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):
Secondary bacterial keratitis
Blurred vision secondary to epithelial irregularity, neovascularization, or corneal scarring
Corneal perforation following stromal melting
Stage 1 of neurotrophic keratopathy 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
Stage 3 is characterized as follows:
May result in perforation
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.
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, 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.
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:
Surgery for trigeminal neuralgia
Neoplasia (acoustic neuroma)
Familial dysautonomia (Riley-Day syndrome)
Familial corneal hypesthesia
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:
Vitamin A deficiency
Iatrogenic causes are as follows:
Contact lens wear
Trauma to ciliary nerves by laser treatment and surgery
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 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.
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.
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.
Treatment for stage 1 neurotrophic keratopathy 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
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 keratopathy.
Gaudilla et al note 20% autologous topical serum is an effective treatment for stages 1 and 2 neurotrophic keratopathy.
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.
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 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 :
Conjunctival flap - Effective, but poor cosmetic and visual result
Amniotic membrane transplantation
Repair of a deep ulceration
The following can be used in ulceration repair:
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
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 for neurotrophic keratopathy may include the following:
Nerve growth factor - Has been shown to induce healing of stage 3 keratopathy in an open, uncontrolled study[23, 24, 25]
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
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.
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.
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.
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