for Respiratory Failure (e.g. Guillain Barre Syndrome)
- Requires urgent evaluation
- Sensory Neuropathy: Herpes Zoster
- Subacute over days to weeks
- Chronic over months to years
- Accounts for most cases of Neuropathy
- Consider Medication Causes of Neuropathy, and metabolic disorders
- Acute over hours or days
- Other related history
- Infectious Disease Risks
- HIV Infection risks
- Lyme Disease risks
- Medications
- See Medication Causes of Neuropathy
- Also review herbal use
- Family History
- Neurologic disorders (familial Neuropathy) or skeletal deformity
- Exposures
- Travel History
- Work exposure (e.g. Heavy Metal exposure)
- Recent Immunizations (e.g. Guillain Barre Syndrome associations)
- Past Medical History
- Infectious Disease Risks
VI. Exam
- Perform thorough exam
- Complete Neurologic Exam
- Evaluate for common compression neuropathies (e.g. sciatic nerve, lateral femoral cutaneous, Median Nerve)
- Include vibratory Sensation (128 Hz tuning fork) and monofilament (10-g)
- Cardiopulmonary exam
- Skin Exam
VII. Signs: Sensory
- Pathognomonic neuropathic findings
- Allodynia (pain from non-painful stimulus - such as light touch)
- Hyperalgesia (excessive pain from a painful stimulus)
- Demyelinating or infiltrative Neuropathy
- Loss of vibration sense
- Loss of joint position sense
- Loss of tactile discrimination
-
Axonal Neuropathy
- Sensory modes affected equivalently
- Neuropathy begins distally and moves proximally
- Injured Nerve Cell body cannot pump to axon end
- Results in stocking-and-glove distribution
- Long axons (e.g. legs) lose distal function first
- First: Sensory loss begins in feet
- Next: Deficit progresses proximally to knees
- Next: Hands begin to lose Sensation
- Face is rarely affected (generally short axons)
VIII. Signs: Motor
- Demyelinating or infiltrative Neuropathy
- Early loss of Deep Tendon Reflexes
- Sensory often affected more than motor function
-
Axonal Neuropathy
- Initial: Damage to anterior horn cell at spinal cord
- Weakness
- Muscle wasting
- Muscle Fasciculations
- Later
- Deep Tendon Reflex loss in chronic Neuropathy
- Demyelination may occur secondary to axonal loss
- Differentiate from primary demyelination as above
- Motor loss follows same pattern as for sensory loss
- Distal affected before proximal involvement
- Initial: Damage to anterior horn cell at spinal cord
IX. Causes
- See Medication Causes of Neuropathy
- See Symmetric Peripheral Neuropathy (Polyneuropathy)
- See Asymmetric Peripheral Neuropathy (Mononeuropathy)
- Most common causes
- Idiopathic in >25% of cases
- Diabetes Mellitus (25-50% of diabetic patients)
- Alcoholic Neuropathy
- Nerve compression or injury
- Toxin exposure
- Hereditary Neuropathy causes
- Nutritional Deficiency (e.g. Vitamin B12 Deficiency)
- Painful Neuropathy causes
- Alcoholic Neuropathy
- Amyloidosis
- Chemotherapy
- Diabetic Neuropathy (25-50% of diabetic patients)
- Porphyria
- Neuropathy with autonomic findings
- All painful neuropathies also cause autonomic features
- Paraneoplastic syndrome
- Heavy Metal Toxicity
- Vitamin B12 Deficiency
X. Differential Diagnosis
- Upper Motor Neuron or Central Nervous System disorder
- Myelopathy
- Spinal Cord Syndromes (e.g. syringmyelia, Trauma, Tabes Dorsalis)
XI. Labs: Initial
- Complete Blood Count (CBC)
- Comprehensive metabolic panel (includes Electrolytes, Liver Function Tests, Renal Function tests)
- Erythrocyte Sedimentation Rate or C-Reactive Protein (C-RP)
- Fasting Blood Glucose (or Hemoglobin A1C)
- Thyroid Stimulating Hormone
- Serum Vitamin B12
XII. Labs: Axonal Neuropathy Suspected
- First-line
- Hemoglobin A1C
- HIV Test
- Lyme Antibody test
- Rapid Plasma Reagin (RPR) or VDRL
- Antinuclear Antibody (ANA)
- P-ANCA and C-ANCA
- Second-line (if first-line tests negative or suggest additional specific testing)
- Serum Protein Electrophoresis (SPEP)
- Urine Protein Electrophoresis (UPEP)
- Urine 24 hour collection for Heavy Metals and porphyria
- Paraneoplastic syndrome testing
XIII. Diagnostics
- Indications
- Testing indicated if persistent symptoms or unclear etiology
- Distinguishes axonal and demyelinating types of Peripheral Neuropathy
-
General
- EMG and NCS used in combination
- Differentiate axonal from myelin-infiltrative cause
- See Nerve Conduction Velocity for Interpretation
- Nerve and Muscle Transmission
- Indications
- Nondiagnostic workup for persistent Neuropathy
- Demyelinating condition suspected
- Acute asymmetric, motor or Autonomic Neuropathy
- Needle Electromyography (EMG)
- Nerve Conduction Studies (Nerve Conduction Velocity, NCS)
- Indications
- Nerve biopsy
- Vasculitis
- Amyloidosis
- Sarcoidosis
- Leukodystrophy
- Chronic Inflammatory demyelinating Neuropathy
- Additional studies (not commonly indicated)
XIV. Evaluation
- Obtain initial labs above
- Treat specific evident causes (e.g. Diabetic Neuropathy)
- If symptoms persist, obtain diagnostic studies above
- Type of Neuropathy based on EMG
- Axonal
- Consider second-line and third-line lab testing as listed above
- Demyelinating
- Uniform: Hereditary Neuropathy
- Nonuniform
- Acute: Guillain-Barre Syndrome
- Subacute or Chronic: Chronic Inflammatory Demyelinating Polyneuropathy
- Axonal
XV. Precautions: Red Flags
- Progressive ascending weakness (risk of Respiratory Failure, e.g. Guillain Barre Syndrome)
-
Central Nervous System Lesion Symptoms
- Altered speech or Swallowing
- Ataxia or Double Vision
- Hemiparesis or Hemiplegia
- Altered bowel or Bladder function (new retention or Incontinence)
- Cranial Nerve Deficit
XVI. Management
- Neurology Consultation indications
- Nondiagnostic Neuropathy evaluation
- Acute or subacute, severe or progressive Neuropathy
- Polyneuropathy or multifocal Neuropathy
- Pure motor Neuropathy
- Autonomic Neuropathy
-
General Measures
- Neuropathic pain tends to be worse at night (when less distracted or trying to initiate sleep)
- Consider physical therapy
- Weight loss
- Eliminate provocative activities (e.g. Compression Neuropathy, poor footwear)
- Non-specific measures
- Warm soaks
- Moisturizing rubs
- Desensitizing massage
- First-line medications: Tricyclic Antidepressants (NNT 3-4)
- Desipramine
- Amitriptyline or Nortriptyline
- Start at 10-30 mg at bedtime
- Goal dose 75-100 mg nightly
- Second-line medications: SNRI (NNT 6-7)
- Duloxetine (Cymbalta)
- Goal dose 60 mg daily
- Venlafaxine
- Duloxetine (Cymbalta)
- Third-line medications (NNT 7-8)
- Gabapentin (Neurontin)
- Goal dose 1800-3600 daily divided three times daily
- Pregabalin (Lyrica)
- Goal dose 300-600 mg daily divided twice daily
- Gabapentin (Neurontin)
- Additional measures
- Consider combining medications listed above
- Lidocaine Patch
- Other medications (typically started by neurology)
- Lamotrigine
- Topomax
- Carbamazepine
XVII. References
- Gallagher in Marx (2002) Rosen's Emergency Med, p. 1506
- Pryse-Phillips in Noble (2001) Primary Care, p. 1579
- Azhary (2010) Am Fam Physician 81(7): 887-92 [PubMed]
- Castelli (2020) Am Fam Physician 102(12): 732-9 [PubMed]
- Finnerup (2015) Lancet Neurol 14(2): 162–73 [PubMed]
- Hughes (2002) BMJ 324(7335): 466-9 [PubMed]