eMedicine Specialties > Ophthalmology > Cornea

Keratopathy, Neurotrophic

Robert H Graham, MD, Senior Associate Consultant, Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona
Mark A Hendrix, MD, Consulting Staff, Department of Ophthalmology, Suburban Hospital, Shady Grove Hospital

Updated: Feb 3, 2009

Introduction

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% develop serious complications.

Of the 40,000-60,000 cases of herpes zoster ophthalmicus occurring each year, 50% have ocular involvement. Of these, 16% 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

History

• 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
  • 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  
  • A cranial nerve examination can help 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.
• External examination
  • Cranial nerve VII function should be assessed not only for its value in localizing the cause of hypesthesia but also 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 provide clues as to the cause of the hypesthesia.
  • Ectropion, lagophthalmos, or thyroid ophthalmopathy increase the risk of progression.
• Ocular surface examination
  • The function of the tear film should be carefully examined for its impact on the management of neurotrophic keratopathy.
  • Corneal sensitivity should be assessed. 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. 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 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.
• 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 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
    • Stromal lysis/melting
    • May result in perforation
• Anterior segment examination 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 lesion or a 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

Differential Diagnoses

Other Problems to Be Considered

Exposure keratopathy
Limbal deficiency
Topical anesthetic abuse

Workup

Laboratory 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. Conjunctival epithelium is negative for cytokeratin 3 and positive for cytokeratin 19.

Imaging Studies

• An MRI of the brain and orbits is obtained 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

Medical Care

• Stage 1
• Topical lubrication with preservative-free artificial tears, gels, and ointments
• Discontinue any topical ocular therapies, especially those that can decrease corneal sensitivity (eg, 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 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
• 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 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 to increase corneal sensitivity.
• Topical pindolol has been reported to speed the 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 of corneal hypesthesia is not apparent or if any associated neurologic deficits are present.

Medication

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.

Antibiotics

The tetracyclines have shown anti-inflammatory and anticollagenolytic activity.

Tetracycline (Sumycin)

May have anticollagenolytic properties that improve symptoms.

Dosing

Adult

250 mg PO bid

Pediatric

Not established

Interactions

Antacids, bismuth, carbamazepine, phenobarbital, and phenytoin can decrease efficacy; methoxyflurane can have synergistic effect and increase risk of nephrotoxicity; warfarin may have increased risk of bleeding secondary to decrease in vitamin K production

Contraindications

Documented hypersensitivity; pregnancy; <8 years; caution if renal or hepatic function impaired

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with impaired renal or hepatic function

Doxycycline (Doryx, Vibramycin, Bio-Tab)

May have anticollagenolytic properties that improve symptoms.

Dosing

Adult

100 mg PO qod

Pediatric

Not established

Interactions

Antacids, bismuth, carbamazepine, phenobarbital, and phenytoin can decrease efficacy of tetracycline; methoxyflurane can have synergistic effect and increase risk of nephrotoxicity; warfarin may have increased risk of bleeding secondary to decrease in vitamin K production

Contraindications

Documented hypersensitivity; pregnancy; <8 years; caution if renal or hepatic function impaired

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with impaired renal or hepatic function

Cycloplegics

These agents relieve pain associated with iridocyclitis.

Atropine solution 1% (Isopto)

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

Dosing

Adult

1 gtt to affected eye(s) qd

Pediatric

Not established

Interactions

Coadministration with other anticholinergics have additive effects

Contraindications

Documented hypersensitivity; anatomically narrow anterior chamber angles

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May blur vision; keep drug away from small children

Lubricants

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

Artificial tears (Celluvisc, Akwa Tears, Murine, Refresh, Tears Naturale)

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

Dosing

Adult

Solution: 1-2 gtt into eye(s) tid/qid prn
Ointment: Apply 0.5-inch ribbon to subconjunctiva hs

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Hyperemia, photophobia, stickiness of eyelashes, ocular discomfort or irritation may occur

Follow-up

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

Miscellaneous

Medicolegal Pitfalls

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

References

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18. 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. Nov-Dec 2007;51(6):442-7. [Medline].

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Keywords

neurotrophic keratopathy, neurotrophic keratitis, neuroparalytic keratitis

Contributor Information and Disclosures

Author

Robert H Graham, MD, Senior Associate Consultant, Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona
Robert H Graham, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, and Arizona Ophthalmological Society
Disclosure: WebMD/eMedicine Salary Employment

Coauthor(s)

Mark A Hendrix, MD, Consulting Staff, Department of Ophthalmology, Suburban Hospital, Shady Grove Hospital
Mark A Hendrix, MD is a member of the following medical societies: American Academy of Ophthalmology and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Co-Chairman of the Cornea Service, Co-Chairman 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, Eye Bank Association of America, Pennsylvania Medical Society, and Philadelphia County Medical Society
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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