Insights into neovascular glaucoma: Pathogenesis and detection of diabetic retinopathy

Neovascular glaucoma (NVG) represents a severe form of secondary glaucoma accompanied by substantial complications and typically results in a poor visual prognosis. NVG is characterised by the emergence of abnormal new blood vessels over the iris and within the iridocorneal angle, which prevents the drainage of aqueous humor and increases intraocular pressure (IOP). Retinal ischemia is the primary cause of NVG, which is commonly associated with conditions such as central retinal vein occlusion and diabetic retinopathy.

Table 1. Classification and stages of diabetic retinopathy⁸

The prevalence rate of NVG has increased globally with the growing population of individuals with diabetes.

Management of NVG focuses on decreasing retinal ischemia through panretinal photocoagulation and the injection of anti-vascular endothelial growth factor (VEGF) agents into the retina to detect retinal ischemia at an early stage.

Pathophysiology of diabetic retinopathy

Type 1 diabetes, also known as juvenile-onset diabetes, is caused by the autoimmune destruction of cells in the pancreas. Type 2 diabetes, also known as adult-onset diabetes, is caused by insulin resistance.¹ India is the emerging diabetes capital of the world; approximately 31.7 million individuals in India had diabetes in 2000; the number is estimated to rise to 79.4 million by 2030.^2,3 

Poor glycemic control can lead to many ocular adverse effects such as cataracts, ocular surface disorders, glaucoma, retinal ischemia and diabetic retinopathy. Diabetic retinopathy is the most common vision-threatening vascular disease of the retina and the most common cause of reversible blindness.⁴ Diabetic retinopathy manifests in two primary forms: nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Altered glucose metabolic pathways and uncontrolled diabetes lead to vascular endothelial damage, microaneurysm, and intraretinal hemorrhage, all of which are classic signs of NPDR. At late stages, retinal ischemia due to vasoconstriction and capillary occlusion causes neovascularisation in the retina, the hallmark of PDR.⁵

The global prevalence of diabetic retinopathy in individuals aged 20 to 79 years with diabetes is 34.6% for any type of diabetic retinopathy and 7.0% for PDR.⁶ The prevalence of diabetic retinopathy is 77.3% in individuals with type 1 diabetes and 25.1% in individuals with type 2 diabetes; of these, approximately 25% to 30% are expected to develop diabetic macular oedema.⁷ With early diagnosis and treatment, a good visual prognosis can be achieved in many patients (Table 1⁸).

Chronic diabetic mellitus leads to the activation of alternate pathways for glucose metabolism, which leads to the activation of cytokines, other growth factors such as VEGF, and vascular endothelial dysfunction. This in turn leads to increased vascular permeability and microvascular occlusion. Microvascular occlusion in the retina causes retinal ischemia, which leads to intraretinal microvascular abnormalities and neovascularisation.⁹

Diabetic retinopathy also affects the Müller cells of the retina. Müller cells help regulate the blood-retinal barrier and retinal blood flow, maintaining the integrity of the retina and supplying nutrients to the retina. The inactivation of the Kir4.1 channel causes continuous potassium intake inside Müller cells, which leads to swelling and dysfunction.¹⁰The fluid accumulation inside Müller cells leads to diabetic macular oedema.¹¹

The clinical signs of diabetic retinopathy are as follows:

• Microaneurysms: The earliest detectable sign of diabetic retinopathy. The diameter of a microaneurysm is 15 to 60 µm.
• Hemorrhages: Weakening of capillary walls leads to dot- and blot-shaped hemorrhages in the inner nuclear and outer plexiform layers of the retina.
• Hard exudates: These are lipoprotein substances that form a ring around the leaking microaneurysm and are located in outer plexiform layers.
• Cotton wool spots: These represent the focal infarcts of retinal arterioles and are located in the retinal nerve fiber layer.
• Neovascularisation: New blood formation in the disc (NVD) that is 1 disc diameter away from the optic disc (NVE) and in the iris (NVI).
• Venous changes: These include looping and dilation and arterial changes such as peripheral narrowing and silver wiring.

Patients with NPDR are mostly asymptomatic. If their condition progresses to PDR, patients may complain of floaters, gradual vision loss and scotomas due to vitreous hemorrhage.¹²

Aetiology of NVG

Table 2. Clinical stages of NVG^16,17,19,26

Many ocular and systemic disorders cause NVG. Among the primary causes linked to the condition, the most prevalent associations are retinal venous obstructive disease (36.1%), diabetic retinopathy (32.2%) and carotid artery obstructive disease (12.9%).¹³

NVG can be triggered by various ocular and systemic conditions, predisposing individuals to this severe form of glaucoma. Ischemic conditions, central retinal vein occlusion, diabetic retinopathy, sickle cell retinopathy, ocular ischemic syndrome and central retinal artery occlusion are significant causes. Inflammatory causes such as uveitis, trauma, retinal vasculitis and endophthalmitis also contribute to NVG. Systemic disorders such as systemic lupus erythematosus, neurofibromatosis type 1, internal carotid artery occlusion and giant cell arteritis also have been associated with this condition. Additionally, surgical procedures such as cataract surgery, vitrectomy and retinal reattachment may precipitate NVG. These diverse ocular and systemic factors underscore the complexity and multifaceted nature of NVG onset and progression.^14-18

Pathophysiology of NVG

NVG arises from the growth of new blood vessels in the retina due to inadequate blood supply, resulting in increased IOP that becomes challenging to manage.¹⁹ Retinal ischemia triggers an imbalance in factors that either promote or inhibit the formation of new blood vessels within the retina, known as angiogenesis. This imbalance disrupts substances that encourage vessel growth (eg, VEGF, hepatocyte growth factor, and insulinlike growth factor) and those that discourage it (eg, TGF-β, thrombospondins and somatostatin).²⁰ VEGF, which is crucial in blood vessel permeability and new blood vessel formation, is produced by various retinal cells, including pericytes, retinal pigment epithelium, nonpigmented ciliary epithelium, Müller cells and ganglion cells. It significantly mediates active neovascularisation in patients with ischemic retinal conditions such as diabetic retinopathy and retinal vein occlusion.²¹ In NVG, VEGF originating from the posterior part of the eye enters the anterior chamber, prompting new blood vessel growth. This process initiates in the iris’ small blood vessels and progresses to the anterior chamber angle. VEGF induces the adherence of white blood cells to blood vessel linings, causing a breakdown in the barrier between the blood and the retina. Prolonged exposure to VEGF165 can lead to ectropion uveae and NVG.²²

Fibroblast growth factors prompt fibroblast multiplication, resulting in the formation of a fibrovascular membrane over the iris and anterior chamber angle. Basic fibroblast growth factor potentially contributes to anterior segment disorders such as NVG and aids in the healing of limbal tissues post glaucoma filtration surgery.²³ This thickened membrane filled with multiplied myofibroblasts obstructs aqueous outflow through the trabecular meshwork. This obstruction initiates a type of glaucoma where the angle initially remains open (open-angle stage of NVG). Subsequently, the membrane contracts, causing the angle to close (angle-closure stage). This elevation in IOP leads to glaucomatous optic neuropathy, potentially resulting in irreversible blindness (Table 2).

Signs and symptoms of NVG

NVG commonly presents as a consistently red and painful eye, often with a noticeable loss of vision.

In the beginning, especially in younger individuals, it may not cause symptoms if the increase in IOP happens slowly and the corneal endothelial cells are healthy.

The signs and symptoms of NVG include, as follows:

1. Visible NVI and NVA
2. Elevated IOP (often exceeding 50 mmHg) with or without corneal oedema
3. Gonioscopically, NVA with partial or complete closure of the angle
4. Fundoscopic features of ophthalmic disorders, such as diabetic retinopathy, and retinal vessels occlusion

Slit-lamp biomicroscopy and gonioscopy are crucial instruments in screening for neovascularisation of the iris. Extremely small NVI might not be easily detected during a slit-lamp examination or gonioscopy. In these early stages, fluorescein angiography (FA) is more useful for detecting rubeosis iridis. Iris FA reveals leakage from these newly formed vessels. Anterior segment indocyanine green angiography offers the benefit of presenting a more detailed view of the vasculature.

The current standard for detecting regions of capillary nonperfusion and NVE or NVD is fundus FA. Dye-based angiography is effective, however, it is contraindicated for individuals with allergies to the dyes. The newest method for evaluating retinal ischemia and neovascularisation is optical coherence tomography angiography.

Patients with nonischemic central retinal vein occlusion usually do not get NVI or NVG unless they have associated diabetic retinopathy or ocular ischemic syndrome. In individuals with diabetes experiencing inadequate glycemic control and advanced untreated posterior segment ischemia, the advancement of NVG may manifest around 12 months following the onset of neovascularisation of the iris.²⁴

NVG poses a significant threat to vision and constitutes an urgent ophthalmic condition. Swift identification and a comprehensive, multidisciplinary approach are imperative to safeguard vision in affected eyes. Development of NVG in patients with preexisting glaucoma following central retinal vein occlusion is influenced by the status of retinal nonperfusion and uncontrolled IOP.²⁵

Effectively managing NVG hinges on promptly addressing the underlying ischemic cause²⁶ and regulating IOP. With the escalating global incidence of diabetes, an anticipated outcome is increased occurrence of NVG associated with diabetic retinopathy.

Therefore, early detection and proper management of proliferative diabetic retinopathy can play a pivotal role in curbing the prevalence of this vision-threatening condition.

References

1. Diagnosis and classification of diabetes mellitus. American Diabetes Association. Accessed November 27, 2023. https://diabetesjournals.org/care/article/32/Supplement_1/S62/25047/Diagnosis-and-Classification-of-Diabetes-Mellitus

2. Guidelines for the Comprehensive Management of DR in India. Aravind Eye Care System; 2008. https[CB1] ://www.iapb.org/wp-content/uploads/2020/12/Guidelines-for-the-Comprehensive-Management-of-DR-in-India.pdf

3. Prevention of Blindness From Diabetes Mellitus. World Health Organization; 2006[CB2] . https://books.google.com/books?hl=en&lr=&id=zfFoDTrVY_EC&oi=fnd&pg=PA6&dq=Prevention+of+Blindness+from+Diabetic+Retinopathy.+Report+of+a+WHO+Consultation,+Geneva+2005&ots=sOdNML0_Jt&sig=LAAJ4SuZUa-bScOZh2lCV2mtMr8

4. Shukla UV, Tripathy K. Diabetic Retinopathy. In: StatPearls [Internet]. StatPearls Publishing; 2023. http[CB3] ://www.ncbi.nlm.nih.gov/books/NBK560805/

5. Lin KY, Hsih W, Lin YB, Wen CY, Chang TJ. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. J Diabetes Investig. 2021;12(8):1322-1325. doi:10.1111/jdi.13480

6. Yau JW, Rogers SL, Kawasaki R, et al; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564. doi:10.2337/dc11-1909

7. Wilkinson-Berka JL, Miller AG. Update on the treatment of diabetic retinopathy. ScientificWorldJournal. 2008;8:98-120. doi:10.1100/tsw.2008.25

8. Wilkinson CP, Ferris FL 3rd, Klein RE, et al; Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003;110(9):1677-1682. doi:10.1016/S0161-6420(03)00475-5

9. Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137-148. doi:10.1016/j.phrs.2015.05.013

10. Curtis TM, Hamilton R, Yong PH, et al. Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products. Diabetologia. 2011;54(3):690-698. doi:10.1007/s00125-010-1971-x

11. Pannicke T, Iandiev I, Wurm A, et al. Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes. 2006;55(3):633-639. doi:10.2337/diabetes.55.03.06.db05-1349

12. Fung TH, Patel B, Wilmot EG, Amoaku WM. Diabetic retinopathy for the non-ophthalmologist. Clin Med (Lond). 2022;22(2):112-116. doi:10.7861/clinmed.2021-0792

13. Brown GC, Magargal LE, Schachat A, Shah H. Neovascular glaucoma. Etiologic considerations. Ophthalmology. 1984;91(4):315-320. doi:10.1016/s0161-6420(84)34293-2

14. Havens SJ, Gulati V. Neovascular glaucoma. Dev Ophthalmol. 2016;55:196-204. doi:10.1159/000431196

15. Ajayi I, Omotoye O, Ajite K, Abah E. Presentation, etiology and treatment outcome of neovascular glaucoma in Ekiti state, South Western Nigeria. Afr Health Sci. 2021;21(3):1266-1272. doi:10.4314/ahs.v21i3.37

16. Rodrigues GB, Abe RY, Zangalli C, et al. Neovascular glaucoma: a review. Int J Retina Vitr. 2016;2:26. doi:10.1186/s40942-016-0051-x

17. Călugăru D, Călugăru M. Etiology, pathogenesis, and diagnosis of neovascular glaucoma. Int J Ophthalmol. 2022;15(6):1005-1010. doi:10.18240/ijo.2022.06.20

18. Barac IR, Pop MD, Gheorghe AI, Taban C. Neovascular secondary glaucoma, etiology and pathogenesis. Rom J Ophthalmol. 2015;59(1):24-28. [CB4]

19. Kumar S, Kumari S, Sinha AK. Neovascular glaucoma: an update on etiopathogenesis, diagnostics and management. Open J Ophthalmol. 2022;12(3):242-258. doi:10.4236/ojoph.2022.123023

20. Simó R, Carrasco E, García-Ramírez M, Hernández C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev. 2006;2(1):71-98. doi:10.2174/157339906775473671

21. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-1487. doi:10.1056/NEJM199412013312203

22. Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114(8):964-970. doi:10.1001/archopht.1996.01100140172010

23. Tripathi RC, Borisuth NS, Tripathi BJ. Detection, quantification, and significance of basic fibroblast growth factor in the aqueous humor of man, cat, dog and pig. Exp Eye Res. 1992;54(3):447-454. doi:10.1016/0014-4835(92)90056-x

24. Fernández-Vigo J, Castro J, Macarro A. Diabetic iris neovascularization. Natural history and treatment. Acta Ophthalmol Scand. 1997;75(1):89-93. doi:10.1111/j.1600-0420.1997.tb00258.x

25. Chen HF, Chen MC, Lai CC, et al. Neovascular glaucoma after central retinal vein occlusion in pre-existing glaucoma. BMC Ophthalmol. 2014;14(1):119. doi:10.1186/1471-2415-14-119

26. Dumbrăveanu L, Cușnir V, Bobescu D. A review of neovascular glaucoma. Etiopathogenesis and treatment. Rom J Ophthalmol. 2021;65(4):315-329. doi:10.22336/rjo.2021.66