Neurotrophic Keratitis 

Updated: Sep 13, 2018
Author: Robert H Graham, MD; Chief Editor: Hampton Roy, Sr, MD 



Neurotrophic keratitis, also known as neurotrophic keratopathy, is a degenerative disease characterized by decreased corneal sensitivity and poor corneal healing. This disorder leaves the cornea susceptible to injury and decreases reflex tearing. Epithelial breakdown can lead to ulceration, infection, melting, and perforation secondary to poor healing. (See Etiology and Pathophysiology.)[1, 2, 3]

Prognostic indicators in neurotrophic keratitis include the degree of sensory loss, the duration of the condition, and the presence of other ocular surface disease. The incidence of neurotrophic keratitis increases with age. (See Presentation and Workup.)


Fifteen percent of anesthetic corneas in the United States develop serious complications; these can include the following (see Etiology and Pathophysiology, Presentation, Workup, Treatment, and Medication):

  • Secondary bacterial keratitis

  • Blurred vision secondary to epithelial irregularity, neovascularization, or corneal scarring

  • Corneal perforation following stromal melting[4]

Mackie classification

Stage 1 of neurotrophic keratitis demonstrates the following:

  • Rose bengal staining of the inferior palpebral conjunctiva

  • Decreased tear breakup time

  • Increased mucous viscosity

  • Punctate epithelial fluorescein staining

Stage 2 is characterized as follows:

  • Epithelial defect - Usually oval and in the superior cornea

  • Defect surrounded by a rim of loose epithelium

  • Edges may become smooth and rolled

  • Stromal swelling with folds in the Descemet membrane

  • Sometimes associated with anterior chamber inflammatory

  • action

Stage 3 is characterized as follows:

  • Stromal lysis/melting

  • May result in perforation

Patient education

Educate all patients with corneal hypesthesia about their condition. Instruct patients to seek evaluation immediately if the eye becomes red or if their vision changes. Patients need to understand that serious conditions may not cause them any pain.

Etiology and Pathophysiology

The common factor in all cases of neurotrophic keratitis is corneal hypesthesia. Sensory nerves exert a trophic influence on the corneal epithelium. The sensory neuromediators acetylcholine, substance P, and calcitonin gene-related peptide have been shown to increase epithelial cell proliferation in vitro.[5]

Denervation, on the other hand, results in decreased cell metabolism, increased permeability, decreased levels of acetylcholine, and decreased cell mitosis. Because a continuous turnover of corneal epithelial cells occurs, this can lead to an epithelial defect even in the absence of injury. Sympathetic neuromediators and prostaglandins decrease epithelial cell mitosis. In fact, ipsilateral sympathetic denervation appears to mitigate the effects of corneal sensory denervation.


The causes of neurotrophic keratitis are conditions that decrease corneal sensitivity. The most common of these are herpetic infections of the cornea, surgery for trigeminal neuralgia, and surgery for acoustic neuroma.[6]

Infectious causes are as follows:

Of the 40,000-60,000 cases of herpes zoster ophthalmicus occurring each year in the United States, 50% have ocular involvement. Of these, 16% demonstrate some form of neurotrophic keratitis.

Causes associated with fifth-nerve palsy are as follows:

  • Surgery for trigeminal neuralgia
  • Neoplasia (acoustic neuroma)
  • Aneurysms
  • Facial trauma
  • Congenital
  • Familial dysautonomia (Riley-Day syndrome)
  • Goldenhar-Gorlin syndrome
  • Möbius syndrome
  • Familial corneal hypesthesia

Topical medications that can cause neurotrophic keratitis are as follows:

  • Anesthetics
  • Timolol
  • Betaxolol
  • Sulfacetamide
  • Diclofenac sodium
  • Ketorolac

Corneal dystrophies include the following:

  • Lattice
  • Granular

Systemic diseases that can cause neurotrophic keratitis are as follows:

  • Diabetes mellitus [8]
  • Vitamin A deficiency
  • Multiple sclerosis

Iatrogenic causes are as follows:

  • Contact lens wear
  • Trauma to ciliary nerves by laser treatment and surgery
  • Corneal incisions
  • Laser in situ keratomileusis (LASIK) [9]

Toxic causes are as follows:

  • Chemical burns
  • Carbon disulfide exposure
  • Hydrogen sulfide exposure

Miscellaneous causes are as follows:

  • Increasing age
  • Dark eye color
  • Adie syndrome



A careful medical and surgical history should be obtained. Inquire about the following:

  • Previous surgical or traumatic injury to the trigeminal nerve, ocular surgery, or laser treatment, which may have damaged the ciliary nerves

  • Previous herpetic eye disease or a history of herpes zoster ophthalmicus[7]

  • Diabetes mellitus[8]

  • Use of topical medications, including potential abuse of topical anesthetics or nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Use of contact lenses

  • Exposure to chemical fumes

Physical Examination

Poor lid closure promotes exposure and can hasten progression, while the presence of scars from surgery, chemical burns, or thermal burns can provide clues as to the cause of the hypesthesia. Ectropion, lagophthalmos, or thyroid ophthalmopathy increase the risk of progression.

Cranial nerve examination

A cranial nerve examination can help to localize the cause of corneal hypesthesia. Pupillary abnormality may indicate pathology of the intraconal orbit or cavernous sinus or may reveal an Adie pupil. Dysfunction of cranial nerves III, IV, and VI may indicate an aneurysm or cavernous sinus pathology. Dysfunction of cranial nerves VII and VIII may indicate acoustic neuroma or injury from its resection.

Cranial nerve VII function should be assessed not only because of its value in localizing the cause of hypesthesia but also because of its prognostic value.

Ocular surface examination

The function of the tear film should be carefully examined for its impact on the management of neurotrophic keratitis.[10, 11] Corneal sensitivity should be assessed as well; to do so, a piece of twisted cotton or the corner of a tissue is used.


A Cochet-Bonnet esthesiometer is a device that can give a quantitative measurement of corneal sensitivity, a determination that is diagnostically and prognostically crucial.

The esthesiometer consists of a nylon filament, which can be extended from the device to different lengths and touched to the cornea until it bends or the patient responds. The small diameter of the instrument allows accurate testing of different areas of the cornea. The shorter the length of filament required, the less sensitive the cornea. In one study, only patients with readings of 2 cm or less developed epithelial sloughing and ulceration.

Slitlamp examination

Slitlamp examination may show indications of the underlying cause of corneal hypesthesia. These include herpetic epithelial disease, stromal scarring from previous infection, lattice or granular stromal dystrophy, and enlarged or beaded corneal nerves from leprosy.

Anterior segment examination

This may reveal iris atrophy from a prior herpetic infection or an anterior chamber inflammatory reaction.

Dilated funduscopy

Optic nerve swelling or pallor may indicate an orbital or retro-orbital lesion. Diabetic retinopathy could indicate the likelihood of diabetic neuropathy. Laser scars from panretinal photocoagulation may indicate ciliary nerve damage.



Diagnostic Considerations

Conditions to consider in the differential diagnosis of neurotrophic keratitis include the following:

  • Exposure keratopathy
  • Limbal deficiency
  • Topical anesthetic abuse

Carefully evaluate patients with herpes simplex or herpes zoster for corneal hypesthesia. Patients undergoing surgery for trigeminal neuralgia or acoustic neuroma should be carefully evaluated postoperatively for corneal hypesthesia.

Differential Diagnoses



Approach Considerations

Lab studies

Any dense stromal infiltrate should be cultured for bacterial keratitis prior to instituting antibiotic therapy.

Viral cultures or immunofluorescence staining may be necessary if herpes simplex or herpes zoster is suspected but is not distinguishable clinically.

Impression cytology may be necessary to rule out limbal deficiency. Corneal epithelium is positive for cytokeratin 3 and negative for cytokeratin 19, while conjunctival epithelium is negative for cytokeratin 3 and positive for cytokeratin 19. If impression cytology from the limbal area shows significant cytokeratin 19 (indicative of conjunctival epithelium) and little cytokeratin 3 (which indicates little corneal epithelium), then the impression cytology would indicate limbal stem cell deficiency.


A magnetic resonance imaging (MRI) scan of the brain and orbits is obtained when any associated neurologic deficit or the etiology of corneal hypesthesia is in doubt.

Histologic Findings

Histologic findings in neurotrophic keratitis are as follows:

  • Decreased epithelial thickness with loss of surface desquamating layer
  • Decreased epithelial cell glycogen
  • Loss of surface cell microvilli
  • Intracellular swelling of remaining surface epithelial cells
  • Areas of abnormal basal lamina
  • Decreased goblet cell density in conjunctiva
  • Increased length of surface microvilli


Approach Considerations

Pharmacologic care for neurotrophic keratitis varies by stage with regard to the number and types of drugs used for treatment.

Surgical care may be necessary in stage 2 or 3 neurotrophic keratitis. Such treatment has 3 goals, as follows:

  • Protect the epithelium by lid closure
  • Close a persistent epithelial defect
  • Repair a deep ulceration

Inpatient care

Patients with stage 3 neurotrophic keratitis should be hospitalized for daily follow-up care until significant improvement is seen.


Consult a neurologist if the cause of corneal hypesthesia is not apparent or if any associated neurologic deficits are present.[12]


Patients with stage 1 neurotrophic keratitis can be monitored on an outpatient basis every 3-7 days.

Patients with stage 2 disease should be monitored on an outpatient basis every 1-2 days until improvement is seen, then every 3-5 days until resolution.


Medications to avoid in patients with neurotrophic keratitis are as follows:

  • Topical corticosteroids - These may increase collagenase activity and stromal melting
  • Topical NSAIDs - These have not shown any benefit in wound healing, and diclofenac and ketorolac use can decrease corneal sensitivity

Pharmacologic Therapy

Treatment for stage 1 neurotrophic keratitis is as follows:

  • Topical lubrication with preservative-free artificial tears, gels, and ointments
  • Discontinuation of any topical ocular therapies, especially those that can decrease corneal sensitivity (eg, timolol, betaxolol, sulfacetamide, diclofenac, ketorolac) or that contain preservatives [13]
  • Reevaluation of the need for systemic drugs, such as neuroleptics, antipsychotics, and antihistamines.
  • Punctal occlusion may need to be considered.
  • Oral tetracycline (250 mg PO bid) or doxycycline (100 mg PO qod) can reduce the amount of mucus produced
  • Weyns et al proposed scleral contact lenses as a valid long-term alternative to standard treatment options in patients with neurotrophic keratitis. [14]
  • Gaudilla et al note 20% autologous topical serum is an effective treatment for stages 1 and 2 neurotrophic keratitis. [15]
  • Lee and Kim reported that oral nicergoline helped heal corneal epithelial defects among patients who did not respond to conventional therapy. Additionally, in patients treated with nicergoline, levels of tear nerve growth factors were higher than levels before treatment. [16]

Stage 2 treatment is as follows:

  • All of stage 1 treatments
  • Topical tetracycline reportedly increases the healing of epithelial defects (not available in an ophthalmic drop preparation)
  • Topical cycloplegia with atropine 1% or scopolamine 0.25% once daily in the presence of anterior chamber inflammation
  • Patients with stage 2 disease are more likely to require surgical intervention than are those with stage 1 disorder

Treatment for stage 3 neurotrophic keratitis is as follows:

  • All of stage 1 and stage 2 treatments
  • Surgical intervention

Surgical Repair of Eyelids, Epithelial Defects, and Ulcerations

Closure of the eyelids

In the presence of severe or total loss of corneal sensation, keratitis sicca, or exposure keratopathy, a lateral tarsorrhaphy, palpebral spring, or botulinum A toxin injection in the levator muscle may prevent progression to stage 2.

Closure of a persistent epithelial defect

Repair options for such lesions include the following[17] :

  • Conjunctival flap - Effective, but poor cosmetic and visual result[18]

  • Amniotic membrane transplantation[19]

Repair of a deep ulceration

The following can be used in ulceration repair:

  • Lamellar keratoplasty

  • Penetrating keratoplasty - For large defects

  • Multilayer amniotic membrane transplantation - Has been used in defects as deep as 90% of the depth of the stroma[20, 21]

  • Cyanoacrylate glue with a soft bandage contact lens - For defects smaller than 2 mm

Medical Care

In August 2018, the FDA approved the first drug for neurotrophic keratitis, cenegermin (Oxervate). Cenegermin is a recombinant nerve growth factor.

Approval was based on the REPARO study (n=156). Patients were randomized 1:1:1 to cenegermin 10 mcg/mL, 20 mcg/mL, or vehicle. At week 4, 19.6% of vehicle-treated patients achieved corneal healing (< 0.5-mm lesion staining) compared with 54.9% receiving cenegermin 10 mcg/mL (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P< 0.001) and 58% receiving cenegermin 20 mcg/mL (P< 0.001).

At week 8, 43.1% of vehicle-treated patients achieved corneal healing compared with 74.5% receiving cenegermin 10 mcg/mL (P = 0.001) and 74% receiving 20 mcg/mL (P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between cenegermin and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled cenegermin treatment remained recurrence free during 48-week follow-up.[22]

Currently not FDA approved, but available in Europe, is a heparin sulfate biomimetic (Cacicol), which acts as a matrix regenerating agent; this agent has been shown to be effective in treating neurotrophic keratitis and to have antiviral effects against HSV-1 and VZV.[23, 24]

Surgical Care

Corneal Re-innervation Surgery

Recent studies have shown that corneal neurotization using contralateral supraorbital or supratrochlear nerves, or via sural nerve transplantation from the calf, can successfully restore corneal sensation and improve ocular surface health in patients with neurotrophic keratitis.[25, 26, 27]



Medication Summary

The first recombinant nerve growth factor, cenegermin, was approved by the FDA in August 2018 for treatment of neurotrophic keratitis. Cenegermin targets the nerve pathology.[28, 29, 30, 22]

Other medications used in the treatment of neurotrophic keratitis, including antibiotics and cycloplegics, are adjunctive to lubrication and surgical intervention. The number and types of medications vary according to the disease stage.

Future treatments[31] for neurotrophic keratitis may include the following:

  • Aldose reductase inhibitor, CT-112 - Has been shown to reverse abnormal morphology of corneal epithelial cells and to increase corneal sensitivity [32]
  • Topical pindolol - Has been reported to speed the healing of epithelial defects in rabbits

Recombinant Human Nerve Growth Factor

Class Summary

The first recombinant form of human nerve growth factor was approved by the FDA in August 2018. Nerve growth factor is an endogenous protein involved in the differentiation and maintenance of neurons, which acts through specific high-affinity (ie, TrkA) and low-affinity (ie, p75NTR) nerve growth factor receptors in the anterior segment of the eye to support corneal innervation and integrity.

Cenegermin (Oxervate)

Cenegermin is indicated for treatment of neurotrophic keratitis. It is an ophthalmic solution instilled in affected eye(s) 6 times each day at 2-hr intervals for 8 weeks.


Class Summary

The tetracyclines have shown anti-inflammatory and anticollagenolytic activity.


Tetracycline may have anticollagenolytic properties that improve symptoms.

Doxycycline (Doryx, Vibramycin, Alodox, Adoxa)

This agent also may have anticollagenolytic properties that improve symptoms.

Ophthalmic Lubricants

Class Summary

The goal of a lubricant is to keep as much moisture in the eye as possible and to reduce irritation.[33]

Artificial tears (Advanced Eye Relief, Murine, Bion Tears, Tears Again, Tears Naturale)

Artificial tears contain the equivalent of 0.9% NaCl and are used to maintain ocular tonicity. They stabilize and thicken precorneal tear film and prolong tear film breakup time, which occurs with dry eye states.


Class Summary

These agents relieve pain associated with iridocyclitis.

Atropine ophthalmic (Isopto, Atropine Care)

This agent acts at parasympathetic sites in smooth muscle to block the response of the sphincter muscle of the iris and the muscle of the ciliary body to acetylcholine, causing mydriasis and cycloplegia.