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Purpose: Corneal neovascularization is the main risk factor for graft rejection after high-risk penetrating keratoplasty (PK). Corneal crosslinking (CXL) has been shown to regress pathological corneal blood and lymphatic vessels and to reduce the risk of graft rejection after high-risk PK experimentally in mice. The aim of this work was to analyze whether CXL is also able to regress corneal neovascularization in patients and is a safe procedure in the context of high-risk PK., Methods: This retrospective case series included 5 patients with progressive corneal neovascularization and the need for high-risk PK because of graft rejection and/or keratitis that received CXL and PK between April 2019 and January 2020. CXL was performed before or in combination with PK and the effect of CXL on corneal neovascularization was assessed morphometrically on slit-lamp images. Patients were followed up to determine the incidence of adverse effects and graft rejection., Results: In 1 case, peripheral corneal CXL was performed first as a single procedure, followed by an additional peripheral CXL procedure combined with PK. In all other cases, peripheral CXL was directly combined with PK. No intraoperative or postoperative complications were observed. Peripheral CXL resulted in a reduction of corneal neovascularization (mean reduction of 70.5% ± 22.7%). Revascularization was not observed. All transplants remained clear and without immune reactions (mean follow-up 16.4 ± 14.9 weeks, range 4-42 weeks)., Conclusions: CXL is able to reduce pathological corneal neovascularization and might therefore be a novel treatment option to improve graft survival after high-risk PK., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This article explores the application of optical coherence tomography angiography (OCTA) in assessing corneal neovascularization (CoNV) and investigates the features of CoNV in eyes with corneal transplantation., Methods: A pilot, case series, observational study was conducted to enroll patients who underwent corneal transplantation including penetrating keratoplasty (PKP) and deep lamellar keratoplasty (DLKP) with or without additional keratolimbal allograft transplantation. All patients were followed with a series of ophthalmologic examinations including slit-lamp photography and were then imaged with the anterior segment OCTA., Results: The study included 15 eyes of 14 patients (12 men; mean age of 37.4 ± 13.3 years), of which 9 eyes had undergone PKP and 6 eyes DLKP. OCTA was able to clearly identify the features of CoNV in eyes with significant CoNV and to confirm the presence of CoNV in eyes suspected of having CoNV. Four types of CoNV (superficial, stromal, fringe, and recipient-bed CoNV) were discovered by OCTA based on their location and depth. Superficial CoNV was mainly discovered in eyes that had undergone PKP (88.9% ± 11.1%), whereas the recipient-bed CoNV, once thought to be located in the host-graft interface, was discovered to grow in the host cornea only in eyes that had undergone DLKP (83.3% ± 16.7%). Comparing the assessment by 2 masked observers revealed a kappa value of 0.94, indicating excellent agreement., Conclusions: OCTA can be useful to visualize CoNV, which may be valuable in assessing corneal graft rejection.

Purpose: To describe a method to assess corneal neovascular (CoNV) complexes and identify feeder vessels for selective arterial fine-needle diathermy (FND)., Methods: In patients with CoNV, color photography and corneal indocyanine green angiography (ICGA) and fluorescein angiography are performed. After injection of indocyanine green and sodium fluorescein dye, videography and single-frame images of the region of interest are recorded. Videography is used to measure the time to leakage to assess vessel maturity to guide medical treatment and to discern afferent from efferent vessels. Single-frame images are then selected to locate the number of afferent vessels for surgery, which are selectively cut with a 25-gauge marked needle for the application of FND., Results: Angiography using fluorescein and indocyanine green allows the characterization of CoNV based on assessment of both morphologic (ICGA) and functional (fluorescein angiography) parameters. The time to leakage of fluorescein dye provides important functional information on vessel maturity and helps discern whether medical treatment should be followed before surgical. ICGA allows the identification and delineation of afferent feeder vessels even in the presence of corneal opacities affecting biomicroscopic visibility. Colocalizing the afferent vessel to a visible venous landmark or branch is helpful for placement of the incision and application of FND. Using the described approach, angiographically identified feeder vessels can be selectively treated by FND with minimal thermal energy applied to the corneoscleral limbus., Conclusions: The described method for angiographically guided assessment of CoNV is a useful approach for guiding the medical and surgical treatment of CoNV.

Purpose: To illustrate the role of corneal angiography in the clinical assessment and surgical treatment of patients with complex corneal neovascularization (CoNV)., Methods: A case series of 3 patients with CoNV is presented whose management was guided by indocyanine green (ICG) and fluorescein corneal angiography. In the first case, there was recurrent lipid exudation into an intrastromal cleft from CoNV; in the second, there was progressive exudation from CoNV at the graft-host interface; in the third, CoNV was associated with rejection after deep anterior lamellar keratoplasty., Results: In the first case, angiography helped to identify and treat the feeder vessels and stop further leakage. In the second case, it was possible using angiography to differentiate CoNV arising from iris and limbal vasculature enabling angiographic-guided fine-needle diathermy with cessation of exudation. In the third case, angiography revealed the location of CoNV in the host-graft interface after deep anterior lamellar keratoplasty, rather than within the corneal stroma., Conclusions: Corneal angiography is a useful diagnostic tool to guide medical and surgical management of CoNV by enabling the localization of vessel depth and topography.

Purpose: To report the outcomes of corneal fine needle diathermy (FND) with adjuvant intrastromal and subconjunctival bevacizumab injection for corneal neovascularization (CN) in children., Methods: Medical records of all children who had undergone FND with adjuvant bevacizumab injection were reviewed retrospectively. Treatment efficacy was evaluated by changes in visual acuity, regression of CN, and clearing of lipid deposits with the aid of slit-lamp color images that were taken before surgical intervention and at last follow-up visit. Postoperative complications were recorded and served to assess the safety of the procedure., Results: Nine eyes of 9 patients were included in the study. The mean age of the patients was 8.4 ± 4.2 years (4-15 years) and the mean follow-up time was 18.7 ± 12.2 months (5-35 months). Three eyes had a history of herpes simplex keratitis (HSK), 3 eyes had complete corneal anesthesia, 2 eyes had CN following suture tract infection after corneal transplant for HSK scar and limbal dermoid excision, and 1 eye had blepharokeratoconjunctivitis. After treatment, 8 eyes had complete CN resolution, and 1 eye with corneal anesthesia following brain tumor resection had partial regression in vessel distribution and size. Lipid deposition clearance lagged behind CN resolution. Mean duration of CN before treatment was 15.3 ± 14.0 months (1-37 months). Mean corrected distance visual acuity before and after surgery was 0.66 ± 0.31 and 0.50 ± 0.37 logMAR, respectively (P = 0.02)., Conclusions: Corneal FND with adjuvant bevacizumab injection is effective at treating sectorial corneal vessels in children.

Purpose: The aim of this study was to describe novel, flap-based tattooing techniques for the treatment of disfiguring corneal scars in blind eyes., Methods: Several new modifications of intrastromal corneal tattooing techniques were performed in 6 patients. In corneas with a low risk of perforation, a large limbus-to-limbus lamellar flap was prepared, and the tattooing dyes were spread over the entire stromal bed. After additional puncturing of the dyes into the stroma, the flap was closed and sutured ("large flap technique"). In fragile corneas where convenient preparation of a large flap was not possible, a central small flap was prepared, and the "pupil" was tattooed in analogy ("small flap technique"). Afterward, the corneal periphery corresponding to the "iris" was tattooed, either by puncturing or injecting the dye into peripheral intrastromal tunnels ("tunnel technique")., Results: Two eyes were tattooed using a large flap, and 4 eyes were tattooed using a small flap. Here, the corneal periphery of 3 eyes was tattooed by puncturing, whereas 1 eye was tattooed using the tunnel technique. All tattooing procedures were performed without complications and with good cosmetic results., Conclusions: These novel, flap-based tattooing techniques are alternatives to previously reported procedures and can be adapted to the individual corneal constitution. Further, the tunnel technique is an easy-to-perform method that provides good tattooing results.

Purpose: The aim of this study was to evaluate the effect of clinical and biochemical effects of subconjunctival bevacizumab injection in eyes with corneal neovascularization (CNV) due to varied etiologies., Methods: This prospective interventional case series included 12 eyes of 12 patients with CNV after failed therapeutic penetrating keratoplasty (4 eyes), viral keratitis (4 eyes), adherent leucoma (2 eyes), and pseudophakic bullous keratopathy (2 eyes). Each eye received 3 doses of 1.25 mg (0.05 mL) of bevacizumab at 1-month intervals. Morphological changes in neovascularization were evaluated at each visit by slit-lamp examination and corneal digital photography. Corneal buttons of 4 eyes that underwent optical penetrating keratoplasty after bevacizumab injections were analyzed for vascular endothelial growth factor (VEGF) expression and were compared with untreated vascularized and normal cadaveric donor corneas., Results: Of the 12 patients, 10 were males and 2 were females. Four eyes received injections in the early phase of vascularization (<12 weeks of onset) of which 3 showed regression of vessels. Eight eyes received bevacizumab in the mature phase (>12 weeks) of which 5 showed regression. The follow-up ranged from 1 to 16 months. Five eyes underwent optical penetrating keratoplasty after receiving the last dose of bevacizumab and maintained graft clarity with no episodes of rejection over a mean follow-up of 9.8 months. Four of these 5 corneal buttons analyzed for VEGF expression revealed clinically significant lower levels of expression as compared with the vascular untreated corneas. No local or systemic adverse effects were noted in any patient., Conclusions: Subconjunctival bevacizumab helps to regress CNV due to a decrease in corneal VEGF levels and might prove beneficial for use in clinical conditions leading to CNV.

Purpose: To evaluate the efficacy and safety of combined feeder vessel coagulation and topical antiangiogenic therapy using bevacizumab in the treatment of mature corneal blood vessels., Methods: Sixteen eyes of 16 patients with mature corneal neovascularization (NV) due to different underlying corneal diseases underwent fine-needle feeder vessel coagulation by diathermy and were treated postoperatively for up to 4 weeks with topical bevacizumab eye drops (containing 5 mg/mL bevacizumab) 5 times a day. Nine patients received an additional subconjunctival bevacizumab injection at the time of cautery., Results: The mean duration of follow-up was 276 ± 147.3 days (range, 29-464 days). Regression of the feeder vessel was observed in 14 eyes. The vascularized area was reduced significantly (P < 0.05). Combined subconjunctival and eye drop antivascular endothelial growth factor treatment was significantly more effective in reducing the vascularized area compared with antivascular endothelial growth factor eye drop therapy alone (P < 0.05). Five patients (5 eyes) needed a second treatment. Thirteen patients (13 eyes) receiving topical bevacizumab treatment combined with feeder vessel coagulation showed stable visual acuity. Two patients had improved visual acuity. One patient had enlarged area of lipid keratopathy despite successful treatment of corneal NV and thus decreased visual acuity. Overall, there was a nonsignificant improvement of best-corrected visual acuity (P > 0.05)., Conclusions: In this pilot study, fine-needle feeder vessel coagulation combined with topical bevacizumab application for treatment of mature corneal NV seemed to be a well-tolerated new treatment option to regress corneal NV. This may not only improve corneal transparency but also "preconditions" such a cornea for future keratoplasty.

Purpose: To report the effect of superficial keratectomy combined with subconjunctival bevacizumab injection in 2 cases of corneal neovascularization (NV)., Methods: An interventional case series was undertaken on 2 patients with corneal NV: 1 due to sclerokeratitis secondary to rheumatoid arthritis and the other due to Terrien marginal degeneration. Both patients underwent superficial keratectomy combined with subconjunctival bevacizumab injection (2.5 mg/0.1 mL)., Results: Corneal NV regressed with the surgical removal and showed no signs of recurrence after 3 months of follow-up. Both patients reported dramatic subjective improvement in their vision within 1-2 weeks. Best corrected visual acuity improved in 1 patient., Conclusion: The combination of superficial keratectomy with subconjunctival injection of bevacizumab may offer a new strategy for the treatment of superficial corneal NV.

Purpose: To describe a technique of corneal vessel occlusion by using electrolysis-needle cautery., Methods: A prospective case series of three patients., Results: Corneal vessels were successfully occluded in all patients. Vessels remained occluded during the first 8 months post-cautery follow up. Two patients needed repeat cautery at 9 and 10 months respectively. Patients found the procedure comfortable. There was no post-operative induced astigmatism., Conclusion: The technique of ENC is simple, effective and controlled. This technique compares favorably and may prove to be more versatile than Fine Needle Diathermy in the occlusion of corneal vessels that lead to lipid keratopathy.

Purpose: To evaluate patients' self-assessment of their symptoms and cosmetic appearance after fluorescein-potentiated argon laser treatment (FPAL) for corneal inflammation associated with neovascularization. To describe the objective effects of FPAL therapy on established corneal neovascularization with secondary corneal edema and lipid keratopathy., Methods: Fifteen patients with corneal neovascularization resulting from various infectious and traumatic etiologies were enrolled in an open, nonrandomized pilot study. Treatment consisted of repeated sessions of intravenous fluorescein, a photosensitizer, combined with blue-green argon laser applications to abnormal corneal vessels. Patients completed a written survey to grade their symptoms and cosmetic appearance prior to treatment and at the end of the follow-up period. Objective changes in signs after FPAL treatment were described by two nonmasked ophthalmologists after slit-lamp examinations and review of serial corneal photographs., Results: Clinical symptoms of blurred vision (p

Purpose: We report a case of atypical bilateral interstitial keratitis associated with Cogan's syndrome., Methods: A 28-year-old man presented with a 2-year history of recurrent bilateral keratitis. Bilateral hearing loss preceded the ocular symptoms by 2 years. The patient also complained of skin nodules, headache, back pain, and arthritis. Corneal finding were consistent with superior stromal keratitis with stromal neovascularization and lipid deposition in the stroma. The patient's audiogram revealed cochlear pathology compatible with Cogan's syndrome (sensorineural deafness)., Results: The patient was treated with topical steroids but eventually required corneal transplantation in the right eye as a consequence of progressive loss of vision secondary to progressive lipid keratopathy. Visual acuity at the patient's most recent follow-up evaluation was 20/40., Conclusion: This case represents an unusual type of interstitial keratitis associated with Cogan's disease. The absence of ocular symptoms at the time of initial ear involvement and the atypical presentation of the keratitis were responsible for the delay in diagnosis in this patient, resulting in hearing impairment.

Purpose: To analyze presence and distribution of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)alpha, and TGFbeta1 in human corneas with neovascularization due to different corneal diseases., Methods: Indirect immunohistochemistry for VEGF, TGFalpha, and TGFbeta1, was performed on paraffin-embedded corneas obtained by keratoplasty. Corneas from each of the four main groups of histopathologic diagnoses associated with corneal neovascularization were analyzed (scarring after keratitis, graft rejection/insufficiency, acute necrotizing keratitis, scarring after mechanical/chemical injury). Subclassification of inflammatory infiltrates was done using immunohistochemistry for CD3 (T-lymphocytes) and CD68 (macrophages)., Results: The analyzed angiogenic factors were detectable in corneas from all four histopathologic groups in a similar distribution; capillary endothelial cells, stromal and intravascular inflammatory cells (T-lymphocytes, macrophages), and basal corneal epithelial cells stained positive for the tested angiogenic factors., Conclusion: The angiogenic factors VEGF, TGFalpha, and TGFbeta1 are detectable in human corneas with neovascularization. Their distribution is quite uniform in different corneal diseases, resulting in corneal angiogenesis. An antiangiogenic therapy inhibiting corneal neovascularization by antagonizing angiogenic factors would have to counteract several angiogenic factors.

Purpose: To determine the efficacy of a one-piece lamellar keratolimbal graft for the treatment of ocular surface disorders involving the limbus and cornea., Methods: A retrospective study of a case series including eight patients with either Stevens-Johnson syndrome (four patients), ocular cicatricial pemphigoid (three patients), or familial subepithelial amyloidosis of the cornea (one case) was performed with a mean follow-up period of 18 months after surgery., Results: Of the eight cases, three patients retained a corneal epithelial appearance upon their latest visit. No statistically significant difference was observed between preoperative visual acuity (0.013) and postoperative acuity (0.082). Stromal neovascularization was observed in all cases. Seven of eight cases experienced persistent epithelial defects (PED), four of which evolved secondary infectious ulcers. Two cases required further surgical intervention to treat PED or infectious ulcers. None of the cases developed glaucoma., Conclusion: A one-piece keratolimbal graft does not seem to offer any advantage over a two-piece limbal and corneal graft in the treatment of severe ocular surface disorders involving the limbus and cornea.

Purpose: Angiogenesis in corneal diseases can necessitate corneal transplantation and induce graft rejection. The aim of this study was to find out the histopathologic prevalence of angiogenesis in human corneas removed during keratoplasty, to establish the histopathologic diagnoses most commonly associated with angiogenesis, and to evaluate the anatomic location of new corneal vessels., Methods: Corneal buttons (2,557) after keratoplasty were sent to and analyzed in our ophthalmopathology laboratory between 1992 and 1996. Of these, 1,278 full-thickness and lamellar corneal buttons were randomly retrieved and evaluated in this study., Results: Of 1,278 human corneal buttons obtained by keratoplasty, 254 (19.9%) showed angiogenesis. Associated histopathologic diagnoses were (a) scarring after keratitis (109, 45.4%); (b) graft rejection and insufficiency (73, 30.4%); (c) acute necrotizing ulcerative keratitis (30, 12.5%); and (d) scarring after mechanical or chemical injuries (28, 11.7%). Histopathologically, new vessels were usually associated with corneal edema or inflammatory cells or both (76%). The most common locations of new vessels were the upper and middle third of the corneal stroma. Only 11% of new vessels were located solely in the deep stromal layers., Conclusion: Angiogenesis is a common histopathologic feature of corneal diseases leading to corneal transplantation and was found in 19.9% of excised human corneal buttons. Systemic or topical antiangiogenic therapy could reduce the need for corneal transplantation and retransplantation.

Corneal allografts were transplanted into inflamed and vascularized graft beds in rabbit eyes. The grafts were examined every 4 days by slit-lamp biomicroscopy and scanning confocal microscopy. Confocal images were recorded with a video camera and computer enhanced in real-time. Layers of the cornea were visualized in serial optical sections parallel to the epithelium. In the third postoperative week, signs of graft rejection were observed; slit-lamp examination revealed a circumferential line of epithelial rejection, along with cloudiness and edema. Vessels were observed growing into the graft. By confocal microscopy, infiltrating cells were seen in the graft stroma. Foci of cells were especially pronounced around the sutures. Scattered leukocyte infiltrates were prominent at capillary terminals. There was an accompanying reduction in the stromal keratocyte density in the region of the infiltrate. Additionally, various degrees of fibrosis were noted around each suture and at the host-graft interface. Confocal microscopy may provide a valuable clinical tool for determining the earliest indicators of an antigraft immune response, and as an aid in the differential diagnosis of other inflammatory conditions of the cornea.

Immunologic rejection is the main cause of corneal graft failure, especially in vascularized corneal beds. The purpose of this study was to investigate the effect of systemic Cyclosporine-A (CsA) on the survival of corneal allografts in heavily vascularized rabbit corneal beds, following alkali burn. Heavy corneal vascularization was induced in one eye of 20 rabbits by alkali burn. Forty-five days later, penetrating keratoplasty was performed in all the heavily vascularized corneas. Twenty-five mg/kg/day of CsA was intramuscularly administered to 10 rabbits for 30 days. The other 10 rabbits were treated with the solvent without CsA and were used as a matched control group. The results show a significant difference in corneal allograft survival between the two groups. All corneal grafts in the untreated group were intensely rejected and vascularized within 3 weeks. Nine of the 10 corneal transplants, in the CsA-treated group, remained transparent without signs of immunologic rejection for > 180 days. In one corneal transplant, minor signs of rejection occurred. We suggest that CsA, when given systemically, is a potent drug in the prevention of immunologic rejection in high-risk corneal transplantations, such as allografts, in heavily vascularized corneas following alkali burn.

Using a vascularized cornea rabbit model closely resembling human high-risk keratoplasty, corneal allografts were performed on three groups of animals that were paired and tested preoperatively by mixed lymphocyte cultures (MLCs). The three groups were group A, unmodified controls with clear corneas; group B, untreated animals with vascularized corneas; and group C, animals treated with topical cyclosporine (CSA) with vascularized corneas. The MLC results were expressed as stimulation indices (SIs) and divided into low (SI < or = 20) and high (SI > 20) responders and were correlated with final outcome of grafts using survival analysis estimates. In group A, five of 13 (38.5%) grafts rejected, the chance of failure depending on the degree of MLC mismatch between donor and recipient (p = 0.02). All allografts in group B rejected regardless of the degree of mismatch. In group C, seven of 12 (58.3%) grafts rejected, indicating that topical CSA significantly improved survival (p = 0.003) compared with group B. Grafts with mild degrees of MLC mismatch (low responders) survived better (p = 0.0003) than did higher degrees of MLC mismatch (high responders), all of which rejected despite treatment. Our results indicate that both corneal vascularization and the degree of donor-recipient matching play important roles in determining corneal graft survival.

A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used in the thermal mode to coagulate blood vessels in a patient with a vascularized corneal leukoma in an attempt to reduce neovascularization before penetrating keratoplasty. Occlusion of the feeder artery at the periphery was followed by a large stromal hemorrhage. A successful keratoplasty was performed 2 days later.

Corneal neovascularization complicates many anterior segment diseases. Corneal laser photocoagulation using yellow light (577 nm) has been shown to reduce corneal neovascularization. No histopathologic studies of the effects of this treatment on the eye have been reported, however. Target (cornea) and nontarget (iris, lens, retina, and choroid) ocular tissue were studied 1, 24, and 48 h and 5 days after yellow dye corneal laser photocoagulation in a rabbit model of corneal neovascularization. Biomicroscopic examination of the corneas revealed intracorneal hemorrhage in five of 24 (21%) eyes of nonpigmented rabbits. Faint lenticular opacities were observed in two eyes of pigmented rabbits 24 h after laser treatment. Histopathologic examination revealed increased cellularity (neutrophils) (p < 0.005) in the cornea, increasing from 1 h after treatment, peaking 24 h later, and persisting past 5 days. Distortion of the corneal lamellae by red blood cells occurred in eyes in which intracorneal hemorrhage developed. These results indicate that corneal laser photocoagulation using yellow light is a relatively safe procedure for reducing corneal neovascularization.