Uveal effusion syndrome is a rare, often misdiagnosed disease marked by fluid accumulation in the suprachoroidal space leading to exudative detachments of the choroid, ciliary body and retina. While uveal effusion syndrome is an idiopathic condition, many cases have been associated with nanophthalmos or scleral abnormalities. UES remains a diagnosis of exclusion as the differential diagnosis for uveal effusions and choroidal detachments remains broad, ranging from inflammatory conditions like posterior uveitis and scleritis, hypotony, trauma or iatrogenic etiologies such as intraocular surgery, tumors and medication adverse effects, particularly with sulfa-based drugs and immune checkpoint inhibitors. In this review, we will discuss the characteristics and evolving management of this challenging and incompletely understood disease.
Background and Epidemiology
Cases of uveal effusion without clear cause were first described by Schepens and Brockurst in 1963.1 The term “uveal effusion syndrome” was coined by J. Donald M. Gass, MD, in 1982 and is reserved for idiopathic cases that arise in the absence of ocular inflammation, and was thought to be due to a primary abnormality of the sclera.2 The exact incidence is unknown, though a recent surveillance study in the U.K. estimated an annual incidence of 1.2 per 10 million.3
UES is often categorized into three subgroups:
• Type 1—nanophthalmic and hypermetropic eye with abnormal sclera;
• Type 2—normal globe size but with abnormal sclera; or
• Type 3—normal globe size and normal sclera.4
In this sense, type 3 UES may be considered a “true idiopathic” condition.5
It can be helpful to differentiate between these three types as the management and outcomes may differ. Both nanophthalmic and idiopathic uveal effusion syndrome can occur in either sex, while the idiopathic form is most commonly seen in middle-aged men.5
Nanophthalmos is a subtype of the small-eye phenotype, like microphthalmia, and is most often bilateral. The incidence isn’t fully known but studies have suggested an incidence of small eye phenotypes around 12 cases per 100,000.6 Unlike microphthalmos, which may have ocular malformations and shortened anterior or posterior segments, nanophthalmic eyes are structurally normal with shortening of both anterior and posterior segments with secondary thickening of choroid and sclera.7
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| Figure 1. Ultra-widefield fundus photo demonstrating choroidal effusions. Photo: Stephen Kim, MD. |
Pathophysiology and Histology
Nanophthalmos arises from arrested development of the eye during embryogenesis and has been described in both autosomal dominant, recessive and sporadic cases.7 Mutations in five genes have been found to be linked to nanophthalmos, with more loci being discovered.
Nanophthalmic eyes have thickened and histologically abnormal sclera with less orderly lamellar arrangement of collagen bundles. The sclera has irregular organization with angling and interweaving of collagen fibrils with abnormal deposition of glycosaminoglycan-like material between collagen bundles,8,9 though this finding isn’t always consistent.10 Based on these findings, a variety of hypotheses have been proposed to explain the pathogenesis of UES.
The abnormal and thickened sclera seen in type 1 and type 2 UES patients was previously proposed to cause an obstruction of venous outflow via the vortex veins, resulting in congestion of the choriocapillaris and subsequent effusion.11 While normal human eyes contain three to eight vortex veins, an absence of vortex veins in some quadrants of the eye has also been observed in UES patients.2 However, after later studies showed favorable response to sclerectomy without vortex vein decompression, vortex vein congestion was thought more likely a secondary change from scleral swelling induced by high protein concentration.
Osmotic forces may also cause fluid retention in the choroidal space and has been the most commonly proposed mechanism for uveal effusion in eyes with abnormal sclera.12 This decrease in scleral permeability has been attributed to increased deposition of glycosaminoglycan-like material in the sclera,9 which is known to reduce diffusion through the sclera.4,8 Reduced scleral protein permeability prevents diffusion of albumin and thus causes fluid retention. Reduced scleral permeability to water has also been proposed to contribute to fluid accumulation and uveal effusion, but studies have confirmed that the sclera has large capacity to remove excess water, which is unlikely to be the only contributing factor.13 Thus, macromolecular diffusion is likely the main driving force and symptom onset occurs later in life due to decreased scleral permeability with age.14
In type 3 UES eyes, histological abnormalities of the sclera are uncommon, while autopsy results show degeneration of the retinal pigment epithelium,4 suggesting that type 3 UES may be mediated by other factors and is a different clinical entity from type 1 and 2.15 Given findings of abnormal choroidal thickness in reported cases, some suggest that type 3 UES cases are related to pachychoroid spectrum disease, characterized by attenuation of the choriocapillaris overlying dilated choroidal veins with progressive RPE dysfunction and neovascularization, leading to fluid accumulation stemming from choriocapillaris hyperpermeability.16
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| Figure 2. B-scan ultrasound demonstrating exudative choroidal detachment as well as exudative retinal detachment at the bottom of the image. Photo: Stephen Kim, MD. |
Clinical Presentation and Diagnosis
UES may be insidious in onset, with choroidal elevation that initially begins in the periphery with vision being minimally affected.10,17 As the disease progresses, accumulation of choroidal fluid outpaces the RPE pump action leading to subretinal fluid accumulation18 and resultant serous retinal detachment that can shift with changes in eye or head position. Once exudative retinal detachment occurs, symptoms progress to include flashes, blurred vision and vision loss. More than two-thirds of cases are bilateral in presentation.
As UES is a diagnosis of exclusion, a careful exam to rule out other potential causes of choroidal effusion is paramount, including scleritis, uveitis, choroidal tumors including melanoma, lymphoma and metastases, hypotony or postoperative inflammation from prior surgery, hypertensive chorioretinopathy and toxic effects from systemic medications such as sulfonamides, immune checkpoint inhibitors and tetracyclines.
The posterior exam often demonstrates choroidal elevation (Figure 1), deep retinal or subretinal exudates, and RPE changes resembling “leopard spots.”4 The anterior segment demonstrates minimal to no anterior chamber cell, unlike cases of choroidal effusion secondary to ocular inflammation. Dilated episcleral blood vessels and blood in Schlemm’s canal secondary to elevated venous pressure may also be seen, but intraocular pressure is within normal limits. Abnormal intraocular pressure should prompt the physician to consider other causes of choroidal effusion.
Nanophthalmic eyes present with high hypermetropic refractive error (average +16 D), shallow anterior chamber, and high lens/eye volume ratio. Diagnostic standards are debated but often considered as an axial length less than 21 mm in addition to other clinical features discussed above.7 Nanopthalmos may also result in angle closure glaucoma and challenges with cataract surgery, which may be gleaned from the patient’s medical history.
Imaging and Testing
A variety of imaging modalities has allowed for characterization of UES, including ultrasound and ultrasound biomicroscopy, indocyanine green angiography, fluorescein angiography and optical coherence tomography.
Ultrasound is the preferred method to evaluate axial length and scleral thickness given its high resolution and accuracy.19 US can be used to identify retinal and choroidal detachments (Figure 2), determine axial length and demonstrate scleral thickening. It can also be useful in excluding inflammatory or neoplastic etiologies of uveal effusion. UBM, with its higher resolution, can detect earlier and more subtle anterior choroidal effusions. It can be used intraoperatively to identify areas of maximal scleral thickening to target sclerostomy placement.20
ICG-A allows for assessment of choroidal vasculature and can demonstrate diffuse granular hyperfluorescence in the early phase with dilated choroidal vessels.21 Choroidal fluid accumulation is seen as persistent hyperfluorescence in the late phase, suggestive of increased choroidal vessel permeability. In contrast, FA in UES doesn’t demonstrate leakage and can be useful in excluding posterior uveitic conditions and central serous chorioretinopathy. Leopard spots may appear as areas of hypofluorescence within hyperfluorescence.
OCT with enhanced-depth imaging (EDI) may be helpful in identifying increased choroidal thickness. Reports have also described hyporeflective areas that may correspond to engorged choroidal veins or expansion of the suprachoroidal space.22 Leopard spots seen on exam may correspond to focal thickening of the RPE on OCT. Studies have also identified increased choroidal thickness with attenuation of the choriocapillaris in type 3 UES cases suggestive of pachychoroid features.15,23
Nonsurgical Management
Multiple medical treatments have been tried in the non-surgical management of UES with limited success. These include steroids, non-steroidal anti-inflammatory drugs, prostaglandin analogs, carbonic anhydrase inhibitors and anti-VEGF injections.
While steroid therapy had previously been considered ineffective in the treatment of UES,17 recent reports have demonstrated a subset of eyes may respond well to oral, periocular and topical steroids and more poorly to surgical treatment.5 Of note, all subjects included in the largest case series using steroid therapy by Wills Eye’s Carol Shields, MD, and her colleagues were type 3 UES patients. Ninety-five percent of eyes in this series had resolution of effusions, and only 5 percent required subsequent surgery. The therapeutic mechanism is unclear but may be related to generalized anti-inflammatory action or membrane stabilization that ameliorates fluid transudation. Another benefit of steroid use may be to rule out other inflammatory causes of uveal effusion.
Topical NSAIDs have been used in postoperative cystoid macular edema to decrease vascular permeability and decrease fluid accumulation. Reports have demonstrated resolution of exudative retinal detachment in patients with UES following long term oral indomethacin24 as well as topical NSAIDs,25 though in the first report, the authors acknowledge that this improvement may have been spontaneous or attributable to concomitant laser photocoagulation as well. Several reports have also treated patients with prostaglandin analogs in conjunction with other medical therapies and have demonstrated resolution of exudative detachments.26,27 Prostaglandins have been observed to increase metalloproteinase levels and reduce scleral collagen levels, resulting in enhanced permeability to macromolecules, which may improve fluid outflow.28
Carbonic anhydrase inhibitors may also improve uveal effusions via their ability to stimulate pumping of fluid in the RPE29 and have been reportedly used in conjunction with topical prostaglandin analogs or surgery in UES.26,27,30 There’s been one reported case of fluid resolution following anti-VEGF monotherapy in UES.31 The therapeutic mechanism is unknown, though may relate to VEGF expression and choroidal vessel permeability. These medications have not been evaluated in any large clinical studies.
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| Figure 3. Creation of a 50- to 75-percent thickness lamellar scleral flap. Photo: Avni Finn, MD. |
Surgical Management
Surgical treatments are aimed at facilitating fluid outflow from the choroid through the sclera. Several surgical methods have been developed to treat UES, including unroofing of the vortex veins, direct fluid drainage and reducing scleral resistance to allow fluid outflow.
Vortex vein decompression via unroofing of veins via sclerectomy has previously been described,11 but isn’t commonly performed due to the high risk of vortex vein amputation and bleeding.32 Sclerectomy without vortex vein decompression is the preferred approach for most surgeons and was first described in 1983 by Dr. Gass.12 This iteration of scleral window is considered safer than vortex vein decompression. Several variations of the procedure have been described centered around the principle of reducing overall choroidal fluid resistance and facilitating outflow, including:
• Quadrantic partial thickness sclerotomy. In the original method, four rectangular 5x7 mm one-half to two-thirds thickness sclerectomies are performed in each quadrant, taking care to avoid the areas anterior to the exit sites of the vortex veins. These sclerectomies are centered 1 to 2 mm anterior to the equator with the long axis oriented circumferentially.33–35
• Extensive circumferential partial-thickness sclerectomy. A 90-percent depth scleral window is excised over 3.25 quadrants, excluding three-quarters of the superotemporal quadrant to avoid damaging the superior oblique muscle. A scleral knife is used to incise the boundaries of the window deep enough to see the bluish hue of the choroid.36
• Full-thickness sclerotomy. A full thickness scleral incision around 6x3 mm with the anterior margin of incision 6 to 8 mm from the corneoscleral limbus is created. The choroid is exposed by dissection and the scleral flap is loosely sutured with 8-0 vicryl at two corners for loose approximation to facilitate drainage.37
Several techniques also include the use of a scleral punch, which allows for more precise posterior extension of sclerostomy windows and may be more protective when held against the choroid due to its rounded shape.32,33,38
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| Figure 4. An oval scleral window is created following corneal blade incision and widening of the incision using a Kelly punch. Photo: Avni Finn, MD. |
We outline the steps used in our technique below:
1. Perform a 360-degree conjunctival peritomy and isolate each of the four rectus muscles with a muscle hook and 2-0 silk tie.
2. Each oblique quadrant should be carefully cleared of Tenon capsule and wet-field diathermy applied to maintain hemostasis.
3. A 5 x 5 mm square is marked in the oblique quadrant with the anterior margin 3 mm posterior to the rectus muscle insertions.
4. A No. 57 scleral blade or similar is used to create a 5 x 5 mm lamellar scleral flap about 50 to 75 percent thickness, starting at the anterior margin and retracting the flap posteriorly (Figure 3).
5. A corneal blade is used to make a 2.5-mm incision through the scleral bed down to choroid.
6. A Kelly trabeculectomy punch is used to widen the incision to an oval scleral window (Figure 4).
7. The scleral flap is excised with scissors.
8. This procedure is repeated in two to four quadrants and then conjunctiva is reapposed at the limbus.
Partial thickness sclerotomies have also been combined with pars plana vitrectomy for internal drainage of subretinal fluid to decrease the risk of choroidal hemorrhage with an external approach,39 though is generally of lower concern nowadays with careful planning.32 While secondary drainage may be performed for very bullous exudative retinal detachments, this is often not necessary.
Adjuvant therapies such as mitomycin C can be applied to the scleral bed or sclerectomy site followed by rinsing with balanced salt solution to prevent postoperative scarring.32,40
Another more recent surgical approach has been described using an Ex-PRESS shunt:41 an oblique sclerotomy is performed with a 25-gauge needle 13 mm posterior to the limbus, followed by oblique insertion of the Ex-PRESS shunt into the sclerotomy site into the suprachoroidal space to facilitate fluid drainage. Choroidal drainage may also be achieved with a guarded diathermy probe40 with a 2-mm penetrating tip inserted into the suprachoroidal space at the equator in the area of the most prominent detachment approximately 12 mm from the limbus. This has been proposed to minimize the size of the wound, though an AC paracentesis is needed to place a 20-gauge infusion line.
Outcomes, Prognosis And Conclusions
The majority of reported cases demonstrate reattachment of the retina and resolution of choroidal effusions after treatment; however, the extent of improvement can depend on type of UES as well as the presence of photoreceptor and RPE damage and pigmentary changes. Changes affecting the fovea contribute to poorer visual outcomes.
Differential outcomes based on UES type were first proposed by
Osaka, Japan’s Masanobu Uyama, MD, who found that subscleral sclerectomy was effective in resolving subretinal fluid in type 1 and 2 UES eyes but not type 3 eyes.4 Other studies have found that RPE granular changes were more common in type 1 UES. Type 2 UES cases were found to have better vision and lower risk of final vision loss compared to type 1 cases, suggesting that they respond more favorably to treatment regardless of medical or surgical management.42
Partially owing to its nature as a diagnosis of exclusion and its low incidence, uveal effusion syndrome continues to present diagnostic and therapeutic challenges. Classification based on its relationship with nanophthalmos and scleropathy may aid in treatment selection and may uncover pathophysiological insights. Though future large-scale, randomized trials are unlikely given its rarity, patients with UES may benefit from multicenter collaborations moving forward to determine the best treatment approaches for this potentially disabling condition.
Dr. Zhang is a PGY-2 at the Vanderbilt Eye Institute, Vanderbilt University Medical Center, in Nashville. Dr. Finn is an Associate Professor at Vanderbilt University Medical Center and director of the surgical retina fellowship at Vanderbilt. The authors have no financial interest in any of the material presented.
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