Neurotrophic Keratitis Can Lead to Loss of Vision if Untreated. Here’s How to Manage It.

Neurotrophic keratitis (NK) is a degenerative corneal disease that is caused by damage to the trigeminal nerve and leads to the desensitization of the corneal nerves.1 When the nerves are damaged, the feedback loop that regulates epithelial cell growth, regeneration, and survival is broken, triggering the progressive loss of corneal sensation. 
NK is considered rare, but prevalence numbers vary. An Intelligent Research in Sight analysis puts prevalence as 21.34 cases per 100,000 patients (0.021%) in the United States, but other studies have lower estimates (Figure).2,3 A retrospective epidemiologic study suggests that its prevalence is likely higher, and underreporting of the disease could be due to a lack of clinician awareness.2

Patients with NK experience decreased or a total absence of corneal sensation, which, if left untreated, can spiral into the breakdown of the corneal epithelium, poor corneal healing, and eventually corneal ulceration, melting, and perforation.4 Patients with NK have deadened corneal nerves, they don’t experience pain and are likely unaware of their disease beyond minor complaints of a red eye and reduced visual acuity.1 It is critical that clinicians are proactive in testing corneal sensitivity to identify patients with NK early in the disease process. 
A stepwise approach to NK treatment is recommended, with selection based off of Mackie classification staging and severity.5 The goal is to support epithelial healing and stimulate the growth of corneal nerves. Until 2018, NK management was largely supportive and did not address the underlying disease pathology.5 That changed with the US Food and Drug Administration (FDA) approval of cenegermin, a recombinant human nerve growth factor that supports corneal innervation and integrity through the differentiation and maintenance of corneal neurons.6

Diagnosing NK Is Half the Battle  

Although it may seem obvious, a key to treating NK is simply testing for it in the first place. A variety of conditions can drive the underlying cause of NK (Table 1)2,5; therefore, clinicians should take a thorough history, listening for clues, such as herpes simplex or herpes zoster infection (NK develops in about 6% and 12% of patients with herpetic keratitis and herpes zoster keratitis, respectively), long-term contact lens wear, long-term use of topical eyedrops with preservatives, previous neurosurgical procedures, and systemic diseases, such as diabetes, among others.5

Corneal sensitivity testing is the pillar of diagnosing NK. Using a cotton wisp from a sterile cotton swab , clinicians should lightly touch the patient’s cornea in all zones (central, superior, inferior, temporal, and nasal) and assess their response, documenting if the sensation was normal, reduced, or absent in each area.5 Quantitative measurements also can be taken using a Cochet-Bonnet aesthesiometer, if available. Other diagnostic considerations include slit lamp examination, corneal staining, Schirmer’s test, corneal cultures, in vivo confocal microscopy, and evaluation for systemic immune disorders.5

NK Treatment Requires a Stepwise Approach

In the event corneal sensation is decreased or absent and/or other clinical characteristics of NK are present, clinicians should refer to the Mackie classification system for treatment guidance based on stage (Table 2).2,5

What is the mechanism of action of cenegermin?
Cenegermin supports corneal innervation and integrity through the differentiation and maintenance of corneal neurons.

For stage 1 (mild) disease, treatment should be focused on optimizing the ocular surface with preservative-free artificial tears, hydrating contacts, and autologous serum tears (AST), among other options. Although AST can be challenging to obtain, at a 20% to 50% concentration, AST has a high success rate in healing epithelial defects within 90 days.7,8 The newest FDA-approved treatment for NK, cenegermin, is approved for stages 2 and 3 (moderate and severe) disease based on the strength of 2, 8-week, randomized, vehicle-controlled, multicenter, double-masked studies 一 NGF0214 ( Identifier: NCT02227147), conducted in the United States, and REPARO ( Identifier: NCT01756456), conducted in Europe.9,10 Across both studies, complete corneal healing in 8 weeks was demonstrated in 70% or more of patients treated with with a topical recombinant human nerve growth factor.9,10 The most common adverse event reported was eye pain, which corresponds with the drug’s effectiveness in waking up the deadened nerves.9,10

Because cenegermin has similar corneal healing rates as amniotic membrane transplantation (AMT), a recent multicenter, observational study from Sacchetti et al sought to compare them in regard to healing, NK recurrence, and patient-reported satisfaction. Although both treatments were effective in healing the cornea, researchers determined that patients treated with cenegermin had fewer recurrences (87% vs 53% over 12 months in the cenegermin and AMT groups, respectively), longer recurrence-free periods, and greater satisfaction rates.11

Additional data on the long-term effect of cenegermin are maturing. For example, Bruscolini et al performed a retrospective chart review of 18 patients with Mackie stage 2 or 3 NK with at least 2 years of follow-up available. Some patients were followed for up to 48 months (n=9) without recurrence of NK, illustrating that a single 8-week treatment regimen with cenegermin has clinical efficacy that can persist for up to 4 years in some patients.12

A recent small retrospective case series of 8 pediatric patients who underwent cenegermin therapy found that 63% experienced clinical improvement. Two patients experienced worsening of their epitheliopathy during cenegermin treatment, with 1 patient having progression of an existing ulcer and a second patient developing a new epithelial defect. The authors concluded that there is “modest support” for cenegermin in pediatric patients with the main benefit being improved corneal epithelial stability. However, they caution that pre-existing corneal scarring may limit visual acuity improvements in pediatric patients and that clinicians must pay close attention to the corneal epithelial status during the 8-week treatment course.13

Pearls for Successful Cenegermin Treatment 

Cenegermin is dosed at 1 drop in the eye needing treatment 6 times a day at 2-hour intervals for 8 weeks. Cenegermin has no contraindications, but patients should remove contact lenses before instilling the drops and wait 15 minutes before reinserting contacts.6 Clinicians should prepare patients for mild ocular pain upon instillation as the cornea heals. 


  1. Semeraro F, Forbice E, Romano V, et al. Neurotrophic keratitisOphthalmologica. 2014;231(4):191-197. Published online Oct. 2, 2013. doi:10.1159/000354380
  1. Saad S, Abdelmassih Y, Saad R, et al. Neurotrophic keratitis: frequency, etiologies, clinical management and outcomesOcul Surf. 2020;18(2):231-236. doi:10.1016/j.jtos.2019.11.008
  1. Bian Y, Ma KK, Hall NE, et al. Neurotrophic keratopathy in the United States: an IRIS® Registry (Intelligent Research in Sight) analysis. Ophthalmology. 2022;S0161-6420(22)00478-X. doi:10.1016/j.ophtha.2022.06.019
  1. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nervesJ Cell Physiol. 2017;232(4):717-724. doi:10.1002/jcp.25623
  1. Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathyProg Retin Eye Res. 2018;66:107-131. doi:10.1016/j.preteyeres.2018.04.003
  1. Oxervate. Prescribing information. Dompé U.S. Inc.; 2019. Accessed August 9, 2022. 
  1. Jeng BH, Dupps WJ Jr. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea. 2009;28(10):1104-1108. doi:10.1097/ICO.0b013e3181a2a7f6
  1. Guadilla AM, Balado P, Baeza A, Merino M. Efectividad del tratamiento con suero autólogo tópico en la queratopatía neurotrófica [Effectiveness of topical autologous serum treatment in neurotrophic keratopathy]. Arch Soc Esp Oftalmol. 2013;88(8):302-306. doi:10.1016/j.oftal.2012.09.033
  1. 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 trialOphthalmology. 2020;127(1):14-26. doi:10.1016/j.ophtha.2019.08.020
  1. Bonini S, Lambiase A, Rama P, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitisOphthalmology. 2018;125(9):1332-1343. doi:10.1016/j.ophtha.2018.02.022
  1. 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 transplantationGraefes Arch Clin Exp Ophthalmol. 2022;260(3):917-925. doi:10.1007/s00417-021-05431-6
  1. Bruscolini A, Marenco M, Albanese GM, Lambiase A, Sacchetti M. Long-term clinical efficacy of topical treatment with recombinant human nerve growth factor in neurotrophic keratopathy: a novel cure for a rare degenerative corneal disease? Orphanet J Rare Dis. 2022;17(1):57. doi:10.1186/s13023-022-02236-6
  2. Hatcher JB, Soifer M, Morales NG, Farooq AV, Perez VL, Shieh C. Aftermarket effects of cenegermin for neurotrophic keratopathy in pediatric patients. Ocul Surf. 2021;21:52-57. doi:10.1016/j.jtos.2021.04.003

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Ophthalmology Advisor had no role in this content’s preparation.

Reviewed August 2022