Improving Outcomes in Neovascular Glaucoma

A core obstacle to neovascular glaucoma (NVG) management and academic discussion is that it is a multidisciplinary problem where the etiology of anterior-segment neovascularization lies in the domain of retina specialists, while the resultant elevated intraocular pressure (IOP) lies in the domain of glaucoma specialists. Diagnosis of NVG is also often delayed, and patients may have already sustained permanent vision loss by the time of presentation. Furthermore, the patients at highest risk of developing NVG are often the most vulnerable in our medical system. To address the barriers to improved outcomes in NVG, multidisciplinary discussions in ophthalmology are needed around the following topics: (1) standardizing the definition and staging of NVG; (2) detecting anterior-segment neovascularization earlier; (3) increasing evidence-based research to improve outcomes; (4) determining the optimal multidisciplinary treatment approach; and (5) increasing patient adherence to treatment. We propose solutions to help address the barriers to improved outcomes.

Standardizing the Definition and Staging of Neovascular Glaucoma

The commonly used definition of NVG is anterior-segment neovascularization (neovascularization of the iris [NVI] or neovascularization of the angle [NVA]) with elevated IOP with or without glaucomatous optic neuropathy. We believe elevated IOP and the presence of peripheral anterior synechiae should be used to classify NVG. The presence of glaucomatous optic neuropathy could be considered in the definition, but it can be difficult to assess during the acute presentation. Consensus panels are needed to define a new NVG classification system, which would help risk stratify patients, determine whether interventions should be tailored to disease stage, and prevent long-term sequelae.

Earlier Detection of Anterior-Segment Neovascularization

The diagnosis of NVG is often delayed because of an asymptomatic early disease course and presentation only when elevated IOP causes pain and decreased vision. A retrospective review found that 25% of eyes presenting with NVI/NVA and IOP < 21 mmHg progressed to NVG, with the majority progressing by 6 months.¹ As such, there is a window of opportunity for improved outcomes if these high-risk patients with normal IOP are identified earlier. Unfortunately, gonioscopy is not performed in all high-risk patients to detect early NVI/NVA. The findings of NVA or peripheral anterior synechiae may be challenging to detect for providers who do not frequently perform gonioscopy. In addition, undilated examination of the iris and angle may not be feasible for all ophthalmology clinic workflows. Early NVI/NVA detection could involve the aid of diagnostic tests such as anterior-segment photographs, iris or gonioscopic angiography,^2–4 and noninvasive anterior-segment OCT angiography (OCTA).^5,6 Although these diagnostic tests have been described in the literature, additional evaluation of their efficacy and utility is needed. One key question that needs to be addressed is the duration between subclinical presentation (NVI/NVA detected on angiography or OCTA) to clinical presentation of NVG.

Additional Evidence-Based Research Needed

Several key areas require further investigation, including choice of treatment for proliferative retinal conditions (anti-vascular endothelial growth factor [VEGF], panretinal photocoagulation [PRP], or both) before and after the development of NVG, as well as the choice of IOP-lowering procedure. The Diabetic Retinopathy Clinical Research Network Protocol S study reported no difference in development of NVG in patients with proliferative diabetic retinopathy (PDR), but it may not have been sufficiently powered to detect minor differences (0%–2%) in NVG incidence after PDR treatment.⁷ A retrospective cohort study suggested that the long-lasting effect of PRP may lead to better outcomes than anti-VEGF alone for long-term prevention of anterior-segment neovascularization in patients with PDR at risk of loss to follow-up or rapid disease progression.⁸ Likewise, updated guidelines are needed for patients with central retinal vein occlusion (CRVO) in the anti-VEGF era because the American Academy of Ophthalmology’s (AAO) Preferred Practice Pattern (PPP) guidelines are largely based on evidence derived from studies conducted before the use of anti-VEGF.⁹ With the increasing use of anti-VEGF for macular edema in CRVO, patients are at risk for developing NVG well beyond the historical 90-day time frame and need continual monitoring.¹⁰ More work is needed to determine whether a combination of anti-VEGF and prophylactic PRP can prevent NVG in CRVO eyes and to elucidate the optimal frequency and duration of follow-up to detect early anterior-segment neovascularization in high-risk patients with CRVO.

Regarding the role of anti-VEGF and PRP after NVG has already developed, the AAO PPP for diabetic retinopathy recommends prompt PRP for high-risk PDR, which includes the presence of anterior-segment neovascularization,¹¹ and the AAO PPP for CRVO recommends PRP when NVI is present.⁹ In a retrospective review of 217 treatment-naïve NVG eyes with light perception or better vision at presentation, receiving at least 1 anti-VEGF injection or PRP session within 1 week of presentation was associated with 20/200 or better vision at 6 months.¹ A few single-center comparative studies suggest that a combination of anti-VEGF and PRP should be given to patients with NVG likely due to the rapid onset of action after anti-VEGF injections compared with PRP.^12,13 As such, it has been proposed that a combination of anti-VEGF and early PRP within 4 weeks of anti-VEGF injection has a promising role for treating high-risk PDR without clinically significant macular edema.¹⁴ Further multicenter prospective research is needed in this area.

Regarding the choice of IOP-lowering procedure after NVG has developed, there have been no published randomized controlled trials to date enrolling only NVG eyes, and data from small to medium-sized retrospective and prospective studies comparing surgical outcomes of trabeculectomy, aqueous shunts, and cyclophotocoagulation in NVG eyes have been equivocal.^15,16 Most studies on IOP-lowering interventions for NVG pool all etiologies of NVG, but the etiology of NVG may affect prognosis and outcome. For example, RVO has been shown to be a risk factor for worse visual prognosis in NVG studies.^1,17,18 Studying NVG outcomes stratified by etiology has been challenging because NVG is a relatively rare disease. Electronic health records and larger databases may be potential avenues for future research.

Improving the Multidisciplinary Treatment Approach

Multidisciplinary treatment models should be reformed to provide streamlined care with a commitment from the patient, glaucoma specialist, and retinal specialist. There is limited evidence regarding current practice patterns for NVG in retina and glaucoma clinics. A lone 2016 survey of glaucoma and retinal specialists found that most providers agreed that anti-VEGF injections should be included in the initial management of NVG given its rapid onset of action, and that stabilized patients should receive PRP, but there was no consensus regarding how to combine glaucoma and retinal interventions or how to manage patients after the initial acute phase.¹⁹ To improve outcomes, a paradigm shift is needed to develop a standardized multidisciplinary treatment protocol for NVG. Consensus panels including both retina and glaucoma specialists are needed to mitigate discrepancies in NVG management and develop care paths for more effective and efficient care delivery. A prospective interventional study from Peking University enrolled 51 eyes with NVG and implemented a comprehensive treatment strategy for NVG.²⁰ All eyes received immediate intravitreal anti-VEGF upon NVG diagnosis, and anti-VEGF injections were continued monthly until full PRP could be completed; trabeculectomy was the primary IOP-lowering procedure, and cataract surgery or vitrectomy was performed as needed. Overall, 100% of eyes that completed the treatment protocol had regression of anterior-segment neovascularization, 93% had stable or improved vision, and 87% had IOP ≤ 21 mmHg up to postoperative month 6. This study, which was performed between 2010 and 2012 (during the anti-VEGF era), highlights the favorable clinical outcomes that can be achieved with close collaboration between glaucoma and retinal specialists who share the patient-centric goal of preserving visual function by controlling the IOP and suppressing the underlying ischemic drive.

Patient Adherence to Treatment

Adherence has been a subject of long-standing interest in patients with glaucoma and retinal conditions, because treatment success requires long-term engagement from the patient. Because complex multidisciplinary care is required to adequately manage NVG, it is important that patients understand the underlying etiology of their NVG and ophthalmic manifestations. However, extensive physician-led patient counseling may not be an option given time constraints in most ophthalmology clinics, so other providers on the care team may need to play a central role in offering patient education.²¹

In conclusion, the detection and management of NVG have substantial room for improvement. Although recent advancements in retinal and glaucoma treatment have increased therapeutic options, guidelines for the care of patients with NVG have not evolved. The ophthalmology community should work synergistically across specialties and with patients to surmount barriers to optimal NVG care.