Anterior segment neovascularization can lead to neovascular glau­­coma. Uncontrolled neovascular glau­coma can potentially cause complete loss of vision or loss of the globe. Early diagnosis and immediate treatment with panretinal laser photocoagulation often leads to regression of neovascularization and lowering of the intraocular pressure if the angle is not totally closed from synechiae or dam­aged from the growth of the fi­bro­vascular membrane over the trabecular meshwork that develops in neovasuclar glaucoma.

Anterior segment neovascularization results from several ocular and systemic diseases that predispose pa­tients to retinal hypoxia and ischemia with subsequent release of angiogenesis factors such as VEGF (vascular en­dothelial growth factor). Although an­giogenesis is important in the development of embryonic and early postnatal de­velopment, in addition to en­do­chondral bone formation, it is also a critical mediator for retinal and anterior segment neovascularization in eyes with neovascular glaucoma (NVG).

The best known anti-angiogenic agents of this class are the VEGF in­hi­bitors such as bevacizumab (Avastin, Genentech) and VEGF 165 (Mac­ugen, OSI/Eyetech). This class of anti-angiogenic agents not only arrests the vascular endothelial cell proliferation and prevents vessel growth, but also induces regression of existing vessels by increasing endothelial cell death.

In February 2004, the Food and Drug Ad­mi­ni­stration ap­proved bevacizumab, a hu­man­ized monoclonal antibody that binds to VEGF, for intravenous administration in patients with colon cancer, in combination with 5-fluorouracil-based che­motherapy regimens. A significant side effect seen with intravenous use of bevacizumab was arterial thromboembolic events, such as cerebral in­farc­tion, transient is­che­mic attacks and myocardial infarction. These events were fatal in some in­stances.

This medication has been used off-label systemically and intravitreally for management of sub­retinal neovascularization in macular degeneration and other disorders. I would like to share with you my experience with bevacizumab in the management and treatment of anterior segment neovascularization and neovascular glaucoma.

 

Case 1

A 62-year-old man with hypertension, diabetes and coronary artery disease presented with painless vision loss in the left eye for three weeks. Best-corrected vision was 20/20 in the right and count fingers in the left with a left afferent papillary defect. In­tra­oc­ular pressures were 12 and 28 mmHg in the right and left eye, re­spectively. Retinal hemorrhages in four quadrants were present in the left fundus, venous tortuosity and macular edema. Gonioscopy OS revealed prominent neovascularization overlying the trabecular meshwork for 12 clock hours, without synechiae. A di­ag­nosis of neovascular glaucoma secondary to central retinal vein oc­clu­sion in the left eye was made and laser panretinal photocoagulation was ap­plied in several sessions over the ensuing three weeks (3,064 spots with diode laser). IOP was 46 mmHg de­spite use of 500 mg oral acetazolamide, and topical latanoprost, Co­sopt and brimonidine. Synechiae de­veloped over one-third of the angle with visible prominent neovascularization elsewhere in the angle (See Figure 1).

Figure 1. Visible, prominent neovascularization in the angle.

As a possible last resort prior to tube implant surgery, the patient was offered an off-label intravitreal injection of bevacizumab. Documented in­formed consent was obtained and 50 uL of bevacizumab (1.25 mg) was injected intravitreally without complication in the left eye.

Figure 2. Total regression of angle neovascularization 13 days after the bevacizumab intravitreal injection.

Two days after injection, neovascularization of the trabecular meshwork decreased substantially and IOP decreased to 18 mmHg on the same in­tensive medical regimen; optical co­herence tomography demonstrated re­solution of macular edema. Thirteen days after injection, the IOP was 17 mmHg without medications, with re­gression of angle neovascularization and macular edema (See Figure 2). Five weeks after injection, IOP was still 19 mmHg without medication and without any evidence of angle and/or iris neovascularization. Four months after injection, IOP increased to 28 mmHg with re­currence of neovascularization of the iris and the angle (See Figure 3). Glau­coma medications were started and more laser panretinal photocoagulation was performed.

Figure 3. Recurrence of the neovascularization in the angle four months after the intravitreal injection of bevacizumab.

Case 2

A 65-year-old female with hypertension presented with a history of decreased vision in the right eye for four weeks. Best corrected visual acuity was count fingers in the right eye and 20/30 in the left eye. Intraocular pressure was 14 mmHg in the right and 12 mmHg in the left. Anterior seg­ment examination revealed neovascularization of iris, and gonioscopy re­vealed rubeosis of the angle for ap­proximately four clock hours, without any synechiae (See Figure 4). Fun­dus examination revealed retinal hemorrhages in four quadrants, venous tortuosity and macular edema. The patient was diagnosed with central retinal vein occlusion and offered an intravitreal injection of bevacizumab off-label instead of panretinal photocoagulation.

After obtaining fully documented in­formed consent, 50 uL of bevacizumab (1.25 mg) was injected intravitreally in the right eye in an un­complicated manner. The rubeosis in the angle started decreasing three days after the injection with total resolution in seven days (See Figure 5) after the injection, with IOP ranging between 10 and 15 mmHg. Two months after the intravitreal injection her IOP remained in the low teens with no recurrence of the rubeosis vessels.

Figure 4. Visible neovascularization of the angle.

Considerations for Future Treatment

Inhibiting angiogenesis is a promising strategy for the treatment of anterior segment neovascularization and neovascular glaucoma, if the angle is not totally closed from the pe­ripheral anterior synechiae or damaged from the fibrovascular membrane. The neo­vas­cularization can recur if the is­che­mic process is not reversed. Se­veral issues should be considered:

 • Can bevacizumab become the only treatment for anterior and posterior segment neovascularization without the need for panretinal pho­to­coagulation that de­stroys the peripheral retina in an in­dividual who al­ready has compromised vision?

Figure 5. Total regression of the angle neovascularization seven days after the bevacizumab intravitreal injection.

 • The phar­ma­cokinetics of the be­vacizumab in the eye. (How long does it last and does it block all the VEGF at once or does it continue blocking until the antibodies are saturated?)

 • Toxicity profile (corneal endothelium, lens and TM) and whether we can inject it in the anterior chamber instead of the posterior chamber.

Further investigations need to be performed to identify bevacizumab's exact role in retinal ischemia and neovascular glaucoma. 

 

Dr. Al-Aswad is an assistant professor of clinical ophthalmology at the Co­lumbia University College of Phy­si­cians and Surgeons, Edward S. Hark­ness Eye Institute. Contact her at (212) 342-0943 or laa2003@columbia.edu.

Other physicians who participated in the management of the two cases are: Michael J. Weiss, MD, PhD; Lu­cian Del Priore, MD, PhD; and Gaetano R. Barile, MD.