|Year : 2018 | Volume
| Issue : 3 | Page : 172-177
Seshadri J Saikumar, Anup Manju, Nair Abhilash
Department of Cataract and Glaucoma, Giridhar Eye Institute, Kochi, Kerala, India
|Date of Web Publication||17-Dec-2018|
Seshadri J Saikumar
Department of Cataract and Glaucoma, Giridhar Eye Institute, Kadavanthra, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
Neovascular glaucoma (NVG) is an intractable secondary glaucoma characterized by the growth of new vessels accompanied by a fibrovascular membrane over the iris and iridocorneal angle. Majority of the cases of NVG are associated with ischemia and hypoxia of retina. The three most common predisposing conditions are ischemic central retinal vein occlusion, proliferative diabetic retinopathy, and ocular ischemic syndrome. Early identification of anterior segment neovascularization followed by prompt treatment is very important to prevent significant visual impairment. A high index of suspicion, with careful anterior segment evaluation and gonioscopy in an undilated pupil, is the key for early detection of neovascularization of iris and angle. Early stages of the disease can be managed with panretinal photocoagulation along with adjunctive use of vascular endothelial growth factor inhibitors with or without intraocular pressure lowering agents. Medical management may not be sufficient in advanced disease and may require surgical intervention.
Keywords: Ischemic central retinal vein occlusion, neovascular glaucoma, panretinal photocoagulation, trabeculectomy, Vascular endothelial growth factor inhibitors
|How to cite this article:|
Saikumar SJ, Manju A, Abhilash N. Neovascular glaucoma. Kerala J Ophthalmol 2018;30:172-7
| Introduction|| |
Neovascular glaucoma (NVG) is a potentially blinding, intractable secondary glaucoma, characterized by the development of new vessels on the iris and/or angle, often resulting in poor visual outcome if not detected and treated aggressively. In 1906, Coats described the histological appearance of new vessels on the iris in a case of central retinal vein occlusion (CRVO). Salus, in 1928, described new vessels over the iris in eyes with diabetic retinopathy (DR). In 1937, with the introduction of gonioscopy, new vessels were visualized in the angle causing progressive angle closure and elevation of intraocular pressure (IOP). In 1963, Weiss et al. first proposed the term “NVG,” while describing a case of glaucoma associated with the presence of new vessels over the iris and angle. NVG has also been called hemorrhagic glaucoma, congestive glaucoma, and rubeotic glaucoma. Majority of NVG patients have severe underlying systemic and ocular pathology and many patients have advanced stage of the disease at presentation. This makes NVG very difficult to treat. However, recent advances in understanding the pathophysiology, and use of vascular endothelial growth factor inhibitors (anti-VEGFs), antifibrotic agents, and glaucoma drainage devices (GDDs) in the management of NVG have resulted in relatively better outcomes.
| Etiology|| |
The most common causes of NVG are CRVO, proliferative DR (PDR), and ocular ischemic syndrome (OIS) [Table 1].
Central retinal vein occlusion
According to central vein occlusion study, the incidence of NVG following CRVO was 16%. One-third of CRVO cases are ischemic at presentation and remaining two-thirds nonischemic, with a conversion to ischemic at a rate of 10% [Figure 1] and [Figure 2]. NVG develops in 45% of ischemic CRVO, with the maximum risk during 1st 7–8 months. NVG is a complication only of ischemic CRVO. Therefore, if a patient is identified with ischemic CRVO, one should have a high index of suspicion for development of NVG. Eyes with nonischemic CRVO do not develop NVG unless there is associated DR or OIS.
A study by Hayreh S S et al. suggested that, in the early acute stage, ischemic CRVO can be reliably differentiated from nonischemic CRVO using information provided by selected diagnostic clinical tests:
- Functional tests: These consist of visual acuity, visual field plotted with a Goldmann perimeter, relative afferent pupillary defect, and electroretinography
- Morphological tests: These consist of ophthalmoscopy and fundus fluorescein angiography (FFA) [Table 2].
|Table 2: Clinical tests to differentiate ischemic central retinal vein occlusion from nonischemic central retinal vein occlusion|
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Proliferative diabetic retinopathy
NVG is more commonly associated with PDR [Figure 3], although it may occur without retinal or optic disc neovascularization. The incidence of neovascularization of iris (NVI) is 65% in PDR due to increased vasoproliferative mediators in the anterior segment. Pars plana vitrectomy (PPV) for PDR increases the incidence of NVI and of NVG, especially if the eye is left aphakic. Presence of rubeosis before vitrectomy or unrepaired retinal detachment after vitrectomy is also risk factors. Intraocular silicone oil, on the other hand, decreases the incidence of NVI. Cataract surgery can lead to the progression of DR and hence increases the risk of NVG. However, an intact posterior capsule has a protective effect.
Ocular ischemic syndrome
OIS is caused by reduced blood flow to the eye which leads to anterior and/or posterior segment ischemia. Anterior segment ischemia causes iris or angle neovascularization and NVG. OIS is most commonly associated with carotid artery occlusive disease. Other less common causes include vascular occlusive disease of the aortic arch, ophthalmic, central retinal, or ciliary arteries.
| Pathogenesis|| |
Majority of the cases of iris and angle neovascularization are associated with hypoxia and ischemia of retina. As a response to tissue hypoxia, vascular endothelial cells secrete pro-angiogenic factors such as VEGF, tumor necrosis factor, insulin growth factor, and platelet-derived growth factor. This, in turn, stimulates a chain reaction characterized by the activation, proliferation, and migration of the endothelial cells and the formation of new blood vessels. Iris and angle neovascularization is associated with the development of a fibrovascular membrane over the anterior surface of the iris and iridocorneal angle. This membrane is difficult to visualize, blocks aqueous humor outflow through trabecular meshwork, and increases the IOP. Subsequently, the contraction of this membrane leads to the development of progressive anterior synechiae and angle closure.
Stages of neovascular glaucoma
NVG can be divided into three stages:
- Rubeosis iridis
- Secondary open-angle glaucoma
- Secondary angle-closure glaucoma.
NVI starts from the pupillary margin as tiny tufts or red spots that can be easily missed unless examined carefully at the slit lamp with an undilated pupil under high magnification [Figure 4]. Rubeosis iridis is usually present before neovascularization of the angle. However, in some cases, neovascularization can start at the angle. Therefore, gonioscopy with an undilated pupil is essential in all high-risk cases to diagnose early angle neovascularization even when pupillary margin and iris are not involved.
Weiss and Gold classification of iris and anterior chamber angle neovascularization.
- Iris Grade 1: Fine surface neovascularization of the pupillary zone of the iris involving <2 quadrants
- Anterior chamber angle Grade 1: Fine neovascular twigs cross scleral spur and ramify on trabecular meshwork involving <2 quadrants
- Iris Grade 2: Surface neovascularization of the pupillary zone of the iris involving more than 2 quadrants
- Anterior chamber angle Grade 2: Neovascular twigs cross scleral spur and ramify on trabecular meshwork involving more than 2 quadrants
- Iris Grade 3: In addition to neovascularization of the pupillary zone, neovascularization of the ciliary zone of the iris and/or ectropion uveae involving 1–3 quadrants
- Anterior chamber angle Grade 3: In addition to neovascularization of trabecular meshwork, peripheral anterior synechiae (PAS) involving 1–3 quadrants
- Iris Grade 4: Neovascularization of the ciliary zone of the iris and/or ectropion uveae involving 3+ quadrants
- Anterior chamber angle Grade 4: PAS involving 3+ quadrants.
Secondary open-angle glaucoma
The new vessels from the pupillary margin grow radially on the surface of the iris toward the angle, cross the ciliary body band and scleral spur on to the trabecular meshwork [Figure 5]. A fibrovascular membrane, invisible on gonioscopy, accompanies the new vessels, blocks the trabecular meshwork, and raises the IOP.
Secondary angle-closure glaucoma
In the late stage, myofibroblasts in the fibrovascular membrane proliferate and contract to form PAS and cause angle-closure glaucoma.
The clinical features of advanced stage of NVG are as follows [Figure 6]:
|Figure 6: Anterior segment photograph of advanced glaucoma with florid iris neovascularization and ectropion uveae|
Click here to view
- Severe decrease in visual acuity
- Eye pain
- Conjunctival and episcleral congestion
- Corneal edema
- Aqueous flare
- Very high IOP
- Florid NVI and angle
- Ectropion Uveae
- Synechial angle closure on gonioscopy.
Diagnosis of neovascular glaucoma
A high index of suspicion is required to diagnose early NVG, where IOP is not elevated and only subtle signs are present. Examination of the iris and gonioscopy in an undilated pupil is essential. Fluorescein angiography of the iris can be useful in differentiating iris neovascularization from normal iris vessels as the latter do not leak fluorescein. FFA is important to illustrate the extent and area of retinal ischemia. Electroretinogram also can help in diagnosing retinal ischemia. Recently, anterior segment optical coherence tomography and ultrasound biomicroscopy are being used more frequently for the diagnosis and staging of the disease as they illustrate anterior chamber structures in greater detail.
| Management|| |
Management of NVG can be divided into two types:
- Treatment of underlying disease process responsible for rubeosis
- Treatment of elevated IOP.
| Treatment of Underlying Disease Process|| |
Panretinal photocoagulation (PRP) remains the mainstay in controlling the neovascular drive and should be considered in all cases of NVG when retinal ischemia is present. Furthermore, the success rate of glaucoma filtering surgeries increases with adequate preoperative PRP. The exact mechanism by which PRP works is not clear. It destroys the photoreceptor-retinal pigment epithelium complex, which accounts for the majority of retinal oxygen consumption, allowing oxygen from choroidal circulation to diffuse into the inner retina. This, in turn, decreases the inner retinal hypoxia and reduces the stimulus for release of angiogenic factors. PRP is commonly performed over 1–3 sessions. Additional laser treatment needs to be done until complete regression of new vessels. Sometimes PRP is very difficult or not possible if the view of the fundus is very hazy. In these situations, if the patient needs an intraocular surgery, endocyclophotocoagulation can be performed along with PPV instead of preoperative PRP. The outcome of treatment with PRP is variable, depending on the underlying cause of NVG and also the stage in which the disease was diagnosed. Lang documented complete regression of retinal neovascularization in 67%–77% and normalization of IOP in 42% of diabetic patients treated with PRP. In CRVO, PRP is indicated in the ischemic form and also in anterior segment neovascularization. This is still a matter of controversy. According to Hayreh et al., in their study, approximately one-third of the eyes with iris neovascularization treated with PRP would never have developed NVG. They also reported that eyes with ischemic CRVO always have a large permanent central scotoma, resulting in poor central visual acuity. Following PRP, the large central scotoma combined with severe loss of peripheral visual fields may virtually blind the eye. In OIS, uveal ischemia alone can be responsible for neovascularization and PRP should be performed only if FFA shows retinal ischemia due to retinal capillary obliteration. Furthermore, PRP may paradoxically increase IOP. Surgical carotid endarterectomy would be the best treatment in these cases.
Vascular endothelial growth factor inhibitors
The role of anti-VEGFs in the management of NVG has been studied extensively. Anti-VEGF injection leads to regression of anterior and posterior segment neovascularization and reduction of IOP. Anti-VEGF agents that are currently used include bevacizumab, ranibizumab, and aflibercept. However, there is no evidence available to suggest that either of the agents is superior to others in managing NVG. Intravitreal injection of bevacizumab causes regression of iris and angle neovascularization within 24–48 h compared to PRP, which takes 2–3 weeks. Bevacizumab is also effective in reducing intraocular inflammation and pain, and in a few reports, IOP lowering has been noted in the open-angle stage. However, anti-VEGFs are used only as an adjunct to PRP, medical therapy, and surgery. The most frequent recommendation is the combination of intravitreal anti-VEGF and PRP. Bevacizumab-induced regression of neovascularization is often temporary and recurrence is possible, while PRP provides a more permanent reduction of the ischemic angiogenic stimulus. PRP with adjunctive use of intravitreal anti-VEGF agent along with antiglaucoma medications may be sufficient to control IOP in the open-angle stage of NVG. Surgical intervention for IOP lowering is often required in advanced stage with synechial angle closure. In cases, where PRP is not possible due to media opacities, intravitreal bevacizumab can be given followed by trabeculectomy with mitomycin C (MMC).
A recent study reports that intravitreal aflibercept may be effective for NVI and open-angle stages of NVG. However, repeated intravitreal anti-VEGF injections may cause both transient as well as sustained elevation of IOP. Further research is needed to evaluate the long-term effect of anti-VEGFs, on visual acuity, IOP, and ocular neovascularization, in the management of NVG.
| Treatment of Elevated Intraocular Pressure|| |
Topical antiglaucoma medications which suppress aqueous humor production (Beta blockers, topical carbonic anhydrase inhibitors, and alpha-2 adrenergic agonists) are the first step to reduce IOP. Prostaglandin analogs which work by increasing the uveoscleral outflow are not useful if the angles are closed. Furthermore, prostaglandin analogs cause further breakdown of the blood aqueous barrier with worsening of intraocular inflammation. Pilocarpine is contraindicated as it increases inflammation, causes miosis, worsen synechial angle closure, and decreases uveoscleral outflow. Topical corticosteroids are used concurrently to treat any associated inflammation. Atropine may be used for cycloplegia, to increase uveoscleral outflow and to reduce the incidence of hyphema. Systemic medications such as osmotic agents and oral carbonic anhydrase inhibitors can be given along with topical medications to further reduce IOP. They help to clear the cornea which helps us to make a proper diagnosis and provide appropriate treatment. However, medical therapy is less useful in patients with extensive synechial angle closure.
Glaucoma surgery is helpful in the open-angle stage of NVG, to control IOP until PRP takes effect, and in synechial angle-closure stage, for long-term IOP control. Surgical interventions for NVG include trabeculectomy with antimetabolites, GDDs, and cyclodestructive procedures.
| Trabeculectomy|| |
The success of trabeculectomy alone is limited by severe inflammation associated with NVG. However, the adjunct use of antimetabolites has improved the success rate of trabeculectomy. Intraoperative use of MMC reduces the risk of bleb failure due to subconjunctival scarring. High dose (0.04%) and/or longer duration of contact (2–3 min) of MMC can be used. Subconjunctival use of 5-Fluorouracil (5 FU) or MMC can be considered postoperatively in patients who show early signs of bleb failure or aggressive vascularization. Sisto et al. achieved 54% success rate with the use of intraoperative MMC with a mean follow-up of 18 months and 55% success rate with the use of postoperative 5 FU with a mean follow-up of 35 months. Regression of NVI and reduced intraocular inflammation before surgery increases the success rate of trabeculectomy. With the use of preoperative bevacizumab, success rate may improve up to 95%. Therefore, it is recommended that sufficient PRP and/or anti-VEGF agents should be given before trabeculectomy with MMC. Surgical intervention should be planned within a week of injection of anti-VEGF. Combined cataract and glaucoma surgery can be planned if media is hazy due to cataract, followed by PRP whenever possible. If media is hazy due to vitreous hemorrhage and clarity does not improve after a short period of observation, PPV with endolaser photocoagulation may be considered.
Glaucoma drainage devices
GDDs are considered in the management of NVG when trabeculectomy fails or when there is high risk of failure because of excessive conjunctival scarring. Use of anti-VEGFs is recommended at least 24 h before surgery. The problems with GDD implantation in NVG are early postoperative hypotony, blockage of tube in the anterior chamber and postoperative fibrous encapsulation. Various drainage devices such as Molteno implant, Baerveldt implant, and Ahmed glaucoma valve have been used in the management of NVG and show no statistically significant difference in either IOP lowering effect or overall success. However, some studies have reported that success rate with valve surgeries significantly decreases over time in eyes with NVG.,,,, Furthermore, Shen reported a comparable surgical outcome with augmented trabeculectomy and Ahmed glaucoma valve implantation in eyes with NVG.
Cyclodestruction remains an effective treatment option in eyes with refractory NVG having poor visual prognosis. These procedures destroy the ciliary body to reduce aqueous humor production. They may be highly effective in achieving IOP control. However, it is difficult to titrate the effect on ciliary body and excessive treatment may lead to hypotony and phthisis. Transscleral cyclophotocoagulation or endocyclophotocoagulation may have a lower complication rate compared with cyclocryotherapy.
In painful blind eyes, it is reasonable to try retrobulbar alcohol injection. Some intractable cases may require enucleation or evisceration.
| Conclusion|| |
NVG is a potentially devastating secondary glaucoma and remains a therapeutic challenge. Early diagnosis and proper management are crucial to prevent or reduce the extent of visual loss. Early stage of the disease with open angles can be managed with antiglaucoma medications and PRP along with adjunctive use of anti-VEGF agents. Advanced disease with synechial angle closure resulting in very high IOP may be refractory to antiglaucoma medications and often requires surgical interventions.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]