Advertisement

PentaVision

Glaucoma Physician

Article

Pathology and Management of Neovascular Glaucoma

Multidisciplinary care is key to optimal outcomes.

By: Connie M. Wu, MD
Glaucoma Physician March 1, 2023 Vol Ophthalmology Management 27, Issue March 2023 Page(s): 18-21

Related

Neovascular glaucoma (NVG) is challenging to treat and frequently results in permanent visual impairment. Early diagnosis and prevention are key to the preservation of visual function. A timely and coordinated treatment plan between glaucoma specialists, retina specialists, and primary care physicians can seem like a lot to ask for, especially on a Friday afternoon when NVG seems to preferentially emerge. Evolving diagnostic and treatment approaches may improve outcomes, but further well-designed studies with longer follow up are needed. Additionally, patients often have sociodemographic barriers to treatment and systemic medical comorbidities that may demand prioritization of care.

Early Diagnosis and Prevention

Around three-quarters of cases of NVG are due to proliferative diabetic retinopathy (PDR), ischemic central retinal vein occlusion (CRVO), or ocular ischemic syndrome (OIS).1,2 The incidence of neovascularization of the iris (NVI) among eyes with PDR is reported to be 65%, and 1 in 3 patients who have had NVG in 1 eye due to diabetic disease will develop NVG in their second eye.3 Around 18% to 60% of eyes with ischemic CRVO develop anterior-segment neovascularization.4 Although classically termed “90-day glaucoma,” eyes can develop NVG anytime between 2 weeks to 2 years after the onset of CRVO. Typically, more than 80% of NVI and NVG occur within 6 months of RVO onset. Perfused CRVO usually does not develop neovascularization of NVG unless associated with diabetic retinopathy or ocular ischemic syndrome,4 but, importantly, around 16% of perfused CRVO can become nonperfused within 4 months.5

Ocular ischemic syndrome is often associated with carotid artery occlusive disease and accounts for around 13% of cases of NVG.6 Chronic ocular ischemia is found in 4% to 18% of patients with carotid artery occlusive disease. Ocular ischemic syndrome should be considered in cases of NVI without a defined ocular cause, marked asymmetry of retinopathy, and poor regression of neovascularization despite panretinal photocoagulation (PRP). Coordinating care with the primary care physician to ensure carotid ultrasound is performed and appropriate treatment is provided can reduce morbidity.

Less common causes of NVG include central retinal artery occlusion, which may result in NVI in 3% to 18% of patients between a few months to years later.7 Retinal detachment, intraocular tumors, and uveitis are other causes of NVG, though these cases are rare.

Diagnostic techniques include careful slit lamp examination of the undilated iris, as NVI and neovascularization of the angle (NVA) often present before elevation in intraocular pressure (IOP).8 Use of diagnostic tests, including iris fluorescein angiography (FA), indocyanine green angiography (ICGA), and anterior-segment ocular coherence tomography angiography (OCTA), may aid in early detection of NVI.9,10 Iris FA has the advantage of identifying leakage and hidden NVI.11 Indocyanine green angiography shows less leakage, but its protein bound nature and use of near-infrared wavelengths enable penetration through iris pigment, providing improved visualization of vascular microstructure. Anterior-segment OCTA may be able to show more detailed iris vessel imaging compared to iris FA, but it cannot provide information on leakage or delay of flow and may be more susceptible to motion artifact.12 OCTA more readily highlights NVI in darker irises because of decreased transmission of deeper normal iris vasculature.13 Further studies are needed to assess the efficacy and clinical applicability of iris FA, ICGA, and OCTA.

Gonioscopy remains a useful diagnostic tool, but it can be difficult to perform in the setting of an inflamed eye with a steamy cornea. When a clear view is possible, NVA first appears as abnormal vessels crossing the scleral spur and trabecular meshwork. Later, the vessels form a fibrovascular membrane, which subsequently contracts and causes synechial angle closure that “zips up” the angle, permanently compromising the drainage pathway.

A dilated exam of both eyes is recommended, but it may be limited by corneal edema, poor dilation, or vitreous hemorrhage. It is important to assess for diabetic retinopathy, retinal vein occlusion, and signs of OIS. Wide-angle imaging modalities enable visualization of the peripheral retina to the ora serrata, providing a more comprehensive understanding of the extent of retinal ischemia. If the view is poor, a B-scan ultrasound may be performed to rule out retinal detachment, tumor, or vitreous hemorrhage. When possible, a baseline glaucoma evaluation with visual field testing and/or OCT of the retinal nerve fiber layer and ganglion cell complex is helpful to determine extent of glaucomatous damage and risk of glaucoma progression in both eyes.

Multidisciplinary Treatment

Perhaps the biggest challenge to NVG management is orchestrating a timely treatment approach among various specialists. A multidisciplinary approach is needed to target ischemic factors promoting neovascularization, promptly address elevation in IOP to prevent irreversible glaucomatous damage, and treat any underlying systemic conditions. Treatment continues to evolve, but further research is needed to determine the optimal coordinated approach.

Addressing ischemic factors predominantly lies in the domain of retina specialists and includes anti–vascular endothelial growth factor (VEGF) and PRP. While there has yet to be a prospective randomized trial evaluating the use, dosage, route, and timing of VEGF inhibitor treatment for NVG, there is some evidence to support its use as adjunct therapy to PRP and/or glaucoma surgery. In cases of early neovascularization without synechial angle closure, anti-VEGF combined with PRP may prevent NVG. A retrospective review of 217 treatment-naïve NVG eyes with light perception or better vision found that 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.14

A few single-center comparative studies support a combination of anti-VEGF and PRP treatment for patients with NVG, due to rapid neovascularization regression following anti-VEGF injection.15,16 Regression of neovascularization can begin within 1 day of bevacizumab injection17 and has been shown to result in IOP reduction as early as 1 week.18 Ranibizumab and aflibercept have also been found to reduce IOP and neovascularization in NVG. However, neovascularization and IOP elevation can return if the underlying ischemic disease is not treated or PRP is not performed. Anti-VEGF can buy some time prior to definitive surgical management and reduce the risk of postoperative hyphema.19 Anti-VEGF administered prior to glaucoma drainage device (GDD) implantation has not been found to result in better long-term surgical success but has been associated with better preservation of visual acuity.20

Panretinal photocoagulation remains the preferred standard of treatment in most eyes with neovascularization. There is strong evidence for full PRP for advanced NPDR and PDR to prevent development of NVG, but evidence to support PRP in the prevention of NVG in ischemic CRVO is more controversial. Panretinal photocoagulation is recommended by the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPP) for diabetic retinopathy for high-risk PDR (including NVI or NVA) and the AAO PPP for CRVO when NVI is present.21,22 The Central Retinal Vein Occlusion Study investigating the role of PRP in ischemic CRVO advised frequent follow-up examinations in the early months, including careful undilated iris exam with gonioscopy, and PRP for eyes with at least 2 clock hours of anterior-segment neovascularization.23 Panretinal photocoagulation has been shown to result in lasting regression of NVI and NVA, even among patients who are lost to follow-up.24

Studies of Treatment Approaches

A lack of consensus regarding neovascular glaucoma treatment approaches stems from the fact that there are no published randomized controlled trials involving only NVG eyes. There are equivocal results from small and medium-sized retrospective and prospective studies assessing surgical outcomes of trabeculectomy, aqueous shunts, and cyclophotocoagulation (CPC) in NVG eyes.25,26 The treatment of NVG may need to be tailored based on etiology, because RVO-induced NVG has been correlated with a worse visual prognosis.27 Future studies may make use of big data in the assessment of NVG treatment options stratified by etiology.

Medical therapies are often employed in the acute setting as a temporizing bridge to definitive surgical management, especially for eyes with significant synechial angle closure. Topical therapy aiming to reduce aqueous humor production, including beta-blockers, carbonic anhydrase inhibitors, and alpha-adrenergic agonists, can be useful. Prostaglandin analogues may be less effective and risk further disruption of the blood-aqueous barrier. Pilocarpine may worsen synechial angle closure and should be avoided. The potential conjunctival inflammation that may result from topical Rho kinase inhibitors may be unwelcome in eyes destined for imminent filtering surgery. Cycloplegics and topical corticosteroids can help reduce inflammation and pain. Oral therapy with carbonic anhydrase inhibitors may be helpful but should be used with caution, because patients often have comorbid renal disease. Intravenous mannitol may have a temporizing role in the emergency setting for patients who can medically tolerate a hyperosmotic agent. Anterior-chamber paracentesis carries a high risk of hyphema with subsequent IOP elevation and should be avoided, especially in eyes that have untreated neovascularization.

Surgical Options

Surgical management typically centers around trabeculectomy and GDD implantation. Existing evidence does not clearly favor one over the other. Although the use of antimetabolites has improved overall success rates of trabeculectomy, it still has low long-term success for NVG, ranging from 62% to 82% at 1 year to 50% at 5 years.28 In NVG eyes, high levels of anti-VEGF stimulate angiogenesis, epithelization, and collagen deposition, leading to internal occlusion of the sclerostomy and external conjunctival fibrosis and bleb failure. The addition of intravitreal bevacizumab may have a role in surgical success of trabeculectomy with adjunctive mitomycin C (MMC) among NVG eyes due to diabetes.29 Reports of the Ex-press implant (Alcon) have not found a high rate of success in NVG.30

Glaucoma drainage devices also exhibit a higher rate of failure among NVG eyes. There is no evidence to support a significant difference in surgical success between valved (Ahmed) and nonvalved (Baerveldt, ClearPath, Aurolab, Molteno) devices, and nonvalved devices tend to result in lower long term IOP.31,32 Valved shunts may be favored by glaucoma specialists due to the potential for early IOP reduction and less risk for hypotony in the early postoperative period. The nonvalved Aurolab aqueous drainage implant, developed by a manufacturing branch of Aravind Eye Institute, is based on the Baerveldt prototype with a larger end plate. Studies have found comparable IOP-lowering efficacy and safety profile compared to Ahmed and Baerveldt drainage devices at lower cost ($50 per device). A recent study of 85 neovascular glaucoma eyes found significant reduction of mean IOP and medications after Aurolab aqueous drainage implant surgery, with cumulative rate of failure 34% at 2 years.33

Cyclophotocoagulation has traditionally been reserved for eyes with limited visual potential, because potential complications include persistent hypotony, macular edema, phthisis, inflammation, and pain. Micropulse CPC may reduce the risk of adverse effects from excess thermal energy. A single-center retrospective comparative case series found a lower surgical success rate at 6 months (17% vs 43%) for CPC compared to Ahmed glaucoma valve implantation.34 Endocylophotocoagulation (ECP) may have a role as adjunct therapy, and 1 retrospective series found that pars plana vitrectomy, endoscopic PRP, and ECP may have favorable outcomes compared to standard NVG treatments.35 A small retrospective chart review examining primary CPC combined with anti-VEGF treatment found successful IOP control in 5 out of 7 cases, with preservation of baseline vision ranging from 20/50 to light perception.36

To date, only a handful of case reports have found success for select minimally invasive glaucoma surgeries. One report of gonioscopy-assisted transluminal trabeculotomy (GATT) performed in conjunction with near-monthly anti-VEGF injections in an eye with partial synechial angle closure due to NVG from CRVO achieved IOP control on no medications at 9 months.37 Another case report described the successful use of the Xen-45 microstent (Allergan) with MMC in a patient who was monocular from prior NVG and developed NVG in his only seeing eye. He had comorbidities that prevented him from being able to lay flat for an extended period, so a tube shunt or trabeculectomy were not advised. He underwent a CPC followed by Xen-45 microstent implantation with MMC and intracameral bevacizumab, and 2 years post-surgery maintained good vision and IOP 13 on no medications.38 In general, the role of various MIGS surgical procedures is not well studied in NVG and may not be sufficient to achieve long-term significant reduction in IOP, but further study is warranted to understand the potential role of MIGS for the appropriate NVG patient.

Caring for the Whole Patient

The primary care physician plays an invaluable role in the treatment of any NVG patient. Select patients may further benefit from referral to a cardiologist, endocrinologist, or vascular surgeon. Patients with significant carotid artery occlusive disease with neurologic symptoms, including amaurosis fugax, should be considered for carotid endarterectomy. Resolution of NVI and NVG has been reported with this procedure alone.39

Patients presenting with NVG often have social barriers and comorbid conditions that affect their ability to receive appropriate care. The majority of NVG patients have cardiovascular disease and/or diabetes. It is important to ensure routine evaluation of blood pressure, blood glucose levels, and other cardiovascular risk factors. Patients with NVG have also been found to have reduced life expectancy due to comorbid conditions. Five-year survival is 62% in NVG patients compared to 80% among age-matched and sex-matched controls, with poor presenting visual acuity of the affected eye being correlated with poorer survival.40 Those with NVG and presenting visual acuity of 20/200 or worse had almost 11 years reduction in life expectancy.41

Various sociodemographic factors may preclude patients with NVG from receiving optimal ophthalmic and medical care. Lower income may be correlated with worse visual acuity outcomes following NVG tube shunt surgery.42 It is important to identify and address potential barriers to care to improve patient outcomes.

Conclusion

Neovascular glaucoma continues to be a challenging disease necessitating coordinated multidisciplinary treatment approaches. The lack of consensus and variability of evidence speak to a need for well-designed larger randomized controlled studies with longer follow-up intervals. Potential treatment algorithms may combine anti-VEGF, PRP, and various surgical glaucoma treatment options at strategic intervals with attention to individual patients’ functional needs and access to care. GP

Connie M. Wu, MD, a glaucoma and cataract surgeon, is an assistant professor of clinical ophthalmology at the University of Miami Health System. She reports no relevant disclosures. Reach Dr. Wu at cmw266@med.miami.edu.

References

  1. SooHoo JR, Dueker DK, Kahook MY. Neovascular glaucoma. In: Kahook MY, Shuman J, eds. Chandler and Grant’s Glaucoma. 6th ed. Slack; 2013:309-317.
  2. Ohrt V. The frequency of rubeosis iridis in diabetic patients. Acta Ophthalmol (Copenh). 1971;49(2):301-307. doi:10.1111/j.1755-3768.1971.tb00954.x
  3. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol. 1998;43(3):245-269. doi:10.1016/s0039-6257(98)00035-6
  4. Mocanu C, Barascu D, Marinescu F, Lacrateanu M, Iliusi F, Simionescu C. Neovascular glaucoma—retrospective study. Article in Romanian. Oftalmologia. 2005;49(4):58-65.
  5. Baseline and early natural history report. the Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8):1087-1095. doi:10.1001/archopht.1993.01090080083022
  6. Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007;26(5):470-485. doi:10.1016/j.preteyeres.2007.06.001
  7. Rudkin AK, Lee AW, Chen CS. Ocular neovascularization following central retinal artery occlusion: prevalence and timing of onset. Eur J Ophthalmol. 2010;20(6):1042-1046. doi:10.1177/112067211002000603
  8. John T, Sassani JW, Eagle RC Jr. The myofibroblastic component of rubeosis iridis. Ophthalmology. 1983;90(6):721-728. doi:10.1016/s0161-6420(83)34520-6
  9. S. Li, Z. Wang, P. Li, Y. Dong. Application of iris fluorescein angiography combined with fundus fluorescein angiography in diabetic retinopathy with neovascular glaucoma. Chin J Exp Ophthalmol, 2016;34(12):1112-1115. doi:10.3760/cma.j.issn.2095-0160.2016.12.013
  10. Shiozaki D, Sakimoto S, Shiraki A, et al. Observation of treated iris neovascularization by swept-source–based en-face anterior-segment optical coherence tomography angiography. Sci Rep. 2019;9(1):10262. doi:10.1038/s41598-019-46514-z
  11. Li ZQ, Zhou XX, Lin S, Li JL, Wu JG. Angiography reveals early hiding iris neovascularization after ischemic CRVO. Int J Ophthalmol. 2013;6(2):253-254. doi:10.3980/j.issn.2222-3959.2013.02.28
  12. Roberts PK, Goldstein DA, Fawzi AA. Anterior segment optical coherence tomography angiography for identification of iris vasculature and staging of iris neovascularization: a pilot study. Curr Eye Res. 2017;42(8):1136-1142. doi:10.1080/02713683.2017.1293113
  13. Zett C, Stina DMR, Kato RT, Novais EA, Allemann N. Comparison of anterior segment optical coherence tomography angiography and fluorescein angiography for iris vasculature analysis. Graefes Arch Clin Exp Ophthalmol. 2018;256(4):683-691. doi:10.1007/s00417-018-3935-7
  14. Sastry A, Ryu C, Jiang X, Ameri H. Visual outcomes in eyes with neovascular glaucoma and anterior segment neovascularization without glaucoma. Am J Ophthalmol. 2021;236:1-11.
  15. Olmos LC, Sayed MS, Moraczewski AL, et al. Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab. Eye (Lond). 2016;30(3):463-472. doi:10.1038/eye.2015.259
  16. Sun Y, Liang Y, Zhou P, et al. Anti-VEGF treatment is the key strategy for neovascular glaucoma management in the short term. BMC Ophthalmol. 2016;16(1):150. doi:10.1186/s12886-016-0327-9
  17. Grisanti S, Biester S, Peters S, et al; Tuebingen Bevacizumab Study Group. Intracameral bevacizumab for iris rubeosis. Am J Ophthalmol. 2006;142(1):158-160. doi:10.1016/j.ajo.2006.02.045
  18. Ha JY, Lee TH, Sung MS, Park SW. Efficacy and safety of intracameral bevacizumab for treatment of neovascular glaucoma. Korean J. Ophthalmol. 2017;31(6):538-547. doi:10.3341/kjo.2017.0017
  19. Zhou M, Xu X, Zhang X, Sun X. Clinical outcomes of Ahmed glaucoma valve implantation with or without intravitreal bevacizumab pretreatment for neovascular glaucoma: a systematic review and meta-analysis. J Glaucoma. 2016;25(7):551-557. doi:10.1097/IJG.0000000000000241
  20. Noor NA, Mustafa S, Artini W. Glaucoma drainage device implantation with adjunctive intravitreal bevacizumab in neovascular glaucoma: 3-year experience. Clin Ophthalmol. 2017;11:1417-1422. doi:10.2147/OPTH.S137470
  21. American Academy of Ophthalmology Retina/Vitreous Committee. Diabetic Retinopathy Preferred Practice Pattern 2019. Accessed February 1, 2023. https://www.aaojournal.org/article/S0161-6420(19)32092-5/fulltext
  22. American Academy of Ophthalmology Retina/Vitreous Committee Retinal Vein Occlusions Preferred Practice Pattern Guidelines. Accessed December 27, 2022. https://www.aaojournal.org/article/S0161-6420(19)32096-2/fulltext
  23. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. the Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102(10):1434-1444.
  24. Obeid A, Su D, Patel SN, et al. Outcomes of eyes lost to follow-up with proliferative diabetic retinopathy that received panretinal photocoagulation versus intravitreal anti-vascular endothelial growth factor. Ophthalmology. 2019;126(3):407-413. doi:10.1016/j.ophtha.2018.07.027
  25. Choy BNK, Lai JSM, Yeung JCC, Chan JCH. Randomized comparative trial of diode laser transscleral cyclophotocoagulation versus Ahmed glaucoma valve for neovascular glaucoma in Chinese—a pilot study. Clin Ophthalmol. 2018;12:2545-2552. doi:10.2147/OPTH.S188999
  26. El-Saied HMA, Abdelhakim MASE. Various modalities for management of secondary angle closure neovascular glaucoma in diabetic eyes: 1-year comparative study. Int Ophthalmol. 2021;41(4):1179-1190. doi: 10.1007/s10792-020-01673-1
  27. Medert CM, Sun CQ, Vanner E, Parrish RK 2nd, Wellik SR. The influence of etiology on surgical outcomes in neovascular glaucoma. BMC Ophthalmology. 2021;21(1):440. doi:10.1186/s12886-021-02212-x
  28. Takihara Y, Inatani M, Fukushima M, Iwao K, Iwao M, Tanihara H. Trabeculectomy with mitomycin C for neovascular glaucoma: prognostic factors for surgical failure. Am J Ophthalmol. 2009;147(5):912-918. doi: 10.1016/j.ajo.2008.11.015
  29. Nilforushan N., Es’Haghi A., Miraftabi A., Abolfathzadeh N., Banifatemi M. Trabeculectomy in patients with diabetes: subconjunctival mitomycin C with or without intravitreal bevacizumab. Br J Ophthalmol. 2022;106(5):648-654. doi:10.1136/bjophthalmol-2020-317324
  30. Lyssek-Boroń A, Wylęgała A, Dobrowolski D, Kowalczyk E, Polanowska K, Wylęgała E. Evaluation of EX-PRESS glaucoma implant in elderly diabetic patients after 23G vitrectomy. Clin Interv Aging. 2017;12:653-658. doi: 10.2147/CIA.S128618
  31. Christakis PG, Kalenak JW, Tsai JC, et al. The Ahmed vs Baerveldt study: five-year treatment outcomes. Ophthalmology. 2016;123(10):2093-2102. doi:10.1016/j.ophtha.2016.06.035
  32. Shalaby WS, Myers JS, Razeghinejad R, et al. Outcomes of valved and nonvalved tube shunts in neovascular glaucoma. Ophthalmol Glaucoma. 2021;4(2):182-192. doi: 10.1016/j.ogla.2020.09.010
  33. Gnanavelu S, Puthuran GV, Chiranjeevi KP, et al. Intermediate-term outcomes of the Aurolab aqueous drainage implant in neovascular glaucoma. Br J Ophthalmol. 2021 [Published online ahead of print]. doi:10.1136/bjophthalmol-2021-319999
  34. Shalaby WS, Ganjei AY, Wogu B, et al. Outcomes of Ahmed glaucoma valve and transscleral cyclophotocoagulation in neovascular glaucoma. Indian J Ophthalmol. 2022;70(4):1253-1259. doi: 10.4103/ijo.IJO_2107_21
  35. Marra KV, Wagley S, Omar A, et al. Case-matched comparison of vitrectomy, peripheral retinal endolaser, and endocyclophotocoagulation versus standard care in neovascular glaucoma. Retina. 2015;35(6):1072-1083. doi:10.1097/IAE.0000000000000449
  36. Wang J, Qiu M. Prompt primary cyclophotocoagulation with subsequent aqueous shunt as needed for neovascular glaucoma with synechial angle closure. Invest Ophthalmol Vis Sci. 2022;63(7):3714.
  37. Kanter JA, Amin P, Komati R, et al. Gonioscopy-assisted transluminal trabeculotomy in neovascular glaucoma: salvaging the conventional outflow pathway. Am J Ophthalmol Case Rep. 2022;28:101668. doi:10.1016/j.ajoc.2022.101668
  38. Tailor R, Lalias T. A case of refractory neovascular glaucoma treated with a Xen-45 implant. J Glaucoma. 2018;27(10):929-930. doi:10.1097/IJG.0000000000001033
  39. Neupert JR, Brubaker RF, Kearns TP, Sundt TM. Rapid resolution of venous stasis retinopathy after carotid endarterectomy. Am J Ophthalmol. 1976;81(5):600-602. doi:10.1016/0002-9394(76)90123-9
  40. Zhou Y, Coleman S, Boysen J, et al. Survival in patients with neovascular glaucoma following tube shunt implant or cyclodestructive procedure. J Curr Glaucoma Pract. 2022;16(2):74-78. doi:10.5005/jp-journals-10078-1357
  41. Blanc JP, Molteno AC, Fuller JR, Bevin TH, Herbison P. Life expectancy of patients with neovascular glaucoma drained by Molteno implants. Clin Exp Ophthalmol. 2004;32(4):360-363. doi:10.1111/j.1442-9071.2004.00837.x
  42. Shalaby WS, Arbabi A, Myers JS, et al. Sociodemographic and economic factors in outcomes of tube shunts for neovascular glaucoma. J Curr Glaucoma Pract. 2021;15(2):70-77. doi:10.5005/jp-journals-10078-1303

What to Read Next