Neovascular glaucoma: challenges we have to face

Neovascular glaucoma (NVG) is a blinding, intractable disease, which is difficult to manage. It is referred to as an "end-stage" ocular disease. Conventional treatments for extremely uncontrolled NVG cases include retinal cryotherapy or enucleation. Major advancements in the diagnosis and the treatment of NVG, such as glaucoma drainage implant surgery and anti-vascular endothelial growth factor (anti-VEGF) treatment, have led to a new era in the management of this condition. However, many challenges still remain to be overcome. Managing the underlying disease is the most important aspect of NVG About 40 diseases, including diabetic retinopathy, central retinal ischemia, and vein occlusion, are known to be associated with NVG at present.1,2 However, there is no specific approach to treat the various underlying diseases linked to NVG. The mainstay of the treatment includes panretinal photocoagulation (PRP)3 and an intravitreal injection of anti-VEGF agents.4 Vitrectomy adjunctive PRP can reduce the production of vasoproliferative factors in an ischemic retina. More recently, the use of anti-VEGF agents (pegaptanib, bevacizumab, and ranibizumab) to induce rapid regression of NVG has gained widespread clinical acceptance.4 However, bevacizumab is used as an "off label" application, and ranibizumab is relatively expensive, both of which could limit the use of anti-VEGF treatment in NVG. KH902 is the only anti-VEGF drug developed in China, and a phase II clinical trial of the drug has just been completed. NVG is an extremely aggressive disease that often results in poor visual outcomes Most patients with NVG have severe underlying ocular pathologies as described above. The myriad medical conditions resulting in NVG all lead to a final common pathway of profound retinal ischemia. The extraordinarily high IOP in NVG can further aggravate retinal ischemia, which can make the condition very difficult to treat. Medication for NVG is temporary, less effective, particularly if the angles are closed by synechiae As the trabecular meshwork is damaged permanently in NVG, medical treatment provides very little relief. The various aqueous suppressants, adjunctive systemic administration of carbonic anhydrase inhibitors, and dehydrating agents used in the treatment invariably lower the IOP. There is no role for cholinergic eye drops. Additionally, prostaglandins may not be of much help because they work by increasing the uveal outflow, which may be covered by a neovascularization membrane. Conventional filtering surgery for NVG has a high risk of failure The absolute success rate with trabeculectomy with adjunctive 5-fluorouracil or mitomycin C is low because of the filtering bleb, which easily scars. The literature has reported a success rate of only 11%-33% with trabeculectomy.5,6 Therefore, it is not the first choice for treating NVG. Cyclodestructive procedures could not be realized once and for all Transscleral cyclophotocoagulation is a common method used to lower the IOP in NVG. It is easy to perform and to repeat, and there is a relatively low complication incidence, with a success rate of 59.0%-74.2%.7-9 Although transscleral cyclophotocoagulation can greatly reduce the severe postoperative pain associated with anterior chamber irrigation, this technique still has many shortcomings, including loss of vision, corneal decompensation, inflammation, and hyphema. Additionally, repeat treatments may be necessary to maintain good control of the IOP.10 Glaucoma drainage implant (GDI) surgery offers promise in the treatment of NVG but is not suitable for all patients GDI surgery is gaining wide acceptance as a primary procedure for patients with refractive glaucoma.11-13 GDI surgery provides a time window with a normal range of IOP for the process underlying the disease. Antiglaucomatous surgery can also be undertaken while the patient is undergoing PRP or anti-VEGF therapies. Adjunctive anti-VEGF treatment promotes surgical success rates in NVG. However, it should be noted that NVG still has a poor response to GDI surgery, with variable success rates of 22%-78%.14 In long-term follow-ups, clinical success and survival with GDI surgery were low. Excessive proliferative changes appear to be associated with bleb failure and elevated IOP. Problems selecting the ideal drainage device and moderating the wound healing response are still key problems with this procedure. Anti-VEGF induced regression of neovascularization is often temporary, and recurrence is possible PRP has been shown to provide a more permanent reduction in the ischemic angiogenic stimulus. However, in patients with cloudy media, there is no choice but to administer anti-VEGF treatment. Although anti-VEGF therapy has a surprising ability to induce regression of neovascularization, this regression is often temporary. New studies have shown that, in addition to VEGF, erythropoietin, placenta growth factor, and platelet derived growth factor-D (data not published yet) might also play an important role in NVG.15,16 This could partly explain why ocular neovascularization of the iris does not disappear completely after anti-VEGF therapy. Is surgical intervention still needed when the IOP is reduced by PRP or anti-VEGF treatment When the IOP is controlled by PRP or anti-VEGF treatment, whether further surgical intervention is needed is the subject of significant controversy. Some researchers consider that surgical intervention is not necessary anymore. In contrast, others hold a more aggressive view that the reduction in the IOP provides about a 3-week window for surgical intervention.17 When iris neovascularization recurs, the treatment of regressed neovascularization (via PRP or repeated injections of anti-VEGF) can be easily undertaken because the IOP is maintained well by the surgical treatment. When is the best timing for the surgery Currently, the best time for surgical intervention after anti-VEGF administration is not known. One study suggested that GDI surgery should be performed within 1-2 weeks after receiving anti-VEGF,18 although there is a lack of evidence to support this idea. Our preliminary study confirmed that the ideal timing for surgery might be within 7-10 days after the surgery when the inflammation of the anterior chamber is alleviated (unpublished data). We hope to find a quantitative method to resolve the issue surrounding the best time for surgery. What is the optimal management strategy for NVG The current consensus for NVG management is as follows: Stage I (early stage of glaucoma: the main underlying diseases should be managed through PRP or anti-VEGF. Other approaches, including adjunctive pars plana vitrectomy, endolaser photocoagulation, or cataract extraction, should also be considered in this stage. Stage II (stage of angle open glaucoma): The IOP should be controlled by medications and antiangiogenic therapy alone. Surgical procedures, such as trabeculectomy, may also successful in some cases in this stage. Stage III (stage of angle closure glaucoma): In this stage, medical therapy is never appropriate, and surgical procedures are needed. If the angle is wide enough for tube implantation, GDI surgery should be recommended as the first-line treatment, with or without intravitreal anti-VEGF. The recommended treatment strategy proposed by Olmos contains three key points.18 The first point relates to whether the view is clear. If the eye has clear media, PRP therapy can be initiated. Otherwise, anti-VEGF therapies should be administered. The second point relates to the angle closure. If the anterior chamber angle is still open, it may be possible in some cases to control the IOP with medical and auxiliary therapy, without the need for surgical procedures. If angle is completely closured, a surgical approach is usually necessary because PRP or anti-VEGF alone is insufficient to control the IOP. When surgery is required, GDI surgery should be considered as the first option. The third point relates to whether the patient has useful vision. If so, aggressive therapy (i.e., GDI surgery or trabeculectomy) should be selected. If the patient does not have useful vision, cyclophotocoagulation is recommended. We believe GDI surgery might offer a better quality of life than cyclophotocoagulation. However, further studies are needed to confirm this belief. Thus far, there is a lack of multicenter, prospective, randomized clinical trials to verify the outcomes of NVG management. Furthermore, we are a long way from a satisfactory method to treat NVG and prevent visual loss. Aggressive management of the underlying disease and the prevention of NVG are keys to treating NVG. To reduce the IOP and to preserve visual function are the goals for NVG. At present, NVG still requires individualized treatment, according to the underlying disease, stage of the disease, visual potential, and other complex factors. It should be noted that managing NVG in China is associated with additional challenges because of its severe clinical features, no useful vision at first visit, and in the late course of the disease and easily lost to follow-up.