Corneal neovascularization from extended wear lenses

It is the author's opinion that extended wear lenses should be fit with caution on patients who cannot wear or handle daily wear lenses or adapt to aphakic spectacles. Standard protocol after initial fitting should be to examine the anterior segment with the slit lamp for vascular changes every three months indefinitely without final discharge. Patients who cannot keep all of their follow-up appointments or cannot afford long-term professional fees and lens replacement costs should not be fit with extended wear lenses. It should be stressed to patients that any changes of vision or comfort require an immediate examination by their doctor.     

Corneal neovascularization. Pathogenesis and inhibition

Corneal neovascularization (CNV) can cause significant visual loss because of the scarring and lipid deposition that frequently accompany it. In addition, penetrating keratoplasty in a vascularized recipient carries a significant risk of failure from allograft rejection. Frequently CNV is induced by nonspecific inflammatory stimuli, mediated primarily by polymorphonuclear neutrophils. Neovascularization can also be associated with specific corneal immune reactions, such as herpes simplex keratitis. Immunologically mediated CNV may be more amenable to treatment than CNV that results from nonspecific inflammation. Photodynamic therapy (PDT) following the intravenous injection of hematoporphyrin derivative or purified dihematoporphyrin ether (DHE) has been shown to suppress tumor growth and blood vessel growth in the eye. We have developed a murine model of CNV induced by the intrastromal injection of stimulated lymphocytes or interleukin-2 (IL-2). We have noted corneal DHE retention following its intravenous injection in mice with IL-2 induced CNV. Preliminary studies indicate that PDT can induce regression of CNV in these mice. Other recent studies that have enhanced our understanding of the pathogenesis and treatment of CNV are reviewed, and directions for future research are discussed.     

亲水性软性角膜接触镜所致角膜新生血管临床观察

本文观察了因配戴软性亲水性角膜接触镜而产生角膜新生血管的３３例５９眼，对角膜新生血管的发病机制进行了探讨，指出角膜新生血管的发生与戴镜年限、连续戴镜时间、角膜与镜片的匹配有密切关系，对于此并发症的治疗采用停戴接触镜取得较好效果。     

Corneal neovascularization treated with argon laser.

The argon laser set at 50 mum, 100-150 mW, o-2 s occluded corneal blood vessels in pigmented Dutch rabbits provided the corneal responsible for inducing vascularization was inactive. After arterial treatment with the argon laser retrograde flow in untreated veins was demonstrated by fluorescein angiography. Therefore all corneal new vessels should be treated, not just arteries. Minimal iris damage complicated the laser therapy, but this was not thought necessarily to contraindicate the use of the argon laser to treat corneal blood vessels in man. The iris damage was associated with outpouring of aqueous from the ciliary processes, and it took up to a week for the blood-aqueous barrier to return to its normal state.     

角膜干细胞与角膜表层新生血管

从干细胞角度探讨角膜碱烧伤后表层新生血管的成因。对大鼠角膜缘部进行碱性烧灼造成不同程度的损害，连续观察5周，结果，缘部基底细胞完全破坏者，角膜以新生血管化愈合，而保留缘部基底细胞者，角膜无新生血管化。本实验进一步证实了角膜干细胞缘部基底层定位的观点，提示干细胞对碱性烧伤后阻止角膜的新生血管化，并重建角膜表面的完整性具有重要意义。     

Corneal neovascularization possibly associated with latanoprost therapy

PURPOSE: To report a case of corneal neovascularization possibly associated with latanoprost therapy. METHODS: Case report: A 67-year-old man developed a progressive stromal corneal neovascularization in his right eye within eight months of a corneal trauma. At admission, he was receiving latanoprost 0.005% therapy. His topical medications were rearranged: latanoprost was replaced with carteolol hydrochloride 1% twice daily bilaterally and prednisolone acetate 1% was added twice daily in the right eye. RESULTS: One month later, he presented regression of the corneal neovascularization and an increase in visual acuity. CONCLUSIONS: Latanoprost, an arachidonic acid derivative, could have directly or indirectly stimulated the corneal neovascularization in this patient with a history of nonpenetrating corneal trauma.     

Corneal neovascularization after excimer keratectomy wounds in matrilysin-deficient mice

PURPOSE: Matrilysin, matrix metalloproteinase (MMP)-7, is upregulated in the corneal epithelium during wound healing after excimer keratectomy wounds. The purpose of this study was to determine the role of matrilysin in maintaining corneal avascularity during wound healing. METHODS: Matrilysin-deficient mice (n = 17) and their age-matched wild-type littermates (n = 18) were treated with 193 nm argon-fluoride excimer keratectomy (experiment I). The percentage of corneal surface occupied by neovascularization was measured with a computer image-analysis program adjusted for parallax. In another experiment (experiment II), epithelial closure was monitored with slit lamp biomicroscopy and fluorescein staining, and corneal neovascularization was confirmed by india ink perfusion, electron microscopy, and immunolocalization of CD31 and type IV collagen. Corneal micropocket assays were performed to compare the area of corneal neovascularization in matrilysin-deficient mice and wild-type littermates (experiment III). To determine whether the differences in corneal neovascularization were related to differences in angiogenic factors, the levels of basic fibroblast growth factor (bFGF) were compared with those of vascular endothelial growth factor (VEGF) in matrilysin-deficient and wild-type mouse corneas (experiment IV). RESULTS: The percentages of the corneal surface occupied by neovascularization after excimer laser keratectomy in the matrilysin-deficient mice measured 21.3% +/- 5.2% and 18.7% +/- 5.8% at days 3 and 7, respectively, compared with 5.3% +/- 2.4% and 5.5% +/- 3.4% in the wild-type littermates at days 3 (P < 0.01) and 7, respectively (P < 0.05; experiment I). No significant differences in the rates of epithelial closure of corneal wounds were observed between matrilysin-deficient and wild-type mice after wounding. Corneal neovascularization in the matrilysin-deficient mice was confirmed by india ink present in the corneal stromal blood vessels (extending from the limbus to the wound), immunohistochemical staining, and electron microscopy. Gram, Giemsa, calcofluor white, and acridine orange stains and electron microscopy showed no evidence of corneal infection (experiment II). The area of corneal neovascularization in matrilysin-deficient mice was not significantly different from that of wild-type littermates after implantation of bFGF pellets (0.91 +/- 0.55 mm(2) and 0.77 +/- 0.34 mm(2), respectively; experiment III). The levels of bFGF and VEGF (VEGF, VEGF-B, and VEGF-C) in corneal epithelial cells were not elevated in matrilysin-deficient mice compared with the wild-type mice (experiment IV). CONCLUSIONS: Matrilysin may play an important role in maintaining corneal avascularity during wound healing. The differences in corneal neovascularization between matrilysin-deficient mice and wild-type littermates seem unrelated to the bFGF and VEGF levels in the corneal epithelium.     

Corneal argon laser photocoagulation for neovascularization in penetrating keratoplasty

Corneal argon laser photocoagulation (CALP) was used in 13 patients to treat deep stromal vascular ingrowth. Eight patients had undergone successful penetrating keratoplasty but had developed deep stromal vessels into the graft associated with signs of graft rejection, which did not improve with steroid treatment alone (group 1). After CALP, there was marked regression of the neovascularization with reversal of graft rejection in all eyes. Three additional patients with vascularized corneas, referred for penetrating keratoplasty, underwent CALP preoperatively with obliteration of the vessels (group 2). Two of these patients have since undergone keratoplasty and, in both, the grafts have remained avascular and clear over a 21-month follow-up. Two other patients with corneal injury and progressive corneal opacification and vascularization have also been treated with CALP (group 3). CALP may be a useful adjunct in the treatment of corneal neovascularization. Further clinical studies are needed to define its exact role.     

Corneal neovascularization following short-term wear of soft contact lenses

Between 1980 and 1982 the author treated 9 patients suffering from severe, partly irreversible bilateral damage to the cornea resulting from the use of soft contact lenses. After three months to two years the patients complained of a foreign body sensation, dryness and of a substantial reduction in visual acuity. The high degree of comfort experienced initially encourages patients to wear soft lenses for excessively long periods of time and this can lead to severe complications: while at first there was only slight capillary proliferation at the limbus, superficial and deep vascular proliferation subsequently developed. Use of the soft contact lenses was discontinued and locally applied corticosteroids brought about some improvement. However neovascularization persisted, requiring an intraocular lens implant in one eye - and causing a permanent reduction in the visual acuity of three patients. Wearers of soft contact lenses should be examined regularly by an ophthalmologist (at least twice a year) and should be made aware of the above complications.     

Corneal neovascularization induced by stimulated lymphocytes in inbred mice

The intrastromal implantation of Concanavalin A-stimulated allogeneic lymphocytes induced corneal neovascularization (CNV) in inbred C57BL/6 and BALB/c mice. Control syngeneic stimulated, allogeneic non-stimulated, and allogeneic stimulated irradiated lymphocytes were not angiogenic. CNV induced by allogeneic stimulated lymphocytes in BALB/c recipients was significantly greater than in C57BL/6 recipients. This response reflected host-versus-graft reactivity, since parental recipients responded to F1 hybrid donors, while F1 hybrids did not respond to parental donors. The ability of stimulated lymphocytes to induce CNV may be important in allograft rejection, herpes simplex keratitis, and other corneal immune reactions. The mouse cornea is an excellent model for studying immunologically mediated neovascularization under genetically controlled conditions.     

新的角膜囊袋法诱生的兔角膜新生血管模型

目的研制一种新的具有一致性、可重复性和易于测量的角膜新生血管(CNV)动物模型,为研究新生血管抑制剂提供稳定、可靠的体系。方法明胶海棉蘸取碱性成纤维细胞生长因子(bFGF)500 ng后,再用2%的琼脂糖包裹,将干燥后的小丸植入8只家兔角膜基质层,术后观察4周,墨汁灌注照相,病理组织学检查。结果平均4 d±0.83 d可见新生血管从角膜缘向植入物伸展,且血管成束生长,新生血管范围局限,10 d达最高峰,观察4周未见消退。病理组织学检查,新生血管生长过程中均未见明显的白细胞侵润。结论明胶海绵-bFGF-琼脂糖方法结合角膜囊袋法诱生的兔CNV模型,重复性好,易于在体观察和测定分析。     

Corneal neovascularization after nonmechanical versus mechanical corneal trephination for non-high-risk keratoplasty

PURPOSE: To analyze the influence of mechanical versus nonmechanical trephination of donor and host corneas on superficial, peripheral corneal neovascularization occurring after non-high-risk keratoplasty. METHODS: Patients of the prospective Erlangen non-high-risk keratoplasty study with standardized corneal photographs taken preoperatively and 1 year later were analyzed (n = 184). Slides of these photographs were projected (magnification x100) and corneal vessels graded in a standardized semiquantitative fashion into five categories with regard to limbus, sutures, and host-graft junction in each of 12 corneal sectors. Degree (total increase of grades in the 12 sectors) and maximal extent of corneal neovascularization (maximal centripetal extension of blood vessels) were analyzed. In 32 patients mechanical (17%) and in 152 nonmechanical trephination of host and donor tissue was performed (193-nm excimer laser, 83%). Statistical analysis was done using Fisher's exact and Mann-Whitney test. RESULTS: Corneal neovascularization within the first postoperative year was lower in the nonmechanical [73 of 152 (48%)] compared with mechanical trephination group [24 of 32 (75%); p< 0.01; Mann-Whitney test]. Maximal extent of neovascularization (i.e., vessels reaching the interface or growing beyond) was not yet significantly different between nonmechanical (8%) and mechanical (17%) trephination (p = 0.074). CONCLUSIONS: Nonmechanical trephination using the 193-nm excimer laser in non-high-risk keratoplasties might reduce corneal neovascularization occurring within the first postoperative year. This indicates that in the non-high-risk setting, development of postoperative corneal neovascularization may be affected by the trephination technique and subsequent wound-healing response.     

Corneal endothelial safety following subconjunctival and intrastromal injection of bevacizumab for corneal neovascularization

The purpose of this study is to determine the effect on endothelial cell density and morphology of combined subconjunctival and intracorneal injection of bevacizumab for the treatment of corneal neovascularization (NV). The charts and specular microscopy images of ten consecutive patients with corneal NV, who received combined subconjunctival+intracorneal injections of bevacizumab were reviewed. Patients received three injections of bevacizumab 25 mg/mL (1.25 mg/0.05 mL subconjunctival and 1.25 mg/0.05 mL intrastromal) 4–6 weeks apart. Endothelial cell counts (ECCs) and morphological changes were assessed by non-contact specular microscopy performed at baseline, 1 month after each injection and at 3 and 6 months after the last injection. There were no significant changes in ECCs (p = 0.663), coefficient of variation (p = 0.076), percentage of hexagonal cells (p = 0.931) or mean corneal thickness (p = 0.462) from pre-injection values to the 6-month follow-up values. There were no intraoperative or postoperative complications. In our series, the use of combined subconjunctival and intracorneal bevacizumab did not cause any decrease in ECCs or morphological alterations up to 6 months after the last of three injections. Further studies are required to confirm long-term safety in a larger sample population with longer follow-up, as well as the ideal dose, route of administration and frequency of bevacizumab administration.     

Corneal laser photocoagulation for treatment of neovascularization. Efficacy of 577 nm yellow dye laser.

The authors treated corneal neovascularization in 25 eyes of 23 patients with corneal laser photocoagulation using 577 nm yellow light. Four groups of patients were treated: patients with corneal neovascularization and active graft rejection (group 1); patients with neovascularization before penetrating keratoplasty (PK) (group 2); lipid keratopathy patients with opacification and/or focal edema threatening the visual axis (group 3); and patients with extensive corneal neovascularization, who were not candidates for PK (group 4). Area of neovascularization and clinical outcome were monitored. After corneal laser photocoagulation, there was a statistically significant reduction in the neovascularized area in group 1 from 32% of corneal area to 10%, and in group 3 from 46% to 27%. All five patients in group 1 had resolution of their graft rejection. In group 3, there was a reduction in the area of corneal opacification from 59% of corneal area to 52%. This difference was not statistically significant. Seven of nine patients in group 3 had stabilization or improvement in their vision over a mean of 9.3 months follow-up. There was no significant change in neovascularized area in groups 2 and 4. In group 2, no rejection reactions occurred over a mean of 5.6 months follow-up after PK. In group 4, corneal laser photocoagulation was disappointing.     

Corneal neovascularization in rats as a model for photothrombotic therapy using bacteriochlorin a and an argon laser

Background: The presence of vessels has a negative influence on corneal transplant survival. Closure of such vessels prior to transplantation may improve the transplant results, and this might be achieved by irradiating the vessels with argon laser light after intravenous administration of a photosensitizer, e.g. bacteriochlorin a (BCA). A suture-induced corneal neovascularization model in rats was set up to test this hypothesis. Methods: Suture-induced vessels in the cornea of male Wistar rats were irradiated with argon laser light after intravenous administration of BCA. We applied irradiation of varying energy levels and duration and assessed the changes in the vessels by slit-lamp examination, fluorescein angiography and histology. Results: Suture-induced corneal vessels in the rat could be used effectively to study photothrombosis therapy. Intravenous administration of BCA prior to irradiation (=514.5 nm) of the corneal vessels led to vessel closure at lower energy levels and of longer duration than occurred with laser treatment alone. Conclusion: Suture-induced corneal neovascularization in the rat can be used as a model to study the efficacy of photothrombosis therapy. BCA can be used to enhance the rate and duration of vessel closure.     

Corneal neovascularization and the utility of topical VEGF inhibition: ranibizumab (Lucentis) vs bevacizumab (Avastin)

Corneal avascularity is necessary for the preservation of optimal vision. The cornea maintains a dynamic balance between pro- and antiangiogenic factors that allows it to remain avascular under normal homeostatic conditions; however, corneal avascularity can be compromised by pathologic conditions that negate the cornea’s ”angiogenic privilege.” The clinical relevance of corneal neovascularization has long been recognized, but management of this condition has been hindered by a lack of safe and effective therapeutic modalities. Herein, the etiology, epidemiology, pathogenesis, and treatment of corneal neovascularization are reviewed. Additionally, the authors’ recent findings regarding the clinical utility of topical ranibizumab (Lucentis^®) and bevacizumab (Avastin^®) in the treatment of corneal neovascularization are summarized. These findings clearly indicate that ranibizumab and bevacizumab are safe and effective treatments for corneal neovascularization when appropriate precautions are observed. Although direct comparisons are not conclusive, the results suggest that ranibizumab may be modestly superior to bevacizumab in terms of both onset of action and degree of efficacy. In order to justify the increased cost of ranibizumab, it will be necessary to demonstrate meaningful treatment superiority in a prospective, randomized, head-to-head comparison study.     

板层角膜移植镶嵌术治疗角膜穿孔

目的：通过对角膜深层异物剔除术后发生角膜穿孔的患者实施板层角膜移植镶嵌术的临床观察总结，探讨角膜穿孔的临床治疗方法。方法：对1999年～2002年间5例因角膜深层异物剔除术后发生角膜穿孔、经保守治疗一周无效的患者进行板层角膜移植镶嵌术，对术后一年的临床随访观察资料进行总结讨论。结果：5例患者角膜穿孔均获得良好愈合，术后前房形成良好，眼前节炎症迅速控制，视力恢复快，经一年后视力达0．15～1．0，平均视力0．51。裂隙灯下检查角膜穿孔区轻度瘢痕性浑浊呈半透明状，余处角膜透明，均无新生血管。5例患者虹膜均无前后粘连。角膜曲率及角膜地形图显示轻度陡峭或扁平，无显著改变。结论：板层角膜移植镶嵌术是治疗角膜深层异物剔除术后角膜穿孔的有效方法。     

Choroidal neovascularization

PURPOSE: To review clinicopathologic findings of choroidal neovascularization (CNV) in a historical framework with emphasis on pathobiology and correlation with treatment. DESIGN: Selective literature review combined with authors' experience. RESULTS: Choroidal neovascularization represents a stereotypic, nonspecific response to a specific stimulus. Although CNV differs among patients, the general growth patterns are subretinal pigment epithelium (type 1), subretinal (type 2), or combined. Choroidal neovascularization occurs over time in dynamic stages of initiation, active and involutional. Treatments are now being designed based on modern understanding of CNV growth. CONCLUSIONS: Progress continues to be made concerning understanding the pathobiology and treatment of CNV.