Neovascular Glaucoma Treatment & Management

General principles for treating patients with neovascular glaucoma (NVG) include the following:

• Identifying the underlying etiology is fundamental in the management of NVG.

• CRVO, diabetic retinopathy, CAOD, and CRAO require systemic workup and appropriate intervention to prevent further complications.

• The management of NVG is approached through the following 4 stages that reflect the progression of the disease: prophylactic treatment, early-stage treatment, advanced-stage treatment, and end-stage treatment.

Prophylactic treatment

Most patients are either at high risk for developing NVI/NVG or have early NVI with normal IOP. Prevention of NVG is the single most important aspect in its management.

Reducing the amount of viable retina is known to inhibit and even to reverse new vessel proliferation in the anterior segment. The mainstay in prevention is retinal ablation achieved via panretinal photocoagulation (PRP) or cryophototherapy because of media opacities (ie, corneal edema, cataract, vitreous hemorrhage) or other patient factors. Other treatment options in this stage include goniophotocoagulation.

PRP can be delivered in the following 3 ways: slit lamp delivery system, indirect laser, or endolaser at time of vitrectomy.

The amount of PRP required varies. The Diabetic Retinopathy Study (DRS) guidelines recommend 1200-1500 burns, with a spot size of 500 µm to be applied to the peripheral retina. Many retina specialists recommend 1500-2000 burns, with a spot size of 500-800 µm, using a wide-angle fundus contact lens (eg, Rodenstock). The types of laser include argon, krypton (better with media opacities and retinal hemorrhages), and diode (same utility as krypton laser).

To begin, a 360° peritomy is performed with isolation of the 4 recti muscles. A 2.5-mm retinal cryoprobe is used to create cryoapplication burns just anterior to the equator. Three spots are placed between each rectus muscle. Two additional rows of application are performed posterior to the first so that the third row is just outside the major vascular arcades. In total, 32 cryoapplications are performed under direct visualization. The probe tip remains in contact with the sclera until 70° has been maintained for 5-10 seconds. This procedure causes considerable inflammation, and complications (eg, tractional and exudative retinal detachment, vitreous hemorrhage) can occur.

Goniophotocoagulation, another laser therapy, is performed directly to NVI before the development of NVG. Its role in management of NVG is unclear, and it has not proven to be beneficial in preventing synechial closure of angle or advanced NVG.

All patients should undergo fluorescein angiography to delineate nonischemic CRVO from ischemic CRVO. Virtually no patients with nonischemic CRVO develop NVG. Overall incidence of NVG is 40% for an ischemic CRVO. NVI and NVG can appear from 2 weeks to 2 years. More than 80% of patients with NVI/NVG present within the first 6 months. Of patients with nonischemic CRVO, 15% can convert to ischemic CRVO within 8 months. The strongest predictors of NVI/NVG following CRVO include extensive retinal capillary nonperfusion of intravenous fluorescein angiography (IVFA), extensive retinal hemorrhages, short duration of occlusion, and male sex. In the Central Retinal Vein Occlusion Study, PRP was indicated for IVFA confirmed ischemic CRVO if development of 2 clock hours of NVI occurred or any NVA was present. ^[5] No benefit occurred when prophylactic PRP was performed prior to the development of NVI or NVA when frequent follow-up care was provided.

Prophylactic PRP still is recommended by many retinal specialists before the development of NVI or NVA, especially in case of the following: clear extensive capillary nonperfusion, extensive systemic vascular disease, patient who is monocular, and/or noncompliance or poor follow-up results. Preoperative care is fundamental for all types of cataract surgery, capsulotomy, and vitreous surgery.

For patients with diabetic retinopathy, ensure frequent follow-up care and tight glycemic control. If proliferative diabetic retinopathy exists, then complete PRP is recommended as treatment.

Early-stage treatment

This stage is characterized by the development of a fibrovascular membrane across some or all of the angle, obstructing the trabecular meshwork, and an increase in IOP.

With secondary open-angle glaucoma, treatment is identical to prophylactic treatment and includes PRP (filler PRP if already performed initially), panretinal cryotherapy, and medical therapy.

The most important medical therapy for this stage includes topical atropine 1% to decrease ocular congestion and topical steroids (eg, prednisolone [Pred Forte, Inflamase Forte]) to decrease inflammation. Standard antiglaucoma medications to treat secondary open-angle glaucoma are recommended. Other agents include topical beta-blockers (eg, levobunolol [Betagan], timolol [Timoptic]), topical brimonidine (Alphagan), topical carbonic anhydrase inhibitor (eg, dorzolamide [Trusopt], brinzolamide [Azopt]), and oral carbonic anhydrase inhibitor (eg, acetazolamide [Diamox]). Topical pilocarpine is contraindicated because it may increase inflammation. The role of topical latanoprost (Xalatan) is unclear in the treatment of early NVG.

The successful use of photodynamic therapy with verteporfin directed at the iris and the angle to obliterate neovascularization and to reduce IOP has been reported.

Advanced-stage treatment

This stage is characterized by synechial closure of the angle and secondary angle-closure glaucoma.

PRP is still the initial and most important treatment, both to prevent further NVI/NVA and angle closure and to prepare the eye for surgical intervention (see Surgical Care). Surgical intervention is indicated in eyes with potential for useful vision.

Medical therapy is indicated, with topical atropine and steroids being the most important agents. Antiglaucoma medications, topical beta-blockers, and carbonic anhydrase inhibitors are also recommended. The role of topical brimonidine and latanoprost in advanced disease is unclear. Topical pilocarpine and echothiophate iodide are contraindicated (may cause increased inflammation and hyperemia). Oral glycerol and intravenous mannitol are recommended only if IOP is elevated symptomatically.

Anti-VEGF therapy

Antivascular endothelial growth factor is frequently used for various conditions in which VEGF release is induced in response to retinal ischemia. It is still under study as an adjunct ^[6] or alternative treatment for NVG. Anti-VEGFs such as bevacizumab (Avastin), pegaptanib sodium (Macugen), and ranibizumab (Lucentis) block angiogenic factors that promote the formation of new vessels, reversing the neovascularization process. ^{[7, 8, 9]} The initial use of anti-VEGF agents for the treatment of retinal neovascularization has been expanded to include other pathology such as neovascular glaucoma. ^[10] The quantity of growth factors in the aqueous decrease after intraocular injection of anti-VEGFs, decreasing further progression of angular damage secondary to IOP increments. ^[11] However, other investigators have reported a lack of efficacy of intravitreal bevacizumab in the treatment of neovascularization of the iris and iridocorneal angle but support its use for diabetic retinopathy and central vein occlusion. ^{[12, 13]}

Several studies propose the use of anti-VEGF agents with traditional treatments such as panretinal photocoagulation (PRP), with or without additional surgery and vary in the timing, combination, and place of injection (intracameral or intravitreal, or both simultaneously). The most frequent recommendation by various authors for treatment is the adjunct combination of intravitreal bevacizumab/panretinal photocoagulation for the treatment of neovascular glaucoma (NVG) instead of PRP alone or as alternative treatment when visibility of the posterior segment is difficult due to opacities of the media (eg, hemorrhage). ^[14]

Although intravitreal, and less commonly intracameral, delivery of anti-VEGF agents is preferred for the management of NVG, several authors describe different protocols of treatment according to the stage of disease and the possible underlying cause as standardized guidelines of NVG treatment with anti-VEGFs have not yet been established.

Several reports about the favorable response to intravitreal anti-VEGF agents in NVG have been published. In a review of 26 original papers between 2006 and August 2008, efficacy and safety of the procedure in 127 eyes was analyzed in a series of cases: None had been performed in a clinical randomized controlled assay. The efficacy calculated in the sample was 68.7%, and the recurrence rate was 18.6% at 4.2 months of follow-up. Ophthalmic complications were under 0.78%, and no systemic complications were found. ^[15]

Intravitreal bevacizumab is the most frequent anti-VEGF adjunct treatment used for NVG due to the lower cost. Systematic review of the efficacy and safety of intravitreal bevacizumab (IVB) in the treatment of neovascular glaucoma (NVG) establishes bevacizumab is well tolerated, effectively stabilizes INV activity, and controls IOP in patients with INV when used alone and at an early-stage of NVG. ^[16]

Randomized clinical trials are now being reported. Intraocular doses described for treatment with bevacizumab are 1 mg/0.05 mL, 1.25 mg/0.05 mL, or 2.5 mg/0.05 mL, according to the stage and recurrence of NVG.

In a case of ocular ischemic syndrome, a single injection of intravitreal bevacizumab (1.25 mg/0.05 mL injection) detained all signs of neovascularization just one day after injection but failed to control IOP. ^[17]

Postintravitreal injection of a single dose of bevacizumab (1.25 mg) promotes quick response of pain relief 1 week postinjection; ^[18] this safely facilitates further surgical intervention to lower IOP when treating refractory NVG.

End-stage treatment

This stage is characterized by complete angle closure by peripheral anterior synechiae with no remaining useful vision.

The primary goal of treatment in this stage is pain control. Medical therapy includes topical atropine 1% and steroids. If corneal decompensation occurs, use a bandage contact lens. Cyclodestructive procedures are performed if medical therapy fails to provide symptomatic relief. With cyclocryotherapy, the IOP-lowering effect is achieved by destroying secretory ciliary epithelium and/or reducing blood flow to the ciliary body. It is indicated as a last resort only if relief of pain is the main goal. In a large series, 34% of eyes achieved IOP of less than 25 mm Hg; however, 34% of eyes became phthisical and 57% of eyes lost all light perception. Other complications include sympathetic ophthalmia and anterior segment ischemia.

With Nd:YAG laser transscleral cyclophotocoagulation, 2 approaches, contact and noncontact, are used. In the contact approach, one study reported a 40% decrease in IOP to less than 19 mm Hg in eyes with NVG. In the noncontact approach, out of 27 eyes with NVG, only 15% achieved satisfactory IOP control.

The results of diode laser transscleral cyclophotocoagulation are similar to Nd:YAG cyclophotocoagulation.

Direct laser cyclophotocoagulation is performed under direct observation using the argon laser. Two approaches, transpupil or with endoscopy, are used. Its role in NVG management is secondary. Success in controlling IOP is limited (may have less inflammation and pain versus cyclocryotherapy).

Retrobulbar alcohol injection is indicated after all medical and surgical options have been explored and the patient does not want an enucleation. Complications include external ophthalmoplegia and blepharoptosis. Enucleation is indicated only if intractable pain is not relieved by any other treatment modality.

Surgical care is indicated in patients with remaining useful vision. Preoperative care is fundamental to the postoperative success of any surgical intervention.

With surgical care, ensure that adequate PRP is completed to reduce vasoproliferative stimulus. Atropine and steroids are indicated to decrease inflammation, and antiglaucoma medication is indicated to decrease IOP. Wait approximately 3-4 weeks to allow the eye to quiet down.

Trabeculectomy with or without antifibrotic therapy and valve implant surgery

Surgical modalities include trabeculectomy with or without an antifibrotic agent and valve implant surgery. ^[8]

Trabeculectomy with the antifibrotic agents mitomycin-C and 5-fluorouracil (5-FU) is one modality. Trabeculectomy in NVG has a significant failure rate. Using standard trabeculectomy (without antifibrosis), an IOP of less than 25 mm Hg on one medication or less has been reported to occur in 67-100% of patients in 3 studies. Using injections of 5-FU subconjunctivally in the postoperative period, the surgical success has been reported to be 68% over 3 years. Inject 0.1 mL of 5 mg/mL 5-FU subconjunctivally either superiorly above the bleb or inferiorly (just above the lower fornix). Mitomycin-C used intraoperatively has been shown to be more effective than 5-FU in routine trabeculectomies. No significant follow-up studies exist on the use of mitomycin-C with trabeculectomy in NVG.

A retrospective cohort study from January 1994 to March 2007 of 101 eyes found that the prognostic factors for failure of trabeculectomy with MMC for NVG were younger age and previous vitrectomy in patients with NVG, having a fellow eye with NVG in patients with disease caused by diabetic retinopathy, and persistent proliferative membrane and/or retinal detachment after vitrectomy. ^[19]

Valve implant surgery is another modality and is indicated when trabeculectomy fails or extensive conjunctival scarring exists, thereby preventing a standard filtering procedure. Molteno, Krupin, and Ahmed valve implants commonly are used. ^[20] One large series using the Krupin valve reported 79% of eyes with NVG had a 67% success rate in controlling IOP (< 24 mm Hg) with mean follow-up of 23 months. Long-term results are mixed. Using the Molteno implant, 60 eyes with NVG achieved a satisfactory IOP (< 21 mm Hg) and maintenance of visual acuity over 5 years of only 10.3%. If combined with the need for vitrectomy, consideration of pars plana tube-shunt insertion may reduce anterior segment complications.

Complications include postoperative hypotony with associated complications, blockage of internal fistula, blockage of external filtration site (fibrosis of the filtering bleb), and corneal endothelial loss.

Adjunct anti-VEGF therapy

In a short case series, the use of intracameral bevacizumab prior to trabeculectomy with MMC improved NVG. ^[21]

The postoperative inhibition of angiogenesis after glaucoma surgery has also been described. Possible routes of bevacizumab administration are subconjunctival application during trabeculectomy, postoperative needling, or intravitreal injection during a filtrating procedure. ^[22]

Bevacizumab has also been injected into the silicone oil in eyes with neovascular glaucoma after vitrectomy for advanced diabetic retinopathy with favorable outcomes. ^[23]

Intravitreal bevacizumab is useful to safely and effectively implant an aqueous shunting tube in eyes with severe NVG and intractable IOP, in addition to postoperative panretinal photocoagulation that reduces the recurrence of neovascular activity improving the success rate of aqueous shunting surgery. ^[24]

Ophthalmologists should provide long-term follow-up care for patients with neovascular glaucoma (NVG), closely monitoring for any worsening in the patient's condition.

Intensity of follow-up care is related to the conditions predisposing the patient to the development of NVG (ie, CRVO, diabetic retinopathy).