AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Neurotrophic keratopathy is a degenerative disease characterized by decreased corneal sensitivity and poor corneal healing. This disease leaves the cornea susceptible to injury and decreases reflex tearing. Epithelial breakdown can lead to ulceration, infection, melting, and perforation secondary to poor healing.

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.

Denervation 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.

Frequency

United States

Of anesthetic corneas, 15% will develop serious complications. Of the 40,000-60,000 cases of herpes zoster ophthalmicus occurring each year, 50% will have ocular involvement. Of these, 16% will demonstrate some form of neurotrophic keratopathy.

Mortality/Morbidity

• Blurred vision secondary to epithelial irregularity, neovascularization, or corneal scarring
• Secondary infection of nonhealing epithelial defects
• Corneal perforation following stromal melting

Race

No racial differences exist.

Sex

No gender differences exist.

Age

The incidence of neurotrophic keratopathy increases with age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• A careful medical and surgical history should be taken searching for 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
  • Diabetes mellitus
  • 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

• Cranial nerve examination can help to localize the cause for 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.
• External examination
• • Assess cranial nerve VII function not only for its value in localizing the cause of hypesthesia but for its prognostic value. Poor lid closure promotes exposure and can hasten progression.
  • The presence of scars from surgery, chemical burns, or thermal burns can give clues to the cause of the hypesthesia.
  • Ectropion, lagophthalmos, or thyroid ophthalmopathy increase the risk of progression.
• Ocular surface examination
• • Carefully examine the function of the tear film for its impact on the management of neurotrophic keratopathy.
  • Assess corneal sensitivity. Complete this assessment with a piece of twisted cotton or the corner of a tissue. A Cochet-Bonnet esthesiometer is a device that can give a quantitative measurement of corneal sensitivity. It 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 those patients with readings of 2 cm or less developed epithelial sloughing and ulceration.
  • Slit lamp examination may show indications of the underlying cause for 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.
• The Mackie classification for neurotrophic keratopathy
• • Stage 1
    • Rose bengal staining of the inferior palpebral conjunctiva
    • Decreased tear break-up time
    • Increased mucous viscosity
    • Punctate epithelial fluorescein staining
  • Stage 2
    • Epithelial defect, usually oval and in the superior cornea
    • Defect surrounded by rim of loose epithelium
    • Edges may become smooth and rolled
    • Stromal swelling with folds in Descemet membrane
    • Sometimes associated with anterior chamber inflammatory
      action
  • Stage 3
    • Stromal lysis/melting
    • May result in perforation
• Anterior segment examination may reveal iris atrophy from prior herpetic infection or an anterior chamber inflammatory reaction.
• Dilated funduscopy
• • Optic nerve swelling or pallor may indicate an orbital or retroorbital lesion. Diabetic retinopathy could indicate the likelihood of diabetic neuropathy.
  • Laser scars from panretinal photocoagulation may indicate ciliary nerve damage.

Causes

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.

• Infection
• • Herpes simplex
  • Herpes zoster
  • Leprosy
• Fifth nerve palsy
• • 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
• • Anesthetics
  • Timolol
  • Betaxolol
  • Sulfacetamide
  • Diclofenac sodium
  • Ketorolac
• Corneal dystrophies
• • Lattice
  • Granular
• Systemic disease
• • Diabetes mellitus
  • Vitamin A deficiency
  • Multiple sclerosis
• Iatrogenic
• • Contact lens wear
  • Trauma to ciliary nerves by laser treatment and surgery
  • Corneal incisions
  • Laser in situ keratomileusis (LASIK)
• Toxic
• • Chemical burns
  • Carbon disulfide exposure
  • Hydrogen sulfide exposure
• Miscellaneous
• • Increasing age
  • Dark eye color
  • Adie syndrome

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Exposure keratopathy
Limbal deficiency
Topical anesthetic abuse

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Bacterial cultures: 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. Conjunctival epithelium is negative for cytokeratin 3 and positive for cytokeratin 19.

Imaging Studies

• Obtain an MRI of the brain and orbits when any associated neurologic deficit or the etiology of corneal hypesthesia is in doubt.

Procedures

• Corneal esthesiometry: Measurement of corneal sensitivity is crucial for diagnosis and prognosis.

Histologic Findings

• 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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Stage 1
  • Topical lubrication with preservative-free artificial tears, gels, and ointments
  • Discontinue any topical ocular therapy, especially those that can decrease corneal sensitivity (timolol, betaxolol, sulfacetamide, diclofenac, ketorolac) or contain preservatives.
  • Reevaluate 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 every other day can reduce the amount of mucus produced.
• Stage 2
  • All of stage 1 treatments
  • Topical tetracycline has been reported to increase 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
  • More likely to require surgical intervention than stage 1
• Stage 3
  • All of stage 1 and stage 2 treatments
  • Surgical intervention
• Medications to avoid
  • Topical corticosteroids may increase collagenase activity and increase stromal melting.
  • Topical NSAIDs have not shown any benefit in wound healing and diclofenac and ketorolac use can decrease corneal sensitivity.
• Future treatments
• • Nerve growth factor has been shown to induce healing of stage 3 keratopathy in one open, uncontrolled study.
  • Aldose reductase inhibitor, CT-112, has been shown to reverse abnormal morphology of corneal epithelial cells and increase corneal sensitivity.
  • Topical pindolol has been reported to speed healing of epithelial defects in rabbits.

Surgical Care

Surgical care for neurotrophic keratopathy has 3 goals, as follows: (1) to protect the epithelium by lid closure, (2) to close a persistent epithelial defect, and (3) to repair a deep ulceration.

• Closure of the lids - 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
• • Conjunctival flap - Effective but poor cosmetic and visual result
  • Amniotic membrane transplantation
• Repair of a deep ulceration
• • Lamellar keratoplasty
  • Penetrating keratoplasty - For large defects
  • Multilayer amniotic membrane transplantation - Has been used in defects as deep as 90% of the stroma
  • Cyanoacrylate glue with a soft bandage contact lens - For defects smaller than 2.0 mm

Consultations

Consult a neurologist if the cause for corneal hypesthesia is not apparent or if any associated neurologic deficits are present.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medications are available that can improve corneal sensitivity. The medications used in the treatment of neurotrophic keratopathy are adjunctive to lubrication and surgical intervention.

Drug Category: Antibiotics

The tetracyclines have shown anti-inflammatory and anticollagenolytic activity.

Drug Category: Cycloplegics

These agents relieve pain associated with iridocyclitis.

Drug Category: Lubricants

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

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

Further Outpatient Care

• Patients with stage 1 neurotrophic keratopathy can be monitored on an outpatient basis every 3-7 days.
• Patients with stage 2 neurotrophic keratopathy should be monitored on an outpatient basis every 1-2 days until improvement is seen, then every 3-5 days until resolution.

Deterrence/Prevention

• Educate all patients with corneal hypesthesia about their condition.
• Carefully evaluate patients with herpes simplex or herpes zoster for corneal hypesthesia.
• Carefully evaluate patients undergoing surgery for trigeminal neuralgia or acoustic neuroma for corneal hypesthesia postoperatively.

Complications

• Corneal perforation
• Secondary bacterial keratitis
• Permanent decrease in acuity from corneal scarring and irregular astigmatism

Prognosis

• Negative prognostic indicators include degree of sensory loss, duration of condition, and presence of other ocular surface disease.

Patient Education

• Instruct these patients to seek evaluation immediately if the eye becomes red or if the vision changes. They need to understand that serious conditions may not cause them any pain.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose and treat aggressively
• Failure to identify an underlying cause for corneal hypesthesia, such as a tumor or aneurysm

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Allen VD, Malinovsky V. Management of neurotrophic keratopathy. Cont Lens Anterior Eye. Sep 2003;26(3):161-5. [Medline].
• Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. Jul 2000;107(7):1347-51; discussion 1351-2. [Medline].
• Bonini S, Rama P, Olzi D. Neurotrophic keratitis. Eye. Nov 2003;17(8):989-95. [Medline].
• Cavanagh HD, Colley AM. The molecular basis of neurotrophic keratitis. Acta Ophthalmol Suppl. 1989;192:115-34. [Medline].
• Cohen EJ, Rapuano CJ. Neurotrophic keratopathy. In: Friedberg MA, Rapuano CJ, eds. Wills Eye Hospital office and emergency room diagnosis and treatment of eye. 54-55.
• Fogle JA, Kenyon KR, Foster CS. Tissue adhesive arrests stromal melting in human cornea. Am J Ophthalmol. 1980;89:795-802. [Medline].
• Groos EB. Neurotrophic keratitis. In: Krachmer JH, ed. Cornea: Fundamentals of Corneal and External Disease. St. Louis: Mosby;1997: 1339-62.
• 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. Mar 1995;119(3):288-94. [Medline].
• Kruse FE, Rohrschneider K, Volcker HE. Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology. 1999;106:1504-1510. [Medline].
• Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy. Curr Opin Ophthalmol. Aug 1999;10(4):270-6. [Medline].
• Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. Apr 23 1998;338(17):1174-80. [Medline].
• Latvala T, Linna T, Tervo T. Corneal nerve recovery after photorefractive keratectomy and laser in situ keratomileusis. Int Ophthalmol Clin. 1996;36:21-27. [Medline].
• Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye. Oct 7 2005;[Medline].
• Lugo M, Arentsen JJ. Treatment of neurotrophic ulcers with conjunctival flaps. Am J Ophthalmol. May 15 1987;103(5):711-2. [Medline].
• Mackie IA. Neuroparalytic keratitis. In: Fraunfelder F, Roy FH, eds. Current Ocular Therapy. 5th ed. Philadelphia: WB Saunders; 2000;369-371.
• Matsumoto Y, Dogru M, Goto E. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. Jun 2004;111(6):1115-20. [Medline].
• Parmar DN, Alizadeh H, Awwad ST. Ocular surface restoration using non-surgical transplantation of tissue-cultured human amniotic epithelial cells. Am J Ophthalmol. Feb 2006;141(2):299-307. [Medline].
• 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. Dec 2001;85(12):1455-63. [Medline].
• Schrader S, Wedel T, Moll R. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol. Mar 17 2006;[Medline].
• Solomon A, Meller D, Prabhasawat P. Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology. Apr 2002;109(4):694-703. [Medline].

Article Last Updated: Aug 24, 2006