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Arch Ophthalmol. 2002;120:215-217.

Impaired adhesion, migration, and/or mitosis can compromise corneal epithelial healing. Persistent epithelial defects can progress to ulceration, perforation, or endophthalmitis. Currently, our options are limited to methods that address the underlying cause of the epithelial defect. In addition to addressing exposure keratopathy, mechanical irritation to the eye, and systemic diseases, clinicians supplement the tear film, minimize the mechanical aspects of delayed wound healing, and use collagenolytic enzyme inhibitors. Specific therapy includes preservative-free artificial tears, pressure patching, bandage contact lens, and N-acetylcysteine. The more recent use of nerve growth factor,¹ amniotic membrane transplantation,^2-4 and scleral lens² has been reported. Nonsurgical therapeutic options have limited effect, and surgical procedures such as lamellar or penetrating keratoplasty become necessary to preserve the anatomic integrity of the globe. Vision-threatening procedures (Gunderson flap, tarsorrhaphy, evisceration, or enucleation) may also become necessary.

Recently, growth factors,^{1, 5-8} neuropeptides,^5-8 and fibronectin⁶ have promoted epithelial wound healing. Topical substance P (SP) and insulinlike growth factor 1 (IGF-1) circumvented surgical intervention in this case.

Report of a Case
A 79-year-old monocular woman with a persistent epithelial defect following penetrating keratoplasty in the left eye visited the University of Wisconsin (Madison) Cornea Service for consultation.

Her medical history was significant for Fuchs endothelial dystrophy, cataracts, and primary repair of a traumatic ruptured globe with subsequent evisceration of the right eye. In her pseudophakic left eye, penetrating keratoplasty was performed. A small suture tract leak and a small epithelial defect associated with a trace graft override were present on the first day following surgery. The suture tract leak healed quickly.

The defect persisted despite discontinuing polymyxin B sulfate, adding erythromycin, and reducing the frequency of 1% prednisolone. Four postoperative months of artificial tears, pressure patching, bandage contact lens, autologous serum combined with artificial tears, and anterior stromal micropuncture were ineffective at healing the defect.

The defect and the threat of complications persisted. At consultation, her pinhole visual acuity was 20/80 OS; medications included erythromycin and 0.2% brimonidine tartrate for ocular hypertension. The anesthetic epithelial defect measured 1.0 x 2.0 mm (Figure 1). The sutures were intact. Graft override still occurred adjacent to the epithelial defect.

View larger version (31K): [in this window] [in a new window] Figure 1. Epithelial defect adjacent to region of graft override.

This elderly monocular woman was offered an option of vision-threatening surgical procedures or topical SP with IGF-1. The patient understood the investigational and compassionate-use nature of SP and IGF-1. Informed consent was obtained.

Sterile SP (250 µg/mL) and IGF-1 (1.0 µg /mL) were prepared, dispensed, refrigerated, and discarded after 1 week. One drop of each compound was administered every 15 minutes for 2 hours each morning and night for the first week. Polymyxin B and brimonidine were continued. This treatment frequency was chosen on the basis of in vitro data (Christopher J. Murphy, DVM, PhD oral communication, January 2001), suggesting a persistent trophic effect after 2 hours of cellular contact with SP.

Complete healing occurred within 1 week (Figure 2). Symptomatic itching was mild and temporary. Her epithelium remained intact during a 2-week taper of SP and IGF-1 administration. Polymyxin B and both SP and IGF-1 were discontinued at the end of the second and third weeks of treatment, respectively. Her epithelium remained intact on follow-up examination at 3 weeks after discontinuing therapy, and it has remained healed without epithelial breakdown throughout the ensuing 8 months.

View larger version (27K): [in this window] [in a new window] Figure 2. Intact epithelium after treatment with topical substance P and insulinlike growth factor 1. Fine superficial punctate staining and a whorl pattern lie in the previously defective area.

Comment
Our armamentarium for corneal epithelial wound healing is limited. The trigeminal nerve and the neuropeptide it releases, SP, contribute to the maintenance of healthy corneal epithelium. Substance P has been shown to be synergistic with IGF-1 in the promotion of cellular processes conducive to wound healing.⁵

Three reported cases describe the complete resurfacing of persistent epithelial defects in human corneas in response to SP used synergistically with IGF-1.^6-8 Our patient responded to this therapy and did not require surgical intervention, suggesting a therapeutic advantage of this combined therapy. Our case, collectively with those cited, demonstrates the need for prospective clinical trials to declare the clinical value of this treatment modality in preventing the devastating consequences of nonhealing epithelial defects.

AUTHOR INFORMATION
This study was supported by an unrestricted grant from Research to Prevent Blindness Inc (New York, NY), and grants EY1252601 and EY10841-04 from the National Institutes of Health, Bethesda, Md.

Catherine H. Lee, MD; Amanda L. Whiteman, DVM; Christopher J. Murphy, DVM, PhD; Neal P. Barney, MD
Madison, Wis

Peter B. Taylor, MD
Fond du Lac, Wis

Ted W. Reid, PhD
Lubbock, Tex

Corresponding author and reprints: Neal P. Barney, MD, Department of Ophthalmology and Visual Sciences, University of Wisconsin, 2870 University Ave, Suite 206, Madison, WI 53705 (e-mail: npbarney{at}facstaff.wisc.edu).

REFERENCES
1. Lambiase A, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338:1174-1180. FREE FULL TEXT 2. Rosenthal P, Cotter JM, Baum J. Treatment of persistent corneal epithelial defect with extended wear of a fluid-ventilated gas-permeable scleral contact lens. Am J Ophthalmol. 2000;130:33-41. PUBMED 3. Tsubota K, Satake Y, Ohyama M, et al. Surgical reconstruction of the ocular surface in advanced cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol. 1996;122:38-52. ISI | PUBMED 4. Lee S, Tseng SCG. Amniotic membrane transplantation for persistent epithelial defects with ulceration. Am J Ophthalmol. 1997;123:303-312. ISI | PUBMED 5. Nishida T, Nakamura M, Ofuji K, Reid T, Mannis M, Murphy CJ. Synergistic effects of SP with ILGF-1 on corneal epithelial cell migration. J Cell Physiol. 1996;169:159-166. FULL TEXT | ISI | PUBMED 6. Morishige N, Komatsubara T, Chikama T, Nishida T. Direct observation of corneal nerve fibres in neurotrophic keratopathy by confocal biomicroscopy. Lancet. 1999;354:1613-1614. FULL TEXT | ISI | PUBMED 7. Chikama T, Fukuda K, Morishige N, Nishida T. Treatment of neurotrophic keratopathy with substance-P-derived peptide (FGLM) and insulin-like growth factor I [letter]. Lancet. 1998;351:1783-1784. FULL TEXT | ISI | PUBMED 8. Brown S, Lamberts D, Reid T, Nishida T, Murphy CJ. Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor-1. Arch Ophthalmol. 1997;115:926-927. ISI | PUBMED

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