Medical Advancements in the Treatment of Neurotrophic Keratitis
A 56-year-old woman with a history of recurrent herpes simplex virus (HSV) keratitis of the right eye and stage 3 neurotrophic keratitis (NK) with a large central corneal ulcer presents with worsening corneal sensitivity. She was initially diagnosed with HSV keratitis in 2018 and later diagnosed with stage 3 NK with a corneal ulcer in 2020. She was initially treated with preservative-free artificial tears, ganciclovir ophthalmic gel, corticosteroid ophthalmic solution, and oral acyclovir. She underwent amniotic membrane transplantation (AMT) 2 months prior. Recombinant human nerve growth factor (rhNGF) topical therapy with cenegermin ophthalmic solution is being considered.
Neurotrophic keratitis (NK) is a rare degenerative corneal disease caused by damage to the trigeminal nerve, resulting in a progressive loss of corneal sensation. Patients with NK experience a breakdown of the corneal epithelium, poor corneal healing, and, if left untreated, eventual corneal ulceration, melting, and perforation.2
NK is challenging to diagnose and may go undetected for years because patients are frequently unaware of their condition, rarely noticing anything beyond minor vision fluctuation, as desensitized corneal nerves suppress feelings of pain. Because advanced stage NK is associated with worse outcomes and lower final best corrected-distance visual acuity, it is essential that clinicians identify NK in its early stages.3 Clinicians should proactively screen for NK by testing corneal sensitivity and taking a complete clinical history as part of a routine eye exam. Herpes simplex virus (HSV) keratitis is a common cause of NK, and patients should be asked directly if they have a history of HSV infection as part of a standard ophthalmic workup. Other causes of NK include systemic diseases such as diabetes, severe dry eye disease, long-term contact lens wear, and ocular surgery, among others.3-5 Clinicians should be suspicious of NK in patients with this history, particularly in patients with HSV infection.
Corneal sensitivity can be tested at the slit lamp by lightly touching each corneal zone using a cotton wisp from a sterile cotton ball or strand of unflavored dental floss. Importantly, sensitivity should be tested before any examination eyedrops are instilled. Clinical examination for corneal sensitivity, signs of dryness, ocular surface disease, and lagophthalmos should be undertaken.3
If corneal sensitivity is diminished and an NK diagnosis is made, clinicians should refer to the Mackie classification system to determine severity and develop a treatment plan, as a step-wise management approach by severity is recommended.3 Mackie classification stage 1 (mild) disease includes irregularities in the corneal epithelium, stage 2 (moderate) disease includes persistent epithelial defects, and stage 3 (severe/end-stage) includes corneal ulcer that may progress to melting and perforation.4
Traditional stage-based treatments for NK include perseverative-free artificial tears (stage 1), serum drops (stage 2), scleral lenses (stage 2), amniotic membrane transplantation (AMT) (stage 3), and most recently, cenegermin 0.002% ophthalmic solution (stage 3).4 Cenegermin is a recombinant form of human nerve growth factor (NGF), a neurotrophin that promotes tear production and corneal healing; stimulates the regeneration, proliferation, and differentiation of corneal epithelial cells; and supports corneal innervation. Cenegermin is the only medical therapy for NK approved by the US Food and Drug Administration.6
Multiple studies have established the safety and efficacy of cenegermin, with complete corneal healing in 8 weeks in more than 70% of patients.7,8 The most common adverse events are eye pain, indicating the agent’s effectiveness in restoring corneal sensitivity, followed by ocular hyperemia, eye inflammation, increased lacrimation, corneal deposits, and foreign body sensation.1 Interestingly, the corneal healing rates of AMT and cenegermin for NK are similar. However, more patients treated with cenegermin were recurrence free 12 months post-treatment than those treated with AMT (87% vs 53%, respectively) and patients treated with cenegermin had longer recurrence-free intervals and higher satisfaction rates.2
Published case reports detail the success of cenegermin after other therapies have failed. For example, Ahuja et al described an 84-year-old patient who developed stage 3 NK (corneal ulcer) due to a combination of contributing factors, including chronic ocular surface disease, previous ocular surgery, and diabetes. Despite multiple treatment strategies, including serum drops, AMT, bandage contacts, and others, the patient inevitably relapsed. The patient was prescribed cenegermin 6 times daily for 8 weeks and experienced improvement in vision and epithelial defect within 5 weeks of beginning treatment. After 8 weeks, the epithelial defect completely resolved.6
Garcia-Delpech et al reported a case series of 5 patients with stage 2 or 3 NK who were treated with cenegermin 0.002% ophthalmic solution 6 times daily for 8 weeks. Patients were prescribed cenegermin after prior conventional topical treatments. Complete corneal healing occurred in 3 of the 5 patients, with trends of improvement in visual acuity and corneal sensitivity. All patients remained free of recurrence after 4 years of follow-up. The authors concluded that cenegermin was effective and well tolerated in the healing of corneal ulcers with a trend of improvement of visual acuity and corneal sensitivity.9
In summary, NK is challenging to diagnose and manage, requiring clinicians to proactively screen patients for this potentially devastating condition. Although several treatments can safely and effectively heal the cornea, cenegermin has the added benefit of longer recurrence-free intervals than standard treatments.
1. OxervateTM. Prescribing information. Dompé US Inc; 2018 Accessed February 7, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761094s000lbl.pdf
2. Sacchetti M, Komaiha C, Bruscolini A, et al. Long-term clinical outcome and satisfaction survey in patients with neurotrophic keratopathy after treatment with cenegermin eye drops or amniotic membrane transplantation. Graefes Arch Clin Exp Ophthalmol. 2022;260(3):917-925. doi:10.1007/s00417-021-05431-6
3. Saad S, Abdelmassih Y, Saad R, et al. Neurotrophic keratitis: frequency, etiologies, clinical management and outcomes. Ocul Surf. 2020;18(2):231-236. doi:10.1016/j.jtos.2019.11.008
4. NaPier E, Camacho M, McDevitt TF, Sweeney AR. Neurotrophic keratopathy: current challenges and future prospects. Ann Med. 2022;54(1):666-673. doi:10.1080/07853890.2022.2045035
5. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017;232(4):717-724. doi:10.1002/jcp.25623
6. Ahuja AS, Bowden FW III, Robben JL. A novel treatment for neurotrophic corneal ulcer using topical cenegermin (OXERVATE™) containing recombinant human nerve growth factor. Cureus. 2020;12(11):e11724. doi:10.7759/cureus.11724
7. Pflugfelder SC, Massaro-Giordano M, Perez VL, et al. Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial. Ophthalmology. 2020;127(1):14-26. doi:10.1016/j.ophtha.2019.08.020
8. Bonini S, Lambiase A, Rama P, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332-1343. doi:10.1016/j.ophtha.2018.02.022
9. García-Delpech S, Udaondo P, Fernández-Santodomingo AS, García-Teillard D. Neurotrophic keratopathy treated with topical recombinant human nerve growth factor (cenegermin): case series study with long-term follow-up. Case Rep Ophthalmol. 2022;13(2):663-670. doi:10.1159/000525923
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Reviewed June 2023