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Fundus Fluorescein Angiography
C H A P T E R
8 Fundus Fluorescein Angiography Roy Schwartz, Sobha Sivaprasad NIHR Biomedical Research Centre, Moorfields Eye Hospital, London, United Kingdom
Central serous chorioretinopathy (CSCR) is characterized by a focal or multifocal leak at the level of the retinal pigment epithelium (RPE), often in conjunction with a serous pigment epithelial detachment (PED). An active leak is characterized by angiographic pooling of fluorescein dye into the subretinal space.1 With the availability of newer imaging modalities such as spectral-domain optical coherence tomography (SD-OCT) (see Chapter 10), FA is not always mandatory for the diagnosis of CSCR. It is helpful, however, in confirming the diagnosis when in doubt and serves as a guide for laser treatment of eccentric leaks or photodynamic therapy.2–4 Acute CSCR usually presents with a single leakage site, although rarely two or more sites can be seen (Fig. 1).2 When more than one site of leakage is observed, a single site usually is responsible for the ongoing episode.5 The area most commonly affected is the superonasal retina, possibly because of a higher metabolic rate within the RPE in the proximity of the papillomacular bundle.6, 7 Sometimes, no leakage can be seen on fluorescein angiography in spite of the presence of a serous detachment seen clinically or on OCT. According to Gass, failure to find evidence of a leak angiographically in such patients should suggest either a leak outside the macular area, usually superiorly; a spontaneously sealed leaking area, suggesting that the detachment will disappear subsequently; the presence of a peripheral retinal hole or choroidal tumor, usually superiorly; a congenital optic nerve pit; or the presence of idiopathic uveal effusion syndrome. 8 Only a few studies reported cases without leakage. Khalil et al. examined 51 patients with active CSCR. Of those, 19.6% demonstrated no leakage on FA in spite of the existence of a serous detachment seen on OCT.9 They explained this observation as either the presence of PEDs in the center of nonleaking CSCR (explaining that these can show pooling of fluid after the 10– 15 minutes of FA), or possible self-sealing of the leaking site, as previously explained by Gass. Garg et al. investigated 100 patients with CSCR in 1982, before the availability of OCT. Of those, 10 did not show any leakage on FA. Four were diagnosed as rhegmatogenous retinal detachment, four were in the healing stage, and two were diagnosed as cystoid macular edema.10 Cystoid macular edema can be a sign of chronic CSCR, and leakage is not always
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FIG. 1 Multifocal central serous chorioretinopathy. Fluorescein angiography of a 44-year-old woman presenting with multifocal central serous chorioretinopathy (CSCR) in the right eye, with repeated episodes over several months. Visual acuity was 6/5 in the right eye. (A) 38 seconds. Several hyperreflective foci can be seen in the macula. (B) 8:26 minutes. Leakage can be seen from several of the foci, corresponding with active CSCR foci showing an inkblot pattern.
evident on FA. In a study by Iida at al. examining eight eyes of seven patients with chronic CSCR with spontaneous resolution of the subretinal fluid in the macula, four eyes had cystoid changes seen on OCT, but with only a window defect seen on FA.11 A variety of patterns can be seen on fluorescein angiography (FA) in acute CSCR.
INKBLOT PATTERN With the inkblot pattern, the leakage starts as a pinpoint in the early phase and gradually enlarges concentrically in the late phase to appear as an inkblot (Fig. 2). This leak usually represents a slow diffusion of the dye through an incomplete or healing defect in the RPE.1, 12
SMOKESTACK PATTERN The smokestack pattern is less frequent, appearing only in about 10%–15% of patients with acute CSCR. As with the inkblot pattern, the smokestack pattern starts as a pinpoint in the early phase. Later, however, the hyperfluorescence ascends vertically in the subretinal space, then expands laterally.12 Extending either nasally or temporally, the resulting shape resembles a smokestack (Fig. 3). Often the ascending column of dye spreads in all directions, resembling a mushroom or umbrella.13 Some investigators have documented change in direction of the ascending dye with change of posture of the patient.14, 15 Presumably, the smokestack pattern occurs because of molecular weight differences between the dye and the components of the subretinal fluid and because of convection currents within the subretinal fluid.1
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Evolution of Typical Leakage
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FIG. 2 Inkblot pattern in a patient with central serous chorioretinopathy. Fluorescein angiography of the left eye of a 58-year-old man presenting with acute central serous chorioretinopathy. Visual acuity was 6/9 in the right eye. (A–D) A peripapillary focus of hyperfluorescence first showing as a pinpoint lesion (A, 23 seconds) and gradually enlarging concentrically to appear as an inkblot (D, 8:13 minutes).
This pattern has been shown to be more frequent in first acute episodes, and is less common in recurrent or chronic episodes. It also appears to be more common when the area of CSCR is larger than one disc diameter.13 In spite of this distinction between the two patterns, multiple foci can be seen in the same eye depicting both inkblot and smokestack patterns.16
EVOLUTION OF TYPICAL LEAKAGE Gomez-Ulla et al. demonstrated the chronological relationship between PEDs and the typical smokestack leakage of CSCR in a 47-year-old woman. On initial examination, a PED was seen clinically, with FA showing progressive hyperfluorescence corresponding to a serous PED. Three months later, FA showed a progressive filling of the persistent PED, this time with a focus of leakage near its upper margin that became a smokestack image and partial filling of the subretinal space, suggestive of CSCR.17 The authors hypothesized that an “unexplained process” in the RPE might have led to the change.
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FIG. 3 Smokestack pattern in a patient with central serous chorioretinopathy. Fluorescein angiography of a 42-year-old man with acute central serous chorioretinopathy in the right eye. Visual acuity was 6/9 in that eye. (A–C) A central focus of hyperfluorescence starting as a pinpoint (A, 45 seconds) and ascending vertically in the subretinal space (B, 5:10 minutes) until it expands laterally (C, 10:50 minutes).
Later, Gass provided the explanation in the form of a small hole forming in the RPE through which the dye passes in the transformation between a PED and a CSCR lesion. The hole often is located at the margin of, and occasionally within, the dome of the detached RPE.8 Yoshioka et al. created a monkey animal model closely resembling human CSCR induced by repeated intravenous injections of adrenalin. Fluorescein angiography confirmed findings consistent with human CSCR. Histopathology of the enucleated eyes demonstrated the sporadic presence of spaces at the basal region of RPE cells and between adjacent cells. Electron microscopic view of the pigment epithelial cells showed that basal infoldings of the RPE cells were remarkably enlarged to form wide spaces, but the intercellular junctional complex between the basal infoldings and the basal lamina of the RPE cell was preserved. Although separation of the intercellular gap junction between adjacent cells was noted, the tight junction was intact.18
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Manifestation of Previous Episodes on Fluorescein Angiography
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THE SIGNIFICANCE OF LEAKAGE INTENSITY ON FLUORESCEIN ANGIOGRAPHY Because choroidal vasodilation and leakage through the RPE are key mechanisms leading to CSCR,5 and the resorption of the subretinal fluid depends on the pumping capacity of RPE cells, the intensity of RPE leakage and choroidal hyperpermeability can influence the duration of acute episodes. In a study by Daruich et al. following 31 patients with acute CSCR, a trend was seen between intense fluorescein leakage (measured as the ratio of fluorescein expansion between midphase and early phase of the angiogram) and longer episodes (P = .074). 19 Although the results are not statistically significant, probably because of the relatively small sample size, this might be a useful marker in the assessment of patients with acute disease.
CHRONIC CENTRAL SEROUS CHORIORETINOPATHY In cases of chronic CSCR, FA shows diffuse RPE window defect and patchy hyperfluorescence because of RPE atrophy (Fig. 4).12 Multiple focal areas of staining often are revealed, usually most prominent near the superior aspect of the multiple zones of hyperfluorescence that correspond to areas of RPE atrophy. The atrophy and staining frequently are prominent in the juxtapapillary region of both eyes.8
MANIFESTATION OF PREVIOUS EPISODES ON FLUORESCEIN ANGIOGRAPHY Sequelae of previous episodes appear as hyperfluorescent areas because of increased transmission through localized RPE defects (Fig. 5). 5 These can appear in areas of previously known central CSCR, discovered because of visual disturbance, or in areas of peripheral lesions previously unnoticed by the patient because of their extramacular location. Such findings also can be found in the fellow, often asymptomatic, eye. A study by Levine et al. that followed 14 eyes of 13 patients with documented spontaneous resolution of symptomatic macular CSCR aimed to determine the fate of the RPE as viewed angiographically. In the initially affected eyes, nonleaking RPE defects developed inside the areas of previous serous detachment in all cases. Nonleaking RPE defects had developed outside these areas in 43% of eyes. Additionally, 42% of fellow eyes had signs of RPE window defects.20 Bujarborua et al. studied the FA features of 70 unilateral symptomatic CSCR patients. Findings in the asymptomatic fellow eye included a window defect in 31.42% of cases, RPE atrophy in 4.28%, PED in 32.85%, fluorescein leak in 31.42%, depigmented patches in 14.28%, and pigment clumps in 4.29%. Sixty-one percent of fellow eyes had evidence of chronic subclinical CSCR, whereas 38% had features of clinically healed CSCR.21 The abundance of angiographic findings in fellow asymptomatic eyes shows that, in many patients, CSC might be a bilateral, asymmetrical, chronic disease.
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FIG. 4 Chronic central serous chorioretinopathy. Fluorescein angiography of a 71-year-old man with chronic central serous chorioretinopathy. Visual acuity in that eye was 6/9. (A–D) progression of fluorescein angiography starting at 42 seconds (A) and ending at 5 minutes and 48 seconds (D). Findings include a window defect, as well as patchy hyperfluorescent areas signifying RPE atrophy. A central area of staining is seen in the last image.
FIG. 5 Evidence of prior episodes of central serous chorioretinopathy on fluorescein angiography. Fluorescein angiography of a 45-year-old man with previous and recurrent multifocal central serous chorioretinopathy. Visual acuity was 6/5 in the right eye, and 6/12 in the left eye. (A) Right eye, 3 minutes and 37 seconds. Several areas of localized pigment epithelial defects can be seen as a window defect on fluorescein angiography, corresponding to previous episodes of active CSCR in that area. (B) Left eye, 1 minute and 22 seconds. Two active inkblot foci can be seen superiorly and superonasally to the optic disc. In the macula, areas of pigment epithelial defects appear as markers of previous active foci.
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FLUORESCEIN ANGIOGRAPHY COMPARED TO OTHER IMAGING MODALITIES (FIG. 6) Fundus Autofluorescence Fundus autofluorescence (FAF) allows for noninvasive detection of CSCR at different phases of the disease (see Chapter 7). Although both FA and FAF allow for the distinction of different disease phases (acute, chronic, evidence of previous episodes), each demonstrates
FIG. 6 Comparison of fluorescein angiography to other imaging modalities in central serous chorioretinopathy. Multimodal imaging of a 55-year-old man with chronic central serous chrorioretinopathy (CSCR) of the left eye. Visual acuity was 6/6 in that eye. (A) fluorescein angiography (FA) (4 minutes and 56 seconds), demonstrating perifoveal staining and some leakage. (B) Optical coherence tomography showing a small amount of subretinal fluid. (C) Indocyanine green angiography taken at the same time as FA demonstrating choroidal hyperpermeability in the form of hyperfluorescence. Dilated choroidal vessels are seen inferiorly to the area of hyperfluorescence. (D) Fundus autofluorescence, showing a patch of hyperfluorescence suggestive of the chronicity of the condition.
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these phases uniquely. The combination of both modalities, usually achieved easily using the same device, assists in reaching the correct diagnosis. In the acute stage, focal leakage points show as areas of hypoautofluorescence, unlike the hyperfluorescent foci of FA. The subretinal fluid also results in hypoautofluorescence (either confluent or granular22), resulting from the masking effect of the fluid, unlike the hyperautofluorescence of FA resulting from pooling of the dye. When the disease becomes chronic, with resolution of the fluid, FAF shows increasing hyperautofluorescence (diffuse or punctate22) because of the accumulation of nonshed fluorophores. Finally, a pathognomonic finding seen on FAF of chronic CSCR are hypofluorescent gravitational tracks not seen on FA, with a thin border of surrounding hyperautofluorescence.12
Indocyanine Green Angiography Indocyanine green angiography (ICGA) (see Chapter 9) shows a delay in choroidal filling in the early phase with hypofluorescent areas because of choriocapillaries nonperfusion. In the mid-stage of the angiogram, areas of hyperfluorescence indicate either choroidal hyperpermeability or the presence of fibrin.1 In the late phase, there is either washout or persistent hyperfluorescence. Punctate hyperfluorescent spots also are seen frequently in the mid-late phases in the majority of patients with active disease.12 The benefit of ICGA over FA alone is the ability to demonstrate choroidal abnormalities that cannot be detected with FA. Additionally, ICGA can demonstrate dilation of choroidal vessels, a finding that has led to the inclusion of CSCR in the spectrum of pachychoroid diseases (see Chapter 2).
Optical Coherence Tomography Spectral domain optical coherence tomography (SD-OCT) (see Chapter 10) adds to the information learned from FA by providing high-resolution cross-sectional images of the macula. In CSCR, it can demonstrate the serous detachment as well as PEDs, a distinction that is not always possible with the use of FA as a single imaging modality. Technologies such as enhanced-depth imaging OCT or swept-source OCT frequently can demonstrate a thickened choroid (pachychoroid), which, along with choroidal dilatation on ICGA, aid in the characterization of CSCR as belonging to the pachychoroid spectrum of diseases, as previously mentioned. FA cannot demonstrate these changes. Also as mentioned previously, one of the advantages of FA is its possible use as a guide for laser treatment of eccentric leaks or photodynamic therapy. Recent literature, however, shows that treatment guidance can be done using other, noninvasive modalities such as OCT. A study by Maltsev et al. on 48 patients with CSC attempted to colocalize leakage points seen on FA with PEDs and areas of photoreceptor outer segment layer thinning on OCT.23 Using retromode confocal scanning laser ophthalmoscopy, they showed that coincidence with PED was found in 80% of leakage points, and thinning of the photoreceptor outer segment layer was found in 90.4% of those. The mean distance from the upper border of neurosensory detachment to the leakage point was 27.3% ± 13.0% of the vertical dimension of the neurosensory detachment. These data demonstrate that, in patients with nonresolving chronic CSCR who are considered candidates for laser photocoagulation treatment, OCT might be sufficient
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as guidance for treatment if they have a small single PED localizing in the upper 1/3–1/2 of the neurosensory detachment area with an area of photoreceptor outer segment thinning above this PED. In many cases, SD-OCT can be sufficient for the diagnosis of CSCR, because it can demonstrate the subretinal fluid and PEDs without the need for the invasive FA. Furthermore, Yannuzzi et al. showed that central hyporeflective subretinal hyporeflective lucency foci on SD-OCT surrounded by hyperreflective fibrin correlate with active leakage on FA. In some cases, the lucent area could be visualized as communicating with a defect in the RPE. En face imaging of the lucency revealed a smokestack appearance, and resolution of the leak correlated with the disappearance of the lucency on SD-OCT.24
THE USE OF FLUORESCEIN ANGIOGRAPHY IN CHOROIDAL NEOVASCULARIZATION Choroidal neovascularization is a complication of CSCR, and FA helps to confirm the diagnosis. If associated with polypoidal vasculopathy, however, ICG has better diagnostic potential.
THE ROLE OF FLUORESCEIN ANGIOGRAPHY IN DIFFERENTIATING FROM CENTRAL SEROUS CHORIORETINOPATHY MASQUERADES Age-Related Macular Degeneration Neovascular age-related macular degeneration (AMD) can present similarly to CSCR. As previously discussed, the most common presentation of acute CSCR is the inkblot pattern, wherein a dot of hyperfluorescence increases in size and intensity of fluoresence, similar to a small area of choroidal neovascularization (CNV). In patients older than 50, the diagnosis of AMD should be considered. In addition to the clinical appearance of a CNV on biomicroscopy and its appearance on OCT, FA can provide helpful clues. Drusen can be seen as hyperfluorescent foci because of staining, and their presence bilaterally can confirm the diagnosis of AMD. Areas of blocked fluorescence might appear, signifying hemorrhage, which is usually not a part of the presentation in CSCR. Additionally, although the pinpoint leak in CSCR is small relative to a large area of subretinal fluid, in AMD the area of leakage on angiography usually corresponds more closely to the area of subretinal fluid (Fig. 7).
Optic Disc Pit Optic disc pits are focal excavations in the temporal aspect of the optic nerve head communicating the vitreous cavity with the subretinal space and the subarachnoid space. 12 In the case of subretinal detachment, FA will demonstrate absence of leakage, helping to distinguish the condition from CSCR (Fig. 8).
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FIG. 7 Fluorescein angiography photograph of choroidal neovascularization associated with age-related macular degeneration. Fluorescein angiography (FA) of the left eye of a 66-year-old woman with previously known age- related macular degeneration presenting with visual deterioration. FA demonstrates an area of hyperfluorescence in a lacy pattern corresponding to a classic choroidal neovascularization. A streak of blocked hypofluorescence appears vertically on its nasal side, caused by hemorrhage.
FIG. 8 Optic disc pit. Multimodal imaging of a 35-year-old man presenting with left eye metamorphopsia. Color photograph (A) shows an optic disc pit, and optical coherence tomography (B) shows subretinal fluid, similar to the picture seen with central serous chorioretinopathy (CSCR). (C) Fluorescein angiography shows staining of an area of peripapillary atrophy, without the leakage expected with CSCR. II. IMAGING
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Vogt-Koyanagi-Harada Disease Vogt-Koyanagi-Harada (VKH) disease is a multisystemic disorder with bilateral granulomatous panuveitis. It often presents with multiple serous retinal detachments mimicking CSCR.12 Fluorescein angiography shows multifocal pinpoint leaks. Although this can resemble multifocal CSCR, the combination of systemic signs (such as headaches and tinnitus), presence of granulomatous inflammatory changes in the eye, and the multitude of focal hyperfluorescent areas on FA help point at a diagnosis of VKH (Fig. 9).
Posterior Scleritis Posterior scleritis, another inflammatory etiology, also can present with subretinal fluid, mimicking CSCR. FA can show multiple pinpoint leakage foci, further confounding the diagnosis. The presentation, however, usually includes ocular pain, unlike the painless visual loss occurring in CSCR. The correct diagnosis can be reached by the demonstration of choroidal folding on fundus examination or OCT as well as the pathognomonic T-sign by ultrasonography, caused by thickening of the posterior sclera.
Dome-Shaped Macula Dome-shaped macula (DSM) is a forward bulge of the macula within a posterior pole staphyloma in myopic patients, which can involve fluctuating central serous detachments in about 50% of these eyes.25 FA can show pinpoint leakage, similar to CSCR. The diagnosis can be reached by observing the dome shape of the macula on OCT and by ruling out the presence of CNV with the aid of OCT angiography (Fig. 10).
FIG. 9 Fluorescein angiography photograph of a patient with Vogt-Koyanagi-Harada disease. Fluorescein angiography (FA) of a 31-year-old man with Vogt-Koyanagi-Harada disease. This condition presents on FA with multiple pinpoint areas of leakage, sometimes called “starry sky” because of its unique appearance.
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FIG. 10 Dome-shaped macula. Multimodal imaging of a 50-year-old myopic woman with dome-shaped macula (DSM). (A) optical coherence tomography showing the characteristic dome-shape of the central macula, along with subretinal fluid. (B and C) fluorescein angiography shows central leakage.
FLUORESCEIN ANGIOGRAPHY IN THE BULLOUS VARIANT OF CENTRAL SEROUS CHORIORETINOPATHY CSCR may take a rare form of large, usually multiple, sectors of bullous serous retinal and/or RPE detachments. Typical features include greater numbers and sizes of areas of choroidal hyperpermeability and bullous retinal detachments, which often extend inferiorly by gravitation. 26 These patients might be misdiagnosed as having a rhegmatogenous retinal detachment, multifocal chorioretinitis, a metastatic process, VKH, or uveal effusion. FA demonstrates multiple serous PEDs. Combined with the underlying shifting subretinal fluid, an accurate diagnosis can be made.8 (See also Chapter 15.)
THE ROLE OF PERIPHERAL IMAGES/WIDE FIELD/ EXTRAMACULAR FLUORESCEIN ANGIOGRAPHY Peripheral fields can be useful to assess the extent of multifocal CSCR or the length of gravitational tracts caused by the condition. Widefield angiograms also can help to distinguish typical CSCR from peripheral lesions such as a retinal hole that can cause subretinal fluid to track to the center.
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REFERENCES 95
References 1. Freund KB, Sarraf D, Mieler WF, Yannuzzi LA, Shields CL. The Retinal Atlas. 2nd ed. Cambridge, MA: Elsevier; 2017. 2. Burumcek E, Mudun A, Karacorlu S, Arslan MO. Laser photocoagulation for persistent central serous retinopathy: results of long-term follow-up. Ophthalmology. 1997;104(4):616–622. http://www.ncbi.nlm.nih.gov/ pubmed/9111253. Accessed 4 June 2018. 3. Malik KJ, Sampat KM, Mansouri A, Steiner JN, Glaser BM. Low-intensity/high-density subthreshold micropulse diode laser for chronic central serous chorioretinopathy. Retina. 2015;35(3):532–536. https://doi. org/10.1097/IAE.0000000000000285. 4. Kim KS, Lee WK, Lee SB. Half-dose photodynamic therapy targeting the leakage point on the fluorescein angiography in acute central serous chorioretinopathy: a pilot study. Am J Ophthalmol. 2014;157(2). https://doi. org/10.1016/j.ajo.2013.10.013. 366–373.e1. 5. Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82–118. https://doi.org/10.1016/j.preteyeres.2015.05.003. 6. Mutlak JA, Dutton GN. Fluorescein angiographic features of acute central serous retinopathy: a retrospective study. Acta Ophthalmol. 1989;67(4):467–469. 7. Spitznas M, Huke J. Number, shape, and topography of leakage points in acute type I central serous retinopathy. Graefes Arch Clin Exp Ophthalmol. 1987;225(6):437–440. http://www.ncbi.nlm.nih.gov/pubmed/3678855. Accessed 9 June 2018. 8. Agarwal A. Gass’ Atlas of Macular Diseases. 5th ed. Cambridge, MA: Elsevier; 2012. 9. Khalil M, Malik TG, Chaudhary QL, Shafiq MM. Angiographic patterns and tomographic findings in central serous chorioretinopathy revisited. Pak J Med Health Sci. 2015;9(4):1409–1413. 10. Garg SP, Tewari HK, Khosia PK, Azad RV. Fluorescein angiography in central serous retinopathy. Indian J Ophthalmol. 1982;30:593–596. 11. Iida T, Yannuzzi LA, Spaide RF, Borodoker N, Carvalho CA, Negrao S. Cystoid macular degeneration in chronic central serous chorioretinopathy. Retina. 2003;23(1):1–7. quiz 137-138. 12. Lam D, Das S, Liu S, Lee V, Lu L. Ryan’s Retina. In: Ryan’s Retina. 6th ed. Cambridge, MA: Elsevier; 2018:1465–1483. 13. Bujarborua D, Nagpal PN, Deka M. Smokestack leak in central serous chorioretinopathy. Graefe’s Arch Clin Exp Ophthalmol. 2010;248(3):339–351. https://doi.org/10.1007/s00417-009-1212-5. 14. Shimizu K, Tobari I. Central serous retinopathy dynamics of subretinal fluid. Mod Probl Ophthalmol. 1971;9:152–157. 15. Yannuzzi LA, Gitter KA, Schatz H, et al. Central serous chorioretinopathy. In: The Macula – A Comprehensive Text and Atlas. Baltimore: Williams & Wilkins; 1979:145–165. 16. Gurung RL. Numerous smokestack and inkblot pattern leaks in central serous chorioretinopathy. JAMA Ophthalmol. 2017;135(5):e170128. https://doi.org/10.1001/jamaophthalmol.2017.0128. 17. Gómez-Ulla F, Vázquez JM, Rodríguez-Cid MJ, Des J, González F. Central serous chorioretinopathy following pigment epithelium detachment: fluorescein and indocyanine green angiography follow-up. Acta Ophthalmol Scand. 2000;78(2):232–234. http://www.ncbi.nlm.nih.gov/pubmed/10794266. Accessed 9 June 2018. 18. Yoshioka H, Katsume Y, Akune H, Nagasaki H. Experimental central serous chorioretinopathy. IV: Fluorescein angiography and electron microscopy during spontaneous healing process. Kurume Med J. 1984;31(2):89–99. http://www.ncbi.nlm.nih.gov/pubmed/6521425. Accessed 9 June 2018. 19. Daruich A, Matet A, Marchionno L, et al. Acute central serous chorioretinopathy: factors influencing episode duration. Retina. 2017;37(10):1905. 20. Levine R, Brucker AJ, Robinson F. Long-term follow-up of idiopathic central serous chorioretinopathy by fluorescein angiography. Ophthalmology. 1989;96(6):854–859. http://www.ncbi.nlm.nih.gov/pubmed/2740080. Accessed 9 June 2018. 21. Bujarborua D, Chatterjee S, Choudhury A, Bori G, Sarma AK. Fluorescein angiographic features of asymptomatic eyes in central serous chorioretinopathy. Retina. 2005;25(4):422–429. http://www.ncbi.nlm.nih.gov/ pubmed/15933587. Accessed 9 June 2018. 22. Zola M, Chatziralli I, Menon D, Schwartz R, Hykin P, Sivaprasad S. Evolution of fundus autofluorescence patterns over time in patients with chronic central serous chorioretinopathy. Acta Ophthalmol. 2018; https://doi. org/10.1111/aos.13742.
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Maltsev DS, Kulikov AN, Chhablani J. Topography-guided identification of leakage point in central serous chorioretinopathy: a base for fluorescein angiography-free focal laser photocoagulation. Br J Ophthalmol. 2018. bjophthalmol—2017. Yannuzzi NA, Mrejen S, Capuano V, Bhavsar KV, Querques G, Freund KB. A central hyporeflective subretinal lucency correlates with a region of focal leakage on fluorescein angiography in eyes with central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging Retina. 2015;46(8):832–836. https://doi. org/10.3928/23258160-20150909-07. Caillaux V, Gaucher D, Gualino V, Massin P, Tadayoni R, Gaudric A. Morphologic characterization of domeshaped macula in myopic eyes with serous macular detachment. Am J Ophthalmol. 2013;156(5):958–967. Liegl R, Ulbig MW. Central serous chorioretinopathy. Ophthalmologica. 2014;232(2):65–76. https://doi. org/10.1159/000360014.
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8 Fundus Fluorescein Angiography Roy Schwartz, Sobha Sivaprasad NIHR Biomedical Research Centre, Moorfields Eye Hospital, London, United Kingdom
Central serous chorioretinopathy (CSCR) is characterized by a focal or multifocal leak at the level of the retinal pigment epithelium (RPE), often in conjunction with a serous pigment epithelial detachment (PED). An active leak is characterized by angiographic pooling of fluorescein dye into the subretinal space.1 With the availability of newer imaging modalities such as spectral-domain optical coherence tomography (SD-OCT) (see Chapter 10), FA is not always mandatory for the diagnosis of CSCR. It is helpful, however, in confirming the diagnosis when in doubt and serves as a guide for laser treatment of eccentric leaks or photodynamic therapy.2–4 Acute CSCR usually presents with a single leakage site, although rarely two or more sites can be seen (Fig. 1).2 When more than one site of leakage is observed, a single site usually is responsible for the ongoing episode.5 The area most commonly affected is the superonasal retina, possibly because of a higher metabolic rate within the RPE in the proximity of the papillomacular bundle.6, 7 Sometimes, no leakage can be seen on fluorescein angiography in spite of the presence of a serous detachment seen clinically or on OCT. According to Gass, failure to find evidence of a leak angiographically in such patients should suggest either a leak outside the macular area, usually superiorly; a spontaneously sealed leaking area, suggesting that the detachment will disappear subsequently; the presence of a peripheral retinal hole or choroidal tumor, usually superiorly; a congenital optic nerve pit; or the presence of idiopathic uveal effusion syndrome. 8 Only a few studies reported cases without leakage. Khalil et al. examined 51 patients with active CSCR. Of those, 19.6% demonstrated no leakage on FA in spite of the existence of a serous detachment seen on OCT.9 They explained this observation as either the presence of PEDs in the center of nonleaking CSCR (explaining that these can show pooling of fluid after the 10– 15 minutes of FA), or possible self-sealing of the leaking site, as previously explained by Gass. Garg et al. investigated 100 patients with CSCR in 1982, before the availability of OCT. Of those, 10 did not show any leakage on FA. Four were diagnosed as rhegmatogenous retinal detachment, four were in the healing stage, and two were diagnosed as cystoid macular edema.10 Cystoid macular edema can be a sign of chronic CSCR, and leakage is not always
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FIG. 1 Multifocal central serous chorioretinopathy. Fluorescein angiography of a 44-year-old woman presenting with multifocal central serous chorioretinopathy (CSCR) in the right eye, with repeated episodes over several months. Visual acuity was 6/5 in the right eye. (A) 38 seconds. Several hyperreflective foci can be seen in the macula. (B) 8:26 minutes. Leakage can be seen from several of the foci, corresponding with active CSCR foci showing an inkblot pattern.
evident on FA. In a study by Iida at al. examining eight eyes of seven patients with chronic CSCR with spontaneous resolution of the subretinal fluid in the macula, four eyes had cystoid changes seen on OCT, but with only a window defect seen on FA.11 A variety of patterns can be seen on fluorescein angiography (FA) in acute CSCR.
INKBLOT PATTERN With the inkblot pattern, the leakage starts as a pinpoint in the early phase and gradually enlarges concentrically in the late phase to appear as an inkblot (Fig. 2). This leak usually represents a slow diffusion of the dye through an incomplete or healing defect in the RPE.1, 12
SMOKESTACK PATTERN The smokestack pattern is less frequent, appearing only in about 10%–15% of patients with acute CSCR. As with the inkblot pattern, the smokestack pattern starts as a pinpoint in the early phase. Later, however, the hyperfluorescence ascends vertically in the subretinal space, then expands laterally.12 Extending either nasally or temporally, the resulting shape resembles a smokestack (Fig. 3). Often the ascending column of dye spreads in all directions, resembling a mushroom or umbrella.13 Some investigators have documented change in direction of the ascending dye with change of posture of the patient.14, 15 Presumably, the smokestack pattern occurs because of molecular weight differences between the dye and the components of the subretinal fluid and because of convection currents within the subretinal fluid.1
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FIG. 2 Inkblot pattern in a patient with central serous chorioretinopathy. Fluorescein angiography of the left eye of a 58-year-old man presenting with acute central serous chorioretinopathy. Visual acuity was 6/9 in the right eye. (A–D) A peripapillary focus of hyperfluorescence first showing as a pinpoint lesion (A, 23 seconds) and gradually enlarging concentrically to appear as an inkblot (D, 8:13 minutes).
This pattern has been shown to be more frequent in first acute episodes, and is less common in recurrent or chronic episodes. It also appears to be more common when the area of CSCR is larger than one disc diameter.13 In spite of this distinction between the two patterns, multiple foci can be seen in the same eye depicting both inkblot and smokestack patterns.16
EVOLUTION OF TYPICAL LEAKAGE Gomez-Ulla et al. demonstrated the chronological relationship between PEDs and the typical smokestack leakage of CSCR in a 47-year-old woman. On initial examination, a PED was seen clinically, with FA showing progressive hyperfluorescence corresponding to a serous PED. Three months later, FA showed a progressive filling of the persistent PED, this time with a focus of leakage near its upper margin that became a smokestack image and partial filling of the subretinal space, suggestive of CSCR.17 The authors hypothesized that an “unexplained process” in the RPE might have led to the change.
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FIG. 3 Smokestack pattern in a patient with central serous chorioretinopathy. Fluorescein angiography of a 42-year-old man with acute central serous chorioretinopathy in the right eye. Visual acuity was 6/9 in that eye. (A–C) A central focus of hyperfluorescence starting as a pinpoint (A, 45 seconds) and ascending vertically in the subretinal space (B, 5:10 minutes) until it expands laterally (C, 10:50 minutes).
Later, Gass provided the explanation in the form of a small hole forming in the RPE through which the dye passes in the transformation between a PED and a CSCR lesion. The hole often is located at the margin of, and occasionally within, the dome of the detached RPE.8 Yoshioka et al. created a monkey animal model closely resembling human CSCR induced by repeated intravenous injections of adrenalin. Fluorescein angiography confirmed findings consistent with human CSCR. Histopathology of the enucleated eyes demonstrated the sporadic presence of spaces at the basal region of RPE cells and between adjacent cells. Electron microscopic view of the pigment epithelial cells showed that basal infoldings of the RPE cells were remarkably enlarged to form wide spaces, but the intercellular junctional complex between the basal infoldings and the basal lamina of the RPE cell was preserved. Although separation of the intercellular gap junction between adjacent cells was noted, the tight junction was intact.18
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THE SIGNIFICANCE OF LEAKAGE INTENSITY ON FLUORESCEIN ANGIOGRAPHY Because choroidal vasodilation and leakage through the RPE are key mechanisms leading to CSCR,5 and the resorption of the subretinal fluid depends on the pumping capacity of RPE cells, the intensity of RPE leakage and choroidal hyperpermeability can influence the duration of acute episodes. In a study by Daruich et al. following 31 patients with acute CSCR, a trend was seen between intense fluorescein leakage (measured as the ratio of fluorescein expansion between midphase and early phase of the angiogram) and longer episodes (P = .074). 19 Although the results are not statistically significant, probably because of the relatively small sample size, this might be a useful marker in the assessment of patients with acute disease.
CHRONIC CENTRAL SEROUS CHORIORETINOPATHY In cases of chronic CSCR, FA shows diffuse RPE window defect and patchy hyperfluorescence because of RPE atrophy (Fig. 4).12 Multiple focal areas of staining often are revealed, usually most prominent near the superior aspect of the multiple zones of hyperfluorescence that correspond to areas of RPE atrophy. The atrophy and staining frequently are prominent in the juxtapapillary region of both eyes.8
MANIFESTATION OF PREVIOUS EPISODES ON FLUORESCEIN ANGIOGRAPHY Sequelae of previous episodes appear as hyperfluorescent areas because of increased transmission through localized RPE defects (Fig. 5). 5 These can appear in areas of previously known central CSCR, discovered because of visual disturbance, or in areas of peripheral lesions previously unnoticed by the patient because of their extramacular location. Such findings also can be found in the fellow, often asymptomatic, eye. A study by Levine et al. that followed 14 eyes of 13 patients with documented spontaneous resolution of symptomatic macular CSCR aimed to determine the fate of the RPE as viewed angiographically. In the initially affected eyes, nonleaking RPE defects developed inside the areas of previous serous detachment in all cases. Nonleaking RPE defects had developed outside these areas in 43% of eyes. Additionally, 42% of fellow eyes had signs of RPE window defects.20 Bujarborua et al. studied the FA features of 70 unilateral symptomatic CSCR patients. Findings in the asymptomatic fellow eye included a window defect in 31.42% of cases, RPE atrophy in 4.28%, PED in 32.85%, fluorescein leak in 31.42%, depigmented patches in 14.28%, and pigment clumps in 4.29%. Sixty-one percent of fellow eyes had evidence of chronic subclinical CSCR, whereas 38% had features of clinically healed CSCR.21 The abundance of angiographic findings in fellow asymptomatic eyes shows that, in many patients, CSC might be a bilateral, asymmetrical, chronic disease.
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FIG. 4 Chronic central serous chorioretinopathy. Fluorescein angiography of a 71-year-old man with chronic central serous chorioretinopathy. Visual acuity in that eye was 6/9. (A–D) progression of fluorescein angiography starting at 42 seconds (A) and ending at 5 minutes and 48 seconds (D). Findings include a window defect, as well as patchy hyperfluorescent areas signifying RPE atrophy. A central area of staining is seen in the last image.
FIG. 5 Evidence of prior episodes of central serous chorioretinopathy on fluorescein angiography. Fluorescein angiography of a 45-year-old man with previous and recurrent multifocal central serous chorioretinopathy. Visual acuity was 6/5 in the right eye, and 6/12 in the left eye. (A) Right eye, 3 minutes and 37 seconds. Several areas of localized pigment epithelial defects can be seen as a window defect on fluorescein angiography, corresponding to previous episodes of active CSCR in that area. (B) Left eye, 1 minute and 22 seconds. Two active inkblot foci can be seen superiorly and superonasally to the optic disc. In the macula, areas of pigment epithelial defects appear as markers of previous active foci.
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FLUORESCEIN ANGIOGRAPHY COMPARED TO OTHER IMAGING MODALITIES (FIG. 6) Fundus Autofluorescence Fundus autofluorescence (FAF) allows for noninvasive detection of CSCR at different phases of the disease (see Chapter 7). Although both FA and FAF allow for the distinction of different disease phases (acute, chronic, evidence of previous episodes), each demonstrates
FIG. 6 Comparison of fluorescein angiography to other imaging modalities in central serous chorioretinopathy. Multimodal imaging of a 55-year-old man with chronic central serous chrorioretinopathy (CSCR) of the left eye. Visual acuity was 6/6 in that eye. (A) fluorescein angiography (FA) (4 minutes and 56 seconds), demonstrating perifoveal staining and some leakage. (B) Optical coherence tomography showing a small amount of subretinal fluid. (C) Indocyanine green angiography taken at the same time as FA demonstrating choroidal hyperpermeability in the form of hyperfluorescence. Dilated choroidal vessels are seen inferiorly to the area of hyperfluorescence. (D) Fundus autofluorescence, showing a patch of hyperfluorescence suggestive of the chronicity of the condition.
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these phases uniquely. The combination of both modalities, usually achieved easily using the same device, assists in reaching the correct diagnosis. In the acute stage, focal leakage points show as areas of hypoautofluorescence, unlike the hyperfluorescent foci of FA. The subretinal fluid also results in hypoautofluorescence (either confluent or granular22), resulting from the masking effect of the fluid, unlike the hyperautofluorescence of FA resulting from pooling of the dye. When the disease becomes chronic, with resolution of the fluid, FAF shows increasing hyperautofluorescence (diffuse or punctate22) because of the accumulation of nonshed fluorophores. Finally, a pathognomonic finding seen on FAF of chronic CSCR are hypofluorescent gravitational tracks not seen on FA, with a thin border of surrounding hyperautofluorescence.12
Indocyanine Green Angiography Indocyanine green angiography (ICGA) (see Chapter 9) shows a delay in choroidal filling in the early phase with hypofluorescent areas because of choriocapillaries nonperfusion. In the mid-stage of the angiogram, areas of hyperfluorescence indicate either choroidal hyperpermeability or the presence of fibrin.1 In the late phase, there is either washout or persistent hyperfluorescence. Punctate hyperfluorescent spots also are seen frequently in the mid-late phases in the majority of patients with active disease.12 The benefit of ICGA over FA alone is the ability to demonstrate choroidal abnormalities that cannot be detected with FA. Additionally, ICGA can demonstrate dilation of choroidal vessels, a finding that has led to the inclusion of CSCR in the spectrum of pachychoroid diseases (see Chapter 2).
Optical Coherence Tomography Spectral domain optical coherence tomography (SD-OCT) (see Chapter 10) adds to the information learned from FA by providing high-resolution cross-sectional images of the macula. In CSCR, it can demonstrate the serous detachment as well as PEDs, a distinction that is not always possible with the use of FA as a single imaging modality. Technologies such as enhanced-depth imaging OCT or swept-source OCT frequently can demonstrate a thickened choroid (pachychoroid), which, along with choroidal dilatation on ICGA, aid in the characterization of CSCR as belonging to the pachychoroid spectrum of diseases, as previously mentioned. FA cannot demonstrate these changes. Also as mentioned previously, one of the advantages of FA is its possible use as a guide for laser treatment of eccentric leaks or photodynamic therapy. Recent literature, however, shows that treatment guidance can be done using other, noninvasive modalities such as OCT. A study by Maltsev et al. on 48 patients with CSC attempted to colocalize leakage points seen on FA with PEDs and areas of photoreceptor outer segment layer thinning on OCT.23 Using retromode confocal scanning laser ophthalmoscopy, they showed that coincidence with PED was found in 80% of leakage points, and thinning of the photoreceptor outer segment layer was found in 90.4% of those. The mean distance from the upper border of neurosensory detachment to the leakage point was 27.3% ± 13.0% of the vertical dimension of the neurosensory detachment. These data demonstrate that, in patients with nonresolving chronic CSCR who are considered candidates for laser photocoagulation treatment, OCT might be sufficient
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as guidance for treatment if they have a small single PED localizing in the upper 1/3–1/2 of the neurosensory detachment area with an area of photoreceptor outer segment thinning above this PED. In many cases, SD-OCT can be sufficient for the diagnosis of CSCR, because it can demonstrate the subretinal fluid and PEDs without the need for the invasive FA. Furthermore, Yannuzzi et al. showed that central hyporeflective subretinal hyporeflective lucency foci on SD-OCT surrounded by hyperreflective fibrin correlate with active leakage on FA. In some cases, the lucent area could be visualized as communicating with a defect in the RPE. En face imaging of the lucency revealed a smokestack appearance, and resolution of the leak correlated with the disappearance of the lucency on SD-OCT.24
THE USE OF FLUORESCEIN ANGIOGRAPHY IN CHOROIDAL NEOVASCULARIZATION Choroidal neovascularization is a complication of CSCR, and FA helps to confirm the diagnosis. If associated with polypoidal vasculopathy, however, ICG has better diagnostic potential.
THE ROLE OF FLUORESCEIN ANGIOGRAPHY IN DIFFERENTIATING FROM CENTRAL SEROUS CHORIORETINOPATHY MASQUERADES Age-Related Macular Degeneration Neovascular age-related macular degeneration (AMD) can present similarly to CSCR. As previously discussed, the most common presentation of acute CSCR is the inkblot pattern, wherein a dot of hyperfluorescence increases in size and intensity of fluoresence, similar to a small area of choroidal neovascularization (CNV). In patients older than 50, the diagnosis of AMD should be considered. In addition to the clinical appearance of a CNV on biomicroscopy and its appearance on OCT, FA can provide helpful clues. Drusen can be seen as hyperfluorescent foci because of staining, and their presence bilaterally can confirm the diagnosis of AMD. Areas of blocked fluorescence might appear, signifying hemorrhage, which is usually not a part of the presentation in CSCR. Additionally, although the pinpoint leak in CSCR is small relative to a large area of subretinal fluid, in AMD the area of leakage on angiography usually corresponds more closely to the area of subretinal fluid (Fig. 7).
Optic Disc Pit Optic disc pits are focal excavations in the temporal aspect of the optic nerve head communicating the vitreous cavity with the subretinal space and the subarachnoid space. 12 In the case of subretinal detachment, FA will demonstrate absence of leakage, helping to distinguish the condition from CSCR (Fig. 8).
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FIG. 7 Fluorescein angiography photograph of choroidal neovascularization associated with age-related macular degeneration. Fluorescein angiography (FA) of the left eye of a 66-year-old woman with previously known age- related macular degeneration presenting with visual deterioration. FA demonstrates an area of hyperfluorescence in a lacy pattern corresponding to a classic choroidal neovascularization. A streak of blocked hypofluorescence appears vertically on its nasal side, caused by hemorrhage.
FIG. 8 Optic disc pit. Multimodal imaging of a 35-year-old man presenting with left eye metamorphopsia. Color photograph (A) shows an optic disc pit, and optical coherence tomography (B) shows subretinal fluid, similar to the picture seen with central serous chorioretinopathy (CSCR). (C) Fluorescein angiography shows staining of an area of peripapillary atrophy, without the leakage expected with CSCR. II. IMAGING
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Vogt-Koyanagi-Harada Disease Vogt-Koyanagi-Harada (VKH) disease is a multisystemic disorder with bilateral granulomatous panuveitis. It often presents with multiple serous retinal detachments mimicking CSCR.12 Fluorescein angiography shows multifocal pinpoint leaks. Although this can resemble multifocal CSCR, the combination of systemic signs (such as headaches and tinnitus), presence of granulomatous inflammatory changes in the eye, and the multitude of focal hyperfluorescent areas on FA help point at a diagnosis of VKH (Fig. 9).
Posterior Scleritis Posterior scleritis, another inflammatory etiology, also can present with subretinal fluid, mimicking CSCR. FA can show multiple pinpoint leakage foci, further confounding the diagnosis. The presentation, however, usually includes ocular pain, unlike the painless visual loss occurring in CSCR. The correct diagnosis can be reached by the demonstration of choroidal folding on fundus examination or OCT as well as the pathognomonic T-sign by ultrasonography, caused by thickening of the posterior sclera.
Dome-Shaped Macula Dome-shaped macula (DSM) is a forward bulge of the macula within a posterior pole staphyloma in myopic patients, which can involve fluctuating central serous detachments in about 50% of these eyes.25 FA can show pinpoint leakage, similar to CSCR. The diagnosis can be reached by observing the dome shape of the macula on OCT and by ruling out the presence of CNV with the aid of OCT angiography (Fig. 10).
FIG. 9 Fluorescein angiography photograph of a patient with Vogt-Koyanagi-Harada disease. Fluorescein angiography (FA) of a 31-year-old man with Vogt-Koyanagi-Harada disease. This condition presents on FA with multiple pinpoint areas of leakage, sometimes called “starry sky” because of its unique appearance.
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FIG. 10 Dome-shaped macula. Multimodal imaging of a 50-year-old myopic woman with dome-shaped macula (DSM). (A) optical coherence tomography showing the characteristic dome-shape of the central macula, along with subretinal fluid. (B and C) fluorescein angiography shows central leakage.
FLUORESCEIN ANGIOGRAPHY IN THE BULLOUS VARIANT OF CENTRAL SEROUS CHORIORETINOPATHY CSCR may take a rare form of large, usually multiple, sectors of bullous serous retinal and/or RPE detachments. Typical features include greater numbers and sizes of areas of choroidal hyperpermeability and bullous retinal detachments, which often extend inferiorly by gravitation. 26 These patients might be misdiagnosed as having a rhegmatogenous retinal detachment, multifocal chorioretinitis, a metastatic process, VKH, or uveal effusion. FA demonstrates multiple serous PEDs. Combined with the underlying shifting subretinal fluid, an accurate diagnosis can be made.8 (See also Chapter 15.)
THE ROLE OF PERIPHERAL IMAGES/WIDE FIELD/ EXTRAMACULAR FLUORESCEIN ANGIOGRAPHY Peripheral fields can be useful to assess the extent of multifocal CSCR or the length of gravitational tracts caused by the condition. Widefield angiograms also can help to distinguish typical CSCR from peripheral lesions such as a retinal hole that can cause subretinal fluid to track to the center.
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