Herpetic Eye Disease Study: A Controlled Trial of Topical Corticosteroids for Herpes Simplex Stromal Keratitis.

PURPOSE: To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis. METHODS: The authors performed a randomized, double-masked, placebo-con- trolled, multicenter clinical trial of 106 patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before study enrollment. Patients were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone phosphate; n = 57); both regimens were tapered over 10 weeks. Both groups received topical trifluridine. Visual acuity assessment and slit-lamp biomicroscopy were performed weekly for 10 weeks, every other week for an additional 6 weeks or until removal from the trial, and at 6 months after randomization. RESULTS: The time to treatment failure (defined by specific criteria as persistent or progressive stromal keratouveitis or an adverse event) was significantly longer in the steroid group compared with the placebo group. Compared with placebo, corticosteroid therapy reduced the risk of persistent or progressive stromal keratouveitis by 68%. The time from randomization to resolution of stromal keratitis and uveitis was significantly shorter in the steroid group compared with the placebo group even though both groups included patients who were removed from the study and treated with topical corticosteroids according to best medical judgment. Nineteen (33%) of the steroid-treated patients and 11 (22%) of the placebo-treated patients completed the 10 weeks of protocol therapy and had stable, noninflamed corneas after 16 weeks. At 6 months after randomization, no clinically or statistically significant differences in visual outcome or recurrent herpetic eye disease were identified between the steroid and placebo groups. CONCLUSIONS: The topical corticosteroid regimen used in this study was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of herpes simplex stromal keratitis. Postponing steroids during careful observation for a few weeks delayed resolution of stromal keratitis but had no detrimental effect as assessed by visual outcome at 6 months.

Clinical outcomes of combined versus separate carbachol and brimonidine drops in correcting presbyopia.

BACKGROUND: To test and compare in a masked fashion the efficacy of using a parasympathomimetic drug (3% carbachol) and an alpha-2 agonist (0.2% brimonidine) in both combined and separate forms to create optically beneficial miosis to pharmacologically improve vision in presbyopia. METHODS: A prospective, double-masked, randomized, controlled clinical trial was conducted. Ten naturally emmetropic and presbyopic subjects between 42 and 58 years old with uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion. All subjects received 3% carbachol and 0.2% brimonidine in both combined and separate forms, 3% carbachol alone and 0.2% brimonidine (control) alone in their non-dominant eye in a crossover manner with one week washout between tests. The subjects' pupil sizes and both near and distance visual acuities will be evaluated pre- and post-treatment at 1, 2, 4, and 8 h, by a masked examiner at the same room illumination. RESULTS: Statistically significant improvement in mean near visual acuity (NVA) was achieved in all subjects who received combined 3% carbachol and 0.2% brimonidine in the same formula compared with those who received separate forms or carbachol alone or brimonidine alone (P < 0.0001). CONCLUSION: Based on the data, the combined solution demonstrated greater efficacy than the other solutions that were tested. Improving the depth of focus by making the pupil small caused statistically significant improvement in near visual acuity, with no change in binocular distance vision. TRIAL REGISTRATION: ACTRN12616001565437. Registered 11 November 2016.

The practical detection of mmp-9 diagnoses ocular surface disease and may help prevent its complications.

PURPOSE: To evaluate the importance and practicality of testing for matrix metalloproteinase 9 (MMP-9) in dry eye and ocular surface disease. This enzyme, which can cause tissue damage, seems also to be the most reliable diagnostic indicator of ocular surface disease. METHODS: Enzyme-linked immunosorbent assay, polymerase chain reaction, diffusion, and InflammaDry, a new rapid immunoassay by RPS (Rapid Pathogen Screening Inc). RESULTS: MMP-9 measurement is sensitive and accurate for diagnosing dry eye and ocular surface disease and compares favorably in both sensitivity and specificity against the existing methods of dry eye diagnosis. Abnormal elevations of MMP-9 may predict post-laser in situ keratomileusis complications and refractive complications such as epithelial ingrowth and corneal ulceration. The presence of elevated MMP-9 on the ocular surface will identify those patients who should receive antiinflammatory therapy, such as cyclosporine, and may predict those patients who will respond to this therapy. CONCLUSIONS: A rapid in-office test that is sensitive for identifying inflammatory dry eye and ocular surface disease may facilitate better preoperative management of the ocular surface. Optimization of the ocular surface perioperatively would be expected to reduce complications from laser in situ keratomileusis and other surgeries that often make the underlying disease worse. This test may also indicate the need for antiinflammatory therapies, such as cyclosporine or steroids, and also may predict those patients who are more likely to respond.

Ganciclovir ophthalmic gel 0.15%: safety and efficacy of a new treatment for herpes simplex keratitis.

BACKGROUND: Until the availability of ganciclovir ophthalmic gel in 2009, the only option for treating herpes simplex (HSV) keratitis in the USA has been trifluridine (TFT), a compound with tolerability issues related to its nonselective inhibition of DNA replication in both normal cells and virus-infected cells. Ganciclovir has selective pharmacologic activity on viral thymidine kinase and a lower potential for toxicity to healthy human cells. Our objective was to evaluate safety and efficacy findings reported with the use of ganciclovir ophthalmic gel, both for HSV keratitis and other potential clinical indications. METHODS: Clinical and preclinical data with ganciclovir were identified through a comprehensive electronic search of PubMed and Medline, using the search terms ganciclovir, ganciclovir 0.15% ophthalmic gel, acyclovir, acyclovir ointment 3%, herpes simplex keratitis, treatment of herpes simplex keratitis, and adenoviral keratoconjunctivitis. The authors were also granted access to previously unpublished ganciclovir surveillance safety data from Bausch & Lomb, Inc. RESULTS: No clinical data comparing ganciclovir ophthalmic gel to 1% trifluorothymidine (TFT) for HSV keratitis could be identified. Four international, randomized, multicenter clinical trials have demonstrated that ganciclovir gel is at least as effective as acyclovir ointment for the treatment of HSV keratitis. Ganciclovir gel was better tolerated, with lower rates of blurred vision, eye irritation, and punctate keratitis. Recent data also indicate it may hold promise as a treatment for adenoviral keratoconjunctivitis. Worldwide safety surveillance data collected over the past 10-15 years in over 30 countries suggests an extremely low rate of spontaneously reported adverse events with ganciclovir ophthalmic gel. CONCLUSIONS: Current data suggest that ganciclovir ophthalmic gel has similar efficacy as acyclovir ointment for the treatment of HSV keratitis and is better tolerated. Clinical head-to-head studies comparing ganciclovir and TFT would be of great interest, especially for US physicians.

Descemetic versus pre-descemetic lamellar keratoplasty: clinical and confocal study.

PURPOSE: To compare the clinical findings and confocal microscopic features of the lamellar interface after 2 types of deep anterior lamellar keratoplasty (DALK): Descemetic with total stromal resection versus pre-Descemetic with deep stromal dissection. METHODS: Twenty eyes of 20 patients who had corneal disease with healthy endothelium were treated by DALK using the air technique. Baring of Descemet membrane (DM) was achieved for 12 eyes (Descemetic group). A fine stromal layer was left in 8 eyes (pre-Descemetic group). Visual acuity, interface clarity, corneal topography, confocal microscopy, and endothelial cell count were analyzed. RESULTS: DM microperforation occurred in 2 eyes (10%). No patient required conversion to penetrating keratoplasty (PKP) intraoperatively. Presumed stromal rejection occurred in 1 eye that was excluded from the study. In the Descemetic group, 90.9% achieved final best-corrected visual acuity (BCVA) of 20/30 or better; in the pre-Descemetic group, 75% achieved final BCVA of 20/30 or better. No statistically significant difference in mean visual outcomes was found between groups. The reflectivity of activated keratocytes at the interface was less in the Descemetic than that in the pre-Descemetic group. Ten to 12 weeks after pre-Descemetic DALK and 4 to 6 weeks after Descemetic DALK, keratocyte morphology and reflectivity had returned to normal. Mean combined topographic astigmatism was 2.17 ± 0.75 diopters (D) at 6 months (sutures out). CONCLUSIONS: The depth of the lamellar bed, smoothness, and healing process at the interface are the keys to optimal visual acuity. Although dissection to bare DM is more difficult, keratocyte activation and interface haze were less, but differences in final visual acuity were not significant.

Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated?

Most humans are infected with herpes simplex virus (HSV) type 1 in early childhood and remain latently infected throughout life. While most individuals have mild or no symptoms, some will develop destructive HSV keratitis. Ocular infection with HSV-1 and its associated sequelae account for the majority of corneal blindness in industrialized nations. Neuronal latency in the peripheral ganglia is established when transcription of the viral genome is repressed (silenced) except for the latency-associated transcripts and microRNAs. The functions of latency-associated transcripts have been investigated since 1987. Roles have been suggested relating to reactivation, establishment of latency, neuronal protection, antiapoptosis, apoptosis, virulence and asymptomatic shedding. Here, we review HSV-1 latent infections, reactivation, recurrent disease and antiviral therapies for the ocular HSV diseases.

Adenovirus advances: new diagnostic and therapeutic options.

PURPOSE OF REVIEW: Adenoviral infection is common, can be severe, and may cause significant morbidity. RECENT FINDINGS: Ophthalmologists and optometrists are often guilty of spreading adenovirus because it is highly contagious and has 53 serotypes with variable morphology. Adenovirus is often difficult to diagnose based on clinical appearance and, in the early stages, is associated with a red eye or superficial keratitis common to herpes and other infections. This difficulty results in the indiscriminate use of antibiotics, which are expensive and of no established value in treating a viral infection. The difficulty of accurate diagnosis also makes the use of newer proposed treatments less valuable and even potentially hazardous. SUMMARY: New diagnostic tests such as the Rapid Pathogen Screening (RPS) Adeno Detector that are practical, rapid, and inexpensive to use in the office may obviate these problems.

In vitro synergism of trifluorothymidine and ganciclovir against HSV-1.

PURPOSE: To determine whether trifluorothymidine (TFT) and ganciclovir (GCV) are synergistic against herpes simplex virus type 1 (HSV-1). METHODS: TFT and GCV activity against 12 strains of HSV-1 (including an acyclovir-resistant strain) was measured by plaque-forming unit (PFU) inhibition. Cellular toxicity was assessed with an MTT dye reduction assay. Synergism was determined by calculating fractional inhibitory concentration (FIC indices) based on PFU reduction. RESULTS: Concentrations of TFT resulting in 50% inhibition of PFUs (IC(50)) of acyclovir-susceptible HSV-1 strains ranged from 3.07 ± 0.36 to 12.52 ± 0.61 µM. GCV IC(50) values ranged from 0.40 ± 0.02 to 1.59 ± 0.14 µM. IC(50) values of TFT and GCV against the acyclovir-resistant strain were 15.40 ± 3.17 and 93.00 ± 9.64 µM, respectively. Concentrations of TFT or GCV resulting in 50% cell cytotoxicity (CC(50)) were 0.99 ± 0.01 and 92.91 ± 8.92 µM, respectively. TFT and GCV combined (10:1) were 10 times more potent against all acyclovir-susceptible HSV-1 strains. For 8 of 12 HSV-1 strains, the IC(50) of TFT and GCV combined was lower than the CC(50) of either drug. For acyclovir-susceptible HSV-1 strains, TFT and GCV combined generated a FIC index of <0.5, suggesting strong synergism between the two drugs. The FIC value for TFT and GCV combined against the acyclovir-resistant HSV-1 strain was 0.84, indicating nonantagonism. CONCLUSIONS: TFT and GCV are synergistic against acyclovir-susceptible HSV-1 at concentrations significantly less toxic than if each antiviral were used as a sole agent.

Effect of high versus low oral doses of valacyclovir on herpes simplex virus-1 DNA shedding into tears of latently infected rabbits.

PURPOSE: To assess the effect of high doses of valacyclovir (VCV) on HSV-1 DNA shedding into tears of latently infected rabbits. METHODS: Three oral doses of VCV were tested. Corneas were inoculated with HSV-1, and latent infection was allowed to establish. Starting on postinoculation (PI) day 28, tear swabs were collected once daily for 6 consecutive days before treatment. The rabbits were placed in five balanced groups: group 1 had no treatment, group 2 received placebo, group 3 received 7 mg/kg VCV, group 4 received 70 mg/kg, and group 5 received 140 mg/kg. The treatment was administered by oral gavage twice daily, starting on PI day 36 and continuing for 14 days. The ocular swabs were collected beginning on PI day 40 and continuing for 10 days. RESULTS: The mean copy number of HSV-1 DNA before treatment was 370+/-70, 569+/-273, 368+/-86, 408+/-108, and 396+/-91, and the mean HSV-1 DNA copy number after treatment was 232+/-183, 564+/-186, 518+/-122, 67+/-63, and 13+/-7 in groups 1 to 5, respectively. CONCLUSIONS: There was no observable toxicity in any group. The 70- and 140-mg/kg doses of VCV significantly reduced the HSV-1 DNA copy number, compared with that of the other three groups. A daily dose of 500 mg (approximately 7 mg/kg) VCV in healthy human volunteers did not suppress HSV-1 DNA shedding in tears and saliva. Thus, higher doses of VCV may be necessary to reduce asymptomatic shedding in healthy human subjects.

Confocal microscopy of corneal wound healing after deep lamellar keratoplasty in rabbits.

OBJECTIVE: To compare wound healing and morphologic characteristics of the host-donor interface in rabbit corneas after maximum-depth and near-Descemet membrane anterior lamellar keratoplasty. DESIGN: Descriptive analysis of confocal microscopy images after 2 types of deep lamellar keratoplasty (deep stromal dissection vs total stromal resection). METHODS: Deep anterior lamellar keratoplasty (DALK) was performed in 16 rabbit eyes, with exposure of the Descemet membrane in 8 eyes (deep group) and deep stromal dissection to near the Descemet membrane in 8 eyes (near group). A full-thickness graft devoid of endothelium and Descemet membrane was sutured in place. Confocal examination of lamellar interface and wound edge was performed throughout 6 months. RESULTS: Four days postoperatively, confocal microscopy revealed numerous highly reflective keratocytes at and adjacent to the interface in all eyes, fewer in the deep than the near group. Keratocyte density and reflectivity returned to normal at 4 to 6 weeks (deep) and 8 to 10 weeks (near) postoperatively. CONCLUSIONS: In the deep group, the smooth interface showed less scarring. In the near group, stroma-to-stroma healing stimulated more activated keratocytes and hence more haze. Successful DALK requires minimal central healing for clarity but significant suture-stimulated healing at the edge to prevent corneal bulge. CLINICAL RELEVANCE: Deep anterior lamellar keratoplasty is rarely accompanied by rejection, avoids entrance into the anterior chamber, and can be performed with tissue that does not have living keratocytes. Interface healing is a determinant of the final visual acuity; depth of the lamellar bed is a major determinant of the healing response. Although dissection to bare the Descemet membrane is more difficult, there is less keratocyte activation and scarring.

A double-blind placebo-controlled study to evaluate valacyclovir alone and with aspirin for asymptomatic HSV-1 DNA shedding in human tears and saliva.

PURPOSE: To test the effect of valacyclovir alone and with aspirin on the asymptomatic shedding of HSV-1 DNA in tears and saliva of healthy individuals. METHOD. The subjects (n = 45) were randomized into three groups without regard to age, sex, or race. Group 1 (n = 14) received the placebo, group 2 (n = 15) received a dose of 500 mg valacyclovir once daily, and group 3 (n = 16) received a dose of 500 mg valacyclovir once daily and 350 mg aspirin twice daily for 30 days. Ocular and oral swabs were collected twice daily for 30 days. DNA was extracted from all swabs and HSV-1 DNA copy numbers were determined. Statistical analysis was performed to compare the DNA copy numbers of the three groups. RESULTS: There was no significant difference in the HSV-1 DNA copy numbers in the tears or saliva among any of the three treatment groups. The mean copy numbers +/- SE of mean (SEM) of HSV-1 DNA in tears were 340 +/- 35, 1074 +/- 320, and 630 +/- 51 for groups 1, 2, and 3, and in saliva were 238 +/- 35, 963 +/- 462, and 493 +/- 25, respectively, for groups 1, 2, and 3. CONCLUSIONS: No correlation was found between HSV-1 shedding and valacyclovir and valacyclovir with aspirin treatment. The HSV-1 DNA copy number was not reduced by treatment with 500 mg of valacyclovir daily or with a combination of daily valacyclovir (500 mg) plus twice-daily doses of aspirin (350 mg) over 30 days.

Slitlamp biomicroscopy and photographic image analysis of herpes simplex virus stromal keratitis.

OBJECTIVE: To validate photographic bioimaging for evaluating the severity of herpes simplex virus keratitis. METHODS: Stromal keratitis of patients in the Herpetic Eye Disease Study was clinically measured with a slitbeam micrometer and then photographed at trial entry. Calibrated images of 169 eyes were analyzed for the size, location, and density of stromal keratitis and endotheliitis, with shape factor as a function of area and perimeter. Validity was assessed by comparing clinical and computerized measurements and by correlating the keratitis area with visual acuity. Logistic regression explored characteristics associated with larger or denser corneal inflammation. RESULTS: Stromal keratitis had a median area of 22.4 mm(2) (interquartile range, 12.8-31.6 mm(2)) with a median shape factor of 0.69 (interquartile range, 0.56-0.79); 126 eyes (75%) had their midpoint within 2 mm of the cornea's geometric center. Photoanalytical area estimates of herpetic stromal keratitis correlated closely with clinical measurements (correlation coefficient, 0.83). Eyes with larger stromal keratitis had worse vision (correlation coefficient, 0.32) and were more likely to have iritis (P = .01). Necrotizing stromal keratitis was significantly whiter (P = .02). CONCLUSIONS: Image analysis validly assesses the disciform geometry of herpetic stromal keratitis and confirms that increased severity is associated with uveitis and reduced vision.

WITHDRAWN: Synergistic interaction of aciclovir and a helicase-primase inhibitor, BAY 57-1293, against herpes simplex virus type 1.

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Heat-induced reactivation of HSV-1 in latent mice: upregulation in the TG of CD83 and other immune response genes and their LAT-ICP0 locus.

PURPOSE: To determine changes in host gene expression in HSV-1 latent trigeminal ganglia (TG) after hyperthermic stress. METHODS: Scarified corneas of 6-week-old female BALB/c mice were inoculated with either HSV-1 17Syn(+) (high phenotypic reactivator) or 17DeltaPst(LAT(-)) (low phenotypic reactivator) at 10(4) plaque-forming units/eye. At 28 days after infection, viral reactivation was induced in some of the infected mice with hyperthermic stress, and the mice were killed after 1 hour. Heat-treated uninfected mice served as the control. Labeled cRNA derived from TG-isolated total RNA was hybridized to 430 2.0 chips containing 14,000 mouse genes. Gene expression was confirmed by quantitative real-time PCR. RESULTS: There was no difference in gene expression in the non-heat-treated mice. Gene expression in the TG of each of the heat-treated mouse groups (17Syn(+), 17DeltaPst(LAT(-)) and uninfected) yielded upregulation of more than twofold of a group of the same genes, designated as heat stress-induced gene expression. Twenty-nine genes (0.2%) were significantly upregulated (2- to 17-fold) when the heat stress-induced gene expression was subtracted from the gene expression of 17Syn(+) latent TG relative to 17DeltaPst(LAT(-)) latent TG 1 hour after mouse hyperthermic stress. Nine host adaptive immunity genes comprising Ig molecules, CD83, CD8A, ADA, and CCL8 were the largest subset upregulated, and all were confirmed by real-time PCR. Others identified included genes involved in hypothalamic-pituitary gland functions. CONCLUSIONS: Hyperthermic stress-induced reactivation of the HSV-1 high phenotypic reactivator can upregulate gene expression involved in B-cell function and in T-cell function. CD83 is implicated in HSV-1 latency, suggesting it could also be involved in immune-mediated mechanisms of viral reactivation.

Effective treatment of ocular HSK with a human apolipoprotein E mimetic peptide in a mouse eye model.

PURPOSE: To evaluate efficacy of the small apolipoprotein E (apoE) mimetic dimer peptide (apoEdp) in the treatment of herpetic stromal keratitis in a mouse ocular model and determine its therapeutic effects against HSV-1-induced inflammatory cytokines. METHODS: Female C57Bl/6 mice were corneally infected with HSV-1 strain KOS-GFP; topical treatment was initiated 24 hours after infection and continued for 10 consecutive days. Treatment groups were 1% apoEdp, 1% trifluorothymidine (TFT), and phosphate-buffered saline (PBS). The incidence and severity of stromal keratitis were monitored by slit lamp examination in a masked fashion. Infectious HSV-1 titer in eye swabs and alteration in inflammatory cytokines were determined in the early postinfection period by real-time RT-PCR. RESULTS: One percent apoEdp treatment, which significantly reduced the incidence and severity of HSK, was equal to the effect of 1% TFT; both groups had significantly lower incidence and severity than the placebo treatment group. The in vivo mouse ocular model results of apoEdp therapy correlated with accelerated clearance of virus from eye swabs. Topical 1% apoEdp treatment in mice significantly downregulated gene expression of mouse proinflammatory cytokines. CONCLUSIONS: These results suggest that topical treatment with apoE peptide has efficacy against HSK through anti-HSV-1 and anti-inflammatory activities.

The high prevalence of herpes simplex virus type 1 DNA in human trigeminal ganglia is not a function of age or gender.

The purpose of this study was to determine the presence and copy numbers of herpes simplex virus type 1 (HSV-1) DNA in human trigeminal ganglia (TG) with respect to age, gender, and postmortem interval (PMI). Human TG (n = 174, obtained from the Oregon Brain Bank, with data on age, gender, and PMI) were analyzed for HSV-1 DNA copies (HSV-1 DNA polymerase gene) by using real-time PCR. We found that 89.1% (131/147) of subjects and 90.1% (155/174) of TG contained HSV-1 DNA. The copy numbers of HSV-1 DNA in the positives ranged from very high (>10(6)) to very low (5). These data confirm and strengthen our previous findings that subjects were positive for HSV-1 DNA in tears (46/50; 92%) and saliva (47/50; 94%). These TG data and tear and saliva data demonstrated considerable variability in copy numbers of HSV-1 DNA per subject. Statistical analysis showed no significant relationship between gender and copy number, age and copy number, or PMI and copy number for each pair of variables. A factorial analysis of gender, age, and PMI with respect to copy number also showed no statistical significance. This is the first study that provides statistical analysis that documents that the prevalence of HSV-1 DNA in the human TG is not a function of either gender or age.

Ocular HSV-1 latency, reactivation and recurrent disease.

Ocular infection with HSV-1 continues to be a serious clinical problem despite the availability of effective antivirals. Primary infection with HSV-1 can involve ocular and adenaxial sites and can manifest as blepharitis, conjunctivitis, or corneal epithelial keratitis. After initial ocular infection, HSV-1 can establish latent infection in the trigeminal ganglia for the lifetime of the host. During latency, the viral genome is retained in the neuron without producing viral proteins. However, abundant transcription occurs at the region encoding the latency-associated transcript, which may play significant roles in the maintenance of latency as well as neuronal reactivation. Many host and viral factors are involved in HSV-1 reactivation from latency. HSV-1 DNA is shed into tears and saliva of most adults, but in most cases this does not result in lesions. Recurrent disease occurs as HSV-1 is carried by anterograde transport to the original site of infection, or any other site innervated by the latently infected ganglia, and can reinfect the ocular tissues. Recurrent corneal disease can lead to corneal scarring, thinning, stromal opacity and neovascularization and, eventually, blindness. In spite of intensive antiviral and anti-inflammatory therapy, a significant percentage of patients do not respond to chemotherapy for herpetic necrotizing stromal keratitis. Therefore, the development of therapies that would reduce asymptomatic viral shedding and lower the risks of recurrent disease and transmission of the virus is key to decreasing the morbidity of ocular herpetic disease. This review will highlight basic HSV-1 virology, and will compare the animal models of latency, reactivation, and recurrent ocular disease to the current clinical data.

Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection.

PURPOSE: The aim of this study was to evaluate the effect of BAY 57-1293, a helicase-primase inhibitor, on herpes simplex virus type 1 (HSV-1) reactivation in mice and its efficacy on established disease in rabbits. METHODS: BALB/c mice latent for McKrae-strain HSV-1 were reactivated via heat stress, treated with BAY 57-1293, and their corneas were swabbed for virus or the trigeminal ganglia (TG) obtained for quantification of viral DNA. New Zealand white rabbits were infected and treated topically or orally in comparison with trifluridine or valacyclovir. RESULTS: Oral BAY 57-1293 suppressed reactivation in HSV-1-infected mice and reduced the viral load in TG up to four orders of magnitude. In the rabbits, the therapeutic efficacies of topical BAY 57-1293 and trifluridine were similar. Once-daily oral BAY 57-1293 was significantly more effective than valacyclovir and as effective as twice a day topical trifluridine. CONCLUSIONS: BAY 57-1293 may be more effective than valacyclovir, without the cytotoxicity or potential healing retardation seen with trifluridine. Oral BAY 57-1293 may be a substitute for eye drops as an effective treatment for herpetic keratitis and might be useful in treating stromal keratitis and iritis, as well as preventing recurrences of ocular herpes.

Healing process at the flap edge in its influence in the development of corneal ectasia after LASIK.

PURPOSE: Post-laser in situ keratomileusis (LASIK) corneal ectasia is a progressive deformation of the gross corneal anatomy that occurs after surgery. However, this is a rare event even after deep lamellar keratoplasty. We hypothesize that the strength of the lamellar keratoplasty wound is derived from the sutures that enhance the wound edge healing response. This study compares, in a rabbit model, the stability of previously sutured and unsutured microkeratome flaps. METHODS: Unilateral 160-micro m-thick LASIK flaps using a mechanical microkeratome was performed in 20 rabbit eyes. Animals were then divided in two groups: In group A, the flap was left without sutures. In group B, the flap was sutured with 12 interrupted 10/0 nylon stitches that were removed after 3 weeks under general anesthesia. Six weeks after surgery, all rabbits had corneal topographies performed at their baseline intraocular pressure (IOP) (14 mmHg) and at two artificially increased pressures (25 and 45 mmHg) using an anterior chamber maintainer implanted in the inferior limbal area. The animals were humanely euthanized, and immunohistological analysis of the corneas was performed. RESULTS: A delta K1 value, which indicates the difference in the simulated keratometric value at baseline and the one measured at 25 mmHg, was calculated for all eyes. It showed a mean steepening effect of 2.74 D +/- 0.38 D in group A compared with 1.08 D +/- 0.27 D in group B (p < 0.05). Similarly, a delta K2 value, which indicates the difference in the simulated keratometric value at baseline and the one obtained at 45 mmHg, was registered. It showed a mean steepening effect of 3.02 D +/- 0.87 D in group A compared with 0.75 D +/- 0.44 D in group B (p < 0.05). Six weeks after surgery, the peripheral flap interface in group B consisted of 14.3% +/- 4.15% of positive monoclonal mouse anti-alpha smooth muscle actin (alpha-SMA) cells compared with 4.18 +/- 3.76% in group A (p < 0.05). CONCLUSIONS: The addition of sutures in the corneal flap after LASIK appears to reduce the amount of corneal steepening when the IOP is artificially increased up to 25 mmHg in this rabbit model. Our results suggest that an increase in the amount of myofibroblastas induced by the sutures may be responsible for this behavior. Corneal ectasia may be related to the clinically observed lack of corneal wound-healing at the edge of the flap that allows the cornea to bulge. By stimulating a stronger wound-healing response at the edge of the flap, the cornea may better resist steepening under increased IOP conditions and improve the long-term stability of LASIK surgery in borderline thin corneas.