The cornea is the most richly innervated structure in the body; in neurotrophic keratopathy (NK), this inherent feature is compromised. NK is a degenerative condition that involves partial or complete absence of corneal sensitivity as a result of damage to the trigeminal-corneal pathway anywhere from brainstem to the corneal nerves.1 This leads to a variety of corneal pathologies, including surface irregularities, epithelial defects, stromal ulceration, and even corneal perforation.1 Although it has a relatively low incidence (at about 5/10,000 people), it is an important diagnosis to keep in mind—if left untreated, it can progress to severe and sometimes permanent vision loss.1
There are numerous underlying ocular and systemic conditions which, through different mechanisms, can compromise corneal sensory innervation. Ultimately, this impaired sensation leads to the reduction of protective corneal reflexes and trophic neuromodulators that are essential for wound healing, metabolism, and vitality of the ocular surface. Some etiologies of NK are gradual and insidious, while others are more rapidly progressive. We will discuss these below.
Toxicity to the Ocular Surface
The most common ocular causes of NK are those that directly damage either cornea or corneal nerve via viral infections, chemical (including topical medications), and physical (including surgical) damage.1 NK develops in almost 6% of herpetic keratitis cases, with herpes simplex virus (HSV) having a much higher prevalence than herpes zoster virus (HZV).2,3 Chronic use of topical drugs such as anesthetics, glaucoma medications, antivirals, antibiotics, and NSAIDs can all cause corneal toxicity. Benzalkonium chloride (BAK) is often used as a preservative in topical medications, including over-the-counter (OTC) artificial tears; this may reduce corneal sensitivity by damaging nerves and therefore impact corneal epithelial healing.1,4
Dry eye syndrome can also potentiate and/or aggravate NK.1,4,5 Chronic inflammation and irritation of the ocular surface can be due to a myriad of ocular causes, such as meibomian gland dysfunction, blepharitis, ocular rosacea, corneal dystrophies, lagophthalmos, entropion, and ectropion.1,4,5
Ocular trauma, physical and chemical burns, contact lens abuse, and irradiation to cornea are some other forms of physical damage to the ocular surface that can potentiate NK.5
Surgical conditions associated with NK
Several ocular procedures may either damage corneal or ciliary nerves. Corneal procedures, such as laser assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), limbal relaxing incisions (LRI), penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), as well as collagen cross linking (CXL), have been associated with NK.6-10 Endothelial keratoplasties (DSAEK or DMEK), however, may not be significantly associated—this may be due to less manipulation of the ocular surface and smaller incision sizes.11
In some cases, blepharoplasties may also be associated with corneal nerve damage; this is usually secondary to the inadvertent creation of exposure keratopathy.12
Even retinal procedures such as pars plana vitrectomy (PPV) and panretinal photocoagulation (PRP) have been associated with the development or worsening of neurotrophic keratopathy.13,14
Some neurosurgical procedures may induce NK. Surgery for trigeminal neuralgia, acoustic neuroma, microvascular decompression, balloon compression, radiofrequency thermocoagulation, and gamma knife radiosurgery may also induce permanent damage to the trigeminal nerve with subsequent production of corneal anesthesia.15
Systemic conditions associated with NK
Systemic diseases that cause neuropathies, such as diabetes, Sjogren Syndrome, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and thyroid disease may lead to progressive damage to the trigeminal nerve.1,5,16 Some rare congenital conditions such as Moebius syndrome, Riley-Day syndrome, Goldenhar-Gorlin syndrome are associated with congenital corneal anesthesia secondary to damage to the trigeminal nerve.17
Neurological conditions due to aneurysm, stroke, or palsies; facial trauma, intracranial and intraorbital tumors can all permanently damage the trigeminal-corneal pathway at different levels.15,18 NK of various stages may result from these neurologic conditions. In addition, side effects of chemoradiation therapy and other systemic drugs such as antihistamines, diuretics, beta-blockers, and antipsychotics have been associated with trigeminal nerve toxicities.15,16,18
Sensory innervation of the cornea is derived from the ophthalmic and maxillary divisions of the trigeminal nerve as well as by autonomic nerves.1 Corneal nerves and corneal epithelial cells support each other mutually through the release of trophic factors that promote epithelial cell proliferation, migration, and differentiation as well as nerve development and survival.1,5,19,20
Additionally, corneal nerves provide important protective and growth functions that play an essential role in tear production and preservation of the normal metabolism and function of the ocular surface.19-21 Corneal epithelial cells release various neurotrophic modulators including nerve growth factor (NGF), fundamental in ocular surface homeostasis and wound healing.19 An interruption of corneal innervation may result in altered epithelial morphology and function, poor tear film, and delayed wound healing. Impairment of corneal sensory innervation is seen to be linked with the release of pro-inflammatory substances that attenuate the protective reflexes and trophic neuromodulators essential for the vitality of ocular surface tissues.5,19
Normal corneal sensitivity is greatest at its center and decreases towards the periphery; this correlates with the distribution of the sensory nerve terminals.19,21 Touching the cornea triggers one of the most sensitive protective reflexes of the human body—the corneal blink reflex.1,19-21 This reflex is triggered by mechanical, chemical and thermal stimuli involving two different reflex arcs: the motor arc, which elicits blinking, and the autonomous arc, which stimulates tear secretion.19-21 Thus, reduction of corneal sensitivity impairs these two reflex arcs with an alteration of production and stability of the tear film. The threshold of sensitivity, especially in the center of the cornea, is exceedingly low in NK; this is therefore used as an important diagnostic and prognostic factor.20
Pathogenesis of NK is multifactorial in origin due to changes at various tissue and cellular levels. It is common to note chronic inflammation of the ocular surface involving the cornea as well as conjunctiva.5,19,20 Corneal denervation causes decreased vitality, metabolism, and mitosis of the epithelium with subsequent disruption of epithelial cells due to intracellular swelling and loss of microvilli.19-21 This leads to disorganization of Bowman’s membrane—and if untreated, can progress to stromal melting and scarring, as well as corneal neovascularization.21 Chronic conjunctival inflammation leads to squamous metaplasia of conjunctival epithelium with a decrease in goblet cell density: this leads to less mucus production into the tears, and thus a poorer quality tear film.5,19-21 A decreased quantity of tears and/or quality of the tear film creates a hyperosmolar state and can lead to a diminished limbal stem cell population.5,22,23 A decrease in limbal stem cells impairs corneal healing and regeneration.
With an unstable tear film and ocular surface, nociceptors are also activated and may release pro-inflammatory substances such as endothelin, substance-P, neurokinin-A, and most significantly matrix metalloproteinases (MMPs), which can contribute to the creation of an epithelial defect. If corneal inflammation if left unchecked, it can progress to stromal damage including melts, ulcers, and even corneal perforation.5,11,20
Making a Diagnosis
Coming to a definitive diagnosis for NK requires a thorough evaluation, including a detailed history with a focus on the etiologies mentioned earlier, complete ocular exam, and measurement of corneal sensitivity. Assessment of the disease stage at the time of presentation is important as it determines treatment options.
Since corneal sensory innervation is compromised in NK, patients may not have ocular surface symptoms. However, changes in vision may be reported due to punctate keratopathy, irregular epithelium or epithelial defects, scarring, or edema.19,20
A careful slit lamp examination of the cornea and its surrounding structures is necessary to rule in or rule out certain mechanisms of pathology that may aid in early diagnosis and prompt treatment of NK. Additionally, clinical signs of NK may be broken down into 3 stages, per the Mackie classification.20,24
Stage-I is characterized by epithelial irregularities without epithelial defect. There may be accompanying punctate keratopathy, corneal edema, epithelial hyperplasia/irregularity, conjunctival staining, increased tear viscosity and decreased tear breakup time (TBUT).5,19-21
Stage-II is characterized by persistent epithelial defect (PED) without stromal involvement. The PED is commonly located paracentrally in the superior half of the cornea.5,11,19-21 It usually takes on an oval shape with characteristically smooth and rolled margins due to impaired epithelial healing. Descemet's folds and anterior chamber inflammation may be observed.11,19-21
Stage-III is characterized by deeper stromal involvement leading to ulceration, melting and possibly corneal perforation.11,19-21
Besides the signs mentioned above, slit lamp exam may reveal ocular surface and adnexal findings related to/contributing to NK. For example, eyelid abnormalities such as lagophthalmos, ectropion/entropion, and lid scarring may relate to chronic corneal exposure, loss of sensation and formation of PED.11,19-21,24 Corneal scars may indicate previous surgery, injury or infections. Superficial corneal neovascularization, stromal scarring, and patchy iris atrophy may be suggestive of previous herpetic infections.2,5,11 Ocular surface staining with vital dyes (e.g. fluorescein or lissamine green) can be used to assess corneal and conjunctival epithelial integrity.
Defects in tear film production should be evaluated: increased tear osmolarity, decreased tear volume on Schirmer’s test, decrease in TBUT, and decreased rate of blinking can all be suggestive of NK.5,11 Even fundus exam may reveal clues to NK diagnosis, as changes due to diabetic retinopathy (commonly seen with neuropathies), scars from laser treatments, and optic nerve abnormalities due to intracranial pathology may point the ophthalmologist in the direction of proper treatment and further steps in workup.11-13
Other Diagnostic Procedures
Testing Corneal Sensation: As the hallmark of NK is lack of normal sensation, testing for corneal sensation is key to diagnosis. Normal corneal sensitivity is greatest at its center and decreases towards the periphery.11 The threshold of sensitivity, especially in the center of the cornea, gets exceedingly low in NK and should be used as an important diagnostic and prognostic factor.11,19
A simple quantitative measure for corneal sensation is testing if the patient is able to feel a wisp of cotton or tissue. A qualitative measure can be performed using aesthesiometry.11,24 This is done with a Cochet-Bonnet contact aesthesiometer or CRCERT-Belmonte non-contact aesthesiometer.24 Here, a filament of specific length is touched to the patients unanesthetized cornea; the length of the filament needed to elicit sensation is recorded, and can be used to objectively record severity of NK, as well as a marker for improvement during treatment.11,24
Confocal Microscopy: In vivo confocal microscopy (IVCM) is a noninvasive imaging technique that allows the in vivo study of different layers of the ocular surface at a cellular level. Specifically, it can evaluate corneal nerve morphology. Significant reduction of corneal nerve density is strongly correlated with decreased corneal sensation in NK, and can help confirm diagnosis in certain cases.11,19-21,24
Differential and Important Diagnostic Considerations
NK should always be suspected in case of a significant discrepancy between corneal signs and ocular symptoms. Out of all the corneal signs, corneal anesthesia (or hypoesthesia) is the hallmark of NK.11, 24 However, certain conditions may mimic these signs to a certain degree, such as severe dry eye syndrome, certain drug toxicities, contact lens overuse and its complications, exposure keratitis, physical or chemical injury, and limbal cell deficiency.5,11,19-21 Corneal ulcers purely due to NK are typically sterile (but may get superimposed infections); although past herpetic corneal infection could be an underlying mechanism towards the development of NK.2,3,11 Furthermore, active herpetic infections can also cause ulcers and hypoesthesia, but they differ clinically from NK in time of onset, appearance, and involvement of deeper ocular structures.1-3 Ulcers caused by Acanthamoeba are commonly very painful. However, rarely, they can also be associated with some degree of corneal anesthesia.25
The management of NK is typically stage dependent. Therefore, an early diagnosis and treatment is very important to improve outcome. Stages I and II can usually be managed with medications/conservatively, whereas stage III may require more invasive/surgical treatments.1,11,19-21 The goal of any management plan is to promote healing and prevent complications. Other aspects to consider are minimizing corneal exposure, decreasing inflammation with suitable medication, minimizing risk of superimposed infections (topical antibiotics, if needed) and creating an environment to help re-epithelialize and restore corneal nerves.11 If possible, any of the underlying etiological mechanisms mentioned earlier should be truncated. Topical medications with preservatives, for any stage, should be avoided as they can worsen epithelial toxicity.5,11,19-21 Topical NSAIDs have not shown to benefit in healing and have shown to further decrease corneal sensitivity, hence should be avoided as well.26 Below we outline a brief review of Stage-based therapies for NK.
Management of Stage-I
The goals of treatment here aim at healing the corneal epithelium and prevention of progression to more advanced stages of NK. At this stage, frequent application of preservative-free artificial eye drops and lubricant ointments is suggested. Punctal plugs may be beneficial as well. Prompt treatment of ocular surface disease and limbal stem cell deficiency is necessary. Topical cyclosporine may be used as well, as it appears to reduce inflammation and improve the tear film, however, it has not been shown to improve corneal sensitivity.1,5,11,19-21 Topical autologous serum eye drops contain growth factors, neuromodulators, cytokines and vitamins that can help promote epithelial cell proliferation, migration and differentiation required for corneal homeostasis and wound healing.27,28 Topical corticosteroids can be administered to control inflammation cautiously, as they may inhibit the healing process and in rare cases increase risk of stromal melting.29
Management of Stage-II
Treatment here aims to promote healing of persistent epithelial defects and prevent progression to stromal ulceration.1,11,19 Frequent monitoring may be required as an ulcer may develop without any symptoms. In addition to topical lubricants, a topical antibiotic is often recommended to prevent superinfection.1 Therapeutic soft contact lenses or patching may be employed to promote corneal healing as they can maintain a fluid layer in stable contact with the cornea and protect it from constant friction induced by the eyelids blinking.11
Cenegermin (Oxervate™) is the first FDA approved topical medication for NK that contains recombinant human nerve growth factor (rhNGF).19-21 Its topical administration has been shown to promote corneal healing and repair nerve damage on the ocular surface associated with NK.30-32 Two randomized clinical trials have demonstrated its efficacy over vehicle in a selective population of patients with NK stage II or III.33,34 The FDA recommended dose of 20mcg/ml vials is six times daily for 8 weeks.33,34 Ocular pain is a notable side effect—some think this may be related to restoration corneal sensitivity.19-21,33,34
Amniotic membrane placement can be preemptively considered in this stage as well as it provides mechanical protection, releases growth factors and supports epithelial cell adhesion and proliferation.5,11,28
Management of Stage-III
Here, treatment is focused on ulcer healing and preventing corneal perforation. Often, more invasive measures are needed to manage eyes that have reached this severity of NK. In addition to the treatment management strategies for stages I and II, N-acetylcysteine, oral tetracycline and medroxyprogesterone can be prescribed in case of stromal melting with some success.11,28 If the treatment response of an ulcer is very slow, or if there is impending perforation or frank corneal perforation, surgical management becomes inevitable.
Surgeries focused towards reducing the width of palpebral fissure can minimize corneal exposure and maintain a healing environment for slow healing corneal ulcers due to NK.
Tarsorrhaphy In this technique, eyelids are partially sutured together from the lateral canthus, reducing the width of the palpebral fissure, protecting the cornea from traumatic rubbing of the eyelids and decreasing tear evaporation rate.11,29
Botulinum induced ptosis. Another method of decreasing corneal exposure is injection of botulinum toxin into the levator palpebrae superioris muscle. This temporarily paralyzes the muscle, inducing ptosis and may be used as an effective alternative to surgical tarsorrhaphy as it permits easier exam of ocular surface.1,11,29
Conjunctival (Gundersen) flap. In this technique, a conjunctival flap is fashioned and mobilized from the upper bulbar conjunctiva and sutured to the conjunctiva at the lower limbus to cover the affected cornea. It provides metabolic and mechanical support for corneal healing.1,11,31 Conjunctival blood vessels transport nutrients and growth factors to the corneal surface. This aims to restore anatomical integrity of the ocular surface but sacrifices visual function. However, it can be reversed surgically once the ocular surface has adequately healed.
Amniotic membrane placement When placed on slow-healing ulcers, an amniotic membrane can offer mechanical protection. It also releases growth factors and supports epithelial cell adhesion and proliferation to aid in healing.1,11,19
Small perforations can be easily sealed with the application of cyanoacrylate glue and soft bandage contact lens. An amniotic membrane can also be placed.1,11
Large perforations require penetrating or lamellar keratoplasty to be performed. However, due to persistent corneal anesthesia, wound healing may be impaired and there is a high risk of recurrence of corneal ulceration in the graft.1,11,19 This is probably the reason for lower success rate of corneal transplantation in patients with NK.
Neurotization and nerve reconstruction is well established for use in reinnervation of peripheral nerve injuries. Corneal neurotization for the management of NK is a newer treatment modality with promising results and has prompted many studies to further examine this procedure.35,36 Results thus far reveal neurotization leads to improvement in corneal sensation, improvement in visual acuity, and reduction of symptoms for months to years after surgery.36
Direct neurotization: This is the transposition of the supraorbital and/or supratrochlear nerves to the affected area. Contralateral healthy supraorbital and supratrochlear nerves are harvested through a large coronal incision, tunneled across the bridge of the nose, and inserted around the limbus of the anesthetic eye.35,36
Indirect neurotization: This is the transposition of the sural nerve. Autograft is anastomosed to the supratrochlear nerve and then tunneled through the upper eyelid incision. It enables management of bilateral NK and avoids large bicoronal incisions.35,36
Depending on the stage, close monitoring and frequent follow up may be required. The length of treatment is difficult to be estimated: depending on the underlying mechanism it may even be for life.1,11 Symptoms may remit and relapse during treatment.1,11 Hence, patients must be educated openly about the nature of their condition, the importance of close follow up and good compliance to ensure better outcomes. Educating accompanying family members and involving primary care doctors in patient education may also improve compliance and outcomes.
Prognosis of NK depends on a number of factors—the stage of the disease, degree of anesthesia, other ocular surface diseases, and underlying systemic diseases. For ophthalmologists managing NK, proper staging and aggressive early treatment planning, as well as the involvement of a supportive team can lead to the best possible outcome.
- Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clinical ophthalmology 2014;8:571-9.
- Dworkin R.H., Johnson R.W., Breuer J. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007;44(Suppl. 1):S1–26.
- Labetoulle M, Auquier P, Conrad H, Crochard A, Daniloski M, Bouee S, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology. 2005;112(5):888–95.
- Labbe A, Alalwani H, Van Went C, Brasnu E, Georgescu D, Baudouin C. The relationship between subbasal nerve morphology and corneal sensation in ocular surface disease. Invest Ophthalmol Vis Sci 2012;53(8):4926-31.
- TFOS DEWS II REPORT. Ocul Surf 2017; 15(3):269-283
- Kauffmann T, Bodanowitz S, Hesse L, Kroll P. Corneal reinnervation after photorefractive keratectomy and laser in situ keratomileusis: an in vivo study with a confocal videomicroscope. German journal of ophthalmology 1996;5:508-12.
- Wilson SE. Laser in situ keratomileusis-induced (presumed) neurotrophic epitheliopathy. Ophthalmology 2001;108:1082-7.
- Wilson SE, Ambrosio R. Laser in situ keratomileusis-induced neurotrophic epitheliopathy. American journal of ophthalmology 2001;132:405-6.
- 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. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2014;252:1779-87.
- Wasilewski D, Mello GH, Moreira H. Impact of collagen crosslinking on corneal sensitivity in keratoconus patients. Cornea 2013;32:899-902.
- Kumar RL, Koenig SB, Covert DJ. Corneal sensation after descemet stripping and automated endothelial keratoplasty. Cornea 2010;29:13-8.
- Versura P, Giannaccara G, Pellegrini M, Sebastiani S, Campos E. Neurotrophic keratitis: current challenges and future prospects. Eye and Brain. 2018; 10: 37-45
- Banerjee PJ, Chandra A, Sullivan PM, Charteris DG. Neurotrophic corneal ulceration after retinal detachment surgery with retinectomy and endolaser: a case series. JAMA ophthalmology 2014;132:750-2.
- Tinley CG, Gray RH. Routine, single session, indirect laser for proliferative diabetic retinopathy. Eye 2009;23:1819-23.
- Lambiase A, Sacchetti M, Mastropasqua A, Bonini S. Corneal changes in neurosurgically induced neurotrophic keratitis. JAMA Ophthalmolol. 2013; 131(12):1547-1553
- Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye 2006;20:837-9.
- Morishige N, Morita Y, Yamada N, Nishida T, Sonoda KH. Congenital hypoplastic trigeminal nerve revealed by manifestation of corneal disorders likely caused by neural factor deficiency. Case reports in ophthalmology 2014;5:181-5.
- Bonzano C, Bonzano E, Cutolo C, et al. (March 12, 2018) A Case of Neurotrophic Keratopathy Concomitant to Brain Metastasis. Cureus 10(3): e2309. doi:10.7759/cureus.2309
- Coassin M, Lambiase A, Costa N, et al. Efficacy of topical nerve growth factor treatment in dogs affected by dry eye. Graefe’s Arch Clin Exp Ophthalmol 2005;243(2):151-5
- Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000; 107:1347-51.
- Ferrari G, Hajrasouliha AR, Sadrai Z, Ueno H, Chauhan SK, Dana R. Nerves and neovessels inhibit each other in the cornea. Investigative ophthalmology & visual science 2013;54:813-20.
- Ueno H, Ferrari G, Hattori T, et al. Dependence of corneal stem/progenitor cells on ocular surface innervation. Investigative ophthalmology & visual science 2012;53:867-72
- Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care 2008; 14(3 Suppl):S102-6. Review.
- Golebiowski B, Papas E, Stapleton F. Assessing the sensory function of the ocular surface: implications of use of a non-contact air jet aesthesiometer versus the Cochet-Bonnet aesthesiometer. Experimental eye research 2011;92:408-13.
- Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update 2009. American journal of ophthalmology 2009;148:487-99 e2.
- Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal agents and corneal wound healing. Archives of ophthalmology 1990;108:577-83.
- Jeng BH, Dupps WJ, Jr. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea 2009;28:1104-8
- Turkoglu E, Celik E, Alagoz G. A comparison of the efficacy of autologous serum eye drops with amniotic membrane transplantation in neurotrophic keratitis. Seminars in ophthalmology 2014;29:119-26.
- Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye 2003;17:989-95.
- Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347-51; discussion 51-2.
- Lambiase A, Bonini S, Aloe L, Rama P, Bonini S. Anti-inflammatory and healing properties of nerve growth factor in immune corneal ulcers with stromal melting. Archives of ophthalmology 2000;118:1446-9.
- Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. The New England journal of medicine 1998;338:1174-80.
- 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. Ophthalmol. 2018;125(9):1332–433.
- 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. Ophthalmol. 2020;127(1):14–6.
- Terzis JK, Dryer MM, Bodner BI. Corneal neurotization: a novel solution to neurotrophic keratopathy. Plast Reconstr Surg. 2009 Jan;123(1):112-20
- Ting DSJ, Figueiredo GS, Henein C, et al. Corneal neurotization for neurotrophic keratopathy: clinical outcomes and in vivo confocal microscopic and histopathological findings. Cornea 2018; 37:641–646.