Michael A. Thiel

Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts.

Purpose: To evaluate the efficacy of ultraviolet-corneal cross-linking (CXL) for treating infectious melting keratitis. Methods: Five patients with infectious keratitis associated with corneal melting were treated with CXL at the outpatient departments of the Institut für Refraktive und Ophthalmo-Chirurgie and the eye hospital at the University of Zurich. CXL was performed when the infection did not respond to systemic and topical antibiotic therapy. Follow-up after cross-linking ranged from 1 to 9 months. Results: In all cases, the progression of corneal melting was halted after CXL treatment. Emergency keratoplasty was not necessary in any of the 5 cases presented. Conclusions: CXL is a promising option for treating patients with therapy-refractory infectious keratitis to avoid emergency keratoplasty.

Voriconazole Concentration in Human Aqueous Humor and Plasma during Topical or Combined Topical and Systemic Administration for Fungal Keratitis

ABSTRACT Voriconazole (VRC) is an antifungal drug that effectively treats keratitis caused by yeasts and molds when administered orally. We retrospectively evaluated clinical outcomes and plasma and aqueous humor drug concentrations in five patients with fungal keratitis and one patient with posttraumatic endophthalmitis who were treated with VRC. VRC was administered either topically (1% eye drops every hour) or orally (400 mg twice a day). Plasma and aqueous humor samples from affected eyes were taken 12 h after oral administration or 1 h after eye drop application. The drug concentration was measured by liquid chromatography with UV or mass spectrometric detection. All six patients responded well to VRC treatment. The VRC concentration ranged from 2.93 to 3.40 mg/liter in the aqueous humor and from 3.20 to 4.20 mg/liter in the plasma after combined oral and topical treatment. Topical administration alone resulted in highly variable trough VRC concentrations of 0.61 to 3.30 mg/liter in the aqueous humor. VRC concentrations were above the MIC for Candida albicans Aspergillus fumigatus and clinical improvement was seen in all four patients with C. albicans and A. fumigatus keratitis. Combined orally and topically administered VRC resulted in aqueous humor drug concentrations of ≥2.93 mg/liter, which is above the VRC MIC for most fungi. Topical VRC treatment resulted in an aqueous humor drug concentration >0.61 mg/liter, which is above the MIC for most Candida species. The results from this small series of patients suggest that both topical and combined systemic and topical VRC therapy can be effective in treating fungal keratitis. Furthermore, the data provide preliminary support for initiation of VRC treatment with a combined topical and systemic administration until the causative fungus and its MIC are identified.

Efficient Intraocular Penetration of Topical Anti–TNF-α Single-Chain Antibody (ESBA105) to Anterior and Posterior Segment without Penetration Enhancer

PURPOSE This study was designed to characterize ocular penetration pathways of ESBA105, a topically administered single-chain antibody (scFv) against tumor necrosis factor (TNF)-alpha, to the anterior and posterior segment of the eye. METHODS Fresh enucleated whole eyes and isolated corneas of rabbits mounted in perfusion chambers were used for ex vivo penetration studies. In vivo pharmacokinetics and ocular biodistribution of ESBA105 after intravitreal injection or topical administration as eye drops were investigated in rabbits. RESULTS After topical administration as eye drops, without a penetration enhancer, ESBA105 reached therapeutic levels in the anterior and posterior segment of the eye. ESBA105 migrated to aqueous humor via corneal penetration and vitreous and retina via intrascleral penetration pathways. In vivo, ESBA105 had a significantly prolonged elimination half-life in the vitreous of 25 hours compared with its serum half-life of 7 hours after i.v. administration. Therefore, based on frequency of topical dosing, a buildup of ESBA105 to distinct steady state levels in the vitreous could be achieved. CONCLUSIONS Topically administered ESBA105 quickly reaches therapeutic levels in the anterior and posterior segment without any need for a penetration enhancer. Drug penetration and ocular biodistribution patterns of ESBA105 applied as eye drops appear highly attractive for clinical use to treat TNF-alpha dependant diseases of the eye.

GS-101 Antisense Oligonucleotide Eye Drops Inhibit Corneal Neovascularization Interim Results of a Randomized Phase II Trial

PURPOSE Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the most significant preoperative and postoperative risk factors for graft rejection after corneal transplantation. The aim of this study was to test tolerability and efficacy of gene signal (GS)-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1, versus placebo on inhibition of progressive corneal neovascularization. DESIGN Randomized, double-blind, multicenter, phase II clinical study. PARTICIPANTS AND CONTROLS Interim analysis on 40 patients with progressive corneal neovascularization resulting from various underlying diseases being nonresponsive to conventional therapy. INTERVENTIONS Four groups of 10 patients were treated for 3 months in this dose-finding study comparing 3 doses of GS-101 (eye drops twice daily; 43, 86, and 172 microg/day total) with placebo (10 patients per group). MAIN OUTCOME MEASURES The primary end point was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques. RESULTS GS-101 eye drops were well tolerated. All serious and 95% of all other adverse events were categorized by the investigators as unrelated. In 3 patients, there was a potentially related side effect of ocular surface discomfort. At a dose of 86 microg/day (43 microg/drop), GS-101 eye drops produced a significant inhibition and regression of corneal neovascularization (-2.04+/-1.57% of total corneal area; P = 0.0047), whereas the low dose tended to stabilize it (0.07+/-2.94%; P = 0.2088) compared with placebo (0.89+/-2.15%), where corneal neovascularization progressed in all patients. There was no apparent benefit to the higher dose (1.60+/-7.63%). CONCLUSIONS The interim results of this phase II study suggest that GS-101 eye drops at an optimal dose of 86 microg/day are an effective and noninvasive approach specifically to inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. Safety concerns were not detected. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Comparison and reproducibility of corneal thickness and curvature readings obtained by the Galilei and the Orbscan II analysis systems

PURPOSE: To compare central corneal thickness (CCT) and keratometry readings using the Galilei dual Scheimpflug analyzer, the Orbscan II anterior segment analysis system, and the Sonogage ultrasound (US) pachymeter. SETTING: Lucerne Eye Clinic, Cantonal Hospital, Lucerne, Switzerland. METHODS: In a prospective single‐center study, 85 eyes of 45 healthy volunteers were examined with the Orbscan II and Galilei systems in random order followed by Sonogage US pachymetry. The CCT and keratometry measurements were compared using a paired t test. To assess the intraobserver and interobserver reproducibility of the 2 keratometers, 9 volunteers were examined 3 times by 4 independent observers and the intraclass correlation coefficient (ICC) was calculated. RESULTS: The mean CCT was 551.7 μm ± 36.6 (SD) with the Galilei, 554.8 ± 45.1 μm with the Orbscan II, and 558.5 ± 38.4 μm with the Sonogage. The CCT readings of the Galilei and Orbscan II did not differ significantly (P = .12). The mean keratometry readings with the Galilei and Orbscan II were similar, although both the steep (Ks) and flat (Kf) axes tended to be flatter with the Galilei system. The ICCs for CCT, Kf, and Ks were high with both keratometers (0.98, 0.97, 0.84 for Galilei and 0.97, 0.96, 0.95 for Orbscan II, respectively), indicating that variation in measurements was mainly due to true subject‐to‐subject variation rather than observer error. CONCLUSION: Keratometry and pachymetry readings with the Galilei and Orbscan II systems showed good concordance and high reproducibility, which would allow the examinations to be delegated to nonmedical personnel.

Corneal calcification following intensified treatment with sodium hyaluronate artificial tears

Aim: To report a potential adverse effect of intensified treatment with sodium hyaluronate artificial tears. Methods: Five cases of deep calcium deposition in the cornea associated with ocular surface disease and frequent use of hyaluronic acid artificial tears are described. All patients used one formulation of phosphate buffered hyaluronate eye drops when rapid calcification developed. All eyes required corneal graft surgery for visual rehabilitation. Specimens at keratoplasty were available for light microscopy and investigation by dispersive x ray analysis. The phosphate concentration in the medication used for topical treatment was measured and compared to alternative hyaluronate preparations. Results: Light microscopy showed dense mineralisation of the entire stroma. The crystalline deposits consisted of hydroxyapatite, Ca5(PO4)3OH. A 50-fold higher concentration of phosphate was measured in the sodium hyaluronate eye drops used for treatment (50.9 mmol/l) when compared with normal serum. The other hyaluronate formulations showed phosphate concentrations from <0.1 mmol/l to 10.9 mmol/l. Conclusions: The hyaluronate artificial tear formulation “Hylo-Comod” favours the formation of insoluble crystalline calcium phosphate deposits in presence of epithelial keratopathy. This is because of its high phosphate concentration and typically frequent instillation. Manufacturers and prescribers should be aware that topical preparations may contain considerable amounts of phosphate which may lead to sight threatening corneal complications.

Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis.

Topic To quantify the gain in visual acuity and serious side effects of ranibizumab, bevacizumab and aflibercept in age-related macular degeneration (AMD). Clinical relevance There is an ongoing debate about the optimal treatment of AMD with these three antivascular endothelial growth factor (anti-VEGF) treatments. Methods Network meta-analyses. (Pre)Medline, EMBASE, SCOPUS, Cochrane Library (until April 2013), Science Citation Index and reference lists were searched for placebo-controlled randomised trials or head-to-head comparisons. Outcomes were 1-year follow-up data of visual acuity (letters gained) and serious (vascular death, any death, stroke, myocardial infarction, transient ischaemic attack) and thrombotic events. Two investigators independently assessed eligibility and quality of included studies and extracted data. Results 11 trials (enrolling 8341 patients) assessing five active treatments were included. Compared with placebo, all anti-VEGF treatments had a significantly higher percentage of letters gained: ranibizumab 0.3 mg 2.39% (95% CI 1.59 to 3.19; p<0.001), ranibizumab 0.5 mg 3.56% (95% CI 2.58 to 4.13; p<0.001), bevacizumab 1.25 mg 2.14% (95% CI 0.47 to 3.82; p=0.012), aflibercept 0.5 mg 2.91% (95% CI 0.99 to 4.82; p=0.003) and aflibercept 2 mg 3.44% (95% CI 1.73 to 5.14; p<0.001). Compared with placebo, serious side effects were higher in all other treatments: ranibizumab 0.3 mg 4.41% (95% CI 3.42 to 5.40; p<0.001), ranibizumab 0.5 mg 5.33% (95% CI 4.37 to 6.30; p<0.001), bevacizumab 1.25 mg 5.58% (95% CI 3.567 to 7.60; p<0.001), aflibercept 0.5 mg 5.65% (95% CI (3.28 to 8.02; p<0.001) and aflibercept 2 mg 5.29% (95% CI 3.18 to 7.39; p<0.001). Compared with placebo, systemic thrombotic events also occurred more often in all other treatments. Conclusions The study revealed only a modest superiority of aflibercept 2 mg and ranibizumab 0.5 mg over other formulations and dosages.

Original articleGS-101 Antisense Oligonucleotide Eye Drops Inhibit Corneal Neovascularization: Interim Results of a Randomized Phase II Trial

PURPOSE Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the most significant preoperative and postoperative risk factors for graft rejection after corneal transplantation. The aim of this study was to test tolerability and efficacy of gene signal (GS)-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1, versus placebo on inhibition of progressive corneal neovascularization. DESIGN Randomized, double-blind, multicenter, phase II clinical study. PARTICIPANTS AND CONTROLS Interim analysis on 40 patients with progressive corneal neovascularization resulting from various underlying diseases being nonresponsive to conventional therapy. INTERVENTIONS Four groups of 10 patients were treated for 3 months in this dose-finding study comparing 3 doses of GS-101 (eye drops twice daily; 43, 86, and 172 microg/day total) with placebo (10 patients per group). MAIN OUTCOME MEASURES The primary end point was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques. RESULTS GS-101 eye drops were well tolerated. All serious and 95% of all other adverse events were categorized by the investigators as unrelated. In 3 patients, there was a potentially related side effect of ocular surface discomfort. At a dose of 86 microg/day (43 microg/drop), GS-101 eye drops produced a significant inhibition and regression of corneal neovascularization (-2.04+/-1.57% of total corneal area; P = 0.0047), whereas the low dose tended to stabilize it (0.07+/-2.94%; P = 0.2088) compared with placebo (0.89+/-2.15%), where corneal neovascularization progressed in all patients. There was no apparent benefit to the higher dose (1.60+/-7.63%). CONCLUSIONS The interim results of this phase II study suggest that GS-101 eye drops at an optimal dose of 86 microg/day are an effective and noninvasive approach specifically to inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. Safety concerns were not detected. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Morphological and immunohistochemical changes after corneal cross-linking.

Purpose: To present light and electron microscopic as well as immunohistochemical findings after corneal cross-linking (CXL). Methods: Six keratoconus corneas after CXL, 12 keratoconus corneas without CXL, and 7 normal corneas were examined by light microscopy, indirect immunohistochemistry using antibodies against proapoptotic BAX, antiapoptotic survivin, and BCL-2, and anti–smooth muscle actin and, in part, by transmission electron microscopy. Direct immunofluorescence with 4′6-diamidino-2-phenylindole was performed to analyze keratocytes/area in the anterior, middle, posterior, peripheral, and central corneal stroma. Results: The period between CXL and keratoplasty ranged from 5 to 30 months. All keratoconus corneas showed the typical histological changes. Increased proapoptotic BAX expression and/or antiapoptotic survivin expression were noticed in keratocytes and endothelium in 2 keratoconus specimens after CXL. Smooth muscle actin was only observed in subepithelial scar tissue of 2 keratoconus corneas without CXL. Keratoconus corneas after CXL revealed a significant reduction in keratocyte counts in the entire cornea (P = 0.003) compared with keratoconus corneas without CXL and normal corneas. This difference was because of a loss of keratocytes in the anterior (P = 0.014) and middle (P = 0.024) corneal stroma. Keratocytes in CXL corneas were reduced in the center (P = 0.028) and the periphery (P = 0.047). Conclusions: CXL in human keratoconus can cause considerable morphologic corneal changes up to 30 months postoperatively. Especially noteworthy is a long-lasting, maybe permanent, keratocyte loss in the anterior and middle corneal stroma involving the central and peripheral cornea. As long-term corneal damage after CXL is of genuine concern, particular care should be taken to perform this procedure only in accordance with investigational protocols.

Corneal Cross-Linking as Supplementary Treatment Option in Melting Keratitis: A Case Series

BACKGROUND Corneal melting represents a serious condition that can result in corneal perforation and loss of vision. Treatment options include topical and systemic immunosuppression, cyanoacrylate gluing, and emergency keratoplasty, depending on the underlying disease and the stage of corneal melt. Recently, corneal cross-linking (CXL) has emerged as an additional treatment option. The present study evaluates whether CXL induces a clinical improvement in melting keratitis not responding to conventional treatment. HISTORY AND SIGNS Six patients undergoing CXL for corneal melting of variable origin (including bacterial, fungal and Acanthamoeba keratitis) were reviewed retrospectively. THERAPY AND OUTCOME Treatment parameters included riboflavin application following UV irradiation with a wavelength of 370 nm and an irradiance of 3 mW/cm2 for 30 minutes. Four patients with corneal melting due to contact lens-related infectious keratitis showed healing without any need for further interventions up to date. In two patients, CXL stabilized the melting cornea and facilitated additional surgical procedures. CONCLUSIONS By stabilizing corneal collagen fibres, CXL seems to represent an effective option to re-establish corneal integrity in the event of pending perforations. In established perforations, CXL facilitates further emergency procedures by stiffening the tissue.