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Neuropathy

Clinical Aspects of Neuropathy
Overview
  • Affects ~ 20 million people in the US.
  • Classifications
    • Polyneuropathy (if many nerves affected)
    • Mononeuropathy (single, isolated nerves)
    • Radiculopathy (nerve roots)
  • Most common cause in the US is diabetic polyneuropathy (distal, symmetric, "dying-back neuropathy")
Physical Exam Findings
Muscle Stretch Reflexes
  • Absent/Reduced
    • In distal, symmetric polyneuropathy (most common form), ankle reflexes will be the first to be lost.
Sensation
  • Absent/Reduced
    • In distal, symmetric polyneuropathy (most common form), "there is a stocking-glove distribution pattern of sensory loss" with sensation being lost in toes, first.
Motor
  • Variable
    • In distal, symmetric polyneuropathy (most common form), since this is a "dying-back neuropathy", most common pattern of weakness is wasting/weakness at the ends of limbs (distally) that slowly works its way proximally: manifests first with changes in the feet and can lead to "neuropathic foot".
    • Prolonged, chronic neuropathy will lead to disuse atrophy.
Gait
  • Wide-based, unsteady
Etiologies
  • Physical injury
    • Trauma
    • Repetitive injury (eg, carpal tunnel syndrome: mononeuropathy of median nerve, distally)
  • Metabolic and endocrine disorders
    • Diabetes mellitus
    • Hypothyroidism
    • Hepatopathy (liver disease)
    • Growth hormone abnormalities (ie, acromegaly)
  • Vasculopathy
    • Vasculitis
    • Small vessel ischemia from diabetes
  • Autoimmune disease (chronic)
    • Sjogren’s syndrome
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
  • Autoimmune disease (acute)
    • Guillain-Barré syndrome (acute inflammatory demyelinating polyneuropathy (AIDP))
    • AIDP with progression to CIDP
  • Renal disease
  • Cancer
    • Lymphoma
    • Paraneoplastic-related neuropathy
    • Chemotherapies
  • Neuromas
  • Viruses
    • Herpes varicella zoster (shingles)
    • Human immunodeficiency virus (HIV)
    • Epstein-Barr virus
    • West Nile virus
    • Cytomegalovirus
  • Bacteria
    • Lyme disease
    • Diphtheria
    • Leprosy (key world-wide cause of neuropathy)
  • Tick-borne infection
    • Virus or Bacteria
  • Toxins
    • Medications (eg, certain chemotherapies, amiodarone, dapsone, thalidomide, INH, nitrofurantoin, hydralazine, etc...)
    • Environmental/Industrial (lead, mercury, and arsenic, insecticides, solvents)
    • Alcohol (chronic, heavy)
Recommended References:
  • https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet
  • https://www.foundationforpn.org/wp-content/uploads/2016/10/Medications-that-Can-Cause-Peripheral-Neuropathy.pdf
Histopathology of Neuropathy
Healthy Nerve
  • We show the neuron (the cell body), axon (transmits signals to/from the cell body), and nerve terminals.
  • Within the cell body, lies a nucleus and Nissl bodies, which are granular bodies that are the site of protein synthesis – we'll see how they are affected by Wallerian degeneration in a moment.
  • We draw myelin sheaths around the axon, which help increase action potential conduction speed – we address this further in the acute neuropathies tutorial.
Wallerian Degeneration
  • For Wallerian (aka anterograde) degeneration, we redraw the cell body and the myelinated proximal nerve stump.
  • Distal to this, we show that the axon has been transected.
    • This disrupts transport, causes rapid inflow of extracellular ions (most notably calcium), axonal swelling and nerve degeneration.
  • The distal portion of the axon disintegrates (is phagocytized) via Wallerian (aka anterograde) degeneration.
  • We show myelin ovoids, fragments of myelin debris, because myelin degradation quickly follows the axon disintegration.
    • Retrograde degeneration also occurs in the proximal direction to the first node of Ranvier. Retraction bulbs form at the proximal and distal stumps.
  • Now, we show that via proximodistal axon regeneration, axons sprout from the proximal nerve stump (called regenerative sprouting) to cross the transection site and then track down the distal nerve stump – we'll address this along with nerve regeneration.
  • Before that, however, the cell body switches to chromatolysis (chromatin disintegration).
    • The cell body swells; there is eccentric displacement of the nucleus; and the Nissl substance is marginalized to the periphery of the cell body.
    • Chromatolysis is a reactive state of high protein synthesis to meet the demand of axon regeneration.
Nerve Regeneration
  • We show segmental remyelination, which results in stretches of short, thin (ie, hypomyelinated) internodes.
  • The changes are segmental because many demyelinating neuropathies result in segmental damage.
Next, we illustrate axonal regeneration from regenerative sprouting:
  • Show numerous terminals coated with thin myelin sheaths – again, regenerative myelin thinner and the axon terminals are also thinner than normal.
    • We saw these sprouts emerged from the damaged proximal stump in the previous diagram. Via proximodistal advancement, they crossed the transection site, elongated through growth cone advancement to enter Schwann cell tubes and advanced distally to reinnervate the original target site.
Nerve Regeneration Details
Regeneration Timing
  • Proximodistal advancement process occurs at ~ 1mm/day (or 1 inch/month).
  • Muscle degeneration via fibrofatty transformation occurs at 20 - 24 months.
    • Thus, nerve injury that occurs > than 24 inches from the muscle will not be successful – the muscle with undergo fibrofatty transformation before the regenerated axon will reach it.
    • Also, note that reinnervation can fail from neuroma formation at the lesion site. Neuroma refers to axon tangling that occurs from fibroblast proliferation that obstructs or misdirects the regenerating axon sprouts.
    • As well, we'll see that the endoneurium (aka endoneurial tube) thickens during axon degeneration and it can unfortunately thicken to the point where the tube is too narrow for the axon to advance through it.
Classification of Nerve Injuries
Seddon Classification System of Nerve Injury
  • Neuropraxia: Focal myelin injury (myelin disruption)
Axonotmesis: Axon injury with preservation of other nerve elements (endoneurium, perineurium, and epineurium). * Wallerian degeneration and nerve regeneration occur.
  • Neurotmesis: Think – Disconnection of entire nerve (complete nerve trunk (peripheral nerve) injury) – all elements (axon, endoneurium, perineurium, and epineurium) are disconnected. Surgical repair is required.
Sunderland Classification System of Nerve Injury
  • Grades 1 – 5
    • Grade 1: Neuropraxia
    • Grade 2: Axonotmesis
    • Grade 3: Axonotmesis + Endoneurium
    • Grade 4: Axonotmesis + Endoneurium + Perineurium
    • Grade 5: Neurotmesis
Collateral Sprouting
  • Chemical signals also induce collateral sprouting from neighboring uninjured axons. If the lesion to the nerve is incomplete, meaning there are still intact axons, then collateral sprouting can occur from them to improve innervation to the denervated tissue.
  • The force the muscle can exert is a reflection of the fibers that innervate it NOT the number of axons available – thus these muscles are innervated by fewer axons but equivalent fibers, called the anterior horn cell innervation ratio.
    • On EMG, we see that these motor units are larger because they have to innervate a larger number of muscle fibers.
    • The innervation ratio can increase to 5-fold normal via collateral sprouting.
  • Via collateral sprouting, the muscle fiber pattern changes to reflect the anterior horn cells that innervate it because the fiber type is determined not by the anterior horn cell.
    • There is a loss of the normal checkerboard pattern typically seen on muscle biopsy.

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