Examining an Important Orphan Disease: Neurotrophic Keratitis/Keratopathy and Its Treatment

Introduction

Neurotrophic keratitis/keratopathy (NK) is a rare disease—also called an orphan disease—that significantly affects the cornea. French physiologist Magendie is credited with initially describing NK, which he termed “neuroparalytic keratosis.” In 1824, he experimentally demonstrated the association between corneal damage and impaired nerve function, particularly the trigeminal nerve.¹

Symptoms of NK include redness, diminished corneal sensation, dry eyes, photophobia, and blurred vision. Treatment for NK is designed to promote healing and prevent disease progression.

NK is a degenerative corneal disease | Image credit: © My Ocean studio | stock.adobe.com

Disease Overview, Classification, and a Brief Comparison With Dry Eye Disease

NK is a degenerative corneal disease resulting from diminished corneal innervation. A characteristic feature of NK includes decreased or absent corneal sensitivity, which leads to breakdown of the epithelium, loss of healing, and eventually to corneal ulceration and perforation.²

NK is classified as an orphan disease. In the United States, an orphan disease is one that affects fewer than 200,000 individuals. However, according to the World Health Organization, an orphan disease is one that affects less than 6.5 to 10 people per 10,000 individuals.³

NK is caused by damage to the trigeminal nerve or its branches. Ocular and systemic conditions linked to damage to the fifth cranial nerve (i.e., the trigeminal nerve) may lead to the development of NK.² The most common causes of NK are viral infection (e.g., herpes simplex and herpes zoster), chemical burns, chronic use of contact lenses, corneal surgery, ablative procedures for trigeminal neuralgia, and surgical procedures for reduction of jaw fractures.⁴ Interestingly, topical ocular medications, such diclofenac sodium, have been associated with nerve damage and the development of NK.⁵ Additionally, systemic diseases such as diabetes mellitus and multiple sclerosis may contribute to the development of NK.⁵

Corneal nerves are crucial for maintaining the integrity, growth, and healing of the corneal epithelium. Damage to these sensory nerves is thought to significantly alter neuromodulator levels, impacting the vitality and metabolism of epithelial cells. This impairment can hinder cell division and ultimately cause epithelial breakdown. Furthermore, involvement of sensory nerves can reduce the natural lacrimation reflex, thereby worsening the damage. This leads to reduced thickness of the corneal epithelium, intracellular swelling, loss of microvilli, and abnormal basal lamina production. These disruptions in morphology and metabolism result in recurring or persistent epithelial issues that may, in turn, progress to corneal ulceration, melting, and perforation. Various chemical mediators, such as nerve growth factor (NGF) and substance P, are believed to contribute to the development of neurotrophic keratitis.⁶

Due to the lack of corneal sensation, patients are frequently asymptomatic. Occasionally, they may exhibit redness and vision blurriness stemming from ongoing issues like persistent epithelial defects, corneal swelling, or scarring. Past episodes of redness, eye discomfort, cutaneous blistering, or scarring may indicate prior herpetic infections.²

The main feature of this disease is reduced or absent corneal sensation. The disease is classified into 3 stages by the Mackie classification, which are based on the severity of corneal damage. The stages of NK encompass epithelial changes (stage 1), persistent epithelial defects (stage 2), and corneal ulceration (stage 3)²:

• Stage 1 shows changes in the corneal epithelium with dryness and cloudiness, accompanied by superficial punctate keratopathy and corneal swelling.
• Stage 2 reveals recurrent or persistent epithelial defects typically found at the upper half of the cornea in oval or circular shapes.
• Stage 3 presents as a corneal ulcer involving the stroma, which may progress to stromal melting (a condition in which the corneal epithelium breaks down and is accompanied by thinning of the cornea’s inner layer) and potentially corneal perforation.

Dry eye disease (DED), also known as keratoconjunctivitis sicca (KCS), is another disease affecting the ocular surface. DED is considered an inflammatory disease with symptoms including redness, discomfort, itching, and photophobia.^7,8

Globally, the prevalence of DED varies between 5% and 34%, with prevalence increasing substantially with age. The large variations in prevalence figures are attributed to differences in several factors, such as geographical differences. For example, a study in 1977 noted that 11.7% of the German population had symptoms of ocular dryness.⁷

The proposed underlying pathogenesis of DED includes hyperosmolarity of the tear film and inflammation of the eye surface and lacrimal gland.⁹ DED is divided into 2 treatment-based subgroups: aqueous-deficient DED (dry eye with reduced tear production) and hyper-evaporative DED (dry eye with enhanced evaporation of the tear film). Treatment for DED, which is based upon disease severity, consists primarily of eyelid hygiene, artificial tears, anti-inflammatory agents, topical corticosteroids, and topical cyclosporine (Restasis; AbbVie).^7,8

NK and DED can have similar symptoms, which may make it difficult for clinicians to differentiate them. NK stems from decreased corneal innervation (i.e., impaired functioning of the trigeminal nerve), whereas ocular inflammation and tear film hyperosmolarity are the hallmarks of DED.^2,9

Finally, there are profound complications of NK and DED, which bear some similarities. Severe cases of NK can lead to complications of corneal ulceration, stromal melting, and vision loss. In late stages or in severe forms of DED, complications may include filamentary keratitis, persistent epithelial defects, corneal ulceration, and vision loss.^2,7

Current Pharmacologic and Surgical Treatment Modalities

The prognosis associated with NK depends on the severity of the disease. Generally, it is accepted that the more severe the impairment of corneal sensitivity, the higher the likelihood of NK progression.⁴

Importantly, all topical agents should be discontinued due to their damaging effects on the ocular surface epithelium. Because they may impair the prognosis of NK, all ocular surface-associated disorders,such as exposure keratitis, need to be addressed accordingly.⁴

Treatment of NK should be based on the severity of the disease. For example, treatment for stage 1 disease targets improvement of epithelial quality and transparency, as well as the avoidance of epithelial breakdown. In more severe cases of NK, particularly those with corneal ulcers and stromal melting, immediate action is required to prevent stromal lysis and perforation.⁴

In all stages of disease severity, the use of preservative-free artificial tears may assist in the improvement of the corneal surface. Notably, topical steroids have been proposed to control ocular inflammation associated with NK; however, steroids should be used with great caution due to the increased risk of corneal melting and perforation via inhibition of stromal healing.⁴ In addition, topical nonsteroidal anti-inflammatory drugs may also hinder the healing process, and thus, should be avoided.¹⁰

Regarding stage 1 disease, treatment is chiefly based on lubrication (e.g., artificial tears, artificial tear ointment, eyelid taping, and punctal plugs). Notably, lubrication should be used on a scheduled basis instead of an as-needed approach because signs of insufficient treatment may not be apparent to the patient.⁴

Regarding stage 2 disease, treatment goals encompass the promotion of epithelial healing and the prevention of disease progression to corneal ulcers. Treatment options for stage 2 disease include therapeutic contact lenses, topical autologous/allogenic serum, surgical tarsorrhaphy, and botulinum toxin injection.^11-15

Stage 3 disease, due to its advanced form, can be difficult to treat. Several surgical approaches for advanced disease include amniotic membrane transplantation, conjunctival (Gundersen) flap, and corneal neurotization.^16-18

Topical cyclosporine (cyclosporine ophthalmic emulsion), which is classified as a calcineurin inhibitor immunosuppressant, is FDA-approved to increase tear production in individuals with ocular inflammation associated with DED.¹⁹ However, individuals currently using topical anti-inflammatory agents or punctal plugs do not experience enhanced tear production with topical cyclosporine. Notably, cyclosporine ophthalmic emulsion has been shown to relive the signs and symptoms of DED in approximately 50% of patients.⁸ Interestingly, topical cyclosporine has also been used off label for the treatment of NK.^20,21

In a case report, clinicians examined a patient with a documented history of recurrent herpes simplex virus-1 keratitis (HSK) and secondary NK. A prior physician treated the patient unsuccessfully for 6 months using a bandage contact lens, antibiotic solution, and artificial tears. Within 4 weeks, treatment with topical cyclosporine resolved the patient’s epithelial defect. The authors of the case report suggest the early use of topical cyclosporine for the management of NK could be beneficial.²⁰

In a respective, observational study, researchers evaluated the effectiveness and tolerability of cyclosporine ophthalmic emulsion for the treatment of NK secondary to HSK. The study involved 15 patients with a history of HSK and secondary NK, which was classified as either stage 2 or stage 3. All study participants received a treatment regimen consisting of topical cyclosporine (1 drop 4 times daily), a silicone hydrogel bandage contact lens, and ganciclovir ophthalmic gel (Zirgan; Bausch + Lomb). Following achievement of corneal healing, the dosage of topical cyclosporine was reduced (1 drop twice daily) and continued for an additional 2 months, while other treatments were discontinued. At the conclusion of the study, the authors noted the regimen of topical cyclosporine, in combination with a silicone hydrogel bandage contact lens and topical ganciclovir, effectively treated NK from HSK without problematic adverse events.²¹

To summarize, there is some evidence for using topical cyclosporine in the treatment of NK.^20,21 For patients with NK, the clinical benefits of topical cyclosporine are likely associated with the drug’s ability to increase tear production and diminish inflammatory mediators, such as IL-2.²² Despite the lack of controlled trials, topical cyclosporine may prove useful for patients failing to respond to conventional therapy.

Novel and Emerging Pharmacologic Treatment Approaches

Cenegermin was approved by the FDA in 2018 | Image credit: © H_Ko | stock.adobe.com

A novel pharmacologic option for the treatment of advanced NK is a topical formulation of recombinant human nerve growth factor, cenegermin (Oxervate; Dompé).^23,24 Cenegermin was approved by the FDA in 2018. Notably, it is the first ophthalmic topical biologic. Prior to the approval of cenegermin, surgical intervention was the only available treatment for advanced NK.²⁵ Following installation, cenegermin is converted via enzymatic hydrolysis into its active form, which is NGF. Subsequently, NGF binds to receptors in the anterior segment of the eye. By interacting with these receptors, NGF enhances sensory nerve growth, differentiation, and survival.²⁶

Cenegermin is commercially available as a multidose vial that contains a clear and colorless solution. The FDA-approved dosage is 1 drop of solution into the affected eye(s) 6 time a daily (at 2-hour intervals) for 8 weeks. Completing the entire 8-week course is critical for the success of treatment with cenegermin.²⁵ Prior to installation, contact lenses should be removed and may be reinserted following a 15-minute interval. In addition, any other topical ophthalmic drops should be administered at least 15 minutes apart to prevent dilution of the active ingredients.²⁷

Due to the importance of proper storage, cenegermin is supplied via an insulted pack in weekly cartons. The weekly cantons contain 7 multi-dose vials (1 vial per day of the week) and an accompanying delivery system kit. The kit contains important items such as vial adaptors and pipettes, which are required to ensure proper administration.²⁸ Importantly, cenegermin is stored in a freezer at the pharmacy and must be placed in a refrigerator in the original cartoon as soon as possible (no later than 5 hours after receiving the medication from the pharmacy). Cenegermin may be stored for up to 14 days if kept at 36°F to 46°F (2°C to 8°C). Prior to installation, it is recommended to allow the vial to thaw at room temperature for 30 minutes.²⁸

Eye pain is the most common adverse effect (AE) associated with cenegermin, occurring in approximately 16% of users. Interestingly, eye pain may arise along with the occurrence of corneal healing. Other AEs occurring in 1% to 10% of patients include corneal deposits, foreign body sensation, ocular hyperemia, ocular inflammation, photophobia, tearing, and headache.²⁹

Remarkably, most patient do not experience AEs due to the low likelihood of systemic absorption. Following administration of cenegermin, patients can mitigate the potential for systemic absorption by gently applying pressure to the tear duct at the corner of the eye for 1 minute after installation and subsequently wiping away any excess solution with a tissue.³⁰

The safety and efficacy of cenegermin was determined through 2 randomized trials: REPARO (Study NGB0212) and Study NGF0214. REPARO involved patients with stage 2 or stage 3 NK in a single eye, whereas Study NGF0214 enrolled patients with NK in 1 or both eyes.^31,32

The purpose of REPARO was to evaluate cenegermin for the treatment of moderate-to-severe NK. The phase 2 study comprised 156 patients randomized 1:1:1 to cenegermin 10 mcg/mL, cenegermin 20 mcg/mL, or vehicle (i.e., placebo) for 8 weeks. Treatment consisted of 6 drops per day and participants had a follow-up duration of either 48 or 56 weeks. Safety was analyzed in all patients who received study treatment, while efficacy was by intention-to-treat (ITT).³¹ An ITT analysis, which is based on the initial treatment and not the treatment received by participants, ignores medication non-adherence, protocol deviations, and withdrawal from the study. ITT is often used to evaluate the real-world effects of a treatment.³³

The main outcome measure of REPARO was corneal healing, which was defined as less than 0.5 mm maximum diameter of fluorescein staining in the lesion area. Corneal healing was evaluated by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. In addition, corneal healing was reexamined post hoc by masked central readers with a more conservative measure (0 mm staining in the lesion area and no other persistent staining).³¹

For the primary end point, 19.6% of vehicle-treated patient attained corneal healing (less than 0.5 mm lesion staining) versus 54.9% of patients receiving cenegermin 10 mcg/mL (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P<0.001) and 58.0% of those receiving cenegermin 20 mcg/mL (+38.4%; 97.06% CI, 18.96–57.83; P<0.001).³¹

For the key secondary end point, 43.1% of vehicle-treated patients achieved corneal healing versus 74.5% of those receiving cenegermin 10 mcg/mL (+31.4%; 97.06% CI, 11.25–51.49; P=0.001) and 74.0% of patients receiving cenegermin 20 mcg/mL (+30.9%; 97.06% CI, 10.60–51.13; P=0.002). Using the more conservative measure (0 mm lesion staining and no other persistent staining), the post hoc analysis of corneal healing sustained statistically significant differences between cenegermin and vehicle at weeks 4 and 8. Importantly, over 96% of patients who recovered following cenegermin treatment stayed free from recurrence during the follow-up period. Treatment with topical cenegermin was generally well tolerated with adverse effects that were mostly mild and temporary.³¹

The researchers of Study NGF0214 examined the utility of cenegermin in patients with neurotrophic persistent epithelial defect with or without stromal thinning. The study involved 48 patients randomized 1:1 to cenegermin 20 mcg/mL or vehicle eye drops. As with REPARO, treatment involved 6 drops daily for 8 weeks. Subsequently, the patients entered a 24-week follow-up period. All patients who received study drug were assessed for safety, whereas efficacy was analyzed via ITT.³² 

Following 8 weeks of masked treatment, the primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer). The key secondary end point was corneal healing at four weeks of masked treatment. Other secondary variables included the following: overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week eight.³²

At week 8, the conventional assessment of corneal healing (less than 0.5 mm of fluorescein staining in the greatest dimension of the lesion area) reached statistical significance. Compared with 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) attained less than 0.5 mm of lesion staining (+40.4%; 95% CI, 14.2%–66.6%; P=0.006). Additionally, at week 8, the conservative assessment of corneal healing (0 mm lesion staining and no other residual staining) showed statistically significant differences; compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0-mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%–73.1%; P<0.001).³²

Regarding the key secondary end point, the conservative measure of corneal healing showed statistical significance at week 4. In comparison to the vehicle, patients who were treated with cenegermin showed statistically significant decreases in lesion size and disease progression rates during masked treatment. As with REPARO, cenegermin was well tolerated with localized adverse effects.³²

Both clinical trials showed cenegermin is safe and more effective than vehicle in promoting healing of moderate-to-severe NK (conclusion of REPARO), and cenegermin treatment showed higher rates of corneal healing than vehicle in NK associated with nonhealing corneal defects (conclusion of NGF0214).^31,32

Finally, a study analyzing the long-term clinical efficacy (i.e., rate of lesion recurrence) of topical cenegermin showed that the effects of a single 8-week treatment persisted for up to 48 months. Additionally, the researchers noted treatment with cenegermin resulted in significant improvements in corneal sensitivity and tear production.³⁴

According to the package insert, cenegermin is indicated for the treatment of NK, including mild, moderate, and severe cases.²⁹ The approval of cenegermin for all stages of NK is a prominent aspect of the topical agent. Notably, Neel Desai, MD, director of cornea, cataract, and retractive services at the Eye Institute of West Florida in Tampa, stated in a news release, “Oxervate is approved for the treatment of NK regardless of stage, which is important to remember for a clinician like me who is more concerned with risk of progression than disease stage. I remind myself that I am able to achieve complete corneal healing with Oxervate, which I prefer to the palliative options I used to employ. This makes us more effective when treating disease.”³⁵

Some emerging treatments for NK include RGN-259 ophthalmic solution (RegeneRx) and CSB-001 ophthalmic solution (oremepermin-alpha; Claris Biotherapeutics).^36-38 RGN-259 containes the regenerative protein thymosin beta 4 and is an eye drop that is under development to reduce damage and enhance healing for ophthalmic indications that include DED and NK.^36,37 RGN-259 (thymosin beta 4) works by stimulating cell migration, cell survival, stem cell recruitment, and cytoprotection via reduction of inflammation and oxidative stress.³⁶

Oremepermin-alpha is a recombinant human variant hepatocyte growth factor. It is being studied in a randomized, double-blind, vehicle-controlled trial for its ability to accelerate and enhance the quality of corneal healing in patients with NK. Because oremepermin-alpha has epitheliotropic, anti-inflammatory, and anti-fibrotic properties, researchers are suggesting that the topical ocular biologic solution could be a safe and effective option for the treatment of corneal diseases.³⁸

Patient Education and Shared Decision-Making

Shared decision-making (SDM) plays a pivotal role in enhancing patient autonomy, improving treatment adherence, and optimizing treatment outcomes. In addition, patients need to be well-informed about their condition, treatment options, and the importance of adherence to prescribed therapies.

SDM can be viewed as a collaborative approach to care by which clinicians assist their patients in analyzing available care options, the risks and benefits of the care options, and the selection of the best therapeutic option. Subsequently, the patient will need to be educated on appropriate aspects of their care plan, such as monitoring for AEs and the importance of adherence.³⁹

There are 4 forms of SDM that can be used to address the patient’s unique clinical situation: matching preferences, reconciling conflicts, problem-solving, and making of meaning. In matching preferences, patients and clinicians examine features (i.e., costs, safety, effectiveness) of the available treatment modalities and match them with the patient’s goals and preferences.³⁹ In the case of treating advanced NK, clinicians may want to discuss the features of surgicalinterventions (possible complications from surgery, etc.) compared to cenegermin, which has administration complexities.

In the reconciliation of conflicts, clinicians may use a collaborative process in assisting the patient explain the rationale for their position while reconciling their rationale with the various potential outcomes. In an example using a patient with significant NK, this form of SDM may prove valuable in the determination of curtailing the driving privileges in an elderly patient with potentially dangerous levels of visual impairments.³⁹

Conclusion

NK is a degenerative corneal disease that is classified as a rare, or orphan, disease. NK has 3 stages of increasing severity: stage 1 (epithelial changes), stage 2 (persistent epithelial defects), and stage 3 (corneal ulceration). Treatment ranges from lubrication, which is the primary method for stage 1 disease, to surgical interventions (amniotic membrane transplantation, conjunctival flap, and corneal neurotization) for advanced NK. Cenegermin is a novel agent that is topically administered for the treatment of NK. Patients receiving treatment with cenegermin should be educated on proper administration and storage, as well as the importance of adherence.

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