New Insights into the Diagnosis and Treatment of Neurotrophic Keratopathy

Clinical Practice JOHN E. SUTPHIN, MD, SECTION EDITOR

New Insights into the Diagnosis and Treatment of Neurotrophic Keratopathy KENNETH MARK GOINS, MD ABSTRACT Abnormalities of the ocular surface can be acquired or inherited disorders of the central nervous system. Loss of neural stimulation from the sensory division of the trigeminal nerve or from the autonomic nervous system can have devastating consequences on corneal epithelial wound healing and the precorneal tear film, leading to decreased vision. The pathogenesis of neurotrophic keratopathy is reviewed, and treatment modalites are recommended. KEY WORDS corneal nerves, corneal wound healing, diabetes mellitus, dry eye syndrome, familial dysautonomia, Gasserian ganglion, herpes simplex, herpes zoster ophthalmicus, ocular surgery, substance P

I. INTRODUCTION iseases affecting the cornea are a major cause of blindness worldwide.1 Neurotrophic keratopathy is a significant cause of corneal blindness that is frequently under-reported. As the aging adult population increases in developed countries, the number of patients with neuropathy-related corneal disease from diabetes mellitus, ocular herpes simplex, neoplasia, and ophthalmic surgery will also increase. The increase in neuropathic keratopathy will present challenges to ophthalmologists and may also produce additional financial stress on our health care system.

D

Accepted for publication March 2005. From the Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA Supported in part by Research to Prevent Blindness and the Iowa Lions Eye Bank Single copy reprint requests to: Kenneth M. Goins, MD (address below). Corresponding author: Kenneth Mark Goins, MD, Associate Professor of Clinical Ophthalmology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 11290B PFP, Iowa City, IA 52242-1091. Tel: 319-356-2861; Fax: 319-356-0363 (FAX); Email: [email protected]. The author has no commercial interest in any product or concept discussed in this article. Abbreviations are printed in boldface where they first appear with their definitions. ©2005 Ethis Communications, Inc. The Ocular Surface ISSN: 15420124. Goins, KM. New Insights into the Diagnosis and Treatment of Neurotrophic Keratopathy. 2005;3(2):96-110.

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II. DEFINITION Neurotrophic keratopathy is a generalized clinical term that refers to an abnormality in the central nervous system that results in a dysfunctional ocular surface. The disease may be manifested by reduced Snellen visual acuity due to a compromised ocular surface, persistent corneal epithelial defect, stromal opacification, vascular ingrowth, and stromal melt. Most clinical cases of neurotrophic keratopathy are caused by herpes simplex or varicella zoster viral infections of the trigeminal ganglion or by trigeminal nerve damage associated with ocular surgery, orbital or head surgery, head trauma, aneurysms, or intracranial disease.2 The finding that ocular surgery can induce the disease is of increasing importance today, given the popularity of laser refractive surgery, during which the microkeratome used to create a corneal flap causes temporary injury to corneal innervation. Magendie was the first to describe the degenerative changes in the cornea after the trigeminal nerve was cut.3 His original hypothesis was that the changes were caused by an interruption of activity of specific trophic fibers in the trigeminal nerve of sympathetic origin; however, this was later disproved. Recent findings suggest that disruption of sympathetic innervation may result in Horner’s syndrome and corneal endothelial decompensation.4 III. PATHOGENESIS Although the precipitating causes of neurotrophic keratopathy may vary, one common pathway is typically present in all cases. An abnormality may be present in corneal sensory innervation or in the autonomic nervous system pathway that is responsible for tear secretion. Frequent primary ocular causes include infection with herpes simplex and varicella zoster viruses. The absence of substance P, a neurotransmitter in the trigeminal nerve, has been speculated as a cause of neurotrophic keratopathy.5 Loss of this sensory information results in an aqueous tear deficiency and epithelial breakdown. In a rat model of neurotrophic keratopathy, it has been shown that topical administration of substance P and insulin-like growth factor improves corneal barrier function and stimulates corneal epithelial wound healing.5-6

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NEUROTROPHIC KERATOPATHY / Goins OUTLINE I. Introduction II. Definition III. Pathogenesis A. Ocular disease 1. Herpes simplex 2. Herpes zoster B. Systemic disease 1. Diabetes mellitus 2. Sjogren syndrome 3. Reduced nasolacrimal stimulation C. Hereditary factors D. External factors 1. Contact lens wear 2. Trauma E. Iatrogenic factors 1. Topical medications 2. Refractive surgery 3. Corneal transplantation 4. Cyclodestructive procedures of the ciliary body 5. Trigeminal nerve ablation 6. Excision of cerebellopontine angle tumors 7. Maxillofacial surgery F. Aging process 1. Reduced corneal sensation 2. Decreased lacrimal gland function 3. Impaired response of autonomic nervous system IV. Diagnosis A. Slit lamp examination B. Corneal sensation measurement C. Visualization of corneal nerves V. Management A. Topical therapies 1. Collagenase inhibition 2. Epidermal growth factor 3. Nerve growth factor 4. Autologous serum 5. Acetylcholine 1% and aneurin 2.5% B. Systemic therapies 1. Corticosteroids 2. Tetracyclines C. Adjunctive therapies 1. Punctal occlusion 2. Protective goggles and moisture chambers 3. Botulinum toxin A 4. Contact lenses D. Surgical management 1. Amniotic membrane transplantation 2. Conjunctival flap 3. Cyanoacrylate and fibrin adhesive 4. Tarsorrhaphy 5. Keratoplasty VI. Future directions

Cavanagh et al suggest that the endogenous proliferation of corneal epithelial cells is regulated by a bidirectional control process that is characterized by an adrenergic, cAMPdependent “off” and a cholinergic, muscarinic cGMP-dependent “on” response.7 It is suspected that exogenous substances that raise intracellular cAMP levels, such as isoproterenol or PGE1, reduce epithelial mitosis. On the other hand, acetylcholine (ACH) raises intranuclear cGMP levels, which increases mitosis of epithelial cells. This regulatory system may explain the permanent depression of epithelial mitosis associated with the decreased intracellular ACH levels that are produced by total corneal denervation. A. Ocular disease as a primary stimulant

1. Herpes simplex Herpes simplex virus is a significant health concern, as genital infections are increasing in epidemic proportions.8 In the future, this may lead to an increased incidence of ocular herpes simplex. The economic impact is substantial, as measured in days of active disease, time away from work, and expense of physician visits and medications. Loss of corneal sensation is a common feature of ocular herpes simplex infection of the cornea. Patients with ocular herpes simplex frequently develop a localized, trophic epithelial lesion, often referred to as metaherpetic keratitis. This refers to a persistent trophic epithelial ulceration in the absence of positive viral cultures or polymerase chain reaction (PCR) analysis for herpes simplex (Figure 1).Epithelialization of the cornea may be retarded due to suppression of limbal stem cells from chronic use of topical antiviral therapy and from poor wound healing related to the concomitant use of topical steroids to control associated keratouveitis. 2. Herpes zoster Recurrent varicella zoster infection that is manifested by inflammation of the ophthalmic division of the trigeminal nerve is a common ocular finding. Approximately 50-75% of patients with herpes zoster ophthalmicus (HZO) display ocular complications.9 An ocular surface disorder can develop secondary to impaired sensory function, which leads to chronic epitheliopathy and subsequent loss of vision. In a retrospective study by Severson et al, neurotrophic keratitis was less frequent among patients who received antiviral therapy.10 In addition, the development of a serious inflammatory complication was associated with a delay in antiviral therapy. Most importantly, adverse outcomes were less probable in patients treated with oral antiviral medications. These findings support the early and routine use of systemic antiviral therapy for acute herpes zoster ophthalmicus. B. Systemic disease as a primary stimulant

1. Diabetes mellitus Prolonged hyperglycemia can have a detrimental effect on corneal nerve function due to accumulation of polyol byproducts. In diabetes mellitus, the enzyme al-

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nificant factor in the development of a poor ocular surface in Sjogren syndrome.

Figure 1. Slit lamp photograph of a metaherpetic lesion secondary to neurotrophic keratopathy related to herpes simplex virus.

dose reductase converts excess glucose to sorbitol in a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner. Sorbitol accumulates in the cells, which results in the disruption and death of the cells. Depletion of NADPH due to aldose reductase activity reduces intracellular glutathione, an endogenous antioxidant. These factors lead to the development of various diabetic neuropathies, including neurotrophic keratopathy. Previous studies have shown that corneal sensation is decreased in patients with insulin-dependent and non-insulin-dependent diabetes.11 As a result, diabetic patients may develop tear hyposecretion and keratopathy.12-16 Contrary to the expected outcome, insulin-dependent diabetics have been shown to display better corneal sensitivity than their non-insulin-dependent counterparts. Diabetics with blue irides are reported to have lower corneal sensitivity than those with brown irides. Topical and oral aldose reductase inhibitors may improve corneal sensation and corneal re-epithelialization.17,18 2. Sjogren syndrome Sjogren syndrome refers to a generalized autoimmune disorder with dry eye as its predominant manifestation. It can occur as a primary disorder or as a secondary disorder related to rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis. The dry eye is usually associated with a primary dysfunction in lacrimal gland secretion secondary to immune destruction. Trigeminal sensory neuropathy has been described in 4-8% patients with primary Sjogren syndrome.19,20 The etiology is unclear; however, studies suggest that it may involve vasculitis or lymphocytic inflammation of nerve cell ganglia.21,22 Electrophysiological studies of the trigeminal nerve suggest an abnormality in the neurons of the Gassserian ganglion rather than in the trigeminal axons.23 Confocal biomicroscopy of the subbasal nerve plexus of the cornea in Sjogren patients may show morphological abnormalities, providing further evidence for neurotrophic keratopathy as a mechanism for dry eye.24,25 Therefore, in some patients, neurotrophic keratopathy may be a sig98

3. Reduced nasolacrimal stimulation In addition to corneal sensation as a stimulus for tear secretion, the nasal mucosa is a highly innervated tissue, which provides additional sensory information that stimulates tear secretion. It has been shown that aqueous tear production decreases after the nasal mucosa is anesthetized.26 This implies that patients with diseased or damaged nasal mucosa are susceptible to the development of neurotrophic keratopathy. A decrease in lacrimation in neurotrophic keratopathy has been described after Vidian nerve neurectomy to relieve the symptoms of nasal allergy.27-29 Similarly, even in the absence of specific disease of the nasal mucosa, the nasal-lacrimal reflex may be absent in patients with neurotrophic keratopathy.30 C. Hereditary factors

There may be a genetic predisposition to neurotrophic keratopathy. For example, familial dysautonomia, or the Riley-Day syndrome, is an autosomal recessive disorder that is found almost exclusively in Ashkenazic Jews. It is characterized by partial or complete absence of plasma dopamine-beta-hydroxylase, leading to a deficiency of norepinephrine and epinephrine and increased homovanillic acid in the plasma and urine.31 Similarly, children with congenital insensitivity to pain with anhidrosis may have an absence of corneal sensation and persistent corneal epithelial defects.32,33 Yagev et al reported the clinical findings of 15 Bedouin children with a mean age of 3.75 years.33 Corneal opacities were present in 10 children, and neurotrophic ulceration was seen in 7. Concomitant systemic manifestations included hyperpyrexia, moderate mental retardation, and hyoptonicity with absent superficial sensation to light touch. Donaghy et al reported a hereditary sensory neuropathy with neurotrophic keratitis in three affected members of a Kashmiri family that were the progeny of consanguineous marriages.34 An autosomal recessive inheritance is suggested. The condition was associated with loss of pain and temperature sensation in the limbs. Sural nerve biopsy showed a selectively reduced small myelinated nerve fiber population. Other congenital disorders associated with neurotrophic keratopathy include the Goldenhar-Gorlin syndrome.35 It is suspected that aplasia or hypoplasia of the trigeminal nuclei result in neuroparalytic keratitis. D. External factors:

1. Contact lens wear Both soft and rigid gas permeable lenses produce a loss of corneal sensitivity; however, the mechanism of threshold sensitivity loss is different.36-38 The extent of sensitivity loss is not related to the duration of lens wear and appears to plateau after the first few months of wear.37

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It has been noted that when long-term polymethylmethacrylate (PMMA) contact lens wearers switch to rigid gas permeable lenses, an increase in lens awareness may occur, suggesting a secondary increase in corneal sensation.39 Corneal threshold sensitivity has been shown to decrease to normal values within a few weeks after refitting with gas permeable lenses, perhaps because of the improved oxygen delivery to the cornea that is associated with modern gas permeable lenses. 2. Trauma Neurotrophic keratopathy has been reported to be associated with craniofacial trauma,40,41 fractures of the mandible,42,43 and superior orbital fissure syndrome.44 The condition may result from damage to the trigeminal nerve nucleus, root, ganglion, or a segment of the ophthalmic and/or maxillary divisions. E. Iatrogenic factors

1. Topical medications Neurotrophic keratopathy may be associated with the use of topical eye medications. Common offenders include nonsteroidal anti-inflammatory drugs,45,46 anesthetics,4749 beta-blockers,50-52 carbonic anhydrase inhibitors,53and antibiotics.54,55 Prolonged use of these medications should be avoided in patients with known neurotrophic keratopathy. Of particular concern should be the chronic use commercial fluoroquinolone agents, a commonly prescribed antibiotic class in ophthalmology. Studies have shown that topical fluoroquinolones stimulate the expression of corneal collagenases (MMP- and MMP-8) and gelatinases (MMP-2 and MMP-9), which could have a detrimental effect on corneal wound healing and may stimulate keratolysis.56 In addition, one should consider that long-term use of any topical medication can lead to a stem cell deficiency, which can further complicate matters. Topical antiviral and fortified antibiotic preparations are frequently associated with stem cell deficiency. 2. Refractive surgery Corneal innervation is primarily supplied by the long posterior ciliary nerves, which traverse in parallel to the long ciliary arteries at the 3 and 9 o’clock locations of the limbal region.57 These nerves bifurcate and become oriented in a vertical distribution. They initially enter the cornea in the middle third of the stroma and course anteriorly, forming the subbasal plexus, just beneath Bowman’s layer. It is generally accepted that corneal sensation is decreased after laser refractive surgery due to alterations in the subbasal nerve plexus. In excimer photorefractive keratectomy (PRK), there is a significant reduction in corneal sensitivity within the central ablation zone, as measured with Cochet-Bonnet aesthesiometry. However, when evaluating corrections up to –6.00 diopters, ablation depth and treatment zone diameter do not appear to be clinically important determinants of corneal hypoaesthesia.58

Figure 2. Slit lamp photograph of neurotrophic keratopathy after PKP displaying a neurotrophic line.

For laser in-situ keratomileusis (LASIK), it has been documented that corneal sensation is greatest near the hinge and decreases toward the central cornea and the peripheral cornea away from the hinge.59 It is postulated that a superior hinged flap transects the main branches of the long posterior corneal nerves, which enter the corneal limbus at 3 and 9 o’clock, leading to more severe loss of corneal sensation and secondary dry eye. Previous studies suggest that mean corneal sensation is greater in corneas with a nasal-hinge flap compared to corneas with a surperior hinge flap.60 In a study of moderate to severe myopia, corneal sensation was evaluated after PRK and LASIK.61 Corneal sensation was significantly greater after LASIK than after PRK. 3. Corneal transplantation Penetrating keratoplasty involves a large transection of the corneal nerves in the subepithelial plexus, leading to some degree of neurotrophic keratopathy in many cases. Rao et al evaluated corneal sensitivity using the CochetBonnet aesthesiometer and found that the central area of penetrating keratoplasty buttons never recover normal sensitivity, even up to 32 years after surgery.62 Gong re-

Figure 3. Slit lamp photograph with fluorescein stain of neurotrophic keratopathy after PKP, displaying a neurotrophic line.

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ported that corneal sensitivity after keratoplasty returned to normal in 50% of eyes without concomitant herpes simplex infection, with a follow-up time ranging from 7-22 years.63 In comparison, only 17.2% of eyes with concomitant herpes simplex infection regained normal corneal sensitivity during the same follow-up period.63 In our experience, we have observed that it can take months to years before a normal ocular surface is restored in some patients after penetrating keratoplasty. Often the patient presents with central punctate epithelial keratopathy, a neurotrophic epitheilial line, and/or anterior corneal haze (Figures 2 and 3). At this stage, silicone or thermal punctal occlusion is beneficial in most cases. The use of a therapeutic bandage contact lens could also be beneficial. The impact of deep lamellar endothelial keratoplasty (DLEK) on the occurrence of neurotrophic keratopathy remains unclear. Initial observations suggest that the subbasal plexus of corneal nerves are partially spared after DLEK; however, this must be verified with confocal biomicroscopy and aesthesiometry measurements.

6. Excision of cerebellopontine angle tumors Neurotrophic keratopathy may occur after the excision of cerebellopontine angle tumors. Facial nerve paralysis has been reported to occur in 45% of patients after surgery.73 The severity of disease is worsened when both the V and VII cranial nerves are affected, leading to exposure keratopathy and persistent corneal epithelial defects. Corneal hypoesthesia and a poor Bell’s phenomenon are the most important factors in predicting corneal complications after cerebellopontine angle surgery.

4. Cyclodestructive procedures of the ciliary body Neurotrophic keratitis has been previously associated with cyclocryotherapy. Miele et al reported the development of neuroparalytic ulcers in two patients approximately 2 months after cyclocryocoagulation for the management of secondary glaucoma.64 Neurotrophic keratitis may also be associated with other types of cyclodestructive procedures. Johnson has reported the occurrence of neurotrophic corneal defects after ciliary body ablation with a contact diode laser.65 Ophthalmologists should be aware of this potential complication, as the patient population receiving this treatment may have diabetes mellitus or viral keratouveitis, which further compromises corneal innervation. In contrast, block excision of the ciliary body for the management of anterior uveal tumors rarely creates a neurotrophic keratopathy. Groh et al reported the outcome of block excision of anterior uveal tumors or cystic epithelial ingrowth located at the 3 or 9 o’clock position of the limbus.66 Only 1 of 27 patients (3.7%) exhibited a moderate neurotrophic ulcer in the postoperative period.

F. Aging process

5. Trigeminal nerve ablation Neurotrophic keratopathy is a recognized complication of the neurosurgical treatment of trigeminal neuralgia, although the incidence of clinically significant corneal epithelial breakdown is exceedingly low, between 12%.67-71In terms of complications concerning sensory loss of cornea, it is suggested that radiofrequency rhizotomy carried the lowest risk of complication, followed by glycerol rhizotomy and microvascular decompression.72 It is suggested that the failure to produce clinical corneal symptoms after trigeminal ablation, despite a documented decrease in corneal sensation, may be attributed to the selective fiber destruction technique employed in radiofrequency rhizotomy with preservation of other myelinated nerves that maintain corneal nutrition.70 100

7. Maxillofacial surgery Although complications following maxillary osteotomies are rare, neuroparalytic keratitis has been previously described.74 It is suspected that ophthalmic complications that occur are caused by indirect injury to neurovascular structures or from fractures extending to the base of the skull or orbit during pterygomaxillary dysjunction using an osteotome or from maxillary downfracture. 1. Reduced corneal sensation It has been documented that corneal sensation decreases with increasing age.75,76 Similarly, investigators have reported a decrease in tear function with the aging process.77,78 It is postulated that reduced corneal sensation may decrease the stimulus for lacrimal gland secretion, leading to an increased frequency of dry eye in the fifth to sixth decade of life. 2. Decreased lacrimal gland function Certain degenerative changes in the lacrimal gland can contribute to a reduction of aqueous tear production with increased age. Atrophy of secretory acini, secretory duct obstruction, ascending periductal fibrosis, obliteration of adjacent blood vessels, and lymphocytic infiltration are age-related changes that have been observed in human lacrimal gland histopathologic specimens.79,80 3. Impaired response of autonomic nervous system A concomitant decrease in the function of parasympathetic and sympathetic innervation to the lacrimal gland may be associated with aging. There is an association of autonomic nervous system related defects in tear function and connective tissue disease.81 Pupillometry can be used to study the autonomic nervous system by evaluating constriction latency time and latency of maximum constriction velocity. In rheumatoid arthritis, pupil parasympathetic dysfunction has been shown to be correlated with ocular dryness.82 This represents an alternative neural pathway defect that contributes to the development of neurotrophic keratopathy. IV. DIAGNOSIS The diagnostic characteristics of neurotrophic keratopathy are outlined in Table 1.

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NEUROTROPHIC KERATOPATHY / Goins A. Slit lamp examination

Within hours of nerve injury to the cornea, squamous epithelial cells at the ocular surface become swollen, lose their prominent surface microvilli, and slough off at an accelerated rate into the tear film.83,84 Three clinical stages of neurotrophic keratopathy have been described by Mackie.83 In clinical stage 1 (Figure 4), the first clinical sign may be conjunctival hyperemia, which is manifested as an immediate result of trigeminal nerve dysfunction. This can be regarded as a forewarning of future trouble, and prompt treatment may reduce severe complications. There may be diffuse interpalpebral staining of the cornea and conjunctiva with rose bengal or lissamine green. This is associated with a decreased tear film breakup time and a secondary increase in tear mucous viscosity. There may be diffuse punctate epithelial stain with fluorescein and scattered facets of dried epithelium (Gaule spots). In clinical stage 2 (Figure 5), there is an acute loss of corneal epithelium and a surrounding rim of loose epithelium. This may be accompanied by anterior chamber cells and flare, eventually forming a hypopyon, especially after placement of a therapeutic bandage contact lens. The corneal stroma becomes edematous, while the edges of the epithelial defect become smooth and rolled with time. Fluorescein sodium adheres to the exposed stroma and extends below the epithelial border, outlining the epithelial lip. In clinical stage 3 (Figure 6 A and B), an indolent destruction of the corneal stroma occurs. Improper use of topical corticosteroids, NSAIDs, and antibiotics at this point may lead to worsening of the process. Prompt treatment is necessary, as stromal lysis may result in corneal perforation. B. Corneal sensation measurement

Corneal sensation can be assessed by contact and noncontact methods. Cochet-Bonnet aesthesiometry, a contact method, has been the standard of care for many years in corneal and external disease.85 The Cochet-Bonnet method directly stimulates corneal nerves by pressing a nylon thread against the anterior corneal surface. A long nylon thread (6 cm) is used initially, providing the lowest stimulus intensity. As the thread is shortened, the stimulus intensity is increased. The subject is asked to respond whenever the stimulus is felt. An objective measurement of threshold sensitivity can then be recorded. Two major types of non-contact aesthesiometry methods have been described, with use of air as described by Murphy86 and air mixed with carbon dioxide as described by Belmonte.87,88Non-contact corneal aesthesiometry stimulates the corneal nerves by releasing a controlled pulse of air at a predetermined pressure (in millibars).86 The air-jet, which is positioned 1 cm away from the corneal surface, delivers the pulse of air (0.9 sec duration), using a slit lamp attachment. The subject indicates verbally whether the stimulus is felt. The pressure of the pulse can be modified, thereby allowing a stimulus threshold to be determined. Comparison studies suggest that the contact and noncontact corneal aesthesiometry methods cannot be used

Table 1. Neurotrophic Keratopathy Diagnosis and Treatment Algorithm Diagnosis: ● Slit lamp exam ⴑ Stage 1—conjunctival hyperemia, diffuse interpalpebral stain, epithelial slough, stromal vascularization ⴑ Stage 2—oval interpalpebral epithelial defect with rolled edges, anterior chamber cell and flare reaction, stromal edema ⴑ Stage 3—stromal lysis that may progress to perforation ● Schirmer test ⴑ Usually reduced with and without anesthesia ⴑ May also be reduced with nasal stimulation ● Aesthesiometry ⴑ The reduction in corneal sensation may be quantified with either contact or non-contact methods ● Confocal biomicroscopy ⴑ Absent subbasal nerve plexus in severe cases ⴑ Visible nerve sprouts in subbasal region may suggest recovery Treatment: ● Stage 1 ⴑ Preservative free tear substitutes ⴑ Punctal occlusion ⴑ Bandage contact lens ⴑ Moisture chamber and protective goggles ⴑ Correction of eyelid abnormality (entropion, ectropion, trichiasis, incomplete blink response) ● Stage 2 ⴑ Stage 1 treatment modalities ⴑ Culture for bacteria, fungus, and Herpes simplex virus ⴑ Topical antibiotic QID (initial treatment with a 4th generation fluoroquinolone, later switching to trimethoprim/polymyxin B if long-term preventative therapy is necessary) ⴑ Oral Acyclovir 400 to 800 mg QID for active herpes simplex or varicella zoster keratouveitis ⴑ Oral Doxycycline 100 mg po BID ⴑ Topical autologous serum application 6 times daily ⴑ Topical Scopolamine 0.25% QID for uveitis ⴑ Oral Prednisone 60 mg po daily for uveitis, then tapered when desired effect has been reached ⴑ Tarsorrhaphy for recalcitrant cases ● Stage 3 ⴑ Stage 1 and 2 treatment modalities ⴑ N-acetylcysteine 10% QID ⴑ Topical Medroxyprogesterone 1% QID ⴑ Corneal tissue adhesive ⴑ Amniotic membrane transplantation ⴑ Conjunctival flap ⴑ Keratoplasty

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Figure 4. Slit lamp photograph of grade 1 neurotrophic keratopathy after keratoplasty. White haze and sloughing of the epithelium is seen on the central graft.

interchangeably, because each method assesses a different component of corneal sensation. The nylon thread of the Cochet-Bonnet technique is more likely to stimulate Aδ = corneal nerve fibers, which respond to mechanical pressure.86 The Aδ fibers are arranged parallel to the anterior corneal surface, at the basal epithelial layer. On the other hand, the non-contact methods possess a significant thermal element, which is more likely to be perceived by C corneal nerve fibers.87 These fibers reach up from the basal cell layer nerve plexus to within one cell layer of the epithelial surface. Because of their proximity to the corneal surface, C fibers may be more sensitive to small changes in stimulus intensity. For this reason, it is suggested that the non-contact methods may more accurately allow threshold sensitivity determination.

keratopathy.89 In diabetic patients with peripheral neuropathy, corneal nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes.90 Diabetic patients with these in vivo confocal biomicroscopic changes may be at greater risk for postoperative dry eye and epithelial erosion after ophthalmic surgery (i.e., LASIK). In patients with varicella zoster-related neurotrophic keratitis, confocal biomicroscopy can be used to stage the severity of disease. For example, if no subbasal nerve plexus is present, a more severe and prolonged keratopathy can be expected. Early nerve regeneration can be demonstrated with confocal biomicroscopy, which gives the physician further evidence that partial recovery of tear function is near (Figure 7). Corneas after LASIK demonstrate an approximately 90% decrease in the number of subbasal and stromal nerve fibers. Reinnervation occurs; however, the number of nerve fibers remains less than half of that prior to LASIK.91 In contrast, the decreased corneal sensitivity in contact lens wearers is not accompanied by decreased nerve fiber

C. Visualization of corneal nerves

In vivo confocal biomicroscopy can be used to help evaluate corneal nerve morphology in neurotrophic

A

B Figure 5. Slit lamp photograph of grade 2 neurotrophic keratopathy related to herpes zoster. An oval-shaped epithelial defect is present in the interpalpebral region of the cornea. Underlying pigmented keratic precipitates are present consistent with active zoster keratouveitis.

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Figure 6. A. Slit lamp photograph of grade 3 neurotrophic keratopathy in herpes zoster. Six months after being affected, this patient presented with a large inferior region of opacification and an epithelial defect (corneal sensation 0 mm with Cochet Bonnet aesthesiometry). B. Slit beam photograph of the lesion confirms the presence of significant stromal lysis that is approching Descemet’s membrane. Tarsorrhaphy prevented corneal perforation.

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bundle density.92 In addition, the hypoxia and acidosis that is associated with long-term daily contact lens wear does not appear to have an effect on keratocyte density. V. MANAGEMENT Management of neurotrophic keratopathy begins with elimination of topical medications and preservatives, which can impair corneal maturation and potentiate corneal anesthesia. The presence of facial nerve paresis, nocturnal lagophthalmos, entropion, ectropion, and trichiasis must be determined and treated, as chronic exposure keratopathy and eyelid abnormalities can have serious deleterious consequences on maintenance of the ocular surface. Often, it is unclear whether a concomitant infectious keratitis component is present, so obtaining corneal scrapings for gram stain and cultures for bacteria, fungus, and virus may be important. Confocal biomicroscopy can be used to identify acanthamoemba or other atypical organisms that can create a chronic persistent corneal epitheliopathy. To improve the health of the ocular surface, numerous medical and surgical treatment modalities have been used. Frequent use of preservative-free artificial tear supplements is important. Because surgical intervention to restore the ocular surface often fails, current ophthalmic research is directed toward medical therapy. Specifically, the use of nerve growth factors and autologous serum are recognized as being essential in the management of neurotrophic keratopathy.

A treatment algorithm for neurotrophic keratopathy is presented in Table 1. A. Topical therapies

A

B

C

D Figure 7. A. Slit lamp photograph of healed neurotrophic ulcer due to varicella zoster keratitis in right eye. The white scar beneath the visual axis created a large degree of irregular astimatism. B. Slit lamp photograph of normal contralateral left eye. C. Confocal biomicroscopy of central cornea of the right eye with no discernible subbasal plexus. Early subbasal nerve sprouts can be seen, consistent with corneal nerve regeneration. D. Confocal biomicroscopy of central cornea of the unaffected left eye with a well-defined subbasal nerve plexus.

1. Collagenase inhibition Long-term de-epithelialization of the cornea can lead to a gradual increase in collagenase production in the corneal stroma, leading to eventual perforation. Topical tetracycline ointment (not available in the United States), 10-20% N-acetylcysteine (dosage every 1-2 hours), and 1% Medroxyprogesterone (dosage QID) may be useful in reducing the stimulus for corneal melting. 2. Epidermal growth factor Daniele et al have reported the successful use of mouse-derived epidermal growth factor (m-EGF) in three patients with persistent corneal epithelial defects secondary to neurotrophic keratitis.93 The clinical response was dramatic; however, widespread use may be limited due to cost and sterility issues. 3. Nerve growth factor Murine nerve growth factor (Mngf) has been used by a number of investigators in the management of neurotrophic keratopathy.94-100 It has been shown that topical administration of mNGF to neurotrophic corneal ulcers improves corneal sensitivity and promotes corneal epithelial wound healing. Bonini has reported the outcome of 45 eyes of 43 consecutive patients with stage 2 to 3 neurotrophic keratopathy.95 Each patient received mNGF 200 μg/ml every 2 hours for 2 days, followed by one drop six times daily until the ulcer healed. All patients had resolution of the persistent corneal epithelial defect after 12 days to 6 weeks of treatment. A statistically significant improvement in Snellen vision and corneal sensitivity was documented. Periocular pain and hyperemia were local side effects during treatment. 4. Autologous serum The use of autologous serum to treat ocular surface disorders is not a new concept. The first reported use of au-

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tologous serum was by Fox et al in 1984 for the management of keratoconjunctivitis sicca related to Sjogren syndrome.101 A 3-week course of 50% autologous serum in 0.9% sodium chloride solution improved dry eye symptoms and conjunctival staining pattern in 30 eyes of 15 patients.Subsequently, Tsubota et al reported that clinical symptoms and rose bengal/ fluorescein staining improved after a 4-week course of 20% autologous serum drops (dosage 6-10 times daily) in a Sjogren syndrome population.102 Other investigators have reported the clinical usefulness of autologous serum with use of various concentrations and duration of therapy in the management of severe dry eye, graft versus host disease, and superior limbic keratoconjunctivitis.103-105 In contrast to these findings, Tananuvat et al reported in 2001 that 20% autologous serum applied six times daily to patients with severe dry eye syndrome did not result in a statistically significant difference compared to 0.9% sodium chloride solution, in a prospective, placebo-controlled study.106 In the specific management of neurotrophic keratopathy, Matsumoto et al reported the effect of 20% autologous serum (dosage 5-10 times daily) in 14 eyes of 11 patients in a retrospective study.107 The epithelial defects healed completely in all eyes within 6-32 days (mean, 17.1 ± 8.0 days). The mean pretreatment corneal sensitivity was 11.8 ± 11.6 mm, which increased to 30.0 ± 22.9 mm after treatment at the last follow-up. Substantial levels of nerve growth factor, insulin growth factor, and substance P were detected in the autologous serum, demonstrating the importance of nerve modulators in the management of neurotrophic keratitis. 5. Acetylcholine 1% and Aneurin 2.5% Dufour et al described a positive response in the treatment of five patients with neurotrophic keratopathy, using Acetylcholine 1% and Aneurin 2.5% (thiamine) to enhance the duration of effect.108 Later research findings disclosed that the corneal epithelium has a high concentration of acetylcholine.109,110 In addition, acetylcholine is expressed by the corneal epithelium instead of being contained within cholinergic nerve fibers. In vitro findings have shown that acetylcholine stimulates epithelial cell DNA synthesis.111,112 Therefore, the topical application of acetylcholine or its derivatives to persistent corneal epithelial defects may be advantageous, as suggested by some animal models.113,114 However, other models have not validated this treatment modality.115 B. Systemic therapies

1. Corticosteroids Frequent use of topical steroid eyedrops in the presence of neurotrophic keratopathy may be associated with corneal perforation due to activation of collagenases. Therefore, administration of systemic corticosteroids may be preferred for controlling severe inflammation in clinical situations such as zoster keratouveitis. On the other hand, long-term use of oral corticosteroids can be complicated by many side effects, including secondary glaucoma, systemic hypertension, and diabetes mellitus. Therefore, longterm use should be avoided whenever possible. 104

2. Tetracyclines The use of systemic tetracyclines helps promote ocular surface stability by improving the precorneal tear film through its action on meibomian gland secretions and by inhibiting collagenase and matrix metalloproteinases within the corneal stroma.116 Tetracyclines inhibit collagenases produced by neutrophils more readily than those produced by fibroblasts.117,118 Tetracyclines are significant inhibitors of epithelial gelatinases, which provides a protective effect against the digestion of basement membrane and subepithelial connective tissue that is mediated by epithelial cells.119 Because of these beneficial effects, systemic tetracycline should be used in cases of persistent epithelial defect and neurotrophic keratopathy. Gastrointestinal upset, vaginal yeast infection, and skin photosensitivity are common adverse reactions. C. Adjunctive therapies

1. Punctal occlusion To preserve the existing precorneal tear film volume, occlusion of the lacrimal punctum may be needed.120 Two methods of punctal occlusion are commonly used, silicone or acrylic intubation and thermal cauterization. Argon laser photocoagulation and suture closure of the punctum are alternative, but less frequently used, methods. Recanalization of the punctum is common after argon laser photocoagulation, whereas chronic retention of a suture near the punctum can provide a focus for infection. Tai et al have recently reported the efficacy of silicone punctal plug therapy.121 This study reiterates that the main problem with silicone punctal plugs, in general, is a shortterm retention time, with approximately 49.4% of implants having a mean survival time of 85.1 ± 7.3 weeks. Therefore, careful choice of plug size is necessary to prevent early extrusion. Because the retention rate of second plugs is documented to be less, at approximately 32%, other treatment modalities may be needed to manage severe ocular surface disorders. For recalcitrant cases, thermal occlusion of the lacrimal punctum is often recommended. 2. Protective goggles and moisture chambers Minimizing the flow of air over the cornea may prevent desiccation of the ocular surface. Eyeglasses may provide a physical barrier to harmful physical stimuli. Prosthetic devices made of polyurethane plastic can be coupled to eyeglasses, thereby creating a moisture chamber that slows down the evaporation of tears.122 In a randomized, controlled study, polyethylene moisture chambers were as effective as artificial tears and lubricating ointment in preventing corneal epithelial breakdown in intensive care patients.123 Moisture chambers can be used in certain cases as an alternative to tarsorrhaphy. 3. Botulinum toxin A When injected into the levator palpebrae superioris muscle, Botulinum toxin A produces a temporary, flaccid ptosis, which may be beneficial in the management of persistent corneal epithelial defects. This treatment modality serves as an alternative to tarsorrhaphy. Kirkness et al reported the

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benefits of the resultant protective ptosis, which was used to aid healing in 21 cases of indolent corneal ulceration and 4 cases of neurotrophic keratopathy.124 In this series of patients, 90% of the indolent ulcers healed completely. In all but one case, the cornea was completely covered by the lid. The mean time for levator function recovery was 8.5 weeks. Superior rectus underaction was a common side effect, occurring in approximately two-thirds of patients. However, normal superior rectus function returned in approximately 6 weeks. In a similar study, Gusek-Schneider et al investigated the use of Botulinum toxin A in 21 patients with indolent corneal ulceration.125 In 13 patients (61.8%), complete epithelialization occurred, while in 4 patients (19%), an additional tarsorrhaphy was necessary. In three patients, no healing was observed. The mean time to complete corneal epithelialization was approximately 3.8 weeks. The mean time to complete levator function was 12.4 weeks. 4. Contact lenses Therapeutic bandage contact lenses may help prevent further corneal breakdown and promote epithelialization of the neurotrophic ulcer. A recent survey found that in North America, the Acuvue®‚ (Johnson & Johnson) and Focus®‚ Night & Day™ (CIBA Vision) lenses were most commonly used for therapeutic purposes.126 In a study of 50 eyes of 50 consecutive patients with various types of corneal epitheliopathies, the Focus Night & Day lens was found to be safe and effective when used continuously for a mean time of 3 months (range 3 days to 12 months).127 Both silicone hydrogel soft contact lenses and rigid gas permeable scleral contact lens designs may be efficacious and preferred in the management of neurotrophic keratopathy because of their high oxygen permeability (Dk value). Fluidventilated, gas permeable scleral lenses (Boston Scleral Lens) have been shown to be a valuable treatment modality for the disabling ocular pain and photophobia associated with Stevens-Johnson syndrome, toxic epidermal necrolysis, and cicatricial pemphigoid.128 These lenses may be useful for neurotrophic keratopathy also. They provide an oxygenated aqueous environment over the corneal epithelium and a barrier to the desiccating effect of exposure to air and from the friction from eyelid blinking. Although the therapeutic use of contact lenses may facilitate corneal epithelial wound healing, the risk for microbial keratitis cannot be overlooked. Prophylactic antibiotic treatment is necessary to prevent infection from opportunistic organisms; however, long-term use encourages the development of antibiotic resistance and toxicity to limbal stem cells. For this reason, it is suggested that a conversion from extended to daily wear should commence as soon as the corneal epithelium has remained intact for approximately 24-48 hours.128 D. Surgical management

1. Amniotic membrane transplantation Amniotic membrane transplantation (AMT) promotes corneal epithelial wound healing by reducing inflammation

through expression of interleukin-10 and by providing type VI collagen and laminin, which are crucial for epithelial cell attachment. Single or multiple layer amniotic membrane grafts can be used to treat deep corneal ulcers.129-133 Kruse et al reported the use of multilayer AMT to treat 11 consecutive corneal ulcers refractory to conventional treatment (six herpes simplex and five other forms of neurotrophic keratitis).129 All corneal epithelial defects healed within 4 weeks. Two patients with neurotrophic ulceration had recurrent disease. Subsequently, Dekaris et al evaluated the efficacy of single versus multilayer AMT in the management of deep corneal ulcers in 28 patients.130 Monolayer AMT was successful in 64%, while the multilayer AMT success rate was 72%, suggesting that a multilayer AMT technique may be preferred in neurotrophic keratitis. Histologic findings after amniotic membrane transplantation demonstrated that in corneas without stromal vascularization, the amniotic membrane is slowly absorbed, whereas it is rapidly absorbed in the presence of stromal vascularization.134 Once resorbed, the amniotic membrane is replaced by new fibrotic stroma, which helps maintain corneal thickness. Both long-term retention of the amniotic membrane graft and the formation of new fibrotic stroma can compromise corneal transparency and vision in the healing process. Amniotic membrane transplantation is an effective treatment alternative for persistent corneal epithelial defect due to neurotrophic keratopathy. It is a simple procedure, and it avoids allograft rejection, which is commonly seen after penetrating keratoplasty. 2. Conjunctival flap The use of the conjunctival flap procedure to manage ocular surface disorders was first described in the 1870s by Scholer and later popularized by Gundersen in 1958.135,136 Today, partial or complete conjunctival flap procedures are successfully used for the management of many ocular surface disorders, including bullous keratopathy, neurotrophic keratitis, recalcitrant keratitis, and persistent corneal epithelial defects.137 There are several potential negative aspects to use of the conjunctival flap. First, the patient may experience significant obscuration of vision. Second, the examination of the anterior and posterior segment may be difficult for the ophthalmologist. Third, the penetration of topical ophthalmic medications may be impaired. Fourth, corneal perforation can occur beneath the flap; eyes with herpes simplex keratitis may be prone to this complication.138,139 On the other hand, visual acuity may actually improve, as reported in three of seven patients (43%) after conjunctival flap placement for neurotrophic keratitis.140 If visualization of the posterior segment is not possible, B-mode ultrasonography may be beneficial. The potential risk of corneal breakdown and perforation is markedly reduced, which may allow the use of topical ophthalmic preparations that were contraindicated prior to surgery. The use of topical 1% medroxyprogersterone may be useful to prevent corneal perforation after surgery.

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3. Cyanoacrylate and fibrin adhesive Cyanoacrylate tissue adhesive may be effective in temporarily closing corneal perforations smaller than 3 mm in size, while displaying a significant bacteriostatic effect.141 Fibrin glue provides faster healing and induces significantly less corneal vascularization, but it requires a significantly longer time for adhesive plug formation.142 In the event of descemetocele formation or corneal perforation, the temporary use of a customized, glued-on hard contact lens before penetrating keratoplasty may facilitate trephination of a soft eye.143 4. Tarsorrhaphy Tarsorrhaphy remains the mainstay of treatment in many cases of neurotrophic keratopathy. Within days of lid suturing, the corneal epithelium may be regenerated and corneal transparency restored in many cases. Permanent or temporary tarsorrhaphy may be useful for neurotrophic keratopathy.144-146 However, it should be noted that some cases are recalcitrant even to tarsorrhaphy. These patients may benefit from additional treatment modalities, such as autologous serum, to promote epithelial wound healing. It is important to leave the lid adhesion in place for an extended period of time. Six months should be the minimum, and 12 months is the average time for lid adhesion, prior to reduction. In some cases, however, 12 months may not be long enough. If corneal breakdown occurs after tarsorrhaphy reduction, the lid adhesion must be repeated. 5. Keratoplasty In general, penetrating keratoplasty that is performed in presence of neurotrophic keratopathy would be at great risk of failure due to aqueous tear deficiency, poor epithelial wound healing, and neovascularization. In cases of stage III neurotrophic keratitis with perforation, a multilayer amniotic membrane transplant or lamellar keratoplasty may be preferred for small corneal defects. Larger defects may require either a lamellar keratoplasty or a penetrating keratoplasty. The most significant retrospective information regarding the efficacy of penetrating keratoplasty in neurotrophic keratopathy is related to management of varicella zoster keratopathy.147-150 These studies emphasize that a good visual outcome and stable ocular surface can occur after keratoplasty for varicella zoster keratitis. In two studies, the higher success rate may be related to the fact that surgery was delayed until many years after the initial inflammation.148-150 This time delay in surgical intervention may have allowed corneal re-innervation to occur, thereby improving aqueous tear secretion and the ocular surface. In all cases, frequent follow-up visits and the careful maintenance of the ocular surface through the use of preservative-free lubricants, judicious use of topical steroids, and appropriate use of tarsorrhaphy improve the chances for success.150 VI. FUTURE DIRECTIONS Current ophthalmic research is focused on the use of topical nerve growth factors to restore normal trigeminal nerve function and corneal epithelial cell turnover in neurotrophic 106

keratopathy. Autologous serum provides the necessary nerve growth factors and has been shown to be extremely beneficial in management. However, manufacturing and product labeling issues with respect to use of autologous serum present a continuing problem for the ophthalmologist. Preventative therapy of neurotrophic keratopathy is important. The early use of aldose reductase inhibitors may have great promise in the prevention and treatment of trigeminal neuropathy caused by diabetes mellitus. In addition, it is hoped that childhood immunization for varicella zoster virus causes a change in the natural history of the disease, leading to a reduction in the incidence of herpes zoster ophthalmicus in adults. REFERENCES 1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ 2001;79:214-22 2. Davis EA, Dohlman CH. Neurotrophic keratitis. Int Ophthalmol Clin 2001;41:1-11 3. Magendie M. Del’influence de la cinqieme paire de nerfs sur la nutrition et les functions del’oeil. J Physiol 1824;4:176-82 4. Zamir E, Chowers I, Banin E, Frucht-Pery J. Neurotrophic corneal endothelial failure complicating acute Horner syndrome. Ophthalmology 1999;106:1692-6 5. Nagano T, Nakamura M, Nakata K, et al. Effects of substance P and ICF-1 in corneal epithelial barrier function and wound healing in a rat model of neurotrophic keratopathy. Invest Ophthalmol Vis Sci 2003;44:3810-5 6. Nakamura M, Kawahara M, Nakata K, Nishida T. Restoration of corneal epithelial barrier function and wound healing by substance P and IGF-1 in rats with capsaicin-induced neurotrophic keratopathy. Invest Ophthalmol Vis Sci 2003;44:2937-40 7. Cavanagh HD, Colley AM. The molecular basis of neurotrophic keratitis. Acta Ophthalmol Suppl 1989; 192:115-134 8. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea 2001;20:1-13 9. Cobo LM. Corneal complications of herpes zoster ophthalmicus: prevention and treatment. Cornea 1988;7:50-6 10. Severson EA, Baratz KH, Hodge DO Burke JP. Herpes zoster ophthalmicus in Olmsted County, Minnesota – have systemic antivirals made a difference? Arch Ophthalmol 2003;121:386-90 11. Ruben ST. Corneal sensation in insulin dependent and noninsulin dependent diabetics with proliferative retinopathy. Acta Ophthalmol (Copenh) 1994; 72(5):576-80 12. Foulks GN, Thoft RA, Perry HD, Tolentino FI. Factors related to corneal epithelial complications after closed vitrectomy in diabetics. Arch Ophthalmol 1979; 97:1076-8 13. Goebbels M. Tear secretion and tear film function in insulindependent diabetics. Br J Ophthalmol 2000; 84:19-21 14. Hyndiuk RA, Kazarian EL, Schultz,RO, Seideman S. Neurotrophic corneal ulcers in diabetes mellitus. Arch Ophthalmol 1977; 95:2193-6 15. Schwartz DE. Corneal sensitivity in diabetics. Arch Ophthalmol 1974; 91:174-8 16. Stolwijk TR, van Best JA, BoorJP, et al. Corneal epithelial barrier function after oxybuprocanine provocation in diabetes.

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