Peripheral neuropathy is a broad term referring to any disorder of the peripheral nerves and therefore has many causes and many interesting pathologies. As such, this is something the average neurologist sees countless times, and consequently is a high-yield topic on many examinations such as the shelf, RITE®, and board exams!

Authors: Brian Hanrahan MD, Steven Gangloff MD

Chapter Multimedia Content

Table of Contents

Table of Contents


  • Polyneuropathy is defined as a neuropathic disease that involves many nerves in a generalized distribution.
  • Causes of peripheral polyneuropathy can be either axonal and/or demyelinating.

Small fiber polyneuropathy

  • Presents with burning/tingling pain, usually felt to be more significant while trying to go to sleep.
  • Causes of small fiber neuropathy are diverse but include diabetes, B12 deficiency, chronic alcohol use, autoimmune diseases (i.e. Sjörgren syndrome), amyloidosis, chemotherapeutic agents, HIV, leprosy, and Fabry’s disease.
  • Diagnostic testing:
    • Skin biopsy to evaluate small fiber density.
    • Quantitative sudomotor axon test (QSART) to evaluate postganglionic sympathetic sudomotor axons.
      • It is abnormal in 75% of patients with distal small fiber neuropathy.
  • Patients with small fiber neuropathy can also have concurrent autonomic neuropathy.
  • Further details of small fiber neuropathy are outlined in the Pain Syndromes chapter.

Acquired Neuropathies

Systemic disease causes of neuropathy

  • Responsible for one-third of all neuropathies (most common cause).
  • Can present as a small fiber polyneuropathy, large fiber peripheral polyneuropathy, multifocal neuropathy, mononeuropathy, and/or lumbosacral plexopathy.
    • Commonly manifests as a distal symmetric polyneuropathy, typically in a “stocking-glove” distribution.
  • EMG testing will show axonal pathology.
  • Pathology: Thickened blood vessels with basement membrane reduplication.
  • Patients should be screened with a hemoglobin A1c level, fasting glucose, or a 2-hour glucose tolerance test.
  • Presents with distal axonal sensorimotor polyneuropathy which leads to limb weakness or difficulty weaning off of artificial ventilation.
  • Sepsis, SIRS, and multiorgan failure are risk factors.
    • Patients with critical illness neuropathy may also have concurrent critical illness myopathy.
  • Diagnostic studies may include EMG showing spontaneous activity (i.e. fibrillations) and nerve conduction studies (NCS) showing normal velocity and amplitude reduction.
  • Symptoms can take months to years to recover and one-third of patients never walk independently again.
  • Seen in patients with poor diets: Chronic alcoholism, post-gastric bypass, and nitrous oxide abuse.
    • Strict vegan diets may also lead to this deficiency, but this would take years to develop.
    • Other causes include atrophic gastritis, Crohn’s disease, celiac disease, and enteritis.
  • Symptoms are generally symmetrical and may present as peripheral neuropathy, subacute combined degeneration, or even neuropsychiatric conditions.
  • If B12 levels are borderline abnormal, you should check methylmalonic acid and homocysteine levels if the concern is high.
  • See the Toxicology chapter for more details.
  • Presents similarly to B12 deficiency.
  • Seen in patients with a malabsorption disorder or from excessive zinc intake.
  • May also be seen in genetic diseases such as Menke’s disease.
  • Peripheral neuropathy can be seen in patients with polyarteritis nodosa, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, giant cell arteritis, lupus, and Wegener’s granulomatosis.
  • HIV-related distal symmetric polyneuropathy is the most common neurological complication of HIV, affecting 50% of patients. 
  • Concurrent treatment with nucleoside reverse-transcriptase inhibitors (NRTIs) like didanosine, zalcitabine, and stavudine increases the risk of HIV-related neuropathy.
  • Chronic hypothyroidism can present with mono- or polyneuropathy due to compression of nerves.
  • Presents as a chronic demyelinating disorder that can be similar phenotypically to those with CIDP.
  • Seen in about 28-50% of hepatitis C patients.
  • POEMS is an acronym for Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes.
  • Occurs due to high levels of serum vascular endothelial growth factor (VEGF) and low levels of erythropoietin.
  • Patients develop a progressive symmetric, length-dependent sensorimotor polyneuropathy.
  • Organomegaly presents as hepatomegaly and/or splenomegaly.
  • Possible endocrinopathies are diabetes mellitus, hypogonadism, and hypothyroidism.
  • “M protein” represents the production of monoclonal proteins. This can be secondary to MGUS, plasmacytoma, osteolytic myeloma, and osteosclerotic myeloma.
    • Osteosclerotic and osteolytic myelomas can usually be detected on a bone survey.
  • “Skin changes” represent focal or generalized hyperpigmentation and/or skin thickening.
  • Serum levels of VEGF normalize in response to therapy.

Can be sporadic or hereditary (see familial amyloid polyneuropathy below)


Log in to View the Remaining 60-90% of Page Content!


New Subscriber? Use this form!

(Or, Click Here to learn about our institution/group pricing)
  • Full access to all site content, including a 1000+ question bank, 36 text chapters, 50 EMG cases, 550+ diagnostic images, 100+ EEGs, 850+ flashcards, "NYKN Sessions", and more!
    Full access to all site content, including a 1000+ question bank, 36 text chapters, 50 EMG cases, 550+ diagnostic images, 100+ EEGs, 850+ flashcards, "NYKN Sessions", and more!
    Full access to all site content, including a 1000+ question bank, 36 text chapters, 50 EMG cases, 550+ diagnostic images, 100+ EEGs, 850+ flashcards, "NYKN Sessions", and more!
    You have selected a Group Membership. After a successful payment you will be able to invite up to %s additional members.
    Applying discount code. Please wait...
  • Payment Details

  • Billing Details

  • If entered, this will appear on the invoice, replacing the First and Last Name.

Table of Contents

Table of Contents