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)

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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Related Studies

Ontology: Peripheral Neuropathy (C0031117)

Definition (MSHCZE) Nemoci periferního nervového systému, tzn. nemoci probíhající mimo oblast mozku a míchy, jsou sem zahrnuty nemoci nervových kořenů, ganglií, plexů, autonomních nervů, smyslových nervů a hybných nervů.
Definition (MEDLINEPLUS)

Your peripheral nerves are the ones outside your brain and spinal cord. Like static on a telephone line, peripheral nerve disorders distort or interrupt the messages between the brain and the rest of the body.

There are more than 100 kinds of peripheral nerve disorders. They can affect one nerve or many nerves. Some are the result of other diseases, like diabetic nerve problems. Others, like Guillain-Barre syndrome, happen after a virus infection. Still others are from nerve compression, like carpal tunnel syndrome or thoracic outlet syndrome. In some cases, like complex regional pain syndrome and brachial plexus injuries, the problem begins after an injury. Some people are born with peripheral nerve disorders.

Symptoms often start gradually, and then get worse. They include

  • Numbness
  • Pain
  • Burning or tingling
  • Muscle weakness
  • Sensitivity to touch

Treatment aims to treat any underlying problem, reduce pain and control symptoms.

NIH: National Institute of Neurological Disorders and Stroke

Definition (NCI) A non-neoplastic or neoplastic disorder that affects the peripheral nervous system.
Definition (MSH) Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves.
Definition (CSP) diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves.
Concepts Disease or Syndrome (T047)
MSH D010523
ICD9 350-359.99
ICD10 G64
SnomedCT 42658009, 302226006, 155064004, 264554005, 193264002, 155100008, 155080009, 267706009, 193088006
English Nerve Disease, Peripheral, Nerve Diseases, Peripheral, Peripheral Nerve Diseases, Disorders of the peripheral nervous system, PNS Diseases, Peripheral Nervous System Disease, Peripheral Nervous System Diseases, PNS Disease, NEUROPATHY PERIPHERAL, PERIPHERAL NEUROPATHY, Peripheral nervous sys.dis.NOS, Peripheral nervous system dis., Peripheral nervous system disorder NOS, Peripheral nervous system disorders, PNS DIS, PERIPHERAL NERVOUS SYSTEM DIS, PERIPHERAL NERVE DIS, PNS PERIPHERAL NERVOUS SYSTEM DIS, PN - Peripheral neuropathy, peripheral nervous system disorder, peripheral neuropathy (diagnosis), peripheral neuropathy, PNS disorder, peripheral neuropathy (physical finding), Peripheral neuropathies, PNS (Peripheral Nervous System) Diseases, Peripheral Nervous System Disorders, Neuropathy, Peripheral, Peripheral Neuropathies, Disorder of peripheral nervous system NOS, Peripheral Nervous System Diseases [Disease/Finding], Peripheral nerve disorder, Peripheral neuropathy, peripheral nerve disorder, peripheral nerve disease, peripheral nerve diseases, peripheral nerve disorders, Neuropathy;peripheral, peripheral neuropathies, Peripheral nerve disorder NOS, Peripheral neuropathy NOS, Peripheral Nerve Disorders, disorders of peripheral nervous system, disorders of peripheral nervous system (diagnosis), Peripheral nervous system disorders (disorder), Peripheral nervous system disorder NOS (disorder), Nerves, Peripheral--Diseases, Disorder of Peripheral Nervous System, Peripheral Nerve Disease, Neuropathy peripheral, Peripheral nerve disease, Disorder of the peripheral nervous system (disorder), Disorder of the peripheral nervous system, Peripheral nerve disease (disorder), neuropathy; peripheral, peripheral; nervous system, disorder, peripheral; neuropathic, Disorder of the peripheral nervous system, NOS, Peripheral nerve disorder, NOS, Peripheral neuropathy, NOS, Peripheral Nervous System Disorder, DISORDERS OF THE PERIPHERAL NERVOUS SYSTEM, Peripheral Neuropathy
Italian Neuropatia periferica, Neuropatia periferica NAS, Neuropatie periferiche, Malattie dei nervi periferici, Malattie del SNP, Malattie del sistema nervoso periferico
Dutch perifere neuropathie NAO, perifere zenuwafwijking NAO, neuropathie; perifeer, perifeer; neuropathie, perifeer; zenuwstelsel, aandoening, neuropathie perifeer, perifere neuropathieën, Neuropathie, perifere, Perifeerzenuwstelselziekte, Perifeerzenuwstelselziekten, Perifere neuropathie, Periferezenuwziekte, Ziekte, perifeerzenuwstelsel-, Ziekten, perifeerzenuwstelsel-
French Trouble nerveux périphérique SAI, Neuropathie périphérique SAI, NEUROPATHIE PERIPHERIQUE, Neuropathie périphérique, Neuropathies périphériques, Maladies du système nerveux périphérique
German periphere Neuropathie NNB, Erkrankung peripherer Nerven NNB, NEUROPATHIE PERIPHER, periphere Neuropathie, Peripheres Nervensystem, Krankheiten, Periphere Nervenkrankheiten, Periphere Neuropathien
Portuguese Afecção de nervo periférico NE, Neuropatia periférica NE, NEUROPATIA PERIFERICA, Neuropatia periférica, Neuropatias periféricas, Doenças do Sistema Nervoso Periférico, Doenças dos Nervos Periféricos, Neuropatias Periféricas
Spanish Neuropatía periférica NEOM, Alteración de un nervio periférico NEOM, NEUROPATIA PERIFERICA, enfermedad de nervio periférico (trastorno), enfermedad de nervio periférico, neuropatía periférica (trastorno), trastorno de los nervios periféricos, PN - neuropatía Periférica, trastorno del sistema nervioso periférico, SAI, trastornos del sistema nervioso periférico, trastornos del sistema nervioso periférico (trastorno), trastorno del sistema nervioso periférico, SAI (trastorno), Peripheral nervous system disorder NOS, neuropatía periférica, trastorno del sistema nervioso periférico (trastorno), trastorno del sistema nervioso periférico, Neuropatía periférica, Neuropatías periféricas, Enfermedades de los Nervios Periféricos, Enfermedades del Sistema Nervioso Periférico, Neuropatías Periféricas
Japanese 末梢神経障害NOS, マッショウシンケイショウガイNOS, マッショウセイニューロパチーNOS, 末梢性ニューロパチー, 末梢性ニューロパチーNOS, マッショウセイニューロパチー, 末梢神経系疾患, 末梢神経疾患
Swedish Perifera nervsystemets sjukdomar
Finnish Ääreishermoston sairaudet
Russian NERVNOI SISTEMY PERIFERICHESKOI BOLEZNI, NERVOV PERIFERICHESKIKH BOLEZNI, НЕРВНОЙ СИСТЕМЫ ПЕРИФЕРИЧЕСКОЙ БОЛЕЗНИ, НЕРВОВ ПЕРИФЕРИЧЕСКИХ БОЛЕЗНИ
Czech Neuropatie periferní, Periferní neuropatie NOS, Porucha periferního nervu NOS, Periferní neuropatie, periferní nervový systém - nemoci, nemoci periferního nervového systému
Croatian PERIFERNI ŽIVČANI SUSTAV, BOLESTI
Polish Neuropatie obwodowe, Choroby układu nerwowego obwodowego, Choroby nerwów obwodowych, Choroby obwodowego układu nerwowego
Hungarian Peripheriás neuropathia, Peripheriás ideg betegség k.m.n., Peripheriás neuropathiák, Peripheriás neuropathia k.m.n.
Norwegian Sykdommer i det perifere nervesystemet, Perifere nevropatier

Ontology: Neuropathy (C0442874)

Definition (CHV) nervous system disorder
Definition (CHV) nervous system disorder
Definition (CHV) nervous system disorder
Definition (NCI_NCI-GLOSS) A nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in different parts of the body. It usually begins in the hands or feet and gets worse over time. Neuropathy may be caused by physical injury, infection, toxic substances, disease (such as cancer, diabetes, kidney failure, or malnutrition), or drugs, including anticancer drugs.
Definition (NCI) A disorder affecting the cranial nerves or the peripheral nervous system. It is manifested with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.
Concepts Disease or Syndrome (T047)
ICD10 G62.9
SnomedCT 42658009, 277317008, 193167000, 277878001, 386033004, 264554005
English nerve disorders, nerve disorders (diagnosis), Neuropathy NOS, Neuropathy - (NOS), neuropathies, disorders neuropathy, neuropathy, neuropathy (diagnosis), Neuropathy (nerve damage), NEUROPATHY, Neuropathy (disorder), nerve; disorder, Neuropathy, NOS, Neuropathy
Spanish Neuropatía, Neuropatía NEOM, Neuropatía (NEOM), NEUROPATIA, neuropatía (trastorno), neuropatía
Italian Neuropatia NAS, Neuropatia, Neuropatia - (NAS)
French Neuropathie SAI, Neuropathie, NEUROPATHIE
Dutch neuropathie (NAO), neuropathie NAO, neuropathie, zenuw; aandoening
German Neuropathie, Neuropathie NNB, Neuropathie - (NNB), NEUROPATHIE
Portuguese Neuropatia, Neuropatia NE, NEUROPATIA
Japanese ニューロパチー, ニューロパチーNOS, ニューロパチー(NOS), ニューロパチー, ニューロパチーNOS
Czech Neuropatie, Neuropatie - (NOS), Neuropatie NOS
Hungarian Neuropathia, Neuropathia k.m.n., Neuropathia - (k.m.n.)