Acquired ectropion uveae (AEU) is a condition in which the iris pigment epithelium prolapses or protrudes onto the anterior surface of the iris. It is also called acquired iris ectropion. It commonly occurs near the pupil but can also occur in other parts of the iris.
Ectropion uveae can be congenital or acquired. Congenital ectropion uveae (CEU) results from delayed development of neural crest cells and is generally non-progressive. In contrast, AEU is secondary to various underlying diseases such as ischemia, inflammation, or tumors, and follows a progressive course 1).
AEU is encountered much more frequently than the congenital form. The prevalence varies greatly depending on the underlying disease.
Congenital ectropion uveae is caused by delayed development of neural crest cells, with the iris stroma and sphincter muscle remaining normal, and is usually non-progressive. Acquired ectropion uveae is caused by traction of the iris stroma and sphincter muscle anteriorly due to fibrovascular membrane or corneal endothelial cell proliferation, accompanied by peripheral anterior synechiae and progression 1). For details, see the section on Pathophysiology.
Mild cases may have no subjective symptoms. When accompanied by elevated intraocular pressure, the following symptoms appear.
Findings depend on the underlying disease. Conditions that caused neovascularization, such as retinal vein occlusion, proliferative diabetic retinopathy, chronic retinal detachment, and arterial occlusion, are observed.
The causes of AEU are diverse.
Ischemic
Diabetic retinopathy: NVI associated with retinal capillary nonperfusion
Central retinal vein occlusion (CRVO): High frequency in ischemic type
Ocular ischemic syndrome: Due to carotid occlusive disease
Proliferative chronic retinal detachment: Long-term retinal ischemia
Non-ischemic
ICE syndrome: Abnormal proliferation of corneal endothelial cells
NF-1: Corneal endothelial proliferation + neurofibroma infiltration1)
Trauma: Fibrous membrane formation after blunt ocular trauma
Inflammation: Severe iritis/uveitis
Tumor: Iris melanoma, metastatic tumor
Uveitis is a disease that frequently complicates glaucoma, and about 20% of uveitis patients have glaucoma 3). Aqueous outflow obstruction due to iridocyclitis is classified into acute type (trabecular meshwork accumulation of inflammatory cells, trabecular edema, angle closure due to ciliary body swelling) and chronic type (scar formation, angle coverage by membranous tissue) 2)3).
Angle rubeosis (neovascularization) due to chronic inflammation is also seen in Behçet’s disease and juvenile chronic iridocyclitis, and can cause AEU.
When diabetic retinopathy progresses, retinal ischemia leads to iris neovascularization (NVI), which causes AEU. However, it does not occur in all diabetic patients and can be prevented by controlling blood glucose and blood pressure and regular fundus examinations.
Diagnosis of AEU is mainly performed by slit-lamp microscopy and gonioscopy.
Diseases that should be differentiated from AEU are listed below.
| Disease | Key points for differentiation | Features |
|---|---|---|
| Congenital uveal ectropion | Non-progressive, no peripheral anterior synechiae | Normal stroma and sphincter muscle |
| Axenfeld-Rieger syndrome | Bilateral, associated with systemic abnormalities | Posterior embryotoxon is characteristic |
| ICE syndrome | Unilateral, more common in women | Abnormal proliferation of corneal endothelial cells |
In congenital ectropion uveae, the iris stroma and sphincter muscle are preserved, whereas in AEU these structures are also inverted, which is an important distinguishing feature. Axenfeld-Rieger syndrome is bilateral, characterized by a posterior embryotoxon where Schwalbe’s line is located anterior to the limbus, and may be associated with sensorineural hearing loss and cardiac or craniofacial abnormalities.
Treatment of AEU is based on addressing the underlying disease. The treatment system for NVI/NVG, the most frequent cause, is described below.
The EGS Guidelines (5th edition) recommend treatment of NVG divided into treatment of the underlying disease/retinal ischemia and intraocular pressure management 2).
| Treatment Stage | Content |
|---|---|
| Treatment of underlying disease | Intravitreal anti-VEGF injection, retinal photocoagulation/cryocoagulation |
| Intraocular pressure management | Antihypertensives (topical/systemic), filtering surgery (with antimetabolites), tube shunt, cyclodestructive procedures |
In AEU associated with uveitis, the goal is simultaneous treatment of inflammation and intraocular pressure 2). Anti-inflammatory therapy with steroids (topical and systemic) and intraocular pressure management with antihypertensive agents are performed concurrently. Steroids themselves can cause elevated intraocular pressure, so careful monitoring is necessary 3).
Antihypertensive eye drops are used in the order of beta-blockers, prostaglandin analogs, and carbonic anhydrase inhibitors. If intraocular pressure elevation is severe, oral carbonic anhydrase inhibitors and intravenous D-mannitol are added.
Surgery is considered when intraocular pressure cannot be adequately controlled with drug therapy (antihypertensive eye drops, anti-VEGF therapy). In NVG, tube shunt surgery is commonly chosen. Even in cases with extensive angle closure such as NF-1, there are reports of good intraocular pressure control with tube shunt surgery 1).
AEU occurs in various underlying diseases but shares a common pathophysiological mechanism.
The central mechanism is the formation of a contractile fibrovascular membrane on the anterior surface of the iris. This membrane pulls the posterior pigment epithelium around the pupillary margin, the iris sphincter muscle, and the iris stroma forward, causing tractional curling. At the same time, it covers and occludes the trabecular meshwork, leading to increased intraocular pressure.
In NVG, retinal ischemia leads to the production of angiogenic factors such as VEGF, resulting in abnormal new blood vessels on the anterior iris (iris rubeosis) 2). Initially, it presents as open-angle glaucoma with elevated intraocular pressure, but as the fibrovascular membrane contracts, it progresses to synechial angle closure 2).
Aqueous outflow obstruction due to uveitis is classified into acute and chronic types 3).
When posterior synechiae become circumferential, iris bombe due to pupillary block occurs, leading to further elevation of intraocular pressure. Steroid treatment itself also contributes to increased intraocular pressure in some patients 2).
In NF-1, proliferation of corneal endothelial cells similar to ICE syndrome is considered the cause of uveal ectropion 1). Edward et al.’s histological study confirmed corneal endothelial cell overgrowth in all 5 eyes with NF-1, and gene expression analysis showed loss of neurofibromin (NF1 gene product) and increased MAPK (mitogen-activated protein kinase) expression 1). Corneal endothelial cells cross Schwalbe’s line, invade the trabecular meshwork, and cause Descemetization of the angle, iris atrophy, pupillary deviation, and uveal ectropion.
Both share a common mechanism: abnormal proliferation of corneal endothelial cells invades the angle and causes uveal ectropion 1). However, in NF-1, endothelial cell proliferation is due to loss of neurofibromin, which differs from ICE syndrome at the molecular level.
Esfandiari et al. (2022) reported a case of progressive AEU and secondary angle-closure glaucoma associated with NF-11). An 11-year-old Hispanic boy with mild pupillary irregularity and uveal ectropion at age 3 showed AEU extending from 8 to 4 o’clock, with complete closure of the superior angle. IOP was 28 mmHg at age 6 and reached 35 mmHg at age 9 under maximum medical therapy. A Baerveldt glaucoma implant (BGI 101-350) was placed in the inferonasal quadrant, achieving good IOP control of 11-18 mmHg over 29 months postoperatively.
In the same report, postoperative specular microscopy revealed decreased endothelial density, polymegathism, and pleomorphism in the superior cornea of the affected eye, supporting the hypothesis of corneal endothelial cell proliferation in NF-11).
Histopathological examination of 5 eyes with NF-1 and unilateral glaucoma confirmed uveal ectropion and corneal endothelial overgrowth in all cases1). Gene expression analysis in one case showed loss of neurofibromin and increased MAPK expression in corneal endothelial cells. It has been hypothesized that AEU results from corneal endothelial cell proliferation and angle invasion.
The progressive nature of AEU in NF-1 has been observed from childhood over long periods, suggesting the importance of regular anterior segment evaluation and intraocular pressure monitoring1).
