CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

carcinoma and metastatic liver can- Branch Retinal Artery cer 2 years previously and had un- Occlusion Caused dergone total gastrectomy and partial by an Embolus of resection of the liver. He had no his- Metastatic Gastric tory of hypertension, diabetes melli- tus, heart disease, or cerebral infarc- Adenocarcinoma tion. On examination, the corrected visual acuity was 20/30 OD and light We report a case of branch retinal perception OS. Intraocular pres- artery occlusion caused by an em- sures were 13 mm Hg OD and 10 bolus of metastatic gastric adeno- mm Hg OS. A relative afferent - carcinoma. A 67-year-old man lary defect was observed in the left sought treatment for sudden visual eye. External and slitlamp examina- loss in his left eye. He had a medi- tions were unremarkable bilater- Figure 1. A funduscopic photograph shows cal history of gastric cancer with liver ally. Funduscopic examination re- milky-white retinal edema in the supratemporal . Findings on fundu- vealed milky-white retinal edema quadrant, which is compatible with branch scopic examination included local- consistent with branch retinal ar- retinal artery occlusion. Note also the yellowish-white subretinal mass surrounded by ized edema of the inner con- tery occlusion in the supratemporal shallow superior to the sistent with a supratemporal branch quadrant and a yellowish-white sub- equator of the left eye. retinal artery occlusion and a yel- retinal mass surrounded by shallow lowish-white subretinal mass sur- retinal detachment in the superior croscopic examination of the tu- rounded by shallow retinal detach- quadrant of the left eye (Figure 1). mor disclosed extensive infiltra- ment superior to the equator. Ultrasonography disclosed a tion of the choroidal stroma by cords Histopathological and immunohis- mass with strong internal echoes in and lobules of a malignant epithe- tochemical examinations of the eye the same region, suggestive of a sub- lial neoplasm consistent with meta- obtained post mortem showed posi- retinal tumor. The provisional di- static mucin-secreting adenocarci- tive staining of the choroidal tu- agnosis of the mass lesion was meta- noma. The tumor cells formed mor for epithelial membrane and static adenocarcinoma to the tubules and glandular structures carcinoembryonic antigens. In ad- associated with branch retinal ar- (Figure 2A), and the periodic acid– dition, an embolus of tumor cells was tery occlusion. Fluorescein angio- Schiff and alcian blue stains con- found to cause occlusion of the reti- graphic and computed tomo- firmed the presence of numerous in- nal artery. graphic examinations could not be tracytoplasmic vacuoles of mucin Occlusion of the retinal artery performed because of the patient’s (Figure 2B). Immunohistochemi- is mostly ascribed to either embo- poor general condition. Laboratory cal stains showed intense positive lus, thrombus, or vasculitis. It is values included a carcinoembry- immunoreactivity for epithelial strongly associated with carotid ath- onic antigen level of 722 ng/mL (ref- membrane antigen (Figure 3A) and eromatous plaque or cardiac valvu- erence level, Ͻ5 ng/mL) and a car- carcinoembryonic antigen (Figure lar diseases with vegetation. Other bohydrate antigen 19-9 level of 2567 3B). The histopathological find- causes, such as atrial myxoma, tem- U/mL (reference level, Ͻ37 U/mL). ings of the choroidal metastasis re- poral arteritis, periarteritis nodosa, Cultures of arterial blood were nega- sembled the patient’s primary tu- and systemic lupus erythematosus, tive for bacteria, and splenomegaly mor (Figure 4) and were consistent have been described but are rela- was absent. A chest radiograph with a moderately well-differenti- tively rare.1 Embolism caused by showed no concrete evidence of a ated gastric adenocarcinoma. A mi- neoplastic cells is extremely rare.2,3 metastatic tumor. Three weeks af- crometastasis was also identified in We report a case of gastric adeno- ter admission, the patient died be- the inferior to the carcinoma that metastasized to the cause of the deterioration of his gen- muscle. In addition, an embolus of choroid and occluded a branch reti- eral condition. Both eyes were tumor cells was found to totally oc- nal artery with an embolus of car- obtained post mortem, fixed in for- clude the lumen of the supratempo- cinoma cells. maldehyde, and processed rou- ral retinal arteriole near the tinely for light microscopy. Macro- (Figure 5). The cytological char- Report of a Case. A 67-year-old man scopic examination disclosed a solid acteristics of the tumor embolus was referred to our clinic for sud- tumor with a mottled dark-brown were quite similar to those of the den visual loss in his left eye. He had color that measured 12 mmϫ6mm choroidal tumor. The right eye was been diagnosed with gastric adeno- in the choroid of the left eye. Mi- normal on gross examination, and

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Figure 2. A, Hematoxylin-eosin staining shows the tumor to be a moderately well-differentiated adenocarcinoma based on the presence of tubulelike or glandlike structures. B, Positive periodic acid–Schiff staining is indicative of mucin production by carcinoma cells, especially by cells forming glandlike structures (original magnification ϫ180).

A B

Figure 3. A, Positive immunostaining for epithelial membrane antigen on the membrane of cells is related to the tubulelike or glandlike structures of the tumor. B, Diffuse and strongly positive immunostaining for carcinoembryonic antigen of the tumor is shown (original magnification ϫ180).

Figure 4. A representative microphotograph shows moderately Figure 5. The retinal artery is completely occluded by a tumor embolus well-differentiated adenocarcinoma of the stomach. The section was taken (original magnification ϫ180). from the surgical specimen (original magnification ϫ180).

there were no particular histopatho- metastatic adenocarcinoma. Histo- pathological and immunohisto- logical changes. pathological examination also con- chemical studies, including posi- firmed that the supratemporal reti- tive immunoreactivity markers for Comment. The present study clearly nal arteriole was occluded by an epithelial membrane antigen and shows that the choroidal tumor was embolus of tumor cells. The histo- carcinoembryonic antigen, are con-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sistent with metastatic gastric ad- noma to the choroid that had branch both implants, though the patient re- enocarcinoma; a primary tumor with retinal artery occlusion due to a tu- portedminimalvisualdeficit.Wethen known hepatic metastasis had been mor embolus. Ophthalmologists investigated the effect of rifabutin on treated 2 years earlier. The patient should be aware of this cause of 3differentcommonIOLmaterialsand is presumed to have died from wide- in their differen- found that it only affected silicone. spread systemic metastases be- tial diagnoses of retinal artery oc- Though rifabutin is well known to cause postmortem examination was clusion in patients with a history of cause discoloration of body fluids and limited to the eyes. malignancy. soft contact lenses, this case illustrates To our knowledge, retinal ar- thisprocessoccurringinIOLimplants. tery occlusion caused by an embo- Hisashi Masuda, MD Rifabutin is indicated for pro- lism of tumor cells is very rare, and Akihiro Ohira, MD, PhD phylaxis against Mycobacterium there are only a few reports that Yuzo Shibuya, MD avium complex (MAC), which is pri- clearly describe this condition. Oc- Taiji Takanashi, MD marily seen as a coinfection with hu- clusion of the central retinal artery by Liliam Pineda, MD man virus (HIV). chondrosarcoma and bronchial car- Takayuki Harada, MD, PhD Shown to cause discoloration in cer- cinoma cells was described by Burde Izumo, Japan tain body fluids, including tears, sa- and Henkind2 and Tarkkanen et al,3 liva, and perspiration, rifabutin pre- respectively. Zamora et al4 reported The authors have no proprietary in- scribing guidelines specifically a case of branch retinal artery occlu- terest in any aspect of this report. caution that soft contact lenses may sion in a patient with papillary fibro- Corresponding author and re- be permanently stained subse- elastoma of the mitral valve, but there prints: Akihiro Ohira, MD, PhD, De- quent to its use.1 However, to our was no histopathological demonstra- partment of Ophthalmology, Shimane knowledge, the occurrence in an IOL tion of the embolus. Metastasis of car- Medical University, 89-1 Enya, Izumo, has not been documented. We de- cinoma cells to the retina alone ap- Shimane 693-8501, Japan (e-mail: scribe a patient who developed a bi- pears to be a rare event. Smoleroff and [email protected]). lateral discoloration of her silicone Agatston5 reported a case of gastro- IOLs. esophageal carcinoma that metasta- 1. Ros MA, Magargal LE, Uram M. Branch retinal artery obstruction: a review of 201 eyes. Ann Oph- sized into the nerve fiber layer of the thalmol. 1989;21:103-107. Report of a Case. A 63-year-old retina. Shields et al6 studied 520 eyes 2. Burde RM, Henkind P. Retinal artery occlusion woman had bilateral extrac- in the absence of a cherry red spot. Surv Oph- tions with silicone IOL implants with uveal metastasis and found only thalmol. 1982;27:181-186. 5 to have metastatic lesions in the 3. Tarkkanen A, Merenmeies L, Makinen J. Em- (model SI30NB; Allergan Inc, Ir- retina. bolism of the central retinal artery secondary to vine, Calif) in early 1995. Shortly af- metastatic carcinoma. Acta Ophthalmol. 1973; However, there was no descrip- 51:25-33. ter a normal eye examination, she be- tion of arterial occlusion in their se- 4. Zamora RL, Adelberg DA, Berger AS, et al. Branch gana101⁄2-month course of 300 mg ries. In patients with end-stage dis- retinal artery occlusion caused by a mitral valve of rifabutin, by mouth, once daily for papillary fibroelastoma. Am J Ophthalmol. 1995; ease, particularly those with 119:325-329. chronic pulmonary MAC. At annual malignancies, embolism due to bac- 5. Smoleroff JW, Agatston SA. Metastatic carci- follow-up, both IOLs were noted to noma of the retina: report of a case, with patho- be discolored, and rifabutin therapy terial endocarditis, nonbacterial logic observations. Arch Ophthalmol. 1934;12: thrombotic endocarditis, or thrombi 359-365. was discontinued. formed with disseminated intravas- 6. Shields CL, Shields JA, Gross NE, et al. Survey Slitlamp examination revealed a of 520 eyes with uveal metastases. Ophthalmol- cular coagulation syndrome may be ogy. 1997;104:1265-1276. distinct rose-color in both IOLs encountered in the retinal artery.7,8 7. Deppisch LM, Fayemi AO. Non-bacterial throm- (Figure 1). The remainder of the ex- In the present case, there was no botic endocarditis. Am Heart J. 1976;92:723- 729. strong clinical or laboratory evi- 8. Cogan DG. Ocular involvement in dissemi- dence of infection, valvular dis- nated intravascular coagulopathy. Arch Ophthal- mol. 1975;93:1-8. eases, or disseminated intravascular 9. Weiss L. Cell adhesion molecules: a critical ex- coagulation. Complete obstruction of amination of their role in metastasis. Invasion Me- the arterial lumen by the tumor em- tastasis. 1994-1995;14:192-197. bolus as shown in our case is uncom- mon, whereas venous and lym- phatic invasion by malignant cells is more common because it can be ob- served in routine surgical speci- Discoloration of Intraocular mens. A major factor that contrib- Subsequent utes to the formation of tumor emboli to Rifabutin Use is the expression of adhesion mol- ecules,9 but emboligenic factors such A 63-year-old woman developed dis- as those mentioned above may ac- coloration of the silicone intraocular celerate their formation. lens (IOL) implants in both eyes af- Figure 1. Slitlamp photograph of the lens shows In conclusion, we report a clini- ter receiving 300 mg of rifabutin by rose-colored discoloration of the intraocular lens (double arrows) contrasted against capsular 1 copathological correlation of a case mouth, once daily, for 10 ⁄2 months. remnants that are not covered by the intraocular of metastatic gastric adenocarci- Examination revealed a rose color to lens (single arrows).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sion of Ophthalmology, Fletcher Allen A B C D Health Care, UHC Fourth Floor, Bur- lington, VT 05405 (e-mail: airwin@ vtmednet.org).

1. Physicians’ Desk Reference. 53rd ed. Montvale, NJ: Medical Economics Co; 1999:2501-2502. 2. Knight PM. Discoloration of a silicone intraocu- E lar lens 6 weeks after surgery [letter]. Arch Oph- thalmol. 1991;109:1494-1496. 3. Centers for Disease Control and Prevention Web site. Nontuberculous Mycobacteria Reported to the Public Health Laboratory Information System by State Public Health Laboratories: United States, 1993-1996. NTM Report 1999:1-51. Available at: http://www.cdc.gov/ncidod/dastlr/TB Figure 2. Comparison photograph of 4 intraocular lenses after immersion in concentrated rifabutin /ntmfinal.pdf. Accessed August 30, 2001. solution at 24 hours. A, Silicon (Allergan SI30NB; Allergan Inc, Irvine, Calif). B, Silicon (AA4204VF; 4. Zimmerli W, Widmer AF, Blatter M, Frei R, Staar Surgical, Monrovia, Calif). C, Acrylic (MA30BA; Alcon Surgical, Forth Worth, Tex). D, Polymethyl Ochsner PE. Role of rifampin for treatment of methacrylate (UV80F2; Ciba Vision Ophthalmics, Duluth, Ga). E, Cross section of Allergan lens. orthopedic implant-related staphylococcal in- fections: a randomized controlled trial. JAMA. 1998;279:1537-1541. amination was unremarkable, with vi- sonal communication, G. Kropid- sual acuity correctable to 20/20 OU. lowski, Allergan Inc). Finally, sili- That both IOLs were equally and cone IOLs placed in a rifabutin simultaneously stained is likely to ac- solution may dramatically discolor. Delayed Luxation count for the lack of perceived color In a laboratory investigation, of a Lens Nucleus shift. No further change in IOL colora- lenses from 4 different manufactur- After Vitrectomy tion has been noted since discovery. ers representing 3 materials were im- Thus, the IOLs were not removed. mersed for 1 week in a concentrated Accidental lens damage occurs less rifabutin solution. The discoloration than 1% of the time during vitrec- Comment. Silicone IOL engineer- fully penetrated the lens, rather than tomy for diabetic and ing has achieved a high degree of layering on as a film (Figure 2). Only may necessitate concurrent lensec- long-term optical clarity so that re- the silicone lenses placed in this so- tomy.1,2 We report an unusual late ports of decreased clarity have be- lution discolored. complication of pars plana vitrecto- come rare (approximately 0.07%).2 These findings have potential my—delayed luxation of the lens This case represents a potentially sig- implications for our elderly popu- nucleus. nificant effect on the patient’s qual- lation, as many of these individuals ity of life because the stained lenses may have already received silicone Report of a Case. A 52-year-old man are intraocular. IOLs by the time that they develop with a 20-year history of diabetes The rifamycins are recognized MAC or infection from implanta- mellitus sought treatment at the as “standard-of-care” drugs against tion of orthopedic hardware. Phy- Parkland Memorial Hospital Oph- both tuberculous and atypical my- sicians should be thus cautioned in thalmology Clinic, Dallas, Tex, be- cobacterial infections. Use of these their use of rifabutin in patients with cause of redness and in drugs is increasing because the inci- silicone IOLs, and that acrylic or the left eye for 3 days. One year pre- dence of MAC has dramatically in- polymethyl methacrylate lenses may viously, he underwent vitrectomy creased among both HIV-infected and be better suited for patients in whom in the left eye for proliferative dia- immunocompetent individuals dur- opportunistic infections are likely. betic retinopathy complicated by ing the last decade. High rates of in- nonclearing vitreous hemorrhage crease are currently being reported in Daniel Fuller Jones, MD and neovascular . Four patients older than 50 years.3 Addi- Alan Emory Irwin, MD months prior to the current devel- tionally, these drugs are being proven Burlington, Vt opment, he underwent a second useful against Staphylococcus in or- vitrectomy in the same eye for re- thopedic cases such as after im- We wish to thank Linda Ritchie, LPN- current vitreous hemorrhage. The planted devices or osteomyelitis.4 COA, Fernando Corrada, CRA, Kem- surgeon noted no intraoperative Multiple factors point to rifabu- per Alston, MD, and Fletcher Allen complications, including lens touch tin as the most likely cause of stain- Health Care Pharmacy, Burlington, Vt. with the instruments. On the first ing here. First, rifabutin has been Neither Dr Jones nor Dr Irwin day after the second vitrectomy, best- shown to stain soft contact lenses has any proprietary or commercial in- corrected visual acuity was 20/400 (typically silicone). None of the pa- terest in any company manufactur- OS, and a new posterior subcapsu- tient’s other medications are known ing any of the drugs or IOLs named lar cataract was noted. to cause discoloration of body flu- in this case report. On examination of the left eye, ids. The timing of the staining, rela- Dr Jones is now a pathology resi- best-corrected visual acuity was hand tive to her initiation of rifabutin dent at Jefferson Medical College Hos- motion at 1 ft. Circumcorneal hy- therapy, is consistent with rifabutin pital, Philadelphia, Pa. peremia and keratic precipitates were as the cause. Allergan has received no Corresponding author and re- noted on slitlamp biomicroscopy. similar reports of discoloration (per- prints: Alan Emory Irwin, MD, Divi- The anterior chamber was deep, with

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 1. A slitlamp photograph of the left eye shows a wrinkled anterior lens capsule with an opacified white anterior lens cortex.

a moderate inflammatory reaction and visible lens particles. Neovas- cularization of the was present Figure 2. A B-scan ultrasonogram of the left eye shows a lens nucleus that is dislocated at the pupillary margin but not in the into the posterior segment. angle of the anterior chamber on go- nioscopy. The anterior lens cap- sule was displaced posteriorly and forming cataract extraction after vi- sis (LASIK) indicates that most are di- was wrinkled with an opacified an- trectomy. rectly attributable to the creation of terior cortex, obstructing the view a corneal flap.1,2 In their examina- of the fundus (Figure 1). The lens David H. Ren, MD, PhD tion of 1000 consecutive cases of pa- nucleus and posterior lens capsule Preston H. Blomquist, MD tients who had undergone LASIK, were not seen. Intraocular pressure Suri N. Appa, MD Gimbel and colleagues1 identified 32 was 12 mm Hg. B-scan ultrasonog- Kamel M. Itani, MD intraoperative and 18 postoperative raphy revealed that the lens nucleus Dallas, Tex complications, most of which could was resting on the retina (Figure 2). be related to issues of flap anatomy, The patient was treated with a This study was supported in part by an including incomplete passes, thin topical corticosteroid and cyclople- unrestricted grant from Research to flaps, buttonholes, flap shrinkage and gia for phacoantigenic and un- Prevent Blindness, Inc, New York, NY. flap dislocation with subsequent de- derwent pars plana lensectomy 5 days The authors have no propri- velopment of striae, and epithelial in- later. At the time of the operation, the etary or financial interest in the ma- growth. Stulting and colleagues2 re- anterior capsule and zonules were in- terial discussed in this article. ported complications encountered in tact, but a large rent was found in the Corresponding author and re- a series of 1062 cases of patients who inferior posterior capsule. prints: Preston H. Blomquist, MD, De- had undergone LASIK, and identi- partment of Ophthalmology, Univer- fied 27 intraoperative and 40 post- Comment. After lens-sparing vitrec- sity of Texas Southwestern Medical operative complications, all of which tomy, the lens tends to fall slightly Center, 5323 Harry Hines Blvd, Dal- were directly related to the corneal posteriorly, making accidental lens las, TX 75390-9057 (e-mail: preston flap with the exception of 2 cases of touch more likely during repeat vi- [email protected]). . trectomy.3 Our patient likely had an Although most complications iatrogenic defect in the posterior cap- 1. Oyakawa RT, Schachat AP, Michels RG, Rice TA. can be resolved with acceptable vi- Complications of vitreous surgery for diabetic sule prior to luxation. The acute and retinopathy, I: intraoperative complications. Oph- sual outcomes, persistent flap ir- persistent posterior subcapsular cata- thalmology. 1983;90:517-521. regularity or opacification will re- ract seen after the second vitrec- 2. Novak MA, Rice TA, Michels RG, Auer C. The sult in decreased vision. Since crystalline lens after vitrectomy for diabetic reti- tomy in our patient was likely due nopathy. Ophthalmology. 1984;91:1480-1484. epithelialization of the underlying to direct trauma to the posterior lens. 3. Faulborn J, Conway BP, Machemer R. Surgical stromal bed might provide a more complications of pars plana vitreous surgery. We theorize that increased intracap- Ophthalmology. 1978;85:116-125. regular surface, amputation of the of- sular volume secondary to lens hy- fending flap might be considered a dration caused extension of the pos- reasonable intervention to address terior capsule defect and allowed the persistent flap problems. It is there- lens nucleus to fall into the poste- Refractive, Topographic, fore important to understand the rior segment of the eye. and Visual Effects of Flap healing pattern of the corneal bed Luxation of the lens nucleus is Amputation Following Laser following flap creation and ex- an unusual late complication of vi- In Situ Keratomileusis cimer laser ablation in terms of lens trectomy. Cataract surgeons should power, topography, regularity, and be aware of the possibility of occult A review of complications associ- scar formation. In our experience, posterior capsule damage when per- ated with laser in situ keratomileu- most cases of flap amputation have

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 cisco Refractive Surgery Service for further consultation in May 2001, ap- proximately 2 years after LASIK and flap amputation of the left eye. At that Right Eye Left Eye time, she complained of fluctuating vision in the left eye that at its best re- mained blurred. She also reported ghosting and glare. Examination dis- closed an uncorrected visual acuity of 20/25 OD and 20/80 OS. The vision of the left eye improved to 20/25 with a refraction of –3.25+3.25ϫ70. Slitlamp biomicroscopic exami- nation of the right eye showed a well- positioned, nasally hinged corneal flap, but coarse, diffuse epitheliopa- thy. There was no evidence of sub- epithelial or stromal haze or scar- ring, except for a normal degree of scar formation outlining the edges Figure 1. Case 1. Corneal topography of both eyes. Although the overall powers of the central corneal of the corneal flap. Slitlamp exami- curvatures are similar, the left eye shows greater irregularity, as represented by the elevated surface nation of the left eye showed a subtle, asymmetry index (SAI). SimK indicates simulated keratometry; MinK, minimum keratometry; PVA, predicted visual acuity; CYL, cylinder; and SRI, surface regularity index. vertically oriented elevation of the corneal surface at the hinge of the amputated flap. There was no evi- followed infectious keratitis and flap tended toward the entrance pupil. dence of subepithelial or stromal melting that results in some degree The flap was elevated and the inter- scarring, either at the former loca- of scarring and opacification of the face epithelium, removed. Approxi- tion of the flap edge or over the cen- underlying corneal bed. Conse- mately 2 weeks later, the epithelial tral . However, there was a quently, it has been difficult to pre- ingrowth had recurred, so the flap moderate degree of epithelial irregu- dict what the optical qualities of the was amputated. larity evident without instillation of uninflamed stromal bed might have The patient was treated with a fluorescein sodium dye. Fluores- been. We document herein the cor- bandage contact lens, and ciprofloxa- cein sodium staining revealed coarse, neal findings in 2 patients who un- cin hydrochloride solution was ap- diffuse epitheliopathy concen- derwent early flap amputation for plied every 3 hours. No corticoste- trated over the central cornea and an noninflammatory epithelial in- roids were applied. During the next area of irregular surface contour that growth following LASIK. 5 days, the epithelial defect created by appeared to involve the central area removal of the flap closed, the ban- of corneal dissection that produced Report of Cases. Case 1. A 46-year- dage contact lens was removed, and the amputated flap. old woman with a history of recur- the patient was prescribed diclo- Computerized corneal map- rent corneal erosion and an exami- fenac sodium solution for occa- ping (Figure 1) confirmed the rela- nation finding consistent with map- sional use up to 3 times daily and tive irregularity of the left eye. A to- dot-fingerprint dystrophy underwent artificial tears for lubrication. Ap- pographic map of the right eye bilateral LASIK for the correction of proximately 1 week after closure of (Tomey Topographic Modeling Sys- an error of –6.75+0.50ϫ100 OD the epithelial defect, the uncor- tem, version 2.3.6J; Tomey Corp, and –7.00+0.25ϫ072 OS. An au- rected visual acuity in the left eye was Waltham, Mass) showed a simu- tomated microkeratome (Auto- 20/100. Automated refraction iden- lated keratometry reading of mated Corneal Shaper [ACS]; tified an error of –5.50+3.50ϫ159, 40.01ϫ41.07@91° with a surface Bausch & Lomb Surgical, Roches- but the corresponding visual acuity regularity index of 0.52 and a sur- ter, NY) was used to create the cor- was not recorded. Topical corticoste- face asymmetry index of 0.18. How- neal flaps with nasally located roids were prescribed for applica- ever, a topographic map of the left hinges, followed by ablation with an tion 3 times daily and discontinued eye produced a simulated keratom- excimer laser (VISX Star; VISX, Inc, after 1 month. During the next 6 etry reading of 40.90ϫ42.51@103° Santa Clara, Calif). An epithelial de- months, the corneal haze in the left with a surface regularity index of fect was produced during surgery in eye was not recorded as being any 0.50 and a surface asymmetry in- the left eye. A bandage soft contact greater than 1+. However, at 9 months dex of 1.25. On comparing the right lens was placed, but a defect per- after flap amputation, the uncor- and left eyes, a markedly asymmetri- sisted at the first follow-up visit 1 day rected vision was recorded as 20/ cal reflex was also observed on reti- later. Approximately 3 weeks later, 100, correcting to 20/40 with a re- noscopy with significantly greater ir- epithelial ingrowth along the inter- fraction of –1.50+0.25ϫ171. regularity noted in the left eye. face of the corneal flap and the bed The patient was referred to the Although a relatively high de- was identified at the hinge and ex- University of California, San Fran- gree of was noted in the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 left eye, the spherical equivalent was calculated to be –1.625 diopters (D). Since the refraction in the right eye was –1.50+1.00ϫ090, anisometro- pia was limited, so spectacles were prescribed to improve visual func- tion. Case 2. A 33-year-old man un- derwent bilateral LASIK for the cor- rection of an error of –1.75+0.50ϫ30 OD and –2.00+0.25ϫ160 OS. An au- tomatedmicrokeratome(ACS;Bausch & Lomb Surgical) was used to create the corneal flaps. A large epithelial de- fect was created in the left eye, so the flapwasrepositionedwithoutexcimer laser ablation. A bandage contact lens was placed to promote epithelial heal- ing.Approximately2monthslater,the patient returned to surgery. A corneal Figure 2. Case 2. Slitlamp photograph of the left eye. Note within the slit beam a band of scarring that flap with a nasal hinge was created in outlines the perimeter of the flap, but relative clearing of the central cornea overlying the entrance pupil. the left cornea using an automated mi- crokeratome (ACS; Bausch & Lomb Surgical), and the ablation was per- duced to 1 drop per day and then The irregularity of the left eye’s formedusinganexcimerlaser.Anepi- discontinued. corneal surface was confirmed by thelial defect was noted at the end of The patient complained of poor computerized corneal mapping the procedure, and a bandage contact vision and nighttime glare and halo (Figure 3). A topographic map of lens was kept in place for the next 3 and was referred to the University the right eye produced a simulated days. One week after surgery, uncor- of California, San Francisco Refrac- keratometry reading of 42.27 ϫ rected vision was 20/40 OS, correct- tive Surgery Service for consulta- 43.32@84°, with a surface regular- ing to 20/25 with a refraction of tion in May 2001, approximately 18 ity index of 0.11 and a surface asym- –1.00+1.50ϫ20. No significant epi- months after LASIK and subse- metry index of 0.50. However, a to- thelial ingrowth was noted. quent flap amputation of the left eye. pographic map of the left eye showed Two weeks later, the patient re- Examination at that time disclosed a simulated keratometry reading of turned with the complaint of ocular an uncorrected visual acuity of 20/25 43.57ϫ 46.40@115°, with a sur- discomfort in the left eye. Uncor- OD, correcting to 20/20 with a re- face regularity index of 1.62 and a rected vision was 20/30−. Epithelial fraction of –0.50+0.50ϫ55, and an surface asymmetry index of 0.86. On ingrowth was noted along the nasal uncorrected visual acuity of 20/60 comparing the right and left eyes, a hinge, with extension toward the en- OS, correcting to 20/20− with a re- markedly asymmetrical reflex was trance pupil. At that visit, the flap was fraction of –3.75+3.75ϫ 97. also observed on retinoscopy, with lifted to remove the interface epithe- Pachymetry readings were 532 µm markedly greater irregularity noted lium, and the epithelium overlying OD and 439 µm OS. in the left eye. the flap was noted to be friable. On Slitlamp biomicroscopic exami- Since the acuity in the left eye the basis of anticipated difficulties nation of the right eye showed a well- could be corrected to 20/20− with a with recurrent epithelial ingrowth, positioned, nasally hinged corneal flap relatively low degree of anisometro- the flap was amputated and a ban- with mild central subepithelial opaci- pia based on spherical equivalent, dage contact lens was placed. Cipro- fication, whereas slitlamp examina- spectacles were recommended, but floxacin and diclofenac solutions tion of the left eye was remarkable for the patient adamantly refused to con- were prescribed 4 times daily. The mild vertical linear elevation at the site sider spectacle correction. Rigid con- epithelial defect healed during the of the transected hinge, a semicircle tact lenses were also suggested, but next few days, and 1 week after flap of subepithelial haze reminiscent of the patient elected to forgo fitting. amputation the uncorrected visual surface photorefractive keratectomy acuity was 20/200, correcting to (PRK)–associated scarring that ap- Comment. The findings from large 20/60 with a refraction of –5.00 peared to outline the perimeter of the reported series of complications seen +1.50ϫ100. The ciprofloxacin so- flap, and a relatively lucent central in consecutive cases of patients who lution was discontinued, and corti- cornea overlying the entrance pupil. have undergone LASIK suggest that costeroid drops were prescribed (Figure 2) The surface of the cen- most complications can be attrib- for use 3 times daily. Two months tral cornea appeared to be relatively uted to abnormalities of the corneal later, the uncorrected vision was smooth, but upon instillation of fluo- flap that translate to irregularity or 20/100, correcting to 20/50− with a rescein sodium solution, inspection opacification of the anterior cor- refraction of –4.75+2.00ϫ105. of the tear film pattern indicated an nea.1,2 If amputation of the corneal flap The corticosteroid therapy was re- irregular surface. were followed by reepithelialization

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 nificant corneal smoothing occurs from 3 months to 12 months after PRK, presumably as a result of stro- mal healing and remodeling. Using Right Eye Left Eye very high-frequency ultrasound scan- ning, Reinstein and colleagues5 ex- amined that had undergone LASIK and reported regional varia- tions in epithelial thickness that tended to compensate for underly- ing stromal irregularity, thereby re- ducing corneal irregularity. In the 2 cases we present, it is discouraging that reduced best spectacle-cor- rected visual acuity with correspond- ingly elevated indices of asymmetry and irregularity was evident 18 months and 2 years after flap ampu- tation. Therefore, it is questionable how much further improvement in Figure 3. Case 2. Corneal topography of both eyes. The left eye shows significant astigmatism with the surface regularity might occur dur- rule and elevated irregularity compared with the right eye, as represented by elevated surface regularity ing subsequent months or years. (SRI) and surface asymmetry indices (SAI). Other abbreviations are explained in the legend to Figure 1. In neither case was there sub- stantial scarring of the corneal stroma and smoothing of the corneal sur- which results in irregular astigma- overlying the entrance pupil that was face (analogous to corneal healing af- tism that limits best spectacle- subjected to excimer ablation. High ter surface PRK) without the intro- corrected vision. degrees of corrected duction of significant scarring, Under normal circumstances, by surface PRK are expected to be as- refractive error, or irregularity, then irregularity of the surface of the stro- sociated with a greater risk of scar- this approach might prove useful in mal bed is expected to be matched ring, and it has been suggested that addressing most postsurgical com- by corresponding irregularity of the this scarring is related to the depth plications of LASIK. Unfortunately, undersurface of the flap, so that if an of the ablation performed.6 How- few reports in the literature provide irregular flap is created and then re- ever, after flap amputation, rela- a guide to the clinical course that can placed precisely with a “lock and tively deep layers of the cornea were be expected after flap amputation in key” effect, little change on the an- exposed to the epithelium after heal- the uninfected cornea. Patel and col- terior corneal surface is expected. If ing, and no significant haze was re- leagues3 recently reported a case of a regular refractive ablation is per- corded throughout the healing pe- traumatic flap dislocation that was fol- formed on the exposed stromal bed, riod. This finding suggests that the lowed by loss of the flap. After heal- some degree of underlying irregu- risk for haze formation in PRK prob- ing of the stromal bed, the patient’s larity should be translated through ably goes beyond simple consider- uncorrected vision was 20/40, im- the ablation so that as the surfaces ations of exposure of the deeper proving to 20/20 with a refraction of are reapposed precisely, matching stroma devoid of Bowman mem- –1.00+1.00ϫ135. the bed to the underside of the flap, brane to healing epithelium. Rather, However, as our 2 cases dem- the composite effect on the surface these cases suggest that flap ampu- onstrate, it cannot be assumed that of the eye should be attenuation of tation is not necessarily followed by a regular surface will result after re- the irregularity. As our 2 cases sug- significant central corneal haze and moval of the flap. The irregular my- gest, this attenuating effect is lost if scarring. opic astigmatism we observed im- the flap is removed to expose the Nevertheless, the refractive and plies that the curvature of the stromal bed. topographic outcomes of our 2 pa- stromal bed might not precisely re- Over time, remodeling of the tients indicate that there is a substan- flect that of the anterior surface of epithelium might have a smoothing tial risk for refractive change and in- the overlying flap. This finding sug- effect on the exposed stromal bed, im- duction of irregular astigmatism gests that the flap might vary in proving best spectacle-corrected vi- following flap amputation. Any char- thickness from one region to an- sual acuity. After this improvement, acteristic pattern of induced astig- other, leading to variability in the residual regular spherocylindrical er- matism is probably related to the path curvature of the stromal bed cre- ror can be corrected with spectacles, followed by the microkeratome in ated. Patterns of variability in thick- hydrophilic contact lenses, or a stan- creating the flap, which in turn will ness may well differ from one mi- dard spherocylindrical excimer la- be related to the particular design of crokeratome to another, and this ser treatment. In a topographic ex- the microkeratome. Since there were variability is expected to contrib- amination of eyes treated with no other flap-related abnormalities ute to the development of irregular- excimer laser, Abbas and col- beyond epithelial ingrowth in these ity in the contour of the stromal bed, leagues4 have demonstrated that sig- cases, we surmise that flap amputa-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 tion was performed because it was 7. Dastgheib KA, Clinch TE, Manche EE, Hersh P, 200 OD and 20/20 OS. A dilated fun- Ramsey J. Sloughing of corneal epithelium and seen as a definitive treatment of the wound healing complications associated with la- dus examination of the right eye re- ingrowth that would produce accept- ser in situ keratomileusis in patients with epi- vealed a nonischemic CRVO with able surface smoothing over time. thelial basement membrane dystrophy. Am J Oph- significantly increased macular thalmol. 2000;130:297-303. The first patient we describe had edema (Figure 1A). Optical coher- a history of recurrent erosion syn- ence tomography (OCT) revealed a drome, which presents an increased diffusely thickened retina as well as risk for epithelial ingrowth, keratoly- cystic foveal changes (Figure 1B). Intravitreous Triamcinolone sis, flap melting, and loss of best cor- The patient was observed for an ad- rected visual acuity.7 For this rea- Acetonide as Treatment ditional month, and when there was son, LASIK is not recommended in for no improvement in the degree of the setting of anterior basement mem- From Central Retinal macular thickening or visual acu- brane disease, and PRK should be Vein Occlusion ity, an intravitreous injection of 4 mg considered. Such severe complica- (40 mg in 1.0 mL) of triamcinolone tions might indeed ultimately neces- Central retinal vein occlusion acetonide was given in the right eye. sitate flap amputation, but no such (CRVO) is a common retinal vascu- Follow-up 1 month later progression was seen in the cases re- lar disorder that can lead to signifi- showed a return of visual acuity to ported herein. Therefore, based on cant visual disability. Persistent 20/25 OD, with complete resolu- the observed long-term clinical macular edema is one of the major tion of macular edema on both clini- course, we suggest that in the ab- complications associated with cal examination (Figure 2A) and sence of compelling indications (such CRVO. The Central Vein Occlu- OCT (Figure 2B). Intraocular pres- as gross flap irregularities or inter- sion Study1 evaluated the efficacy of sure was unchanged, and the im- face infection in which the flap might macular grid laser photocoagula- provement in visual acuity and clini- limit antibiotics penetration), flap tion in patients with macular edema cal examination results remained at amputation should be a last resort in caused by CRVO. This study did not the 6-month follow-up. the management of flap complica- find a difference in visual acuity be- Case 2. A 67-year-old man had tions. tween treated and untreated eyes at a 1-month history of decreased vi- any stage during the follow-up pe- sual acuity in the left eye. Examina- Stephen D. McLeod, MD riod. Therefore, there is currently no tion revealed a best-corrected vi- Douglas Holsclaw, MD proven management for macular sual acuity of 20/20 OD and 20/200 Salena Lee, OD edema in the setting of CRVO. The OS. Anterior segment examination San Francisco, Calif purpose of this interventional case results were remarkable for 2+ report is to describe the clinical nuclear sclerosis in both eyes. His in- Corresponding author: Stephen D. course of 2 patients with macular traocular pressure was 10 mm Hg McLeod, MD, Department of Ophthal- edema secondary to CRVO who un- OU. A dilated fundus examination mology, University of California San derwent intravitreous injection of tri- revealed a normal fundus in the right Francisco, 10 Kirkham St, K-301, San amcinolone acetonide. eye. Examination of the left fundus Francisco, CA 94143 (e-mail: smcleod revealed findings consistent with @itsa.ucsf.edu). Report of Cases. Case 1. A 57-year- an ischemic CRVO. Foveal thick- old man had a 2-month history of ness was greater than 600 µm on 1. Gimbel HV, Penno EE, van Westenbrugge JA, decreased visual acuity in his right OCT. Ferensowicz M, Furlong MT. Incidence and man- agement of intraoperative and early postopera- eye. On initial examination, his best- The patient was followed up at tive complications in 1000 consecutive laser in corrected visual acuity was 20/40 OD 2-month intervals for the next 8 situ keratomileusis cases. Ophthalmology. 1998; and 20/20 OS. Results of anterior months. Although the intraretinal 105:1839-1847. 2. Stulting RD, Carr JD, Thompson KP, Waring GO segment examination were remark- hemorrhage cleared significantly, 3rd, Wiley WM, Walker JG. Complications of able only for 2+ nuclear sclerosis in there was neither improvement in vi- laser in situ keratomileusis for the correction of both eyes. Intraocular pressure was sual acuity nor a decrease in the . Ophthalmology. 1999;106:13-20. 3. Patel CK, Hanson R, McDonald B, Cox N. Late 15 mm Hg OD and 19 mm Hg OS. amount of macular edema noted on dislocation of a LASIK flap caused by a finger- A dilated fundus examination re- clinical examination or OCT. nail [published correction appears in Arch Oph- thalmol. 2002;120:180]. Arch Ophthalmol. 2001; vealed findings consistent with Because there was no clinical 119:447-449. nonischemic CRVO in the right eye. improvement, an intravitreous in- 4. Abbas UL, Hersh PS, and the Summit PRK Macular edema was present. Fun- jection of 4 mg of triamcinolone ace- Study Group. Late natural history of corneal topography after excimer laser photorefractive dus examination results were nor- tonide (40 mg in 1.0 mL) was given. keratectomy. Ophthalmology. 2001;108:953- mal in the left eye. Figure 3 shows the extensive macu- 959. Slitlamp biomicroscopy re- lar edema noted on both slitlamp 5. Reinstein DZ, Silverman RH, Sutton HF, Cole- man DJ. Very high-frequency ultrasound cor- vealed some improvement in the de- biomicroscopy and OCT 5 days be- neal analysis identifies anatomic correlates of op- gree of macular edema in the right fore treatment. Three weeks follow- tical complications of lamellar refractive surgery: anatomic diagnosis in lamellar surgery. Ophthal- eye during the next 2 months. How- ing treatment, his visual acuity im- mology. 1999;106:474-482. ever, 8 months after initial exami- proved to 20/100 OS, and a fundus 6. Moller-Pedersen T, Cavanagh HD, Petroll WM, nation, his visual acuity had de- examination revealed a significant Jester JV. Corneal haze development after PRK is regulated by volume of stromal tissue re- creased further. Examination at that decrease in macular edema. Foveal moved. Cornea. 1998;17:627-639. time revealed a visual acuity of 20/ thickness measured with OCT was

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A B

Figure 1. A, Color fundus photograph of the right eye shows nonischemic central retinal vein occlusion complicated by macular edema before intravitreous injection of triamcinolone acetonide. Visual acuity was 20/200. B, Optical coherence tomogram of the right eye shows a diffusely thickened retina (to 600 µm) before intravitreous injection of triamcinolone acetonide.

A B

Figure 2. A, Color fundus photograph of the right eye 1 month following intravitreous injection of triamcinolone acetonide shows resolution of macular edema. B, Optical coherence tomogram of the right eye 1 month following intravitreous injection of triamcinolone acetonide shows restoration of normal foveal architecture. The central foveal thickness measured 100 µm.

A B

Figure 3. A, Color fundus photograph of the left eye shows ischemic central retinal vein occlusion complicated by macular edema before intravitreous injection of triamcinolone acetonide. This photograph was taken 8 months after initial examination, and although there was reduction in the amount of intraretinal hemorrhage, significant macular edema persisted. Visual acuity was 20/200. B, Optical coherence tomogram of the left eye shows cystic foveal changes and a diffusely thickened retina (to Ͼ600 µm) before intravitreous injection of triamcinolone acetonide.

100 µm. At the 2-month follow-up, 20/400. Macular edema was noted Comment. Triamcinolone ace- there continued to be a reduction in on slitlamp biomicroscopy, and fo- tonide is a corticosteroid that is com- macular edema on clinical exami- veal thickness was 500 µm on OCT. mercially available, inexpensive, and nation and OCT (Figure 4). No further intervention was at- commonly used as a periocular in- The patient did well until 3 tempted at this point, and the pa- jection for the treatment of cystoid months following the injection, tient has been observed with no macular edema occurring second- when his visual acuity decreased to change in his clinical status. ary to uveitis or resulting from in-

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Figure 4. A, Color fundus photograph of the left eye 2 months following intravitreous injection of triamcinolone acetonide shows resolution of macular edema. A reduction in the amount of intraretinal hemorrhage can also be noted. B, Optical coherence tomogram of the left eye 2 months following intravitreous injection of triamcinolone acetonide shows resolution of macular edema. The central foveal thickness measured 100 µm.

traocular surgery. Intravitreous tri- month following intravitreous injec- Corresponding author and reprints: amcinolone acetonide has been used tion. This effect, however, was tran- Michael S. Ip, MD, University of Wis- experimentally in the prevention or sient; a decrease in visual acuity and consin–Madison, Department of treatment of proliferative vitreoreti- an increase in macular edema oc- Ophthalmology and Visual Sciences, nopathy, retinal neovasculariza- curred 3 months following injec- 600 Highland Ave, F4/336, Madison, tion, choroidal neovascularization, tion. This may be related to the se- WI 53792 (e-mail: msip@facstaff and most recently for macular edema verity of ischemic CRVO. A single .wisc.edu). secondary to .2 injection of triamcinolone acetonide 1. Evaluation of grid pattern photocoagulation for In these 2 patients, we at- may remain in the vitreous cavity for macular edema in central vein occlusion: the tempted to reduce macular edema up to 3 months following injection.5 Central Vein Occlusion Study Group M report. secondary to CRVO by injecting tri- It is possible that 1 injection of intra- Ophthalmology. 1995;102:1425-1433. 2. Jonas JB, Sofker A. Intraocular injection of crys- amcinolone acetonide into the vitre- vitreous triamcinolone lasting 3 talline cortisone as adjunctive treatment of dia- ous cavity. Intravitreous injection of months in the vitreous cavity may be betic macular edema. Am J Ophthalmol. 2001; 132:425-427. triamcinolone acetonide has been sufficient treatment for macular 3. McCuen BW, Bessler M, Tano Y, Chandler D, shown to have minimal adverse ef- edema caused by nonischemic CRVO Machemer R. The lack of toxicity of intravit- fects in both animal and clinical stud- but not for macular edema caused by really administered triamcinolone acetonide. Am 3,4 J Ophthalmol. 1981;91:785-788. ies. Triamcinolone acetonide may ischemic CRVO. A repeated injec- 4. Danis RP, Ciulla TA, Pratt LM, Anliker W. In- reduce macular edema, possibly by tion might again have reduced the travitreal triamcinolone acetonide in exudative reducing the breakdown of the macular edema and improved visual age-related . Retina. 2000; 20:244-250. blood-retinal barrier, nonspecifical- acuity in the patient with ischemic 5. Jonas JB, Hayler JK, Sofker A, Panda-Jonas S. In- ly inhibiting the arachadonic acid CRVO. travitreal injection of crystallinecortisone as an adjunctive treatment of proliferative diabetic reti- pathway, or downregulating vascu- In the absence of a definite role nopathy. Am J Ophthalmol. 2001;131:468-471. lar endothelial growth factor. for macular laser photocoagulation Intravitreous triamcinolone in the setting of macular edema from acetonide induced a prompt ana- CRVO, intravitreous injection of tri- tomic and functional improvement amcinolone acetonide may be a vi- Intravitreal Antivirals in our patient with nonischemic able treatment option. The 2 pa- in the Management CRVO (case 1). The visual acuity of tients described previously had a this patient improved from 20/200 prompt anatomic and functional re- of Patients With Acquired to 20/25 in 1 month. Additionally, sponse, although the need for re- Immunodeficiency the thickness of the central fovea, as peated treatment and possible ad- Syndrome With Progressive measured by OCT, was reduced verse effects should be investigated Outer Retinal Necrosis from 600 µm to 100 µm in 1 month. further. No adverse effects such as In the patient with ischemic retinal detachment, endophthalmi- Retinal infection with herpes vari- CRVO (case 2), intravitreous triam- tis, cataract, or glaucoma occurred cella zoster in patients with ac- cinolone acetonide also appeared to in this series. Further study is war- quired immunodeficiency syn- produce significant but temporary ranted to evaluate the safety and ef- drome (AIDS) usually produces anatomic benefit. Visual acuity im- ficacy of this promising treatment multifocal outer retinal whitening provement was noted but was less modality for CRVO complicated by that rapidly progresses to conflu- dramatic than in the patient with macular edema. ent, full-thickness retinal necrosis. nonischemic CRVO. As in the pa- This form of necrotizing herpetic tient with nonischemic CRVO, the Michael S. Ip, MD retinopathy, known as progressive central foveal thickness was reduced K. S. Kumar, MD outer retinal necrosis, differs from rapidly and dramatically during 1 Madison, Wis acute retinal necrosis syndrome

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 nosis.2 A subsequent study of 20 pa- Table 1. Patient Demographics and Baseline Data* tients with progressive outer retinal necrosis treated with intravenous an- Extraocular Duration of tivirals reported 19 (49%) of 39 eyes Patient/Sex/Age, y Race Manifestations Follow-up, mo progressing to no light perception 1/M/38 A VZV 4 within 6 months.3 The outcomes of 2/M/38 W VZV 6 3/M/32 W None 6 patients treated with more than 1 in- 4/F/27 A VZV 11 travenous antiviral agent were sta- 5/F/38 H VZV 20 tistically better than those who re- 6/F/36 A None 30 ceived only a single drug, but only 7/M/33 A None 10 4 (10%) of 39 eyes achieved a vi- sual acuity of 20/80 or better. In a *A indicates African American; VZV, cutaneous varicella-zoster virus infection; W, white; and H, more recent study of 6 patients with Hispanic. progressive outer retinal necrosis treated with combination intrave- principally in the lack of promi- ing laser. One laser-treated retina sub- nous antivirals, a final visual acuity nent intraocular inflammation.1 sequently detached. All 4 nonde- of 20/80 or better was achieved in Treatment with intravenous antivi- tached that were not treated only 2 (22%) of 9 treated eyes.4 In ral therapy alone has been associ- with the demarcating laser subse- contrast, 5 (45%) of the 12 eyes ated with a disappointing visual quently detached. treated with both intravenous and prognosis.2 We report the visual out- Allpatientsreceivedintravenous intravitreal antivirals (35% of the 14 comes associated with the use of ganciclovir sodium and foscarnet; 1 total eyes) in the current series had combination systemic and intravit- patient also received intravenous acy- a final visual acuity of 20/80 or bet- real antivirals in the management of clovir. Two patients (4 eyes) re- ter. Five of the 7 eyes with final vi- 7 patients with AIDS with progres- ceived intravitreal injections of gan- sual outcomes that were light per- sive outer retinal necrosis. ciclovir sodium (2 mg/0.05 mL) and ception or no light perception had foscarnet (1.2 mg/0.05 mL). The re- hand motions to no light percep- Report of Cases. There were 4 men maining 5 patients (7 eyes) received tion at the time of diagnosis. and 3 women with AIDS (mean age, intravitreal injections of ganciclovir Rhegmatogenous retinal de- 34.6 years [range, 27-38 years]) sodium (2 mg/0.05 mL). A median of tachment also contributes to poor vi- (Table 1). Two of the 7 patients had 6 injections (range, 3-15 injections) sual outcome and occurred in about a history of cutaneous varicella- during 14 days (range, 6-88 days) 70% of eyes in the prior series,2-4 in zoster virus infection and 1 had en- were given per eye. Two eyes with which most retinas detached after cephalitis. Six of 7 patients had bi- light perception vision were not in- treatment was begun. In the cur- lateral involvement at the time of the jected. One eye with hand motion vi- rent series, there was a similar total diagnosis of , and the re- sion and retinal detachment recov- rate of detachments, with 35% de- maining patient developed involve- ered a visual acuity of 20/80 after tached at the time of diagnosis and ment of the fellow eye within a injections and retinal detachment re- 35% detaching subsequently. How- 2-month period. Median follow-up pair. Three other eyes with hand mo- ever, in the current series, 1 (20%) was 10 months, with a range of 4 to tions or worse vision were injected of 5 retinas treated with a demar- 30 months. All 7 patients demon- and had poor visual outcomes. cating laser subsequently detached strated clinical features consistent Five (45%) of 11 treated eyes compared with 4 (100%) of 4 un- with progressive outer retinal ne- achieved a final visual acuity of 20/80 treated retinas. The more rapid heal- crosis. or better, and only 2 (18%) of the ing from the use of intravitreal an- Median visual acuity at the time 11 treated eyes progressed to no light tivirals together with the use of a of diagnosis was 20/80 (Table 2). The perception vision. All patients main- prophylactic demarcating laser may visual acuity in 8 eyes ranged from tained a visual acuity of 20/400 or have contributed to the reduced rate 20/20 to 20/80 and 6 eyes were hand better in at least 1 eye. No progres- of retinal detachment after treat- motions to no light perception. All sion of disease occurred during in- ment was begun. patients were able to see at least 20/ travitreal treatment. Recurrent dis- The limitations of comparing re- 60 in at least 1 eye. Retinal lesions ease occurred in only 1 eye and was sults of the current series with re- were present in zone 3 in all 14 eyes: treated successfully by resumption sults reported in historical controls only in zone 3 in 3 eyes (21%); only of both intravenous and intravit- should be noted. For instance, the in zones 3 and 2 in 3 eyes (21%); and real ganciclovir and foscarnet original series of patients was re- in all 3 zones in 8 eyes (57%). No pa- therapy. ported soon after the recognition of tient had lesions confined to only progressive outer retinal necrosis as zones 1 or 2. Three of 7 patients (5 Comment. In the original series of a syndrome2; earlier recognition and eyes) had retinal detachment at di- 38 patients with progressive outer treatment might have improved the agnosis, and 3 detachments involved retinal necrosis treated with intra- prognosis in these eyes. In addition, the macula. Of the 9 retinas that were venous antivirals alone, 42 (67%) of most patients in the originally re- not detached at diagnosis, 5 were 63 eyes progressed to no light per- ported series were treated with in- treated with a prophylactic demarcat- ception within 4 weeks after diag- travenous acyclovir rather than gan-

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Interval Initial Time Between Initial Visual Final Visual No. of Period of Examination Acuity Visual Patient Eye Acuity Therapy Injections Injections, d RD and RD, mo (RD) Surgery Complications Acuity 1 OD HM IV ganciclovir sodium 3 6 No ...... None None NLP and foscarnet, intravitreal ganciclovir and foscarnet (both eyes) OS 20/60 8 30 ...... 20/50 2 OD 20/25 IV ganciclovir and 6 14 No ...... None None 20/40 foscarnet, intravitreal ganciclovir and foscarnet (both eyes) OS 20/60 6 14 ...... 20/50 3 OD HM IV ganciclovir and 9 23 Yes 0 HM PPV, silicone oil, None 20/80 foscarnet, intravitreal retinectomy ganciclovir (both eyes) OS LP 5 10 Yes 0 LP LP 4 OD LP IV acyclovir, ganciclovir, ...... Yes 0 LP None None NLP and foscarnet, intravitreal ganciclovir (left eye) OS 20/20 15 88 Yes 0 20/20 PPV, silicone oil 20/40 5 OD 20/20 IV ganciclovir and 15 72 No ...... None , 20/50 foscarnet, intravitreal cataract ganciclovir (right eye) OS LP ...... Yes 0 LP None NLP 6 OD 20/80 IV ganciclovir and 6 20 No ...... Cataract Cataract 20/400 foscarnet, intravitreal extraction/ ganciclovir (right eye) PCIOL5 OS 20/50 ...... Yes 3 10/200 PPV, fluid-air Cataract exchange, silicone oil, cataract extraction/ PCIOL 7 OD NLP IV ganciclovir and 5 10 Yes 7 NLP None Papillopathy NLP foscarnet, intravitreal ganciclovir (both eyes) OS 20/60 5 10 No ...... None 20/80

*RD indicates retinal detachment; HM, hand motions; IV, intravenous; NLP, no light perception; PPV, pars plana vitrectomy; LP, light perception; PCIOL, posterior chamber intraocular lens; and ellipses, not applicable.

ciclovir, foscarnet, or combination does not permit precise quantifica- ficult to define optimal treatment. Our systemic antiviral therapy.2 More- tion of the baseline extent of dis- preferred regimen for intravitreal over, the current use of highly active ease, which would be necessary, for treatment is to inject intravitreous antiretroviral therapy (HAART) likely instance, to accurately assess the ganciclovir sodium (2 mg/0.05 mL) influences the prognosis of progres- efficacy of laser demarcation in and foscarnet (1.2 mg/0.05 mL) 3 sive outer retinal necrosis as it does preventing retinal detachment. times weekly for 2 weeks, followed with cytomegalovirus retinitis. How- Published information on vi- by maintenance therapy of injec- ever, in the current series, only 2 pa- sual outcomes following the use of in- tions once or twice per week as in- tients were being treated with HAART travitreal antivirals in the manage- dicated until the retinitis is stabi- (either because the patients were ini- ment of progressive outer retinal ne- lized. Laser photocoagulation to tially examined before the wide- crosis is limited, consisting of only demarcate necrotizing retinitis is ap- spread use of HAART or because of 3reports.5-7 Three(50%)of6involved plied whenever possible. Because cen- noncompliance with medical eyes of the reported 4 patients tral nervous system involvement can therapy). Finally, although the zones achieved a final visual acuity of 20/ occur in association with necrotiz- of retinal involvement were known 80 or better with intravitreal therapy. ing herpetic retinitis,8 we also use sys- for the patients in the current series, Progressive outer retinal necro- temic antiviral therapy. Our pre- the retrospective nature of this study sis remains rare enough that it is dif- ferred regimen is intravenous

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ganciclovir or oral valganciclovir at ter (PD) exotropic was induction doses for 3 weeks and in- Atypical observed in the right eye. Intraocu- travenous foscarnet at induction Presentations: A Challenge lar pressures were 19 mm Hg OD doses for 2 weeks, followed by main- for the Treating and 21 mm Hg OS. tenance antiviral therapy with oral Ophthalmologist Indirect ophthalmoscopy per- valganciclovir and intravenous fos- formed under anesthesia revealed an carnet until complete healing is An intraocular procedure in a child elevated exophytic mass in the right achieved. A successful transition to with retinoblastoma represents one inferotemporal retina, measuring oral valganciclovir or valacyclovir can of the few situations in which an 10ϫ11ϫ8mm(Figure 1). The often be made after several weeks of ophthalmologist can produce a dis- subretinal mass, which appeared yel- combination antivirals even if there ease that may be fatal to the pa- low and lipid filled, was associated is no improvement in the immune tient. It is always important to con- with a total, exudative retinal de- system. sider retinoblastoma, even in tachment. Scattered subretinal lipid, An appropriate control group children who are atypical in age or as well as retinal pigment epithelial with which to compare the poor appearance for this disease. change, was found throughout the prognosis of progressive outer reti- retina. The majority of the retinal nal necrosis treated with intrave- Report of Cases. Case 1. A 19- vasculature appeared normal, al- nous antivirals alone2-4 would be nec- month-old boy with a medical his- though prominent telangiectatic ves- essary to draw definitive conclusions. tory of malrotation of the intes- sels, confirmed by intraoperative However, combination systemic and tines who had recently undergone fluorescein angiography, were noted intravitreal antiviral therapy may be their surgical repair, was referred for overlying the tumor mass. No in- associated with improved efficacy in evaluation of in his right trinsic calcification of the mass was achieving disease resolution, main- eye. His ocular history was signifi- noted on ultrasonography. The left taining disease remission, and pre- cant for strabismus at 6 months of eye demonstrated a normal disc, ves- serving visual acuity. age that was attributed to promi- sels, macula, and periphery. nent epicanthal folds. At approxi- Orbital and cerebral computed Ingrid U. Scott, MD, MPH mately 19 months of age, his right tomographic scans demonstrated Khoa M. Luu, BS eye clearly deviated, and he was re- right microophthalmia, with a non- Janet L. Davis, MD ferred to a pediatric ophthalmolo- calcified minimally enhancing nodu- Miami, Fla gist who subsequently referred the lar mass along the posterior wall of patient to the ocular unit the right , as well as focal sub- This study was supported in part by at the University of California, San ependymal calcifications. Magnetic Research to Prevent Blindness Inc, Francisco (UCSF). resonance imaging revealed cortical New York, NY. On examination at UCSF, the tubers and subependymal hamarto- Corresponding author and re- patient demonstrated visual fixa- mas within the brain parenchyma. No prints: Janet L. Davis, MD, Bascom tion that was not central and not giant cell astrocytoma was noted. Palmer Eye Institute, PO Box 016880, steady in the right eye, with central These radiographic findings were be- Miami, FL 33101. steady and maintained fixation in the lieved to be characteristic of tuber-

1. Holland GN. Standard diagnostic criteria for the patient’s left eye. A 15–prism diop- ous sclerosis. acute retinal necrosis syndrome. Am J Ophthal- mol. 1994;117:663-667. 2. Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syn- drome: a variant of necrotizing herpetic reti- nopathy in patients with AIDS. Ophthalmology. 1994;101:1488-1502. 3. Moorthy RS, Weinberg DV, Teich SA, et al. Man- agement of varicella zoster retinitis in AIDS. Br J Ophthalmol. 1997;81:189-194. 4. Ciulla TA, Rutledge BK, Morley MG, Duker JS. The progressive outer retinal necrosis syn- drome: successful treatment with combination antiviral therapy. Ophthalmic Surg Lasers. 1998; 29:198-206. 5. Spaide RF, Martin DF, Teich SA, et al. Success- ful treatment of progressive outer retinal necro- sis syndrome. Retina. 1996;16:479-487. 6. Meffert SA, Kertes PJ, Lim P, et al. Successful treatment of progressive outer retinal necrosis using high-dose intravitreal ganciclovir. Retina. 1997;17:560-562. 7. Perez-Blazquez E, Traspas R, Marin IM, Mon- tero M. Intravitreal ganciclovir treatment in pro- gressive outer retinal necrosis. Am J Ophthal- mol. 1997;124:418-421. 8. Rostad SW, Olson K, McDougall J, Shaw CM, Alvord EC. Transsynapticspread of varicella zos- ter virus through the : a mecha- nism ofviral dissemination in the central ner- vous system. Hum Pathol. 1989;20:174-179. Figure 1. Yellow subretinal mass with associated subretinal fluid and scattered subretinal lipids.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 The patient was noted as hav- ing diffuse ash-leaf spots on derma- tologic examination (Figure 2). Infectious serologies for toxoplas- mosis, rubella, cytomegalovirus, her- pes simplex virus type 1, and her- pes simplex virus 2 were negative. The differential diagnosis in- cluded retinal astrocytoma, Coats disease, persistent hyperplastic pri- mary vitreous, or an atypical pre- sentation of retinoblastoma. Subse- quent examination of the right eye was remarkable for an intraocular pressure of 53 mm Hg, iris neovas- cularization, and a total retinal detachment. The right eye was enu- cleated and replaced with a hydroxy- apatite implant. Pathologic exami- nation results revealed necrotic retinoblastoma with a secondary Figure 2. Hypopigmented macules consistent with the clinical appearance of ash-leaf spots. Coats-like response. There was no involvement of the . To Computed tomographic scans dem- a baseball. She was found to have a date, this child has remained free of onstrated high attenuation of the solid retinal detachment with white retinoblastoma in the orbit and in the right vitreous, suggesting that the flocculent material under the retina contralateral eye for 26 months. The vitreous was filled with protein- and within the vitreous cavity, patient was referred to a pediatric aceous material. Additionally, 2 cal- though she denied having any vi- neurologist for management of tu- cifications were seen within the sual symptoms. A review of family berous sclerosis with central ner- anterolateral aspect of the . photographs showed evidence of vous system involvement. The child The differential diagnosis in- left eye leukocoria lasting for 30 remains asymptomatic from this dis- cluded Coats disease with dystro- months. ease process. phic calcification; however, given the Examination at UCSF demon- Case 2. A previously healthy results of the diagnostic studies, reti- strated a visual acuity of 20/20 OD 6-year-old boy who had undergone noblastoma could not be excluded. and no light perception OS. Intra- an undiagnostic anterior chamber With no light perception visual acu- ocular pressures were 16 mm Hg OD and vitreous tap in Ecuador was re- ity and rapidly increasing intraocu- and 20 mm Hg OS. Slitlamp exami- ferred to UCSF for further consid- lar pressure, the blind eye was nation showed diffuse rubeosis iridi- eration of a mass in his right globe. enucleated. tis in the left eye, as well as snow- Findings from an extensive workup Pathologic inspection revealed white material in the vitreous that for infectious disease performed in diffuse retinoblastoma with an exten- aggregated into clumps and was with- Ecuador were negative. He had been sive necrotic tumor. Focal areas of cal- out intrinsic vasculature (Figure 3). given a preliminary diagnosis of cification invaded the optic nerve but A shallow and diffuse retinal detach- Coats disease. did not extend posterior to the lamina ment was observed posteriorly. On He first visited UCSF under a cribrosa. Results of a full metastatic fluorescein angiography, a poste- regimen of topical fluorometho- workup were negative; however, since rior tumor mass was noted in the left lone and atropine for his right eye. this child had previously had a drain- eye, along with vitreous opacities and On examination, his visual acuity age procedure and an anterior cham- iris rubeosis. Ultrasonography failed was no light perception OD and ber tap, the UCSF tumor board rec- to demonstrate any intrinsic calci- 20/20 OS. Leukocoria was present in ommended 6 months of adjuvant fication. the right eye. Slitlamp examination . The boy completed 6 During examination while the of his right eye was remarkable for cycles of combination carboplatin, patient was under anesthesia, nei- shallow and inferior iridocorneal ad- etoposide, and vincristine, which he ther normal retinal structures nor the hesions, a neovascularized iris, and tolerated well. He has relocated to the optic nerve could be visualized. The retrolenticular opacification in the United States and receives regular fol- vitreous demonstrated a confluent anterior vitreous. Intraocular pres- low-up monitoring. To date, after 32 ocular process that had the appear- sure was 45 mm Hg OD. Indirect months of follow-up, he continues to ance of inflammation, but that po- ophthalmoscopy revealed a de- be without evidence of retinoblas- tentially represented vitreous seed- tached and diffusely thickened retina toma recurrence. ing from retinoblastoma. without a visible focal mass. Ultra- Case 3. A previously healthy Computed tomographic scans sonography confirmed a detached 9-year-old girl visited her ophthal- demonstrated a high-density mass retina with rare intraretinal calcifi- mologist with a retinal detachment involving her posterior and supero- cation and no focal mass lesion. following trauma to her left eye from lateral left globe. The mass was with-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 In the third case, a 9-year-old girl had a clinical appearance suggestive of uveitis. The cellular material that filled the vitreal space showed no in- trinsic calcification and was without intrinsic vascularity. Because the child was 9 years old at the time of exami- nation, retinoblastoma was, again, a relatively low consideration. Al- though retinoblastoma becomes less frequent with older age, it has been described in adult populations.6 Should this child have demon- strated effective vision, a vitreous as- pirate and biopsy (as recommended by several retina specialists) could have been performed. Children with retinoblastoma undergoing intraocu- lar procedures may require bone mar- row transplantation for cure. Even Figure 3. Slitlamp photograph of vitreous cells as the clinical presentation of retinoblastoma in a 9-year-old. with aggressive treatment, many suc- cumb to disseminated disease once out intrinsic calcification and was was also judged to be small, involv- the integrity of the globe has been vio- thought unlikely to be a retinoblas- ing persistent hyperplastic primary lated by an intraocular procedure. toma, especially in light of the child’s vitreous in the differential diagnosis. In summary, the treating oph- advanced age. The clinical presentation, however, thalmologist should retain a high in- The differential diagnosis in- was most consistent with Coats dis- dex of suspicion for retinoblastoma cluded a massive reaction in the vit- ease, and retinoblastoma with a in all children with intraocular dis- reous cells to an inflammatory or in- prominent Coats-like response was ease, even those who present with an fectious process vs retinoblastoma. confirmed by the pathology report. No atypical appearance or at an advanced Since the eye was blind as a result evidence of intrinsic calcification was age. Children with no view of the pos- of iris neovascularization, an enucle- found within this tumor. terior pole who have histories of ation was performed. In the second case, a 6-year-old trauma and may harbor oc- Pathologic inspection revealed boy was referred from Ecuador with cult retinoblastoma. Children with necrotic retinoblastoma cells, which a diagnosis of Coats disease. The re- uveitic or Coats-like scenarios may spared the choroid but invaded the sults of clinical imaging scans at UCSF alsorepresentunusualmanifestations optic nerve posterior to the lamina suggested proteinaceous material of this disease. Unless retinoblastoma cribrosa. Results of a systemic workup within the vitreous and no focal tu- is considered, improper actions may for metastasis were negative. The pa- mor mass. However, the presence of be undertaken, resulting in a poten- tient’s case was presented to the UCSF calcification on computed tomo- tial increase in morbidity and mor- tumor board, which recommended graphic scans, which could have been tality for patients with this disease. adjuvant chemotherapy. She under- consistent with dystrophic calcifica- Sharon McCaffery, MD went a 6-month course of carbopla- tion in Coats disease, increased sus- Mark R. Wieland, MD tin, etoposide, and vincristine, and to picion for retinoblastoma. Use of con- Joan M. O’Brien, MD date, she has been without recur- trast magnetic resonance imaging has San Francisco, Calif rence for 16 months. increased the sensitivity in distin- guishing Coats disease from retino- Kim L. Cooper, MD Comment. Atypical cases of retino- blastoma.3 Enhancement of de- Mark R. Wieland, MD blastoma may lead to diagnostic di- tached sensory retina with the absence Stanford, Calif lemmas. In the first case, a 19-month- of intraocular enhancement follow- Robert T. Wendel, MD old boy was referred for leukocoria. ing gadolinium–diethylenetriamine Davis, Calif The diagnosis of retinoblastoma was pentaacetic acid (DPTA) treatment fa- Corresponding author: Joan M. O’Brien, 4 complicated by magnetic resonance vors a diagnosis of Coats disease. MD, Ocular Oncology Division, De- imaging findings consistent with tu- Some difficulty remains, however, in partment of Ophthalmology, Univer- berous sclerosis. This made the pos- differentiating retinoblastoma from sity of California San Francisco, 10 Ko- 5 sibility of an intraocular astrocytic advanced Coats disease. Despite the ret Way, Room K-301, Box 0730, San hamartoma likely, since approxi- older age at presentation, retinoblas- Francisco, CA 94143-0730 (e-mail: mately half of all patients with tuber- toma was confirmed histopathologi- [email protected]). ous sclerosis demonstrate retinal cally. He unfortunately underwent 6 hamartomas.1 Atypical retinal astro- months of adjuvant chemotherapy be- 1. Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis. Arch Ophthalmol. cytomas with peculiar neovascular- cause of the procedure that was per- 1976;94:1277-1280. ization have been reported.2 The eye formed in Ecuador. 2. Jost BF, Olk RJ. Atypical retintis proliferans, reti-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 nal telangiectasis, and vitreous hemorrhage in a pa- went an orbital biopsy to confirm the after completion of treatment with rit- tient with tuberous sclerosis. Retina. 1986;6:53-56. 90 3. Kaufamn LM, Mafee MF, Song CD. Retinoblas- diagnosis and the histologic classifi- uximab and Y ibritumomab tiux- toma and simulating lesions: role of CT, MR im- cation of the orbital lymphoma. Pa- etan. The only adverse effects re- aging and use of Gd-DTPA contrast enhance- tients 1, 2, and 3 received intrave- ported by the 4 patients were mild ment. Radiol Clin North Am. 1998;36:1101-1117. 4. Edward DA, Mafee MF, Garcia-Valenzuela EG, nous rituximab (Rituxan; Genentech, neutropenia and thrombocytopenia. Weiss RA. Coats’ disease and persistent hyper- Inc, South San Francisco, Calif), 375 plastic primary vitreous: role of MR imaging and 2 CT. Radiol Clin North Am. 1998;36:1119-1131. mg/m weekly for 4 weeks. Patient 4 Comment. Monoclonal antibodies 5. Steidl SM, Hirose T, Sang D, Hartnett ME. Dif- received intravenous rituximab, 250 can be used to recruit a patient’s im- ficulties in excluding the diagnosis of retino- mg/m2, followed approximately 1 mune system to target antigens that blastoma in cases of advanced Coats’ disease: a clinicopathologic report. Ophthalmologica. 1996; week later by a second infusion of rit- are expressed on cancer cells. Ritux- 210:336-400. uximab, 250 mg/m2, and yttrium 90– imab is the first monoclonal anti- 6. Biswas J, Mani B, Shanmugam MP, et al. Reti- labeled (90Y) ibritumomab tiuxetan body licensed by the US Food and noblastoma in adults: report of three cases and 8 review of the literature. Surv Ophthalmol. 2000; (Zevalin; IDEC Pharmaceuticals Cor- Drug Administration to treat NHL. 44:409-414. poration, San Diego, Calif), 0.4 Rituximab is a genetically engi- mCi/kg (14.8 MBq/kg). neered chimeric (murine-human) In all 4 patients, the histologic monoclonal antibody directed against Immunotherapy for features of the orbital lesion were the CD20 antigen found on the sur- Low-Grade Non-Hodgkin similar to the previously established face of normal and malignant B cells. Secondary Lymphoma histologic classification of lym- Multicenter studies have demon- of the Orbit phoma. The histologic type in each strated its efficacy against relapsed patient, as confirmed by examina- or refractory low-grade, CD20- Lymphoid tumors are the most com- tion of an orbital biopsy specimen, positive, B-cell follicular NHL.9-11 In mon primary orbital malignancy.1,2 was considered low grade. All pa- these trials, up to 60% of patients with However, they constitute only about tients had nearly complete resolu- follicular lymphomas and a third of 2% of all nodal and extranodal lym- tion of their orbital lymphoma and re- patients with diffuse large cell and phomas.3 Most published reports ad- mained without evidence of orbital mantle cell lymphomas achieved ob- vocate the use of external beam ra- disease at most recent follow-up (Oc- jective remissions.12-14 diotherapy or systemic chemotherapy tober 2001). Two patients had pro- In vitro, rituximab is capable of for the treatment of orbital lym- gression of lymphoma in other sites mediating antibody-dependent cell- phoma.4-7 Recent reports have sug- and received alternative therapy. The mediated cytotoxicity and comple- gested that immunotherapy may also follow-up time after completion of im- ment-dependent cytotoxicity of be effective in the treatment of low- munotherapy ranged from 6 to 22 CD20-expressing tumor cells.15 Di- grade non-Hodgkin lymphoma months (mean, 14.5 months). rect effects have also been observed, (NHL).8-10 We describe 4 patients in Figure 1 shows the orbital mass in including the induction of apoptosis whom orbital NHL was treated ef- patient 3, before and 3 months after in some B-cell NHL cell lines.16 In ad- fectively with immunotherapy us- completion of treatment with ritux- dition, rituximab can sensitize tu- ing anti-CD20 monoclonal antibod- imab. Figure 2 shows the orbital le- mor cells to the cytotoxic effects of ies. To our knowledge, there are no sion in patient 4, before and 2 months conventional chemotherapy. Thus, previously published reports of monoclonal antibody therapy for Table 1. Clinical Features of Patients With Orbital Lymphoma NHL of the orbit. Treated With Immunotherapy*

Report of Cases. Between October Patient No./Sex/Age, y Bilateral Histologic Type† Treatment 1999 and May 2001, 4 patients with 1/F/68 No Small lymphocytic Rituximab the diagnosis of NHL of the orbit were 2/F/68 No Follicular small cleaved Rituximab treated at our institution with immu- 3/F/83 No Follicular small cleaved Rituximab notherapy using monoclonal anti- 4/M/77 Yes Follicular mixed Rituximab; yttrium 90–labeled bodies to CD20. When initially ex- ibritumomab tiuxetan amined by us, all 4 patients had orbital lymphoma as a secondary ex- *All patients had a B-cell immunophenotype and an initial lymphoma stage of IV. tranodal site of involvement of pre- †Based on examination of the orbital biopsy specimen. viously diagnosed NHL. For each pa- tient, clinical records and imaging Table 2. Ann Arbor Staging System for Lymphoma studies were reviewed to establish the diagnosis and document response. Stage Description Table 1 summarizes the clinical fea- I Involvement of a single lymph node region or lymphoid structure (eg, spleen or tures, histologic classification, im- Waldeyer ring) munophenotype, and disease stage at II Involvement of Ն2 lymph node regions on same side of diaphragm or localized Ն the time of diagnosis of orbital lym- involvement of an extranodal lymphoid structure and of 1 lymph node region on same side of diaphragm phoma for each patient. Table 2 III Involvement of lymph nodes on both sides of diaphragm summarizes the staging system used IV Involvement of Ն2 extranodal sites or liver or bone marrow in our series. All 4 patients under-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A B

Figure 1. Postcontrast magnetic resonance imaging scans of the orbit in patient 3. A, Before monoclonal antibody treatment, an infiltrative mass involving the left orbit is seen (arrows). B, Three months after treatment with rituximab, the orbital mass is much smaller.

A B

Figure 2. Computed tomographic scans of the orbit in patient 4. A, Before monoclonal antibody treatment, a mass in the inferior left orbit is seen (arrows). B, Two months after administration of rituximab and yttrium 90–labeled ibritumomab tiuxetan, the orbital mass has shrunken considerably. this agent may be a good addition to tumor cells primarily by the emis- Yttrium 90–labeled ibritumomab conventional chemotherapy in cases sion of radioactive particles and there- tiuxetan is a unique compound of refractory NHL. Another advan- fore may be therapeutically effec- composed of a murine monoclonal tage of immunotherapy with ritux- tive, even in hosts with defective antibody (ibritumomab), the imab is that patients can be treated re- immune effector function. Further- linker-chelator tiuxetan, and the petitively, since immune responses more, the beta particles emitted by the radioisotope 90Y, which is securely occur in fewer than 1% of patients. radioligand are tumoricidal over a chelated via the linker. Like its A mechanism for improving the larger area than just the cell to which unlabeled chimeric counterpart, rit- potency of rituximab and the sur- the ligand attaches, allowing for elimi- uximab, 90Y ibritumomab tiuxetan vival benefit it confers is to conju- nation of antigen-negative tumor cells targets the CD20 antigen, which is gate this monoclonal antibody to a ra- by radioactive “cross fire” from neigh- present on 95% of B-cell lympho- dionuclide ligand.17 Several potential boring antigen-positive, antibody- mas.11 Yttrium 90–labeled anti- advantages have been identified that coated cells. Yttrium 90–labeled CD20 antibodies have been associ- favor the use of radiolabeled antibod- ibritumomab tiuxetan is one such ated with response rates of 70% to ies. First, radioimmunoconjugates kill radiolabeled monoclonal antibody. 80% in the treatment of NHL.18

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Since most primary and second- most dosimetry studies, the me- non-Hodgkin’s lymphoma presenting in the or- bit: a report of eight cases. Cancer. 1985;55: ary orbital lymphomas are thought to dian estimated radiation dose ab- 1907-1912. be low-grade B-cell NHL,19 the use of sorbed by various organs after ad- 4. Bairey O, Kremer I, Rakowsky E, Hadar H, Shak- rituximab or its radiolabeled coun- ministration of the radiolabeled lai M. Orbital and adnexal involvement in sys- 90 90 temic non-Hodgkin’s lymphoma. Cancer. 1994; terpart, Y ibritumomab tiuxetan, as antibody Y ibritumomab tiuxetan 73:2395-2399. an alternative treatment modality for ranges from 38 to 340 rad (0.38- 5. Bennett CL, Putterman A, Bitran JD, et al. Stag- orbital lymphomas is intriguing. Tar- 3.40 Gy). The median estimated ra- ing and therapy of orbital lymphomas. Can- cer. 1986;57:1204-1208. geted immunotherapy may offer sev- diation dose absorbed by the tu- 6. Smitt MC, Donaldson SS. Radiotherapy is suc- eral advantages over conventional mor is 1700 rad.22 In contrast, the cessful treatment for orbital lymphoma. Int J Ra- median total dose of radiation from diat Oncol Biol Phys. 1993;26:59-66. chemotherapy or external beam ra- 7. Esik O, Ikeda H, Mukai K, Kaneko A. A retro- diotherapy in the treatment of or- external beam radiotherapy for NHL spective analysis of different modalities for treat- bital lymphomas, including fewer ad- of the orbit is 4000 rad (40 Gy) ment of primary orbital non-Hodgkin’s lym- 7 phomas. Radiother Oncol. 1996;38:13-18. verse effects and the potential for (range, 2000-5000 rad [20-50 Gy]). 8. Leget GA, Czuczman MS. Use of rituximab, the repeated treatments. Our limited experience, with pa- new FDA-approved antibody. Curr Opin On- The toxicity of rituximab in pa- tient 4 in this study, suggested no col. 1998;10:548-551. 9. McLaughlin P, Hagemeister FB, Grillo-Lopez A. tients with NHL has been consider- immediate ocular adverse effects Rituximab in indolent lymphoma: the single- ably less than that of traditional che- from treatment with 90Y ibritu- agent pivotal trial. Semin Oncol. 1999;26:79-86. motherapy; in most patients, momab tiuxetan. 10. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal an- rituximab causes no significant alo- Our small case series provides tibody therapy for relapsed indolent lym- pecia, nausea, or myelosuppression. limited evidence that rituximab or phoma: half of patients respond to a four-dose Common symptoms observed with 90Y ibritumomab tiuxetan can be treatment program. J Clin Oncol. 1998;16:2825- 2833. the initial monoclonal antibody in- used effectively and safely for low- 11. Grillo-Lopez A, Chinn P, Morena R, Varns C, fusion include fever, chills, mild grade B-cell NHL affecting the or- Parker E, Solinger A. Phase I study of IDEC-Y2B8: 90-yttrium labeled anti-CD20 monoclonal an- throat irritation, rash, and, rarely, rig- bit. Larger studies are required to tibody therapy of relapsed non-Hodgkin’s lym- 9,11-14 ors. In general, treatment with study the efficacy of monoclonal an- phoma [abstract]. Blood. 1995;86(suppl):55. rituximab is well tolerated. Fewer tibody treatment for orbital lympho- 12. Coiffier B, Haioun C, Ketterer N, et al. Ritux- imab (anti-CD20 monoclonal antibody) for the than 10% of patients develop more mas and to compare the toxicity pro- treatment of patients with relapsing or refrac- serious symptoms such as broncho- file of immunotherapy with that of tory aggressive lymphoma: a multicenter phase spasm or hypotension. The more se- other, more conventional forms of II study. Blood. 1998;92:1927-1932. 13. Maloney DG, Grillo-Lopez AJ, White CA, et al. rious adverse effects of rituximab are therapy, such as external beam ra- IDEC-C2B8 (Rituximab) anti-CD20 monoclo- observed in patients with high levels diotherapy and chemotherapy. nal antibody therapy in patients with relapsed of malignant B cells circulating in the low-grade non-Hodgkin’s lymphoma. Blood. 1997;90:2188-2195. peripheral blood. For most patients, Bita Esmaeli, MD 14. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, White controlled administration of the ini- James L. Murray, MD CA, Liles TM, Royston I. IDEC-C2B8: results tial infusion by starting at a low dose, M. Amir Ahmadi, MD of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin On- with premedication using acetami- Aresu Naderi, MD col. 1997;15:3266-3274. nophen and diphenhydramine hy- Sanjay Singh, MD 15. Reff ME, Carner K, Chambers KS, et al. Deple- tion of B cells in vivo by a chimeric mouse hu- drochloride and a slow rate escala- Jorge Romaguera, MD man monoclonal antibody to CD20. Blood. tion, results in minimal adverse Houston, Tex 1994;83:435-445. effects. After completion of ritux- Christine A. White, MD 16. Maloney D, Smith B, Appelbaum F. The anti- tumor effect of monoclonal anti-CD20 anti- imab therapy, which typically lasts 1 San Diego, Calif body (Mab) therapy includes direct antiprolif- month, long-term complications are Peter McLaughlin, MD erative activity and induction of apoptosis in unusual. The most common long- CD20 positive non-Hodgkin’s lymphoma (NHL) Houston cell lines [abstract]. Blood. 1996;88(suppl):637. term adverse effect is B-cell deple- 17. Press OW. Radiolabeled antibody therapy of B- tion, which can last 6 to 9 months. Corresponding author: Bita Esmaeli, cell lymphomas. Semin Oncol. 1999;26(5, suppl Rituximab should also pro- MD, Ophthalmology Section, Depart- 14):58-65. 18. 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