sPLA2-IIa participates in ocular surface inflammation in humans with dry eye disease.

PURPOSE: To determine the roles of secretory phospholipase A2-IIa (sPLA2-IIa) in the inflammatory responses of the compromised ocular surface. METHODS: Conjunctival impression cytology (IC) samples and tears were collected from patients with mild to severe non-Sjogren's dry eye disease (DED) and normal controls. The IC samples were analyzed for transcription of sPLA2-IIa and inflammatory cytokine/chemokine genes using quantitative real-time RT-PCR (qRT2-PCR) and pathway-focus PCR-array. The tear samples were analyzed for 13 inflammatory cytokines and chemokines with Millipore 13-Plex kit. Finally, sPLA2-IIa-treated human conjunctival epithelial cell (HCjE) cultures were analyzed with a pathway-focused PCR array. RESULTS: Transcription of sPLA2-IIa was significantly increased in severe DED patients as compared to those of mild DED patients and normal controls. The transcription of inflammatory cytokines (IL-1ß, IL-4, IL-6, IL-17, TNF-α, IFN-γ), chemokines (IL-8, CXCL10, CXCL11, CXCL-14, CCR6, LTB) and matrix metalloproteinase 9 (MMP9) were simultaneously increased in the same IC samples of DED. Concentrations of IL-6 and IL-8 in tears were significantly higher in DED patients than those of the controls and positively correlated to DED severity scores. On the other hand, IL-2, IL-4, IL-10, IL-12 and IFN-γ were significantly lower in DED patients than those in the controls and inversely correlated to DEWS scores. Single treatment of sPLA2-IIa, IL-1ß or TNF-α of HCjE cells induced minimal to no PGE2 production. When sPLA2-IIa was added to HCjE cells that were pre-treated with pro-inflammatory cytokines (TNF-α or IL-1ß), significant stimulation of PGE2 production was observed, concurrent with the extensive transcriptional changes of many inflammatory cytokines/chemokines and their receptors. CONCLUSION: sPLA2-IIa activity was elevated and not only associated with inflammatory changes in DED patient samples, but was also found to cooperate with TNF- α and IL-1ß to induce inflammatory response in human conjunctival epithelial cells. Understanding the roles of sPLA2-IIa in ocular surface inflammation may lead to better strategies for the treatment of chronic inflammation associated with DED and other ocular inflammatory conditions.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Analysis of viral DNA in isolates from patients with recurrent herpetic keratitis.

Isolates were obtained from 10 patients with recurrent herpes simplex type 1 infection of the eye, lids, or mouth. The viral DNA of successive isolates from each patients was analyzed by restriction endonuclease fingerprinting. Evaluation of the DNA banding patterns of all isolates by means of two different enzymes, performed in a masked fashion, demonstrated that all of the isolates from any one patient had the same genetic makeup. These results indicate that recurrent herpes infections of the eye and face in humans are caused not by unrelated, serial infections but rather by reactivation of the same latent virus that remains in the ganglion over a period of years.

Layer-by-layer desquamation of corneal epithelium and maturation of tear-facing membranes.

A method to devitalize single layers of apically exposed rabbit corneal epithelial cells through the use of digitonin is described. Devitalized cells exfoliate spontaneously as loosely cohesive, trypan-blue-stained layers, exposing underlying viable cells. Repeated application of this devitalization-exfoliation methodology results in the gradual elimination of each of the epithelial cells. The generation of corneal surfaces composed of the tear-facing membranes of all intraepithelial cell types--subsurface, wing, and basal--is thus attainable. Exposed surfaces were studied with respect to microanatomy, the binding of lectins, and the adherence of Pseudomonas aeruginosa. Microprojections (microvilli or microplicae) were absent in the basal cells but were present in all suprabasal layers, and increased gradually in density as cells approached the surface position. Wheat germ agglutinin and concanavalin A were found to bind to the tear-facing membranes of all suprabasal cell layers. The tear-facing membrane of the basal cells, in contrast, was not labeled. Within each labeled layer, the magnitude of lectin binding differed markedly from cell to cell; lectin binding decreased as the cellular area exposed to the tear surface increased. Pseudomonas were found exclusively at microprojection-free cellular areas, suggesting that inhibition of attachment is linked to the ontogeny of these microprojections.

Therapeutic dilemmas in external ocular diseases.

Three ocular conditions continue to pose therapeutic dilemmas for the practising clinician. Acanthamoeba keratitis, which presents with ocular pain, redness, tearing, photophobia and lid oedema, should be considered in any chronic, progressive corneal ulceration that is unresponsive to conventional treatment. Although the best treatment for this infection has yet to be defined, surgery should be reserved for those patients with progressive destructive disease or corneal penetration. Topical antibiotics and oral ketoconazole may be beneficial, as may surgical debridement in conjunction with topical antibiotic-antifungal combinations. However, since more than two-thirds of reported cases involve contact lens wearers, patients should be instructed as to the importance of regular lens care regimens. Giant papillary conjunctivitis occurs more frequently in soft contact lens wearers than in those wearing hard lenses, but may also occur in association with ocular prostheses, cataract surgery and corneal transplants. Symptoms of increased lens awareness, mucus accumulation, itching and blurred vision occur. Stopping use of contact lenses usually improves or eliminates these irritating effects, but is not always practical. Thus, resolution or improvement of symptoms while the patient continues to wear contact lenses is desirable, making lens hygiene essential in treatment. Pharmacological treatment includes the use of topical corticosteroids and agents that stabilise mast cells, such as cromolyn sodium. The dry eye syndrome can occur alone or as a part of Sjögren's syndrome. The irritation, redness, and other symptoms associated with ocular dryness are usually treated by preparations of either mucomimetics, polyvinyl alcohol or cellulose derivatives, which provide moisture and prevent evaporation from the surface of the eye.

Ulcerative keratitis. Survey of 30 years' laboratory experience.

During a 30-year period, causative organisms were identified on Gram's stain and culture in 547 of 677 cases of infectious corneal ulcers. Even if no organisms were seen on Gram's stain, culture results were often positive. Staphylococcus was the most common isolate; Moraxella, Pseudomonas, and Streptococcus pneumoniae were the next most frequent pathogens. Only 1% of cases were fungal. Of some help in identifying the causative organism were locations, presence or absence of hypopyon, and perforation of the ulcer. Most marginal lesions were a result of staphylococcal infection; central lesions were more likely to be Gram-negative ulcers. Fungal ulcers were identified by laboratory workup and not by clinical characteristics. Moraxella infection was observed almost exclusively in malnourished patients. Pseudomnas ulcers were often seen in patients with large body burns or patients receiving respiratory assistance. Gentamicin and neomycin were the most effective treatments.

Endothelial damage in monkeys after radial keratotomy performed with a diamond blade.

Anterior radial keratotomy was performed with a diamond blade in ten rhesus monkey eyes. Results were compared with those of a previous study in which a metal blade was used. Histologic assessment showed endothelial degeneration, but fewer edematous endothelial cells, than in the previous study. Specular microscopy demonstrated statistically significant endothelial cell losses (7.99%), when preoperative and three-month postoperative values were compared. Autoradiography showed little cell division in the endothelial cell layer. Cell loss seemed to be repaired mainly by the spreading of neighboring cells. Endothelial cell division is also limited in humans, and the cumulative loss of cells due to surgical trauma combined with continuous damage-related losses and later age-related reductions in cell numbers could produce corneal decompensation in some patients years after radial keratotomy.

Preliminary visual results of pediatric epikeratophakia.

Although cataract surgery is feasible in children with unilateral cataracts, visual rehabilitation depends on optical correction and conscientiously maintained amblyopia therapy. Epikeratophakia for the correction of aphakia was performed in 47 children (50 grafts). Postoperative keratometry readings showed an average increase of 12.68 diopters in early patients. With new tissue-handling techniques, the last eight patients showed an average increase of +16.80 D, with -0.64-D overrefraction for emmetropia. Visual results indicate that epikeratophakia is an effective primary procedure for patients with unilateral traumatic cataracts and that it is superior to leaving vision uncorrected in children who have had unilateral congenital cataracts removed and are contact-lens intolerant. Further studies with younger patients will be necessary to define its role in neonates; however, individual results demonstrate that good vision is obtainable with epikeratophakia.

Photorefractive keratectomy after intrastromal corneal ring segment explantation.

PURPOSE: To describe a case of photorefractive keratectomy after removal of intrastromal corneal ring segments from the cornea. METHODS: During United States Food and Drug Administration Phase III Trials for intrastromal corneal ring segments (ICRS), the implanted segments were removed from the cornea of the right eye of a patient because of dissatisfaction with glare, halos, and fluctuating vision. Ten months after ICRS explantation, the-patient underwent a photorefractive keratectomy procedure to the same eye. RESULTS: One month after removal of the ICRS, the patient's manifest refraction was within +/- 0.50 diopters of his original manifest refraction. Photorefractive keratectomy was planned to the same eye 6 months later. At the first attempt, the epithelium could not be removed with the laser and scrape technique, and residual epithelium was noted at the vertical meridian (12 o'clock) corneal incision site, which had been used for ICRS surgery and explant; therefore, the procedure was aborted. At the second attempt, with a mechanical epithelial brush (AMOILS Epithelial Scrubber; Innova, Inc, Toronto, Canada), the epithelium was removed with ease. After this, photorefractive keratectomy was done without difficulty or complication. At his most recent 8-month postphotorefractive keratectomy examination, the patient had an uncorrected visual acuity of RE: 20/16, with a manifest refraction of -0.75 to 0.75 x 170 degrees, a faint haze at the site of the stromal channel, and a small scar at the incision site on slit-lamp examination. CONCLUSIONS: Intrastromal corneal ring segments can be readily removed from the cornea, if required. In this case, the refraction returned to its preoperative state soon after the explant procedure and remained stable over time. Photorefractive keratectomy was performed as a secondary refractive surgical procedure after the removal of ICRS without difficulty or complication. However, removal of the epithelium is probably best accomplished with the use of an epithelial brush, considering the changes in the epithelial adherence in a postsurgical cornea. Further studies are required to establish the safety and efficacy of secondary refractive surgical procedures after ICRS explantation.

Relative blue-light extinction in lens nucleus related to age and cataract.

The extent of visual function loss from nuclear cataractous change can be estimated by observing the extinction of blue light compared to white light as a function of sagittal lens depth in standard slit lamps. Apparent extinction (loss of transmissivity) of 50% or more of the depth of the lens in blue light of maximal intensity compared to white light at minimal intensity is associated with marked visual loss. However, this transmissivity ratio of 0.5 or less also applies if light intensity remains constant and the blue filter is simply moved in and out of the light beam. Therefore, if 50% or more of the lens appears dark to blue-filtered light, nuclear changes have significantly decreased effective visual acuity. Relative blue-light extinction associated with nuclear change that may be amenable to surgical correction can thus be distinguished from the extinction effect caused by age alone.

Presumed toxoplasmic retinochoroiditis in four siblings.

Four siblings in an East Indian family showed typical ophthalmoscopic findings of toxoplasmic retinochoroiditis. Serologic data confirmed exposure to Toxoplasma gondii and the results of other tests excluded other etiologic agents. Three siblings had documented episodes of ocular inflammation consistent with recurrent toxoplasmic retinochoroiditis. The fourth sibling developed a de novo lesion following an illness consistent with systemic toxoplasmosis.

Corticosteroid therapy after anterior radial keratotomy in Primates.

Anterior radial keratotomy was performed on nine Green monkey eyes. Four of these eyes received subconjunctival corticosteroid injections immediately after surgery and three times thereafter at three-week intervals. Two eyes received subconjunctival physiologic salt solution injections on the same schedule. Three eyes received no injections after surgery. Although endothelial cell loss in the first week after surgery was reduced in the drug-treated eyes, there were no statistically significant differences in cell densities at nine months after surgery. Corticosteroid therapy after anterior radial keratotomy appeared to confer no long-range benefits in terms of the numbers of corneal endothelial cells in these primate eyes.

Histologic and electron microscopic assessment of endothelial damage produced by anterior radial keratotomy in the monkey cornea.

We performed anterior radial keratotomy on the right eyes of nine rhesus monkeys, making eight incisions of various depths from 0.36 to 0.5 mm with a No. 76-A Beaver blade. After three months, corneal buttons were obtained from the operated on eyes of seven monkeys by penetrating keratoplasty and two monkeys were killed, and both operated and unoperated on eyes were enucleated. We examined the specimens by scanning and transmission electron microscopy. We saw linear protrusions on the posterior cornea beneath and parallel to the radial keratotomy incisions in all cases. There were swollen endothelial cells at the central cornea in three eyes. In eight corneas, we saw damaged endothelial cells with invading inflammatory cells. The control eyes showed no abnormal histologic findings. These findings suggested that deeper incisions cause more endothelial damage, possibly in relation to structural weakness produced in the cornea. We think that cuts in Bowman's membrane and in the stromal tissue may cause corneal stretching, resulting in a continuing process of injury to the endothelial cell layer. There may be long-term, continuing damage to the corneal endothelium after anterior radial keratotomy.

Acyclovir in the treatment of herpetic stromal disease.

Seventeen patients (ten women and seven men, 23 to 72 years old) with stromal herpetic disease were treated with topical and oral acyclovir for 14 days. Of the 12 patients with disciform edema, five showed minimal improvement, four showed no change, and three showed worsening of their disease. Of the five patients with necrotizing stromal keratitis, one improved, one showed no change, and three became worse. The patients who had been treated with corticosteroids previously had a statistically significantly worse outcome than those who had not been so treated. One patient with necrotizing stromal keratitis showed virus particles in tissue specimens obtained by superficial lamellar keratectomy. Thus, acyclovir was not effective in the treatment of disciform edema or necrotizing stromal keratitis. Further studies are needed to ascertain whether the drug is therapeutically ineffective or whether acyclovir did not reach the stroma in amounts sufficient to affect the course of stromal disease in the human eye.

Adjustability of refractive effect for corneal ring segments.

PURPOSE: To evaluate the safety and efficacy of adjustability of the refractive effect of intrastromal corneal ring segments (ICRS, Intacs). METHODS: Data from four patients who had their initial Intacs removed and exchanged for new Intacs of different thickness sizes during a United States Food and Drug Adminstration Phase II clinical trial were evaluated with regard to segment size, reasons for exchange, duration within the cornea before exchange procedure, loss or change of spectacle-corrected visual acuity, change of uncorrected visual acuity, manifest refraction, cycloplegic refraction, topography after exchange, and stability of refraction. RESULTS: The exchange procedure was performed in two patients due to undercorrection and in two for overcorrection. The length of time the segments remained in the cornea after initial surgery varied from 6 to 15 months (mean, 10.25 +/- 4.03 mo). The most recent examination occurred between 4 to 18 months (mean, 10.0 +/- 6.32 mo) following the exchange procedure and showed improved uncorrected visual acuity with a range from 20/16 to 20/20 and a gain of 2 to 7 lines of uncorrected visual acuity compared to baseline. No eyes lost any lines of spectacle-corrected visual acuity following the exchange procedure and all preserved their preoperative spectacle-corrected visual acuity of 20/16. The intended refractive correction was achieved in the first few days of the exchange procedure and remained stable. CONCLUSION: In these four eyes that were over- or undercorrected after initial Intacs placement, segment thickness sizes were exchanged after 6, 8, 12, and 15 months without complication and with final uncorrected visual acuities of 20/16 to 20/20.

Topographic predicted corneal acuity with intrastromal corneal ring segments.

PURPOSE: To evaluate predicted optical quality of the central anterior corneal surface before and after the intrastromal corneal ring segment (ICRS) refractive procedure using a clinical videokeratoscope and software index developed for that purpose. METHODS: Predicted corneal acuity, a topographically derived index provided with the EyeSys System 2000 videokeratscope, representing potential optical quality of the cornea, was assessed preoperatively and at postoperative month 3 in 94 eyes that received an ICRS to treat -1.00 to -6.00 D of myopia. Predicted corneal acuity was calculated by determining the difference between a measured cornea and its best-fit ellipses for reflected ring circumferences within the central 3 mm diameter zone. RESULTS: Preoperative predicted corneal acuity was 20/10 in 92 of 94 eyes (98%). At month 3 after the ICRS procedure, 48 (51%) of moderately myopic eyes were corrected to 20/20 or better, 96% (90 eyes) were corrected to 20/40 or better, and 98% of eyes (92 eyes) had a predicted corneal acuity of 20/10. For the eyes with a predicted corneal acuity of 20/10, spectacle-corrected visual acuity was normally distributed between 20/10 and 20/25. CONCLUSION: Predicted corneal acuity did not change significantly from baseline in eyes with an ICRS. This suggests that topographic irregularities in the central 3 mm of the cornea detectable by predicted corneal acuity software were not induced in the central cornea with the ICRS.

Intrastomal corneal ring segments: reversibility of refractive effect.

PURPOSE: To evaluate the reversibility of refractive effect following removal of the ICRS (intrastromal corneal ring segments; Intacs). METHODS: Data from 34 eyes from which ICRS were removed during United States FDA Phase II and III clinical trials were evaluated with regard to segment size, loss or change of best spectacle-corrected visual acuity (BSCVA), any change of uncorrected visual acuity (UCVA), manifest spherical equivalent refraction, manifest cylinder refraction, stability of manifest cylinder refraction, and subjective visual symptoms. RESULTS: Out of 725 initial or contralateral eyes placed with the ICRS during Phase II and III clinical trials, segments were removed from 34 eyes (4.7%). Other than one (1/725, 0.1%) safety related ICRS removal, 30/725 (4.1%) were due to visual symptoms. ICRS removal was accomplished under topical anesthesia without complications in all eyes. The mean length of time the segments remained in the cornea after initial surgery was 10.3 +/- 5.4 months. At 3 months after ICRS removal, 21 eyes had monitored data available and were within +/-1 line or 10 letters of their preoperative BSCVA. Twenty eyes (20/21, 95%) returned to within +/-1.00 D of their preoperative manifest spherical equivalent refraction. All eyes had a stable refraction at the 3-month examination after removal, and a manifest spherical equivalent refraction within +/-1.00 D of their 1-month examination after removal. Nineteen eyes (19/21, 90%) returned to within +/-2 lines and 16 eyes (16/21, 76%) returned to within +/-1 line of preoperative UCVA. CONCLUSION: The ICRS (Intacs) was easily and safely removed, and eyes returned to preoperative refractive status within 3 months.

Effects of topical timolol (0.5%) and betaxolol (0.5%) on corneal sensitivity.

There are conflicting reports on the propensity of topical beta blockers to produce corneal anaesthesia. We measured corneal sensitivity thresholds quantitatively for 10 minutes following the administration of one drop of topical timolol maleate (0.5%), betaxolol hydrochloride (0.5%), or saline in 30 eyes of 18 normal subjects in a randomised, double-masked study. Most subjects had insignificant changes in corneal sensitivity thresholds. We identified, however, a subgroup of four subjects (five eyes) that had a marked and prolonged increase of corneal sensitivity threshold (corneal anaesthesia) after timolol (three eyes) and betaxolol (two eyes). The group mean age of these 'responders' (49.0 years) was significantly greater (p less than 0.005) than that of the non-responders (35.0). We recommend periodic measurements of corneal sensitivity in older patients receiving topical timolol or betaxolol, especially when given in higher concentrations, to identify responders, who may be at risk of developing keratitis.

Ophthalmia neonatorum: study of a decade of experience at the Mount Sinai Hospital.

We reviewed the charts of neonates who received a diagnosis of conjunctivitis or ophthalmia neonatorum during a 10-year period at the Mount Sinai Hospital, New York City. Ninety-five cases were discovered, four of these were born elsewhere and were not subject to our protocol, which at present consists of intramuscular penicillin and topical tetracycline ointment (1%). The 91 cases represent an incidence of 3.1 cases per 1000 live births (9.1/year), an incidence approximately equal to that reported in other published studies. The clinical characteristics examined were: age, sex, race, birth weight, gestational age, Apgar scores, presence or absence of fever or other systemic illnesses, complications, type of delivery, time of year, incubation period, presence and type of discharge, uni- or bilaterality, Gram stain, Giemsa stain, culture results, antibiotic disc sensitivities, cervical culture, antibiotic therapy, sequelae, and type of prophylaxis received. Seven aetiological diagnostic categories were established: gonococcal (3%), chlamydial (3%), staphylococcal (30%), other pathogens (25%), chemical conjunctivitis (7%), culture negative/normal flora (22%), and unobtainable (10%). This distribution differs from others published. In contrast with other studies, moreover, we found few gonococcal and no chlamydial cases in neonates subject to the Mount Sinai Hospital treatment protocol. Correlation of clinical characteristics and aetiological categories showed no statistically significant trend. So far there have been no cases of ophthalmia neonatorum, treated as on our protocol, caused by penicillin resistant gonococci or chlamydiae.

Rapid diagnosis of ocular herpes simplex infections.

BACKGROUND: The Surecell herpes (HSV) test kit is a test for detecting the presence of herpes simplex viral antigen by means of a monoclonal antibody based immunoassay. The test has proved to be highly sensitive and specific in diagnosing genital, oral, and dermatological herpes infections. METHODS: In this study, samples from patients with ocular keratitis were evaluated by tissue cultures and the Surecell test. The eyes of New Zealand rabbits were then inoculated with HSV type 1 acute keratitis, acute Staphylococcus keratitis, and HSV type 1 postkeratitis (healed corneas). Tear film samples collected from each eye with a cotton swab were evaluated by routine culture (A-549 monolayers) and by the Surecell test with and without prior placement of the swab in Hank's medium. RESULTS: The Surecell system had a 70% sensitivity and a 100% specificity in the detection of HSV antigen in ocular infections, and was shown to be a quick, efficient, and accurate method of testing for HSV antigen in humans. CONCLUSION: These results from humans and rabbits indicate that the Surecell test, which requires no special equipment, can be a useful in office adjunct in the clinical diagnosis of ocular herpes simplex.