Residency · Residency · Ophthalmology
Secondary Glaucomas: Pseudoexfoliation, Pigment Dispersion, and Neovascular
Pseudoexfoliation Glaucoma (PXG)
Pathophysiology
Pseudoexfoliation syndrome (PXF) is a systemic disorder of extracellular matrix metabolism associated with the lysyl oxidase-like 1 (LOXL1) gene. Abnormal fibrillar material is produced and deposits throughout the eye -- on the lens capsule, zonules, ciliary body, iris, trabecular meshwork, and conjunctiva. IOP elevation results from obstruction of the trabecular meshwork by a combination of PXF material and liberated pigment. A hallmark feature of PXF is progressive zonular weakness, which increases the risk of lens subluxation and creates significant challenges during cataract surgery. Pseudoexfoliation is the most common identifiable cause of secondary open-angle glaucoma worldwide.
Clinical Features
The classic slit lamp finding is a bull's-eye pattern on the anterior lens capsule consisting of a central disc of PXF material, a clear intermediate zone (scraped clean by pupillary movement), and a peripheral granular zone. Peripupillary atrophy of the iris pigment epithelium produces transillumination defects at the pupillary margin. On gonioscopy, the Sampaolesi line -- pigment deposited anterior to Schwalbe line -- is the most specific finding. PXF is often asymmetric or initially unilateral, though the contralateral eye develops the condition in approximately 40% of patients by 15 years. Compared with POAG, pseudoexfoliation glaucoma produces higher IOP spikes, wider diurnal fluctuation, and a more aggressive clinical course with faster visual field progression.
Management Considerations
PXF responds well to SLT, though lower energy settings should be used due to the heavy angle pigmentation. Medical therapy follows the same approach as POAG but often requires earlier surgical intervention because of the more aggressive disease course. Trabeculectomy has a higher failure rate in PXF due to increased fibrosis. When these patients require cataract surgery, the surgeon must anticipate weak zonules and prepare accordingly with capsular tension rings, capsular hooks, and a gentle hydrodissection technique. MIGS should be considered at the time of cataract surgery.
<image>Slit-lamp photograph showing classic pseudoexfoliation material on the anterior lens capsule with the characteristic bull's-eye pattern of central disc, clear intermediate zone, and peripheral granular ring</image>
Pigmentary Glaucoma (PG)
Pathophysiology
Pigment dispersion syndrome (PDS) results from mechanical rubbing of the posterior iris pigment epithelium against the anterior zonular packets. This contact is promoted by a concave iris configuration caused by reverse pupillary block, in which a relative pressure differential keeps the iris bowed posteriorly toward the lens and zonules. The liberated pigment granules circulate in the aqueous and deposit throughout the trabecular meshwork, progressively obstructing outflow. The classic diagnostic triad consists of a Krukenberg spindle on the corneal endothelium, mid-peripheral iris transillumination defects, and dense trabecular meshwork pigmentation. Conversion from pigment dispersion syndrome to pigmentary glaucoma occurs in approximately 10% of patients by five years and 15% by 15 years.
Demographics and Clinical Features
Pigmentary glaucoma typically affects young myopic males in their twenties to forties, and the condition is bilateral and symmetric. Exercise and pupillary dilation can precipitate pigment showers and acute IOP spikes. The Krukenberg spindle is a characteristic vertical deposit of pigment on the corneal endothelium, formed by convection currents in the anterior chamber. Gonioscopy reveals dense, homogeneous trabecular meshwork pigmentation through 360 degrees, with the greatest concentration posteriorly. Mid-peripheral radial iris transillumination defects produce a distinctive spoke-like pattern. Pigment may also deposit on the posterior lens capsule in a pattern known as the Zentmayer or Scheie stripe.
Natural History
An important feature of pigmentary glaucoma is that IOP may actually decrease with age as the iris becomes more rigid and less concave, reducing the mechanical contact with the zonules and diminishing pigment liberation. This creates the phenomenon of "burned-out" pigmentary glaucoma, in which IOP normalizes but the glaucomatous optic neuropathy that occurred during the active phase of pigment dispersion persists. It is important to distinguish PDS from pseudoexfoliation: PDS patients are younger, myopic, and have different iris and trabecular meshwork findings.
Management
All standard classes of glaucoma medications are effective in pigmentary glaucoma. SLT produces a good response, but very low energy settings (0.3 to 0.5 mJ) must be used due to the heavy pigmentation, as higher energy risks triggering a significant IOP spike. Laser peripheral iridotomy has been proposed as a treatment to theoretically eliminate the reverse pupillary block and reduce iris concavity; while there is some evidence that it reduces pigment liberation, the IOP benefit remains unclear, and LPI is not universally recommended for PDS. Surgical intervention with trabeculectomy, tube shunt, or MIGS is pursued for cases that cannot be controlled medically.
<image>Gonioscopy view of pigmentary glaucoma showing dense, homogeneous 360-degree trabecular meshwork pigmentation compared to normal angle pigmentation</image>
Neovascular Glaucoma (NVG)
Pathophysiology
Neovascular glaucoma is driven by retinal ischemia, which stimulates production of vascular endothelial growth factor (VEGF). VEGF causes neovascularization of the iris (rubeosis iridis) and the anterior chamber angle. A fibrovascular membrane grows over the trabecular meshwork, initially causing a secondary open-angle glaucoma by obstructing outflow. As this membrane matures and contracts, it pulls the iris into contact with the meshwork, forming peripheral anterior synechiae and producing synechial angle closure. The final common pathway is refractory IOP elevation accompanied by severe pain and vision loss.
Stages
| Stage | Name | Findings | IOP | Angle |
|---|---|---|---|---|
| 1 | Rubeosis iridis | Fine neovascular tufts at pupillary margin | Normal or mildly elevated | Open |
| 2 | Open-angle NVG | Fibrovascular membrane over TM | Elevated | Open (membrane obstructs outflow) |
| 3 | Synechial angle-closure NVG | Membrane contraction, PAS formation | Severely elevated | Closed (synechial) |
Etiology
The two most common causes, each accounting for approximately one-third of cases, are proliferative diabetic retinopathy and ischemic central retinal vein occlusion. NVG developing after ischemic CRVO is classically called "100-day glaucoma" because it typically appears approximately three months after the vascular event. Other causes include ocular ischemic syndrome from carotid stenosis, central retinal artery occlusion, chronic retinal detachment, intraocular tumors (choroidal melanoma, retinoblastoma), and radiation retinopathy.
Management: Treat the Underlying Ischemia
Treatment of NVG requires addressing both the IOP and the underlying retinal ischemia. Intravitreal anti-VEGF injection (bevacizumab or ranibizumab) is the first-line acute treatment. It produces rapid regression of neovascularization within days, but its effect is temporary; it buys time and enables subsequent surgical intervention by reducing intraoperative bleeding. Panretinal photocoagulation is the definitive treatment for the retinal ischemia driving VEGF production and must be performed as soon as media clarity allows. PRP reduces the ischemic stimulus and prevents recurrence.
IOP management employs topical aqueous suppressants including beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors. Prostaglandin analogs may have limited efficacy in the setting of intraocular inflammation. Atropine provides comfort and helps reduce inflammation, and topical corticosteroids control the associated anterior segment inflammation. When medical therapy fails to control IOP, surgical options include a glaucoma drainage device (the Ahmed valve is often preferred because it provides immediate IOP reduction), trabeculectomy with MMC (though it has a higher failure rate in NVG), and cyclophotocoagulation for refractory cases or eyes with poor visual potential.
<image>Clinical photograph of neovascular glaucoma showing rubeosis iridis with fine neovascular tufts at the pupillary margin and over the iris surface, with associated ectropion uveae</image>
Steroid-Induced Glaucoma
Pathophysiology
Corticosteroids cause IOP elevation by increasing extracellular matrix deposition within the trabecular meshwork and reducing the phagocytic activity of trabecular meshwork endothelial cells. These changes increase resistance to aqueous outflow and produce morphological alterations in the meshwork that are similar to those seen in POAG. Genetic susceptibility plays an important role: approximately 5% of the general population are steroid responders who develop a clinically significant IOP rise with corticosteroid use.
Risk Factors for Steroid Response
Risk factors for a steroid-induced IOP rise include pre-existing POAG or a family history of glaucoma, high myopia, diabetes mellitus, and young age (children are more susceptible than adults). The route of steroid administration matters: the risk is highest with topical ocular steroids, followed by periocular injection, intravitreal implants, and lowest with inhaled or systemic steroids.
Clinical Features
IOP elevation typically develops within two to six weeks of starting topical steroid use. After intravitreal steroid implants such as dexamethasone or fluocinolone, the IOP rise may not manifest for weeks to months. The angle remains open on gonioscopy. If the IOP elevation goes unrecognized and persists, it can cause optic nerve damage that is indistinguishable from POAG.
Management
The first step is to discontinue or reduce the steroid if clinically feasible. Switching to a lower-potency steroid or a "soft steroid" that is rapidly deactivated (such as fluorometholone or loteprednol) can maintain anti-inflammatory efficacy while reducing the IOP effect. IOP-lowering medications are used as needed. Surgical intervention is rarely required if the steroid can be stopped. For intravitreal implants such as fluocinolone acetonide, surgical explantation may be necessary if IOP remains uncontrollable.
Clinical Pearls
The fellow eye should always be examined in pseudoexfoliation, as subclinical PXF material may be present before it becomes obvious. Dilation should be performed carefully in pigment dispersion syndrome, as it can trigger pigment liberation and an acute IOP spike; IOP should be checked 30 to 60 minutes after dilation. In neovascular glaucoma, anti-VEGF buys time but PRP is the definitive treatment -- anti-VEGF must never be relied upon alone. The term "100-day glaucoma" should prompt vigilant screening of ischemic CRVO patients for iris and angle neovascularization at every visit for the first six months. Undilated gonioscopy should be performed to detect early angle neovascularization before rubeosis becomes clinically visible on slit lamp examination. In any patient with unexplained IOP elevation, all routes of steroid exposure (topical, periocular, intravitreal, inhaled, nasal, dermatologic, and systemic) should be investigated. While steroid-induced IOP elevation is usually reversible after discontinuation, any optic nerve damage that has occurred is permanent.
References
- Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45(4):265-315.
- Campbell DG. Pigmentary dispersion and glaucoma: a new theory. Arch Ophthalmol. 1979;97(9):1667-1672.
- Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007;26(5):470-485.
- SooHoo JR, Seibold LK, Kahook MY. The link between intravitreal antivascular endothelial growth factor injections and glaucoma. Curr Opin Ophthalmol. 2014;25(2):127-133.
- American Academy of Ophthalmology. Basic and Clinical Science Course, Section 10: Glaucoma.
