How does neurotrophic keratitis happen?

ByDoug Rett, OD, FAAO

Because my last post discussed herpes zoster ophthalmicus and the vaccine recently developed to fight shingles, I thought we could continue the theme this month and learn about a related disease process: neurotrophic keratitis.

I recently gave a lecture about herpetic keratitis and researched neurotrophic keratitis while preparing for it and found there was a lot I didn’t know.

Of course, we all know that herpes infection can cause decreased corneal sensitivity and that if you suspect herpes, it’s important to check corneal sensitivity. But how exactly does decreased sensitivity cause corneal problems? And how can it get so bad as some of the photos you see on an image search? I realized I only had a partial understanding of the disease process, so I thought we could dig a little deeper into it this month.

I think an apt analogy for neurotrophic keratitis is that it’s the diabetic foot ulcer of the eye. It’s a wound that starts small and superficial but then ulcerates deeper, potentially causing severe loss of tissue. Remember, it’s the corneal epithelial cells that contain the nerve endings, so it’s the epithelial cells where all of the damage starts in neurotrophic keratitis.

A decrease or lack of sensation in the corneal epithelium causes three main effects. First, the cornea is more prone to occult injury. Small abrasions that would normally prompt a trip to the eye doctor’s office – or at least some self-dosed artificial tears – go unnoticed. Second, with lack of innervation comes decrease in reflex tearing and blink rates. This does not help the first effect and makes a regular type of dry eye much worse. Punctate epithelial erosions turn into coalesced epithelial defects as the dried epithelial cells break down. Third, the healing rate of epithelial cell injury is reduced. This is the final (literal) insult to injury and has a complicated pathophysiology we’ll try to break down.

As epithelial cells die, their rate of recovery is dictated by how fast the cells can undergo mitosis. Epithelial cell mitosis (in the cornea and the skin) is reduced by cAMP (cyclic adenosine monophosphate) and increased by cGMP (cyclic guanosine monophosphate). Substances like androgens (see the article about androgens and dry eye) and prostaglandins raise cAMP levels, thus, slowing epithelial cell recovery. Substances like acetylcholine (ACh) raise cGMP levels, thus, increasing epithelial cell recovery. And ACh is derived from sensory neurons, the kind that are lost in neurotrophic keratitis.

Understanding this pathophysiology also helps us understand the pattern of ulcers from neurotrophic keratitis. If you look at those pictures in your image search of neurotrophic keratitis, you’ll see that they’re always centrally located (and often inferocentral): You don’t see any at the limbus. This is because corneal epithelial cell migration is centripetal and comes in from the limbus to the center (or, specifically, inferocentral, like we discussed in the article about amiodarone keratopathy). So a neurotrophic corneal ulcer is mostly about the inability of the cornea to fully replace the epithelial cells that die off – and not to mention they are dying off at a faster-than-normal rate given the increased dryness.

The etiologies of neurotrophic keratitis are multiple and include surgery, trauma, diabetes and even corneal dystrophies, but herpetic is the most common. Specifically, herpes zoster virus promotes more classic neurotrophic lesions than does herpes simplex virus and can even occur without history of classic viral epithelial infection. In addition, worrisomely, contact with capsaicin (the active ingredient in peppers and pepper spray) has been shown in many studies to cause neurotrophic keratitis ranging from mild to severe.

Speaking of clinical appearance, there are three stages of neurotrophic keratitis. Stage 1 shows classic dry eye findings like decreased tear break-up time and the presence of punctate epithelial erosions. In stage 2 the clinician will find an epithelial defect with a surrounding rim of loose epithelium and stromal edema. The borders of the epithelial defect in neurotrophic keratitis are almost always described as “smooth and rolled” (which will help differentiate it from the classic herpetic epithelial lesion: the dendrite). With stage 3 comes stromal lysis and the risk of corneal perforation.

Neurotrophic keratitis cases are notoriously difficult to treat and are best managed by aggressive lubrication early in the disease process, before one has to worry about stage 2 or 3. So keep neurotrophic keratitis on your differential when you have an epithelial lesion that doesn’t seem to heal like you think it should. Herpetic infection (and, thus, the risk of neurotrophic keratitis) is much more common than our patients will tell us.

Also, remember that if you diagnose neurotrophic keratitis, don’t just assume herpes and stop there. You are essentially diagnosing a weakness/palsy in the fifth cranial nerve, and further (especially adjacent) cranial nerve testing should be performed to check for other etiologies like neoplasm.

And finally, always ask about any prior herpetic infections, and never take any history of herpetic disease off the chart. Even if the infection happened years ago, risk of recurrence and risk of neurotrophic keratitis is forever with that patient.

References:

Baker KS, et al. Invest Ophthalmol Vis Sci. 1993;34:137.

Krachmer, Mannis, Holland. Cornea. 3rd ed. Mosby Elsevier. 2011

Lambiase A, et al. Ophthalmol. Vis. Sci. 2012;doi:10.1167/iovs.12-10593.

Nagano T, et al. Invest Ophthalmol Vis Sci. 2003;doi:10.1167/iovs.03-0189.

Cavanagh HD, et al. Acta Ophthalmol Suppl. 1989;192:115.