Outcomes of mitomycin C intravascular chemoembolization (MICE) in refractory corneal neovascularization after failed keratoplasty.

Corneal neovascularization is a determinant of corneal graft survival and preservation of immune privilege after keratoplasty. We report the outcomes in 2 patients with failed corneal grafts who underwent mitomycin C (MMC) intravascular chemoembolization (MICE) in the affected eye. A 30-year-old woman with failed penetrating keratoplasty (PK) in the right eye was started on prednisolone acetate eyedrops. Graft sutures were removed, and bevacizumab was injected subconjunctivally. The eye remained intermittently painful, and MICE was performed on the main feeding vessel, with regression of the vessels apparent within the first day following the procedure. The second case was a 40-year-old man who had a history of repaired penetrating injury in the left eye followed by failed PK. Prednisolone acetate eyedrops were initiated, and corneal sutures were removed. The patient failed to improve with three subconjunctival injections of bevacizumab. MICE was performed, but in this case neovascularization did not regress until 20 weeks post-procedure. MMC is thought to inhibit vascular endothelial cell proliferation, but its use in corneal injection is debated. In these cases, MICE was not associated with any concerning adverse events.

[Clinical analysis of penetrating keratoplasty for infants with congenital corneal opacity].

Objective: To investigate the corneal graft survival and related risk factors of primary penetrating keratoplasty in congenital corneal opacity infants. Methods: It was a retrospective cohort study. Data were collected from forty-two infants (51 eyes) who were aged ≤12 months and diagnosed with congenital corneal opacity in Beijing Tongren Hospital and Beijing Anzhen Hospital from January 1, 2017 to January 31, 2018. The mean age at surgery was (5.7±2.2) months (3-12 months). The mean follow-up duration was (28.6±2.6) months (24-33 months). All the patients underwent penetrating keratoplasty. The status of the corneal grafts and complications were observed and recorded during the regular follow-up. The survival probabilities were estimated by using the Kaplan-Meier and Log-rank test. The graft survival between different influence factors was analyzed by using the χ2 test. Results: The Kaplan-Meier survival rates for penetrating keratoplasty were 84.3% (43/51) at 6 months, 78.4% (40/51) at 12 months and 60.8% (31/51) at the last follow-up. The presence of corneal neovascularization was significantly correlated with graft failure (χ²=5.264, P=0.022). The graft survival differed between eyes receiving combined surgery and mere penetrating keratoplasty and in eyes with varied surgical indications (P=0.039, <0.01). Increased intraocular pressure (7 eyes, 13.7%) and persistent epithelial defects (7 eyes, 13.7%) were the most common postoperative complications, followed by complicated cataract (4 eyes, 7.8%) and posterior capsule opacification (2 eyes, 3.9%). Conclusions: The graft survival rate was satisfactory following pediatric keratoplasty although it had a tendency to decrease with the follow-up time. Corneal neovascularization was a major risk factor of graft failure. Surgical indications and procedures also had a certain effect on the graft survival.

Bevacizumab in High-Risk Corneal Transplantation: A Pilot Multicenter Prospective Randomized Control Trial.

PURPOSE: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. DESIGN: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. PARTICIPANTS: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. METHODS: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. MAIN OUTCOME MEASURE: The 52-week endothelial immune rejection rate. RESULTS: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis. CONCLUSIONS: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.

Corneal Crosslinking to Regress Pathologic Corneal Neovascularization Before High-Risk Keratoplasty.

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.

Antiangiogenesis Effect of Albendazole on the Cornea.

Purpose: To investigate the anti-(lymph)angiogenic and anti-inflammatory effects of albendazole and to study whether these effects are additive with bevacizumab therapy in a murine corneal suture model. Methods: Corneal neovascularization (NV) and lymphangiogenesis (LY) were compared in a corneal suture model after administration of a subconjunctival injection of albendazole, bevacizumab, dexamethasone, or phosphate-buffered saline (PBS). Immunohistochemical staining and analysis were performed in each group. Real-time polymerase chain reaction (RT-PCR) was performed to quantify the expression of inflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin-6), vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, and VEGFR-3. To evaluate the additive effect of albendazole, corneal NV and LY were also analyzed in a combined group of albendazole and bevacizumab therapy and the additive effect was compared with that in the group of double dose of bevacizumab. Results: The albendazole group showed less NV and less LY compared with the PBS control group (P < 0.01). When albendazole was combined with bevacizumab therapy, a significant decrease in NV and LY was seen compared with bevacizumab treatment alone, and with albendazole alone (all P values <0.05). The combination group showed better antilymphangiogenesis effect than the group of double dose bevacizumab. The albendazole-treated group showed reduced expression of VEGF-A, VEGF-C, TNF-alpha, and VEGFR-2 compared with corneas from the PBS group (P value <0.05 in all respective comparisons). Conclusion: Albendazole significantly decreased NV and LY in the cornea. This beneficial effect is additively enhanced when combined with bevacizumab treatment.

Localization of Corneal Neovascularization Using Optical Coherence Tomography Angiography.

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.

The Effect of 0.5% Timolol Maleate on Corneal(Lymph)Angiogenesis in a Murine Suture Model.

PURPOSE: To investigate the anti(lymph)angiogenic and anti-inflammatory effects of 0.5% timolol maleate in a murine corneal suture model. METHODS: Corneal neovascularization and lymphangiogenesis were compared in groups of mice that underwent corneal suture and were subsequently administered a subconjunctival injection of 0.5% timolol maleate, dexamethasone, or phosphate-buffered saline (PBS). Immunohistochemical staining and analysis were performed in each group. Real-time polymerase chain reaction (RT-PCR) was performed to quantify the expression of inflammatory cytokines [TNF-alpha and interleukin (IL)-6], vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, and VEGFR-3. RESULTS: When corneas from the timolol-treated group were compared to the PBS-treated group, we observed decreases in angiogenesis, lymphangiogenesis, and inflammatory infiltration in the timolol-treated group (P value <0.05 in all respective comparisons). Corneas from the timolol-treated group showed reduced expression of VEGF-A, VEGF-C, TNF-alpha, IL-6, VEGFR-2, and VEGFR-3 compared to corneas from the PBS group (P value <0.05 in all respective comparisons). CONCLUSION: Blocking adrenergic signaling in the cornea with 0.5% timolol maleate decreased corneal neovascularization and lymphangiogenesis.

Variaciones en la técnica del trasplante limbar autólogo / Variations in the technique for autologous limbal transplantation

OBJETIVO: Presentar los resultados del uso de un único segmento de autoinjerto limbar combinado con trasplante de membrana amniótica y epiteliectomías conjuntivales sectoriales secuenciales postoperatorias en 2 pacientes con insuficiencia límbica unilateral total. CONCLUSIONES: Un solo segmento de autoinjerto limbal junto con el trasplante de membrana amniótica puede ser suficiente para restaurar una superficie corneal estable, siendo en ocasiones necesario realizar en el postoperatorio epiteliectomías conjuntivales secuenciales en zonas remanentes de epitelio anómalo

OBJECTIVE: To present the results on the use of a single block limbal autograft, combined with amniotic membrane transplantation and sectoral sequential postoperative epitheliectomy of the conjunctiva in 2 patients with unilateral total limbal stem cell deficiency. CONCLUSIONS: A single block limbal autograft combined with amniotic membrane transplantation may be sufficient to restore a stable corneal surface, but sometimes sequential sectoral conjunctival epitheliectomy may be required to treat anomalous epithelial remnants

Degeneración nodular de Salzmann / Salzmann's nodular degeneration

La degeneración nodular de Von Salzmann constituye una entidad clínico-patológica en la que aparecen nódulos lisos y opacos, blanco grisáceos o algo azulados en las capas anteriores de la córnea. La afectación suele ser bilateral y los nódulos tienden a disponerse en anillo sobre la media periferia corneal. Pueden estar relacionados o no con un proceso inflamatorio previo y su tratamiento puede ser sintomático o quirúrgico si compromete el área pupilar y con ella la visión del paciente.Se presenta un paciente masculino, de 57 años de edad, coloración de la piel blanca, quien acudió a la consulta y refirió enrojecimiento de ambos ojos (predominio del ojo derecho), con picor, escozor y lagrimeo, de más de 6 meses de evolución. Asociado a esto notó una zona de color blanquecina en ambos ojos. En la exploración oftalmológica se observaron lesiones blanquecinas sobrelevadas de aspecto hialino, en el tercio inferior de la córnea en el ojo derecho y en el ojo izquierdo hacia la región nasal. Se concluye que el caso presenta una degeneración nodular de Salzmann(AU)

Von Salzmann nodular degeneration constitutes a clinical pathological condition in which flat and opaque, white-grayish or bluish nodules appear in the anterior layers of the cornea. The effect is usually bilateral and the nodules tend to spread in a ring form upon the corneal peripheral media. It can be related or not with previous inflammatory process and its treatment can be symptomatic or surgical if the papillary area and the patient's vision are compromised. Here is the case of a 57 years-old male Caucasian patient, who went to the doctor´s and complained of reddened eyes (mainly the right eye), itching and tearing for more than six months. In addition to this, he observed a whitish area in both eyes. The eye screening showed overelevated whitish lesions of hyaline aspect in the lower third of the right eye cornea and in the left eye towards the nasal region. It was concluded that this is a case of Von Salzmann nodular degeneration(AU)

Degeneración nodular de Salzmann / Salzmann's nodular degeneration

La degeneración nodular de Von Salzmann constituye una entidad clínico-patológica en la que aparecen nódulos lisos y opacos, blanco grisáceos o algo azulados en las capas anteriores de la córnea. La afectación suele ser bilateral y los nódulos tienden a disponerse en anillo sobre la media periferia corneal. Pueden estar relacionados o no con un proceso inflamatorio previo y su tratamiento puede ser sintomático o quirúrgico si compromete el área pupilar y con ella la visión del paciente.Se presenta un paciente masculino, de 57 años de edad, coloración de la piel blanca, quien acudió a la consulta y refirió enrojecimiento de ambos ojos (predominio del ojo derecho), con picor, escozor y lagrimeo, de más de 6 meses de evolución. Asociado a esto notó una zona de color blanquecina en ambos ojos. En la exploración oftalmológica se observaron lesiones blanquecinas sobrelevadas de aspecto hialino, en el tercio inferior de la córnea en el ojo derecho y en el ojo izquierdo hacia la región nasal. Se concluye que el caso presenta una degeneración nodular de Salzmann(AU)

Von Salzmann nodular degeneration constitutes a clinical pathological condition in which flat and opaque, white-grayish or bluish nodules appear in the anterior layers of the cornea. The effect is usually bilateral and the nodules tend to spread in a ring form upon the corneal peripheral media. It can be related or not with previous inflammatory process and its treatment can be symptomatic or surgical if the papillary area and the patient's vision are compromised. Here is the case of a 57 years-old male Caucasian patient, who went to the doctor´s and complained of reddened eyes (mainly the right eye), itching and tearing for more than six months. In addition to this, he observed a whitish area in both eyes. The eye screening showed overelevated whitish lesions of hyaline aspect in the lower third of the right eye cornea and in the left eye towards the nasal region. It was concluded that this is a case of Von Salzmann nodular degeneration(AU)

Method for Angiographically Guided Fine-Needle Diathermy in the Treatment of Corneal Neovascularization.

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.

Ocular surface reconstruction in limbal stem cell deficiency.

The purpose of our review was to familiarize the readers with the new concepts in ocular surface diseases and reconstruction. Limbal stem cell deficiency is characterized by the progressive invasion of conjunctival epithelial cells onto the cornea, superficial vascularisation, destruction of the corneal basement membrane, and chronic inflammatory cell infiltration. Depending on the severity of the disease and the time passed from the primary injury amniotic membrane transplantation, keratolimbal allograft and autograft are the available treatments hoping that, in the nearest future, stem cell transplantation and tissue engineering will become the usual therapeutic choices.

Corneal Indocyanine Green Angiography to Guide Medical and Surgical Management of Corneal Neovascularization.

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.

[Current treatments for corneal neovascularization]. / Traitements actuels de la néovascularisation cornéenne.

The extension of blood vessels into the normally avascular stroma defines corneal neovascularization. Though this phenomenon, pathophysiological and clinical features are well characterized, therapeutic modalities have been hindered by a lack of safe, efficacious and non-controversial treatments. In this literature review, we focus on available therapeutic options in light of recent evidence provided by animal and clinical studies. First, this review will focus on pharmacological treatments that target angiogenesis. The low cost and market availability of bevacizumab make it the first anti-angiogenic therapy choice, and it has demonstrable efficacy in reducing corneal neovascularization when administered topically or subconjunctivally. However, novel anti-angiogenic molecules targeting the intracellular pathways of angiogenesis (siRNA, antisense oligonucleotides) provide a promising alternative. Laser therapy (direct photocoagulation or photo-dynamic therapy) and fine needle diathermy also find a place in the treatment of stabilized corneal neovascularization alone or in association with anti-angiogenic therapy. Additionally, ocular surface reconstruction using amniotic membrane graft or limbal stem cell transplantation is essential when corneal neovascularization is secondary to primary or acquired limbal deficiency.

Corneal Fine Needle Diathermy With Adjuvant Bevacizumab to Treat Corneal Neovascularization in Children.

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.

Novel lamellar, flap-based tattooing techniques for corneal opacities in scarred and vascularized blind eyes.

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.

The corneal pocket assay.

The cornea in most species is physiologically avascular, and thus this assay allows the measurement of newly formed vessels. The continuous monitoring of neovascular growth in the same animal allows the evaluation of drugs acting as suppressors or stimulators of angiogenesis. Under anesthesia a micropocket is produced in the cornea thickness and the angiogenesis stimulus (tumor tissue, cell suspension, growth factor) is placed into the pocket in order to induce vascular outgrowth from the limbal capillaries. Neovascular development and progression can be modified by the presence of locally released or applied inhibitory factors or by systemic treatments. In this chapter the experimental details of the avascular cornea assay, the technical challenges, and advantages and disadvantages in different species are discussed. Protocols for local drug treatment and tissue sampling for histology and pharmacokinetic profile are reported.