In this episode of Interventional Mindset, Dr. Beckman reviews how neurotrophic keratitis (NK) can go misdiagnosed as mechanical dry eye or other ocular surface disease (OSD), and various treatment approaches to address the inflammation and decreased corneal sensitivity caused by the condition.
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Overview of neurotrophic keratitis
Neurotrophic keratitis is a condition that can be easy to miss for clinicians and surgeons alike, Dr. Beckman highlighted that you have to be aware of how to screen and treat NK, since conventional OSD treatments may not treat the underlying condition, and other medications, such as those used to treat glaucoma, may exacerbate the condition.
Based on his clinical experience, Dr. Beckman recommended that when screening patients for NK, there are two key factors to carefully assess:
- Decreased corneal sensitivity or sensation.
- Signs of keratitis—specifically central to inferocentral.
For a patient with signs that potentially point to NK, such as corneal staining, he advised a pivot to aggressive testing to identify the problem, as patients often do not report symptoms because they have reduced corneal sensation.
Classifying neurotrophic keratitis
According to the Mackie classification system, NK can be organized into three stages based on the severity of corneal damage.
- Stage 1: Corneal epithelial changes observed, seen with diffuse staining, and the presence of superficial punctate keratopathy and corneal edema.1
- Stage 2: Persistent and non-healing epithelial defect with no corneal ulceration or thinning.1
- Stage 3: Presence of corneal ulceration and/or thinning with stromal involvement that can progress to corneal perforation.1
When Dr. Beckman observes a patient with ocular surface dysfunction, one of the main diagnostic tests that he orders is corneal staining, this is critical for neurotrophic keratitis because it can highlight a salient feature of the condition. For a patient with significant corneal staining, he recommends assessing corneal sensation as that will determine whether or not the dry eye cause is neurotrophic.
Similarly, for dry eye patients, Dr. Beckman advised surgeons to measure corneal sensitivity early on in the treatment process to ensure that the patient’s ocular surface dysfunction is not neurogenic in nature.
Evaluating decreased corneal sensitivity caused by NK
While esthesiometers are often employed in clinical trials, these devices can be rather expensive, thereby limiting practice usage. Other more accessible methods to assess corneal sensitivity include creating a wisp from a cotton-tipped applicator or using unwaxed dental floss.
Dr. Beckman prefers to use rolled-up tissue paper. His protocol for measuring corneal sensation is as follows: he rolls up a piece of tissue paper into a sharp point, has the patient stare straight ahead, and then approaches them with the tissue paper from the side to prevent blinking when they see the object coming closer. Then he touches the tissue paper to the cornea and evaluates the reaction, grading it out of three levels: normal, decreased sensitivity, and absent.
A patient with a normal reflex will likely blink and withdraw, while patients with decreased sensitivity often have a delayed reaction or react only to increased pressure on the cornea. Lastly, someone with absent corneal sensitivity will not respond at all to the device (or rolled-up tissue paper) coming into contact with their cornea.
Generally, in clinical trials, when measuring corneal sensitivity, clinicians assess quadrants of the cornea (and occasionally a center circle) for increased specificity of the corneal sensitivity. This is less commonplace in clinical practice, but if Dr. Beckman suspects a patient has neurotrophic keratitis and sees a normal response to the corneal sensitivity test, occasionally, he takes the extra step to check the various quadrants individually.
Identifying and treating neurotrophic keratitis
A helpful clue for identifying NK when treating dry eye patients is to look for those who appear to have dry eye with high osmolarity, rapid tear breakup time, a positive matrix metalloproteinase 9 (MMP-9) test, or any other diagnostic test that indicates the patient’s eyes should be dry and/or burning, but they don’t report any of these symptoms.
Additionally, these patients may express that they don’t use eye drops since their eyes don’t feel irritated.
Taking a thorough patient history to assess patients for NK
Taking a thorough patient history is critical to identifying and managing patients with NK, as there are many different root causes for a neurotrophic cornea. First, Dr. Beckman advised clinicians to look at the patient’s medical history to see if they have systemic diseases (i.e., diabetes, multiple sclerosis, other neurologic conditions, etc.) or a history of ocular surgery, such as laser in situ keratomileusis (LASIK) or corneal transplants.
As corneal nerves are cut during corneal transplants, this is a more common surgical cause of decreased corneal sensation. Other medical events that can be associated with NK are strokes, nerve palsies, or facial surgery, all of which cause a loss of nerve input.
Ocular toxicity is another common and often overlooked NK component. An example of this could be a glaucoma patient on three different eye drops with preservatives that can chronically damage the ocular surface (specifically the epithelial surface), causing the neurotrophic condition. Similarly, contact lens overwear might be a root cause of neurotrophic keratitis, as this can reduce oxygen exposure/permeation to the cornea. Further, the contact lens can act as a bandage that shields the patient from the loss of corneal sensation, increasing the level of difficulty in recognizing NK.
Factoring in patient employment and a history of Herpesviridae infection
An additional consideration is the patient’s work location. Some examples could be the work environment where there are chemicals in the air, such as hairdressers, an archaeologist uncovering fossils in the desert, or construction areas that can lead to a neurotrophic cornea.
Subsequently, Dr. Beckman highlighted that neurotrophic keratitis can become a chicken or egg situation in which a patient may have a mechanical condition with their lids, such as entropion, where their lashes rub against the cornea breaking down the surface. Once this occurs, it sets an NK “domino effect” into motion considering if the patient doesn’t heal fully, the problem can continue to progress through the aforementioned Mackie stages.
Lastly, Herpesviridae (Herpes simplex [HSV] and zoster [HZO]) are the two most common infections that can lead to a neurotrophic cornea. Interestingly, these are often unilateral, so if Dr. Beckman sees a patient with unilateral NK and can’t identify a mechanical source of the problem, he looks for other clues of a previous herpes infection, such as iris atrophy or a history of cold sores.
These features within patient history can help the clinician target key signs and symptoms of neurotrophic keratitis to prevent misdiagnosis or added damage to the cornea.
Assessing neurotrophic keratitis with an eye exam
When evaluating a patient who has shown potential signs of NK, the eye exam initially resembles a dry eye evaluation. Dr. Beckman generally observes that NK patients have fluctuating vision and decreased vision with fatigue.
For example, he often has seen patients for cataract evaluations who explain that they can read for an hour and then have to stop due to blurring or fluctuating vision. Although cataracts do not cause rapid visual fluctuation, he recognized that this problem was likely caused by the tear film; nevertheless, due to the reduced corneal sensation, these patients often do not have the perception of dryness or burning.
Dr. Beckman explained that he has encountered this issue with diabetic patients. He outlines to them that, similar to how diabetic patients can have ulcers on the bottom of their feet and not be able to feel it, they may not feel the dryness on their cornea. Consequently, it can be helpful to remember that ocular symptoms that patients notice tend to be eye fatigue and blurred vision over a period of time.
Prescribing treatments for neurotrophic keratitis
For patients with signs of dry eye who are suspected of having NK, Dr. Beckman prefers to treat them initially like a dry eye patient; he recommends frequent use of lubricating artificial tears, commercially-available dry eye medications such as cyclosporine, lifitegrast, and varenicline nasal spray, or over-the-counter drops. Many patients respond well to this initial treatment because it addresses the dryness and inflammation on the ocular surface.
Additionally, he prescribes steroids for NK patients to help acutely diminish the inflammatory response, though he advised to be mindful of prolonged steroid use with a reminder to measure intraocular pressure. Subsequently, his preference is to prescribe short pulses of steroids for acute flare-ups. If further treatment is required, Dr. Beckman turns to autologous serum tears, amniotic membrane extracts, or amniotic membranes to stimulate the healing of the epithelium.
To treat patients experiencing NK caused by ocular toxicity from eye drops, clinicians can also switch patients to preservative-free medications or, in cases of ocular toxicity specifically from glaucoma drops, consider a selective laser trabeculoplasty (SLT) to reduce the medication burden. When patients need a more interventional approach to treat NK, tarsorrhaphy, whether temporary or permanent, can be used to decrease exposure. If a patient has NK due to a systemic autoimmune disease, the clinician may need to treat that or refer the patient to a specialist for further treatment. It’s valuable to remember that if left untreated, NK can progress and result in thin and perforated corneas.
Using Oxervate to treat neurotrophic keratitis
If the initial treatment approach does not suffice, Dr. Beckman treats NK using Oxervate (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL), Dompé), a recombinant human nerve growth factor (NGF) eye drop solution that mimics the natural NGF in the eye to stimulate nerve regrowth in the cornea. In the original clinical studies, investigators found that over 70% of patients developed complete corneal healing after finishing a course of Oxervate,2 and about 80% of those patients maintained a complete intact epithelium after 1 year.3
The typical course for Oxervate is dosed six times daily for 8 weeks; Dr. Beckman has found that patients tend to tolerate it well, and around week 2 or 3 of treatment, patients may report feeling pain as the cornea undergoes reinnervation. For patients who don’t heal completely after a completed course of Oxervate, Dr. Beckman recommends a second or even third course; as, ultimately, the key to treating NK is early detection and aggressive treatment.
Conclusion
Dr. Beckman recommended that clinicians and surgeons keep in mind that having a thorough understanding of how neurotrophic keratitis presents in patients and how to assess patients for signs and symptoms will lead to improved treatment outcomes.
It’s important to address all possible etiologies of NK, such as ocular toxicity, medications, previous ocular surgeries, systemic diseases, environmental conditions, and behaviors, to target the exact root cause. This will help surgeons and clinicians more proactively identify NK earlier in the course of the disease.
