The Latest Approaches in Diagnosis, Classification, and Treatment of Neurotrophic Keratitis

The Latest Approaches in Diagnosis, Classification, and Treatment of Neurotrophic Keratitis

October 20, 2022

Neurotrophic keratitis (NK) is an orphan disease, affecting fewer than 1.6 per 10,000 people. NK develops in 6.0% of patients with herpes simplex keratitis, 12.8% of patients with herpes zoster keratitis, and 2.8% of patients with postsurgi­cal nerve damage.

Taken together, there are only about 65,000 cases in the United States. However, its actual incidence is likely much higher because it’s frequently un- or misdiagnosed. Several chronic diseases, such as dry eye syndrome, exposure keratopa­thy, contact lens-related disorders, and others, may mimic NK.

Further, although expert opinions on its diagnosis and treatment have been published in the literature, no formal guidelines exist, making NK a particularly challenging eye disease. Early diagnosis and severity-based treatment are keys to recovery and preventing further corneal damage.


Defining Neurotrophic Keratitis

NK is a degenerative corneal disease in which there is damage to the trigeminal nerve that results in a loss of corneal sensation. The hallmark of NK is decreased or no sensation in the presence of corneal irregularities/damage.

This is different from neuropathic pain, in which you have a patient who is extremely symptomatic, but who has no staining on ocular surface tests, otherwise known as pain without stain.

The corneal damage and loss in sensation are the resultant breakdown of the corneal epi­thelial layer that comes with impaired corneal healing, persistent epithelial defects, corneal ulceration, stromal melting, and perfo­ration. These are the patients you remember in the middle of the night, hoping you’re treating them as best as you can.

You want to take a particular look at patients who have dry eye contact lens-related disorders, blepharitis, exposure keratopathy, stem cell deficiency, topical drug toxicity, and chemical injury because they might have concurrent disease or undiagnosed NK.

Corneal Innervation

We all know how sensitive the cornea is; in fact, it’s thought to be the most innervated tissue in the human body. The innervation pattern isn’t just for the sensation aspect, it’s critical to the maintenance of the ocular surface homeostasis, which includes tear film homeostasis as well. The corneal epithe­lial cells are in a supportive relationship with the corneal nerves.

They work together. Any deficits in either creates a feedback loop, which can make things worse. We know the corneal nerves main­tain the corneal integrity, and they cause the important protective functions like blinking. If you get something in your eye, you’re going to blink and tear, assuming those nerves can generate those signals. Also importantly, there’s trophic support, neuropeptides, substance P—all these things are floating around in the tear film and are in the tissues promoting cell proliferation, migration, and adhesion, which maintain that smooth barrier on the ocular sur­face.

If there’s damage to the corneal nerves and thereby a loss of corneal sensation, then you get a feedback loop in which you have epithelial breakdown and poor healing. The cycle continues.

The Etiology of Neurotrophic Keratitis

There are a number of things that can be related or have been shown to be associated with NK, such as herpes simplex and zoster, diabetes, and certain topical medications that are used for common conditions like glaucoma. We see a lot of diabetic eye disease in my practice.

Stepping back to think about the concurrent possibility of having NK associated with a diabetic patient is important. There can be long-standing corneal dystro­phies. Fifth-nerve palsy can lead to NK as well. You have to keep all this in the back of your mind.

If you have a new patient or you haven’t gone through his or her history with NK in mind, it may be worth revisiting some of these aspects. You can have a patient with diabetes who develops NK who also has dry eye or might be taking glaucoma medications.

Dry eye, blepharitis, topical drug toxicity, and limbal cell deficiency are just a few examples of comorbidities that can confound the diagnosis of NK and worsen the prognosis. This is why a thorough diagnostic exam and work­up, while always being considerate of some of these underlying etiologies, is very important.

To summarize, there are two different things related to the nerve malfunction, which is central to NK: impairment of trophic supply and impairment of trigeminal reflexes. Impairment of tro­phic supply leads to corneal epithelial alterations and impairment of corneal healing.

This is important because that’s what keeps the cells talking to one another and maintaining their adhesions in being able to heal themselves. Impaired trigeminal reflexes reduces tear film production and blink rate.

All these things taken together will result in corneal epithelial breakdown. That process needs to be halted so that you can return to the normal homeo­stasis, and things can begin to work together again.

Causes of impaired trigeminal nerves include strokes, brain tumors, LASIK or other ocular surgery, chronic use of topical med­ications, and corneal dystrophies. Strokes and brain tumors may not be top of mind when you’re looking at a patient with NK, but topical medication use and corneal dystrophies should be.

Clinical Presentation of Neurotrophic Keratitis

Where does NK start, and how does it evolve? Does the patient have diabetes? Have they had refractive surgery? Are they a long-time wearer of contact lenses? So many of these cases present in the practice every single day and you have to keep your mind open to some of the causes. A case his­tory is critical in triggering that thought process.

You can’t make the diagnosis unless it’s part of your differential. If you’re not thinking about it, then you’ll never make the diagnosis; it has to be top of mind. It’s a no-brainer to identify the persistent epithelial defects and the corneal ulcerations that might represent NK. But how do we identify them earlier? In addition to thinking about it, I think we need to test for it. I’ve started checking corneal sensation in every person who walks in with the potential of ocular surface disease.

Even if it’s a simple dry eye consult, we check for corneal sensation. We have to start somewhere. People just don’t walk in with a corneal ulcer, and that’s the begin­ning. The beginning is decreased sensation and the epithelium intact.

Decreased sensation is an early symptom. But, as we all know, signs and symptoms of ocular surface disease don’t always correlate. Why is that? Why do you see these corneas that are absolutely horrible and the patient doesn’t have this sensa­tion?

Their complaints are typically vision related, that they can’t get a consistent prescription. The whole idea of stain without pain is something we must keep in mind. The biggest change we’ve made within our practice is establishing what is normal versus abnormal corneal sensitivity to answer some of these questions.

Neurosensory abnormality was recently added to some definitions of ocular surface disease, which is incredibly important; it helps us understand why signs and symptoms don’t always align.

If we see any recalcitrant punctate epithelial keratopathy (PEK), that should alert us to do some tests. Because when it becomes more pronounced with a persistent epithelial defect, when we start having stromal involvement, when we start to see melting and perforations, that’s advanced NK.

We think our challenge as cli­nicians is, how early can we be on the lookout to establish this as part of the differential diagnosis?


Taking clinical history is critical to diagnosing NK. One that’s pretty obvious is someone on a prostaglandin analogue, which we know decreases some corneal sensitivity. That’s why those patients develop profound dry eye at such a high percentage.

Corneal sensitivity testing must become a routine part of our ocu­lar surface disease workup. Other diagnostics include a complete eye exam, corneal staining, corneal cultures to rule out bacterial infection, in vivo confocal microscopy, and an evaluation for auto­immune disease and other systemic immune disorders.

Of course, you’re going to look at staining, and you’re going to do some of the other tests. You may or may not want to do a Schirmer test.

Taking a good history, testing corneal sensitivity, staining, and looking at the cornea are important. When we look at NK, it really is impaired function of the fifth cranial nerve. That can happen in many different ways, but it starts with reduced corneal sensitiv­ity.

That initial phase we see may not be a persistent epithelial defect per se; it could be recalcitrant PEK that will not heal, and that patient is not responding to the typical treatment that would address that in ocular surface conditions.

When we start seeing recalcitrant PEK, we should start looking at corneal sensitivity and see if that is perhaps one of our differential diagnosis. Because if not, it will lead to that persistent epithelial defect that will not heal and eventually go on to become a corneal ulcer.

We certainly want to identify it at a much earlier stage. In the primary opto­metric practice, we’re in a perfect position to be able to identify those much earlier.

In looking at some of the facts about corneal sensation, it tends to be greatest in the central cornea. However, in elderly patients, it is more sensitive in the periphery. It does tend to drop as we get down to the limbus, and it falls with age as well.

It’s not effected by iris color, and tends to be more sensitive in the tem­poral limbus and inferior limbus. Just like all these neuropathic disorders in diabetes, we tend to see reduced corneal sensation in diabetic patients.