Deepen Your Understanding of Uveal Effusion Syndrome

Difficult to diagnose, this sight-threatening condition can be treated with surgery.

TIMOTHY L. JACKSON, PhD, FRCOphth

Uveal effusion syndrome (UES) is an extremely rare but potentially serious condition characterized by choroidal fluid collections, often in association with serous retinal detachment. UES is often misdiagnosed. Vision can be severely reduced, and both eyes are ultimately involved in a majority of patients.

This syndrome is reported to occur most typically in middle-aged men, but it has been reported in children as young as 11 years old,¹ and females account for 50% of cases in some series.²

There are two types of UES: idiopathic and nanophthalmic.³ The former occurs in emmetropic eyes or those with low refractive error, whereas the latter occurs in eyes with nanophthalmia and high hyperopia.

PATHOGENESIS OF UVEAL EFFUSION SYNDROME

There are several hypotheses regarding the pathogenesis of UES, but the most compelling theories relate to a primary abnormality of the sclera, with secondary effects on trans-scleral protein permeability and compression of the vortex veins.

In the human eye, the suprachoroidal space is not served by lymphatics. It might therefore be predicted that protein escaping from the choriocapillaris would lead to osmotic fluid retention. However, this potential problem is circumvented in healthy eyes because proteins can diffuse across the sclera.⁴ As a result, the osmotic gradient across the sclera is near to zero. Gass proposed that this normal egress of protein across the sclera is impaired in UES eyes,⁵ resulting in secondary fluid retention in the suprachoroidal space.

There are histological studies to support Gass's hypothesis. Most light and electron microscope studies show amorphous material expanding the space between scleral collagen fibers.The composition of this material is not certain, but it may well be a proteoglycan, with an appearance similar to glycosaminoglycans.⁶ Some authors have suggested that UES is a form of mucopolysaccharidosis, with deposition of dermatan sulphate with some chondroitin sulfate.⁷ Another commonly observed feature is disruption and disorganization of the collagen fibers and thickening of the sclera. Many of these histological features are associated with nanophthalmos, rather than UES per se; however, they are also observed in eyes with idiopathic UES.²

Jackson and coinvestigators tested diffusion of high molecular weight dextrans across sclera obtained during surgery for UES.² They confirmed that some patients had low diffusion coefficients, and this lends further support to Gass's hypothesis.

An alternative theory on the pathogenesis of UES relates to compression of the vortex veins by thickened abnormal sclera. The strongest evidence in support of this hypothesis comes from clinical studies. Yue et al. undertook surgical decompression of the vortex veins in patients with UES, with subsequent resolution of the effusions.⁸

It seems likely then that disturbed osmotic and hydrostatic forces lead to UES. The osmotic forces occur secondary to reduced trans-scleral protein diffusion, with the hydrostatic forces secondary to vortex vein compression. The relative contribution of each mechanism is hard to quantify and may vary between individuals.³

CLINICAL FEATURES

The defining feature of UES is choroidal effusions. These may begin as an isolated peripheral elevation, but they can expand to involve much or all of the peripheral choroid. The degree of elevation varies, but it is often possible to visualize the ora serrata without indentation (Figure 1). There is usually an associated serous retinal detachment, with shifting subretinal fluid. Serous retinal detachment of the fovea is the main cause of vision loss. Chronic subretinal fluid may lead to secondary changes in the retinal pigment epithelium, resulting in a so-called leopard-spot fundus. The disease typically follows a relapsing/remitting course.

Figure 1. Characteristic peripheral choroidal elevation secondary to uveal effusion syndrome. COURTESY OF PAUL SULLIVAN, MD

Patients who have nanophthalmia may have associated findings, such as high hyperopia and a history of angleclosure glaucoma. The exact definition of nanophthalmia is unclear, but an axial length of less than 21 mm is a reasonable, if arbitrary, cut-off.⁹

DIFFERENTIAL DIAGNOSIS

Many conditions can cause uveal effusions, but the term UES is reserved for those patients where the effusions occur as a primary event, rather than secondary to another cause such as hypotony or scleritis. In this sense, UES is a diagnosis of exclusion. In general, it is much easier to diagnose nanophthalmic UES than idiopathic UES.

One of the key features is a lack of inflammation or severe pain, which is helpful in excluding scleritis. A second important observation is a normal or near-normal intraocular pressure, which excludes many diseases in which choroidal effu sions occur secondary to hypotony.

Choroidal melanoma and multifocal, atypical central serous retinopathy can both produce choroidal elevation and should be considered. Retinitis pigmentosa can produce fundus pigmentation that may mimic the leopard-spot fundus of UES, but high-magnification biomicroscopy reveals that pigment is intraretinal in retinitis pigmentosa.

Chronic rhegmatogenous retinal detachment can be one of the more difficult diagnoses to exclude, as it can produce subretinal fluid and secondary RPE changes. To help exclude chronic rhegmatogenous retinal detachment, it is important to carefully examine the retinal periphery, look for vitreous pigment (tobacco dust), and note that choroidal elevation is uncommon in rhegmatogenous retinal detachment, unless mediated by hypotony. Unlike the serous retinal detachment of UES, rhegmatogenous retinal detachment does not produce shifting subretinal fluid.

INVESTIGATIONS

Uveal effusion syndrome is primarily a clinical diagnosis, but it is important to measure refraction and axial length. B-mode ocular ultrasound of the posterior sclera is also helpful. Scleral thickening is well described, especially in nanophthalmic UES, but it can also occur in idiopathic UES. As an approximate guide, a posterior scleral thickness of greater than 2 mm is abnormal, and significantly more than the expected normal value of 1 mm.¹⁰ It should be noted, however, that scleritis may also be associated with scleral thickening and that posterior scleritis can occur in the absence of visible anterior scleral inflammation. Furthermore, recent studies indicate that UES may not always be associated with a measurable increase in scleral thickness, with mean values only 20% greater than controls in one series.¹¹

Surgical scleral specimens should be sent for light microscopy and, ideally, scanning electron microscopy. It is common to stain with conventional agents, such as hematoxylin and eosin. These will be sufficient to show the disordered collagen arrangements, but staining with Alcian blue will better identify acid mucins (including glycosaminglycans) that are deposited between the collagen fibers. Scanning electron microscopy may reveal collections of degenerate collagen fibrils (Figure 2) and it is possible that these may produce some of the amorphous collections seen on light microscopy (Figure 3).

Figure 2. Electron microscopy of scleral tissue obtained during surgery for UES. The arrow (inset) shows degenerated collagen fibers forming what appears to be a small interfibrillary deposit. The main image shows a much larger deposit approximately 3 nm in width (line).

Figure 3. Photomicrograph showing an excised scleral specimen stained with toludine blue. There is loss of the normal lamellar arrangement of collagen fibers, with an amorphous blue deposit expanding the interfibrillary spaces.

It is possible to measure the diffusion coefficient of scleral samples excised during surgery for UES.² This may help confirm reduced scleral permeability in affected individuals, but it is not in itself sufficient to confirm or refute a clinical diagnosis and this research investigation is not designed to replace conventional analysis of scleral histology.

TREATMENT

Small peripheral uveal effusions may be observed, but if the serous subretinal fluid involves or threatens the fovea, then surgery is indicated. For this reason, regular clinic review is appropriate.

There are reports of UES being successfully treated with vortex vein decompression, but the most common surgical treatment is full-thickness scleral decompression, based on a technique described by Gass.⁵ Surgery involves dissection of an approximately 5 mm by 7 mm, 50% partial-thickness, scleral flap (Figures 4A and 4B). These are sited near to the equator, between the rectus muscles, taking care to avoid the vortex veins. Within the scleral bed, a full-thickness opening is created (Figure 4C), with careful dissection down to the level of the choroid. This produces egress of proteinaceous fluid and it is commonly observed that the sclera is more thickened and rigid than in healthy eyes.¹² If the egress of fluid is occurring in a controlled manner, then the external scleral flap is excised and sent for histology. Some surgeons do not excise the overlying scleral flap for primary surgery, but instead suture it loosely back into position.¹³

Figure 4. A partial-thickness incision is made (A) to delineate the extent and depth of the scleral dissection (B), in which a crescent blade creates a scleral flap overlying a thinned scleral bed. Within this area, a full-thickness scleral opening is created (C), with choroid visible. IMAGES APPEAR WITH PERMISSION OF ELSEVIER, PREVIOUSLY PUBLISHED IN: ELAGOUZ M, STANESCU-SEGALL D, JACKSON TL. UVEAL EFFUSION SYNDROME. SURV OPHTHALMOL. 2010;55:134-145.

The sclerostomies are repeated in each quadrant, producing direct fistulae between the suprachoroidal and sub-Tenon's spaces. The conjunctiva is then replaced at the limbus and sutured securely.

The success rate of surgery is variable and depends on the definition of success. One multicenter case series defined anatomic success as full resolution of the effusions within three months of a single operation.² By this definition, 50% of primary operations were successful. Of the remainder, roughly half had a partial success and half failed to show any improvement. Another large series reported resolution of the effusions in 83% of cases by six months, increasing to a 96% final success rate if eyes undergoing reoperation were considered.¹²

Some authors have attempted to reduce the woundhealing response and maintain fistula patency by the application of topical mitomycin C,¹⁴ and this may be especially appropriate for young patients¹⁵ or those undergoing reoperation.¹⁶ Systemic corticosteroids are not thought to be effective.

PROGNOSIS

Following surgery, almost a quarter of eyes develop recurrent disease.¹² Fellow eye involvement occurs in two-thirds of cases, with half eventually requiring surgery.²

The visual prognosis is variable. A large series reported that surgery resulted in a visual improvement of two or more lines in 56% of cases, with 35% of cases demonstrating stable vision and 9% showing reduced acuity.¹²

CONCLUSION

The majority of patients with choroidal effusions will have an identifiable cause, such as hypotony or inflammation. In a minority of cases, no cause can be found, and these patients are thought to have an intrinsic scleral abnormality that results in UES.

It is commonplace that UES is initially misdiagnosed, and this is to be expected given its rarity. However, it is important to maintain an index of suspicion as surgery for UES produces an outcome that is better than the natural history. RP

REFERENCES

1. Casswell AG, Gregor ZJ, Bird AC. The surgical management of uveal effusion syndrome. Eye.1987;1:115-119.
2. Jackson TL, Hussain A, Morley AM et al. Scleral hydraulic conductivity and macromolecular diffusion in patients with uveal effusion syndrome. Invest Ophthalmol Vis Sci. 2008;49:5033-5040.
3. Elagouz M, Stanescu-Segall D, Jackson TL. Uveal effusion syndrome. Surv Ophthalmol. 2010 Mar 4;55(2):134-145.
4. Bill A. Movement of albumin and dextran through the sclera. Arch Ophthalmol. 1965;74:248-252.
5. Gass JDM. Uveal effusion syndrome: A new hypothesis concerning pathogenesis and technique of surgical treatment. Retina. 1983;3:159-163.
6. Ward RC, Gragoudas ES, Pon DM, Albert DM. Abnormal scleral findings in uveal effusion syndrome. Am J Ophthalmol. 1988;106:139-146.
7. Forrester JV, Lee WR, Kerr PR, Dua HS. The uveal effusion syndrome and trans-scleral flow. Eye. 1990;4:354-365.
8. Yue BYJT, Duvall J, Goldberg MF, et al. Nanophthalmic sclera: Morphologic and tissue culture studies. Ophthalmology. 1986;93:534.
9. Brockhurst RJ. Vortex vein decompression for nanophthalmic uveal effusion. Arch Ophthalmol. 1980;98:1987-1990.
10. Olsen TW, Aaberg SY, Geroski DH, Edelhauser HF. Human sclera: thickness and surface area Am J Ophthalmol. 1998;125:237-241.
11. Lam A, Sambursky RP, Maguire JI. Measurement of scleral thickness in uveal effusion syndrome. Am J Ophthalmol. 2005;140:329-331.
12. Johnson MW, Gass JDM. Surgical management of the idiopathic uveal effusion syndrome. Ophthalmology. 1990;97:778-785.
13. Uyama M, Takahashi K, Kozaki J, et al. Uveal effusion syndrome—clinical features, surgical treatment, histologic examination of the sclera, and pathophysiology. Ophthalmology. 2000;107:441-449.
14. Akduman L, Adelberg DA, Del Priore LV. Nanophthalmic uveal effusion managed with scleral windows and topical mitomycin-C. Ophthalmic Surg Lasers. 1997;28:325-327.
15. Suzuki Y, Nishina S, Azuma N. Scleral window surgery and topical mitomycin C for nanophthalmic uveal effusion complicated by renal failure. Graefe's Arch Clin Exp Ophthalmol. 2007;245:755-757.
16. Sabrosa NA, Smith HB, Maclaren RE. Scleral punch method with topical mitomycin C for safe revision of failed deep sclerectomy in nanophthalmic uveal effusion syndrome. Graefes Arch Clin Exp Ophthalmol. 2009;247:999-1001.