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All About Neurotrophic Keratitis

June 28, 2022

Neurotrophic keratitis is a degenerative corneal disease caused by impairment of corneal sensory innervation.

It is characterized by decreased or absent corneal sensation, leading to epithelial breakdown, impairment of healing, and ultimately to the development of corneal ulceration, melting and perforation.

The cornea is the clear (transparent) outer layer of the eye. It functions like a window that focuses the entry of light into the eye.

The cornea bends light allowing it to pass through the pupil of the eye, eventually reaching the retina, where specialized cells called cones and rods convert light to nerve impulses. These impulses travel along the optic nerve to the brain to become images.

Neurotrophic keratitis is caused when the nerves that serve (innervate) the cornea cannot function properly; these nerves carry impulses that help the cornea function. Neurotrophic keratitis causes reduced sensitivity of the cornea.

When the cornea senses stimulation or pressure, the eyelids will close and tears will be produced to protect the cornea and the eye. Because these nerves do not function properly in neurotrophic keratitis, the outer layer of the cornea, called the epithelium, can break down, resulting in an epithelial defect.

In more advanced neurotrophic keratitis, an interior layer called the cornea stroma can break down as well, resulting in thinning of the cornea.

Neurotrophic Keratitis is the impairment of corneal trigeminal innervation, which disrupts ocular surface homeostasis. It is classically defined by absence of pain, due to the abnormalities in the trigeminal pathway that has caused an interruption in corneal hemostasis.

In a healthy eye that has a normal ocular surface, motor nerves control blinking, and the autonomic system controls the release of neuromodulators that stimulate tear production through a feedback loop that maintains a healthy ocular surface barrier.

Ultimately, corneal epithelial integrity is disrupted in NK, resulting in an interruption in the barrier to the underlying tissue. The condition is staged according to the Mackie classification system for the purpose of determining the most appropriate treatment protocol.

• Stage 1 NK (mild). This is the most common, and is characterized by the presence of punctate epithelial keratopathy or erosions.

It may occur in a diffuse pattern, such as is seen in Sjögren’s syndrome or graft-versus-host disease, or it may be localized to the inferior portion of the cornea, as we may see in patients who have lagophthalmos after a Bell’s palsy or in Parkinson’s disease, in which the patient’s poor blink response leads to corneal breakdown.

• Stage 2 NK (moderate). This stage of the condition is characterized by the presence of a persistent epithelial defect, as we may see after a patient has undergone multiple ocular surgeries.

• Stage 3 NK (severe). This is characterized by a corneal ulcer that has stromal involvement and thinning.

This stage is dangerous, as it has a significant risk of progression to corneal perforation or infection. Specifically, the underlying stroma can progressively deteriorate without the protective barrier provided by an intact epithelium.

Neurotrophic keratitis (NK) is a challenging condition to diagnose and treat. For one, patients who have it seldom complain of any symptoms. For another, it is a degenerative condition that can alter corneal healing and cause vision loss.  

Due to a recent expanding array of treatment options and, therefore, a focus on clinician education, there has been an increased awareness of NK.

In an effort to keep the condition on our diagnostic radar, here we discuss the evidence needed for a definitive diagnosis and the current treatment options available to rehabilitate the ocular surface in these patients.

The Evidence Needed

The evidence that leads to a definitive diagnosis of NK is:

• Symptoms. A lack of corneal sensation tends to negate symptoms in these patients. That said, these patients may complain of blurry vision, resulting from corneal edema, the irregular epithelium, persistent epithelial corneal defects, or corneal scarring.

• Patient history. NK is the end result of a variety of conditions that may work alone or in concert to disrupt the ocular surface.

Identifying NK’s underlying cause is the key to initiation of treatment. The most common etiologies include herpes simplex keratitis, toxicity from the long-term use of ophthalmic drops (e.g., preserved glaucoma drops, artificial tears, etc.), long-term contact lens wear, or a history of ocular surgery (e.g., corneal refractive surgery, retinal or glaucoma surgery, or multiple ocular procedures).

Many of these conditions develop gradually over several years, during which time the NK is not recognized or treated adequately.

Oftentimes, the condition is even exacerbated by attempted treatments, such as the use of further preserved OTC lubricant drops or continued insult by the inciting cause.

• Slit lamp exam. A thorough slit lamp examination, including fluorescein staining, aids in determining whether there is a disruption of the corneal epithelium, and defining the stage of the NK. It is famously said that NK causes “stain without pain.”

• Corneal sensation assessment. In the past, we think many of us were inattentive to NK. Today, however, we feel we are collectively doing a much better job of evaluating corneal sensation during exams, as we now realize the lack of corneal sensation in these patients often precludes them from seeing us at the outset.

The easiest ways to test corneal sensitivity include the use of a cotton wisp from a sterile swab, or from a strand of dental floss.

Alternatively, there are more standardized ways to assess corneal sensitivity, such as via a handheld aesthesiometer, like the Cochet-Bonnet aesthesiometer, (however this is rarely available, or utilized in standard clinical practice).

Something else to keep in mind: Since most cases of NK are unilateral, the patient’s other eye can serve as a built-in control for comparison, and the patient can also self-report the difference during the test.

However, there are some rare systemic bilateral etiologies, such as diabetes or multiple sclerosis, in which there is no patientspecific control.

A caveat: Anesthetic and dilating drops, often instilled in the patient by the technician prior to the doctor seeing the patient, will nullify the results of corneal sensitivity testing, so the patient should be scheduled for a follow-up visit during which they receive no anesthetic or dilating drops before seeing the physician.

Though some doctors test only centrally, it can be helpful to test in the 5 zones (central, superior, inferior, temporal, and nasal), as doing so documents the severity of the NK, and helps track response to treatment.

In addition, it is easy to document whether sensation is absent, normal, or diminished in each of the 5 zones.

Rehabilitating the Ocular Surface

Ideally, the patient should be treated as early as possible in the disease process to avoid permanent, visually debilitating consequences. There are a variety of treatment options available for NK.

The protocol is to treat the cause of the patient’s NK, any underlying dry eye disease (DED), and the effect of the NK itself:

• Treatments for causes. A common condition that results in NK is herpetic keratitis. Once this disease is brought under control with the use of oral and/or topical antivirals, the patient may require topical steroids, and aggressive lubrication with preservative-free artificial tears for the NK itself.

In another case, the underlying cause may be a systemic condition, such as graft-versus-host disease (GVHD), systemic lupus or multiple sclerosis, which may require treatment with oral steroids.

In still other incidences of NK, the removal of an inciting toxic agent (such as a glaucoma drop) may be a key component of the treatment regimen.

Should the patient have lagophthalmos, or incomplete or absent blink response, lid interventions, including tape tarsorrhaphies, temporary suture tarsorrhaphies, or permanent tarsorrhaphies, can be an integral component of the treatment, and healing process.

This is because NK can be worse in such patients due to this very significant comorbidity. The take home message: The lid architecture and position should always be thoroughly evaluated in these patients.

• Treatments for underlying DED. I have prescribed inflammatory inhibitors to stabilize any underlying DED condition, as doing so helps improve the ocular surface, which facilitates treatment of the NK.

(We need to remember that many of our NK patients have other comorbid ocular conditions, such as DED and glaucoma, that complicate the disease course.)

Additionally, punctal plugs, a dissolvable punctal insert, in-office lid treatment procedures, intense pulsed light, and ocular nutritional supplements may be used to help control concomitant ocular surface disease.

• Treatments for NK itself. The following are available: A. Artificial tears/gels and ointments: Aggressive (6 to 8 times a day, or more) lubrication with preservative-free artificial tears of increasing viscosity improves ocular surface protection.

Thick gels and ointments can help provide a barrier to environmental insults. B. Amniotic membranes: These contain anti-microbial and antiinflammatory properties, and low immunogenicity.

C. Contact lenses: While wearing contact lenses can cause NK, various types of extended-wear contact lenses are useful in protecting the ocular surface and temporizing the situation, while other treatments are taking effect.

Also, bandage lenses can be used in conjunction with dried amniotic membranes and antibiotic drops to provide a matrix for healing. For long-term NK conditions that often may be associated with chronic systemic and/or ocular diseases, such as GVHD and Sjögren’s syndrome, respectively, scleral contact lenses are a very helpful adjunct to care.

This is because they vault the corneal surface, and provide a lens fluid reservoir that constantly lubricates the ocular surface.

D. Topical steroids: These are often an essential tool in advanced stages of NK. Of course, while topical steroids can be a tremendous tool in managing inflammation in these patients, they may be associated with corneal thinning, cataract formation, and elevations in IOP with long-term use.

Therefore, low-dose preservative-free steroids should be considered in stabilizing disease progression in these patients.

E. Autologous serum tears: Autologous serum contains proteins (lysozyme, lactoferrin, albumin, and immunoglobulins), growth factors (epidermal growth factor), vitamins A and C, antioxidants, and electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium).

The mechanism of action of autologous serum eye drops is to mimic the biochemical properties of natural basal tears (but in a highly concentrated form) to heal the ocular surface epithelium. These tears can be used alone, or placed within the reservoir of a scleral lens to facilitate healing.

F. Cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL): Known as Oxervate (Dompé), this is a recombinant human nerve growth factor in the form of a topical agent dosed 6 times a day for an 8-week course.

Oxervate was approved in August 2018 as an orphan drug for NK. Oxervate was shown safe and effective in the corneal healing of moderate-tosevere NK.

G. Antibiotic drops: NK patients are at risk for developing bacterial superinfections due to their epithelial defect creating a break-down of the natural barrier to microorganisms. For this reason, it is often helpful to protect the patient with a topical antibiotic drop.

Given the lack of sensation in these cases, an infection could easily go undiagnosed until it is advanced due to the lack of symptoms.

 Conjunctival flap/Gunderson flap with/without a tarsorrhaphy: In severe cases in which corneal thinning is more advanced, and potentially associated with a risk of perforation, the ocular surface may be stabilized by advancement of the perilimbal conjunctiva over the corneal surface.

A temporary or permanent tarsorrhaphy is a helpful adjunct in such advanced cases. Getting a Head Start NK may be more common than initially thought, thanks to a fresh focus on the condition spurred by recent treatment offerings.

There are many different etiologies of NK, however all of them are characterized by impaired trigeminal innervation. Recognizing the diagnosis allows us to intervene earlier in the disease process in an attempt to avoid the potential severe sequelae that can ensue.

We are fortunate to have a variety of tools that help us to treat these patients more effectively than ever before.