Neurotrophic Keratitis

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Assigned status Update Pending by Cat Nguyen Burkat, MD FACS on July 30, 2019.

Disease Entity

Neurotrophic keratitis, neurotrophic keratopathy (NK)


NK is a corneal degenerative disease characterized by a reduction or absence of corneal sensitivity. In NK, corneal innervation by the trigeminal nerve is impaired.


The epidemiology of NK is still uncertain. As a rare disease, its estimated prevalence is less than 50/100,000 individuals.[1]


Every ocular or systemic condition which alters corneal sensory innervation—which runs from the cornea itself to the pontine trigeminal nucleus—can result in NK.

  • Most common ocular conditions associated with NK are herpes keratitis (zoster and simplex), topical anesthetic abuse, chemical and physical burns, contact lens abuse, topical drug toxicity, irradiation to eye or adnexa, and corneal surgery.
  • Ocular surgery can also induce NK.
  • With regards to corneal procedures, both laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) have been linked to NK.[2] [3][4]The incidence of transient nerve damage, however, seems to be significantly higher in LASIK than in PRK.[5] Corneal transplantation surgery, and specifically penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) can cause some degree of corneal denervation. Specifically, lower corneal sensitivity has been reported 12 months after surgery,[6] although NK in the setting of a PK is not a common finding. Endothelial keratoplasties (DSAEK or DMEK) does not significantly affect central corneal sensitivity and, thus, may not be associated with NK.[7] A reduction of corneal sensation was also observed in keratoconus eyes following collagen crosslinking.[8]
  • Vitrectomy for retinal detachment and photocoagulation to treat diabetic retinopathy have been associated with development or worsening of NK.[9]
  • Routine, single session, indirect laser for proliferative diabetic retinopathy has also been reported as a possible cause of NK.[10]
  • Non-ocular causes include neurosurgical procedures or trauma damaging the fifth cranial nerve, stroke, aneurisms, multiple sclerosis, intracranial masses (e.g. VIII c.n. neurinoma), diabetes (NK has been described as the sole sign of diabetes in a patient),[11] leprosy, vitamin A deficiency, and drugs (narcoleptics and antipsychotics). Congenital hypoplasia of the trigeminal nerve has also been described in association with NK.[12]

Risk Factors

Risk factors for NK are those related with the underlying etiology.

General Pathology

A number of histological alterations are seen in corneas of patients with NK, including thinning/disruption of the epithelial layer, cytoplasmic swelling of epithelial cells, loss of microvilli, disorganization of Bowman’s membrane, stromal melting/scarring and corneal neovascularization. The conjunctiva is also involved with a reduction in goblet cell density and in cell-surface microplicae. Evidence in animal models suggests that NK may also affect corneal neovascularization[13] and stem cell populations.[14]



Medical and surgical history should be accurately reviewed, with a special stress on ocular and systemic conditions discussed in the Etiology section.


Since corneal sensory innervation is impaired in NK, patients do not commonly complain of ocular surface symptoms. This makes NK particularly challenging, as patients may seek medical advice months or years after the disease has started. Sometimes, however, blurred vision can be reported due to irregular epithelium or epithelial defects (PED), scarring, or edema.

Physical Examination

Clinical presentation of NK ranges from subtle corneal surface irregularities to corneal melting and perforation. NK is usually graded in three different stages in accordance to the “Mackie classification”.[15]

  • Stage I is characterized by hyperplasia and/or irregularity of the epithelium, evolving to punctate keratopathy, corneal edema, neovascularization, stromal scarring.
  • Stage II is defined by a recurrent or persistent epithelial defects or a PED, most commonly in the superior half of the cornea. The PED is usually oval in shape and its margins are characteristically smooth and rolled due to impaired epithelial healing.
  • In stage III, stromal involvement leads to corneal ulcer, melting and perforation.

Diagnostic Procedures

  • Corneal sensitivity should be evaluated in patients with suspected NK. Corneal sensitivity can be roughly assessed using a cotton swab or quantitatively determined with a corneal aesthesiometer (e.g. Cochet-Bonnet contact aesthesiometer, CRCERT-Belmonte non-contact aesthesiometer).[16]
  • Corneal staining with fluorescein is performed in order to highlight epithelial changes. Other vital stains (i.e. lissamine green or rose Bengal) can be used to evaluate corneal/conjunctival integrity.
  • Schirmer test should be performed to evaluate tear production, which can be impaired as a result of reduction in corneal sensitivity.
  • It should be noted that any eye drops should be applied AFTER having tested corneal sensitivity as they could otherwise alter this measurement.
  • Corneal scrapings and cultures can be performed to exclude bacterial, viral, fungal or parasitic infections, which may be associated with reduced corneal sensitivity.

Differential Diagnosis

The finding of a corneal lesion in absence of ocular symptoms (due to corneal anesthesia) is highly suspicious of NK. However, early-stage NK should be differentiated from other disorders, including dry eye, topical drug toxicity, exposure keratitis, contact lens abuse, chemical injury and limbal stem cells deficiency, which can also be associated with some degree of NK. The fact that herpes infections also reduce corneal sensitivity should be kept in mind, since pure NK is sterile. Acanthamoeba keratitis often causes intense ocular pain, but it should be noted that it can also be associated with some degree of corneal anesthesia.[17]


General Management

The management of NK aims to promote corneal healing and avoid complications. Patients with NK should use preservative free eye medications, as epithelial drug toxicity could complicate the disease. Ocular surface diseases other than/associated with NK (i.e. dye eye, blepharitis, exposure keratitis, limbal stem cell deficiency) should be properly treated. Topical NSAIDs should be avoided in patients with NK because they did not show any benefit in healing and they can further decrease corneal sensitivity.[18] Therapy of NK depends on disease stage.

  • In punctate keratopathy (stage I), the therapeutic goal is to improve the quality and transparence of epithelium and to avoid epithelial breakdown. At this stage, frequent application of preservative free artificial eye drops and lubricant ointments is suggested. In cases of persistent keratopathy, autologous serum could be used. Also, therapeutic soft contact lens could improve the quality of vision in some cases.
  • If a PED (stage II) develops, the aim of the therapy is to promote PED healing and prevent the development of a corneal ulcer. Treatment includes (i) the use of unpreserved artificial tears, lubricant ointments, (ii) therapeutic soft contact lenses or patching, (iii) topical autologous serum application,[19][20] (iv) amniotic membrane grafting,[20] (v) tarsorrhaphy or botulinum induced ptosis, and (vi) topical Nerve Growth Factor application. Antibiotic eye drops can be prescribed to prevent bacterial infections.[1] Topical corticosteroids can be administered to control inflammation cautiously, as they could induce stromal melting.[21]
  • In stage III NK, therapy focuses on ulcer healing and prevention of corneal perforation. In addition to the therapy suggested for stages 1 and 2, N-acetilcysteine, oral tetracycline and medroxyprogesterone can be prescribed in case of stromal melting.

Recombinant Human Nerve Growth Factor (rhNGF), administered topically, showed promising results, as it achieved complete corneal healing in all patients treated affected by stages II and III disease.[22][23][24] A recent randomized clinical trial is studying safety and efficacy of recombinant human Nerve Growth Factor (rhNGF) in stage II-III NK.

ReGeneraTing Agent (RGTA) polymer eye drops (Cacicol20®, OTR3, Paris, France) have also been proposed to treat NK but its efficacy has to be confirmed. In a clinical study, they promoted neurotrophic ulcer healing in 8 out of 11 eyes (73%) after 8.7 weeks.[25]

Finally, if corneal perforation occurs, the treatment varies: in case of small size the application of cyanoacrylate glue and soft bandage contact lens or amniotic membrane is performed. In case of a larger defect a tectonic perforating or lamellar keratoplasty can be performed.

Surgical Management

In recent years, Corneal neurotization has become an increasingly explored topic in the management of neurotrophic keratitis. Neurotization of the cornea typically transfers the supraorbital or supratrochlear nerve to either directly or indirectly with a nerve graft (i.e. sural nerve) to the neurotrophic cornea. Neurotization and nerve reconstruction is well established for use in reinnervation of peripheral nerve injuries[26] . Corneal neurotization was first investigated in 2009[27] with promising results and prompted many studies to further examine this procedure.

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[27][28][29][30][31]. It is worth noting that neurotization of the cornea is an extensive surgery that requires a high level of experience shared between Neurosurgery, Cornea, and Oculoplastics.


The follow-up of NK depends on disease stage. Patients with stage I disease should be closely monitored on an outpatient basis, due to the risk of asymptomatic disease progression. In stage II, patients should be evaluated on outpatient basis more frequently, ideally every 1-2 days, until improvement occurs. In stage III, admission to an inpatient unit should be considered until the risk of perforation is reduced.[32]


Prognosis of patients affected by NK depends on disease stage, degree of anaesthesia and association with other ocular surface diseases. The surgical outcome of keratoplasty in patients affected by NK is generally poor due to impairment in wound healing and risk of PED recurrence.

Additional Resources

  1. AAO, Basic and Clinical Science Course. Section 8: External Disease and Cornea, 2015-2016.
  2. AAO, Focal Points: Neurotrophic Keratitis, Module #2, 2003.


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