Neovascular glaucoma (NVG) is a potentially devastating sequela of serious underlying ocular and/or systemic diseases. The ocular diseases responsible for neovascularization of the iris (NVI) or neovascularization of the angle (NVA) that ultimately lead to NVG are almost always ischemic in nature. Under hypoxic conditions, diffusible angiogenic factors, including vascular endothelial growth factor, have been detected in the human and animal retina and vitreous, promoting new vessel growth. Clinically, the three most common conditions responsible for NVG are diabetic retinopathy, central retinal vein occlusion and carotid artery obstructive disease.
Anterior segment neovascularization involving the iris, the angle or both is accompanied by the formation of a fibrovascular membrane that is seen histologically. This membrane initially obstructs the aqueous outflow through the trabecular meshwork and results in open-angle glaucoma, which may be amenable to pharmacological management of the elevated IOP and to panretinal photocoagulation (PRP) of the underlying ischemic disease. However, as the disease progresses, the proliferating myofibroblasts of the fibrovascular membrane contract, leading to ectropion uveae, peripheral anterior synechiae and, ultimately, total synechial angle closure. This stage is not reversible by PRP. The resultant secondary glaucoma is often refractory to pharmacological management and requires surgical intervention.
Diagnosis and Detection
Key elements in managing patients with NVG are an awareness of the underlying diseases responsible for this condition and astute clinical examination.
Diabetes mellitus. Diabetes accounts for approximately one-third of cases of NVG. The prevalence of NVG is significantly higher in diabetics with proliferative diabetic retinopathy as compared with all diabetics. The incidence of NVG in diabetes is further increased in patients who have undergone vitrectomy and lensectomy. Breach of the posterior capsule from a complicated cataract extraction or even from Nd:YAG laser capsulotomy may allow angiogenic factors to gain access to the anterior segment more readily, accelerating formation of NVI or NVA.
Central retinal vein occlusion. NVG is seen more commonly in ischemic central retinal vein occlusion as compared with the nonischemic variant. It is important to keep in mind that the Central Vein Occlusion Study demonstrated a conversion rate from nonischemic to ischemic central retinal vein occlusion in about one-third of cases. Therefore, patients presenting with central retinal vein occlusion need to be followed closely over time to monitor for early signs of neovascularization.
Carotid artery obstructive disease. This is the third most common cause of NVG and is the one most likely to be missed or misdiagnosed because these patients may have an atypical presentation. They may present with low IOP, despite the presence of NVI and NVA, due to decreased perfusion of the ciliary body resulting in reduced aqueous production. Carotid artery obstructive disease should be strongly considered if IOP is decreased in any of these settings:
the absence of retinal detachment,
the presence of markedly asymmetric diabetic retinopathy,
the presence of persistent NVI after PRP, or
a still-unidentified etiology for NVG after full ocular examination.
It is imperative to recognize the significance of carotid artery obstruction since prompt diagnosis and treatment can save not only the eye but also the patient’s life.
Once a detailed history is obtained from the patient presenting with elevated IOP, a comprehensive ocular examination is required for early detection of neovascularization. Particular attention must be directed to the pupillary margin, the angle structures and the dilated fundus exam. In many cases, anterior segment neovascularization may be first seen at the pupillary margin under high magnification. In some cases, NVA may precede NVI. Pupillary reactions and electroretinography have been used to predict the development of NVI. Iris and angle fluorescein angiography have been shown to confirm the presence of clinically visible NVI and NVA and to identify subclinical neovascularization. Although these tools can aid in the early detection of neovascularization, they are expensive and often not readily available. In contrast, nondilated gonioscopy is an easy, cost-effective and quick office procedure for the early detection of NVA.
Treatment of Underlying Disease
The management of NVG involves both reducing elevated IOP and treating the underlying disease that led to the ischemic insult that initiated the anterior segment neovascularization.
Panretinal photocoagulation. This is the procedure of choice for ischemic retinal disease, and it has been shown to reduce and eliminate anterior segment neovascularization. PRP may stabilize IOP in the open-angle glaucoma stage of NVG and may improve the outcome of filtration surgery, if performed preoperatively. The mechanism by which PRP works is unclear. Since the outer photoreceptor–retinal pigment epithelium complex accounts for the majority of total retinal oxygen consumption, PRP may decrease retinal oxygen demand by destroying this outer layer. This may allow choroidal oxygen to diffuse into the inner retina, decreasing not only inner retinal hypoxia but also reducing the stimulus for release of angiogenic factors. PRP should be performed at the earliest sign of neovascularization. Striga and coworkers emphasized the need for adequate treatment with PRP.1 Treatment with 1,200 to 1,600 spots resulted in regression of NVI in a significantly higher percentage of eyes compared with those that received fewer spots.
In cases where PRP cannot be performed because of media opacity, panretinal cryotherapy and/or transscleral diode laser retinopexy can be used for retinal ablation. Another option to consider in such cases is to use endolaser or indirect PRP during pars plana vitrectomy and, if needed, lensectomy.2
Treatment of Elevated IOP
Pharmacological treatment. Pharmacological management of elevated IOP is usually accomplished with aqueous suppressants. Anticholinergics should be avoided since they can increase inflammation and worsen synechial closure. Prostaglandins may not be very effective in these eyes since the presence of synechiae limits the flow of aqueous via the uveoscleral pathway. Topical corticosteroids can be used for inflammation, and cycloplegic agents can be used for pain control. Topical glycerin may help to clear corneal edema, facilitating accurate diagnosis and delivery of PRP if required. Osmotic agents may provide acute but transient lowering of IOP by reducing vitreous volume. Most cases of NVG are refractory to pharmacological treatment and require surgical intervention, if early diagnosis or prophylactic treatment with PRP is delayed. There is no general consensus regarding the best surgical approach.
Trabeculectomy. Filtration surgery for NVG has limited success. It is usually complicated by intraoperative bleeding and progression of the fibrovascular membrane postoperatively. PRP treatment, by reducing active NVI and NVA, may decrease intra- and postoperative complications. Use of antimetabolites may improve the outcome. Tsai and colleagues reported a success rate of approximately 30 percent at five years with the use of 5-fluorouracil at the time of trabeculectomy.3
Aqueous drainage implants. Variable success rates have been described with aqueous drainage implants. As with glaucoma filtration surgery, success rates decrease over time. No significant differences have been noted among the various types of implants.
Mermoud and coworkers used Molteno implants in 60 eyes with NVG. They reported a success rate of 62 percent at one year, but only 10 percent at five years.4 In this study, eyes with NVG secondary to central retinal vein occlusion had a worse prognosis compared with eyes with NVG due to diabetic retinopathy.
Sidoti and colleagues, using Baerveldt implants in 36 eyes, reported a success rate of close to 80 percent at one year, but only 56 percent at 18 months.5
Cases of pars plana drainage device implantation with vitrectomy have been reported to provide satisfactory IOP control.6 Most studies indicate that despite exhaustive measures to lower IOP, the majority of eyes have a poor visual outcome because of advanced underlying systemic vascular disease.
Cyclodestruction. Cyclodestructive procedures using either Nd:YAG or diode lasers have been used to destroy the ciliary body to reduce aqueous humor production. Although these laser procedures may have a lower complication rate compared with cyclocryotherapy, the number of eyes with significant visual loss remains high and the long-term success rate and treatment protocol are not well established.
Alcohol injection/enucleation. These procedures offer alternative options for pain control in eyes that are unlikely to derive any potential benefit from laser or surgical intervention for glaucoma.
Neovascular glaucoma remains a therapeutic challenge. Early detection of neovascularization and prophylactic treatment with PRP directed at the ischemic retina are key elements in preventing a visually devastating outcome of this disease. Randomized, prospective clinical trials are needed to compare the three main surgical modalities: filtration surgery, aqueous drainage implants and cyclodestruction. Current research on ocular angiogenesis and the advent of new pharmacological agents with activity against vascular endothelial growth factors may increase our treatment options for combating this serious disease.
1 Striga, M. et al. Ophthalmologica 1993;207:144–147.
2 EyeNet 2001;5(7):35-37.
3 Tsai, J. C. et al. Ophthalmology 1995;102:887–892.
4 Mermoud, A. et al. Ophthalmology 1993; 100:897–902.
5 Sidoti, P. A. et al. Ophthalmology 1995;102:1107–1118.
6 Chalam, K. V. et al. Clin Sci 2002;33:383–393.
Ocular and Extraocular Conditions Predisposing to NVI and NVG
- Diabetic retinopathy
- Central retinal vein occlusion
- Central retinal artery occlusion
- Branch retinal vein occlusion
- Branch retinal artery occlusion
- Chronic retinal detachment
- Hemorrhagic retinal diseases
- Sickle cell retinopathy
- Stickler’s syndrome
- Retinopathy of prematurity
- Eales’ disease
- Coats’ disease
- Chronic uveitis of any etiology
- Sympathetic ophthalmia
- Choroidal melanoma
- Iris melanoma
- Ciliary body melanoma
- Nd:YAG capsulotomy
- Cataract extraction
- Carotid endarterectomy
- Pars plana vitrectomy
- Pars plana lensectomy
- Radiation treatment
- Carotid artery obstructive disease
- Carotid cavernous fistula
- Internal carotid artery occlusion
Adapted with permission from M. B. Shields’ Textbook of Glaucoma, 4th ed. Baltimore: Williams & Wilkins, 1998, 270.