**4. Clinical presentations**

Corneal neovascularization which arises from the limbus, conjunctiva, and iris can lead to a reduction in the clarity of the cornea and visual acuity because of edema, scarring, intracorneal lipid and protein deposition, and persistent inflammation. Additionally, there is a robust associa‐ tion between the presence of corneal neovascularization and corneal graft rejection with the risk increasing as more quadrants are affected by vessels (**Figure 5**) [4–7]. The presence of corneal neo‐ vascularization can also cause intraoperative bleeding, which can be associated with hyphema.

Abnormal vessels may invade the cornea at different planes depending on the location and nature of the inflammatory stimulus. Corneal neovascularization has three clinical patterns, based on the depth of involvement. The first type, superficial vascularization, results from ocular surface disease (**Figure 6**). The second type is stromal vessels, which results from alkaline injury or stromal keratitis (**Figure 7**). The third is deep vessels overlying Descemet's membrane, which can be associated with interstitial keratitis or HSV keratitis, or after deep anterior lamellar keratoplasty (**Figure 8**) [1, 8, 9, 22]. Mixed patterns are often observed clini‐

**Figure 5.** Endothelial corneal graft rejection in a high‐risk graft. Active old corneal vessels (arrow) arising from the limbus sharply dip into a deep suture track and continue to the graft in an eye that underwent penetrating keratoplasty. The presence of keratic precipitates (asterisk) indicates an episode of endothelial graft rejection.

neovascularization [28, 29]. Improved understanding of the molecular mechanisms of vascularization has enabled identification of specific factors that suppress angiogenesis to maintain the avascularity of the cornea. Because several molecules are involved in corneal

Corneal neovascularization which arises from the limbus, conjunctiva, and iris can lead to a reduction in the clarity of the cornea and visual acuity because of edema, scarring, intracorneal lipid and protein deposition, and persistent inflammation. Additionally, there is a robust associa‐ tion between the presence of corneal neovascularization and corneal graft rejection with the risk increasing as more quadrants are affected by vessels (**Figure 5**) [4–7]. The presence of corneal neo‐ vascularization can also cause intraoperative bleeding, which can be associated with hyphema. Abnormal vessels may invade the cornea at different planes depending on the location and nature of the inflammatory stimulus. Corneal neovascularization has three clinical patterns, based on the depth of involvement. The first type, superficial vascularization, results from ocular surface disease (**Figure 6**). The second type is stromal vessels, which results from alkaline injury or stromal keratitis (**Figure 7**). The third is deep vessels overlying Descemet's membrane, which can be associated with interstitial keratitis or HSV keratitis, or after deep anterior lamellar keratoplasty (**Figure 8**) [1, 8, 9, 22]. Mixed patterns are often observed clini‐

**Figure 5.** Endothelial corneal graft rejection in a high‐risk graft. Active old corneal vessels (arrow) arising from the limbus sharply dip into a deep suture track and continue to the graft in an eye that underwent penetrating keratoplasty.

The presence of keratic precipitates (asterisk) indicates an episode of endothelial graft rejection.

neovascularization, a multipronged approach is desirable.

62 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

**4. Clinical presentations**

**Figure 6.** Phlyctenular keratitis. Superficial corneal vascularization (arrow) is evident in an eye with severe blepharitis. Adjacent stroma shows edema and infiltration.

**Figure 7.** Deep stromal vascularization in an eye with recurrent herpes simplex stromal keratitis. Active young, bright red, brush‐like vessels (asterisks) invade in to the corneal stroma.

**Figure 8.** Partially regressed vessels with lipid keratopathy (asterisk) at the donor‐recipient interface in a patient who underwent deep anterior lamellar keratoplasty (DALK). Vessels arising from the limbus sharply dip into a deep suture track and continue to the deep lamellar plane created by the DALK procedure, before fanning out. The vessels are dull red with a slow circulation, and some parts of the complex are less visible or have undergone attrition.

cally. The level of vascularization is chiefly related to the level of pathology rather than to the etiology. Superficial corneal pathology results in superficial vascularization, and deep pathol‐ ogy results in deep vessels. Often when the disease process extends through the thickness of the cornea, superficial and deep vessels are seen in the same cornea.

A detailed clinical evaluation of corneal neovascularization, including extension (the num‐ ber of quadrants involved) and depth, is crucial for treatment planning. In addition to the extent and level of corneal vascularization, the state of vessel activity is also important [30]. Clinically, corneal vascularization can be classified as active young, active old, mature, par‐ tially regressed, and regressed. This often corresponds with the stage of activity or chronicity of the disease. Active young vessels are freshly formed vessels that are full of blood, appear bright red in color, have minimal surrounding fibrous tissue sheathing, and are actively progressing in the cornea with a well‐defined arborizing network of fine (capillary) vessels (**Figures 4A** and **7**). The corneal stroma surrounding the vessels shows signs of leakage and edema. Active old vessels appear less bright and maintain a brisk circulation (**Figure 5**). This represents the stage when the vessels have reached and surrounded or covered the offending lesion in the cornea. Their progression ceases but consolidation continues. Mature vessels are relatively large vessels, with minimal arborization and regressed or absent capillary net‐ works, seen to persist in scar tissue or in the corneal stroma after the corneal pathology has healed. These vessels contain blood and maintain a circulation (**Figure 9**). Partially regressed vessels are seen when the corneal pathology has abated in response to therapy or the arrival

**Figure 9.** Mature vessels in the corneal stroma after the improvement of corneal ulcer (asterisk). The vessels are relatively large, with minimal arborization and regressed or absent capillary networks. These vessels which persist in scar tissue contain blood and maintain a circulation.

of corneal vessels. The circulation in the vascular complex is relatively slow, the vessels are less engorged, and some parts of the complex have become less visible or undergo attrition (**Figures 4B** and **8**). Regressed (ghost) vessels present as fine white lines mirroring the mor‐ phology of the original vessels. These do not have an active circulation, and the cornea where they are located is not edematous. Although clinically undetectable, lymphangiogenesis almost always accompanies hemangiogenesis in the cornea [31].
