Central serous chorioretinopathy

Central serous chorioretinopathy (CSCR) is a relatively benign retinal disease characterized by a circular area of serous detachment of the posterior retina usually in young and middle-aged healthy persons. While CSCR is mostly self-limiting, there are clinical variants of this disease that have atypical presentations and may reduce the vision tremendously. Most of these atypical CSCR or variant CSCR are associated with excessive accumulation of fluid beneath the sensory retina or RPE. These atypical manifestations can be separated into two major categories: acute bullous retinal detachment and chronic CSCR.

Bullous retinal detachment

Some patients with acute bullous retinal detachment (bullous RD) may have the following medical history: long-term corticosteroid taken for systemic diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or renal or cardiac transplantation; regular taking of herb drugs (some may contain steroid-like ingredients or have steroid added to the drug); or be under steroid treatment for presumed Harada disease. Other affected patients do not have a specific history of steroid intake.

Bullous RD usually has an acute onset with simultaneous or sequential involvement of the two eyes. Fundus examinations reveal multiple areas of serous RD in the posterior retina with lower bullous RD. There may be multiple retinal pigment epithelial detachment (RPED) and one or more grayish or yellow patches of subretinal exudates mimicking focal chorioretinitis (Fig. 96.1). In some cases, retinal folds may form by the contraction of fibrinous patches or fibrotic membrane or bands on the outer surface of the detached retina. Small scattered yellowish granular subretinal deposits may have a tendency to settle along the retinal vessels (Fig. 96.2). The vitreous is usually clear, but may have 1–2 plus cells. The disc is not hyperemic.

Fig. 96.1 Subretinal fibrin-like deposition mimicking chorioretinitis in a case of acute bullous detachment.

Fig. 96.2 Exudates along retinal vessels in a case of bullous retinal detachment.

Fluorescein angiography shows multiple hyperfluorescent spots or patches with late enlargement; intense fluorescein leakage from the edge of the RPE detachment may be seen and correlates with the focal grayish-white or yellow patches seen in the color fundus. Retinal vessels show no leakage.

Indocyanine green angiography shows ill-defined hyperfluorescent area, which may become more intense in the late phase, suggesting choroidal permeability alteration.

Optical coherence tomography may show retinal pigment epithelial detachment with or without sensory detachment adjacent to or overlying it; the subretinal fluid may be clear or slightly turbid with multiple granular deposits above RPE and on the outer surface of the detached retina, sometimes forming incomplete septa within the subretinal space (Fig. 96.3); subretinal fibrinous mount with surrounding sensory detachment may be seen.²

Fig. 96.3 Optical coherence tomography image in a case of acute bullous detachment showing subretinal incomplete vertical septa.

Complications of bullous RD include: large RPE tear; broad retinal folding; submacular plaques or fibrotic bands; peripheral paravascular exudates; peripheral retinal telangiectasia, occlusion, or even fibrovascular proliferation.^2,3 Peripheral vascular changes may be secondary to long-standing sensory detachment.

In treating bullous RD, systemic steroids should be discontinued; patients should keep the head elevated during sleep to prevent fluid shifting to the macular area; FA-guided laser to the leaking points may decrease the subretinal fluid. Once the fluid level recedes, FA should be repeated to identify persistent leaking points and other leaking sites previously hidden by the detached retina. Multiple sessions of laser treatment are usually needed for complete fluid reabsorption. If subretinal fluid (SRF) persists after the above measurements, external drainage of SRF may be undertaken.⁴ Care should be taken to make sure that the surgical drainage site is posterior enough to access the subretinal space, which is in the dependent area. Alternatively, pars plana vitrectomy with perfluorocarbon liquid injection and simultaneous external drainage through anterior sclerotomy may be performed, followed by focal laser to the exposed leaking sites and air–fluid exchange. The effect of vitrectomy with internal drainage and silicone oil tamponade is controversial. Recently, bevacizumab injection has been shown to rapidly reduce active fluid leakage into the subretinal space as well as decrease the deposition of fibrinous or proteinaceous substances.⁵ Photodynamic therapy (PDT) with reduced fluence may also reduce choroidal hyperpermeability and facilitate subretinal fluid reabsorption with RPE tear being the major complication.⁶ Prognosis of bullous RD is variable and is affected by the duration of macular detachment, the presence of submacular fibrosis, the development of submacular RPE tears, and occurrence of fibrovascular proliferation under the macula or in the periphery.

Differential diagnoses of bullous RD include diseases associated with large areas of retinal detachment. Harada disease is the most common disease confused with bullous detachment. Both have bilateral exudative detachment with multiple leaking sites and normal retinal vasculatures. Hyperemic discs, vitreous cells, pin-point leaking spots, subretinal RPE folding radiating from the disc, choroidal thickening, and the unique OCT pictures showing outer retinal septated spaces containing optically heterogeneous substances favor the diagnosis of Harada disease. Misdiagnosis may lead to the use of steroid and aggravation of bullous RD. The condition may sometimes be mistaken for rhegmatogenous RD and wrongly operated upon. Other causes of unilateral or bilateral exudative RD should be ruled out, such as: hypertensive retinopathy, collagen vascular diseases, leukemia, toxemia, choroidal metastasis, uveal effusion, posterior scleritis, multifocal choroiditis (tuberculosis, syphilis, lyme), chorioretinitis, sarcoidosis, and lymphoma. Polypoidal choroidal vasculopathy (PCV) may mimic CSCR, and severe PCV without subretinal hemorrhage may have similar manifestations to bullous detachment.

Chronic CSCR

Because of the characteristic angiographic picture of multiple areas of RPE disturbance with late staining or mild leakage, the condition is also named RPE decompensation, diffuse retinal pigment epitheliopathy. This entity should not be confused with typical CSCR with persistent subretinal fluid. It is more commonly seen in middle-aged patients of Latino or Asian extraction. Personal and medical history may elicit chronic steroid usage.

Typical clinical manifestation is the multiple poorly defined areas of chronic persistent or recurrent retinal detachment in the posterior pole. Subtle or obvious areas of RPE changes are noted in the posterior pole and in the juxtapapillary regions; gravity tract forming vertical band or reverse funnel-shaped depigmentation, along with pigment migration or bone-spicule pattern of pigmentary changes within the tract and in the inferior part of the retina are usually found (Fig. 96.4); shallow or bullous detachment in the inferior retina is a frequent finding.

Fig. 96.4 Retinal pigment epithelium changes and gravity tract in a case of chronic central serous chorioretinopathy.

FA may show patchy hyperfluorescent areas or mottled hyperfluorescent areas corresponding to, and more obvious than, those areas of pigmentary changes found ophthalmoscopically. These areas may show late dye leakage or staining of different degrees. Round enlarging spots or jet spots commonly seen in typical CSCR may be noticed within or in between the hyperfluorescent areas. Band- or reverse funnel-shaped gravity tract of window defect changes are usually present. Peripheral vessels within the area of retinal detachment may show leakage, vascular occlusion or neovascularization.

OCT examination may reveal subretinal fluid under the macula or several areas of retinal detachment separated by attached retina; some may have localized submacular fluid similar to acute CSCR. There may be cystic changes in the overlying retina, suggesting chronic condition.

Photocoagulation remains the main treatment method. Conventional laser or the more recently developed MicroPulse laser to leaking points and areas of RPE changes with late fluorescein staining and leakage may stop the leakage.⁷ PDT with reduced fluence has been advocated to treat leaking points and areas with late oozing shown in FA with good effect. Intravitreal bevacizumab has also been shown to have therapeutic effect.⁸ However, the prognosis is guarded because of multiple recurrence and permanent macular RPE disturbance.

Uveal effusion syndrome

Patients with idiopathic uveal effusion syndrome (IUES) are usually middle-aged men with normal ocular size, presenting with unilateral or bilateral serous choroidal, ciliary, and retinal detachment. There may be central vision decrease or distortion secondary to macular serous detachment or upper visual field defect from lower part serous retinal detachment. External eye examination may reveal episcleral vessel dilatation; the anterior chamber is usually free of cells; intraocular pressure (IOP) is normal; there may be blood in the Schlemm’s canal; vitreous cells are common findings. Initial disease severity ranges from macular serous detachment with insignificant ciliary and choroidal detachment to obvious ciliochoroidal detachment and bullous retinal detachment. The protein concentration of the subretinal fluid is 2.5–3 times that of the normal plasma. The fellow eye may be affected within a few weeks or a few months after lesions developed in the first eye. The disease may have a protracted course, with wax and wane of the subretinal fluid, eventually leaving areas of mixed RPE atrophy and pigment clumps, arranging in a leopard-spot pattern. Some patients may develop a yellowish plaque of exudation in the macular area or severe chorioretinal degeneration causing visual field loss.

FA may not show specific leaking points in the early stage of the disease. As disease progresses, FA may highlight the leopard-spot pattern, which was not obvious in fundus examination; choroidal perfusion may be slow, and focal leaking areas in multiple places may be seen.

Ultrasonography or ultrasound biomicroscopy (UBM) can clearly demonstrate ciliochoroidal detachment, and usually form an annular pattern in the periphery, even before detectable fundus changes. There is no thickened sclera and subtenon fluid adjacent to the optic nerve to form the classic T-sign of the posterior ocular coat typical of posterior scleritis.

Histopathological examination shows accumulation of protein-rich extracellular materials in the suprachoroidal and subretinal spaces. Choroidal vessels are dilated without inflammatory cell infiltration. Subarachnoid space around the optic disc is enlarged. The sclera shows deranged fibers with deposition of glycosaminoglycans within.⁹ Cell culture of the scleral cells reveals intracellular deposition of a glycogen-like substance.¹⁰

The pathogenesis is unclear, possibly related to congenital anomaly of the sclera and vortex veins hypoplasia. Excessive glycosaminoglycans accumulate within the sclera combined with defective vortex veins resulting in decreased drainage of extravasated protein through scleral emissary channels of the transscleral outflow pathway; fluid drainage is also compromised from the decreased function of uveoscleral outflow pathways, leading to excessive protein and fluid accumulation in the suprachoroidal space. Later on, the protein and fluid enter the subretinal space when the extracellular protein concentration becomes equal to that within the vessels. Protein in the suprachoroidal space around the disc may gain access to the subarachnoid space and subdural space resulting in an increase in the CSF protein content even without pleocytosis in 50% of the patients.¹¹ Forrester and associates believe that IUES is a kind of ocular mucopolysaccharidosis, with the initial defect resting in the proteodermatan synthesis and/or degradation of the fibroblast of the sclera.¹² Other evidence also shows that abnormal mucopolysaccharides of the sclera play an important role in the pathogenesis of IUES. IOP is usually within normal limits because the IOP rising tendency from uveoscleral outflow obstruction is neutralized by decreased aqueous production from the ciliochoroidal detachment.

Best treatment methods have been debated. Vortex vein decompression with scleral resection was initially advocated to treat uveal effusion associated with nanophthalmos. Gass believed that the treatment effect had less to do with vortex vein decompression than with scleral resection to facilitate protein and fluid drainage through the sclera.¹³ He suggested partial-thickness sclerectomies or full-thickness sclerectomies. After treatment, exudation may gradually disappear within a few months. However, chorioretinal degeneration may continue to develop from chronic mild recurrence of exudation or abnormal metabolism of mucopolysaccharide.

Other diseases capable of causing uveal effusion include: nanophthalmos, dural arteriovenous fistula, scleritis, Harada disease, diffuse tumors of the uveal tract, prolonged hypotony, etc..

Leopard-spot pigmentation may appear in systemic large cell lymphoma, leukemia, bilateral uveal melanocytic proliferation, and organ transplant chorioretinopathy.

Coats disease

This is a non-familial developmental retinal vasculopathy. The disease is more common in males, is usually unilaterally affected and may occur in infants. Symptoms often develop in children or young adults; one-third had symptoms onset over 30 years of age. All vessels, arteries and veins alike, would be affected, showing telangiectasis combined with a large amount of hard exudates; hemorrhagic retinopathy is occasionally seen. On the other hand, a minor form of the disease mainly involving juxtafoveolar areas may occur; decreased vision will not occur until adulthood when hard exudates and edema develop in the macula. The prognosis is directly influenced by the size of the involved area. Occasionally, other vascular anomalies may appear in the lesion eye or the fellow eye, such as macular macrovessels or arterial tortuosity (Fig. 96.5). The condition may be occasionally associated with other abnormalities such as progressive facial hemiatrophy, facial scapulohumeral muscular dystrophy and deafness, or Alport syndrome.¹⁴ It may rarely accompany systemic vascular anomalies.

Fig. 96.5 Retinal arterial tortuosity in a case of Coats disease. The fundus picture shows dense macular exudates with submacular fibrosis, retinochoroidal anastomosis, indicated by arrowheads.

Fundus examinations reveal changes of various severities. The mild form presents with focal telangiectasia and microaneurysms usually at the temporal side of the macula, with or without mild hard exudates. The moderate form ranges from cystoid macular edema with significant hard exudates surrounding the area containing telangiectatic vessels or microaneurysms, to the more extensive vascular abnormalities with massive exudates which may gain access to the subretinal space. The severe form shows wide and scattered vascular lesions, with hard exudates accumulating around the disc and in the posterior pole, causing exudative detachment. The macula may be detached with massive intra- and subretinal exudates, which later may transform to organized subretinal disciform mass or atrophic scar. These changes are likely to be found in infants and children, who visit the ophthalmic clinic because of manifest strabismus secondary to unilateral poor vision or abnormal red reflex from massive exudates in the posterior pole. The accumulation of exudates in the macula may be due to gravity-induced migration of subretinal exudates toward the central area during sleep. The deposition of lipid-rich substance along with macrophage evolves into fibrous tissue. Retinal or choroidal vessels may grow into the lesion to form a disciform scar. The most advanced form presents with bullous detachment with the retina coming in direct contact with the crystalline lens; cholesterol crystals accumulate in the subretinal space.¹⁵ There may be dilated abnormal vessels, hard exudates or hemorrhage on the surface or in the retina. However, the abnormal tortuous vessels do not dip into the subretinal space, a sign typical of exophytic retinoblastoma.

FA clearly demonstrates aneurysmal dilatation of retinal vessels, including arteries, veins and capillaries; capillary nonperfusion is also obvious. Normal-appearing vessels do not show dye leakage. Cystoid macular edema may be noted.

The clinical course varies. The macula may not be involved initially until later in life if the lesions are peripherally located, especially in the lower part of the retina. Some severe cases develop increasing capillary nonperfusion leading to neovascularization with subsequent vitreous hemorrhage, vitreous membrane formation, exudative and traction retinal detachment, neovascular glaucoma, resulting in no light perception; others may develop intraocular inflammation or even acute orbital cellulitis secondary to stimulation from toxic products. Some patients develop peripheral elevated, organized exudative nodule or mass, yellowish in color and mixed with hemorrhagic patches, similar to granuloma, exophytic retinal capillary hemangioma or melanoma. Occasionally, spontaneous resolution may occur.

Histopathological studies show irregular dilatation of affected retinal arteries, veins and capillaries; PAS-positive exudates may be seen in the outer retinal layer; lipid-laden macrophages are seen in the outer retina and the subretinal space. In the severe form of the disease in infants, severe vascular endothelial proliferation and hemorrhagic infarction may be observed. Genetic testing has revealed a somatic mutation on the NDP gene on chromosome Xp11.2.

Treatment usually involves laser or cryo aiming at the lesions to decrease exudates and preserve vision (Fig. 96.6). For severe exudative detachment, external drainage should be performed first, followed by cryo to the abnormal vessels. Scleral buckling may facilitate retina reattachment, enhance cryo effect and promote regression of abnormal vessels. However, new lesions may develop in nearby or remote areas. Follow-up is crucial to detect and treat new lesions. Sector panretinal photocoagulation (PRP) may be used for a nonperfusion area. For severe cases, vitrectomy to release vitreous traction with external subretinal fluid drainage, laser or cryo may be considered. Recently, repeated intravitreal injection of bevacizumab has been reported to reduce subretinal fluid, facilitating subsequent laser or cryo.¹⁶

Fig. 96.6 (A) Coats disease. (B) Resolution of hard exudates 1 year after peripheral cryotherapy to the abnormal vascular structures.

Differential diagnoses include all possible causes of white pupil in infants. Localized telangiectasis associated with arterial and venous aneurysms and exudates may be similar to cavernous hemangioma of the retina, acquired retinal macroaneurysm, old branch retinal vein occlusion, bilateral multiple retinal arterial aneurysms with neuroretinitis.

Accelerated hypertension and pregnancy-induced hypertension

Prolonged or severe hypertension may damage the retinal vascular system, choroidal circulation, and disc circulation. The difference in vascular structures, autoregulation and tissue resistance determines the different susceptibility of these three systems to increased blood pressure. Hypertension-induced choroidopathy is the main category that causes exudative retinal detachment.

While chronic moderate hypertension is rarely associated with choroidopathy, choroidal ischemia is more frequently associated with accelerated hypertension. Unlike retinal circulation, choroidal vessels do not possess autoregulation; the blood flow during fluctuation of systemic blood pressure is mainly regulated by sympathetic tone. When blood pressure is high, raised sympathetic tone can prevent direct pressure damage to the choriocapillaries; however, if there is a rapid rise in blood pressure, excessively increased sympathetic tone may prompt severe constriction of choroidal arteries and arterioles, leading to ischemic changes of the choriocapillaries. Choroidopathy may be separated into three stages: (1) acute ischemic phase; (2) chronic occlusive phase; (3) chronic reparative phase.¹⁷ In the first two phases, fundus examination may observe white or reddish patches in the outer retina, possibly caused by RPE necrosis; exudative detachment is often present. FA may show a large confluent area or scattered areas of choroidal filling delay; in the mid and late phases, multiple dots or a mosaic pattern of hyperfluorescence from RPE leakage may be seen. In the reparative phase, large areas of irregular REP atrophy, Elschnig spots (central hyperpigmented and peripheral hypopigmented lesion of RPE changes), or Siegrist spots (spots of pigmentary changes similar to Elschnig spots arranged linearly along choroidal vessels in the equatorial region) may be seen; exudative detachment disappears, but choroidal delayed filling remains.

Pregnancy-induced hypertension

About 1–2% of pregnant women develop exudative retinal detachment pre- or immediately post-delivery, causing visual impairment. Exudative detachment may be limited to the macular area or appear as bullous detachment. The retina may or may not show cotton-wool patches or other changes secondary to hypertension retinopathy (Fig. 96.7). Yellowish-white patches of RPE necrosis may be seen. FA shows delayed choroidal filling and multiple leaking points where RPE has been damaged. After delivery, with control of hypertension, exudative detachment rapidly subsides. Most patients have good visual recovery. The posterior pole may show RPE changes forming hyperpigmented lines or patches mixed with yellow spots of RPE atrophy. The bilateral changes may be mistaken for macular dystrophy. Severe cases may have extensive exudative detachment. Widespread RPE changes similar to tapetoretinal dystrophy and severely compromised vision may result. The cause of chorioretinal changes in pregnancy-induced hypertension is not clear. Blood pressure may not be very high before the onset of exudative detachment. Affected patients may have other symptoms and signs related to disseminated intravascular coagulation, such as hemolysis, low platelet count, and elevation of liver enzymes. It is possible that mechanisms capable of inducing disseminated intravascular coagulation (see below) are also functional in the choroid, causing choroidal ischemia, RPE damage and exudative detachment.

Fig. 96.7 Color photograph (A) and fluorescein angiography image (B) showing exudative retinal detachment and multiple subretinal yellow patches in a case of pregnancy-induced hypertension.

Diabetic retinopathy

Severe diabetic macular edema may sometimes accompany localized macular detachment. Fluid leaking out from the vessels first accumulates within the retina; beyond a certain critical point, fluid may gain access into the subretinal space causing sensory detachment. Severe macular edema not only leads to detachment but may be associated with massive hard exudates (Fig. 96.8). Hard exudates are one of the independent risk factors for vision decrease.¹⁸ In addition to vascular hyperpermeability related to diabetic vasculopathy, taut posterior hyaloid membrane may also contribute to macular edema and localized detachment either from the mechanical traction force or from traction-induced increased vascular permeability.

Fig. 96.8 Color photograph (A) and optical coherence tomography image (B) showing massive hard exudates with macular cystic changes and sensory retinal detachment in diabetic retinopathy.

Clinically, early fundus changes leading to severe macular edema may present as a central retinal vein occlusion-like picture with flame-shaped hemorrhage around the disc and scattered perivascular exudates but without fluorescein angiographic evidence of disc leakage and venous delayed filling. In other cases, multiple clusters of microaneurysms may distribute in the posterior pole, accompanied by significant capillary nonperfusion. Sensory detachment and massive exudates may later develop. Exudative detachment combined with macular edema represents severe break down of the inner retinal barrier. Laser alone has little effect in such cases. Multiple sessions of intravitreal anti-VEGF (vascular endothelial growth factors) alone or in combination with subtenon or intravitreal steroid administration may effectively flatten down the retina in most cases. The effect has not been confirmed if subsequent focal laser to the leaking vascular segments or microaneurysms may obtain a more lasting effect. In some cases, exudative detachment is present without significant cystoid macular edema. It may be because the edema is in a resolving phase; thus the response to treatment may be quicker. In severe cases, exudates may consolidate and deposit within or below the macula. If the condition does not improve after several sessions of medical treatment, pars plana vitrectomy combined with hyaloid membrane removal may be performed to reduce edema and hard exudates (Fig. 96.9).¹⁹ Because the development of massive hard exudates indicates that the retina is in a relatively hypoxic state or has already gone into the early proliferative stage, panretinal photocoagulation during the operation is required to inhibit production of angiogenic factors, which may induce further macular edema or neovascularization, leading to postoperative vitreous hemorrhage or even neovascular glaucoma.¹⁹ In the case of pre-existing posterior vitreous detachment, epiretinal membrane peeling and internal limiting membrane peeling may be considered.²⁰ Massive exudates usually form submacular plaques, affecting vision severely. After surgery, the plaque may reduce in size but does not disappear completely, leaving residual fibrosis or crystal-like deposition, causing permanent decrease of vision. Surgical removal of subretinal exudates through iatrogenic retinotomy has been reported²¹; the effect has not been firmly established. Patients with severe edema should have a systemic check-up, including blood pressure, blood lipid, and renal function; any abnormalities should be treated, as these may interfere with local response to the treatment.

Fig. 96.9 (A) Excessive hard exudates in a case of diabetic retinopathy. (B) Reabsorption of hard exudates 8 months after vitrectomy, posterior hyaloid removal, and scattered laser. Best-corrected visual acuity improved from 20/800 to 20/200.

Vascular occlusive diseases

Severe retinal vein occlusion occasionally is accompanied by serous retinal detachment. Exudative detachment has been described in branch, hemispherical, and central retinal vein occlusion (CRVO). Vascular leakage from congested retinal veins outside the macular area is the major source of subretinal fluid at the fovea. In addition, ischemic retina produces angiogenic factors, such as VEGF, which in turn increase vascular permeability. Both increased intravascular pressure and vascular permeability cause leakage of fluid and blood components into the subretinal space. In eyes with retinal vein occlusion, serous RD is typically located beneath the fovea, and the height of the RD was greatest in the fovea (Fig. 96.10).

Fig. 96.10 Color photograph (A) and optical coherence tomography image (B) showing central retinal vein occlusion with marked macular edema and localized sensory macular detachment.

Recent studies with OCT revealed that macular serous retinal detachment is a common complication of retinal vein occlusion. Serous RD secondary to branch retinal vein occlusion was first described by Spaide et al.²² Of the 14 eyes included in that study, 10 (71.4%) had serous RD. Yamaguchi et al. studied 109 eyes with branch retinal vein occlusion (BRVO) by OCT examination, and found that the incidence of serous RD is higher in the group with major BRVO (63%) than in the group with macular BRVO (21%).²³ Ozdemir et al. found a high incidence (81.8%) of serous macular detachment in CRVO.²⁴ In a series of 91 patients with retinal vein occlusion examined by OCT, Tsujikawa et al. reported that 76 eyes (83.5%) had serous RD involving the fovea.²⁵ They suggested from their observations that in eyes with retinal vein occlusion, a small pointed RD developed initially just beneath the fovea, but subsequently changed into a dome-shaped RD; the foveal architecture, especially that of the Müller cell cone might be involved in the formation of serous RD.

Application of laser photocoagulation to the affected area of branch retinal vein occlusion has been reported to treat serous RD and can lead to resolution of subretinal fluid. The beneficial effect of laser treatment may be due to the ablation of ischemic retina, decrease of the production of VEGF, closure of incompetent vessels, and stimulation of RPE to enhance the reabsorption of fluid. Intravitreal injection of triamcinolone or bevacizumab has been reported to treat serous RD due to retinal vein occlusion^26,27; repeated injection may be necessary for frequent recurrence of macular edema.

The visual prognosis of serous RD in retinal vein occlusion is variable. In an eye with serous RD associated with retinal vein occlusion, the outer retinal discontinuity does not necessarily lead to poor vision. If the surrounding outer segment of the foveal photoreceptors is preserved, good visual acuity will retain after macular edema and serous RD resolve. However, even after complete resolution of the macular edema and serous RD, diffuse disorganization of the outer photoreceptor layer beneath the fovea often results in poor visual acuity (see Fig. 96.11, online). In addition, a dome-shaped RD sometimes accompanies a focal defect of the outer segment of the photoreceptors above the serous RD. When the defect involves the fovea, visual prognosis is usually poor.

Fig. 96.11 (A) Optical coherence tomography image showing severe macular edema in a case of nonischemic central retinal vein occlusion. (B) Resolution of macular edema after intravitreal bevacizumab 1.25 mg and posterior subtenon triamcinolone acetonide 40 mg.

Collagen vascular diseases

Collagen vascular diseases such as systemic lupus chorioretinopathy during exacerbation of the disease activity may show similar choroidopathy and retinopathy as hypertension-induced changes. Blood pressure may or may not be high. Exudative detachment may develop secondary to breakdown of outer retinal barriers from RPE damage. It should be noticed that exudative detachment can also appear during the quiescent phase of the disease when large doses of steroid treatment have been given, similar to CSCR with bullous RD. While steroid should be used in the first condition, it should be withheld or reduced when CSCR-like condition develops.

Vogt–Koyanagi–Harada syndrome

Vogt–Koyanagi–Harada (VKH) syndrome is a multisystem inflammatory disease capable of causing neurological, ocular, and cutaneous symptoms. The ocular involvement includes anterior and posterior uveitis. Multiple serous retinal detachments (SRD) with congested disc are the typical finding. Bullous retinal detachment may appear in severe cases. VKH has been found to be linked with human leukocyte antigen DR4 (HLA-DR4) and HLA-DRw53, with strongest associated risk for HLA-DRB1*0405 haplotype.

These associations are high in many populations, including Japanese, Hispanic, Korean, Indian, Italian, Mexican, and Chinese.²⁸

The course of VKH includes three phases: acute, convalescent, and chronic phases. The presentation of VKH usually starts with headache, associated with or followed by red eye, blurred vision, tinnitus, and vertigo. Ophthalmic signs include anterior chamber and vitreous cellular reaction and multiple patchy SRD or bullous detachment. In mild form, the vitreous cells are scanty; only mild choroidal folding with slightly hyperemic disc may be seen. The symptoms of headache along with disc edema and mild pleocytosis in cerebral spinal fluid may be mistakenly diagnosed as aseptic meningitis.

FA shows an early patchy choroidal hypofluorescent area with later multiple pinpoint leakage and dye pooling, usually forming multiple lobulated pattern. The early hypofluorescence and late hyperfluorescence of the scattered mildly elevated yellowish-white lesions may resemble acute posterior multifocal placoid pigment epitheliopathy. ICGA may show early hyperfluorescent choroidal stromal vessels and diffuse late choroidal hyperfluorescence.

OCT has unique features. In addition to the usual pattern of subretinal fluid accumulation, the subretinal space may develop cystic spaces external to the external limiting membrane (Fig. 96.12); the floors of the cystoid spaces consist mainly of a membranous structure, continuous with the line representing the junction of the photoreceptor inner and outer segments in attached areas. It has been suggested the membranous structures are composed not only of inflammatory products, but also of retinal tissue, probably the outer segment.

Fig. 96.12 Optical coherence tomography image in a case of Vogt–Koyanagi–Harada syndrome showing multilobulated sensory detachment and cysts formation in the outer retinal area.

The treatment of choice in acute stage is high-dose corticosteroid. Some advocate the use of pulse therapy with methylprednisolone 1 g daily in divided doses followed by gradual tapering over 2–3 months. Insufficient dosage may result in more frequent relapse of the disease. When steroid is tapered too early or too fast, recurrence of serous detachment may occur. Restarting high-dose steroid or supplementary periocular injection of triamcinolone may be required. In severe cases of VKH, immunosuppressive treatment may be needed. The prognosis is usually good unless there is chronic inflammation or choroidal neovascularization.

In the convalescent stage, there may be skin and hair changes, including hair loss, alopecia, and vitiligo 2–3 months after the disease onset. Sunset glow appearance of the fundus, which indicates diffuse loss of melanin pigment in the RPE and the choroid, may develop. Pigmented lines radiating from the disc after the subsidence of choroidal thickening indicate previous acute inflammation (Fig. 96.13). Scattered punched out whitish lesions in the peripheral retina (corresponding to the histological diagnosis of Dalen–Fuchs nodules) are often visible. Recurrence after the convalescent stage usually takes the form of chronic iritis instead of exudative detachment. Subfoveal choroidal neovascularization may occur in around 2% of patients with VKH and may require intravitreal injection of an anti-VEGF agent.

Fig. 96.13 Fluorescein angiography highlighting the radiating pigmented line in a case of convalescent Vogt–Koyanagi–Harada syndrome.

Around 10–20% of VKH may evolve into chronic inflammation. Chronic inflammation manifests as chronic anterior uveitis in most cases. The management of chronic VKH frequently involves the use of cyclosporine. It is the chronic anterior uveitis that results in most of the complications from this disease, such as cataract and glaucoma.

Sympathetic ophthalmia (SO)

SO is a bilateral granulomatous uveitis that occurs after ocular trauma or intraocular surgery to an eye. The disease incidence is about 0.3% of eyes with nonsurgical ocular wounds; it is 0.01% for surgical wounds. The inflammation may develop in the contralateral sympathizing eye as short as 2 weeks after trauma to the initial exciting eye. About half of the cases develop this disorder within 1 year after injury. In surgically induced SO, although this disorder is more likely to occur in eyes suffering from multiple intraocular surgeries for complicated vitreoretinal lesions, simple transscleral subretinal fluid drainage procedure has been reported to be associated with SO.²⁹

SO has various types of fundus changes; from one similar to multifocal choroiditis with minimal subretinal fluid to one resembling VKH with evident exudative detachment. The clinical course and treatment response resemble those of VKH in many aspects.

The presenting symptoms include blurred vision, especially accommodation deficit-associated near vision reduction; redness; and ocular pain. The classic clinical signs include cells in the anterior and posterior chambers, multiple patchy or confluent serous detachments, peripheral scattered cream-colored patches corresponding to Dalen–Fuchs nodules. FA also shows early multiple pinpoint leakage and late subretinal pooling. At the convalescent stage, skin and hair changes can also appear. The mainstay of treatment is corticosteroid. In corticosteroid-resistant cases, immunosuppressive agents may be required. Choroidal neovascular membrane can occur at the late stage. The treatment of choice for CNV is anti-VEGF agents.

Posterior scleritis

The presenting symptoms of posterior scleritis are blurred vision and ocular pain associated with eye movement. Clinical signs include serous retinal detachment, choroidal folding on fundus examination, multiple pinpoint leakage in FA and the pathognomonic T-sign by ultrasonography. When there is additional disc swelling and proptosis, CT scan or MRI should be performed to rule out pseudotumor. In rare conditions, posterior scleritis may present with solitary mass instead of diffuse scleritis.³⁰

Posterior scleritis is a subgroup of scleritis, which also includes anterior scleritis. The etiology and treatment of posterior scleritis are similar to those of anterior scleritis, except that the anterior necrotizing type is very rare in posterior scleritis. Reports from most university or tertiary referral centers found that about half of the scleritis cases were associated with systemic diseases. Rheumatoid arthritis is the most commonly associated systemic disease, followed by Wegener granulomatosis and relapsing polychondritis. In community-based referral practice, one-third of the scleritis cases are associated with systemic diseases; most develop after the diagnosis of the systemic disease. Rheumatoid arthritis is the leading cause, with spondyloarthropathy and infectious origin being the second and the third most common etiologies.³¹ Other systemic diseases associated with scleritis include: Cogan syndrome, herpes simplex and zoster, aspergillosis, inflammatory bowel disease and sarcoidosis.

Topical corticosteroid only is successful in controlling scleritis in less than 10% of cases. Noninfectious, non-necrotizing scleritis should be initially treated with topical corticosteroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with necrotizing scleritis or those with non-necrotizing scleritis recalcitrant to NSAIDs are often started on oral prednisone. If the patient does not respond to the treatment within a month, immunomodulatory therapy (IMT) may be introduced. Steroid-sparing IMT may include: antimetabolites (i.e., methotrexate azathioprine, and mycophenolate mofetil); alkylating agents (i.e., chlorambucil and cyclophosphamide); T-cell inhibitors (i.e., cyclosporine and tacrolimus); TNF-α inhibitors (i.e., infliximab or adalimumab), and rituximab – a chimeric monoclonal antibody against CD-20 found on B cells. Subconjunctival and subtenon’s triamcinolone injections are another therapeutic alternative.³²

Infections associated with exudative detachment

Many pathogens, including bacteria, rickettsia, fungus, and viruses have been reported to be able to infect either the choroid or the retina and result in exudative retinal detachment. Increased choroidal vascular permeability from infection-induced inflammation, is the major reason for the fluid accumulation. The visual recovery after appropriate treatment varies.

Age-related macular degeneration and polypoidal choroidal vasculopathy

In age-related macular degeneration (AMD) with choroidal neovascularization, serous and hemorrhagic detachment of the retina occurs frequently. The neovascular membrane causes leakage of serous exudates and red blood cells into the sub-RPE space and subsequently into the sub-sensory retinal space. Fundus examination typically reveals a light-grayish elevated mass corresponding to a serous and hemorrhagic detachment of the RPE and sensory retina. This mass-like lesion should be differentiated from choroidal melanoma. FA is helpful in the differential diagnosis. In AMD with choroidal neovascularization, the new vessels leak and present as a hyperfluorescent area, and the hemorrhagic lesion shows hypofluorescence because it is blocked by the subretinal blood. A melanoma shows mottled hyperfluorescence in the early phase and increased staining in the late phase. In addition, a mass-like lesion induced by choroidal neovascularization tends to change configurations within a short period of time. A disciform scar eventually evolves from choroidal neovascularization with massive exudates. Extensive hemorrhagic macular detachment may lead to a breakthrough vitreous hemorrhage; the color of the vitreous opacity tends to be yellow instead of red, indicating the presence of old blood or blood degeneration products in the vitreous. In rare cases, massive hemorrhage from active lesion or disciform scar may cause severe hemorrhagic choroidal and retinal detachment (Fig. 96.14).

Fig. 96.14 Massive subretinal, sub-retinal pigment epithelium, and suprachoroidal hemorrhage in a case of age-related macular degeneration.

Polypoidal choroidal vasculopathy has been recognized recently as a distinct exudative macular disorder.³⁹ It is generally thought to be a primary choroidal vascular abnormality characterized by two distinct components: a complex of branching vascular networks and multiple, terminal, reddish-orange, aneurysms, or polypoidal lesions. Clinically, PCV shows multiple, recurrent serosanguineous detachments of the RPE and neurosensory retina secondary to leakage and bleeding from choroidal vascular lesions (Fig. 96.15).⁴⁰ It may be a cause of severe hemorrhagic choroidal and retinal detachment. Whether PCV is a variant of exudative AMD has not been definitively determined. However, there are significant differences between PCV and exudative AMD in the demographic profile, fundus pictures, natural history, visual outcomes, and response to different treatment modalities. ICGA to identify the characteristic polypoidal vascular dilations is the main method for definite diagnosis of PCV. Recently, OCT has been used extensively to study exudative macular lesions. OCT images can also distinguish the exudative changes associated with PCV from that with exudative AMD. In the study reported by Ozawa et al., serous RD were observed in 78% of the eyes with PCV and in 53% of the eyes with exudative AMD.⁴¹ In addition, eyes with a PCV had a greater height of serous RD, and a higher incidence of large sensory detachment than eyes with exudative AMD. The active polypoidal lesions tend to leak more severely and the fluid from polypoidal lesions may leak into the subretinal space through the RPE and cause large serous RD although polypoidal lesions are situated beneath the RPE.

Fig. 96.15 Color fundus photograph in a case of polypoidal choroidal vasculopathy showing multiple orange-colored subretinal nodules, hemorrhagic retinal pigment epithelial detachment, subretinal hemorrhage and sensory detachment.

In some cases of PCV, a serous neurosensory detachment at the macula without hemorrhage is the major clinical feature associated with RPE atrophy. FA only shows multifocal areas of granular hyperfluorescence. This type of PCV can masquerade as CSCR. ICGA might help to establish a more definitive diagnosis. Yannuzzi et al. reported a series of 13 patients who were previously diagnosed with CSC, but with further evaluation and follow-up, were diagnosed with PCV.⁴² These eyes showed the characteristics of exudative macular detachments with a small-caliber, polypoidal vascular abnormality revealed by ICGA. Therefore, the authors recommended that ICGA should be done in the following situations: (1) patients not at risk of CSC, based on age, sex, or race; (2) eyes with persistent serous detachment at the macula associated with lipid accumulation; and (3) recurrent serous detachments with subretinal blood.

The serosanguineous retinal detachments in AMD or PCV can be managed by surgical intervention. Pneumatic displacement of submacular hemorrhage from the macula by intravitreal injection of expansile gas with or without tPA is now the first treatment of choice in most cases (see Fig. 96.16, online).⁴³ Major complications include vitreous hemorrhage and rhegmatogenous retinal detachment. Vitrectomy with subretinal injection of tissue plasminogen activator (tPA) and use of perfluorocarbon liquid to evacuate the liquefied clot from the submacular space has been reported.⁴⁴ Oshima et al. described the surgical results of patients with massive subretinal hemorrhage extending to the periphery and involving two or more quadrants with hemorrhagic and bullous retinal detachment.⁴⁵ TPA was injected intravitreally 12–24 hours preoperatively; vitrectomy was performed with peripheral retinotomy, drainage of the subretinal hemorrhage through the retinotomy using perfluorocarbon liquid, and finally gas tamponade with postoperative prone positioning. However, the final visual outcome is limited by the underlying macular pathology.

Fig. 96.16 (A) Massive subretinal hemorrhage in a case of polypoidal choroidal vasculopathy. (B) Reabsorption of the blood after pneumatic displacement with 0.2 mL C₃F₈ and intravitreal injection of bevacizumab 1.25 mg.

Choroidal hemangioma

Choroidal hemangioma (CH) can be separated into the focal, solitary type and the diffuse choroidal thickening type. Both may be associated with extensive exudative retinal detachment.

Patients with focal choroidal hemangioma are mostly middle-aged men or women, complaining of unilateral vision decrease or distortion. Fundus examinations may find localized elevated orange-colored lesions ranging in size from 2 disc diameters (DD) to 10 DD in the juxtapapillary, macular, or extramacular area in the posterior pole. The surface is usually smooth, but retinal thickening with cystic space may be seen above the lesion. Yellow specks or yellowish-white plaque of fibrous metaplasia sometimes exist between the tumor and the overlying retina. The lesion usually does not have pigmentary proliferation within but may have a mild hyperpigmented ring around it. Exudative detachment above and surrounding the tumor or in the inferior peripheral retina, may develop. Cystoid macular edema (CME) may be present when the macula is involved. Gravity tract of pigmentary disturbance may be seen between the tumor and the lower detached retina. Although the detachment is usually limited, severe bullous detachment may occur (see Fig. 96.17, online). Vision is affected by the presence of submacular tumor, submacular fluid or CME.

Fig. 96.17 Bullous retinal detachment in a case of solitary choroidal hemangioma.

FA shows the characteristic features of perfusion of large vessels within the tumor in the pre-arterial phase followed by irregular hyperfluorescence on the tumor surface; a multiloculated pattern of cystoid macular edema may appear in the late phase.⁴⁶ A ring of hypofluorescence may be seen surrounding the tumor. In small tumors without significant retinal or pigmentary changes, the lesion shows only mild hyperfluorescence, sometimes difficult to distinguish from the surrounding normal choroid. ICGA examination can demonstrate tumor vessels in the early phase more clearly.

OCT demonstrates choroidal elevation, RPE disturbance, cystic change in the overlying retina, and subretinal fluid (Fig. 96.18). Schisis-like change may be seen in the outer retina over or adjacent to the tumor, sometimes during treatment sessions of PDT or transpupillary thermotherapy (TTT). Ultrasonography shows high internal reflectivity.⁴⁷

Fig. 96.18 Optical coherence tomography images in a case of choroidal hemangioma showing macular fluid pocket and cystic changes overlying the tumor.

Histologically, cavernous choroidal hemangioma consists of large, dilated, thin-walled vessels with few stromal tissues, and blends into surrounding normal choroidal vessels.

Tumors not causing macular changes do not need treatment. Conventionally, an extramacular tumor with submacular fluid accumulation is treated with a laser, aiming at the leaking tumor surface. Multiple sessions of treatment may be necessary to obtain submacular fluid reabsorption. The tumor size may or may not be reduced with this treatment modality. ICGA-enhanced diode laser is another treatment option to facilitate fluid reabsorption. Recently, TTT and PDT have been advocated to treat the tumor.^48,49 With one or a few sessions of treatment at an interval of 2–3 months, fluid reabsorption and tumor reduction, and in some instances, complete flattening down of the tumor may occur (see Fig. 96.19, online). Large tumors may be treated with transscleral cryotherapy, thermotherapy, external beam irradiation, or episcleral plaque. In severe cases, the tumor may be hidden under the detached retina, thus inaccessible to laser or other treatment. In such cases, surgical drainage of the subretinal fluid may be performed to re-expose the tumor for a better treatment effect. Alternatively, repeated injection of bevacizumab may be used to facilitate fluid reabsorption.⁵⁰ The effect of this treatment has not been well established.

Fig. 96.19 (A) Optical coherence tomography image of the macular area in a case with upper part choroidal hemangioma showing submacular fluid and intraretinal cysts. (B) Resolution of the macular changes after photodynamic therapy to the choroidal hemangioma.

The second type is Sturge–Weber syndrome with diffuse choroidal hemangioma. Compared with the fellow eye, the lesion eye has a more reddish fundus background color; normal choroidal markings are not visible (Fig. 96.20). This may be the only significant fundus finding in some cases. Most cases had mild tortuosity of retinal vessels or scattered pigmentary changes of various degrees. Ultrasonography may detect a thickened choroid. Other more severely affected cases may present with bullous RD, associated with glaucoma secondary to increase resistance of aqueous outflow or abnormalities of the trabecular meshwork. There may be focal choroidal thickening in addition to diffuse thickening. FA may show minimal abnormality or only patchy hypofluorescent and hyperfluorescent areas from pigmentary disturbance. Late phase leakage and cystoid space may be seen in cases with exudative retinal detachment.

Fig. 96.20 Diffuse choroidal hemangioma with dark red background color, indistinct choroidal markings, and tortuous retinal vessels.

Glaucoma in Sturge–Weber syndrome is difficult to control with medication and usually requires operation. Filtering operation is frequently complicated by severe choroidal detachment, with spontaneous recovery in most cases. For exudative detachment with potentially useful vision, Argon laser photocoagulation may be performed to the leaking area to facilitate subretinal fluid reabsorption. Other treatment modalities include low-dose external beam irradiation (1200–2000 cGy) divided into several sessions.⁵¹ Recently, PDT applied with multiple spots and sessions has been used to treat diffuse choroidal hemangioma aiming to reduce exudative detachment as well as choroidal thickness.⁵² Further studies may be needed to confirm its usage.

Choroidal melanoma

Choroidal melanoma is commonly associated with exudative retinal detachment. The tumor lesion is often found during a routine eye examination or during specific fundus check-up for blurred vision or visual field defect secondary to a macula involved sensory detachment or enlarged tumor itself. Flashing lights may be a complaint during tumor growth or tumor invading into the retina.

Melanoma often presents as a wide-based or dome-shaped pigmented mass under the retina (see Fig. 96.21, online). A small tumor may contain orange pigment on the surface and part or the entire lesion may be amelanotic. Exudative detachment may develop above and surrounding the tumor or in the lower dependent part away from the tumor location. During tumor growth, choroidal melanoma may invade choroidal capillaries, leading to subretinal hemorrhage. It may later break through the Bruch’s membrane to form a pigmented or amelanotic mushroom-like lesion. Tumor vessels may be visible, especially if the part above the Bruch’s membrane is amelanotic. When the tumor breaks through the Bruch’s membrane, it may cause choroidal, subretinal, or vitreous hemorrhage. Melanoma may invade the optic disc causing disc edema. When invading the vitreous, it may cause pigment dispersion within the vitreous and pigment deposition on the surface of the retina. When invading the retina, the drainage vein may become tortuous and engorged. Rarely, the tumor may assume a diffuse growing pattern causing diffuse choroidal thickening.⁵³ Clinically the diffuse lesion is a more aggressive type than the dome-shaped lesion, and more likely to invade the optic disc and spread outside the sclera, thus having a much worse prognosis.

Fig. 96.21 Malignant choroidal melanoma inferior to the macula.

Histopathologic studies have shown that different tumors may contain different types of cells: spindle A, B, epithelioid cells, or mixed cell types. Epithelioid cell type has the worse visual prognosis. On FA, a typical lesion shows early pinpoint hyperfluorescence with late leakage. If there is a Bruch’s membrane breakthrough, both tumor vessels and retinal vessels can be seen, presenting the so-called double-circulation sign.⁵⁴ ICGA may show tumor vessels in the late stage. Ultrasonography is valuable in showing the size, height and nodular extraocular extension. Typical lesions present as dome- or mushroom-shaped choroidal elevation with acoustic hollowness and choroidal excavation. A scan usually shows an initial spike with rapid attenuation in tumors with compact spindle A or B cell types.⁵⁵ The epithelioid cell type is more prone to have a moderate high and low spike within the tumor. MRI inevitably shows the paramagnetic effect of melanin with T1, T2 reverse sign: the lesion shows a hyperdense image in T1 and hypodense in T2, in reverse to the vitreous density (see Fig. 96.22, online).⁵⁶ In uncertain cases, fine-needle biopsy with 25-gauge needle through the pars plana into the tumor to obtain cells may be used for cytological examinations.

Fig. 96.22 Magnetic resonance imaging study of the above-mentioned case showing typical hyperintense T1 (A) and hypointense T2 (B) images with respect to the vitreous.

Malignant melanoma should be differentiated with choroidal nevi. Important points favoring the diagnosis of melanoma include: (1) dome-shaped elevation over 3 mm; (2) orange pigmentation on the surface; (3) sensory detachment over and surrounding the tumor in the absence of choroidal neovascularization; (4) evidence of Bruch’s membrane breakthrough; (5) multiple pinpoint leakage on FA.

Some investigators suggest that any melanocytic lesion having a basal diameter greater than 16 mm and a height more than 3 mm should be considered as malignant; lesions with typical fundus picture and showing signs of growth and a basal diameter greater than 2.5 mm should also be considered as malignant and should be treated as such. Others suggest that size itself is not the only element to consider, and emphasis should be put on signs of acute or chronic changes. The following signs indicate chronic changes and favor a benign condition: (1) the tumor shows areas of fibrous metaplasia, presenting either as a fibrotic plaque or choroidal neovascularization; (2) there is evidence of subretinal pigment clumps or intraretinal pigment migration or gravity tract indicating long-standing exudative detachment; (3) drusen is present.

Treatment choice should consider growth potential, size, location, and age. For a small tumor, laser may be used to treat only the leaking points to promote reabsorption of subretinal fluid if exudative detachment involves the macula.⁵⁷ For definite small-sized malignant melanoma, consider laser or transpupillary thermotherapy.^58,59 Photodynamic therapy has been used with mixed results. For medium-sized or large posterior tumors, radiation with plaque or charged particles may be considered. Co-60 plaques or I-125 episcleral plaques are commonly used.⁶⁰ Ruthenium plaques have also been widely used in Europe.⁶¹ Other treatment options include photoirradiation similar to PDT for AMD, local resection, ultrasonic hyperthermia and irradiation, and radiation plaque with photocoagulation. Teletherapy with γ-knife or cyberknife may be used. Severe inflammatory reaction is the most common complication.

The Collaborative Ocular Melanoma Study (COMS) found that preoperative radiation for large choroidal melanomas (height >8 mm, basal diameter >16 mm) does not improve 5-year survival; enucleation and brachytherapy have a similar rate of survival for medium-sized tumors (height 3–8 mm, basal diameter ≤16 mm).⁶² However, there is evidence from a clinical series that failure to achieve local control after radiation therapy, even when treated by subsequent enucleation, is associated with an increased risk of metastasis.⁶³

Metastatic tumors

Metastatic tumors are the most common malignant neoplasms of the eye,^64,65 with the choroid being the most common site for tumor growth. The breast was the first and the lung the second most common primary site for both choroidal and orbital metastases.⁶⁵ Approximately one-third of patients have no history of primary cancer at the time of ocular diagnosis.⁶⁵ About 50% of these patients fail to have a primary site detected, despite systemic evaluation by medical oncologists. The most common presenting symptom of intraocular metastasis was blurred vision. When visual acuity was affected, it usually decreased to the range of 20/200 to count fingers. Other presenting symptoms included flashes, floaters and pain. The symptom of pain is rarely found in patients with other primary uveal malignancies, such as malignant melanoma.

On fundus examination, typical choroidal metastases show one or more solitary yellow, creamy, flat or slightly elevated lesions with overlying pigment disturbance forming spotted pattern usually located in the posterior retina; bilateral involvement is found in 20–40%, and multifocal in 20%; three-quarters are associated with exudative detachment. It is not possible to determine the origin of the lesions from examining the fundus alone.

FA of most metastatic carcinomas shows hypofluorescence in the arterial and early venous phases and progressive hyperfluorescence in the subsequent frames. Pinpoint foci of hyperfluorescence appear over the tumor in the venous phase and persist in the late angiograms. There may be moderate late hyperfluorescence of the serous subretinal fluid adjacent to the metastatic tumor. FA has limited value in determining the origin of the choroidal tumors, but is useful in differentiating metastatic tumors from non-neoplastic conditions, such as inflammatory processes, subretinal neovascular membranes, and organized hemorrhage.

Ultrasonography shows that metastatic tumors tend to be flat and extend in surface area rather than thickness. Most choroidal metastases have a plateau- or dome-shaped contour and measure approximately 3–4 mm in thickness. Thicker tumors generally were observed with metastases from the gastrointestinal tract, kidney, lung, and prostate. Shield and associates reported that the mean thickness was 4 mm for metastatic gastrointestinal cancers.⁶⁵

A CT scan demonstrates the presence and configuration of intraocular metastases. On MRI, metastatic carcinomas are characteristically isointense or slightly hypertense to the vitreous on T1-weighted images and hypointense to the vitreous on T2-weighted images. They show mild to moderate enhancement with gadolinium-enhanced examination.

Other ancillary ophthalmic procedures may aid in the diagnosis of metastatic tumors, including radioactive phosphorus test, fine-needle aspiration biopsy, and wedge biopsy.

Differential diagnoses of choroidal metastasis include amelanotic melanoma, amelanotic choroidal nevus, choroidal osteoma, choroidal hemangioma, posterior scleritis, and rhegmatogenous retinal detachment.

Workup for a choroidal metastasis includes an MRI of the head to rule out brain metastases and to determine the extent of the tumor. The incidence of central nervous system (CNS) metastases increases from 6% to 28% after development of ocular metastasis.⁶⁶ Patients with an unknown primary site of origin should obtain a thorough physical examination and have a chest radiography and a mammogram. In women without breast cancer, and in men, the evaluation should be directed initially towards the detection of a primary tumor in the lung, alimentary tract, kidney, thyroid, pancreas, and other organs. Kole et al. suggested that PET-CT might be helpful for detecting a malignancy of unknown origin.⁶⁷

Common treatment options include chemotherapy, external beam radiation, plaque radiation, hormone therapy, resection, observation, and combination therapy (Fig. 96.23). TTT has been proposed to enhance reabsorption of subretinal fluid.⁶⁸

Fig. 96.23 Choroidal metastasis in a case of breast adenocarcinoma. Choroidal tumor with localized sensory detachment and subretinal deposit was noted initially (A). Rapid tumor enlargement was noted in subsequent examinations. Resolution of the tumor with widespread RPE changes was noted after systemic chemotherapy. Note the presence of tumor infiltration of the optic disc (B).

Prognosis is poor for patients diagnosed with choroidal metastasis. The average survival time is 8–9 months after diagnosis.⁶⁹ Cutaneous tumors have the worst prognosis (of 1–2 months survival time), and breast tumors have the best prognosis (7–31 months). Data of 36 patients with choroidal metastases were collected in 11 years in a teaching hospital in Taiwan. The mean age was 53.9 ± 12.8 years. The primary sites of tumors were: lung in 18 (50%); breast in eight (22.2%); gastrointestinal tract in three (8.3%); pancreas in two (5.6%); ovary in two (5.6%); kidney in one (2.8%); liver in one (2.8%), and unknown in one (2.8%).⁷⁰

Lymphoma

Primary intraocular lymphoma (PIOL) is a rare disease, and can rarely induce serous retinal detachment. It belongs to a subset of primary central nervous system lymphoma (PCNSL). Up to 80% of PIOL patients have CNS involvement at the time of, or following, PIOL diagnosis. Around one-quarter of PCNSL patients develop intraocular involvement.⁷¹ It is known as the most important cause of the uveitis masquerade syndrome (see Chapter 79, Intermediate uveitis-pars planitis, and Chapter 123, Diagnostic and therapeutic vitrectomy for uveitis). The clinical signs include cellular infiltration of the vitreous, which mimics vitritis, and multiple creamy subretinal infiltrative mounds with surface pigmented clumps (Fig. 96.24). Some cases may show localized subretinal yellowish infiltration with exudative detachment, or intraretinal infiltration resembling acute retinal necrosis. The diagnosis of PIOL requires a high index of suspicion. When elderly patients develop vitreous opacity with vitreous cells, PIOL should be kept in the list of differential diagnosis, especially when the so-called vitritis is refractory to corticosteroid treatment. When there is a suspicion of PIOL, pars plana vitrectomy and lumbar puncture are the two important diagnostic procedures. Cytological examination of the vitreous sample leads to a definite diagnosis. A negative result is likely to occur when patients are receiving treatment with corticosteroid. Some found a higher IL-10 or IL-10 to IL-6 ratio in the vitreous of patients with PIOL. Although the cytokine levels are not diagnostic of PIOL, they are useful adjuncts to the cytological examination. When the clinical suspicion of PIOL is high, and IL-10 level or IL-10:IL-6 ratio is high, even if the initial vitrectomy and lumbar puncture are negative, more aggressive diagnostic procedures are warranted. In some cases with only scanty vitreous infiltration, cytological examination of samples from a subretinal biopsy may be required.⁷²

Fig. 96.24 Intraocular lymphoma showing multiple yellowish subretinal mounts with overlying pigmented clumps.

The treatment of choice for PCNSL, with or without PIOL, is high-dose methotrexate intravenously, which can pass the blood–brain barrier and blood–ocular barrier and reach the therapeutic level in the vitreous. Some advocate additional intravitreal methotrexate (0.4 mg/0.1 mL) injections in patients with PCNSL and PIOL (Fig. 96.25). The side-effects of intravitreal methotrexate injection include corneal epithelial toxicity and cataract. In relapsing cases with intraocular involvement only, treatment success has been reported with intravitreal injection of methotrexate only. In refractory cases, radiotherapy on the brain and the involved eye may be an option. However, recurrence is the rule with radiotherapy only. Intravitreal rituximab is a promising alternative for treatment of PIOL, with no significant side-effect.⁷³

Fig. 96.25 (A) Color fundus photograph in a case of cytology-proven intraocular lymphoma showing massive subretinal infiltration of lymphomatous cells and exudative retinal detachment. (B) Resolution of the exudates after systemic chemotherapy and intravitreal injection of methotrexate.

Leukemia

About 40–70% of the patients with leukemia have eye involvement.⁷⁴ Pathological changes from anterior segment to posterior segment may occur, including corneal ring ulcer, iris infiltration, glaucoma, retinopathy, choroidopathy, and optic neuropathy.⁷⁴ Structural alteration may be caused by direct leukemic cells infiltration or by accompanied hematological abnormalities, such as anemia, hyperviscosity, or both.⁷⁴ Posterior segment manifestations are usually associated with retinal vascular changes, retinal hemorrhage or even retinal infiltrations. Exudative retinal detachment may occasionally be seen secondary to leukemic choroidopathy.⁷⁴

Previous study has shown about half of leukemia cases have uveal infiltration.⁷⁵ Most do not have clinical symptoms or fundus changes. Ultrasonography may show mild choroidal thickening. Some patients may present with localized or diffuse leopard-spot changes secondary to retinal pigment epithelium damage by either extensive leukemic infiltration of the choroid capillaries or chemotherapy. Focal or diffuse choroidal elevation may occasionally be seen from choroidal infiltration of leukemia, especially acute lymphocytic lymphoma. Exudative detachment may occur as well as RPE detachment (Fig. 96.26). When localized, it may be similar to CSCR; in more extensive detachment, FA may show pinpoint leakage secondary to RPE damage, similar to Harada disease, posterior scleritis or other infiltrative diseases of the choroid. Systemic chemotherapy may prompt reabsorption of subretinal fluid.⁷⁶ During this process, numerous yellow exudates-like patches may be seen beneath the retina (Fig. 96.27).

Fig. 96.26 (A) Confluent nodular subretinal infiltration with surrounding exudative detachment in the left eye in a case of acute myelocytic leukemia. (B) Resolution of the lesions with residual subretinal exudates after systemic chemotherapy.

Fig. 96.27 (A) Hemorrhagic choroidal detachment and retinal detachment in a case of acute leukemia. (B) Resolution of the lesions with residual subretinal exudates after systemic chemotherapy.

Optic nerve pit

Optic pit is a congenital defect within the optic nerve head and appears as a gray dimple. It varies in size but on average, is less than one-third of the DD in width. Clinical examination shows a localized excavation of the disc that typically measures less than one half of the DD; 50% of the pits locate on the temporal side, and one-third locate centrally without association with retinal detachment. The incidence of the disease is 1/11 000⁷⁷; 25–75% (40%) are associated with retinal detachment.⁷⁸ The condition is unilateral in 90% of cases. In 85% of cases, the abnormal optic disc is larger than the contralateral one. The color of the pit may be gray, yellow, or less frequently, black. Various juxtapapillary changes including peripapillary retinal pigment epithelial change or choroidal atrophy or both are present in 95%. Visual field defect is caused by retinal elevation in 40% and enlarged optic pit in 60%. The patterns of visual field defect are nasal and temporal steps, altitudinal defects, paracentral scotomas, arcuate scotomas, or generalized or localized constriction.⁷⁷ The macula may show the following changes: serous macular elevation, macular cystic degeneration and schisis formation, or macular mottling without evidence of RD. Schisis and RD may be present simultaneously (see Fig. 96.28, online). There is communication between the schisis cavity or subretinal space and the optic disc pit. Retinal detachment including schisis occurs in 40% of cases, usually extending into the macular region or slightly beyond.⁷⁹ Larger pit, temporal location pit, and macular hole may be predisposing factors for RD. Long-standing serous retinal detachment can eventually lead to cystic degeneration of the macula and loss of pigment in the underlying retinal pigment epithelium. Lamellar and, rarely, a full-thickness macular hole may develop. Spontaneous resolution of the macular detachment is reported in 25% of cases.

Fig. 96.28 Color fundus picture (A) and optical coherence tomography image (B) showing optic pit with macular sensory detachment with subretinal yellow deposit and retinoschisis nasal to the fovea.

The origin of the schisis fluid or subretinal fluid remains controversial. A collie dog model suggested a connection between the vitreous cavity and the subretinal space (India ink).⁸⁰ OCT may show a thin fenestrated sheet of tissue covering the pit. In addition, some patients treated with vitrectomy and tamponade have gas extending into or under the retina postoperatively. Regenbogen et al. proposed the idea that subretinal fluid could be derived from cerebrospinal fluid.^77,81 Lincoff and Kreissig suggested fluid emanating from an optic disc pit was creating a schisis-like separation of the inner layers of the retina. A detachment of the outer layers from pigment epithelium was a secondary process that began in the center of the macula and did not connect with the optic disc pit.⁸²

The natural course of untreated RD was poor. VA eventually may drop to less than 20/100 in 50–80%, especially when macular detachment develops.

Persistent macular elevation may require surgery (Fig. 96.29). The greater the separation between the peripapillary RPE and the retina, the less the chance of a successful treatment. Laser photocoagulation (along the disc margin adjacent to RD), pneumatic displacement, pars plana vitrectomy, pars plana vitrectomy with autologous platelets, and macular buckling (vertically at posterior pole) have been reported.^82–84 Cox and associates compared various surgical modalities. They concluded that combined surgery of vitrectomy, gas injection and laser photocoagulation to the temporal margin of the disc is the most effective therapy.⁸⁴

Fig. 96.29 Color fundus photograph (A) and optical coherence tomography (OCT) image (B) showing optic pit (arrow) with macular sensory detachment. Color fundus photograph (C) and OCT image (D) showing resolution of the subretinal fluid after one procedure of gas tamponade and three sessions of laser photocoagulation on the temporal margin of the disc.

In some cases, macular RD and schisis were noted without a pit. It may be due to a small pit or chronic CSCR. In some of these cases, a sheet of tissue with small fenestration may be detected over the disc margin with OCT.

Differential diagnosis includes: macular schisis with/without optic pit; macular detachment with/without optic pit; central serous chorioretinopathy (CSCR); myopic and age-related macular degeneration; peripapillary detachment in pathologic myopia (PDPM); malignancy; and polypoidal choroidal vasculopathy (PCV).

Morning glory syndrome

Morning glory syndrome (MGS) is a congenital optic disc anomaly caused by abnormal closure of the embryonic fissure with outward herniation of the disc and peripapillary tissues. It is characterized by a large-sized excavated disc overlaid with a tuft of glial tissue on the center, and surrounded by an elevated pigmented ring. Narrow and straight retinal vessels cross the disc margin in a radial pattern. The disease may be diagnosed in infants or young children because of strabismus or other associated anomalies such as cataract, microphthalmos or anterior segment anomaly, or in school age, after vision screening. The visual acuity is usually below 20/200. Some rare cases with minor changes may be found during routine eye examinations.

RD is noted in about one-third of the cases.⁸⁵ It may be confined to the peripapillary area or involve a large part of the entire retina (Fig. 96.30). The detachment may be rhegmatogenous or nonrhegmatogenous; the cause is difficult to determine from clinical presentation alone, although bullous detachment is more likely to occur in rhegmatogenous detachment. Definite diagnosis relies on the identification of retinal breaks, which are usually small and slit-like on the surface or margin of the abnormal disc. Because of poor contrast, retinal breaks are difficult to find preoperatively. During operation, SRF may be seen coming out from the hidden break by active or passive suction.

Fig. 96.30 Color fundus photograph showing a case of morning glory syndrome with sensory retinal detachment of the upper retina.

For nonrhegmatogenous detachment, the condition may undergo spontaneous improvement and recurrence. The source of fluid is debated. There may be communication between the subretinal space and subarachnoid space or the vitreous cavity, as in the optic pit. The fact that certain cases had a successful reattachment after an optic nerve fenestration operation suggests that CSF may be an important source of the subretinal fluid.^86,87

Localized detachment may be observed and more widespread detachment may be treated with vitrectomy, posterior hyaloid and glial tissue removal, internal drainage and laser around the break, if found. Intractable cases may be treated with silicone oil tamponade, although there is a small danger of silicone oil migrating to the optic nerve sheath. Optic nerve fenestration operation may be done for cases that did not respond to vitrectomy.

Postsurgical exudative retinal detachment

Transient exudative detachment in the early postoperative period may sometimes be seen after diabetic vitrectomy, especially if excessive photocoagulation or peripheral cryotherapy has been done. The detachment is usually located in the inferior part; significant fluid is noticed 1 or 2 days after surgery. Sometimes the fluid accumulates in the posterior pole causing severe decrease of vision a few days after surgery. In such cases, ultrasonography demonstrates dome-shaped macular elevation; the condition usually improves within 1–2 weeks. Management of the exudative detachment requires careful examination and proper monitoring of intraocular pressure. If the detachment is associated with abnormally low IOP, rhegmatogenous retinal detachment should be highly suspected.

Exudative detachment may occur after scleral buckling and cryopexy to treat rhegmatogenous retinal detachment.⁸⁸ Excessive high circumferential buckle placement or multiple vortex veins compression may induce choroidal detachment with or without exudative retinal detachment. Old age and a medical history of cardiovascular diseases are risk factors.⁸⁸ Excessive cryopexy may induce exudative retinal detachment causing delayed reabsorption or transient increase of subretinal fluid. As long as retinal breaks sit on the buckle, no specific treatment needs to be done. Choroidal detachment may be treated with systemic steroid especially if the anterior chamber depth becomes shallow or intraocular pressure is high.

External drainage may induce choroidal hemorrhage entering into the subretinal space in the detached area. If subretinal blood deposits under the macula, visual acuity may be greatly compromised. The complication rate is high if drainage is done after cryotherapy because of the engorgement of choroidal vessels. To avoid this complication, one should perform external drainage as infrequently as possible, or shift to vitrectomy when drainage is judged necessary with scleral buckling procedure. Once subretinal hemorrhage and choroidal hemorrhage occur, gas injection with head down position may help to push the blood away from the macula.^89,90 Simultaneous use of intravitreal TPA to better mobilize the blood clot has been advocated.⁹¹

Prolonged hypotony during or after intraocular surgery may induce serous or hemorrhagic choroidal detachment with or without exudative or hemorrhagic retinal detachment. This complication may occur in cataract operations, either phacoemulsification or extracapsular cataract extraction; filtering operation for glaucoma; penetrating keratoplasty; secondary intraocular lens implantation, especially sutured lens; or vitrectomy. The popularization of small gauze vitrectomy may result in more cases experiencing postoperative hypotony secondary to sclerotomy wound leakage, leading to choroidal detachment, particularly in high myopic eyes.⁹² Indications and timing for surgical intervention depend on the extent of the detachment, the degree of blood clot lysis within the suprachoroidal space, the level of intraocular pressure, severity of the symptoms, and whether or not rhegmatogenous retinal detachment exists. Additional information available online.

Serous choroidal detachment with normal intraocular pressure and without rhegmatogenous retinal detachment can be safely followed. High intraocular pressure not controllable by medication, loss of intraocular contents, and a high suspicion of rhegmatogenous retinal detachment are indications for surgery. A 1–2-week waiting period is required for the partial lysis of the suprachoroidal blood clot. During surgery, the surgeon should make certain that the tip of the infusion canula is placed within the intraocular cavity. Drainage sclerotomy should be placed where choroid is most elevated. Suprachoroidal drainage and intraocular infusion should proceed at the same time to keep intraocular pressure and to obtain a maximal drainage. Pars plana vitrectomy is then performed to release vitreous traction, followed by perfluorocarbon liquid infusion to settle the retina and push the residual blood out through the drainage sclerotomy.

Disseminated intravascular coagulopathy

Disseminated intravascular coagulopathy (DIC) may result in an abnormal clotting state. A variety of systemic conditions are associated with DIC, including malignancy, malignant or pregnancy-induced hypertension, abruptio placentae, collagen vascular diseases, sepsis, and organ transplantation. DIC tends to cause excessive fibrin clot formation, leading to occlusion of small blood vessels in the choroidal, rather than the retinal circulation. This is thought to be caused by rapid deceleration, followed by stasis of blood in the choriocapillaries. The thrombus formation results in fibrinoid necrosis and disruption of the overlying RPE, which may result in serous RD.

Post-organ transplantation or hemodialysis exudative detachment

There are two types of fundus changes: type 1 has orange-colored RPE proliferation mixed with RPE atrophic changes, forming a leopard-spot pattern, associated with exudative retinal detachment. FA shows multiple RPE leaking points. Subretinal fluid usually disappears within weeks or months; recurrence is common. The onset of the lesions may not be related to graft rejection. Most patients are under steroid, or other antimetabolites treatment such as cyclosporine or azathioprine. The lesions are compatible with acute RPE damage. The underlying cause may be due to choroidal ischemia secondary to localized intravascular coagulopathy. The other type shows multifocal RPE detachment associated with subretinal serofibrinous substance and bullous detachment, similar to atypical CSCR.^93,94 The condition tends to develop in patients under hemodialysis or after kidney transplantation. Most reported hemodialysis cases were taking systemic steroids. The pathogenesis may be similar to those inducing atypical CSCR.

Miscellaneous

Other conditions associated with localized or extensive exudative retinal detachment include familial exudative vitreoretinopathy, acute exudative polymorphous vitelliform maculopathy, retinoblastoma, reactive lymphoid hyperplasia, bilateral diffuse uveal melanocytic proliferation, carotid-cavernous fistula, and systemic diseases such as chronic renal failure, hypoalbuminemia.