Background Corneal neurotrophic ulcers associated with impairmentof sensory innervation of the cornea may lead to loss of vision,and there is no effective treatment for these ulcers. We evaluatedthe effects of nerve growth factor in patients with this disorder.
Methods Twelve patients (14 eyes) with severe corneal neurotrophiculcers associated with corneal anesthesia were treated withtopical nerve growth factor 10 times daily for two days andthen 6 times daily until the ulcers healed. Treatment continuedfor 2 weeks after the ulcers healed, and the patients were thenfollowed for up to 15 months. The evolution of the corneal diseaseduring treatment and follow-up was evaluated by slit-lamp examination,photography, fluorescein-dye testing, and tests of corneal sensitivityand best corrected visual acuity.
Results Corneal healing began 2 to 14 days after the initiationof treatment with nerve growth factor, and all patients hadcomplete healing of their corneal ulcers after 10 days to 6weeks of treatment. Corneal sensitivity improved in 13 eyes,and returned to normal in 2 of the 13 eyes. Corneal integrityand sensitivity were maintained during the follow-up period(range, 3 to 15 months). Best corrected visual acuity increasedprogressively during treatment and follow-up in all patients.There were no systemic or local side effects of treatment.
Conclusions In this preliminary, uncontrolled study, topicallyapplied exogenous nerve growth factor restored corneal integrityin patients with corneal neurotrophic ulcers.
Several ocular and systemic diseases and circumstances, includingfifth-nerve palsy, viral infections, chemical burns, cornealsurgery, abuse of topical anesthetics, neurotrophic keratitis,diabetes mellitus, and multiple sclerosis, can cause cornealneurotrophic ulcers.1 These ulcers result from loss of the sensoryinnervation of the cornea, which leads to a decrease in thenumber of corneal stem cells,2 decreased metabolic and mitoticrates in the corneal epithelium (which increases cell permeability),3,4and reduced acetylcholine and choline acetyltransferase concentrations.5The result is progressive corneal damage, with epithelial defects,vascularization, opacification, ulceration, and ultimately,perforation, even in the absence of injury or infection. Thestandard treatments consist of covering the eye with a patchor a soft contact lens, tarsorrhaphy, and constructing a conjunctivalflap, but they are often ineffective, and the outcome is oftenloss or severe impairment of vision.
Nerve growth factor is a well-characterized neurotrophin thatis required for the development and survival of selected neurons,including sympathetic and sensory neurons.6 It provides trophicsupport after neuronal injuries and reverses pathologic changesinduced by peripheral-nerve injury.7 In denervated skin, nervegrowth factor induces sensory-neuron sprouting and restoresthe density of nerve growth factor receptors.8,9 Skin ulcerscaused by the impairment of sensory innervation, such as inpatients with diabetes mellitus and leprosy and after trauma,may be the result of decreased concentrations of local nervegrowth factor.10,11
Nerve growth factor receptors have been found on the normaland abnormal cornea and conjunctiva.12,13 In this study, weevaluated the efficacy of topical application of nerve growthfactor in patients with severe noninfectious corneal ulcersdue to corneal anesthesia that were unresponsive to conventionaltherapy.
Methods
Patients
We studied 12 patients (14 eyes) who had noninfectious cornealulcers associated with impaired corneal sensitivity, causedby essential neurotrophic keratitis (5 eyes), chemical burns(3 eyes), abuse of topical anesthetics (2 eyes), surgery fororbital tumor (1 eye), surgery for acoustic neuroma (1 eye),penetrating keratoplasty for unknown reasons (1 eye), and lamellarkeratoplasty for a herpetic vascularized scar (1 eye) (Table 1).The mean age of the patients was 31 years (range, 4 to 56);six were female and six male. All the patients presented withcorneal ulcer without ocular pain and photophobia or other signsof active inflammation (Figure 1A). Corneal ulceration had beenpresent for a mean (±SD) of 45±24 days. All hadreceived conventional treatment, such as artificial tears andcovering the eye with a patch or a soft contact lens,1 and antibioticswith little or no benefit, and were referred to our center becauseof progressive worsening of the ulcer. The criteria for enrollmentin the study were clinical evidence of corneal ulcer that wasunresponsive to conventional therapy and the presence of cornealand conjunctival anesthesia. The exclusion criteria were thepresence of corneal infection and the presence of other oculardiseases.
Figure 1. Photographs of the Eye of a Patient with a Corneal Neurotrophic Ulcer before, during, and after Treatment with Nerve Growth Factor.
The patient had had a corneal ulcer in the right eye for 20 days. Slit-lamp examination showed a large and deep central corneal ulcer overlying a circular edematous area that was approximately 7 mm in diameter (arrows in Panel A). After four days of treatment with nerve growth factor, the corneal ulcer had shrunk to approximately 2 mm in diameter (arrows in Panel B). At this time the patient had eye pain and intense photophobia. After 12 days of treatment, the cornea was completely healed, and treatment was discontinued after 15 days. A central scar (arrows in Panel C) and corneal sensitivity were present. After 12 months of follow-up, the corneal scar was transparent (Panel D) and the patient had a best corrected visual acuity of 0.70.
Before starting treatment with nerve growth factor, the patientswere treated with preservative-free artificial tears (one dropevery two hours) for 10 days. If no tendency to heal was observedor if the ulcer progressed toward ocular perforation, all topicaland systemic treatments were discontinued and topical treatmentwith nerve growth factor was commenced. The study protocol wasapproved by the ethics committee of the Hospital of Venice,and written informed consent was obtained from all patients.
Study Protocol
The patients were evaluated at base line, daily for 1 week duringtreatment with nerve growth factor and then weekly until thecorneal ulcer was completely healed, and thereafter every monthfor up to 12 months after treatment was discontinued. The treatmentused was murine nerve growth factor (200 µg in 1 ml ofbalanced salt solution), purified from submaxillary glands accordingto the method of Bocchini and Angeletti.14 Each patient wastreated in the hospital until corneal healing began (after 2to 14 days). The patients received one drop (approximately 50µl) of nerve growth factor in the conjunctival fornixof the affected eye every two hours from 6 a.m. to midnightfor two days, followed by a dose of one drop six times a dayuntil the ulcer healed. After the ulcer healed, one drop ofa lower concentration of nerve growth factor (100 µg permilliliter) was administered four times daily for two weeks.
Procedures
All patients were evaluated at base line by a complete eye examination(slit-lamp evaluation, tonometry, fundus oculi evaluation whenpossible, photography, fluorescein-dye test, corneal-sensitivitytests, estimation of best corrected visual acuity, and Schirmer'stest). A general history was obtained and physical examinationand routine hematologic and chemical tests were performed torule out systemic disease. Cranial magnetic resonance imagingwas also performed in the patients with essential neurotrophickeratitis to rule out anatomical lesions of the central nervoussystem or the cranial nerves.
The best corrected visual acuity was defined as the best visionthat the eye can achieve after correction of its refractiveerror. Visual acuity was measured by having the patient readthe smallest-possible line on a visual chart and expressed asa fraction of the normal value (normal vision is defined as1.0, or 20/20). Corneal culture was performed to rule out bacterialand fungal infection, and corneal scrapings were analyzed withthe polymerase chain reaction to rule out herpesvirus infection.
Corneal ulcers were classified according to their widest diameterand depth on slit-lamp examination. To test corneal sensitivity,we removed and twisted the tip of a cotton swab and then slowlyadvanced it until it touched the central corneal zone of thepatient.15 All tests of corneal sensitivity were performed between9 and 11 a.m. Corneal sensitivity was considered to be normalif there was a blink reflex when the cornea was touched. Ifthe patient felt contact but had no blink reflex, corneal hypoesthesiawas diagnosed, and if no response was present, corneal anesthesiawas diagnosed. To test for the presence of sensitivity to chemicalstimulation, we determined whether the patient noted a burningsensation after conjunctival instillation of a pungent substance15(a commercial mydriatic drug [Visumidriatic 1 percent, MerckSharp & Dohme]).
The eye examinations were repeated daily while the patient washospitalized, weekly during treatment, and then monthly duringfollow-up. To assess the efficacy of nerve growth factor, weevaluated the results of the slit-lamp examinations, changesin ulcer size, best corrected visual acuity, and changes incorneal sensitivity. The effects of treatment on best correctedvisual acuity were compared with paired t-tests at base line,at the time of discontinuation of therapy, and 6 and 12 monthslater.
Results
All patients had complete resolution of the corneal ulcer after10 days to 6 weeks of treatment with nerve growth factor (Figure 1A,Figure 1B, Figure 1C, Figure 1D, and Figure 2), at whichtime the dosage was reduced for 2 weeks and then discontinued.The mean duration of treatment was 34 days (range, 24 to 56).The healing process began two days after the initiation of treatmentin three patients and within two weeks in the other patients(Table 2). The rate of healing was not related to the severityof the ulcer, its depth in the stroma, the age of the patient,or the cause of the ulcer. The first signs of healing were anadvancement of epithelial cells from the margin toward the centerof the ulcer and the occurrence of mild-to-moderate conjunctivalhyperemia and were accompanied by pain and photophobia in allpatients. Subsequently, superficial or deep corneal neovascularizationoccurred in 9 of the 14 treated eyes. All ocular symptoms disappearedonce the corneal ulcer was completely healed. Corneal sensitivityimproved after ulcer healing in 13 of the 14 eyes (sensitivityreturned to normal in 2 eyes and improved to hypoesthesia in11 eyes), and after healing, all patients reported a burningsensation after conjunctival instillation of a mydriatic drug.
Table 2. Effects of Treatment with Nerve Growth Factor in 12 Patients with Corneal Neurotrophic Ulcers.
After healing of the ulcer, all patients had a corneal scar;both the scarring and the corneal neovascularization disappearedduring follow-up. The improvements in corneal sensitivity andvisual acuity were maintained throughout the follow-up period(Figure 3). Follow-up lasted 3 months in the case of three patients,4 months in four patients, 8 months in two patients, 12 monthsin two patients, and 15 months in one patient. After three months,all patients had photophobia during slit-lamp examination. Onepatient had no corneal contact sensitivity despite the presenceof photophobia during slit-lamp examination and a burning sensationafter the instillation of a mydriatic drug, both of which hadbeen absent before treatment.
Figure 3. Best Corrected Visual Acuity before, during, and after Treatment with Nerve Growth Factor in 12 Patients (14 Eyes) with Corneal Neurotrophic Ulcers from Various Causes.
When compared with the values at base line (mean, 0.03±0.02),best corrected visual acuity significantly improved after healingof the corneal ulcer in all 14 eyes (mean, 0.20±0.02;P<0.001). The improvement was even more evident after 6 months(mean of six eyes, 0.40±0.18; P = 0.002) and 12 months(mean of three eyes, 0.63±0.06; P = 0.002) (Figure 3).
None of the patients had systemic or ocular side effects duringtreatment with nerve growth factor or follow-up. Moreover, nonehad a relapse of their eye disease, and corneal integrity andsensitivity were maintained during follow-up.
Discussion
The results of this study indicate that topical administrationof nerve growth factor is effective therapy for patients withsevere corneal ulcers with sensory-nerve impairment and cornealanesthesia. These ulcers, although uncommon, have devastatingeffects on the cornea, frequently leading to ocular perforationand visual loss. There is no effective medical treatment. Theonly treatment is surgical, with the use of such proceduresas tarsorrhaphy, construction of a conjunctival flap, or lamellaror penetrating keratoplasty.1 The main goal of these proceduresis to preserve the anatomical integrity of the eye; they donot restore visual function. In most cases, the prognosis regardingvisual function is very poor, and relapses of the ulcer arefrequent.
Topical administration of nerve growth factor healed the ulcerin all the patients and improved corneal sensitivity in mostwithin 10 days to 6 weeks, and no patient had a relapse duringfollow-up. The first sign of corneal healing was a line of epithelialcells advancing from the border of the ulcer in associationwith conjunctival hyperemia. These findings suggest that thenerve growth factor had a direct action on the epithelium, inagreement with the results of a previous in vitro study in whichnerve growth factor as well as other growth factors stimulatedthe proliferation and differentiation of rabbit corneal epithelialcells16 and the evidence that human corneal epithelium has high-affinityreceptors for nerve growth factor.13 Nerve growth factor mayalso act indirectly by inducing neurogenic inflammation. Thereis increasing evidence that nerve growth factor stimulates therelease of several neuropeptides and growth factors that canstimulate the healing process.17,18,19,20
During epithelial proliferation, all patients had photophobiaand burning of their eyes during slit-lamp examinations, andmost patients had improvement of corneal sensitivity, whichsuggests functional recovery of corneal innervation. This findingmay be related to the well-known ability of nerve growth factorto induce neuritic sprouting by neuronal cells in vitro andnerve regeneration in vivo in denervated skin, as well as inthe central and peripheral nervous systems after surgical, chemical,or ischemic injury.6,7,8,9,21 Systemic treatment with nervegrowth factor also induces hyperalgesia in animals and healthysubjects.22,23
The murine nerve growth factor that we used is closely homologousto human nerve growth factor.24 Because of its trophic and regenerativeactions on the central and peripheral nervous system,6 nervegrowth factor has been proposed for the treatment of severalneurologic diseases.25 In two clinical studies, intracerebraladministration of murine nerve growth factor in patients withParkinson's disease26 and Alzheimer's disease27 was of somebenefit and caused no side effects. In our study, ophthalmicadministration of murine nerve growth factor produced no localor systemic side effects.
The maintenance of corneal sensitivity after treatment withnerve growth factor suggests that such treatment completelyrestores sensory innervation of the cornea. This possibilityis consistent with the known pathophysiologic role of sensoryinnervation in corneal wound healing. The cornea is a virtuallyavascular tissue, but it has very dense innervation (40 timesmore than the tooth pulp and 400 times more than skin). Thus,any inflammatory reaction and subsequent healing are controlledby this neuronal innervation.28 Experimentally, corneal-nervedamage induces severe alterations in the metabolism and vitalityof the epithelium, and clinically, surgical damage (as may occurduring trigeminal-nerve manipulation or penetrating keratoplasty)or chemical damage (such as that caused by abuse of local anesthetics)of corneal innervation impairs epithelial healing and inducestrophic ulcers.29,30,31
Our results are in line with the current hypothesis of the pathogenesisof corneal neurotrophic ulcers. It has been thought that cornealnerves release a trophic factor that maintains the integrityof the corneal epithelium and that nerve damage compromisesthe integrity.32,33 The finding that exogenous nerve growthfactor restored corneal integrity and sensitivity suggests thatthe progressive corneal damage that occurs in some patientswith corneal sensory-nerve deficits could be due to a deficitof endogenous nerve growth factor. This hypothesis is in agreementwith the effects of this factor in other biologic systems. Forexample, in animals with a targeted mutation of the gene codingfor the low-affinity nerve growth factor receptor, ulcers andlesions of the feet occur,34 and exogenous nerve growth factoraccelerates the rate of wound contraction in mice.35 Moreover,concentrations of nerve growth factor are decreased in ulcerativetissue from patients with systemic conditions such as diabetesmellitus, leprosy, and nerve trauma.10,11
In conclusion, in a preliminary, uncontrolled study, treatmentwith nerve growth factor induced prompt healing and restorationof corneal sensitivity with no local or systemic side effectsin patients with corneal neurotrophic ulcers.
We are indebted to Prof. Rita Levi-Montalcini for her encouragementduring the study and helpful suggestions and discussion.
Source Information
From the Department of Ophthalmology, University of Rome Tor Vergata, Rome (A.L., S.B.); the Division of Ophthalmology, Hospital of Venice SS. Giovanni e Paolo, Venice (A.L., P.R., G.C.); the Institute of Neurobiology, National Research Council, Rome (A.L., L.A.); and the G.B. Bietti Eye Foundation, Rome (S.B.) — all in Italy.
Address reprint requests to Dr. Aloe at the Institute of Neurobiology, National Research Council, Viale Marx 15, 00132 Rome, Italy.
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