OP: Corneal Nerves

What type are the majority of nerves in the cornea? What 3 categories do these fall into? Lastly, where are they derived from?

Most are sensory:

• Mechanical

• Chemical

• Temperature

Derived from ophthalmic branch of trigeminal CN V

Where are nerves in the cornea located generally? Furthermore, where are they myelinated and where do they lose this myelination?

• Nerves only in upper 2/3

• Large % in limbus are myelinated but lose it along with perineurium in corneal stroma

What are the 4 levels of corneal innervation? Roughly how many places do cornea stroma nerves penetrate the stroma? What do they do after entering the stroma?

• Corneal innervation is organized into four levels

  • Corneal stromal nerves

  • Subepithelial nerve plexus

  • Sub-basal nerve plexus

  • Intraepithelial nerve terminals

  • Cornea stroma nerves penetrate the stroma in ~60 places

  • Branch immediately after entering stroma

How are stromal cornea nerves organized and what 2 things are they enclosed by? Where are they found within the stroma? What type of nerve endings do some have? Furthermore, what percent of them have a myelin sheath and when do they lose it? Lastly, what do they retain, lose, and what are they sometimes associated with and why?

• Organized as fascicles enclosed by a basal lamina and Schwann cells

• Stromal nerves are found exclusively in the anterior stroma

• Some stromal nerves have free nerve endings within the stroma

• 20% of stromal nerves have myelin sheath when penetrating the stroma but it is lost shortly upon entering

• Perineurium of fascicle/bundle also lost

• Retain Schwann cell sheath

• Some nerve bundles are intimately associated with keratocytes for an unknown function

What do the distal branches of stromal nerves do? Where does this phenomenon occur more frequently? What does the depth of stroma penetration correlate with as well? Explain this correlation.

• Distal branches of stromal nerves anastomose extensively

• Anastomosis occurs more frequently in the anterior 1/3rd of the central cornea

• Depth of stroma penetration roughly correlates with sensory field size/location

  • More posterior penetration = more central and larger sensory field

  • More anterior penetration = more peripheral and smaller sensory field

Where is the subepithelial nerve plexus located, where is its density the greatest, and what are the 2 anatomically distinct types of nerve bundles within it?

• Located in the anterior stroma immediately beneath Bowman’s membrane

• Density is greater in peripheral vs central cornea

• Two anatomically distinct types of nerve bundles

  • Highly anastomotic meshwork of single axons and thin nerve fascicles beneath Bowman’s layer

  • Bundles that turn 90 degrees, shed their Schwann cells, penetrate Bowman’s membrane and divide into 2-20 thinner nerve fascicles

Where does penetration of Bowman’s membrane by nerve bundles occur most?

• Penetration of Bowman’s membrane by nerve bundles occurs mostly peripherally

What happens after a nerve from the subepithelial nerve plexus penetrates Bowman’s? What does this structure go on to do? Lastly, what does this make up and what interconnects?

• Upon penetration of Bowman’s membrane a nerve fiber from the subepithelial nerve plexus divides into multiple thinner nerve fascicles

• These fascicles branch into multiple parallel daughter fascicles called an epithelial leash

• These epithelial leashes make up the sub-basal nerve plexus

• Adjacent epithelial leashes repeatedly interconnect

What pattern does the sub-basal plexus form? Where is it centered? What is it linked to? Lastly, how far can individual axons in the sub-basal plexus travel and how does the model of this plexus change?

• Sub-basal plexus forms a whorl-like spiral pattern of fibers

• Typically off center (inferior + nasal)

• Linked to basal epithelial cell homeostasis (centripetal migration of basal epithelial cells)

• Individual axons in the sub-basal plexus may travel up to 6 mm

• Plexus is constantly remodeled

What occurs in the intraepithelial nerve terminals? How many intraepithelial nerve fibers result from one sub-basal nerve fiber? How do these endings end? Lastly, what layers of the epithelium do they occur in and with which cells are they most common?

• Single horizontal sub-basal nerves split off, turn 90 degrees, and interdigitate between the basal, wing, and superficial epithelial cells

• Each sub-basal nerve fiber gives 10-20 intraepithelial nerve terminals

• Additional branching occurs

• End as free nerve endings with a bulbous morphology

• Endings occur in all layers of epithelium (most common in basal and wing cells)

What 6 things do bulbous nerve endings contain?

Bulbous nerve endings contain:

• Vesicles filled with excitatory amino acids and neuropeptides

• Mitochondria

• Glycogen particles

• Microtubules

• Neurofilaments

• Sensory ion channels

Write out the pathway of sensory neurons to the cornea.

Cells bodies of corneal sensory neurons reside in the trigeminal ganglion → project through nasociliary nerve → ciliary ganglion → long and short ciliary nerves

What are the two nuclei located in the TBNC and where are each located? What are the three sub-components of the second nucleus?

TBNC (Trigeminal brainstem nuclear complex)

• Principal nucleus (pons)

• Spinal nucleus (medulla)

  • Oralis nucleus

  • Interpolaris nucleus

  • Caudalis nucleus

Where do the nerves pass through in the cornea, limbus, conj, and palpebrae? Where do they synapse?

• Corneal

  • Nerves pass through TG

  • Synapse in caudal portion of the ipsilateral TBNC

• Limbus/conj/palpebrae

  • Nerves pass through TG

  • Synapse in principal nucleus

What are the two axons types present in the cornea and their myelination status? What about the 3 of the limbus/conj/palpebrae?

• Corneal

  • Thin myelinated alpha delta type axons

  • Unmyelinated C type axons

• Limbus/conj/palpebrae

  • Thick myelinated alpha beta

  • Thin myelinated alpha delta type axons

  • Unmyelinated C type axons

What are the three nerve fiber types present in the cornea? What structures does each innervate? What is the myelination status of each? What is the conduction velocity? Lastly, what is the type of sensation each handles?

• A beta (thick)

  • Limbus, palpebrae, conj

  • Myelinated

  • Medium

  • Touch/pressure

• A delta (thin)

  • Cornea (30%)

  • Uvea

  • Myelinated except in cornea

  • Medium

  • Touch/pressure, temperature and pain

• C (thinnest)

  • Cornea (70%)

  • Uvea

  • Non-myelinated

  • Slowest

  • Pain

What are intraepithelial nerve endings classified by? What are the 3 types and what they respond to in the cornea? How about the conjunctiva?

• Intraepithelial nerve endings can be classified by the type of stimuli to which they respond

• 3 types in the cornea

  • Polymodal nociceptors: sensitive to wide variety of sensations including the ones below

  • Mechano-receptors: sensitive to mechanical force

  • Cold thermal receptors: sensitive to temperature

• Conjunctiva

  • “all of the above”

  • Mechano-receptors: don’t necessarily cause pain

  • Polymodal-receptors

  • Pruriceptive receptors: itch receptors

What percent of the total receptors do mechano-nociceptors make up? What fiber type are they? What is their receptor field size and relative coverage of the corneal area? What causes them to fire nerve impulses? What are the 2 limits to this stimulus? Lastly, what is the threshold of activation in comparison to skin and what can this activation result in?

• Mechano-nociceptor

  • 15-20% of total

  • Alpha delta fibers

  • Large receptor field (10% of cornea area)

  • Fire a few nerve impulses with any stimulation

    • Limited ability to distinguish between strength of stimuli

    • Limited ability to distinguish between duration of stimuli

  • Threshold to activate is very low

    • 10 times lower than the skin

    • Activates at a level thought to damage cells

What % of total receptors do cold thermoreceptors make up in the cornea? What fibers do they consist of? When do they discharge, what can increase the rate of their discharge, and what can stop their discharging? Furthermore, how does their impulse frequency change with a small decrease in temperature? What is the size of their receptor field like and where are they most abundant? Lastly, what do they respond to, induce, and what are they responsible for?

• Cold thermoreceptors

  • 10-15% of total

  • Consist of both A delta and C fibers

  • Spontaneously discharges at a low rate without stimulus

    • Rate of discharge increases when <33 degrees celsius

    • Transiently stops discharging when temperature increases

  • Change impulse frequency with a small decrease

  • Small receptive fields throughout cornea; more abundant and smaller peripherally

  • Responds to evaporation and induces reflex basal tearing

  • Responsible for dry sensation

What are the 4 stimuli that activate polymodal nociceptors? What level of each stimuli activates them? How do they compare to cold thermoreceptors and mechano-nociceptors?

Polymodal nociceptors

• Activated by several types of stimuli (polymodal)

  • Heat: will fire > 39-40 celsius

  • Cold (50%): will fire < 29 celsius and less sensitive than cold thermoreceptors

  • pH: <6.5

  • Mechanical forces

    • Very low threshold, even lower than mechano-nociceptors

What % of total receptors do polymodal nociceptors make up in the cornea? What fiber type are they? What does the size of their receptive field look, how do they overlap, and how well are the stimulus localized? Furthermore, how does the discharge of nerve impulses look with a sustained stimulus, what is the firing frequency proportional to, and what two aspects of the stimulus are detected?

• 70% of total

• C type » A delta type

• Large receptive field, often 25% of cornea

  • Stimuli are poorly localized

  • Overlap with limbus/bulbar conj

• Continuous irregular discharge of nerve impulses that persist as long as the stimulus is maintained

  • Firing frequency is roughly proportional to the stimulus intensity

  • Both intensity and duration of stimulus is detected

How many different types, roughly, are there of transient receptor potential channels? What do they determine and where are they embedded?

• Many different types

• Determine the type of stimulus to which the sensory receptors respond

• Embedded in the terminal membranes of nociceptors (and other sensory nerves)

What are the 4 different stimuli that transient receptor potential channels respond to? Furthermore, what allows for determination of stimulus type?

• Different channels respond to distinct stimuli

  • Membrane stretch

  • Temperature

  • pH

  • Chemicals

    • Capsaicin/wasabi

    • Menthol/peppermint

  • Type of stimulus detection is determined by which TRPs (or other stimulus induced ion channels) are present

What does stimulus of a TRP channel cause? What does this facilitate? Lastly, what does this trigger?

• Stimulus causes conformational change in channel protein complex

• Facilitates ion transport across cell membrane

• Triggers depolarization and action potential of nerve

What tool can measure corneal sensitivity? What can it be used to diagnose? How can one measure chemical/thermal/tactile response?

Esthesiometer

• Can be used to diagnose neurotrophic keratopathy (impaired cornea innervation)

• Other esthesiometers can test chemical or thermal sensitivity, or less invasively test tactile response (air puff)

How do the following factors affect corneal sensitivity? Which are major and which are minor?

• Age

• Dry eye

• Acute inflammation

• Long term dry eye

• Refractive surgery

• Contact lens wear

• Time of day

• Iris color

• Gender

Major:

• Age: mechanical sensitivity decreases d/t decrease in nerve density

• Short term:

  • Dry eye: sensitivity increases

  • Acute inflammation: sensitivity increases

• Long term:

  • Reduces sensitivity d/t loss of nerves

  • Refractive surgery reduces sensitivity

  • Contact lens wear can reduce sensitivity

Minor:

• Time of day: lowest upon waking

• Iris color: chemical sensitivity decreases with more pigmentation

• Gender: Sensitivity is slightly greater in women than men