Neovascular, uveitic and steroid-response glaucoma

Neovascular Glaucoma (NVG)

Neovascular glaucoma is an aggressive, vision-threatening secondary glaucoma caused by anterior segment ischemia-induced neovascularization, culminating in fibrovascular closure of the iridocorneal filtration angle.

Etiological Mechanisms

NVG is triggered by severe, widespread posterior segment retinal hypoxia, which stimulates the overproduction and intraocular secretion of Vascular Endothelial Growth Factor (VEGF) and basic fibroblast growth factor (bFGF). These diffusible angiogenic cytokines travel into the posterior chamber and diffuse forward through the pupil into the anterior chamber, inciting pathological neovascularization across the iris stroma and trabecular meshwork. Primary ischemic causes include:

1. Proliferative Diabetic Retinopathy (PDR): A major cause of retinal ischaemia driving NVG; the proportion of cases varies by referral population.
2. Ischaemic Central Retinal Vein Occlusion (CRVO): A major cause of anterior-segment neovascularisation. The conventional CVOS definition used at least $10$ disc areas of capillary non-perfusion on seven-field angiography; this is not ten disc diameters or a directly interchangeable ultra-widefield threshold. The label “100-day glaucoma” is historical: neovascularisation can arise earlier or later, so monitor the iris and angle according to risk and course.
3. Ocular Ischemic Syndrome (OIS): Accounts for 10% to 15% of cases; secondary to severe internal carotid artery stenosis or ophthalmic artery occlusion. Because ciliary hypoperfusion impairs aqueous production, IOP may initially remain normal or low despite angle neovascularization, skyrocketing once anterior chamber perfusion is re-established.

The Four Clinical Stages of NVG

• Stage 1: Pre-Glaucoma (Rubeosis Iridis): Earliest visible sign: delicate, tiny tufts of microvascular capillaries appear at the pupillary border (often at 12:00 or 6:00 o'clock) and on the trabecular meshwork; the anterior chamber angle remains gonioscopically open; IOP is normal.
• Stage 2: Open-Angle NVG: Neovascular vessels cross the scleral spur and arborize profusely across the trabecular meshwork, accompanied by an invisible, translucent fibrovascular membrane composed of myofibroblasts and collagen. This membrane physically covers and plugs the trabecular spaces, causing severe IOP elevation while the angle remains gonioscopically open.
• Stage 3: Angle-Closure NVG: Myofibroblasts within the fibrovascular membrane contract, pulling the peripheral iris forward over the trabecular meshwork in a progressive, zipper-like synechial closure ($360^\circ$ PAS). The pupil exhibits marked ectropion uveae (eversion of the posterior pigmented iris epithelium onto the anterior iris surface). IOP escalates dramatically (often 50–70 mmHg), accompanied by severe corneal microcystic edema, intense ciliary flush, and agonizing pain.
• Stage 4: Absolute Glaucoma: Terminal, irreversible stage characterized by a completely blind eye (no light perception), intractable pain, bullous keratopathy, and dense anterior segment fibrovascular scarring.

Multi-Modal Treatment Protocol

1. Immediate Anti-VEGF Therapy: Intravitreal administration of an anti-VEGF agent (aflibercept, ranibizumab, or bevacizumab) induces rapid, dramatic regression of iris and angle neovascularization within 24 to 48 hours. This temporarily quenches active bleeding and clears the anterior chamber, serving as an indispensable pharmacological bridge to definitive laser or surgery.
2. Retinal treatment: PRP reduces the angiogenic drive in appropriate ischaemic disease. Anti-VEGF is an adjunct, not a guarantee of permanent regression. If media opacity prevents laser, specialist options may include later laser, vitrectomy/endolaser or other approaches selected by anatomy and visual potential.

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Uveitic Glaucoma & Corticosteroid-Induced Glaucoma

Elevated intraocular pressure in patients with intraocular inflammation involves complex mixed open-angle and closed-angle mechanisms.

Mechanisms of Uveitic Glaucoma

• Open-Angle Uveitic Glaucoma:
  • Acute Trabeculitis: Direct inflammatory swelling and endothelial dysfunction of the trabecular meshwork lamellae (characteristic of herpes simplex, varicella zoster, cytomegalovirus anterior uveitis, and Posner-Schlossman syndrome [glaucomatocyclitic crisis]).
  • Mechanical Outflow Blockage: Accumulation of inflammatory cells (polymorphonuclear leukocytes and macrophages), fibrin, and proteinaceous exudates within the intertrabecular spaces.
  • Aqueous Hyperviscosity: Severe breakdown of the blood-aqueous barrier elevates aqueous protein concentration, impeding outflow.
• Closed-Angle Uveitic Glaucoma:
  • Pupillary Block via Seclusio Pupillae: Fibrovascular adhesions bind the entire pupillary margin $360^\circ$ to the anterior lens capsule (annular posterior synechiae), blocking aqueous transit from the posterior to the anterior chamber. The resulting trapped posterior chamber pressure balloons the peripheral iris forward (iris bombé), causing acute or subacute angle closure.
  • Non-Pupillary Block Angle Closure: Forward rotation of the ciliary body resulting from supraciliary effusion and choroidal detachment (e.g., in Vogt-Koyanagi-Harada syndrome); or progressive "creeping" peripheral anterior synechiae (PAS) caused by chronic organization of inflammatory exudates in the angle.

Medical Therapy & Absolute Contraindications in Uveitis

• Anti-Inflammatory Control: Aggressive topical corticosteroids (Prednisolone acetate 1% or Dexamethasone 0.1%) are mandatory to suppress the primary inflammatory stimulus.
• Aqueous Suppressants: Topical beta-blockers, alpha-2 agonists, and carbonic anhydrase inhibitors.
• Mydriatic-Cycloplegics: Topical Atropine 1% or Cyclopentolate 1% are essential to paralyze the ciliary muscle (relieving pain and ciliary spasm), break early posterior synechiae, and prevent seclusio pupillae.
• ABSOLUTE CONTRAINDICATIONS:
  • Pilocarpine and Cholinergic Miotics: Strictly contraindicated. Pilocarpine breaks down the blood-aqueous barrier, exacerbates intraocular inflammation, causes severe ciliary spasm, and accelerates the formation of broad, irreversible posterior and anterior synechiae.
  • Prostaglandin Analogues: Must be used with extreme caution in active uveitis due to their theoretical propensity to exacerbate anterior segment inflammation, trigger cystoid macular edema (CME), and reactivate latent herpes simplex keratitis.

Corticosteroid-Induced Glaucoma (Steroid Response)

Corticosteroids administered via topical, periocular, intraocular, inhaled, or systemic routes can trigger severe secondary open-angle ocular hypertension.

• Pathophysiological Mechanism: Glucocorticoid receptor activation in trabecular meshwork cells causes transcriptional upregulation and accumulation of the glycoprotein myocilin (MYOC), promotes the deposition of glycosaminoglycans and extracellular matrix in the juxtacanalicular meshwork, induces rearrangement of the trabecular cytoskeleton into cross-linked actin networks (CLANs), and suppresses endothelial phagocytic activity, drastically increasing conventional outflow resistance.
• The Armaly-Becker Classification of Genetic Susceptibility:
  • High Responders: Approximately 5% of the general population develop an IOP increase $>15$ mmHg or an absolute IOP exceeding 31 mmHg after 2 to 4 weeks of topical steroid therapy.
  • Intermediate Responders: Approximately 30% of individuals exhibit an IOP elevation of 6 to 15 mmHg.
  • Non-Responders: Approximately 65% experience an IOP increase of $<6$ mmHg.
  • Risk: Established glaucoma, family history and some paediatric/systemic factors increase susceptibility, but a “greater than 90% high responder” rule is unsupported. Monitor pressure during treatment.
• Steroid Formulation Risk: Intravitreal triamcinolone acetonide and intraocular implants (dexamethasone [Ozurdex], fluocinolone [Iluvien]) pose the greatest hypertensive risk, followed by potent topical steroids (difluprednate, prednisolone acetate 1%, dexamethasone 0.1%). "Soft" site-specific steroids (e.g., loteprednol etabonate, fluorometholone) carry a markedly lower propensity for IOP elevation due to rapid enzymatic deactivation into inactive carboxylic acid metabolites.

Interpreting Secondary Mechanisms

LOXL1 variants are associated with PEX but are not diagnostic and do not justify routine folate treatment. PDS may become less active with age, yet pressure and damage still need monitoring; iridotomy can alter iris configuration without established prevention of glaucoma in every PDS patient. For NVG, treat retinal ischaemia and its systemic cause, use anti-VEGF as an adjunct and select laser and surgery by the eye. Conventional CRVO nonperfusion criteria use disc areas and a specified imaging field. Steroid responders vary; not all POAG patients or relatives are high responders. FML is a corticosteroid with pressure risk, not a metabolically inactive ester. In uveitic glaucoma, distinguish active inflammation, steroid response and infection. Avoid withdrawing needed anti-inflammatory treatment indiscriminately.