Cytomegalovirus Retinitis in Patients with Good Syndrome

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

Clinicopathologic Correlation of Idiopathic Polypoidal Choroidal Vasculopathy

Idiopathic polypoidal choroidal vasculopathy (IPCV), a peculiar hemorrhagic disorder of the macula involving serosanguineous detachments of the retinal pigment epithelium (RPE) and neurosensory retina, was first described by Yannuzzi1 at a meeting of the Macula Society in 1982. At the American Academy of Ophthal- mology in 1984, Kleiner and cowork- ers2 described 7 patients with varying degrees of visual loss secondary to multiple recurrent hemorrhages or serous fluid beneath the RPE and Figure 1. Montage fundus photograph of left eye (October 11, 1995) reveals peripapillary red-orange neurosensory retina in the posterior nodular lesions contiguous with elevated, sinuous, tubular lesions extending through the macular region. Note subretinal pigment epithelial hemorrhage superotemporal to the optic disc and the red-orange fundus, and coined the phrase poste- nodular or polypoidal lesions just posterior to the hemorrhage (arrow). Also note the serosanguineous rior uveal bleeding syndrome for this retinal detachment and few hard exudates inferotemporally. condition. In 1985, Stern and co- workers3 published the first report on rettes per day for nearly 30 years. throughout the posterior pole in the “multiple recurrent serosanguine- The patient’s only complaint was oc- early frames (Figure 2A) and block- ous RPE detachments” in 3 middle- casional burning in both eyes with age of fluorescein transmission in the aged black women. In his 1987 at- otherwise normal vision. The best- region of the inferotemporal hem- las, Gass4 described 3 black women corrected visual acuity was 20/25 orrhagic retinal detachment and the with subretinal bleeding from multi- OU. The visual fields were full to fin- superotemporal hemorrhagic RPE centric neovascular networks with or- ger counting in both eyes. No affer- detachment. Mild early hyperfluo- ange sub-RPE plaques or nodules in ent pupillary defect was found. The rescence was present in the regions the peripapillary region. motility was full. Slitlamp examina- corresponding to the elevated red- Several additional reports and tion results were unremarkable. The orange sinuous and tubular lesions case series5-11 and 2 clinicopatho- intraocular pressure was 21 mm Hg in the peripapillary and macular re- logic studies12,13 have been pub- OU. Ophthalmoscopic examina- gions. Hyperfluorescent polypoi- lished. The previously published tion results revealed multiple areas dal lesions with minimal fluores- pathologic reports as well as the cur- of retinal-choroidal elevation with cein leakage were at the posterior rent case may represent end-stage red-orange sinuous and tubular pat- margins of the hemorrhagic detach- disease in IPCV. Herein, we de- terns within the peripapillary and ments (Figure 2B). An indocyanine scribe and correlate the clinicopatho- macular regions in the left eye green (ICG) angiogram was recom- logic findings in an enucleated eye (Figure 1). Superotemporal to the mended; however, the patient re- with IPCV. optic nerve head, a dark red hem- ported a reaction to iodine after a orrhagic pigment epithelial detach- hysterosalpingogram in 1980 and Report of a Case. A 46-year-old ment was found adjacent to a red- was advised not to take iodine. The black woman was referred to one of orange nodular or polypoidal lesion. patient was diagnosed as having us ( J.L.D.) for evaluation of a mass Inferotemporally, a hemorrhagic IPCV, and observation was recom- in the left eye on November 20, retinal detachment appeared as an mended. 1995. Her medical history was sig- orange subretinal mass with focal On August 5, 1996 (about 10 nificant for hypertension for 10 years hard exudate. The right fundus was months after the initial examina- and diabetes mellitus for 6 years (in- unremarkable. A fluorescein angio- tion), the patient had an acute loss sulin-dependent for 3 years). The pa- gram disclosed mottled hypofluo- of vision in the left eye. She had eaten tient had smoked half a pack of ciga- rescence and hyperfluorescence “bad cream cheese” and subse-

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Figure 2. A, Early fluorescein angiogam (20.8 seconds) of the left eye (October 11, 1995) shows irregular linear and nodular areas of hyperfluorescence (arrowheads) in the macular region corresponding to red-orange tubular and polypoidal lesions, respectively, in Figure 1. B, Late fluorescein angiogram (304.2 seconds) of the left eye shows hyperfluorescence without leakage corresponding to the tubular and nodular lesions in the macula. More intense hyperfluorescence is present superotemporal to the optic disc and along the inferotemporal arcade just posterior to the hemorrhagic retinal pigment epithelium and retinal detachments, respectively. Note the polypoidal configuration of the inferotemporal lesion (arrowhead).

Figure 3. Left eye (August 5, 1996) with extensive subretinal and subretinal Figure 4. Left eye (October 13, 1997) with a disciform macular scar and pigment epithelial hemorrhage. Note the elevated red-orange peripapillary persistent elevated, red-orange, nodular, and tubular peripapillary lesions. lesions.

quently developed nausea and vom- ciform scar with subretinal fibro- rior chamber with rare cells, no ru- iting. She awoke the next morning sis in the inferotemporal macula beosis iridis, and a clear lens in the with markedly decreased vision and (Figure 4). Fluorescein angiogra- left eye. Ophthalmoscopic exami- pain in the left eye. The visual acu- phy results revealed early hyperfluo- nation results revealed a hemor- ity was 20/20 OD and hand motions rescence with late leakage of fluo- rhagic retinal detachment in the left OS. The intraocular pressure was 17 rescein in the region of the disciform eye. Echography showed dense mm Hg OU. Ophthalmoscopic ex- scar and RPE transmission defects opacities beneath hemorrhagic kiss- amination results revealed exten- throughout the posterior pole in the ing choroidal vs retinal/RPE detach- sive subretinal and sub-RPE hemor- left eye. ments and a posterior disciform le- rhage in the central macula extending On March 19, 1998, nearly 21⁄2 sion in the left eye. The patient beyond the vascular arcades in the left years after the initial examination, underwent multiple procedures in eye (Figure 3). Surgical removal of the patient returned with marked the left eye, including anterior cham- the hemorrhage was considered but pain and redness in the left eye for ber paracentesis, diode laser cyclo- rejected because of the extensive sub- 1 week. The visual acuity was 20/25 photocoagulation, and retrobulbar RPE hemorrhage. OD and no light perception OS. The alcohol injection. The pain could not On October 13, 1997 (about 2 intraocular pressure was 45 mm Hg be managed adequately, the intra- years after the initial examination), OS. Gonioscopy revealed 270° of ocular pressure rose to 84 mm Hg the visual acuity was 20/20 OD and angle closure without neovascular- OS, and the eye was enucleated, with light perception OS. Ophthalmo- ization and anterior displacement of placement of a hydroxyapatite or- scopic examination results of the left the iris-lens diaphragm in the left bital implant. On December 29, eye disclosed hazy media second- eye. Results of slitlamp examina- 1998, the visual acuity in the right ary to vitreous hemorrhage, persis- tion revealed marked conjunctival eye was stable at 20/25+1, and no tence of the peripapillary elevated hyperemia, microcystic and stro- diabetic retinopathy or IPCV was red-orange tubular lesions, and a dis- mal corneal edema, a shallow ante- found in the right eye.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 gration of the lens epithelium. Fo- thy” was first used by Yannuzzi.1 cal necrosis of the lens epithelium Other phrases used to describe this was present anteriorly. Sub-RPE and condition include “posterior uveal intra–Bruch membrane choroidal bleeding syndrome”6 and “mul- neovascularization (Figure 6A-D) tiple recurrent serosanguineous RPE were noted in the peripapillary re- detachments.”3 In 1990, Yannuzzi et gion nasal and temporal to the op- al,5 Kleiner et al,6 and Perkovich et tic nerve head. The RPE overlying al7 each published 3 small case se- the intra–Bruch membrane choroi- ries of this condition. A total of 28 dal neovascularization was rela- patients (8-11 patients in each study) tively intact with apparent focal were described by the above au- vacuolation (Figure 6B-D). Thin- thors. Demographic features in- walled, cavernous vascular chan- cluded women (96%), black pa- nels (Figure 6A-C) that originated tients (79%), age range of 40 to 79 from branches of the short poste- years (mean age, 58 years), bilat- rior ciliary arteries through defects eral findings (68%), hypertension in Bruch membrane (Figure 6D and (43%), and diabetes mellitus (14%). Figure 5. Photomacrograph of left eye shows bullous serosanguineous retinal detachment E) in the peripapillary region were Clinically, each of the patients had (arrowhead) and hemorrhagic retinal pigment found in the intra–Bruch choroidal predominantly peripapillary orange- epithelium detachment (asterisk). Note also neovascular membrane. Similar cav- red polypoidal subretinal chor- the posterior disciform scar. ernous vascular channels without an oidal lesions that appeared to be apparent muscular layer were also nodular protrusions emanating from Gross examination revealed a in the peripapillary choroid (Fig- the choroid and that were associ- left eye of firm consistency measur- ure 6C). The vessels closest to the ated with serosanguineous detach- ing 23ϫ23.5ϫ21.5 mm, with 3 mm optic nerve head exhibited a mus- ments of the RPE and neurosen- of attached optic nerve. The cornea cularis layer of 1 to 3 cells thick (Fig- sory retina. Fluorescein angiography was hazy and measured 11.5ϫ11 ure 6F). Branches of the short pos- typically revealed early mottled hy- mm in diameter. The pupil mea- terior ciliary arteries focally abutted perfluorescence, with late pooling of sured 6 mm in diameter. There were Bruch membrane in the peripapil- fluorescein and occasional late leak- no transillumination defects. The op- lary region (Figure 6E). A few nodu- age in the region of the polypoidal tic nerve was sectioned close to the lar and calcified drusen were in the lesions. The lesions appeared some- sclera. A horizontal cut was made and peripapillary region. Focal calcium what smaller angiographically than the superior cap was removed. On deposition was in Bruch mem- clinically.5 sectioning, the anterior chamber was brane, particularly in the peripapil- The natural course of the dis- flat, and there was anterior displace- lary region. A disciform scar with ease involved chronic and recur- ment of the iris-lens diaphragm by marked subretinal fibrosis, focal RPE rent hemorrhagic detachments of the dense vitreous hemorrhage and a bul- hyperplasia in a tubuloacinar con- RPE and retina, with retention of lous hemorrhagic retinal detach- figuration, focal bone formation, and good vision in most eyes with or ment (Figure 5). Focal areas of sub- a few blood vessels (subretinal and without treatment. Vitreous hem- RPE and suprachoroidal hemorrhage sub-RPE choroidal neovasculariza- orrhage occurred in 12 patients were found. The sclera was grossly tion) were in the macular region and (43%). Laser photocoagulation was unremarkable. The optic nerve head detached by hemorrhage (Figure associated with resolution of the se- was not visualized. 6G). There were extensive hemor- rosanguineous detachments and sta- Results of microscopic ex- rhagic retinal and bullous RPE bilization or improvement in vi- amination of 250 serial stepped detachments with hemorrhagic ne- sion in 6 of 9 patients.5 The large sections revealed a cornea with intra- crosis (Figure 6A and B). Focal ag- disciform macular scars commonly epithelial edema. The Bowman layer, gregates of chronic inflammatory seen in age-related macular degen- the stroma, and Descemet mem- cells were found in the choroid, cho- eration (ARMD) were not charac- brane were unremarkable. There was roidal neovascular membrane, infe- teristic of this condition. In addi- moderate attenuation of the endo- rior oblique muscle, and episclera. tion, drusen and other vascular, thelium. The iris and lens were dis- There was focal arteriolar sclerosis proliferative, and inflammatory dis- placed forward by extensive intra- within the retina and choroid. Lon- eases of the eye were not typically ocular hemorrhage, with the iris gitudinal sections of the optic nerve seen in these patients. lining the posterior surface of the disclosed a focal area of retrolami- Indocyanine green videoan- cornea. The angle was closed. Hem- nar cavernous optic atrophy. Cross- giography has shown 2 basic cho- orrhagic necrosis with rounding up sections of the optic nerve dis- roidal vascular patterns in IPCV: (1) of pigment and thickening of the closed a focal area of hemorrhagic a branching network of variably basement membrane of the pig- necrosis involving the superior or in- sized vessels in the inner choroid mented ciliary epithelium were seen ferior nerve fiber bundles. (most often in the peripapillary re- in the region of the ciliary body. The gion); and (2) vascular dilations at lens was cataractous with cortical Comment. The phrase “idiopathic the border of the network of ves- globule formation and posterior mi- polypoidal choroidal vasculopa- sels.14 The vessels in the network do

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C D

E F

Figure 6. A, Peripapillary intra-BM CNV (between arrowheads) composed of G thin-walled cavernous vascular channels. Note subretinal hemorrhage (asterisk) (HE; ϫ40). B, Subretinal RPE (intra-BM ϫ10 is between arrowheads) cavernous vascular channels (asterisks) at the posterior margin of hemorrhagic RPE detachment. The upper arrowhead identifies the RPE and inner aspect of BM; the lower arrowhead identifies the outer aspect of BM (PAS; ϫ100). C, Higher-power view of intra-BM CNV (between arrowheads) with thin-walled cavernous vascular channels. The upper arrowhead identifies the RPE and inner aspect of BM; the lower arrowhead identifies the outer aspect of BM. Note the intact overlying RPE with apparent vacuolation and the cavernous vessel in the choroid (asterisk) (PAS; ϫ100). D, Intra-BM CNV with arteriole traversing defect (between arrows) in the peripapillary BM (PAS; ϫ400). E, Branches (asterisks) of a short posterior ciliary artery in juxtapapillary choroid extending to BM (PAS; ϫ250). F, Juxtapapillary intra-BM membrane arteriole (asterisk) with muscularis of 1-3 cell layers thick (PAS; ϫ250). G, Disciform macular scar (asterisk) with focal bone formation (arrow), RPE hyperplasia in a tubuloacinar configuration (arrowhead), and few blood vessels. Note the adjacent subretinal hemorrhage to the right of the disciform scar (HE; ϫ40).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 not follow expected choroidal lobu- lished. MacCumber and cowork- in Bruch membrane were observed. larpatternsandgenerallyappearmore ers12 described a 58-year-old white Focal serosanguineous detachment of numerous than expected from the man with a medical history of insu- the RPE and total detachment of the clinical examination results. Spaide lin-dependent diabetes mellitus for retina were revealed. The demo- and coworkers14 emphasized the fact 38 years, hypertension for 6 years, graphic and historical features as well that the hemorrhagic and serous el- and high myopia (7-8 diopters), who as the findings of intra-Bruch mem- evation of the RPE and retina appear developed bilateral, multiple recur- brane choroidal neovascularization to arise from the edge of the polypoi- rent hemorrhagic detachments of the (CNV), a disciform scar, and exten- dal lesions. Ross and coworkers15 re- sensory retina and RPE that even- sive serosanguineous retinal detach- ported 2 elderly black women with tually led to rubeosis and blindness ment described by Spraul and co- IPCV,retinalarterialmacroaneurysms, in one eye. The peripapillary polyp- workers13 were very similar to the andhypertensiveretinopathyandsug- oidal choroidal nodules character- current case. The histopathologic gested that the pathophysiology of istic of IPCV were not apparent in findings might represent end-stage IPCVmightbeanalogoustohyperten- the clinical photographs published disciform scarring associated with sive changes in the choroidal and reti- by MacCumber et al.12 The visual IPCV. The one published photomi- nal vasculature. acuity was hand motions to light per- crograph shows apparent arteriolar In 1997, Yannuzzi and cowork- ception for 3 years prior to enucle- sclerosis within the choroid but no ers9 reported on the expanding clini- ation. Histopathologic examina- large, thin-walled, cavernous vascu- calspectrumofIPCVandadded20ad- tion results revealed extensive lar channels within Bruch mem- ditionalcasestothe45casespreviously fibrovascular proliferation in the brane, as in the current case. reported in the literature. The average subretinal space and within Bruch A histopathologic report of a le- ageatinitialconsultationwas60years, membrane, 23 choroidal blood ves- sion in a patient with known IPCV with patients typically first seeking ex- sels traversing defects in Bruch mem- was recently published by Shiraga amination between ages 50 and 65 brane, and marked lymphocytic and coworkers.19 A subfoveal cho- years. Idiopathic polypoidal choroi- infiltration of the choroid and fibro- roidal neovascular membrane de- dal vasculopathy was most commonly vascular tissue with both T and B veloped 8 months after pars plana found in deeply pigmented (4.2 pig- cells. Based on the pathologic find- vitrectomy, tissue plasminogen acti- mented: 1 white) women (5 women: ings, the patient was treated with im- vator, and sulfur hexafluoride (SF6) 1man).BlackpersonsandAsiansseem munosuppressive therapy (predni- injection for a submacular hemor- to be at greatest risk for developing sone and cyclophosphamide). The rhage associated with IPCV in a Japa- IPCV. However, among the Japanese, patient subsequently developed vit- nese patient. The patient under- the condition is unilateral in 91% and reous hemorrhage in the remain- went repeated submacular surgery, affects elderly men in 69% of cases.16 ing eye and at least 2 new areas of and results of the histopathologic ex- Age-related macular degeneration is serosanguineous RPE detachment, amination of the excised membrane alsomorecommoninelderlyJapanese with a decrease in visual acuity to 20/ disclosed fibrovascular tissue be- men than in women.16 Isolated IPCV 200 during the ensuing 2 years de- tween the retina and RPE without the lesions have been reported in the pe- spite immunosuppressive therapy. thin-walled cavernous vascular chan- ripheral fundus10 and macula11 with- The intra–Bruch thin-walled cav- nels described in our patient. out apparent peripapillary during in- ernous vascular channels noted in Lafaut and colleagues20 re- volvement. the current case (Figure 6A-C) were ported the histopathologic findings Clinical observations reveal that not observed. The histopathologic of an excised choroidal neovascular the lesions in IPCV typically progress findings might represent end-stage membrane in a patient with ARMD with conversion of the polypoidal disciform scarring associated with whose ICG angiogram disclosed a nodules into enlarging tubular com- IPCV, ARMD, or some other en- polypoidal choroidal vascular pat- ponents (as seen in our patient) and tity, such as multifocal choroiditis tern. Pathologic examination re- associated serosanguineous RPE and associated with progressive subreti- sults revealed a thick sub-RPE intra– retinal detachments. The RPE de- nal fibrosis17 or progressive subreti- Bruch membrane fibrovascular tachment eventually flattens and ex- nal fibrosis and uveitis syndrome.18 membrane with diffuse drusen and tends tangentially in the plane of the Spraul and coworkers13 de- dilated thin-walled vessels that ap- inner choroid.9 Subsequent vari- scribed a 47-year-old black woman peared saccular on serial sections and able RPE atrophy may ensue. Indo- who had a sub-RPE hemorrhage in were located just external to the RPE cyanine green angiography gener- the right eye that was associated with and diffuse drusen. In the published ally discloses early choroidal vascular a reddish-orange subretinal lesion photomicrographs, no muscularis is hyperfluorescence, with uniform in both eyes in the superotemporal apparent in the thin-walled vessels. washout in the later stages, except peripapillary region. The patient sub- In addition, the cavernous configu- when the polypoidal lesions are ac- sequently developed extensive cho- ration of the vessels that was found tively leaking. The ICG character- roidal hemorrhage that led to enucle- in our case was not observed by istics typically observed in classic or ation of the right eye. Histopathologic Lafaut and colleagues.20 occult choroidal neovasculariza- examination results revealed fibro- The histopathologic findings in tion in ARMD are not seen in IPCV.9 vascular membranes within Bruch our case further clarify the natural Two possibly related histo- membrane and between Bruch mem- history of IPCV. The flat orange- pathologic studies have been pub- brane and the RPE. Numerous breaks red vessels noted clinically in the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 peripapillary region in IPCV ap- Histopathologic features of ing of intra–Bruch membrane cho- pear to be branches of the short pos- chronic hypertension were noted in roidal neovascularization might terior ciliary arteries abutting or the retina and choroid in the cur- suggest that IPCV is a form or vari- causing effacement of the RPE (Fig- rent case and in the case reported by ant of ARMD. Occasional drusen and ure 6E and F). The peripapillary net- Spraul and coworkers.13 The choroi- focal calcification within Bruch work of vessels observed on results dal vascular tone is controlled by au- membrane, as observed in our case, of ICG angiography is derived from tonomic (sympathetic) input in con- are pathologic findings that have also these branches of the posterior cili- trast to the autoregulation of the been described in studies of eyes ary arteries. Iijima and coworkers21 retinal vasculature.15,26 Perhaps in- with ARMD. reported the findings on optical co- creased perfusion pressure second- In summary, the network of herence tomography in 2 Japanese ary to hypertension within the arte- peripapillary vessels seen on fluores- patients with IPCV and showed an- riolar branches of the short posterior cein and ICG angiography in IPCV terior protrusion of an orange sub- ciliary arteries and associated vascu- corresponds histopathologically to retinal mass corresponding to a pol- lar shunts (arterial-arterial, arterial- branches of the short posterior cili- ypoidal structure noted on ICG venular, or venular-venular)27 stimu- ary arteries. The elevated polypoi- angiography and contiguity be- lates the prolapse and protrusion of dal and tubular choroidal lesions cor- tween the orange mass (nodule) and these vessels through defects or gaps respond to large thin-walled hemorrhagic detachment of the RPE. in Bruch membrane in the peripap- cavernous vascular channels and ac- The authors suggested that the RPE illary region. With persistently el- companying choroidal neovascular- and Bruch membrane overlying the evated arterial blood pressure, the ization within the Bruch mem- polypoidal structure might receive branches of the short posterior cili- brane. Continuity between the ciliary sustained compression from the un- ary arteries become dilated (cavern- arteries and the intra–Bruch mem- derlying mass, leading to thinning ous) distally along the course of the brane vascular channels may ex- and defects in the RPE and Bruch vessels and internal to the defect or plain the potential catastrophic in- membrane. Age-related changes in gap in Bruch membrane, leading to traocular hemorrhage in IPCV. Bruch membrane, particularly cal- the development of the elevated peri- Hypertension in conjunction with cium deposition and drusen forma- papillary polypoidal lesions. The pol- age-related or degenerative changes tion, in the peripapillary region (as ypoidal and subsequent tubular le- in Bruch membrane may play a role found in the current case) may also sions as described by Yannuzzi and in the development of IPCV. The pre- contribute to defects or cause gaps coworkers9 correspond histopatho- dilection for deeply pigmented indi- in Bruch membrane. These defects logically to the large thin-walled cav- viduals is unexplained. or gaps in Bruch membrane may per- ernous vascular channels (Figure mit the proliferation of choroidal 6A-C) and accompanying choroidal Robert H. Rosa, Jr, MD neovascularization, which is a com- neovascularization observed within Janet L. Davis, MD mon histopathologic finding in each Bruch membrane in the current case. Charles W. G. Eifrig, MD of the reported pathologic studies of In the early stages, the lack of sig- Temple, Tex possible IPCV cases. nificant fluorescein leakage and/or This study was supported in part by the In the original descriptions of staining in IPCV may be due to the Florida Lions Eye Bank, Miami. cases of IPCV,3,5,6 less than 50% of relatively intact RPE (Figure 6B-D) This study was presented in part the total number of patients with overlying the intra–Bruch mem- at the meeting of the Verhoeff- IPCV were documented to have sys- brane choroidal neovascularization Zimmerman Society, Portland, Ore, temic hypertension. However, in a and polypoidal lesions. Dilatation and April 24, 1999. subsequent report and update by attenuation of the blood vessel wall Corresponding author and re- Perkovich and coworkers7 in a small with accompanying disruption of the prints: Robert H. Rosa, Jr, MD, Divi- case series, 8 (89%) of 9 patients had endothelium in the polypoidal lesion of Ophthalmology, Scott and a history of hypertension. The 5-year sions secondary to elevated arterial White Clinic, 2401 S 31st St, Temple, cumulative incidence of CNV in the blood pressure may lead to the leak- TX 76508 (e-mail: rrosa@swmail fellow eye of patients with definite age noted on ICG angiography and .sw.org). hypertension and juxtafoveal or sub- to the serosanguineous detach- 1. Yannuzzi LA. Idiopathic polyploidal choroidal vasculopathy. Presented at: Macula Soci- foveal CNV secondary to ARMD in ments of the retina and RPE. ety Meeting; February 5, 1982; Miami, Fla. the Macular Photocoagulation Study The true relationship between 2. Kleiner RC, Brucker AJ, Johnston RL. Poste- was approximately 50%—indicat- IPCV and hypertension is un- rior uveal bleeding syndrome [abstract]. Oph- thalmology. 1984;91(suppl 9):110. ing a statistically significant sys- known, and other pathogenetic fac- 3. Stern RM, Zakov ZN, Zegarra H, Gutman FA. temic risk factor for CNV.22 Addi- tors are possible. Perhaps the abnor- Multiple recurrent serosanguineous retinal pig- tionally, in the argon laser study23 mal cavernous choroidal vessels ment epithelial detachments in black women. 24 Am J Ophthalmol. 1985;100:560-569. and in the krypton laser study, ap- represent congenital or acquired vas- 4. Gass JDM. Stereoscopic Atlas of Macular Dis- proximately 60% and 55% of the pa- cular anomalies or malformations or eases: Diagnosis and Treatment. Vol 1. St Louis, Mo: CV Mosby; 1987:200. tients, respectively, had definite hy- anatomic variation. The demo- 5. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. pertension. The prevalence of graphic distribution of the disease in Idiopathic polypoidal choroidal vasculopathy hypertension increases with age and patients typically older than 50 years, (IPCV). Retina. 1990;10:1-8. 6. Kleiner RC, Brucker AJ, Johnston RL. The pos- is higher in African Americans com- the possible association with hyper- terior uveal bleeding syndrome. Retina. 1990; pared with white Americans.25 tension,22-24 and the histologic find- 10:9-17.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 7. Perkovich BT, Zakov ZN, Berlin LA, Weiden- second eye of patients with juxtafoveal or sub- occupying 60% of the bulbar sur- thal D, Avins LR. An update on multiple re- foveal choroidal neovascularization second- current serosanguineous retinal pigment epi- ary to age-related macular degeneration. Arch face from the caruncle to the lateral thelial detachments in black women. Retina. Ophthalmol. 1997;115:741-747. conjunctiva, and covering half of the 1990;10:18-26. 23. Macular Photocoagulation Study Group. Ar- cornea (Figure). Computed tomog- 8. Capone A Jr, Wallace RT, Meredith TA. Symp- gon laser photocoagulation for senile macular tomatic choroidal neovascularization in blacks. degeneration: results of a randomized clinical raphy scans revealed preseptal soft Arch Ophthalmol. 1994;112:1091-1097. trial. Arch Ophthalmol. 1982;100:912-918. tissue swelling without an orbital 9. Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, 24. Macular Photocoagulation Study Group. Kryp- Freund KB, Orlock DA. The expanding clini- ton laser photocoagulation for neovascular le- component. The patient preferred 14 cal spectrum of idiopathic polypoidal choroi- sions of age-related macular degeneration: re- days’ observation while receiving dal vasculopathy. Arch Ophthalmol. 1997;115: sults of a randomized clinical trial. Arch topical steroid/antibiotic medica- 478-485. Ophthalmol. 1990;108:816-824. 10. Yannuzzi LA, Nogueira FB, Spaide RF, et al. Id- 25. Clark LT. Primary prevention of cardiovascu- tion, but the mass enlarged to affect iopathic polypoidal choroidal vasculopathy: a lar disease in high-risk patients: physiologic and 75% of the conjunctival surface, in- peripheral lesion. Arch Ophthalmol. 1998;116: demographic risk factor differences between Af- 382-383. rican American and white American popula- ducing lower eyelid ectropion. Di- 11. Moorthy RS, Lyon AT, Rabb MF, Spaide RF, tions. Am J Med. 1999;107:22S-24S. agnostic punch biopsy was per- Yannuzzi LA, Jampol LM. Idiopathic polypoi- 26. Ernest JT. Choroidal circulation. In: Ryan SJ, formed. dal choroidal vasculopathy of the macula. Oph- ed. Retina. Vol 1. St Louis, Mo: Mosby; 1994: thalmology. 1998;105:1380-1385. 76-80. Histopathological examina- 12. MacCumber MW, Dastgheib K, Bressler NM, 27. Yoneya S, Tso MOM. Angioarchitecture of the tion revealed a diffuse infiltrate of et al. Clinicopathologic correlation of the mul- human choroid. Arch Ophthalmol. 1987;105: poorly cohesive medium to large tiple recurrent serosanguineous retinal pig- 681-687. ment epithelial detachments syndrome. Retina. cells, with moderate prominent 1994;14:143-152. nucleoli, and moderate, sometimes 13. Spraul CW, Grossniklaus HE, Lang GK. Idi- eccentric, cytoplasm. Many cells dis- opathische polypose choroidale vaskulopa- Rapidly Progressive T-Cell thie (IPCV). Klin Monatsbl Augenheilkd. 1997; played folded or cleaved nuclei. Ger- 210:405-406. Lymphoma of the minal centers were absent, and nu- 14. Spaide RF, Yannuzzi LA, Slakter JS, Sorenson Conjunctiva J, Orlach DA. Indocyanine green videoangiog- merous mitotic figures were present. raphy of idiopathic polypoidal choroidal vas- Immunohistochemical stains for leu- culopathy. Retina. 1995;15:100-110. Conjunctival lymphoma classically kocyte common antigen (CD45), 15. Ross RD, Gitter KA, Cohen G, Schomaker KS. Idiopathic polypoidal choroidal vasculopathy presents as a salmon-colored infil- UHCL-1 (CD45Ro), and CD8 were associated with retinal arterial macroaneu- trate that evolves slowly over months positive, suggestive of a lymphoid rysm and hypertensive retinopathy. Retina. 1 1996;16:105-111. to years. It is nearly always of B-cell neoplasm of T-cell origin. B-cell 1,2 16. Uyama M, Matsubara T, Fukushima I, et al. Id- lineage. In an analysis of ocular ad- marker, L26 (CD20), was negative. iopathic polypoidal choroidal vasculopathy in nexal lymphoid tumors, 29% were The final diagnosis was peripheral Japanese patients. Arch Ophthalmol. 1999;117: 1035-1042. polyclonal, 68% were monoclonal B- T-cell lymphoma. 17. Cantrill HL, Folk JC. Multifocal choroiditis as- cell proliferations, 2% were indeter- A thorough sytemic examina- sociated with progressive subretinal fibrosis. Am minate, 1% were null cell, and 0% tion revealed no systemic lym- J Ophthalmol. 1986;191:170-180. 18. Kim NK, Chan CC, Belfort R, et al. Histopatho- were monoclonal T-cell prolifera- phoma or mycosis fungoides. The logic and immunohistopathologic features of tions.2 We report an unusual case of patient was treated with 3500 rad (35 subretinal fibrosis and uveitis syndrome. Am J Ophthalmol. 1987;104:15-23. a rapidly progressive conjunctival Gy) of radiotherapy to the left con- 19. Shiraga F, Matsuo T, Yokoe S, et al. Surgical mass that was the first manifesta- junctiva with rapid regression of the treatment of submacular hemorrhage associ- tion of systemic T-cell lymphoma. lymphoma (Figure 1). During her ated with idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol. 1999;128:147- last week of radiotherapy, she ex- 154. Report of a Case. A 72-year-old Af- perienced dysphagia and a 2.72 kg 20. Lafaut BA, Aisenbrey S, Van Den Broecke C, rican American woman developed weight loss. She was discovered to Bartz-Schmidt K, Heimann K. Polypoidal choroidal vascular pattern in age-related macular swelling of her left caruncle that dra- have an obstructive nasopharyn- degeneration: a clinicopathologic correlation. matically enlarged throughout 21 geal mass, and cervical, inguinal, and Retina. 2000;20:650-654. 21. Iijima H, Imai M, Gohdo T, Tsukahara S. Op- days, prompting ocular examina- popliteal lymphadenopathy. On ex- tical coherence tomography of idiopathic pol- tion. Her visual acuity was 20/200 amination of the biopsy specimen, ypoidal choroidal vasculopathy. Am J Ophthal- OD and counting fingers OS from the nasopharyngeal mass proved to mol. 1999;127:301-305. 22. Macular Photocoagulation Study Group. Risk cataracts bilaterally. There was a be T-cell lymphoma, and radio- factors for choroidal neovascularization in the painless, pink, multinodular mass therapy (1300 rad [13 Gy]) was de-

A B C

Clinical course of conjunctival T-cell lymphoma. A, Throughout 21 days, there occurred a dramatic growth of the conjunctival stromal mass, involving 60% of the bulbar conjunctiva. B, Histopathological examination revealed poorly cohesive pleomorphic cells, with prominent nuclei and scanty cytoplasm. Many cells displayed folded or cleaved nuclei, suggestive of T cells (hematoxylin-eosin, original magnification ϫ 250). C, Following 3500 rad (35 Gy) of radiotherapy, the mass completely regressed.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 livered to the site, and there was im- proved to be the first sign of sy- fort, or to the administration of up provement. Systemic chemotherapy, temic T-cell lymphoma. to a 1% concentration of pilocar- using cytoxan, vincristine, and adria- pine eyedrops. Streak retinoscopy re- mycin, was administered for 2 cycles. Carol L. Shields, MD vealed a refraction of OD +3.0 di- The patient maintained poor fol- Jerry A. Shields, MD opter sphere (D sph) and OS +2.5 D low-up for 11 months, and she sub- Ralph C. Eagle, MD sph that remained uninfluenced by sequently died of an unknown cause. Philadelphia, Pa topical application of pilocarpine. Apart from the lack of accommoda- Comment. Lymphomas can be Support was provided by the Eye Tu- tion and pupillary constriction, all broadly classified into Hodgkin and mor Research Foundation, Philadel- ocular findings were normal. No non-Hodgkin types. Non-Hodg- phia, Pa (Dr C. L. Shields); the Paul other pupillary abnormalities were kin lymphomas are a diverse group Kayser International Award of Merit known in the family. The infant was and include monoclonal neo- in Retina Research, Houston, Tex (Dr given spectacles to wear for focus- plasms of B-cell or T-cell lympho- J. A. Shields); and the Noel T. and Sara ing at close distance. Within the fol- cytes. T-cell lymphomas are much L. Simmonds Endowment for Oph- lowing 2 years, a tortuosity of the less common than B-cell lympho- thalmic Pathology, Wills Eye Hospi- retinal arteries with several loops mas and are particularly rare in the tal, Philadelphia (Dr Eagle). near the optic disc became appar- ocular region.1,2 Of the few re- Corresponding author: Carol L. ent. Having now observed the girl for ported cases of ophthalmic T-cell Shields, MD, Ocular Oncology Ser- 9 years, the tortuosity has in- lymphomas, most involved the or- vice, Wills Eye Hospital, 900 Walnut creased while the pupils have not be- bit or eyelid, and followed known St, Philadelphia, PA 19107. come smaller (diameter, OU 6.78 systemic T-cell lymphoma.3,4 Rapid mm). They did not dilate after ad- 1. Shields CL, Shields JA, Carvalho C, Rundle P, progression throughout days to Smith AF. Conjunctival lymphoid tumors: clini- ministration of up to a 5% concen- weeks, and poor systemic progno- cal analysis of 117 cases and relationship to sys- tration of phenylephrine eyedrops. sis was a common feature. Systemi- temic lymphoma. Ophthalmology. 2001;108:979- The iris stroma is hypotrophic, with- 984. cally, however, T-cell lymphoma can 2. Jakobiec FA, Knowles DM. An overview of ocu- out crypts. Diaphanoscopy of the iris progress rapidly in aggressive sub- lar adnexal lymphoid tumors. Trans Am Oph- did not reveal an absence of the pos- types or it can progress slowly as in thalmol Soc. 1989;87:420-442. terior pigmented iris epithelium nor 3. Coupland SE, Foss HD, Assaf C, et al. T-cell and mycosis fungoides. Cook and asso- T/natural killer-cell lymphomas involving ocu- was there any abnormal finding in ciates reviewed 2155 patients at the lar and ocular adnexal tissues: a clinicopatho- the sphincter zone. The axial bul- logic, immunohistochemical, and molecular Mayo Clinic with known cutane- study of seven cases. Ophthalmology. 1999;106: bus length is now OD 19.77 mm and ous T-cell lymphoma, and found in- 2109-2120. OS 20.03 mm. Meanwhile, the re- filtration of the eyelid in 0.3%, and 4. Cook BE, Bartley GB, Pittelkow MR. Ophthal- fraction of +7.75 D sph combined 4 mic abnormalities in patients with cutaneous T- ϫ conjunctiva in 0.05%. Thus, ocu- cell lymphoma. Ophthalmology. 1999;106:1339- with –1.0 cylinder 171° OD and lar involvement with T-cell lym- 1344. +7.25 D sph combined with –1.5 phoma is exquisitely rare. 5. Hu FR, Lin JC, Chiang IP, Yeh KH. T-cell ma- cylϫ172° OS is corrected by mul- lignant lymphoma with conjunctival involve- Using a MEDLINE search, we ment. Am J Ophthalmol. 1998;125:717-719. tifocal glasses. The visual acuity is found one other case of T-cell lym- 0.8 OD and 1.0 OS. The mental de- phoma that initially presented in the velopment of the girl is normal. Her conjunctiva, similar to our case.5 The length and body weight are near the conjunctival tumor in that case also Congenital Mydriasis, third percentile. showed rapid progression. The pa- Failure of Accommodation, Case 2. This prematurely born tient was a 63-year-old woman who and Patent Ductus infant (at 34 weeks’ gestation; weight, presented with bilateral limbal con- Arteriosus 1940 g) had been operated on for a junctival thickening and chemosis large PDA at the age of 2 weeks. The for 20 days, and histopathologic Congenital mydriasis is a very rare diameter of her pupils was 7 mm study revealed T-cell lymphoma.5 abnormality that occurs in combi- without change either to light or to Our patient also had a rapidly en- nation with a failure of accommo- the administration of up to a 1 % con- larging conjunctival mass that be- dation. Herein we describe 2 pa- centration of pilocarpine eyedrops. gan as a caruncular thickening tients in whom these ocular defects There was also no dilatation after and extended in 21 days to involve are associated with patent ductus ar- administration of a 5% concentra- 60% of the bulbar conjunctiva. Both teriosus (PDA). tion of phenylephrine eyedrops (pho- patients were found subsequently tographic measurements). The ex- to have systemic T-cell lymph- Report of Cases. Case 1. This 15- amination with a handheld slitlamp oma, with involvement of maxil- week-old infant was first seen by us revealed a persisting pupillary mem- lary sinus in their case, and naso- 2 weeks after she had undergone sur- brane (a grid of filiform tissue origi- pharynx in our case. Thus, sys- gery for a large PDA.1 Her parents nating midstroma and reaching temic evaluation is particularly had observed the dilated pupils since across the pupil). The iris stroma was important in these cases. In sum- birth. The photographically mea- hypotrophic, without crypts. Diapha- mary, we present an unusual case of sured diameter of the round pupils noscopy showed some small defects a rapidly progressive salmon- was 6.5 mm. They were not reac- of the pigment epithelial layer at the colored conjunctival tumor that tive to light, to an eyelid closure ef- 8- to 9-o’clock position of the left iris

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 periphery. The lens was in its regu- the sphincter muscle tissue. Alterna- Neuro-ophthalmology, University of lar position. Indirect binocular oph- tively, a dysgenesis involving all the Giessen, Friedrichstrasse 18, D-35385 thalmoscopy showed poor pigmen- intraocular muscles can be dis- Giessen(e-mail:michael.h.graef@augen tation of the fundus and a slight cussed. Ataxia and oligophrenia are .med.uni-giessen.de). tortuosity of the retinal arteries. Streak excluded in our case 1, and so far case 1. Graf M. Bilateral congenital mydriasis and lack retinoscopy revealed a refraction of 2 also reveals no findings pointing to of accommodation. Ophthalmologe. 1996;93: OD +3.0 D sph and OS +2.5 D sph Gillespie syndrome.7,8 377-379. that did not change after application An involvement of the ciliary 2. White BV, Fulton MN. A rare pupillary defect inherited by identical twins. J Hered. 1937;28: of 1% pilocarpine eyedrops. There muscle was recently mentioned in a 177-179. was no known family history of other case of congenital mydriasis.3 In most 3. Buys Y, Buncic JR, Enzenauer RW, Mednick E, O’Keefe M. Congenital aplasia of the iris sphinc- pupillary abnormalities. We pre- patients whose cases are reported in ter and dilator muscle. Can J Ophthalmol. 1993; scribed a spectacle correction focus- the literature, it cannot be excluded 28:72-75. ing at arm’s length and have kept the because of their old age.2,4,6 The his- 4. Caccamise WC, Townes PL. Bilateral congenital mydriasis. Am J Ophthalmol. 1976;81:515- infant under observation. tory of one woman whose presbyopic 517. symptoms had not appeared until she 5. Suzuki T, Obara Y, Fujita T, Shoji E. Unilateral was45yearsoldisonlyanecdotal.4 Re- congenital mydriasis. Br J Ophthalmol. 1994;78: Comment. The first 2 reported cases 420. of bilateral congenital mydriasis oc- gardingvisualfunction,mydriasismay 6. Laor N, Korczyn AD. Waardenburg syndrome curred in monozygotic twins.2 More cause some glare and contribute to the with a fixed dilated pupil. Br J Ophthalmol. 1978; 62:491-494. females than males are affected, typi- blur of the retinal image, but the lack 7. Richardson P, Schulenburg WE. Bilateral con- cally bilaterally.1-4 Unilateral congen- of accommodation is the decisive de- genital mydriasis. Br J Ophthalmol. 1992;76:632- ital mydriasis was described,5 once in fect.Topreventamblyopia,correction 633. 8. Quarrell O. Gillespie syndrome reported as bi- a male patient with Waardenburg syn- of the refractive error is indicated with lateral congenital mydriasis. Br J Ophthalmol. drome.6 In hereditary cases, an auto- focusing at arm’s length (if accommo- 1993;77:827-828. somal dominant mode of inheritance dation is impossible) in infancy , and and an X-linked mode with nonviabil- from 6 months onward with the use ity of males were discussed.2,4 of bifocal glasses focusing at arm’s The pathophysiologic correlate length and 1 m, and later by multifo- Cytomegalovirus Retinitis of congenital mydriasis and lack of ac- cal glasses. In addition, sunglasses are in Patients With commodation is not unequivocal so sensible. Good Syndrome far. A complete lack of cholinergic Congenital mydriasis is an ex- sensibility of the iris sphincter and the tremely rare condition, and the inci- Hypogammaglobulinemia and sec- ciliary muscle can be discussed. If dence of extreme PDA is low. Of 15 ondary systemic opportunistic in- complete agenesis of the parasympa- reports—several of which are based fections are recognized associa- thetically innervated muscles were the only on history and are not thor- tions in patients with thymoma,1 and cause, diaphanoscopy of the iris ough—there are 3 well-documented the simultaneous occurrence of thy- should have revealed an absence of cases that bear testimony to an asso- moma and hypogammaglobu- the iris sphincter muscle, but there ciation between bilateral congenital linemia is referred to as Good syn- was only peripheral spotty loss of the mydriasis, insufficiency of accommo- drome.2 posterior pigmented iris epithelium dation, and PDA. Such an associa- We report herein the presen- in 1 eye of our patient 2. In case of tion can therefore hardly be ex- tation, clinical course, and out- (acquired) neurogenic origin, cho- plained by pure chance. As a come of 2 consecutive patients with linergic supersensitivity should be ex- fundamental pathophysiologic vitreous biopsy–proved cytomega- pected, but all the reported cases of mechanism, a receptor defect of the lovirus (CMV) retinitis associated congenital mydriasis showed either smooth muscles of both the eye and with thymoma and immunodefi- no or only poor reaction to pilocar- the media of the ductus arteriosus can ciency but with no evidence of other pine. In one patient, a 4% pilocar- be hypothesized. Further investiga- systemic CMV infection. pine solution constricted the pupil a tion will be necessary to elucidate the little and a 10% phenylephrine solu- frequency and the mechanism of the Report of Cases. Case 1. A 45-year- tion led to a rapid dilatation, suggest- link between a large PDA and a con- old woman was referred to Moor- ing the presence of an iris sphincter genital defect of the ciliary muscle and fields Eye Hospital, London, En- and dilator muscle.4 In our 2 cases an the iris sphincter as well as the tor- gland, in November 1998 with a (congenital) aplasia of the small cells tuosity of the retinal vessels. Any pa- 2-month history of bilateral poste- of the oculomotor complex is imag- tient with a PDA should undergo a rior uveitis that was not respond- inable, leading to an “orthograde careful examination of the function ing to topical treatment. The pa- transsynaptic dysgenesis” of the cor- of the intraocular muscles. tient had no history of ocular disease, responding muscles (the same mecha- and her medical history included a nism can be imagined if a lack of sen- Michael H. Gra¨f,MD thymoma treated by excision and sibility of the cholinergic receptors Andrea Jungherr, MD postoperative radiotherapy in 1996, was the cause), thus also explaining Giessen, Germany myasthenia gravis (positive acetyl- the lack of a response to pilocarpine. choline receptor antibody), vascu- The lack of response to phenyleph- Correspondingauthor:MichaelH.Gra¨f, litis (p–anti-neutrophil cytoplas- rine might be explained by fibrosis of MD, Department of Strabismology and mic antibody positive) with mild

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Figure 1. Funduscopic photograph of the left eye of patient 1 showing mild Figure 2. Funduscopic photograph of the right eye of patient 2 showing vitritis with peripheral cytomegalovirus retinitis. cytomegalovirus retinitis along the inferotemporal vascular arcade with involvement of the macula and optic nerve head.

renal impairment, and recurrent ies for human immunodeficiency vi- infections associated with bronchi- chest infections. She also had had a ruses 1 and 2 and had markedly low ectasis. On examination, her visual recent episode of chicken pox be- IgA levels (44 mg/dL), with mildly acuities were hand movements and fore the onset of ocular symptoms. elevated IgM (199 mg/dL) and IgG 20/20 OS, with a right-sided relative The patient was being treated with (2020 mg/dL) levels. Polymerase afferent pupillary defect. Slitlamp prednisolone, 10 mg/d, and azathio- chain reaction examination of pe- examination showed a mild right prine, 100 mg/d. ripheral blood was negative for CMV anterior uveitis with normal intra- On examination, her visual acu- DNA. The patient’s CD4 cell count ocular pressures. Funduscopic ex- ities were 20/20 OD and 20/40 OS. did not return to normal, and her im- amination showed a moderate vitri- Bilateral mild anterior uveitis was mune status remained unchanged tis and a swollen, hyperemic optic present, with normal intraocular despite cessation of azathioprine disc associated with retinitis along the pressures. Funduscopic examina- therapy. A chest x-ray film was clear, right inferotemporal vascular ar- tion showed a bilateral mild vitritis with no evidence of opportunistic in- cade and affecting the macula associated with bilateral superotem- fection. Because her retinitis was im- (Figure 2). Polymerase chain reac- poral active retinitis (Figure 1). proving after a week of systemic tion examination of a vitreous tap There was also an associated supe- treatment, the patient was dis- confirmed the presence of CMV DNA rotemporal macula-on rhegmatog- charged from the hospital on a regi- and was negative for herpes simplex enous detachment of the retina in the men of oral acyclovir (because the viruses 1 and 2, herpes zoster virus, right eye. A clinical diagnosis of bi- patient preferred not to receive gan- and Epstein-Barr virus DNA.The pa- lateral acute retinal necrosis was ciclovir) and a tapering course of oral tient was treated with topical corti- made, and the patient was treated prednisolone. Six weeks later, the costeroids and repeated intravitreal with intravenous valacyclovir hy- retinitis relapsed in the left eye and injections of foscarnet sodium (2.4 drochloride (10 mg/kg 3 times treatment was changed to intrave- mg each) and oral gancyclovir (1 g daily), oral prednisolone (45 mg/ nous ganciclovir followed by inser- 3 times daily). Despite control of the d), and topical 1% prednisolone ac- tion of a slow-release intravitreal im- retinitis, the patient’s vision failed to etate and 1% cyclopentolate hydro- plant. The retinitis in her left eye improve because of optic atrophy. chloride. The patient subsequently resolved after 1 week, and the gan- Polymerase chain reaction examina- underwent a right vitrectomy with ciclovir implant has been subse- tion of peripheral blood was nega- injection of silicone oil for treat- quently exchanged on a regular ba- tive for CMV DNA. A chest x-ray film ment of her detached retina and bi- sis to control the patient’s disease was not suggestive of any acute op- lateral argon laser to demarcate the because her CD4 cell count has re- portunistic infections, and analysis of areas of active retinitis. Polymerase mained low. blood samples showed a raised CD8 chain reaction examination of a vit- Case 2. A 65-year-old woman cell count of 976 cells/µL (reference reous sample taken during vitrec- was referred to Moorfields Eye Hos- range, 200-900 cells/µL), with a re- tomy was positive for CMV DNA and pital in April 2000 with a 1-week his- duced CD4/CD8 ratio of 0.6 (refer- negative for herpes simplex virus 1 tory of floaters and progressive re- ence range, 0.66-3.52) and a low B and herpes zoster virus DNA. Analy- duction in visual acuity of the right lymphocyte count of 1 (reference sis of blood samples disclosed a eye after a flulike illness that lasted range, 100-500). The patient had no marked selective CD4 T-cell lym- a few days. The patient had no his- serum antibodies for human immu- phocytopenia, with a reduced CD4/ tory of ocular disease, but her medi- nodeficiency viruses 1 and 2, low IgA CD8 ratio of 0.25 (reference range, cal history was remarkable for a ma- (56 mg/dL) and IgM (43 mg/dL) lev- 0.66-3.52) but a normal B cell count. lignant thymoma that had been els, and a normal IgG level (640 The patient had no serum antibod- excised in 1998 and recurrent chest mg/dL).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Comment. About a third of thymo- Clinicians should be aware of this as- OU. Medical history and slitlamp ex- mas are associated with more than 20 sociation, as early recognition and amination findings were unremark- different paraneoplastic syndromes, treatment can improve prognosis. able. Findings from right fundus ex- the 3 most commmon being myas- amination were normal. Left fundus thenia gravis, pure red cell aplasia, and Alexandre C. Assi, BSc, MBBS, examination disclosed a round le- hypogammaglobulinemia (6% of FRCOphth sion that was located at the level of cases).1 The simultaneous occur- Susan Lightman, PhD, FRCP, the retinal pigment epithelium (RPE) rence of thymoma and hypogamma- FRCOphth, FMedSci in the posterior pole (Figure 1A) globulinemia was first described in London, England above the macula and a localized se- 19542 and was referred to as Good syn- rous retinal detachment. Fluores- drome. Other systemic associations re- Correspondingauthorandreprints:Su- cein angiography showed CNV at the ported with thymomas include my- san Lightman, PhD, FRCP, FRCOphth, inferior border of the lesion. Kryp- asthenia gravis, IgG gammopathy, FMedSci,MoorfieldsEyeHospital,City ton laser photocoagulation was ap- disorders of cell-mediated immu- Road, London EC1V 2PD, England plied to the new vessel. Three weeks nity, polyarthropathy, lichen pla- (e-mail: s.lightman @ucl.ac.uk). later an additional angiogram was nus, and hemolytic anemia.3 To the performed (Figure 2A), which was best of our knowledge, the 2 pa- 1. Rosenow EC III, Hurley BT. Disorders of the thy- of better quality than the initial study. tients described herein are the first re- mus: a review. Arch Intern Med. 1984;144:763- This study showed a leopard-spot 770. ported cases of CMV retinitis associ- 2. Good RA. Agammaglobulinaemia: a provoca- pattern at the periphery of the le- ated with the syndrome of thymoma tive experiment of nature. Bull Univ Minn Hosp. sion, with hypofluorescent dots sur- 1954;26:1-19. and immunodeficiency. 3. Benson MK. Mediastinal tumours and cysts. In: rounded by reticular staining with the Recurrent bronchopulmonary Weatherall DJ, Ledingham JGG, Warrell DA, eds. dye. The photocoagulation scar ap- disease often leading to bronchiec- Oxford Textbook of Medicine. Vol 2, section 17. peared dark. B-scan ultrasonogra- 3rd ed. Oxford, England: Oxford University tasis is the most common clinical Press; 1996:2898-2899. phy did not show any signs of calci- presentation of Good syndrome, and 4. Gupta S, Saverymuttu SH, Gibbs JSR, Evans DJ, fication within the lesion. The lesion both our patients had had recur- Hodgson HJ. Watery diarrhea in a patient with appeared to remain stable during a myasthenia gravis, thymoma, and immunode- rent chest infections. Conversely, ficiency. Am J Gastroenterol. 1985;80:877-881. 2-year follow-up. CMV is the opportunistic patho- 5. Kauffman CA, Linnemann CC Jr, Alvira MM. Cy- Case 2. A 27-year-old man con- tomegalovirus encephalitis associated with thy- gen most frequently reported in the moma and immunoglobulin deficiency. Am sulted us because he needed an at- literature and has caused broncho- J Med. 1979;67:724-728. testation to renew his boxing li- pneumonia, watery diarrhea, dis- 6. Shaikh S, Schwab IR, Morse LS. Association of cense. Visual acuity was 20/25 OD ocular toxoplasmosis and thymoma. Retina. 1997; seminated infection, and fatal en- 17:354-356. and 20/20 OS. Medical history and cephalitis.4,5 7. Figuier P, Saragoussi JJ, Cavaille-Coll M, Le Ho- slitlamp examination findings were No retinal lesions have been ang P, Offret H. Toxoplasmose oculaire acquise unremarkable. Results of left fun- et immunode´pression d’origine thymique tumo- previously reported in patients with rale. J Fr Ophtalmol. 1984;7:813-817. dus examination were within nor- Good syndrome and systemic CMV 8. Eiferman RA, Hoffman RS, Pence HL. Good syn- mal limits. Right fundus examina- drome and herpetic keratitis [letter]. Arch Oph- infections. The ocular manifesta- thalmol. 1993;111:736. tion, however, disclosed a deep, tions of this syndrome described in 9. Holland GN, Tufail A, Jordan MC. Cytomega- large, grayish lesion in the interpap- the literature are limited to 2 cases lovirus diseases. In: Pepose JS, Holland GN, illomacular area, with a leopard- 6,7 Wilhelmus KR, eds. Ocular Infection and Immu- of toxoplasma retinitis and 1 case nity. St Louis, Mo: Mosby–Year Book Inc; 1996: spot pattern at its periphery (Fig- of bilateral, nonsimultaneous recur- 1088-1128. ure 1B). A tiny epiretinal membrane rent herpetic keratitis.8 was observed at the inferonasal as- Although CMV disease occurs pect of the macula, which was as- most often in patients with de- sociated with 2 small hemorrhages. pressed cell-mediated immunity, Unilateral, Idiopathic The leopard-spot pattern appeared there is evidence that humoral im- Leopard-Spot Lesion of the more obvious on fluorescein angi- munity plays a protective role against Retinal Pigment Epithelium ography (Figure 2B). Fluorescein an- the virus.9 Before the acquired im- giography also disclosed tortuosity munodeficiency syndrome epi- Several conditions have been de- and kinking of arterioles and ven- demic, fewer than 50 cases of CMV scribed as having a retinal leopard- ules located nasally and inferiorly to retinitis in patients with noncon- spot pattern.1-6 We report a similar the macula. We interpreted these genital CMV disease were reported pattern, observed in 1 eye each of 4 anomalies of the retinal vessels as a in the literature. These cases devel- young patients (Figure 1), and dis- consequence of the epiretinal mem- oped in severely immunocompro- cuss how this condition is distinct brane. B-scan ultrasonography did mised patients with organ trans- from previously described lesions; in not show any signs of calcification plants or a variety of malignancies 2 cases, these leopard-spot lesions within the lesion. Unfortunately, the associated with the use of immuno- were associated with choroidal neo- patient was lost to follow-up. suppressive chemotherapy.9 vascularization (CNV). Case 3. A 16-year-old girl was Therefore, our cases illustrate seen with a complaint of “visual fa- a widening clinical spectrum of CMV Report of Cases. Case 1. A 34-year- tigue.” Visual acuity was 20/20 OU disease in patients with immunode- old man was seen because of meta- with correction (+0.50 OD, 90° ficiency associated with thymoma. morphopsia. Visual acuity was 20/20 +0.25 OS). Medical history and slit-

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C D

Figure 1. Fundus photograph of the posterior pole of cases 1 (A), 2 (B), 3 (C), and 4 (D). Round lesions with peripheral dark dots result in a leopard-spot pattern. The lesions are located at the level of the retinal pigment epithelium (RPE) and include fibrosis, hyperplastic changes of the RPE at the periphery, and thinning and atrophy of the RPE at the center.

lamp examination findings were un- fundus appeared normal, but the low-up), no recurrence has oc- remarkable. The left fundus ap- right fundus showed a deep, oval curred. A previous ophthalmic peared normal. Right fundus exami- macular lesion with a whitish re- examination had been performed 10 nation disclosed an irregular lesion ticular border. A central macular de- years ago because of the patient’s dia- located at the level of the RPE, in the tachment was also observed (Fig- betes. The medical report at that time papillomacular area, with dark dots ure 1D). Fluorescein angiography described a visual acuity of 20/20 surrounded by a whitish reticular net showed a leopard-spot–patterned le- OU, pigmentary alterations of the (Figure 1C). The leopard-spot pat- sion associated with a juxtafoveal right fundus, but no suggestion of tern appeared more obvious on fluo- CNV (Figure 2D). A feeder vessel diabetic retinopathy. An angio- rescein angiography (Figure 2C). was observed in the early frames gram had also been performed (Fig- Follow-up was limited to 6 months, with leakage of dye on late frames ure 3E). Comparison of previous and but there was no change during this (Figure 3A-B). Indocyanine green recent angiographies disclosed time. angiography also showed the CNV marked progression of the leopard- Case 4. A 24-year-old man was on early frames and a hypofluores- spot lesion. seen for visual loss and metamor- cent lesion on late frames (Figure phopsia of the right eye. Visual acu- 3C-D). The reticular peripheral net Comment. Herein, we have de- ity was 20/128 OD and 20/20 OS. that was hyperfluorescent on fluo- scribed 4 young patients, 3 men and Medical history revealed type 2 dia- rescein angiography appeared hy- 1 girl, who presented with a round le- betes mellitus, which was diag- pofluorescent on indocyanine green sion of one posterior pole. The le- nosed when the patient was 2 years angiography. B-scan ultrasonogra- sion had a leopard-spot pattern ob- old and treated solely by diet. His phy did not reveal any signs of cho- served on color fundus photographs mother also had type 2 diabetes roidal calcification. The CNV was and, more obviously, with fluores- mellitus. Slitlamp examination find- then treated with krypton laser pho- cein angiography. B-scan ultrasonog- ings were unremarkable. The left tocoagulation. To date (6-month fol- raphy, performed in 3 cases, did not

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Figure 2. Fluorescein angiography of cases 1 (A), 2 (B), 3 (C), and 4 (D). The leopard-spot pattern appears to be localized at the periphery of the lesion in each case. Fluorescein angiography is consistent with thinning and atrophy of the RPE at the center of the lesion (A and B). In one case, it also showed anomalies of retinal vasculature: tortuosity and kinking of arterioles and venules in a localized part of the retina (B).

reveal any calcification. Choroidal quently observed in patients receiv- vere ocular trauma. Moreover, a trau- neovascularization was observed in 2 ing high doses of corticosteroids. matic origin appeared particularly un- patients, in one case at the border of None of our patients had previous likely in case 4, for whom comparison the lesion and in one case within the episodes consistent with typical of recent and previous angiograms leopard-spot lesion. chronic idiopathic central serous cho- showed marked changes (Figure 3). Several systemic conditions may rioretinopathy, and none received In this case, one could assume that be associated with a leopard-spot pat- corticosteroids. Furthermore, chronic secondary hyperplastic changes fol- tern of the fundus, including leuke- idiopathic central serous chorioreti- lowed initial sequelae of trauma; how- mia, systemic form of large-cell non- nopathy is unlikely to develop in a ever, a lack of recollection of severe Hodgkin lymphoma, systemic carci- 16-year-old girl (case 3). trauma in all patients and demonstra- noma with bilateral diffuse uveal Trauma should be taken seri- tion of evolution of the lesions in one melanocytic proliferation, and idio- ously as a possible cause of the pat- case led us to hypothesize that a trau- pathic uveal effusion syndrome.1-5 tern observed in the present cases. matic cause is unlikely. However, ocu- However, all of these acute conditions Traumatic choroidopathy can result lar trauma cannot be ruled out be- appeardifferentlyfromtheasymptom- from acute contusion necrosis of the cause it could have occurred during atic pattern observed in our patients, RPE. Rupture in the inner choroid infancy or childhood without any rec- whose troubles were confined to a lo- and RPE may be absent, but hemor- ollection. calized part of the retina, without as- rhagic detachment of the retina is fre- Choroidal or subretinal neo- sociatedsystemicorocularconditions. quently observed. Resolution of the vascularization is an acquired ab- Patients with chronic idio- detachment and hemorrhages may normality observed in many con- pathic central serous chorioretinopa- then reveal varying degrees of RPE at- genital, degenerative, infectious, thy may have a bone corpuscular pat- rophy.7 Case 2 acknowledged many inflammatory, tumoral, and trau- tern of migration of pigment in areas instances of trauma to the face dur- matic processes, some of which are of recurrent and/or chronic serous de- ing his boxing activities. However, more commonly observed in young tachment.6 This pattern is more fre- none of the 4 patients remembered se- patients.8 Among these conditions,

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Figure 3. Case 4. Fluorescein angiography at 24 seconds (A) and 6 minutes (B). Indocyanine green angiography at 36 seconds (C) and 25 minutes (D). Previous fluorescein angiography performed 10 years ago (E). Feeder vessel was present on early frames (A), with marked leakage on late frames (B). The reticular peripheral net, which was hyperfluorescent on fluorescein angiography, appeared hypofluorescent on indocyanine green angiography (C and D). Comparison with a previous angiogram (E) showed marked extension of the peripheral dots.

choroidal osteomas may show a pat- pigment on the surface. The osteo- may reveal the osteoma.9 Case 4 also tern similar to that seen in our pa- blastic activity of osteomas may en- developed CNV with a typical feeder tients. Choroidal osteomas, in sum- capsulate some osteoclastic change. vessel. However, marked attenua- mary, are unique, unilateral tumors Feeder vessels may be observed ex- tion of sound by the tumor ultraso- that arise in the juxtapapillary and iting from the holes in the anterior nographically, which is typical of macular region of young adults.9 surface of the cancellous bone. This choroidal osteomas, could not be They typically have an orange hue process can evolve to true choroi- demonstrated in our study in the 3 but may show some mottling of gray dal neovascular membranes, which patients so tested. In our cases, RPE

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 changes may have facilitated the oc- tion in young patients. Ophthalmology. 1996; tial thromboplastin time, fluores- 103:1241-1244. currence of CNV. 9. Shields CL, Shields JA, Augsburger JJ. Choroi- cent treponemal antibody level, In summary, to our knowl- dal osteoma. Surv Ophthalmol. 1988;33:17-27. VDRL, anticardiolipin antibody level, edge, the peculiar leopard-spot pat- and a carotid ultrasound. tern of the retinal lesion observed in The blood test results were sig- our 4 patients has not been previ- nificant for a hemoglobin level of 19.4 ously reported. Because the cause of Retinal Venous Occlusion g/dL and a hematocrit of 59.4%. The these lesions remains unclear, we have as the Initial Sign of patient was referred to the hematol- designated them as unilateral, idio- Tetralogy of Fallot ogydepartmentforevaluationofpoly- pathic leopard-spot lesions of the RPE. cythemia.Subsequently,hewasfound Lack of histologic analysis precludes Tetralogy of Fallot was originally de- to have decreased oxygen saturation more discussion on the possible etio- scribed in 1888.1 It is primarily en- by arterial blood gas analysis and a car- logic nature of the disorder, which countered in the pediatric population. diac murmur. An increased level of seems to associate fibrosis and hyper- It was described by E´ tienne-Louis A. erythropoietin was found, raising the plastic changes of the RPE at the pe- Fallot to consist of pulmonary atresia, suspicionthatthepolycytemiawasdue riphery of the lesion and thinning and dextroposed aorta, interventricular toanunderlyingconditioncausinghy- atrophy of the RPE at the center. septal defect, and right ventricular hy- poxemia. On further evaluation, a However, we could not rule out pertrophy. Approximately 3% of pa- transesophageal echocardiogram re- trauma as a possible cause of these le- tients survive to age 40 years without vealed the classic tetrad of pulmonic sions, and they may also represent a surgicalintervention.2 Longevityisbe- stenosis, ventricular septal defect, di- similar end stage of different causes. lieved to correlate with greater pulmo- latedoverridingaorta,andsevereright The condition is probably very rare, nary flow and milder degrees of arte- ventricular hypertrophy with a right and its prognosis likely depends on rial desaturation. Herein, we describe to left shunt, consistent with tetralogy whether CNV develops, which was a patient whose cardiac abnormality of Fallot. observed in 2 of our 4 patients. had gone undetected for 50 years un- The patient had never experi- til he came to the eye clinic with vi- enced any symptoms of congenital Salomon Y. Cohen, MD sual complaints. heart disease despite his very active Pascale Massin, MD life as a merchant marine; at the time Gabriel Quentel, MD Report of a Case. A 50-year-old Car- of initial examination, the patient Paris, France ribean man came to the ophthalmol- worked as a construction supervi- ogy clinic complaining of a 5-month sor. On questioning, he reported the Presented in part at the European Fluo- history of blurred vision in the right recent onset of exertional dyspnea, rescein Club Meeting, Creteil, France, eye. He stated that he saw an ophthal- which limited his exercise tolerance December 4, 1994, and at the Annual mologist 5 months earlier when the to 3 or 4 city blocks of walking. A car- Meeting of the Macula Society, symptoms started but failed to return diac catherization was performed and Scottsdale, Ariz, February 28, 2001. for follow-up owing to financial con- the patient ultimately underwent sur- Corresponding author and re- straints. Ten days prior to this visit, gical repair of his congenital cardiac prints: Salomon Y. Cohen, MD, Cen- thepatientreportedhavingsimilarepi- defect. The retinal hemorrhages re- tre Ophtalmologique d’Imagerie et de sodes of blurred vision in the left eye. solved, the vision remained stable, Laser, 11 rue Antoine Bourdelle, 75015 His visual acuity was 20/25 OD and the patient continues to receive Paris, France (e-mail: sycohen@club and 20/30 OS. The pupils, extraocu- regular follow-up. -internet.fr). lar muscles, intraocular pressure read- 1. Gass JDM. Stereoscopic Atlas of Macular Dis- ings, and findings of external and slit- Comment. A CRVO is often a re- eases: Diagnosis and Treatment. 4th ed. St Louis, lamp examinations were unremark- sult of a combination of local and Mo: CV Mosby; 1997:874-877. 2. Kincaid MC, Green WR, Kelley JS. Acute ocular able. Dilated fundus examination systemic factors. The mechanisms leukemia. Am J Ophthalmol. 1979;87:698-702. results revealed superficial hemor- that produce the clinical picture of 3. Gass JDM, Weleber RG, Johnson DR. Non- rhagesintheinferiotemporalquadrant a CRVO can be divided into (1) con- Hodgkin’s lymphoma causing fundus picture simulating fundus flavimaculatus. Retina. 1987; of the retina in the right eye associated ditions that produce a physiologic 7:209-214. with vessel tortuosity. Disc edema as- blockage at the level of the lamina 4. Barr CC, Zimmerman LE, Curtin VT, Font RL. Bilateral diffuse melanocytic uveal tumors asso- sociated with diffuse retinal hemor- cribosa and (2) conditions in which ciated with systemic malignant neoplasms: a re- rhages and dilated tortuous veins was hemodynamic factors result in an cently recognized syndrome. Arch Ophthalmol. seeninthelefteye.Thesefindingswere obstruction to the blood flow. A 1982;100:249-255. 5. Gass JDM, Jallow S. Idiopathic serous detach- consistent with a branch retinal vein combination of these mechanisms ment of the choroid, ciliary body, and retina occlusion in the right eye and a cen- may occur in a patient with a CRVO. (uveal effusion syndrome). Ophthalmology. 1982; tral retinal vein occlusion (CRVO) in Likely causes include atherosclero- 89:1018-1032. 6. Ie D, Yannuzzi LA, Spaide RF, Rabb MF, Blair the left eye. sis of the adjacent central retinal ar- NP, Daily MJ. Subretinal exudative deposits in A workup was initiated and in- tery (causing compression of the central serous chorioretinopathy. Br J Ophthal- mol. 1993;77:349-353. cluded complete blood cell count, vein in the lamina cribosa region and 7. Gitter KA, Slusher M, Justice J Jr. Traumatic hem- erythrocyte sedimentation rate, blood inducing thrombosis in the lumen orrhagic detachment of retinal pigment epithe- pressure evaluation, levels of fasting of the vein), hypertension, optic disc lium. Arch Ophthalmol. 1968;79:729-732. 8. Cohen SY, Laroche A, Leguen Y, Soubrane G, blood glucose and glycosylated he- edema, glaucoma, optic disc dru- Coscas G. Etiology of choroidal neovasculariza- moglobin, prothrombin time, par- sen, elevated homocysteine levels,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 hypercoagulation states (eg, lym- antinuclear antibody levels, hemo- Corresponding author and reprints: phoma, leukemia, antiphospho- globin electrophoresis, cryoglo- Aruoriwo M. Oboh, MD, Department lipid syndrome, activated protein C bulins, antiphospholipid antibody of Ophthalmology, State University of resistance, and polycythemia), vas- levels, and a chest radiograph. A New York, Downstate Medical Cen- culitis (eg, sarcoid, syphilis, sys- complete medical evaluation with at- ter, 450 Clarkson Ave, Box 58, Brook- temic lupus erythematosus), drugs tention to the possibility of cardio- lyn, NY 11203. (eg, oral contraceptives, diuretics), vascular disease is necessary; the 1. Phadke AR, Phadke SA. Acyanotic Fallot’s te- retrobulbar external compression complete workup is best done in tralogy with survival to the age of 70 years. In- (eg, thyroid, orbital tumor), and rare conjunction with an internist. Fre- dian Heart J. 1977;29:46-49. 2. Chin T, Bashour S. Tetralogy of Fallot in the el- causes, such as migraine. quent ophthalmic examinations are derly. Clin Cardiol. 1984;7:453-456. An appropriate workup for a to be performed thereafter. young person who is found to have Although our patient had been SELECTED BIBLIOGRAPHY venous occlusion on initial exami- asymptomatic for many years, he had Anderson RH. What is meant by tertalogy of fal- nation includes blood pressure read- recently developed symptoms caused lot (S,D,I)? Ann Thorac Surg. 1995;59:562-564. ings, fasting blood glucose level, gly- by his cardiac anomaly. As a result, Bertranou EG. Life expectancy without surgery in cosylated hemoglobin level, complete the decision was made to perform sur- tetralogy of Fallot. Am J Cardiol. 1978;42:459-465. Charles C. Central retinal vein occlusion due to blood cell count with differential cell gical repair before any further car- hyperviscosity syndrome. J Emerg Med. 2000;18: count, platelet count, serum protein diac deterioration could ensue. 23-26. electrophoresis, lipid profile, and Tasman W, Jaeger E. Duane’s Clinical Ophthal- mology, Diseases of the Retina and Glaucoma. Phila- rapid plasma reagin/fluorescent Aruoriwo M. Oboh, MD delphia, Pa: J.B. Lippincott Co; 1991. treponemal antibody absorption test. E. Clifford Lazzaro, MD Yoshizumi M, Townsend-Pico W. Essential throm- bocytopenia and central retinal vein occlusion If clinically indicated, this basic Steven Inker, MD withneovascularglaucoma.AmJOphthalmol.1996; workup can be extended to include Brooklyn, NY 121:728-730.

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