Neurotrophic Keratopathy



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 keratopathy include the degree of sensory loss, the duration of the condition, and the presence of other ocular surface disease. The incidence of neurotrophic keratopathy 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):

Mackie classification

Stage 1 of neurotrophic keratopathy demonstrates the following:

Stage 2 is characterized as follows:

Stage 3 is characterized as follows:

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 keratopathy 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 keratopathy 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 keratopathy.

Causes associated with fifth-nerve palsy are as follows:

Topical medications that can cause neurotrophic keratopathy are as follows:

Corneal dystrophies include the following:

Systemic diseases that can cause neurotrophic keratopathy are as follows:

Iatrogenic causes are as follows:

Toxic causes are as follows:

Miscellaneous causes are as follows:


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

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 keratopathy.[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.

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 keratopathy are as follows:

Approach Considerations

Pharmacologic care for neurotrophic keratopathy 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 keratopathy. Such treatment has 3 goals, as follows:

Inpatient care

Patients with stage 3 neurotrophic keratopathy 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 keratopathy 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 keratopathy are as follows:

Pharmacologic Therapy

Treatment for stage 1 neurotrophic keratopathy is as follows:

Stage 2 treatment is as follows:

Treatment for stage 3 neurotrophic keratopathy is as follows:

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] :

Repair of a deep ulceration

The following can be used in ulceration repair:

Medication Summary

No medications are available that can improve corneal sensitivity. The medications used in the treatment of neurotrophic keratopathy, 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[22] for neurotrophic keratopathy may include the following:


Clinical Context:  Tetracycline may have anticollagenolytic properties that improve symptoms.

Doxycycline (Doryx, Vibramycin, Alodox, Adoxa)

Clinical Context:  This agent also may have anticollagenolytic properties that improve symptoms.

Class Summary

The tetracyclines have shown anti-inflammatory and anticollagenolytic activity.

Atropine ophthalmic (Isopto, Atropine Care)

Clinical Context:  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.

Class Summary

These agents relieve pain associated with iridocyclitis.

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

Clinical Context:  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

The goal of a lubricant is to keep as much moisture in the eye as possible and to reduce irritation.[27]


Robert H Graham, MD, Consultant, Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona

Disclosure: Partner received salary from Medscape/WebMD for employment.


Mark A Hendrix, MD, Consulting Staff, Department of Ophthalmology, Suburban Hospital, Shady Grove Hospital

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.


Stephen D Plager, MD, FACS Chief, Department of Ophthalmology, Dominican Hospital; Assistant Clinical Professor, Department of Ophthalmology, Stanford University Hospital

Stephen D Plager, MD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, American Society of Cataract and Refractive Surgery, and California Medical Association

Disclosure: Nothing to disclose.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Institute

Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology

Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; RPS Ownership interest Other; EyeGate Pharma Consulting fee Consulting; Bausch & Lomb Honoraria Speaking and teaching; Bausch & Lomb Consulting; Merck Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment


  1. Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye. 2003 Nov. 17(8):989-95. [View Abstract]
  2. Cohen EJ, Rapuano CJ. Neurotrophic keratopathy. Friedberg MA, Rapuano CJ, eds. Wills Eye Hospital office and emergency room diagnosis and treatment of eye. 54-55.
  3. Groos EB. Neurotrophic keratitis. Krachmer JH, ed. Cornea: Fundamentals of Corneal and External Disease. Mosby: St. Louis; 1997. 1339-62.
  4. Fogle JA, Kenyon KR, Foster CS. Tissue adhesive arrests stromal melting in the human cornea. Am J Ophthalmol. 1980 Jun. 89(6):795-802. [View Abstract]
  5. Okada Y, Reinach PS, Kitano A, Shirai K, Kao WW, Saika S. Neurotrophic keratopathy; its pathophysiology and treatment. Histol Histopathol. 2010 Jun. 25(6):771-80. [View Abstract]
  6. Hauck MJ, Harold Lee H, Timoney PJ, Shoshani Y, Nunery WR. Neurotrophic Corneal Ulcer After Retrobulbar Injection of Chlorpromazine. Ophthal Plast Reconstr Surg. 2011 Nov 11. [View Abstract]
  7. Pavan-Langston D, Dohlman CH. Boston keratoprosthesis treatment of herpes zoster neurotrophic keratopathy. Ophthalmology. 2008 Feb. 115(2 Suppl):S21-3. [View Abstract]
  8. Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye. 2006 Jul. 20(7):837-9. [View Abstract]
  9. Latvala T, Linna T, Tervo T. Corneal nerve recovery after photorefractive keratectomy and laser in situ keratomileusis. Int Ophthalmol Clin. 1996 Fall. 36(4):21-7. [View Abstract]
  10. Allen VD, Malinovsky V. Management of neurotrophic keratopathy. Cont Lens Anterior Eye. 2003 Sep. 26(3):161-5. [View Abstract]
  11. Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy. Curr Opin Ophthalmol. 1999 Aug. 10(4):270-6. [View Abstract]
  12. Reynolds SA, Kabat AG. Therapeutic options for the management of early neurotrophic keratopathy: a case report and review. Optometry. 2006 Oct. 77(10):503-7. [View Abstract]
  13. Mackie IA. Neuroparalytic keratitis. Fraunfelder F, Roy FH, eds. Current Ocular Therapy. 5th ed. Philadelphia: WB Saunders; 2000. 369-371.
  14. Weyns M, Koppen C, Tassignon MJ. Scleral contact lenses as an alternative to tarsorrhaphy for the long-term management of combined exposure and neurotrophic keratopathy. Cornea. 2013 Mar. 32(3):359-61. [View Abstract]
  15. Guadilla AM, Balado P, Baeza A, Merino M. [Effectiveness of topical autologous serum treatment in neurotrophic keratopathy]. Arch Soc Esp Oftalmol. 2013 Aug. 88(8):302-6. [View Abstract]
  16. Lee YC, Kim SY. Treatment of neurotrophic keratopathy with nicergoline. Cornea. 2015 Mar. 34 (3):303-7. [View Abstract]
  17. Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance p-derived peptide and insulin-like growth factor 1. Jpn J Ophthalmol. 2007 Nov-Dec. 51(6):442-7. [View Abstract]
  18. Lugo M, Arentsen JJ. Treatment of neurotrophic ulcers with conjunctival flaps. Am J Ophthalmol. 1987 May 15. 103(5):711-2. [View Abstract]
  19. Prabhasawat P, Tesavibul N, Komolsuradej W. Single and multilayer amniotic membrane transplantation for persistent corneal epithelial defect with and without stromal thinning and perforation. Br J Ophthalmol. 2001 Dec. 85(12):1455-63. [View Abstract]
  20. Kruse FE, Rohrschneider K, Volcker HE. Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology. 1999 Aug. 106(8):1504-10; discussion 1511. [View Abstract]
  21. Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology. 2002 Apr. 109(4):694-703. [View Abstract]
  22. Goins KM. New insights into the diagnosis and treatment of neurotrophic keratopathy. Ocul Surf. 2005 Apr. 3(2):96-110. [View Abstract]
  23. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000 Jul. 107(7):1347-51; discussion 1351-2. [View Abstract]
  24. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998 Apr 23. 338(17):1174-80. [View Abstract]
  25. Lambiase A, Sacchetti M, Bonini S. Nerve growth factor therapy for corneal disease. Curr Opin Ophthalmol. 2012 Jul. 23(4):296-302. [View Abstract]
  26. Hosotani H, Ohashi Y, Yamada M, Tsubota K. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112. Am J Ophthalmol. 1995 Mar. 119(3):288-94. [View Abstract]
  27. Grey F, Carley F, Biswas S, Tromans C. Scleral contact lens management of bilateral exposure and neurotrophic keratopathy. Cont Lens Anterior Eye. 2012 Aug 14. [View Abstract]
  28. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004 Jun. 111(6):1115-20. [View Abstract]
  29. Parmar DN, Alizadeh H, Awwad ST, et al. Ocular surface restoration using non-surgical transplantation of tissue-cultured human amniotic epithelial cells. Am J Ophthalmol. 2006 Feb. 141(2):299-307. [View Abstract]
  30. Schrader S, Wedel T, Moll R, Geerling G. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol. 2006 Oct. 244(10):1345-9. [View Abstract]
  31. Yamada N, Matsuda R, Morishige N, et al. Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulin-like growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy. Br J Ophthalmol. 2008 Jul. 92(7):896-900. [View Abstract]