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Arch Ophthalmol. 2000;118:1446-1449.

Immune corneal ulcers are rare ocular surface diseases with multiple etiologies.¹ Immunosuppressive drugs and systemic or topical steroids may occasionally control the inflammatory process, but in the more severe cases, the ulcer may progress to corneal melting and perforation. No suitable therapy is currently available for these patients.¹ In a recent uncontrolled study, topically applied exogenous nerve growth factor (NGF) restored corneal integrity in patients with corneal neurotrophic ulcers.² Nerve growth factor might promote corneal healing and is implicated in functional activity of inflammatory cells on the ocular surface.^3-5

We evaluated the efficacy of topical murine NGF⁶ treatment in 4 patients (Table 1) with severe corneal melting as a consequence of immune-related corneal peripheral ulcers. The patients received 1 drop of NGF solution (10 µg of NGF dissolved in 50 µL of saline solution, 0.9% of sodium chloride) in the conjunctival fornix every 2 hours (from 6 AM to 12 PM), for 2 days, 6 times a day until the ulcer healed. After the ulcer was completely healed, the dose was reduced to 5 µg in 50 µL of solution 4 times daily for 2 weeks.² In each case, the corneal ulcer completely healed with NGF treatment. Written informed consent was obtained from the patients, and the study was approved by the local ethics committee.

View this table: [in this window] [in a new window] Table 1. Characteristics of Patients Enrolled in the Study*

Report of Cases
Case 1

A 56-year-old man with rheumatoid arthritis and recurrent acute episodes of keratoconjunctivitis and blepharitis, both of which were responsive to topical steroids, developed a peripheral corneal ulcer and scleritis in the left eye (Figure 1, left). Treatment with systemic steroids and methotrexate failed while systemic plus topical steroid therapy induced an improvement in inflammation but a deterioration of the corneal ulcer, which increased in depth, became enlarged, and developed melting and neovascularization. After 5 days of NGF treatment, the ulcer displayed a healing process characterized by epithelium growth through the ulcer's edges. During the first few days, the patient experienced a local increase in pain and photophobia that progressively disappeared along with the inflammatory reaction. The ulcer healed completely after 21 days of treatment (Figure 1, right).

View larger version (48K): [in this window] [in a new window] Figure 1. Left, A patient affected by rheumatoid arthritis developed a peripheral corneal ulcer associated with stromal melting. Right, The ulcer healed completely after 21 days of nerve growth factor treatment.

Case 2

A 63-year-old woman underwent cataract extraction and after 2 months developed necrotizing scleritis with subsequent exposition of choroid. The patient was treated with topical and systemic steroids and immunosuppressive drugs. To avoid the impending risk of eye perforation, we performed a scleral patch to cover the area of dehiscence. The patient had a chronic inflammatory reaction during the postsurgical period despite topical treatment with steroids and systemic immunosuppressive therapy. One month later the patient developed a relapse of the scleromalacia, associated with a peripheral corneal ulcer (Figure 2, left). As the eye started to develop stromal melting, topical steroid therapy was replaced by nonpreserved artificial tears; however, the inflammation and ulcer worsened. Topical application of NGF was begun 5 days later. After 7 days, a conjunctival pannus started to cover the ulcer, and a healing process and decrease of inflammation in the area of scleromalacia became apparent. During the first week of NGF treatment, the patient experienced local pain and photophobia. Two months later, the cornea was completely healed with a pannus in the area of the ulcer and the area of dehiscence was markedly reduced. The eye did not show any signs of inflammation (Figure 2, right).

View larger version (38K): [in this window] [in a new window] Figure 2. Left, A patient developed relapse of scleromalacia associated with peripheral corneal ulcer 1 month after a scleral patch was performed following necrotizing scleritis. Right, The corneal ulcer healed completely after 2 months of nerve growth factor treatment.

Case 3

A 45-year-old woman affected by lung tuberculosis had been treated with ethambutol, rifampin, and pyrazinamide. She developed erythema, small leg ulcers, and bilateral peripheral corneal ulcers associated with scleritis. Conjunctival and skin biopsy specimens confirmed the diagnosis of systemic and ocular vasculitis. Despite topical and systemic therapy with steroids, the corneal ulcers worsened and stromal melting developed. After 7 days, the right eye (with the more shallow ulcer) was treated with topical 2% cyclosporine 4 times daily, while the left (with a pre–Descemet membrane ulcer) was treated with topical NGF. The patient complained of increased pain and photophobia in both eyes. Two weeks later, the healing process was evident in both eyes, although a marked inflammatory condition was present in the right eye. After 3 weeks of treatment, the right eye had completely healed with a conjunctival pannus in the area of the ulcer, though inflammation persisted. The left eye was completely healed after 4 weeks. A conjunctival pannus developed in the area of the ulcer and the eye did not show any signs of inflammation. During the following 4 months, the patient continued to have persistent ocular inflammation in the right eye with corneal punctate keratopathy not present in the left eye.

At 4 months' follow-up, the patient was found to have a relapse of the corneal ulcer in the right eye that showed a rapid and progressive worsening despite systemic and topical steroid treatment. After 4 days, topical steroid treatment was replaced with 2% cyclosporine therapy, but no improvement was observed after 10 days. Treatment with NGF was begun in the left eye, and the epithelium started to grow through the ulcer's edges after 7 days. The ulcer healed completely in 2 weeks. At 3 months' follow-up, no relapse of the ulcer was observed in the right eye.

Case 4

A 62-year-old man with recurrent scleritis responsive to topical steroids developed a peripheral corneal ulcer associated with scleritis. The patient was treated with systemic steroids and acetylsalicylic acid for nonspecific arthritis. Systemic treatment did not induce an improvement. When topical steroids were added to the treatment, a reduction of the inflammation was observed; however, the corneal ulcer worsened, becoming deeper and wider, and undergoing stromal melting and neovascularization. After 5 days, topical NGF treatment was begun. During the first days of treatment, the patient experienced transient local pain and photophobia. Healing started after 7 days of NGF treatment and the symptoms progressively disappeared. The inflammatory reaction decreased, and the healing process was complete after 24 days of treatment.

Comment
This study shows that topical application of NGF blocks the inflammatory condition and promotes healing within 2 weeks in patients unresponsive to steroid and immunosuppressive drugs, and affected by severe peripheral corneal ulcers with stromal melting caused by multiple immune etiologies. All the corneal ulcers that we have treated with NGF healed within 8 weeks, and no relapse of the disease was observed in any patient during follow-up (3-12 months) (Table 2). The only adverse effect observed during NGF treatment was local pain and photophobia, which preceded the healing process and disappeared soon after the healing was completed.

View this table: [in this window] [in a new window] Table 2. Effects of Nerve Growth Factor Treatment

The inflammatory responses within and outside the nervous system were associated with a transient increase of NGF.^{4, 7} Moreover, an increase of immune cells expressing NGF receptors has been reported in ocular inflammatory diseases, such as cicatricial pemphigoid and vernal keratoconjunctivitis.⁵ The functional significance of these changes is not known. However, it is possible that NGF is involved in treating ocular inflammation, reducing cell damage, and promoting corneal healing. The hypothesis of the anti-inflammatory role of NGF has already been reported. It has been shown that NGF exerts an anti-inflammatory action on experimentally induced inflammation,^8-9 is 10 times more active than dexamethasone, and 1000 times more active than nonsteroid anti-inflammatory drugs in animals. In addition, a direct action of NGF treatment in promoting healing is consistent with previous in vitro findings, showing that NGF induces proliferation and differentiation of corneal epithelial cells.¹⁰ In addition, clinical observations suggest that NGF treatment restored the corneal integrity and improved the sensitivity of 12 patients with neurotrophic ulcers.² The benefical effect of the interruption of topical steroid administration observed in case 1, and the frequent administration of preservative-free lubricants, might also contribute to corneal healing. A prolonged washout and the presence of concomitant treatments should be carefully assessed in a masked controlled study. However, the experimental data and the good clinical response of all the patients treated with NGF encourage further investigation of the mechanisms of NGF action on corneal diseases and the potential use of NGF in other corneal diseases.

Our data represent the first evidence that topical application of NGF might promote corneal healing and inflammatory recovery in ocular immune diseases unresponsive to existing therapies.

AUTHOR INFORMATION
The contribution of Dr Aloe was supported by Target Project Biotechnology, National Research Council, Rome, Italy, and the G. B. Bietti Eye Foundation, Rome, Italy.

Alessandro Lambiase, MD; Stefano Bonini, MD; Luigi Aloe, PhD
Rome, Italy

Paolo Rama, MD
Venice, Italy

Sergio Bonini, MD
Naples, Italy

Corresponding author: Luigi Aloe, PhD, Institute of Neurobiology, National Research Council, Viale Marx 15/43, 00137 Rome, Italy (e-mail: aloe{at}in.rm.cnr.it).

REFERENCES
1. Donzis PB, Mondino BJ. Management of noninfectious corneal ulcers. Surv Ophthalmol. 1987;32:94-110. FULL TEXT | ISI | PUBMED 2. Lambiase A, Rama P, Bonini St, Caprioglio GC, Aloe L. Topical treatment with nerve growth factor for corneal neurotrophic ulcer. N Engl J Med. 1998;338:1174-1180. FREE FULL TEXT 3. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987;237:1154-1162. FREE FULL TEXT 4. Aloe L, Skaper SD, Leon A, Levi-Montalcini R. Nerve growth factor and autoimmune diseases. Autoimmunity. 1994;19:141-150. ISI | PUBMED 5. Lambiase A, Bonini S, Micera A, Rama P, Bonini S, Aloe L. Expression of nerve growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases. Invest Ophthalmol Vis Sci. 1998;39:1272-1275. FREE FULL TEXT 6. Bocchini V, Angeletti PU. The nerve growth factor: purification as a 30,000-molecular-weight protein. Proc Natl Acad Sci U S A. 1969;64:787-794. FREE FULL TEXT 7. Aloe L, Tuveri MA. Nerve growth factor and autoimmune rheumatic diseases. Clin Exp Rheumatol. 1997;15:433-438. ISI | PUBMED 8. Amico-Roxas M, Caruso A, Leone MG, Scifo R, Vanella A, Scapagnini U. Nerve growth factor inhibits some acute experimental inflammations. Arch Int Pharmacodyn Ther. 1989;299:269-285. ISI | PUBMED 9. Banks BEC, Vernon CA, Warner JA. Nerve growth factor has anti-inflammatory activity in the rat hindpaw oedema test. Neurosci Lett. 1984;47:41-45. FULL TEXT | ISI | PUBMED 10. Kruse FE, Tseng SCG. Growth factors modulate clonal growth and differentiation of cultured rabbit limbal and corneal epithelium. Invest Ophthalmol Vis Sci. 1993;34:1963-1976. FREE FULL TEXT

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