Neurotrophic keratitis (NK) is a degenerative disease caused by damage to the nerves responsible for trigeminal sensory innervation of the cornea, leading to reduced or absent corneal sensation and a spontaneous breakdown of the corneal surface.1 Loss of nerve function results in reduced epithelial cell turnover, compromised wound healing, disrupted blinking and tearing, and painless, persistent corneal defects that can lead to permanent scarring and vision loss when left untreated.2 NK is relatively rare, affecting nearly 65,000 people in the U.S.,3 however this is likely an underestimate as the signs and symptoms in the early stages of NK can be subtle and easily overlooked or misattributed to other conditions.
Until recently, there were no treatments specifically for NK, which made managing the condition challenging even when diagnosed. However, in 2018, after receiving Priority Review, Breakthrough Therapy Designation, Fast Track Status, and classification as an orphan drug, Oxervate® (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL), Dompe U.S. Inc.) received FDA-approval as the first medication indicated for the treatment of NK.4 Additionally, Oxervate® is the first topical biological medication approved for ophthalmic use, as well as the first application of human nerve growth factor as a therapeutic treatment,5 making it an incredible innovation in eye care. This development has fundamentally changed the treatment landscape for NK and placed an even greater importance on early recognition, diagnosis, and treatment of the disease.
Figure 1. Neurotrophic keratitis is a degenerative disease of the cornea caused by damage to the sensory nerves that results in a loss of sensation and a subsequent breakdown of the corneal surface.
What are the roles of the corneal nerves?
The cornea is a highly organized tissue that requires precise homeostatic balance to provide visual function and protection for the eye. The cornea is avascular by necessity to allow for optical clarity, which means it relies heavily on the corneal nerves for nourishment and metabolic support.6,7 This is likely one of the reasons the cornea is the most densely innervated structure in the body with nearly 7,000 nerve endings for square millimeter.6,8,9 This innervation is directly and indirectly responsible for several critical functions of the cornea including sensation,6 routine epithelial cell turnover,10 wound healing,6 blinking,2 lacrimation,11,12 and maintenance of ocular surface homeostasis.6 Therefore, healthy nerve function is critical to maintaining corneal integrity and an environment conducive to optimal ocular surface health.
What happens if the nerves are damaged?
However, if the corneal nerves are damaged there is a breakdown of corneal surface integrity and function. The majority of corneal nerves originate from the ophthalmic branch of the trigeminal nerve,9 so injury to the nerve fibers at any point along this pathway can disrupt nerve function, even damage at the sensory trigeminal nuclei located in the midbrain. Corneal nerve damage diminishes corneal sensation and interrupts trophic support to the rest of the tissue causing epithelial irregularity, disrupted cell turnover, impaired healing, and altered blinking and lacrimation.11,12 Ultimately, these changes compromise the integrity of the corneal surface and lead to nonhealing epithelial defects and ulcers, and even corneal scarring and perforation.2
What causes NK?
There are many potential sources of damage to the corneal nerves and trigeminal pathway including infection, ocular surface disease, injury, systemic disease, medication use, and surgical trauma. Likely the most common source of NK is herpetic infections involving Herpes Simplex and Herpes Zoster.13 Both viruses remain dormant in sensory nerve ganglia, including the trigeminal ganglion14,15 where their presence and reactivation can damage sensory nerves resulting in NK. Chronic ocular surface disease, such as dry eye and exposure keratitis, can also lead to nerve impairment,2 as can injury, especially chemical exposure directly to the ocular surface.16 Damage related to contact lens wear and misuse is another common cause, as chronic hypoxia and microtrauma can induce NK.16
Ocular surgeries are another source of nerve damage. In LASIK and other refractive surgeries, the corneal nerves are directly severed or damaged, either through flap creation or the ablation process.17 Likewise, the corneal nerves are severed during corneal transplantation procedures including penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK).18,19 The corneal nerves can also be injured in other ocular surgeries, including retinal procedures like retinal detachment repair.20,21 Non-ocular surgeries, such as ablative procedures to treat trigeminal neuralgia and tumor removal, may also cause NK22. Iatrogenic nerve damage can be seen in conditions like glaucoma, in which chronic exposure to preservatives like benzalkonium chloride (BAK) occurs with long-term topical drop use.23 The use of timolol and betaxolol, specifically, have been associated with the development of NK, as has use of topical NSAIDs like diclofenac.16,24,25 Similarly, the abuse of topical anesthetics can result in NK.16,24,25
Other causes of NK include systemic diseases that affect the nerves, such as diabetes and multiple sclerosis,2,26 while genetic and congenital conditions like Riley-Day syndrome, Goldenhar-Gorlin syndrome, Moebius syndrome, and familial corneal hypoesthesia may cause NK as well.1 Diabetes is especially a concern, as it is reaching epidemic levels,27 and its propensity to cause peripheral neuropathy confers a risk for NK development, creating a large population at risk for the disease. Additionally, a tumor or aneurysm can lead to compressive injury of the nerves of the trigeminal pathway, while a stroke can cause ischemic damage, which can also result in NK.2,28
What are the signs and symptoms of NK?
The signs and symptoms of NK are directly related to disrupted nerve function and the associated breakdown of the corneal surface. Depending on the signs present, the condition is categorized into one of three stages based on the Mackie Classification System.28 However, the finding that is diagnostic of NK is reduced or absent corneal sensation, which occurs at all stages1,16. Patients may also exhibit conjunctival injection, photophobia, epiphora, tear film dysfunction, and neovascularization at any stage.28-30 Furthermore, NK is degenerative, so if left untreated it will likely progress from a mild to severe stage, making early detection and treatment critical.
Stage 1, mild NK, consists of epithelial disruption which can exist as epithelial irregularity or superficial punctate epithelial keratopathy.28 Symptomatically, these patients may have complaints similar to dry eye including difficulty with prolonged computer use or light sensitivity.
Figure 2. Stage 1; mild NK.
Stage 2, moderate NK, involves the presence of nonhealing, persistent epithelial defects (PEDs).28
Figure 3. Stage 2, moderate NK.
Stage 3, severe NK, includes corneal ulceration with stromal involvement.28 At this stage the patient is at risk for stromal melting, perforation, and scarring that may permanently impact vision.28 In some cases, an anterior chamber reaction with hypopyon formation can occur.28
Figure 4. Stage 3, severe NK.
At Stages 2 or 3, vision may be significantly impacted if an epithelial defect or ulcer occurs centrally. Corneal edema can be present as well.28 The PEDs and ulcers present in NK tend to exhibit smooth, rolled edges, which are characteristic of NK.28
Another defining feature of NK is that any corneal defect present will often be painless, even significant PEDs and ulcers, due to reduced or absent corneal sensation. This phenomenon lends itself to the phrase “stain without pain”, as these lesions will stain with vital dyes, sometimes dramatically, but the patient will exhibit little or no pain in proportion to their clinical signs. This is the reason some NK patients are completely asymptomatic.
How is NK diagnosed?
As stated previously, the ultimate diagnosis of NK is based upon a reduction or absence of corneal sensitivity, which is pathognomonic for the disease.1,16 Therefore, the key to diagnosing NK is sensitivity testing, especially as the signs and symptoms of NK in its early stage can be subtle and nonspecific and mirror other conditions, like dry eye. While corneal sensitivity testing is essential for diagnosing NK, there are several ways this testing can be performed. While the Cochet–Bonnet aesthesiometer is the gold standard for measuring corneal sensitivity, several items commonly found in any clinic can be used to quickly and easily assess nerve function. Some of the most frequently used items include the tip of a tissue, a wisp made from the tip of a cotton tip applicator, or dental floss. Sensitivity is tested by touching the implement to the corneal surface and assessing the patient’s response. If the patient noticeably blinks or recoils that indicates normal sensation. If the patient barely feels the touch or feels nothing, even with greater applied pressure, this indicates reduced or absent sensation. As this is a qualitative test, it is recommended that eye care providers (ECPs) practice sensitivity testing on patients with normal corneal sensitivity to establish a baseline for a normal testing response. Sensitivity can be classified as normal, reduced, or absent, and sensation can be assessed at one location or in multiple areas of the cornea based on practitioner preference. Sensitivity testing must be performed prior to the instillation of any topical anesthetic, and ideally prior to the instillation of any topical drop. If topical anesthetic has been applied before testing could be performed, it is recommended that the patient return at another time for testing.
Figure 5. Reduced or absent corneal sensitivity is diagnostic for NK.
What are the treatments for NK?
The treatment options for NK range from surface lubrication to surgical intervention depending on severity. Artificial tears, autologous serum, soft bandage contact lenses with antibiotic coverage, and amniotic membranes can all be used in the management of NK.2,29 Topical steroids and NSAIDs should be avoided as they impede healing and increase the chance of corneal melting.1,31-33 The goal of these treatments is to stabilize the ocular surface and prevent progression. Likewise, surgical procedures, such as tarsorrhaphy or a conjunctival flap, are used in advanced cases with significant corneal degeneration to protect the corneal surface and prevent further breakdown.2,29 However, none of these treatments address the underlying cause of NK. This is where Oxervate® differs, as it is the only therapy that directly treats the root cause of NK by repairing damaged nerves and restoring their function, which in turn restores corneal surface integrity.34 Additionally, any existing comorbidities, such as dry eye, should also be addressed, especially if they were a causative factor in the initial development of NK.
What is Oxervate®?
Cenegermin-bkbj, the active ingredient in Oxervate,® is a recombinant form of human nerve growth factor (rhNGF), which is structurally identical to endogenous NGF found in ocular tissue.35 NGF is naturally produced by the corneal epithelium, keratocytes, and the lacrimal gland36,37 and is a critical component to the maturation and maintenance of the corneal nerves and the overall health of the cornea.2,6,10 NGF is also capable of repairing and regenerating damaged nerves and enhancing corneal epithelium proliferation and wound healing10,36 through binding to high-affinity TrkA and low-affinity p75NTR NGF receptors.34 Additionally, NGF helps maintain a healthy ocular surface environment by stimulating tear production through the lacrimal gland and ensuring proper blinking through maintenance of corneal innervation and sensation, both of which are critical components of tear film stability.2,10 These various functions of NGF make it an ideal treatment for NK.
Figure 6. Oxervate® is the first FDA-approved medication indicated for the treatment of NK.
What is the REPARO Study?
The REPARO Study was the largest combined population study of patients with NK ever performed.38 The study included a diverse subject pool, with subject ages ranging from 2 years old to over 65, and with varying etiologies of NK.39 The study specifically looked at Stages 2 and 3 of NK, meaning all subjects enrolled had PEDs or ulceration. The patients in the study received Oxervate 6 times per day for 8 weeks, and at the end of this period 72% of subjects demonstrated complete healing which was defined as the absence of staining of the corneal lesion and no persistent staining in the rest of the cornea after 8 weeks of OXERVATE treatment in patients with stage 2/3 NK.39 And at a 48-week follow-up, nearly 80% of these patients displayed sustained healing, demonstrating that Oxervate provides robust, lasting recovery for patients affected by NK.39 Although the trial only looked at Stages 2 and 3, Oxervate is approved for the treatment of all stages of NK.40,41
Figure 7. Endogenous NGF is believed to support corneal integrity through 3 mechanisms
1. Corneal Innervation: The cornea, a highly sensitive tissue, is densely innervated with sensory nerve fibers via the ophthalmic branch of the trigeminal nerve. In neurotrophic keratitis, this corneal innervation is impaired, ultimately impacting the health and function of the cornea (46,47). 2. Tear Secretion: NGF binds receptors on lacrimal glands to promote tear secretion and facilitates sensory-mediated reflex tearing, potentially protecting from pathogens and injury (48,49). 3. Cell Proliferation and Differentiation: NGF stimulates proliferation, differentiation, and survival of corneal epithelial cells (3).
How do you prescribe Oxervate®?
Since its official launch in the U.S. in 2018, over 1,700 eye care professionals have prescribed Oxervate® to treat more than 10,000 patients affected by NK.42 Because Oxervate is an orphan drug with a very specific indication, the prescribing process is slightly different than for the typical medication. Rather than sending the prescription directly to a pharmacy, Oxervate is prescribed through the Dompé CONNECT to Care program. After diagnosing a patient with NK, the ECP or a staff member fills out a short application which the patient signs. The form is then sent to the Dompé CONNECT to Care team, who check the patient’s insurance benefits to see if any prior authorization is required. If Oxervate is covered, the process of sending the medication to the patient is initiated. However, even if coverage is denied, Dompé CONNECT to Care works with several organizations and foundations that help provide financial assistance, so almost every patient who needs Oxervate can receive the medication at a low, affordable cost.
How is Oxervate® used?
After a patient’s prescription is approved, their supply of Oxervate is shipped directly to them. Patients will receive two weeks of therapy at a time. Oxervate is dosed 6 times per day (every 2 hours) for 8 weeks in the affected eye. If the patient is a contact lens wearer, contact lenses should be removed prior to drop instillation, then wait 15 minutes after instillation of the dose before reinserting the contact lenses into the eyes. Dompé’s Oxervate Patient Support Program website (https://Oxervate.com/taking-Oxervate/)43 is an excellent resource for patients, with step-by-step instructions explaining how to use and administer Oxervate. Patients using Oxervate are often seen at 4-week intervals corresponding to the halfway point of treatment, the end of treatment, and one month post-treatment with further follow-ups determined by their presentation at that time.
Figure 8. Oxervate® is dosed 6 times per day for 8 weeks.
What are the side effects of Oxervate®?
Oxervate is extremely well tolerated and there are no contraindications to its use.44 The most common side effect is eye pain, which occurs in about 16% of cases.34 This discomfort can be mild to moderate, and it is helpful to discuss this potential side effect ahead of time and to reassure patients that it is normal and a sign the medication is working, as they are regaining sensation in their nerves. Other less common side effects include hyperemia, inflammation, epiphora, foreign body sensation, and corneal deposits (1-10% of patients).34 These side effects, along with ocular pain, are usually mild and transient.39,45 Oxervate is safe to use in patients as young as 2 years of age. There are no safety data for Oxervate when used during pregnancy or nursing, but animal models showed no adverse effects when used during these periods.44
Visit https://oxervate.com/hcp/#isi for full important safety information.
This is a promotional article about Oxervate® written on Dompe's behalf, and has been reviewed consistent with Dompe US Inc. internal review policies.
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- Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-579.
- Versura P, Giannaccare G, Pellegrini M, Sebastiani S, Campos EC. Neurotrophic keratitis: current challenges and future prospects. Eye Brain. 2018;10:37-45.
- Murri, N. Goodman & Gilman Year in Review Biologics FDA Approvals In: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill Medical, 2018.
- Dompé Receives FDA Approval of Oxervate®, the First Drug for Neurotrophic Keratitis. Eyewire News. https://eyewire.news/news/dompe-receives-fda-approval-of-Oxervate®-a-first-in-class-treatment-of-neurotrophic-keratitis. Published August 23, 2018. Accessed October 28, 2021.
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- Shaheen BS, Bakir M, Jain S. Corneal nerves in health and disease. Surv Ophthalmol. 2014;59(3):263-285.
- Cruzat A, Qazi Y, Hamrah P. In vivo confocal microscopy of corneal nerves in health and disease. Ocul Surf. 2017;15(1):15-47.
- Walker HK. Cranial nerve v: the trigeminal nerve. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Butterworths; 1990.
- 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.
- Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. Cornea. 1996;15(2):135-138.
- Jabbarvand M, Hashemian H, Khodaparast M, Rafatnejad A, Beheshtnejad A, Salami A. Do unilateral herpetic stromal keratitis and neurotrophic ulcers cause bilateral dry eye? Cornea. 2015;34(7):768-772.
- Labetoulle M, Auquier P, Conrad H, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology. 2005;112(5):888-895.
- Ahmad B, Patel BC. Herpes simplex keratitis. In: StatPearls. StatPearls Publishing; 2021.
- Minor M, Payne E. Herpes zoster ophthalmicus. In: StatPearls. StatPearls Publishing; 2021.
- Chang BH, Groos EB Jr: Neurotrophic keratitis; in Krachmer JH, Mannis MJ, Holland EJ eds. Cornea. London, Elsevier, 2011.
- Dohlman TH, Lai EC, Ciralsky JB. Dry eye disease after refractive surgery. Int Ophthalmol Clin. 2016;56(2):101-110.
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- Lin X, Xu B, Sun Y, Zhong J, Huang W, Yuan J. Comparison of deep anterior lamellar keratoplasty and penetrating keratoplasty with respect to postoperative corneal sensitivity and tear film function. Graefes Arch Clin Exp Ophthalmol. 2014;252(11):1779-1787.
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- Kahook MY, Ammar DA. In vitro toxicity of topical ocular prostaglandin analogs and preservatives on corneal epithelial cells. J Ocul Pharmacol Ther. 2010;26(3):259-263.
- Ammar DA, Noecker RJ, Kahook MY. Effects of benzalkonium chloride-preserved, polyquad-preserved, and sofZia-preserved topical glaucoma medications on human ocular epithelial cells. Adv Ther. 2010;27(11):837-845.
- Hyndiuk RA, Kazarian EL, Schultz RO, Seideman S. Neurotrophic corneal ulcers in diabetes mellitus. Arch Ophthalmol. 1977;95(12):2193-2196.
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- Muzi S, Colafrancesco V, Sornelli F, Mantelli F, Lambiase A, Aloe L. Nerve growth factor in the developing and adult lacrimal glands of rat with and without inherited retinitis pigmentosa. Cornea. 2010;29(10):1163-1168.
- Dompé receives Industry Innovation Award from the National Organization for Rare Disorders for the Development of Oxervate®™ eye drops (cenegermin-bkbj), for neurotrophic keratitis. Dompe.US. https://www.dompe.us/media/press-releases/the-galien-foundation-debuts-2019-prix-galien-usa-nominees-in-best-biotechnology-product-best-pharmaceutical-product-and-best-medical-technology-categories-1. Published March 12, 2019. Accessed October 28, 2021.
- 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.
- About Neurotrophic Keratitis. OXERVATE® (cenegermin-bkbj). https://Oxervate®.com/hcp/neurotrophic-keratopathy/. Published October 8, 2021. Accessed October 28, 2021.
- Saricay LY, Bayraktutar B, Lilley J, Massaro-Giordano M, Hamrah P. Efficacy and Tolerability of Cenegermin for Stage 1 Neurotrophic Keratopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):374.
- OXERVATE® – How it Works and FDA Approval. OXERVATE® (cenegermin-bkbj). Dompé U.S. Inc, Data on File. Dompé U.S. Inc.; 2020. https://Oxervate®.com/hcp/mechanism-of-action/. Published October 8, 2021. Accessed October 28, 2021.
- Taking Oxervate® - OXERVATE® Patient Support Program. OXERVATE® (cenegermin-bkbj). https://Oxervate®.com/taking-Oxervate®/. Published June 17, 2020. Accessed October 28, 2021.
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- 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.
- Müller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and function. Exp Eye Res. 2003 May;76(5):521-542.
- Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-579.
- Mastropasqua L, Massaro-Giordano G, Nubile M, Sachetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J. Cell Physiol. 2017 Apr;232;(4):717-724.
- Muzi S, Colafrancesco V, Sornelli F, et al. Nerve growth factor in the developing and adult lacrimal glands of rat with and without inherited retinitis pigmentosa. Cornea. 2010;29:1163-1168.