Subretinal Fibrosis in Central Serous Chorioretinopathy

Subretinal Fibrosis in Central Serous Chorioretinopathy Howard Schatz, MD, l H. Richard McDonald, MD, l Robert N. Johnson, MD, l Clement K. Chan, MD,2 Alexander R. Irvine, MD/ Alan R. Berger, MD,4 James C. Folk, MD,5 Dennis M. Robertson, MD6 Purpose: To report unusual and heretofore unreported visually damaging manifestations of severe central serous chorioretinopathy. Methods: Case studies. Results: Each of six male patients (average age, 40 years) had a form of severe central serous chorioretinopathy with at least one eye containing fibrin in the subretinal space that then developed into a subretinal fibrotic scar. Scar formation was followed by a tenting up of the macula, vascularization of the fibrosis (subretinal neovascularization), or a retinal pigment epithelial rip. Four of the seven eyes with subretinal fibrosis had severe visual loss (20/400 or worse). Conclusion: Subretinal fibrin and other extracellular matrix molecules appear to stimulate the retinal pigment epithelium to undergo fibrous metaplasia, which results in subretinal fibrotic scar formation and other sequelae, all of which can lead to severe visual loss. Ophthalmology 1995; 102: 1077 -1088

In unusual cases of central serous chorioretinopathy, fibrin can be found in the subretinal space. 1-4 Subretinal fibrin can affect a type of extracellular matrix, stimulating the retinal pigment epithelium to undergo fibrous metaplasia. 5- 8 Subretinal fibrosis can lead to sequelae that cause severe and permanent visual loss. We report seven eyes in six patients with central serous chorioretinopathy in which subretinal fibrin developed, followed by subretinal fibrosis and resultant sequelae that cause severe visual loss. Originally received: October 24, 1994. Revision accepted: February 28, 1995. I Retina Research Fund of St. Mary's Medical Center, San Francisco. 2 Department of Ophthalmology, Lorna Linda University, Lorna Linda, California. 3 Department of Ophthalmology, University of California Medical Center, San Francisco. 4 Department of Ophthalmology, Sunnybrook Health Science Center, University of Toronto, Toronto. 5 Department of Ophthalmology, University ofIowa, College of Medicine, Iowa City. 6 Department of Ophthalmology, Mayo Clinic, Rochester. Supported by the Retina Research Fund of St. Mary's Hospital and Medical Center, San Francisco, California, and by a grant from the Wayne and Gladys Valley Foundation, San Ramon, California. Reprint requests to Howard Schatz, MD, I Daniel Burnham Ct, San Francisco, CA 94109.

Materials and Methods The histories, complete ocular examination records, ophthalmoscopic photographs, and fluorescein angiograms of six patients with previously unreported manifestations of central serous chorioretinopathy were reviewed.

Case Reports Case 1. A 38-year-old Korean man was first seen on December

20, 1990. He had a history of hypertension. Visual acuity was 20/200 in the right eye and 20/25 in the left. There were no

vitreous cells. The right fundus showed a sensory retinal detachment of the posterior pole, retinal striae in the center of the macula, and a large amount of subretinal fibrin. There were a few isolated subretinal fibrin deposits located in the inferior quadrants and a serous retinal detachment inferiorly. fluorescein angiography showed a few, small, retinal pigment epithelial (RPE) detachments and profuse fluorescence under the sensory retina from a few points of RPE leakage (Fig I, top and second rows). The left macula showed RPE changes. A systemic workup was done, yielding normal results. Results of laboratory tests, including complete blood count, angiotensin-converting enzyme, fluorescent titer antibody, VDRL, toxoplasmosis, also were normal. A lumbar puncture showed the cerebrospinal fluid to be normal. There were no neurologic or skin changes associated with Harada disease.

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Top, second, and third rows, Figure 1. Case 1. Top left, the right macula shows a large sensory retinal detachment of the entire macular area and subretinal fibrin. There are retinal striae around the fovea. Top right, arteriovenous phase fluorescein angiogram shows a few small retinal pigment epithelial (RPE) detachments around the right macula and a few areas of early RPE leakage. Second row left, later arteriovenous phase of the angiogram shows an increase of fluorescein leakage into the subretinal space from the RPE lesions, especially nasally and superotemporally. There are other areas of RPE leakage inferiorly. Second row right, late-phase fluorescein angiogram shows marked hyperfluorescent leakage into the subretinal space from two of the RPE lesions, one in the macula and one located superotemporally. The other RPE lesions also leak significantly. Third row, the right macula 2 months later. Most of the fibrin has resolved and is replaced by subretinal fibrosis. The retina in the central macula is slightly tented up-notice the retinal striae. There is a small, flame-shaped hemorrhage superiorly. Bottom, Figure 2. Case 2. Bottom left, the right macula and disc. The retina in the macular area and in the area superonasal to the disc is detached by a deposition of subretinal fibrin. Subretinal fibrosis appears to be developing. Bottom right, 3 months later, the right macula and disc. There is an oval area of subretinal fibrosis (and perhaps some residual fibrin) in the macula. This area is connected by a straight subretinal fibrotic band to an area of subretinal fibrosis superonasal to the disc. The sub retinal fibrotic band is tenting up the retina slightly. There are two isolated patches of subretinal fibrosis, one inferonasal and one inferotemporal to the disc.

Two months later, in February 1991, the patient was reexamined. Visual acuity was 20/400 in the right eye. Most of the subretinal fibrin had resorbed. A subretinal fibrotic scar had developed and slightly tented up the right macula.

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The retinal striae were more prominent (Fig I, third row). The patient was re-examined 2 months later, in May 1991. The left macula showed a fresh sensory retinal detachment and

Schatz et al . Central Serous Chorioretinopathy subretinal fibrin. On fluorescein angiography of the left eye, there was a focal RPE leak. Within 2 months, the subretinal fluid began to resolve in the left eye, and the macula began to flatten spontaneously. In July 1991, visual acuity was counting fingers in the right eye and 20/30 in the left. In the right eye, the sensory retinal detachment of the macula and the subretinal fibrin with fibrosis remained unchanged. The left macula had spontaneously and almost completely reattached; there was focal pigmentary mottling and minimal fibrin.

Comment This patient had severe central serous chorioretinopathy, accompanied by a massive amount of subretinal fibrin under a large sensory retinal detachment of the right macula, as well as an inferior retinal detachment. Over the next 2 months, subretinal fibrosis developed in the right eye. Central serous chorioretinopathy then developed with subretinal fibrin in the left eye. Vision in the right eye continues to be poor due to subretinal fibrosis that tented up the macula. The left macula has reattached spontaneously.

Case 2. A 53-year-old white man was referred in December 1990 with a 3-week history of reduced vision in the right eye. His medical history included cancer of the larynx, which was treated by laryngectomy 7 months previously. He had hypertension and was receiving medication. Visual acuity was hand motions in the right eye and 20/50 in the left. There were no vitreous cells. The right fundus showed a large sensory retinal detachment and subretinal fibrin in the macula and the area superonasal to the disc. Subtle, subretinal fibrosis could be seen through this area of fibrin, and there was a small patch of subretinal fibrosis present inferonasally (Fig 2, bottom left). A serous retinal detachment with shifting fluid was seen inferiorly. No retinal break was found. The left eye showed a few well-demarcated, RPE detachments. Auorescein angiography showed a few irregular RPE detachments in the right macula and marked leakage into the subretinal space. The inferior retinal detachment showed telangiectatic change with nonperfusion. The fluorescein angiogram of the left macula confirmed the RPE detachments. The patient was seen again 3 months later, in March 1991. His vision was unchanged. The subretinal fibrin had developed into subretinal fibrosis. A subretinal fibrotic band ran obliquely from the macula to the area superonasal to the disc and tented up the retina slightly. Two patches of subretinal fibrosis were present inferonasal and inferotemporal to the disc (Fig 2, bottom right). The patient had a persistent detachment of the sensory retina inferiorly.

Comment A large sensory retinal detachment developed with subretinal fibrin, involving the right macula and the area superior and superonasal to the disc, which was caused by marked RPE leakage. The patient also had a secondary serous retinal detachment inferiorly with shifting fluid. Within 3 months, most of the subretinal fibrin had resorbed and was replaced by subretinal fibrosis. A subretinal fibrotic band tented up the retina slightly.

Case 3. A 38-year-old white man was referred in February 1986 because of a recent history of reduced vision in the right eye. He had a long history of intermittent visual reduction in each eye, caused by central serous chorioretinopathy. The right eye had been treated for this condition with laser approximately

10 years before. Nine years ago, an episode was diagnosed in the left eye and it resolved without treatment. Results of the examination in February 1986 showed visual acuity of20/50 in the right eye and 20/25 in the left. The patient was hyperopic (+9.00 diopters in both eyes). Intraocular pressure was normal in each eye. There was a sensory retinal detachment ofthe right macula. Subretinal fibrin was present superior to the papillomacular bundle. Subtle retinal striae were present in the central macula. A small RPE lesion just inferotemporal to the right fovea and an RPE detachment further inferotemporally were also present. There were two areas of shallow sensory retinal detachment in the left macula, one superior and one inferotemporal to the papillomacular bundle. Auorescein angiography confirmed the findings and showed intense fluorescein leakage from the area of RPE leakage above the papillomacular bundle in the right eye. The angiogram of the left eye showed two areas ofRPE leakage, one inferotemporal to the macula and the other superior to the papillomacular bundle. Laser photocoagulation was directed to the area ofRPE leakage in the upper part of the papiIIomacular bundle of the right eye. Within 1 month, the sensory retina of the right eye had reattached and the visual acuity improved to 20/25 in the right eye. The subretinal fibrin had disappeared. The left eye was not treated. The patient returned 7 months later in September 1986 with a history of recent reduced vision in the left eye. Visual acuity was 20/25 in the right eye and 20/50 in the left. Results of examination of the right macula showed that the sensory retina was flat. There were a few RPE changes in the macula. The RPE detachment inferotemporally was the same. In the left eye, there was a large sensory retinal detachment of the temporal macula. Temporally, there was an area of subretinal fibrin and some subretinal fibrosis with a small amount of RPE hyperplasia inferiorly. A rip in the RPE was present adjacent and just temporal to the area of subretinal fibrin and fibrosis. Auorescein angiography confirmed the presence of the RPE detachment inferotemporal to the right macula. In the left eye, fluorescein angiography confirmed the RPE rip in the left eye and showed a profuse amount of RPE leakage in the area temporal to the macula and nasal to the rip. The patient was followed, and visual acuity was reduced to 20/200 in his left eye over the next month. The sensory retinal detachment of the macula had increased in height. The deposition of subretinal fibrin had increased. Laser treatment was directed to the area of RPE leakage, adjacent to the RPE rip, temporal to the left macula. One month later, the sensory retina had flattened completely, and the subretinal fibrin had resorbed. Visual acuity had improved to 20/30 in the left eye. There was a flat laser scar temporal to the macula. The patient was seen and examined 5 years later. Visual acuity was 20/20 in each eye, and each macula was flat. The intraocular pressure was normal. Because of the high hyperopia, a diagnosis of nanophthalmos was considered. Axial length scans were 19.31 mm in the right eye and 19.27 in the left. B-scan ultrasonography suggested choroidal thickening of each eye. The patient currently is being followed.

Comment A 38-year-old patient with a history of bilateral central serous chorioretinopathy and previous laser treatment had recurrent central serous chorioretinopathy in each eye. The right eye had subretinal fibrin. The RPE leakage of the right eye was treated; the retina flattened, and vision improved. At this same time, the left eye had two areas with RPE leakage and shallow sensory retinal detachment. This eye was followed. Seven months later,

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the left macula showed detachment with subretinal fibrin, subretinal fibrosis, and an RPE rip. Laser treatment was directed to the RPE leakage. The sensory retina flattened, and this eye responded well.

Case 4. A 45-year-old white man underwent posterior fossa craniotomy with excision of pontine arteriovenous cryptic malformation. On his fourth postoperative day, he had a low-grade fever, and a diagnosis of aseptic meningitis was made. A lumbar puncture was done-the cerebrospinal fluid showed leukocytes but no organisms. The patient was treated with intravenous antibiotics and steroids. He responded well to treatment and was discharged after 10 days. Six weeks later, in September 1990, the patient noted the sudden onset of reduced vision in his left eye. Visual acuity was 20/20 in the right eye and 20/200 in the left. The right eye showed a small RPE detachment inferonasal to the fovea. The left macula showed a large sensory retinal detachment of the macula and subretinal fibrin in the papillomacular bundle; a subtle band of subretinal fibrosis ran horizontally through the macula just below the fovea. There were striae in the macula. fluorescein angiography showed hypofluorescence of the area of subretinal fibrosis with intense fluorescein leakage in the area of the subretinal fibrin in the papillomacular bundle (Fig 3, top and center left). There was no evidence of choroidal neovascularization in this area. fluorescein angiography confirmed the small RPE detachment in the right macula. The patient was followed. Three months later, in Decem~er 1990, the subretinal fibrin had mostly resorbed. Subretinal fibrosis was present nasal to the fovea in the area where the subretinal fibrin had been. There was a small area ofRPE hyperplasia present on the nasal edge of the fovea. The subretinal fibrosis had become well developed, causing a shallow, tented up detachment of the macula (Fig 3, center right). In August 1991, approximately I year after his neurosurgical procedure, a patch of subretinal neovascularization developed in the left macula associated with traction from the subretinal fibrosis. Visual acuity has remained 20/400 in the left eye and 20/20 in the right (Fig 3, bottom).

Comment This patient had an acute onset of central serous chorioretinopathy with subretinal fibrin after a neurosurgical procedure. The subretinal fibrin resolved. A subretinal fibrotic band tented up the retina. Eventually, the subretinal fibrosis became vascularized with a patch of subretinal neovascularization.

Case 5. A 36-year-old white man was referred for reduced vision in the right eye in November 1989. He had ulcerative colitis and had received systemic steroids periodically for years. On initial examination in November 1989, visual acuity was 20170 in the right eye and 20/20 in the left. The right eye had a sensory retinal detachment of the macula caused by an area of RPE detachment and leakage above the papillomacular bundle. The subretinal fluid was cloudy with fibrin. In the left eye, there was one small RPE detachment above the macula and another in the inferotemporal macula. A diagnosis of central serous chorioretinopathy was made, and no treatment was performed. Over the next few months, the sensory retina in the right eye spontaneously reattached, and visual acuity improved to 20/20. In September 1990, 9'12 months later, visual acuity was 20/ 20 in the right eye and 20/25 in the left. The sensory retina of each macula was flat. 1080

On November 6, 1990, approximately 2 months later, the patient was seen with a 2-week history of reduced vision in the left eye. Visual acuity was 20/20 in the right eye and counting fingers in the left. The sensory retina of the right eye was flat. There was a large sensory detachment of the entire left macula, and above the fovea a large RPE detachment was surrounded by subretinal fluid. Inferotemporally, in the area where an RPE detachment had been seen 1 year previously, there was an oval, reddish RPE detachment encircled by subretinal fibrin. fluorescein angiography showed fluorescence of the superior RPE detachment with a point of profuse RPE leakage from its temporal edge. The fluorescein leaked out of the point of RPE leakage temporally and then inferiorly in a streaming arc. This arc of hyperfluorescence corresponded to the reddish arc surrounded by fibrin seen ophthalmoscopically. The inferotemporal RPE lesion showed marked leakage. The inferior lesion already may have been undergoing subretinal fibrosis (Fig 4, top and center). The patient was seen 2'/2 months later, in January 1991. Visual acuity was 20/20 in the right eye and reduc~d to counting fingers in the left. The left macula was beginning to show organization of the subretinal fibrin into subretinal fibrosis. fluorescein angiography showed RPE leakage at the edge of the RPE detachment above the macula. The leakage point was now at the superior edge of the detachment rather than at the temporal edge. The inferior lesion appeared fibrotic. Laser photocoagulation was directed to the RPE leakage point at the superior edge of the RPE detachment. The patient then was followed. By July 1991 , 7 months after laser treatment to the RPE leak in the left macula, visual acuity was 20/70 in the left eye, and the subretinal fluid and most of the subretinal fibrin had resorbed. The lesion was undergoing fibrotic scarring. The patient was seen December 1991 , 11 months after laser treatment. Visual acuity was 20/30 in the right eye and counting fingers in the left. The subretinal fluid in the left macula had resorbed. A small amount of subretinal fibrin remained in the superior macula. A subretinal fibrotic scar with RPE hyperplasia ran through the fovea. A patch of subretinal neovascularization was present within the fibrosis, inferotemporal to the hyperpigmentation. These vessels were in the area where the leaking RPE lesion initially had been seen more than 2 years previously. Fluorescein angiography confirmed that the fibrotic scar had undergone vascularization at its inferotemporal edge (Fig 4, bottom).

Comment This patient had central serous chorioretinopathy with subretinal fibrin in the right eye that spontaneously resorbed. The same condition developed in the left eye with RPE leakage from a large RPE detachment. A profuse amount of subretinal fibrin formed in the subretinal space and then organized into a subretinal fibrotic scar that became vascularized. It appears that subretinal fibrosis can develop soon after subretinal fibrin forms. In this case, subretinal fibrosis occurred 2'/2 months after the appearance of the subretinal fibrin .

Case 6. A 32-year-old Asian man was seen in July 1984 for reduced vision in the left eye for 3 months. Visual acuity was 20/15 in the right eye and 20/200 in the left. There were no cells in the vitreous of either eye. The RPE detachments were seen in the right macula, and a sensory detachment with subretinal fibrin was seen in the left macula. The left macula also had a small, irregular RPE detachment inferotemporal to the fovea and a shallow and subtle one inferonasal to the fovea. From the superior edge of the inferonasal detachment, fluores-

Schatz et al . Central Serous Chorioretinopathy Figure 3. Case 4. Top left, the left macula. Notice the large patch of subretinal fibrin in the papillomacular bundle and inferiorly. There is a sensory retinal detachment involving most of the macula. There is a subretinal fibrotic band running horizontally under the fovea. There are striae in the macula. Top right, in the midphase angiogram of the left macula, there is a point of retinal pigment epithelial (RPE) leakage nasally. The subretinal fibrotic band is hypofluorescent. There is some hyperfluorescence temporally. Center left, late-phase angiogram of the left macula. Notice the profuse RPE leakage nasally. There is slight staining of the RPE temporally. The fibrotic band has remained hypofluorescent. Center right, the left macula 3 months later. The large area of subretinal fibrin has mostly resorbed. A small amount of fibrin and subretinal fibrosis is present in the papillomacular bundle. The subretinal fibrotic band has become more well defined and appears to be exerting some tractional force on the retina, causing a shallow detachment of the macula. There is an area of RPE hyperplasia in the nasal fovea associated with the fibrosis and fibrin. Retinal striae can be seen throughout the macula. Bottom left, the left macula approximately 1 year after the neurosurgery. Notice the subretinal hemorrhage and dirty-gray membrane within the fovea. The subretinal fibrotic band is readily apparent. The sensory retina appears flat temporally with a shallow detachment in the central macula. The subretinal fibrin and retinal striae are gone. Bottom right, arteriovenous phase angiogram of the left macula. Notice the patch of subretinal neovascularization in the nasal macula. The subretinal fibrotic band and subretinal hemorrhage are hypofluorescent.

cein was seen to leak on angiography (Fig 5, top and second row). Because the RPE leak was close to the fovea, the patient was followed. Five months later, in January 1985, visual acuity was 20/15 in the right eye, and visual acuity had improved to 20/30 in the left. The sensory retinal detachment of the left macula had flattened, and most ofthe subretinal fibrin had resorbed. There was a small amount of subretinal fibrosis in the left macula inferiorly. The shallow RPE detachments, one inferonasal and one inferotemporal, remained approximately the same. Eleven months later, in November 1985, visual acuity was 20/ IS in the right eye and 20/20 in the left. The sensory retina of the left macula was flat, and the shallow RPE detachments were the same. Two years later, in November 1987, the patient was seen because of recent reduced vision in the right eye. Visual acuity

was 20/40 in the right eye and 20/ IS in the left. Results of examination showed a shallow sensory detachment of the right macula and two RPE detachments. There was a small amount of subretinal fibrin located in the central macula. The left macula showed the same RPE detachments, one inferonasal and one inferotemporal to the fovea, although they had enlarged somewhat. The patient was not seen again until November 19, 1991. Visual acuity was 20/20 in the right eye and 20/25 in the left. Subretinal fibrosis with a fibrotic band had developed in the right eye. The subretinal fibrotic band connected two patches of fibrosis, one just below the fovea and one below the disc. The band itself had a vessel running through it. The RPE detachments in the left macula had enlarged slightly. A small amount of subretinal fibrosis was still present inferiorly and it, too, appeared to be vascularized. Choroidal neovascularization had not been

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Figure 4. Case 5. Top left, the left macula. The patient has a well-demarcated retinal pigment epithelial (RPE) detachment superior to the fovea. There is a shallow sensory retinal detachment of the entire macula, and it contains subretina! fibrin. The superior RPE detachment occupies the entire subretinal space anteriorly, and, therefore, the subretina! fibrin is seen only in the sub retinal space surrounding it. There is a reddish arc (arrows) of no subretinal fibrin that corresponds to the RPE leak and streaming of fluorescein. There is a small, reddish, RPE lesion inferotemporal to the fovea that is surrounded by fibrin. Top right, early arteriovenous phase fluorescein angiogram of the left macula. Notice the hyperfluorescence of the RPE detachment above the fovea. There is the beginning of an RPE leak at its temporal edge. The lesion inferotemporal to the fovea shows marked RPE leakage. The central zone of relative hypofluorescence could be the beginning of subretinal fibrosis. Center left, midphase angiogram shows RPE leakage from the temporal edge of the superior RPE detachment and marked leakage from the lesion inferotemporally. Center right, late-phase angiogram shows marked RPE leakage into the sub retinal space from both lesions. Bottom left, the left macula shows subretinal fibrosis in the macula with RPE hyperplasia centrally and what appears to be a vascularized membrane inferotemporally. Most of the subretinal fibrin is gone; there appears to be a small amount superiorly. Bottom right, arteriovenous phase fluorescein angiogram. The superior RPE detachment has flattened and has left an area of depigmentation. The central subretinal fibrosis appears mostly hypofluorescent. There are subretinal new vessels within the subretinal fibrosis inferotemporal to the fovea.

present in either eye before this examination. Fluorescein angiography ·confirmed these findings (Fig 5, third and fourth rows and bottom). The patient was last seen in October 1994. Visual acuity had dropped to 20/100 in the right eye, and it was 20/25 in the left. Subretinal fibrosis had caused loss of the right fovea.

Comment This patient had bilateral RPE detachments and central serous chorioretinopathy. When first seen, he had subretinal fibrin in the left eye. Although this resorbed without treatment, he had a patch of subretinal fibrosis that had become vascularized. In the right eye, a sensory detachment developed with subretinal fibrin due to an RPE leak. This later resorbed, and the patient had subretinal fibrosis and a subretinal fibrotic band that had

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become vascularized. Three years later, visual acuity had dropped to 20/100 in the right eye due to fibrotic scarring.

Results The six patients, all male, ranged in age from 32 to 53 years (average age, 40 years) (Table I). Four were white and two were Asian. Two had hypertension. One patient (case 5) had ulcerative colitis and was receiving steroids. Two had major surgery before central serous chorioretinopathy (case 4 had neurosurgery less than 2 months before visual reduction and was receiving steroids, and

Figure 5. Case 6. Top left, the left macula. There is a plaque of fibrin (arrows) in the central macula. Notice the dark area in the center of the fibrin. This corresponds to the point of retinal pigment epithelial (RPE) leakage. There is a very shallow RPE detachment in the inferonasal part of the macula (see Fig 5, second row right, forfluorescein angiogram). Top right, arteriovenous phase fluorescein angiogram shows fluorescence of the RPE detachment in the lower part of the macula. There is a small RPE leak (arrow) just inferonasal to the fovea at the superior edge of the RPE detachment. The subretinal fibrin causes relative hypofluorescence. Notice the small, irregular, RPE detachment in the inferotemporal portion of the macula. Second row left, late-phase angiogram of the left macula. Notice the increased fluorescence from the RPE leak at the superior edge of the RPE detachment. Notice that the area of subretinal fibrin is relatively hypofluorescent. Second row right, fluorescein angiogram of the right macula. Notice the RPE detachment in the superotemporal macula and the shallow and irregular RPE detachment and RPE abnormalities in the papillomacular bundle. Third row left, the right macula. Notice the subretinal fibrotic band below the papillomacular bundle. It is attached to a plaque of subretinal fibrosis inferior to the fovea on one end and inferior to the disc on the other end. A small, distinct vessel is seen coursing through the fibrotic band (arrow). Third row right, the left macula. There is marked RPE abnormality (depigmentation) throughout the macula. The two RPE detachments, one nasal and one temporal, are very difficult to discern ophthalmoscopically. There is a patch of subretinal fibrosis inferiorly, which appears to be vascularized. Fourth row left, arteriovenous phase fluorescein angiogram shows irregular fluorescence of the RPE in the lower part of the macula. There is a small RPE detachment in the upper part of the macula. The subretinal fibrosis has a vessel coursing through it (arrow). Fourth row right, late-phase angiogram of the right macula. Notice the staining of the abnormal RPE and the subretinal fibrotic band. Bottom, late-phase angiogram of the left macula. Notice the hyperfluorescence of the shallow RPE detachments, one nasally and one inferotemporally, with late staining inferiorly in the area of the subretinal fibrosis. It appears that the subretinal fibrosis has become vascularized (arrow points to subretinal neovascularization).

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Table 1. Patient Data Case Age (yrs)/ No. Race/Sex 1

38/A/M

2

53/W/M

3

38/W/M

4

45/W/M

5

36/W/M

6

32/A/M

Medical History

Involved Eye

Sequelae

Hypertension, cataract OD,20/200* CSCR with subretinal fibrin surgery 2 mos OD - subretinal fibrosis previously - tented up macula; inferior serous retinal detachment Hypertension, surgery OD,HM* CSCR with subretinal fibrin for cancer of larynx - fibrosis-fibrotic .band 7 mos previously tented up retina; also inferior serous retinal detachment, shifting fluid, telangiectatic changes OS, 20/50* CSCR with subretinal fibrin - subretinal fibrosis RPE rip, laser treatment-20/20 hyperopic + 9.00, OU Brain surgery and OS, 20/200* CSCR with subretinal fibrin steroid treatment - subretinal fibrosis 6 wks previously fibrotic band tenting up macula, subretinal neovascularization OS, CF* Ulcerative colitis, CSCR with subretinal fibrin with and without - subretinal fibrotic steroids band, laser treatment, new attack, subretinal fibrin-fibrosis, subretinal neovascularization OD,20/15*; CSCR with subretinal fibrin OS, 20/ - subretinal fibrosis with 200* subretinal neovascularization

Final Vision in Affected Eye

Other Eye

CF

OS, 20/25; CSCR with subretinal fibrin

HM

OS, 20/50; pigment epithelial detachment

20/20

OD, 20/25; right eye treated for CSCR; later CSCR developed with subretinal fibrin OD, 20/20; RPE detachment

20/400

CF

OD, 20/20; CSCR with subretinal fibrin

OD,20/100; OS, 20/25

OU, CSCR with subretinal fibrotic band and subretinal neovascularization

A = Asian; OD = right eye; CSCR = central serous chorioretinopathy; CF = counting fingers; OS = left eye; HM = hand motions; RPE = retinal pigment epithelium; OU = both eyes. 'Subretinal fibrin and subretinal fibrosis developed.

case 2 had laryngectomy 7 months previously). One patient (case I) had cataract surgery 2 months previously. Two patients (cases 4 and 5) had been treated with steroids just before the onset of central serous chorioretinopathy. In two patients (cases 2 and 4), the condition was unilateral with fibrin. In four patients (cases 1, 3, 5, and 6), it was bilateral, with subretinal fibrin in each eye. Of the 12 eyes, 10 had central serous chorioretinopathy with a sensory retinal detachment; all 10 contained subretinal fibrin. Two eyes (cases 1 and 2) had an inferior serous retinal detachment. There was a dark spot in the center of the subretinal fibrin in five eyes that corresponded to the point ofRPE leakage. One patient (case 1) had two spots in the right eye and one spot in the left eye; one eye (case 5) had a stream of fluorescein that caused a dark, red arc; and two eyes (case 3, right eye; case 6, left eye) each had a

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dark spot in the center of the fibrin. Two of the 12 eyes did not have central serous chorioretinopathy with subretinal fibrin but did have one or more RPE detachments; thus, all 12 eyes had either central serous chorioretinopathy with fibrin or RPE detachments, or both. Subretinal fibrin led to subretinal fibrosis in seven of the ten eyes (1 eye of each patient; in case 6, both eyes). A subretinal fibrotic band developed in four eyes (cases 2, 4, 5, and 6). The retina became tented up by the scar tissue in three eyes (cases 1,2, and 4). In four eyes, the subretinal fibrosis became vascularized (cases 4, 5, and 6 [both eyes]). An RPE rip occurred in one eye (case 3). Laser treatment was done to both eyes in case 3 (with good results) and to one eye in case 5 after subretinal fibrosis had begun (with poor results: counting fingers). Four of the patients had recurrent central serous chorioretinopathy with new leaks (cases 1, 3, 5, and 6).

Schatz et al . Central Serous Chorioretinopathy

Discussion All six patients reported in this series had central serous chorioretinopathy in at least one eye, with a sensory retinal detachment and with subretinal fibrin, which was followed by the development of subretinal fibrosis. Central serous chorioretinopathy is a fundus abnormality in which a sensory retinal detachment of the macula occurs, reducing vision. 1,9-18 It affects men more frequently than women (approximately 10: 1). In its acute form, this condition occurs most commonly in patients 30 to 50 years of age, although it has been seen in patients both younger and older. 19 A severe form appears to be more common in Hispanic and Asian patients (2 of our 6 patients were Asian). Central serous chorioretinopathy can range from mild and short-lasting to severe with permanent visual loss. The most common form produces a clear-appearing serous detachment of the macula that reduces vision. 1.11 ,12 Other findings may include one or more RPE detachments and RPE window defects that may be small or broad and ~over large areas. 20 In rare and chronic cases, hard exudate IS seen. In the most severe forms, a large, bullous, inferior retinal detachment occurs, with shifting fluid and no retinal break. 21 - 23 Cases 1 and 2 had a serous, inferior retinal detachment. Retinal vascular telangiectatic changes overlying the chronic sensory retinal detachment have been described. 24 Retinal vascular nonperfusion and neovascularization have been reported. 25 Retinal vascular leakage and cystoid macular edema have been seen to develop in the sensory retinal detachment overlying a retinal pigment epithelial detachment in central serous chorioretinopathy,26 although retinal vascular changes are rare. Chronic subretinal fluid can produce broad areas of RPE depigmentation with vertical tracts of depigmentation (gutters); even bone spicule pigmentation has been reported. 1,16.20,24 In acute central serous chorioretinopathy, fluorescein angiography usually shows one, two, or a few RPE leaks, appearing as spots of hyperfluorescence that increase concentrically in size or as an upward stream of fluorescence ("smokestack,,).27,28 Rarely, downward leaks are seen. 18,27 Case 5 showed a streaming, profuse leakage of fluorescein that curved out and downward. The angiogram may show RPE detachments and also scattered and diffuse or downward, inferior, gutter-like RPE window defects. 1,24 The other eye, in approximately half the patients, shows some RPE changes if not frank central serous chorioretinopathy or RPE detachment. Leaks generally seal on their own, although recurrences are frequent, ranging from approximately 25% to 50% of cases. 1,10,14,15 Four of the patients described in this article had recurrent attacks with new leaks.

Subretinal Fibrin in Central Serous Chorioretinopathy Although subretinal fibrin has been reported in central serous chorioretinopathy, its presence is unusual. 1-3 Using

histochemical stains, de Venecia3 showed that the white subretinal exudate seen ophthalmoscopically in a patient with hypertension and renal disease was, in fact, fibrin. Yoshioka and Katsume 29 ,30 found fibrin platelet clots and a large amount of fibrin within Bruch membrane in experimentally induced central serous chorioretinopathy in monkeys. In his study and review of the literature, Gass2 reported that 90% of pregnant women, in whom central serous chorioretinopathy developed, showed subretinal fibrin deposition in the subretinal space. Gass found fibrin in the subretinal space in 6 (17%) of 42 men with this condition and no women with the condition who were not pregnant. Frank, fibrinous, opacified, subretinal fluid or fibrin clots are a rare occurrence in central serous chorioretinopathy. A literature review of previous reports of central serous chorioretinopathy shows good evidence of subretinal fibrin, although it has not been identified as such. This condition has been described as "yellow, subretinal exUdate"; "plaques"; "spots"; "cloudy subretinal fluid"; or it has not been mentioned or described. 4,23,31-33 There must be a significant hyperpermeability of the choriocapillaris fenestrations to allow a large molecule, such as fibrinogen (340,000 daltons), to escape the choriocapillaris. Fibrin can be found in the subretinal space in other conditions as well. Daicker6 described the passage of fibrin through damaged RPE in traumatic retinal detachments. Hayreh et al 34 found fibrin exudate lying on the surface of the RPE in the subretinal space in monkey models with hypertensive choroidopathy. Fibrin has been found in the subretinal space in patients with chronic rhegmatogenous retinal detachment and proliferative vitreoretinopathy with retroretinal membranes.7,35 Initially, the subretinal fibrin appears as cloudy, subretinal fluid that is turbid and yellowish, causing a pale, hazy appearance to the subretinal fluid, similar to a small amount of milk poured into a glass of water. The cloudiness appears diffuse and poorly demarcated. In such cases, the turbid fluid probably contains too little fibrin to polymerize significantly and form the long or broad, flat clots seen in our patients. Presumably, with a higher concentration of fibrin, the pale-yellow subretinal fluid becomes frankly opaque (cases 1, 2, 4, and 5). The subretinal material conglomerates, becoming a coagulum of fibrin that remodels into a welldemarcated, round or oval, yellow or pale gray, flat, fibrin clot (in case 1, at the first follow-up examination, this appearance had developed, and when first seen, the left eye of case 6 had this appearance). The fibrin may be focal, occupying only a small area within the detachment, or may be very broad, occupying most of the detachment. The fine, small, white, retinal precipitates seen in patients with resolving or chronic central serous chorioretinopathy probably are partly made of fibrin. On angiography, the subretinal fibrin will partially hypofluoresce, and a typical RPE leak or a few leaks with some degree or even profuse leakage may be present. The RPE leak may come from the edge of an RPE detachment. There is sometimes a dark or reddish spot in or near the center of the fibrin plaque. The dark spot usually cor-

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responds to the point of RPE leakage. The fluid leaking from the choriocapillaris has a very low concentration of fibrin or soluble fibrin monomer, so as it flows into the subretinal space, it is clear, a dilutent. This clear fluid moving into the subretinal space allows an unobstructed view of the underlying RPE, which is reddish or dark, in contrast to the surrounding cloudy subretinal fluid. In case 5, a stream of fresh, leaking subretinal fluid formed a dark arc running through the pool of murky, subretinal fibrinous fluid. The stagnant, cloudy, subretinal fluid had probably polymerized to some degree. As the fluid is dispersed in the subretinal space, the fibrin within it further polymerizes with the fibrin already present. The dilutent (water and small molecules) passes through the intact RPE to the choroid, leaving a precipitant of fibrinous subretinal fluid. The subretinal fibrin may be associated with a fairly well-demarcated, moderate, or large-sized RPE detachment (cases 2,5, and 6). Other RPE detachments may be present within the macula. In case 5, the sensory retinal detachment surrounded a very high RPE detachment. The RPE detachment was a prominent, well-demarcated, large, red lesion surrounded by the fibrinous subretinal fluid. In some patients (as in cases 2, 4, and 6), the RPE detachment may be shallow. Eventually, the fibrin plaque diminishes in size (undergoing fibrinolysis) and disappears. These six patients are unique, in that the development of sub retinal fibrosis followed the deposition of subretinal fibrin. This occurred in one eye of each patient and in both eyes of case 6. The sequelae that followed the formation of sub retinal fibrotic scar (i.e., choroidal neovascularization, RPE rip, tenting up of the retina in the macula) have not been reported in central serous chorioretinopathy.

Subretinal Fibrin to Subretinal Fibrosis The six patients reported herein demonstrated that subretinal fibrosis and fibrotic scar formation with contracting bands followed the deposition of fibrin in the subretinal space. In his report of bullous retinal detachment as a form of severe central serous chorioretinopathy, Gass22 reported one patient (case 2) who showed a subretinal fibrotic band that appeared after xenon photocoagulation. In his article on pregnancy with central serous chorioretinopathy and subretinal fibrin, Gass 2 reported that in one patient, a very small patch (approximately 500 JLm) of subretinal fibrosis appeared after the spontaneous resorption of the subretinal fluid and fibrin and reattachment of the retina. Other than these two patients, subretinal fibrosis has not been described in this condition, and there have been no cases reported with the degree and severity of subretinal fibrosis seen in the six patients reported here. In these six patients, the subretinal fibrotic membranes were, for the most part, not pigmented. Cases 3, 4, and 5 had a very small amount of pigment, and the fibrosis was mostly nonpigmented. It appears that fibrotic proliferation of RPE cells occurs without pigment reduplication; RPE cells grown in tissue culture also have this lack of pigmentary reduplication. 36

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Regarding the aspect of fibrin as a necessary ingredient and probable precursor of subretinal fibrosis, many researchers have found fibrin within the proliferating RPE cells. Schwartz et aJ1 studied retroretinal membranes removed surgically from 20 eyes with proliferative vitreoretinopathy. The RPE was the predominant cell type. They also found fibrin within the subretinal scar tissue. Trese et al 35 studied 13 subretinal strands removed at vitrectomy and found RPE cells with fibrin and collagen. Fibrin appears to be the scaffold onto which cells grow and then contract. Vidaurri-Leal and Glaser8 showed that fibrin stimulates the RPE to undergo fibrocytic proliferation and to develop into fibrocyte-like cells. In their study of human RPE cells in culture, they showed that when overlaid by a fibrin clot, the RPE cells tended to lose their normal, epithelial, morphologic features; they then migrate into the overlying clot as fibrocyte-like cells. In Hayreh et al's34 monkey studies, subretinal proliferation of fibrotic scar tissue followed the sensory retinal detachments that contained extremely opaque subretinal fluid that presumably was made of fibrin . Daicker6 described the clinical, histopathologic, and electron microscopy features of retroretinal membranes in four eyes with retinal detachment after trauma. These membranes were composed of fibrin and then secondarily populated by cells. Daicker believed that fibrin was an initiating feature in the development of subretinal fibrotic scar. Daicker postulated that when the RPE is damaged and permits fibrin exudate into the subretinal space, the fibrin membranes act as a scaffold for secondary cellular infiltration. Cleary et al 5 showed, in studies of tractional retinal detachment in monkeys after penetrating trauma, that a fibrin matrix provides orientation for cells to lay down collagen, and that contraction of scar is cell mediated. Thus, it appears that the choriocapillaris must be hyperpermeable to leak a large molecule, such as fibrinogen (which then converts to fibrin). A breakdown of the blood-eye barrier allows release of fibrin and probably other proteins into the subretinal space. Fibrin, probably with the influence of other proteins, acts as a precursor, stimulant, and scaffold to the development of subretinal fibrosis. The release of fibrin into the eye from a breakdown in the blood-eye barrier is a serious ocular event. 6,37-40

Unusual Sequelae Our patients had other very unusual, previously unreported findings with central serous chorioretinopathy. In one patient (case 3, left eye), an RPE rip developed. Presumably, after the deposition of subretinal fibrin, subretinal fibrosis developed. The fibrotic scar cells were connected to the RPE and, in the process of scar contraction, pulled on and ripped the RPE. It is fascinating to see that in this patient there was no RPE leakage from the area of RPE rip and that the subretinal fluid came from an area of leakage nasal to it. The sensory detachment over the rip was almost flat. Subretinal neovascularization or vascularization of fibrous scar occurred in four eyes. It is unknown at this

Schatz et al . Central Serous Chorioretinopathy time whether there is great proliferative potential for these vessels or whether the vascularized scar will remain dormant. It appears that the subretinal fibrosis was the cause of irreversible visual loss and that the vessels are just a finding and do not seem to play a significant role in the final visual acuity. The fluorescein leakage from the vessels has been minimal in each of these patients and the resultant overlying sensory detachment shallow. Visual acuity in both eyes in case 6 has not been changed by the vessels. In case 5, visual acuity improved to 20/70 but dropped to counting fingers when the vessels appeared, although this vision loss could have been due to the subretinal scar. The question arises as to how the vessels become incorporated with fibrin in the subretinal space. It is possible that contraction by the fibrosis pulled a gap or break in Bruch membrane, allowing vessels to enter the subretinal space from the choriocapillaris. It is also possible that endothelial proliferation found its way through Bruch membrane without a break and that the fibrotic proliferation or vasoproliferative protein in the extracellular matrix stimulated the growth of vessels. 41 Three of the eyes (case 1, right eye, 20/400; case 2, right eye, hand motions; case 4, left eye, 20/400) showed a small degree of tenting of the retina by the subretinal fibrosis.

Management The patients reported here have a much more severe form of central serous chorioretinopathy than the typical type. Four of the seven eyes with subretinal fibrin in which fibrosis developed did very poorly (20/400 or worse). Only one untreated eye (case 6, left eye) did well, but the RPE is very abnormal over a broad area in the macula; if this patient should have a recurrence, we believe the prognosis will be poor. From experience with these patients, it seems that when subretinal fibrin is present in a male patient with central serous chorioretinopathy, laser treatment should be encouraged early if the leak is not subfoveal or very close to the central fovea. Both eyes of case 3 were treated early, and despite fairly severe pathologic change (RPE rip), his vision remains good. The left eye of case 5 was treated only after fibrosis began to appear, and this eye has done poorly. The other four eyes that have done poorly (cases 1, 2, 4, and 6 [right eye]) were not treated. In case 1, a very profound leak was present at the edge of the fovea, but perhaps treatment of the other leaks would have been helpful. If a leak is close to the fovea, there is a risk of subretinal neovascularization developing from laser treatment of such a leak.42 But, laser treatment should at least be considered in these severe cases, especially for leaks not close to the fovea and probably even when there are leaks close to the fovea. Laser treatment must be weighed against all the other factors of the case, including severity of RPE changes of the other eye, size of sensory detachment, amount of sub retinal fibrin, amount ofleakage, and existence of systemic hypertension. Steroid use and central serous chorioretinopathy have been reported previously in association. If, in fact, the

choriocapillaris endothelium is damaged in central serous chorioretinopathy and is the factor that leads to hyperpermeability of the choriocapillaris, it is understandable that steroids can prolong or worsen the disease because steroids delay and inhibit endothelial repair. 43- 47

References 1. Gass 10M. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 3rd ed. Vol. 1. St. Louis: CV Mosby, 1987;46-59. 2. Gass 10M. Central serous chorioretinopathy and white subretinal exudation during pregnancy. Arch Ophthalmol 1991 ;109:677-81. 3. de Venecia G. Fluorescein angiographic smoke stack (case presentation at Verhoeff Society Meeting, 1982). As cited in Gass 10M. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 3rd ed. Vol. 1. St. Louis: CV Mosby, 1987;52. 4. Friberg TR, Eller AW. Serous retinal detachment resembling central serous chorioretinopathy following organ transplantation. Graefes Arch Clin Exp Ophthalmol 1990;228:3059. 5. Cleary PE, Minckler OS, Ryan S1. Ultrastructure of traction retinal detachment in rhesus monkey eyes after a posterior penetrating ocular injury. Am 1 Ophthalmol 1980;90:82945. 6. Daicker B. Constricting retroretinal membranes associated with traumatic retinal detachments. Graefes Arch Clin Exp OphthalmoI1985;222:147-53. 7. Schwartz 0, de la Cruz ZC, Green WR, Michels RG. Proliferative vitreoretinopathy. Ultrastructural study of 20 retroretinal membranes removed by vitreous surgery. Retina 1988;8:275-81. 8. Vidaurri-Leal 1S, Glaser BM. Effect of fibrin on morphologic characteristics of retinal pigment epithelial cells. Arch OphthalmoI1984;102:1376-9. 9. Annesley WH 1r, Augsburger 11, Shakin 1L. Ten year followup of photo coagulated central serous choroidopathy. Trans Am Ophthalmol Soc 1981 ;79:335-46. 10. Brancato R, Scialdone A, Pece A, et al. Eight-year followup of central serous chorioretinopathy with and without laser treatment. Graefes Arch Clin Exp Ophthalmol 1987;225: 166-8. 11. Burton TC. Central serous retinopathy. In: Blodi FC, ed. Current Concepts in Ophthalmology. Vol. 3. St. Louis: CV Mosby, 1972;chap 1. 12. Friberg TR, Campagna 1. Central serous chorioretinopathy: an analysis of the clinical morphology using image-processing techniques. Graefes Arch Clin Exp Ophthalmol 1989;227:201-5. 13. Gass 10M. Pathogenesis of disciform detachment of the neuroepithelium. II. Idiopathic central serous choroidopathy. Am 1 Ophthalmol 1967;63:587-615. 14. Gilbert CM, Owens SL, Smith PO, Fine SL. Long-term follow-up of central serous chorioretinopathy. Br 1 Ophthalmol 1984;68:815-20. 15. Klein ML, Van Buskirk EM, Friedman E, et al. Experience with nontreatment of central serous choroidopathy. Arch Ophthalmol 1974;91 :247-50. 16. Levine R, Brucker A1, Robinson F. Long-term follow-up of idiopathic central serous chorioretinopathy by fluorescein angiography. Ophthalmology 1989;96:854-9.

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17. Watzke RC, Burton TC, Woolson RF. Direct and indirect laser photocoagulation of central serous choroidopathy. Am J Ophthalmol 1979;88:914-18. 18. Yannuzzi LA, Gitter KA, Schatz H. The Macula: A Comprehensive Text and Atlas. Baltimore: Williams & Wilkins, 1979;145-65. 19. Schatz H, Madeira D, Johnson RN, McDonald HR. Central serous chorioretinopathy occurring in patients 60 years of age and older. Ophthalmology 1992;99:63-7. 20. Jalkh AE, Jabbour N, Avila MP, et al. Retinal pigment epithelium decompensation. I. Clinical features and natural course. Ophthalmology 1984;91: 1544-8. 21. Benson WE, Shields JA, Annesley WH Jr, Tasman W. Idiopathic central serous chorioretinopathy with bullous retinal detachment. Ann Ophthalmol 1980; 12:9204. 22. Gass JDM. Bullous retinal detachment. An unusual manifestation of idiopathic central serous choroidopathy. Am J Ophthalmol 1973;75:810-21. 23. Tsukahara I, Uyama M. Central serous choroidopathy with bullous retinal detachment. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1978;206: 169-78. 24. Yannuzzi LA, Shakin JL, Fisher YL, Altomonte MA. Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. Ophthalmology 1984;91: 1554-72. 25. Akiyama K, Kawamura M, Ogata T, Tanaka E. Retinal vascular loss in idiopathic central serous chorioretinopathy with bullous retinal detachment. Ophthalmology 1987;94:1605-9. 26. Schatz H, Osterloh MD, McDonald HR, Johnson RN. Development of retinal vascular leakage and cystoid macular oedema secondary to central serous chorioretinopathy. Br J Ophthalmol 1993;77:744-6. 27. Schatz H, Burton TC, Yannuzzi LA, Rabb MF. Interpretation of Fundus Fluorescein Angiography. St. Louis: CV Mosby, 1978. 28. Schatz H. Essential Fluorescein Angiography: A Compendium of 100 Classic Cases. San Anselmo, CA: Pacific Medical Press, 1983. 29. Yoshioka H, Katsume Y. Experimental central serous chorioretinopathy. III: Ultrastructural findings. Jpn J Ophthalmol 1982;26:397-409. 30. Yoshioka H, Katsume Y. Studies on experimental central serous chorioretinopathy. A light and electron microscopy [in Japanese]. Nippon Ganka Gakkai Zasshi 1982;86:738-49. 31. Chumbley LC, Frank RN. Central serous retinopathy and pregnancy. Am J OphthalmoI1974;77:158-60. 32. Fastenberg DM, Ober RR. Central serous choroidopathy in pregnancy. Arch Ophthalmol 1983; 10 1: 1055-8.

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33. Gitter KA, Houser BP, Sarin LK, Justice J Jr. Toxemia of pregnancy. An angiographic interpretation of fundus changes. Arch Ophthalmol 1968;80:449-54. 34. Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignant hypertension. VI. Hypertensive choroidopathy. Ophthalmology 1986;93: 1383-1400. 35. Trese MT, Chandler DB, Machemer R. Subretinal strands: ultrastructural features. Graefes Arch Clin Exp Ophthalmol 1985;223:35-40. 36. Albert DM, Tso MOM, Rabson AS. In vitro growth of pure cultures of retinal pigment epithelium. Arch Ophthalmol 1972;88:63-9. 37. Jaffe GJ, Abrams GW, Williams GA, Han DP. Tissue plasminogen activator for postvitrectomy fibrin formation. Ophthalmology 1990;97: 184-9. 38. Jaffe GJ, Lewis H, Han DP, et al. Treatment ofpostvitrectomy fibrin pupillary block with tissue plasminogen activator. Am J Ophthalmol 1989; 108: 170-5. 39. Sebestyen JG. Fibrinoid syndrome: a severe complication of vitrectomy surgery in diabetics. Ann Ophthalmol 1982; 14: 853-6. 40. Williams GA, Lambrou FH, Jaffe GA, et al. Treatment of postvitrectomy fibrin formation with intraocular tissue plasminogen activator. Arch Ophthalmol 1988;106:10558. 41. Pollack A, Heriot WJ, Henkind P. Cellular processes causing defects in Bruch's membrane following krypton laser photocoagulation. Ophthalmology 1986;93: 1113-19. 42. Schatz H, Yannuzzi LA, Gitter KA. Subretinal neovascularization following argon laser photocoagulation treatment for central serous chorioretinopathy: complication or misdiagnosis? Trans Am Acad Ophthalmol Otolaryngol 1977;83:0P893-906. 43. Yoshioka H, Katsume Y, Akune H. Experimental central serous chorioretinopathy. I. Clinical findings. Jpn J OphthalmoI1981;25:112-8. 44. Yoshioka H, Katsume Y, Ishibashi R. Experimental central serous chorioretinopathy. II. Further clinical findings. Kurume Med J 1981 ;28: 189-96. 45. Williamson J, Nuki G. Macular lesions during systemic therapy with depot tetracosactrin. Br J Ophthalmol 1970;54: 405-9. 46. Wakakura M. Ishikawa S. Central serous chorioretinopathy complicating systemic corticosteroid treatment. Br J Ophthalmol 1984;68:329-31. 47. Bouzas EA, Scott MH, Mastorakos G, et al. Central serous chorioretinopathy in endogenous hypercortisolism. Arch OphthalmoI1993;lll:1229-33.